EA032013B1 - Immediate release abuse-deterrent granulated dosage forms - Google Patents

Abstract

Immediate release oral dosage forms have been described that include anti-abuse characteristics. In particular, the dosage forms described provide an obstacle to abuse by taking several separate doses. In addition, the dosage forms described provide protection against overdose in the event of inadvertently or deliberately taking several separate doses.

Description

The present invention relates to the field of oral dosage forms with anti-abuse characteristics, in particular including immediate release dosage forms containing drugs that are often the subject of abuse.

State of the art

Pharmaceutical products, including prescription and over-the-counter pharmaceuticals, while suitable for improving the health of an individual in need, are also subject to intentional and unintentional abuse and overdose. Examples of frequently abused active pharmaceutical ingredients include psychotropic drugs, anxiolytics, sedative hypnotics, stimulants, sedatives, and analgesics, such as, among others, narcotic analgesics. The complete list of specific frequently abused specific drug compounds may be too long; A short list of some commonly abused drug classes includes opioids and morphine derivatives, barbiturates, amphetamines, ketamine, and other drugs that can cause psychological or physical dependence.

Some typical methods of deliberate drug abuse begin with an abusing individual who takes a solid dosage form, such as an orally administered tablet or capsule, and pulverizes the solid dosage form. The abusing individual may be administered powder by nasal injection (i.e., sniffing) with intranasal administration of the drug into the bloodstream of the abusing individual. Alternatively, the ground dosage form can be combined with a solvent that can dissolve the drug (active pharmaceutical ingredient or API), and a solvent with the dissolved drug can be injected directly into the bloodstream of the abusing individual.

Alternatively, when using immediate release oral dosage forms, the abusing individual may simply take several units (eg, tablets) of the dosage form, for example, simultaneously. Each of several units of the dosage form immediately releases a certain amount of the drug, causing a short-term increase in the concentration of the drug in the bloodstream of the consuming individual and the desired buzz in the consuming individual.

In the pharmaceutical industry, there are many mechanisms for adapting drug compositions and oral dosage forms that may be suitable to prevent the abuse of oral dosage forms.

Pharmaceutical companies have investigated dosage forms that contain a nasal irritant or effervescent agent that can cause irritation or pain in the nasal passages if the dosage form is pulled and then pulled through the nose, thereby preventing abuse through nasal injection. To prevent abuse by injection, pharmaceutical companies have investigated the addition of gelling polymers to dosage forms. If the dosage form is pulverized and combined with a small amount of solvent, the gel-forming polymer may cause the combination to take the form of a highly viscous liquid or gel that cannot be injected. Another possible barrier to abuse may be the addition of an emetic, which can prevent abuse by inducing vomiting when several doses are consumed. Another obstacle to abuse includes the addition of an API antagonist to the dosage form, which substantially blocks the effect of the drug.

Although the pharmaceutical industry has a number of anti-abuse (sometimes referred to as anti-abuse) characteristics suitable for oral dosage forms, there continues to be a need to improve and find new anti-abuse characteristics to prevent or prevent abuse or overdose of active pharmaceutical ingredients.

Essence

The following description relates to oral dosage forms that are suitable

- 1,032,013 for immediate release of the active pharmaceutical ingredient or API.

A dosage form can be formulated to release the API as needed in the immediate release dosage form, and it may include one or a combination of characteristics that prevent or inhibit the abuse of the API. The anti-abuse characteristics described herein can be included in the immediate release dosage form individually or in any combination.

As an anti-abuse characteristic of the first type, a dosage form as described for the prevention or violation of abuse practice, where the dosage form is ground and then combined with a small amount of solvent to form a liquid composition that contains a certain amount of concentrated API and which can be delivered to the abusing individual using a syringe may include a gelling polymer. The gelling polymer can be any polymer that is suitable for achieving this functionality and which can be placed in the dosage form at any position to ensure that the gelling polymer is functioning as described and still providing immediate release of the API. The gelling polymer may be incorporated into the core of the coated core particles or into a dosage form matrix in which the coated core particles are suspended. The core may contain any amount of gelling polymer, such as from 0 to 100% gelling polymer of the total weight of the core. Alternatively, the core in the coated core particle may contain a filler, for example up to 100% filler, since a sugar sphere or a microcrystalline cellulose sphere (up to 100% microcrystalline cellulose spheres, such as microcrystalline cellulose spheres, available under the trade name Celphere® (Celphere®)).

Another type of anti-abuse characteristic may be wax, which alone or with other ingredients, such as a gelling polymer, is effective in preventing abuse practices where the dosage form is ground and combined with a solvent to form a liquid composition that can be abused by blowing through the nose or delivering the abusing individual using a syringe. Wax can further inhibit or prevent grinding of the dosage form by the abusing individual into a powder, since during grinding, the wax is smeared and not crushed or crushed. Like a gel-forming polymer, wax can be incorporated into the dosage form at any position that allows the wax to function as an anti-abuse characteristic, without distorting the immediate release profile of the API. For example, wax can be incorporated into the core of a coated particle. The core may contain any amount of wax, such as from 0 to 100% wax of the total weight of the core, such as up to 50, 75 or 80% by weight of wax of the total weight of the core.

Another type of anti-abuse characteristic may be an excipient or binding agent, which alone or in combination with other ingredients may interfere with abuse practices, where the dosage form is ground and combined with a small amount of solvent to form a liquid composition that can be delivered to the abusing individual using a syringe. The bulking agent or binding agent may prevent or prevent the abrasion of the dosage form by the abusing individual into a powder, since when rubbed, the polymer bulking agent or binding agent is smeared rather than crushed or crushed. The excipient or binding agent can be incorporated into the dosage form by any method and in any position that allows the excipient or binding agent to function as an anti-abuse characteristic, without distorting the immediate release profile of the API. For example, a filler or binding agent may be included in the core of the coated particle. The core may contain any amount of a polymeric filler or binding agent, such as from 0 to 100% filler or binding agent based on the total weight of the core or up to 50, 75 or 80% by weight filler or binding agent based on the total weight of the core.

Another type of abusive feature may be a film layer surrounding or coating the API in dosage form and optionally resistant to dissolution by one or more of the solvents commonly used by abusive individuals to dissolve the API for injection, including water and C ₁ -C 4 alcohols, such like ethanol, methanol and mixtures thereof. The film layer can be obtained from any film material that is applied as a continuous layer on the coated particle in such a position as to enclose and surround the API. Examples of film layers may optionally and preferably provide the properties of a solvent-resistant film, which is a film that slowly or difficultly dissolves in a limited or small volume of one of the solvents commonly used by abusive individuals to dissolve the API dosage form. In order to access the API dosage form, the abusing individual may grind the dosage form and combine the powdered dosage form with a solvent (as described) in an attempt to obtain a solution that contains a concentrated API and

- 2 032013 solvent and which can be effectively injected or sniffed. Being slowly soluble or insoluble in one or more of water or a C ₁ -C ₄ alcohol, such as ethanol, methanol, etc., a solvent-resistant film layer that surrounds the API dosage form can prevent easy access by the abusing individual to the API and its similar manipulations on the API.

In illustrative embodiments, an immediate release dosage form may contain these characteristics in a coated particle, such as a coated core particle. An exemplary coated core particle may comprise a core and one or more layers surrounding the core. In such a coated core particle, the API may be contained in the core, or in one or more layers surrounding the core, or in the core, and in one or more layers surrounding the core. The dosage form may further comprise coated core particles that do not contain an API in the core or in any layer surrounding the core. The core may contain one or more of a gelling polymer, wax, binding agent or filler, alone or in combination. Alternatively, the core may comprise microcrystalline cellulose or a sugar sphere.

A film layer may surround and enclose the core or an API containing layer that is located around the core. The film layer may preferably be a solvent resistant film in the form of a continuous coating that covers the core containing the API, or that covers the API layer or coating located around the core, or that covers the core that does not have an API containing layer or coating located around the core, and does not contain an API.

In various embodiments, the coated particle, as described herein, may be suitable in a dosage form that includes one or more optional anti-abuse characteristics and a matrix, such as a compressed matrix, that is formed to provide immediate release of the API present in the coated particles. An illustrative matrix composition may comprise an additional gelling polymer, a disintegrant, or both an additional gelling polymer and a disintegrant. The expression additional gelling polymer, as used above, means the amount of gelling polymer that is present in addition to the amount of gelling polymer present in the coated particles. The additional gelling polymer as compared to the gelling polymer that is included in the coated particles may be the same or different in character, chemical properties, molecular weight, etc. As a matrix component to facilitate the release of API dosage form, for example, API present in the coated particles, a disintegrant may be useful.

The active pharmaceutical ingredient included in the dosage form, especially in the coated particle, surrounded by a layer of film (for example, solvent-resistant film), can be any active pharmaceutical ingredient that is desirable to be administered orally, and in particular may be a type of active pharmaceutical ingredient, which is often abused. Examples of active pharmaceutical ingredients that are considered frequently abused, among others, include psychotropic drugs, tranquilizers, sedative hypnotics, anxiolytics, stimulants, sedatives, and narcotic analgesics. More specific specific classes of drugs that are often prone to abuse include opioids, barbiturates, benzodiazepines, amphetamines, as well as many other drugs that are known to cause psychological or physical dependence.

Dosage forms as described herein may be suitable as immediate release dosage forms, and may also include abusive characteristics as described. Anti-abuse characteristics can impede or prevent abuse by nasal injection, by injection, and can also be effective in preventing or significantly limiting the successful abuse of commonly used methods (especially using immediate release oral dosage forms) for co-administration of several dosage units. The latter mode of abuse (sometimes referred to as multiple-dose dosing in this document) is often particularly difficult to prevent, especially for immediate release oral dosage forms, making these described dosage forms particularly suitable as abusive oral dosage forms for abuse.

Embodiments of the described dosage forms may be effective in the absence of other types of anti-abuse characteristics, such as nasal irritants, emetics, bitter tastants, and effervescent agents to prevent nasal injection or other forms of abuse, or to include antagonists of the subject

- 3 032013 drugs.

In one aspect, the invention relates to an immediate release dosage form comprising coated core particles. Coated core particles include: a core comprising a gelling polymer; at least one layer surrounding the core; at least one layer comprising a film layer surrounding the core; and an active pharmaceutical ingredient. The active pharmaceutical ingredient is also surrounded by a film layer surrounding the core.

In another aspect, the invention relates to an immediate release dosage form comprising coated core particles. Coated core particles include a core and a layer of active pharmaceutical ingredient surrounding the core. The active pharmaceutical ingredient layer contains the active pharmaceutical ingredient. The core contains less than 5% by weight of the total amount of the active pharmaceutical ingredient in the coated core particles.

In yet another aspect, the invention relates to an immediate release dosage form comprising coated core particles. Coated core particles include: a core and an active pharmaceutical ingredient. The dosage form further comprises a matrix. The matrix contains a disintegrant and an additional amount of gelling polymer.

In another aspect, the invention relates to an immediate release dosage form that comprises two types of coated core particles. One type of coated core particles comprises a core and a layer of active pharmaceutical ingredient surrounding the core, as described above. The core of these particles optionally contains less than 5% by weight of the total API in this coated core particle, and in some cases contains less than 1% by weight of the total API in this coated core, or even does not contain a significant amount API Another type of coated core particles contains a core but does not contain a layer of active pharmaceutical ingredient surrounding the core.

Brief Description of the Drawings

In FIG. 1A, 1B and 1C illustrate embodiments of coated core particles as described in cross-section.

In FIG. 2A and 2B illustrate embodiments of coated core particles as described in cross section.

FIG. 3 is a perspective view of an embodiment of a dosage form as described.

In FIG. Figure 4 shows a chart of the dependence of resistance to abuse in the form of oral administration of several tablets (exceeding therapeutic dosage) - dissolution of hydrocodone bitartrate in 0.1 N HCl, versus time.

In FIG. 5 is a diagram of the dependence of resistance to abuse in the form of oral administration of several tablets (exceeding therapeutic dosage) - dissolution of acetaminophen in 0.1 N HCl, versus time.

In FIG. 6 is a graph of the dependence of resistance to abuse in the form of oral administration of several tablets (exceeding therapeutic dosage) of the dissolution of hydrocodone bitartrate in 0.1 N HCl, versus time.

In FIG. 7 is a diagram of the dependence of resistance to abuse in the form of oral administration of several tablets (exceeding therapeutic dosage) - dissolution of acetaminophen in 0.1 N HCl, versus time.

In FIG. Figure 8 shows a chart of the dependence of resistance to abuse in the form of oral administration of several tablets (exceeding therapeutic dosage) - dissolution of hydrocodone bitartrate in 0.1 N HCl, versus time.

In FIG. 9 is a graph of the dependence of resistance to abuse in the form of oral administration of several tablets (exceeding the therapeutic dosage) - dissolution of acetaminophen in 0.1 N HCl, versus time.

In FIG. 10 is a graph of the dependence of resistance to abuse in the form of oral administration of several tablets (exceeding therapeutic dosage) - dissolution of oxycodone hydrochloride from oxycodone / acetaminophen hydrochloride tablets (5/325 mg / tablet and 7.5 / 325 mg / tablet oxycodone / acetaminophen hydrochloride) medium 0.1 N HCl, from time to time.

In FIG. 11 is a graph of the dependence of resistance to abuse in the form of oral administration of several tablets (exceeding the therapeutic dosage) for dissolving acetaminophen from oxycodone / acetaminophen hydrochloride tablets (5/325 mg / tablet and 7.5 / 325 mg / tablet oxycodone / acetaminophen hydrochloride) in medium 0 , 1 N HCl, on time.

In FIG. 12 is a graph of the dependence of resistance to abuse in the form of oral administration of several tablets (exceeding the therapeutic dosage) of dissolution of bi

- 4,032,013 hydrocodone tartrate from hydrocodone / acetaminophen bitartrate tablets (5/325 mg / tablet and 7.5 / 325 mg / hydrocodone / acetaminophen bitartrate tablets) in 0.1 N HCl, from time to time.

In FIG. 13 is a chart of the dependence of resistance to abuse in the form of oral administration of several tablets (exceeding the therapeutic dosage) for dissolving acetaminophen from hydrocodone / acetaminophen bitartrate tablets (5/325 mg / tablet and 7.5 / 325 mg / tablet hydrocodone / acetaminophen bitartrate) in medium 0 , 1 N HCl, on time.

In FIG. 14 is a graph of the dependence of resistance to abuse in the form of oral administration of several tablets (exceeding therapeutic dosage) for dissolving hydrocodone bitartrate from hydrocodone / acetaminophen bitartrate tablets (10/325 mg / tablet of hydrocodone / acetaminophen bitartrate, tested in the form of intact tablets and crushed tablets) in the medium 0.1 N HCl, over time.

In FIG. 15 is a graph of the dependence of resistance to abuse in the form of oral administration of several tablets (exceeding the therapeutic dosage) for dissolving acetaminophen from hydrocodone / acetaminophen bitartrate tablets (10/325 mg / hydrocodone / acetaminophen bitartrate tablet, tested in the form of intact tablets and crushed tablets) in medium 0 , 1 N HCl, on time.

Detailed description

The present description relates to immediate release dosage forms, which include one or more anti-abuse characteristics to reduce the possibility of a) parenteral abuse, b) abuse by nasal injection (sniffing), and c) abuse by the simultaneous oral administration of several units of an oral dosage form ( tablets or capsules) of the drug. These anti-abuse characteristics are achieved by providing a dosage form comprising certain structural characteristics and certain ingredients that are currently defined as effectively preventing an abusive individual from abusing the intended biological effect of the drug using certain currently widely used methods used to abuse the API . However, a dosage form prepared in such a way as to include one or more of the described anti-abuse characteristics as an obstacle to the abuse of one or more APIs, which often are often susceptible to abuse, can advantageously be prepared so as to provide immediate release of one or more APIs upon normal therapeutic use by oral administration.

As used herein, expressions such as obstruction to abuse and prevention or obstruction or opposition to practices and methods associated with drug abuse and overdose refer to the characteristics of the claimed formulations that provide significant physical and chemical barriers to these practices and methods. The objectives of such containment include ensuring that the practice of abuse is significantly more difficult, and providing the potential abuser with much less desirability, less profitability and less suitability for abuse of any product obtained in attempts to carry out such abuse practices of the claimed formulations. The term immediate release refers to a dosage form which, after oral administration by a human, releases substantially all of the active pharmaceutical ingredient contained in the gastrointestinal tract for biological uptake in a short period of time. Methods for determining the in vitro release profile of a dosage form in order to determine whether a dosage form demonstrates an immediate or extended release dissolution profile are known in the pharmaceutical field. By such methods, in examples of immediate release dosage forms, as described herein, it is possible to determine the ability to release substantially all of the at least one active pharmaceutical ingredient of the same type (e.g., an API that is frequently abused) contained in a dosage form (e.g. at least 75, 80 or 90% by weight of the total amount of API in dosage form) in a solution (e.g., an acidic aqueous solution) with a suitable pH within 240 minutes, for example, in less than 180 minutes, in less than 90 minutes or less than 60, 30, 15, or 5 minutes. For example, the release profile of a dosage form as described herein can be determined by a method in which a dosage form is placed in hydrochloric acid (from 0.01 to 0.1 N) (e.g., aqueous hydrochloric acid) in a volume of up to 900 ml (e.g., 300 or 900 ml, based on various testing methods) at a pH of 1 to 2 and at a temperature of 37 ° C. In certain embodiments, the dosage forms described herein demonstrate that within 60 minutes when administered in therapeutic doses, at least 90% of the API is released, where the release profiles can be estimated by dissolving in 300 ml of 0.1 N HCl medium using a device USP II at a stirrer speed of 50 rpm and 37 ° C. Alternatively, the release profile of the dosage form described herein can be determined by a method in which the dosage form is placed in hydrochloric acid (from 0.01 to 0.1 N) (e.g., aqueous hydrochloric acid) in a volume of up to

- 5,032,013

900 ml (e.g. 300 or 900 ml, based on various testing methods) at a pH of approximately 4.5 (typical for pH conditions in the stomach after eating) and at a temperature of 37 ° C.

The term extended release can be defined as the release after 60 minutes of not more than 95% API, where the release profiles can be estimated, for example, by dissolving in 300 ml of medium 0.1 N HCl using a USP II device at a stirrer speed of 50 rpm and 37 ° C. In certain embodiments, the dosage forms described herein demonstrate:

a release of at least 90% of the API after 60 minutes when administered in therapeutic doses; and a release of not more than 95% API after 60 minutes when administered in excess of therapeutic doses;

where the release profiles can be estimated by dissolving in 300 ml of medium, 1N HCl using a USP II device at a stirrer speed of 50 rpm and 37 ° C. In this context, an excess therapeutic dose should be understood as corresponding to the administration of five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more or twelve or more separate dosage units, for example, tablets, at the same time. It should also be understood that the introduction of several separate dosage units at the same time with sufficient reason may include the introduction of these several doses sequentially for a short period of time, for example, for a period of less than 60 minutes, less than 30 minutes, less than 15 minutes, less than 5 minutes or less than 1 min

Dosage forms as described can be formulated to provide an immediate release profile for the API, and they can also be formulated to include effective or suitable anti-abuse characteristics that are effective in preventing the abuse of this API (e.g., an API that is often prone to abuse), which shows an immediate release profile. It is believed that the combination of an immediate release API with widespread resistance to abuse of the same API by several methods of abuse, including dosing of several tablets as described herein, was previously unknown. More specifically, the dosage form, as described herein, can provide an immediate release profile for the API, and at the same time may include anti-abuse characteristics that provide general barriers to abuse or resistance to abuse of the same API. Also, dosage forms can be more specifically characterized as resistant to certain general methods of abuse, such as 1) abuse by injection (e.g., by sequential steps that include rubbing the dosage form and dissolving the API dosage form), 2) abuse by nasal injection (e.g. also by rubbing and optionally dissolving the API dosage form) and 3) abuse by dosing several tablets by oral administration EMA, which means multiple simultaneous oral or excess quantities of orally administered dosage forms such as tablets or capsules. The third method of abuse, the dosage of several tablets, is especially common for immediate release dosage forms, and it is especially difficult to defend against it by developing the structure of the dosage form or by formulation. Thus, the fact that the dosage forms described herein can be effective in preventing or preventing abuse (or even accidental overdose) by dispensing several tablets may be a particularly suitable characteristic of the dosage forms described herein.

In vitro testing of the illustrative dosage forms as described herein suggests that the illustrative dosage forms provide a barrier against abuse by dosing several tablets. More specifically, in vitro testing of the illustrative dosage forms was carried out by testing the solubility of one or more dosage forms (tablets) in 300 ml of 0.1N HCl, maintained at 37 ° C. using a stirrer speed of 50 rpm. See example 26 (a) and FIGS. 4 and 5 herein. As shown in FIG. 4, 5, 6, 7, 8, and 9, the amount (percentage in tablet) of API (opioid) or APAP (acetaminophen) released into the medium decreases as the number of tablets increases. The data also suggest that the test dosage forms are effective in preventing increased levels of API absorption in an individual who may accidentally take several tablets, preventing or reducing the risk of an inadvertent overdose of the API. (In FIGS. 4 and 5, dosage forms with 1 tablet and 2 tablets are as obtained in Example 3 below, and dosage forms with 5 tablets, 8 tablets and 12 tablets are as obtained in Example 5 below.

The tablets used in FIG. 6, 7, 8 and 9 are as obtained in example 17.

In addition, in vitro testing, as described herein, demonstrates that the illustrative dosage forms prevent abuse by dispensing several tablets, even if the dosage form is ground prior to administration / testing. Specifically, in vitro testing was performed by performing solubility testing of several (twelve) of

6,032,013 milled tablets according to the same protocol as described above for testing intact tablets (i.e., in 300 or 900 ml of 0.1 N HCl, maintained at 37 ° C. using a stirrer speed of 50 rpm). See example 93 and FIG. 14-15 in this document. As shown in figures 1415, the percentage of API (opioid and APAP), which was released on Wednesday, with an increase in the number of crushed tablets decreased. These data suggest that the dosage forms are effective in preventing the absorption of elevated API levels in an individual who has taken several shredded tablets, and thus prevent or reduce the risk of an API overdose. The tablets used in example 94, which receive the data presented in figures 14-15, were obtained, as in as in example 93.)

Thus, dosage forms, as described herein, provide a method for preventing a transient increase in drug concentration in the bloodstream of a patient for whom the drug is prescribed, or in the bloodstream of an abusive individual who is taking the drug for recreational purposes in the event that the patient or the abuser the individual intentionally or unintentionally takes an exceeding therapeutic dose of the drug. In addition, dosage forms, as described herein, provide a method by which an overdose of a drug can be prevented when a patient intentionally or unintentionally takes an excess therapeutic dose of the drug. Exceeding therapeutic means a dose that exceeds the dose that is usually prescribed for therapy, for example, a dose of more than four, five, six, seven, eight, nine, ten, eleven or twelve separate dosage units (e.g. tablets, capsules, etc. d.).

As one of the types of anti-abuse characteristics, the dosage form as described may contain one or more gelling polymers. The gelling polymer may act as an anti-abuse characteristic, disrupting abuse practices where the active pharmaceutical ingredient of the dosage form is dissolved in a small volume of solvent or is readily available or readily isolated when combined with the solvent with a gelling polymer also present. Also, the gelling polymer can prevent or prevent abuse of the API in the dosage form by increasing the viscosity of the combination of the triturated and solvent dosage form (especially with a small volume of solvent) to a viscosity that is high enough to prevent the combination or API from being injected or injected using a syringe. The preferred gel-forming polymer contained in the pulverized dosage form, when diluted in a limited volume (or in a small volume) of a solvent, such as a C _1-4 alcohol (e.g. ethanol or methanol) or water, can form a non-injectable mass in the range from insoluble mass before the gel, to a viscous suspension, each of which exhibits a viscosity that essentially prevents the needle from being injected or injected with a hypodermic needle.

Suitable gelling polymers include one or a combination of polymers that, as part of a dosage form, upon contact with a small volume of solvent, absorb the solvent and swell to form a viscous or semi-viscous material that significantly reduces or minimizes the amount of free solvent that may contain some or the amount of API dissolved and which can be typed into a syringe. Also, the gel-formed polymer can reduce the total amount of drug extracted by the solvent by capturing the drug in a gel-like matrix.

The gelling polymer may be in the dosage form in position and in an amount that together allow the gelling polymer to form a viscous gel when rubbed by the abusing individual of the dosage form and combining the ground dosage form with a solvent. On the other hand, the gelling polymer present in the dosage form preferably does not interfere with the desired dissolution of the dosage form, the desired release (immediate release) of the API from the dosage form, or the acceptance of the API by a patient receiving an intact immediate release dosage form for a given therapeutic purpose. An exemplary position of the gelling polymer is a position in a coated particle that also contains an active pharmaceutical ingredient, for example, in a core or in a coating layer surrounding a core; where a certain amount of the active pharmaceutical ingredient is either in the core or in the coating layer surrounding the core, or in both. Another exemplary position is the position in the matrix used to form a compressed tablet, capsule (eg, compressed capsule), caplet, or other type of dosage form that contains a coated particle that contains an active pharmaceutical ingredient. The gelling polymer may also be in the core or in the layer surrounding the core, coated with a particle that does not contain an active pharmaceutical ingredient.

The gelling polymer may be in the dosage form in any desired amount and in any part or in any position of the structure of the dosage form. The amount of gelling

- 7,032,013 of the polymer can be any suitable amount, which means the amount that can form an abusive viscous mixture or gel if the dosage form is crushed, ground, powdered, etc. and mixed with solvent. A suitable total amount of the gelling polymer in the dosage form may range from 0.5 to 90% by weight of the gelling polymer of the total weight of the dosage form, for example, from 0.7 to 20 or from 2 to 15% by weight of the gelling polymer of the total weight dosage form.

These total amounts of gelling polymer may be in one or more positions of the dosage form to achieve the indicated total amount, for example, in a portion of a coated particle (e.g., in a core), a matrix (e.g., in a pressed matrix) structure that supports and contains coated particles, or in coated particles and in the matrix.

The core (uncovered) of the coated core particle may comprise any suitable amount of a gelling polymer, for example, from 0 to and including 100% gelling polymer in the core of the coated core particle, for example from 10 to 95% by weight of the gelling polymer, based on the total weight the core, for example, from 40 to 85, or from 50 to 75% by weight of the gelling polymer of the total weight of the core.

The amount of gelling polymer described in relation to the total weight of the dosage form located in the core of the polymer of the coated particle of the core may, for example, be in the range of 0.5 to 15% by weight of the gelling polymer (located in the core) of the total weight of the dosage form for example, from 1 to 10% by weight of a gelling polymer (located in the core) of the total weight of the dosage form. The amount of gelling polymer in the matrix of the dosage form can be any desired amount, such as an amount in the range from 0.5 to 15% by weight of the gelling polymer (as an excipient in the matrix) of the total weight of the dosage form, for example, from 1 up to 10% by weight of a gelling polymer (present as an excipient in the matrix) of the total weight of the dosage form.

A suitable gelling polymer may be any polymer material that exhibits the ability to retain a significant portion of the adsorbed solvent in its molecular structure, for example, a solvent that is a solvent otherwise used by the abusing individual to extract the API from the dosage form or milled or pulverized dosage form, solvent, for example, representing water or a C ₁ -C ₄ alcohol, such as ethanol or methanol , etc. Examples of gelling polymers include materials which, when placed in contact with such a solvent, can swell or expand to a very large extent. Swelling or expansion can cause an increase in the volume of the gelling polymer from a dry state by a factor of two to a thousand. More specific examples of gelling polymers include swellable polymers, sometimes referred to as osmopolymers or hydrogels. The gelling polymer may be crosslinked, slightly crosslinked, or highly crosslinked. Crosslinking may include covalent or ionic bonds on the polymer with the ability to swell in the presence of a solvent and not crosslink to dissolve in the solvent upon crosslinking.

The gel-forming polymer after dissolving or dispersing in an aqueous solution or dispersion (for example, in water) at a concentration of 2% w / w. (based on dry material), forms a solution / dispersion with a viscosity of from about 100 to about 200000 mPa-s (for example, from 4000 to 175000 mPa-s and from 4000 to 50,000 mPa-s) as measured at 20 ° C (± 0 , 2 ° C) by the analysis method described in the monograph USP 33 for hypromellose (incorporated by reference herein).

Typically, suitable gelling polymers include pharmaceutically acceptable polymers that undergo an increase in viscosity upon contact with a solvent as described.

Thus, it is known that many examples are suitable, typically including natural and synthetic starches (i.e., modified or pregelatinized modified starch), natural and synthetic celluloses, acrylates and polyalkylene oxides. Examples of natural starches include natural starches, including corn starch, potato starch, rice starch, tapioca starch and wheat starch, hydroxypropyl starch, such as corn hydroxypropyl starch, pea hydroxypropyl starch, and potato starch hydroxypropyl starch. Examples of synthetic starches, i.e., modified or pregelatinized modified starch, include cetylated waxy maize, acid-treated corn starch, acid-treated corn starch, waxy maize, starch, oxidized starch and starch starch. Examples of celluloses include calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, cellulose ethers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and low hydroxyl. Examples of acrylates include eradite RS, RL, NE, NM. Examples of polyalkylene oxides include polyethylene oxide such as POLYOX N10, N80, N60K, WSR-1105 LEO, or WSR-8 032013

301 LEO or WSR-303 LEO.

Thus, examples of suitable gelling polymers include polyethylene oxide, polyvinyl alcohol, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose sodium, hydroxyethyl cellulose, polyacrylic acid and other polyvinyl carboxylic polymers; level of viscosity effective to prevent syringe collection when combined with a small volume of solvent, as described.

Other examples of suitable gelling polymers with sufficiently high molecular weight molecules may include: ethyl cellulose, cellulose acetate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate and cellulose triacetate, cellulose ether, cellulose ether, cellulose ether, cellulose; acrylic resins containing copolymers synthesized from esters of acrylic and methacrylic acids, for example, copolymers of acrylic acid and methacrylic acid, copolymers of methyl methacrylate, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly (acrylic acid), poly (methacrylic acid), a copolymer of alkyl amide and methacrylic acid, poly (methyl methacrylate), polymethacrylate, poly (methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly (methacrylic acid anhydride) and glycidyl methacrylate copolymers.

Illustrative gelling polymers may include natural polymers, such as natural polymers obtained from plants or animals, as well as polymers obtained synthetically. Examples include polyhydroxyalkyl cellulose with a molecular weight of more than 50,000; poly (hydroxyalkyl methacrylate) with a molecular weight of from 5,000 to 5,000,000; poly (vinylpyrrolidone) with a molecular weight of from 100,000 to 3,000,000; anionic and cationic hydrogels; poly (electrolyte) complexes; poly (vinyl alcohol) with a low content of acetate residues; a swelling mixture of agar and carboxymethyl cellulose; a swellable composition containing methyl cellulose mixed with minimally crosslinked agar; simple polyester with a molecular weight of from 10,000 to 6,000,000; a water-swellable copolymer obtained by dispersion of a finely divided maleic anhydride copolymer with styrene, ethylene, propylene or isobutylene; water-swellable polymer of vinyl vinyltam and the like.

Other polymers suitable as a gelling polymer include pectin with a molecular weight in the range of 30,000 to 300,000; polysaccharides such as agar, gum arabic, karaya, tragacanth, alginine and guar; polyacrylamides; water-swellable indene polymers with maleic anhydride; Goodright (Good-rite®), polyacrylic acid with a molecular weight of 80,000 to 200,000; polyoxyethylene polymers polyox (Polyox®) with a molecular weight of from 100,000 to 7,000,000; grafted graft copolymers of starch; Aquacip acrylate polymers (Aqua-Keep®) with a water absorption coefficient of 400 times their initial mass; polyglucan diesters; a mixture of crosslinked polyvinyl alcohol and poly (-vinyl-2-pyrrolidone); poly (ethylene glycol) with a molecular weight of from 4,000 to 100,000.

In various specific embodiments, the gelling polymer may or may include hydroxypropyl methyl cellulose (e.g. hypromellose or HPMC) and hydroxymethyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose and sodium carboxymethyl cellulose. The molecular weight of hydroxypropyl methylcellulose may range from 10,000 to 1,500,000. Examples of suitable commercially available hydroxypropyl methylcellulose polymers include HPMC 1 <100M. K100LV metocel and K4M metocel.

A particular class of gelling polymer is a class of polymers from carbomers, which are polymers derived from acrylic acid (e.g. homopolymers of acrylic acid) and crosslinked with allyl ethers of polyalcohols, e.g., crosslinked with simple polyalkenyl ethers of pentaerythritol or sucrose. Carbomer polymers are hydrophilic and substantially insoluble in water. Instead, these polymers swell when dispersed in water, forming a colloidal, mucus-like dispersion. The carboxyl groups provided by the acrylic acid residues of the polymer backbone are responsible for the specific behavior of the polymers. Particles of this polymer can be considered as a network structure of polymer chains connected by cross-linking. When placed in an environment with a pH above 4-6, this structure can swell in water up to a volume a thousand times larger than the initial (dry) volume (and ten times the initial diameter of the polymer particles) with the formation of a gel. The pKa of these polymers can be 6 ± 0.5. Thus, carboxylate groups protruding from the polymer backbone can ionize at a pH above 6, which causes the repulsion of negatively charged particles, increasing the swelling of the polymer if exposed to a solvent in this pH range. For this reason, the dosage form, as described herein, can preferably include a pH adjuster in such an amount and position in the dosage form to cause the polymer from the carbomer to increase the pH to at least 6, essentially, to neutralize the carboxylate groups. Suitable amount of pH adjuster

- 9 032013 may be from about 1 to about 10 ml mol, or from about 5 to about 9 ml mol, or from about 6 to about 8 ml mol, or from about 7 to about 7.5 ml mol of pH adjuster per gram of carbomer polymer, which is in dosage form. Typically, the pH regulator is in the dosage form of the invention in an amount that is from about 1 to about 5% by weight, or from about 2 to about 4% by weight, or from about 3 to 4% by weight of the total weight of the drug forms.

Carbomer polymers are often referred to in this field using alternative terminology such as, for example, homopolymer carbomer, acrylic acid polymers, carbomers, carbopol, carboxypolymethylene, carboxyvinyl polymer, pemulene, polyacrylic acid and poly (acrylic acid). The USP-NF lists three generalized entries, i.e. for carbomer copolymer, carbomer homopolymer and carbomer interpolymer.

The average reduced weight of certain polymers from carbopolis (carbomers), which may be suitable as a gelling polymer, may be 76 per carboxyl group. Examples of suitable commercially available carbomers include carbopol® 934, 934P NF, carbopol® 974P NF and carbopol® 971P NF, carbopol® 940 and carbopol® 941, carbopol® 71G, commercially available in Lubrizol. Examples of such polymers are described in US patent No. 2798053 and 2909462, the full contents of which are incorporated herein by reference. The theoretical molecular weight ranges of the carbopol ™ range are in the range of 700,000 to 3 billion, a theoretical estimate. For dosage forms, as described herein, a gelling polymer (e.g., carbopol®) may have a molecular weight and viscosity-enhancing characteristics that reduce or significantly impede the ability of the abusive individual to extract APIs from a combination of dosage form and small volume of solvent, as described , while also being recyclable into a compressed dosage form.

Also, the gelling polymer can be characterized by the viscosity of the solution obtained from the gelling polymer. The technical descriptions of the commercially available carbopol ™ polymers indicate that the viscosities of the various carbopol polymers are as follows:

Carbomer type Indicated viscosity (cPz) Carbomer homopolymer type A (regulatory name for carbopol 71G, carbopol 971P and carbopol 981) 4,000 - 11,000 Carbomer homopolymer type B (regulatory 25,000 - name for carbopol 934P and carbopol 934) 45,000 Carbomer homopolymer type C (regulatory 40,000 - name for carbopol 980) 60,000

(viscosities of type A and type B were determined using Brookfield RVT, 20 rpm., neutralized pH 7.3-7.8, 0.5 percent by weight of mucus, rotor No. 5.)

Another example of the type of preferred gelling polymer is the class of xanthan gum polymers, which include natural polymers suitable as 27 hydrocolloids and obtained by fermentation of carbohydrates. The molecular weight of xanthan gum can be approximately 1,000,000. Xanthan gum has been shown to provide particularly effective resistance to extraction in a dosage form as described, and thus may be preferred in dosage forms as described, especially if present in an amount of at least 2 or 3 percent by weight of the total weight of the dosage form.

Without limiting the boundaries of suitable gelling polymers to any particular type or molecular weight, examples of suitable gelling polymers and corresponding suitable molecular weights are shown in the table below.

- 10 032013

Gelling polymer Weighted Average weight Carbomer from 700,000 to 3 billion (according to calculations) NRMS 2910 types K 164000-1200000 HPMC 2910 Type E 20000-746000 Hydroxyethyl cellulose 90000-1300000 Ethyl cellulose 75000-215000 Carboxymethyl cellulose 49000-725000 Carboxymethyl cellulose sodium 49000-725000 Povidone 4000-1300000 Copovidone 47000 Hydroxypropyl cellulose 40000-1150000 Xanthan gum 1,000,000 Polyethylene oxide Average molecular weight: 100000-7000000

The dosage form may optionally include another obstacle to abuse in the form of wax, such as wax / fatty material, as described in co-pending patent application US 2008/0311205, the entire contents of which are incorporated herein by reference. The wax may be a solid wax material that is in the dosage form in a position that prevents the abusing individual from grinding, grinding or otherwise converting the dosage form into powdered powder, which can be abused by blowing through the nose or from which the active pharmaceutical can be easily accessed. the agent and isolate it, for example, by dissolution or extraction using a solvent.

The wax may be in the dosage form in position and amount so as not to impede the desired consumption of the active pharmaceutical ingredient by the patient by oral administration in the immediate release dosage form. An exemplary position is the core of a particle with a coated core, especially a core that also contains a gelling polymer and which may or may not contain an active pharmaceutical ingredient. The wax located in the core of the particle (e.g., coated core particles), which also contains the active pharmaceutical ingredient (e.g., in the core coating layer or in the core), is mixed with the active pharmaceutical ingredient after grinding or grinding, etc. particles. As described previously, the dosage form may also include coated core particles that do not contain an API. Wax located in the core of such a particle (for example, a particle with a coated core) that does not contain API, after grinding, grinding, etc. the dosage form is also mixed with an API (e.g., an API found in an API containing coated core particles that are also in a dosage form). After the wax is mixed with the active pharmaceutical ingredient, an obstacle is created or the dissolution of the active ingredient in a solvent such as water or other effective access by the abusive individual is prevented.

The core (uncovered) of the coated core particle may contain any suitable amount of wax, up to and including 100% wax, for example, from 0.1 to 85% by weight of wax of the total weight of the core, for example, from 15 to 60, or from 25 to 50% by weight of wax of the total mass of the core. In a more general sense, a suitable amount of wax in a dosage form (for example, where the wax is in a coated particle, for example, in the core) can be in the range from 0.05 to 15% by weight of the wax of the total weight of the dosage form, for example, from 0, 1 to 10 or 2 to 5% by weight of wax of the total weight of the dosage form.

The wax may be a waxy (e.g., fatty) material, which is generally hydrophobic and which can be solid or liquid at room temperature, preferably solid at room temperature (25 ° C). Typically, suitable fats include hydrophobic materials based on fatty acid compounds, typically with a hydrophilic / lipophilic balance (HLB) of 6 or less, more preferably 4 or less, and most preferably 2 or less. The melting point of the fat can be any, and fats that are solid at room temperature and with a melting point of at least

- 11 032013 at least 30 ° C, for example at least 40 ° C, for example at least 50 ° C. Suitable fats include fatty acids and esters of fatty acids, which may be substituted or unsubstituted, saturated or unsaturated, and their chain length may be at least 10, 12 or 14 carbon atoms. Esters may include a fatty acid group associated with any of alcohol, glycol or glycerol. With respect to glycerols, mono-, di- and trisubstituted with fatty acids glycerols, as well as mixtures thereof, may be useful.

Suitable wax ingredients include esters of fatty acids, complex. esters of fatty acids and glycerol, derivatives of glycerides with fatty acids, waxes and fatty alcohols, such as, for example, glycerol behenate (also known as glyceryl behenate, glycerin behenate, glycerin indocosanoate) (for example, compritol (COMPRITOL®)), glycerol perlite ), glycerol monostearate, stearoyl macroglycerides (gelucir (GELUCIRE®) 50/13). Other waxes in a more general sense include insect and animal waxes, vegetable waxes, mineral waxes, petroleum waxes, and synthetic waxes; in particular, examples thereof include beeswax, carnauba wax, candelilla wax, mountain wax, uricuri wax, rice bran wax, jojoba wax, microcrystalline wax, cetyl ether wax, cetyl alcohol, anionic emulsifying wax, nonionic emulsifying wax and paraffin wax .

The dosage form may optionally include another obstacle to abuse in the form of a filler material or a binding agent provided to violate abuse practices, where the abusing individual comminutes, grinds, or otherwise converts the dosage form into powdered powder that can be abused by blowing through the nose or from which it is easy to access an active pharmaceutical agent and isolate it, for example, by dissolution or extraction with using a solvent.

The binder or excipient may be in the dosage form in position and in quantity so as not to impede the desired consumption of the active pharmaceutical ingredient by the patient by oral administration in the immediate release dosage form. An exemplary position is a core particle with a coated core. A suitable excipient or binder located in the core of the particle (e.g., coated core particles) that also contains the active pharmaceutical ingredient (e.g., in the core coating layer or in the core) is mixed with the active pharmaceutical ingredient after grinding or grinding and etc. particles. As described previously, the dosage form may also include coated core particles that do not contain an API. A filler or binder located in the core of such a particle (for example, a particle with a coated core) that does not contain API, after grinding, grinding, etc. dosage forms are also mixed with the API (for example, the API contained in the coated API core particles that are also in the dosage form). After the excipient or binding agent is mixed with the active pharmaceutical ingredient, an obstacle is created or the dissolution of the active ingredient in a solvent such as water or other effective access by the abusive individual is prevented.

When present in a core or particle of a dosage form, for example, in a core, coated core particles, excipient or binding agent may be present in any suitable amount, such as from 0 to and including 100% excipient or binding agent (alone or in combination) in the core, particles with a coated core, for example, from 10 to 95% by weight of filler or binding agent (separately or in combination) of the total weight of the core, for example, from 40 to 85 or from 50 to 75% by weight of total th core mass. Examples of cores that contain high levels of filler include spherical particles that contain 100% sugar and spherical particles that contain 100% microcrystalline cellulose. A range of inert spherical fillers, such as these, with particles of a suitable size, are commercially available under the trade name Celphere® and under the trade name Suglets® (sugar spheres also containing starch), including the following: SCP-100 celfer (particle size (μm) 75-212); SCP-102 cellel (particle size (μm) 106212); SCP-203 cellel (particle size (μm) 150-300); SCP-305 cellel (particle size (μm) 300-500); SCP-507 cellel (particle size (μm) 500-710); SCP-708 cellel (particle size (μm) 710-850). Their particle sizes can be considered suitable for any core, as described herein, obtained from a single filler, a gelling polymer, a binding agent, any combination thereof, or any one or combination of materials combined with the API.

Another optional anti-abuse characteristic that can be included in a dosage form as described is a film layer or coating as part of a coated particle core that is located above and surrounds the API. The film layer may also be present as a layer or coating on coated particles that do not contain an API or API layer. The film layer may be any film layer that

- 12 032013 which can be applied as a film layer to coated particles to surround the API or coated particles that do not contain an API or API layer.

The film layer can be obtained from any pharmaceutically acceptable film-forming polymer material, such as one or more of a bonding agent (e.g., as described herein, such as hydroxypropyl cellulose, poly (methyl methacrylates), ethyl cellulose, hydroxypropyl methyl cellulose, hydroxyl methyl cellulose, polyvinyl alcohol, etc. item), a solvent-resistant layer and a pH-sensitive layer (also sometimes referred to as a material or layer opposite in intestinal solubility), for example, eudra Zhita® E 100, and it contains it. The film layer may contain any of these materials separately (for example, the film layer may contain 100 percent of one of these types of materials), or the film layer may contain a combination of two or more of these types of materials.

The solvent-resistant layer is a film layer that slows down or prevents the release of the drug into the solvent (for example, one or more of water, ethanol and methanol), but which allows the normal release of the drug in the gastrointestinal tract when taken as an oral immediate release dosage form. This type of anti-abuse characteristic, for example, a solvent-resistant film, can prevent access to the API dosage form, preventing or making it difficult for the abusive individual to dissolve the intact or powdered solvent dosage form often used by the abusive individual (e.g., water, ethanol, methanol). At the same time, a solvent-resistant film can dissolve at a sufficient rate in the human gastrointestinal tract to provide an immediate release profile. As an abusive feature, this type of solvent-resistant film covers and surrounds the coated API core particles and acts as a film barrier or moderator to prevent or delay access to the API using a solvent.

A solvent-resistant film is a film that does not dissolve lightly or immediately in a small volume of a solvent of the type often used by an abusive individual to dissolve an API, such as any of water or a C ₁ -C ₄ alcohol, such as ethanol or methanol. A small volume refers to the amount of such a solvent that may contain such a quantity of dissolved API that is concentrated enough to be suitable for the abusing individual to realize the intended biological effect of drug abuse, and which can also be administered to abuse the API, for example, a volume that may contain an amount (concentration) of API that is effective in achieving the desired high if administered by injection or injection through the nose, where the volume is also small enough to allow the volume to be administered by injection or injection through the nose. In order for the dosage form to be suitable for abuse as it exists, it is necessary that the abusing individual can access the API in the dosage form and, without undue difficulty, dissolve it in sufficient concentration in a small volume of solvent, which is the volume that can be administered by injection or by blowing through the nose. Typically, a small volume of solvent means 50 ml or less, or 20 ml or less, or 10 ml or less, or 5 ml or less (volumes that can be injected or used for blowing through the nose).

The solvent-resistant film layer can be a film applied to a coated core particle that is difficult to dissolve in a small volume of water or a C ₁ -C ₄ alcohol, such as ethanol or methanol, which does not immediately dissolve in one or several of water or any of C ₁ -C ₄ alcohols, such as methanol or ethanol. Thus, a solvent resistant film delays or prevents the abuser from accessing the API portion of the coated core particle if the coated core particle is placed in one of these solvents. The solvent-resistant film should not be completely or substantially insoluble in any of these solvents or in all of the solvents, and in order for the dosage form to be suitable as an immediate release dosage form, it must be able to provide access to API with sufficient speed in the gastrointestinal tract.

A specific example of a solvent resistant film is a film that exhibits solubility properties that depend on the pH of the solvent. An example of a solvent-resistant film is a film that is substantially or completely insoluble at a pH that exceeds the pH conditions in the human stomach, and which is sufficiently soluble under the pH conditions of the stomach (and gastrointestinal tract) to allow the film to dissolve and release the API at a sufficient rate so that the dosage form can be suitable as an immediate release oral dosage form. The pH sensitive layer is a type of solvent resistant film and can be placed in dosage form around the active

- 13 032013 pharmaceutical ingredient, and it can inhibit access or prevent the access and dissolution of the active pharmaceutical ingredient in a solvent outside the stomach (for example, in a medium with a neutral pH), while still ensuring the effective release of the active pharmaceutical ingredient from the immediate release dosage form when pH less than in the consumer’s stomach. This type of anti-abuse characteristic can prevent or significantly impede an abusive individual from accessing an active pharmaceutical dosage form (for example, in the core of a coated particle of the core or in the layer coated on the core or in the core and layer coated on the core) using a solvent outside the stomach and not having a relatively acidic pH of the stomach, such as water or a C | -C.4 alcohol. such as ethanol, methanol, etc., or a mixture thereof with a pH that exceeds the pH of the human stomach, for example, a pH of more than 4; more than 5; or more than 5.5; or more than 6.

The pH-sensitive layer may be suitable as a solvent-resistant film, and may be formulated as a layer of a coated core particle surrounding, coating or enclosing a portion of the coated core particle that contains the active pharmaceutical ingredient. For example, in a coated core particle, the active pharmaceutical ingredient may optionally be present in the core or layer on the outside of the uncoated or coated core; a solvent-resistant film in the form of a pH-sensitive layer may be in the form of a separate layer surrounding or covering part of the coated particle core, which contains the active pharmaceutical ingredient. The pH-sensitive layer may be in direct contact (adjacent) with the core or with a layer that contains the active pharmaceutical ingredient; alternatively, a coated core particle between the pH sensitive layer and the core or layer that contains the active pharmaceutical ingredient may contain one or more intermediate layers. In addition, the pH-sensitive layer may be contained in the dosage form as a particle layer with a coated core, which does not contain an API layer or any API.

A suitable pH-sensitive layer may contain a polymer or other material that can be placed in the form of a particle layer, as described herein, so as to cover a deeper layer or core that contain the active pharmaceutical ingredient, with the formation of a pH-sensitive film surrounding or coating the active pharmaceutical ingredient. The pH-sensitive film may dissolve when exposed to a liquid with a pH that may be present in the stomach of a consumer of a dosage form, such as a pH below 6 or below 5.5. In order to function as an anti-abuse characteristic, i.e., to prevent or prevent effective access to the active pharmaceutical ingredient, by exposing the dosage form (optionally ground or powdered) to an readily available solvent, the pH sensitive layer may contain a polymer that is not readily it dissolves or essentially does not dissolve at a pH exceeding the pH of the human stomach, for example, a pH of more than 6; being insoluble at pH greater than 6, the pH-sensitive polymer does not dissolve in many solvents readily available and widely used by abusive individuals to extract water-soluble drugs from dosage forms such as water, ethanol, methanol, etc.

Examples of a pH-sensitive polymer suitable in a pH-sensitive layer include a class of intestinally opposed polymers which contain cationic functional groups and which exhibit pH-dependent solubility, as described herein. Examples include polymers that contain basic functional groups, such as amino groups, and which demonstrate solubility under pH conditions in the stomach (human), but not under conditions at a relatively higher pH, for example, not higher than pH 4, 5 or 5.5, or a pH of not higher than 6. More specific examples of such pH-sensitive polymers include copolymers of dimethylaminoethyl methacrylates and neutral methacrylic acid esters; for example, dimethylaminoethyl methacrylate, butyl methacrylates and methyl methacrylates, for example, in a ratio of 2: 1: 1. Examples of such polymers are commercially available under the trade names Eudrazhit® E-100, Eudrazhit® E PO, Eudrazhit® E 12.5 and similar pH-sensitive polymers with functional amino groups. The preferred pH-sensitive polymer is Eraudite E100, but any polymer that is sufficiently hydrophilic at low pH and hydrophobic at higher pH can also be effective, exhibiting pH-dependent solubility, as described, if otherwise it is acceptable for use in a pharmaceutical dosage form, for example, as a non-toxic ingredient in an oral dosage form. Gut-opposite compositions are also described in EP 1694724 B1, entitled pH Sensitive Polymer and Process for Preparation Thereof '(pH-sensitive polymer and method for its preparation).

In the presence of a coating particle containing an active pharmaceutical ingredient

- 14,032,013 dent, solvent-resistant film layer may be present in any amount suitable as an anti-abuse characteristic, such as in the range from 0.1 to 90% by weight of the total weight of the coated particle core, for example from 3 to 50 or 4 to 40% by weight of a solvent resistant polymer of the total weight of the coated core particle. More generally, a suitable amount of a solvent-resistant film or polymer layer in a dosage form can range from 1 to 50% by weight of a solvent-resistant film or polymer layer, based on the total weight of the dosage form, for example, from 2 to 30 or from 3 to 15% by weight of solvent resistant polymer of the total weight of the dosage form. Similarly, if there is a particle that does not contain an API as a coating, the solvent-resistant film layer may be present in any amount suitable as an anti-abuse characteristic, for example, in the same numerical ranges as described above for coating a particle containing API .

The dosage form, as described in the present description, may also preferably contain a disintegrant that functions to cause the dosage form to expand and disintegrate when used, for example, under human stomach conditions, to release the active pharmaceutical ingredient of the dosage form to achieve an immediate release profile. Disintegrants are known ingredients of pharmaceutical dosage forms with many well-known and commercially available examples. Examples of disintegrants include compositions composed of or containing sodium starch glycolate, starch (e.g., corn starch, potato starch, rice starch, tapioca starch, wheat starch, corn starch and peptized starch), croscarmellose sodium, polylamine, polyplasdone XL-10), sodium starch glycolate (explotab® or primojel®), any combination of two or more of the above, and other pharmaceutically acceptable materials formed into particles of such a size, density awn, etc. particles to allow the disintegrant to be processed into a suitable dosage form with immediate release.

The disintegrant can be present in the dosage form with immediate release in any position that provides the desired functioning of the disintegrant, in the form of an increase in volume in the undamaged dosage form after administration, causing the dosage form to be divided into parts and providing the desired immediate release of the active pharmaceutical ingredient from the dosage form in the stomach. One suitable position of the disintegrant may be its position as an excipient component used to be placed in coated core particles that contain the active pharmaceutical ingredient, as described herein, in a dosage form, such as a compressed tablet or capsule.

When included as an excipient in a dosage form, the disintegrant may be present in an amount suitable for obtaining immediate release of API from the dosage form. Examples of suitable disintegrant amounts in an immediate release dosage form, as described herein, can range from 0.5 to 50% by weight of the disintegrant of the total weight of the dosage form, for example, from 1 to 30% by weight of the disintegrant of the total weight dosage form. The amount of disintegrant in the matrix of the dosage form can be consistent with these amounts, for example, the disintegrant can be included in the matrix (for example, the entire dosage form, which differs from the coated particles or API) of the dosage form in an amount in the range from 0.5 to 50% by weight of the disintegrant from the total mass of the matrix, for example, from 1 to 30% by weight of the disintegrant of the total mass of the matrix.

The dosage form described may also contain any of a variety of known and generally accepted pharmaceutical excipients that may be suitable for obtaining the desired processing properties and operational properties of the immediate release dosage form. These excipients include fillers, binders, lubricants, glidants, colorants, pH adjusters, etc., and can be incorporated into coated core particles or into a matrix (e.g., compressed matrix) of a tablet or capsule. A more detailed description of pharmaceutical excipients, which can also be included in the tablets of the present invention, can be found in The Handbook of Pharmaceutical Excipients, 5th ed. (2006).

The pH adjusting agent can be incorporated into the immediate release dosage form as described, for example, in such a position as to affect the pH in a particular position of the dosage form, which is only part of the entire dosage form. By way of example, a pH-adjusting agent in the form of a base can be incorporated at the position of a gelling polymer that contains acidic functional groups to neutralize these acidic functional groups. The amount of pH adjusting agent included in the position of the gelling polymer may be an amount effective to neutralize the acid functional groups of the gelling polymer in this position. More specifically, the component of the dosage form according to the description, which contains a gel-forming polymer with acid functional

- 15,032,013 groups, such as carbopol, may contain a base in such quantity and position to neutralize the acid functional groups of this polymer. The pH adjusting means may be in a position effective to effect such neutralization, for example, in the position of a dosage form that contains a gel-forming polymer with acidic functional groups, for example, in the core of a particle with a coated core, or as part of an excipient that contains a gel-forming polymer with acid functional groups and which functions by binding particles in the form of a dosage form.

Examples of excipients that may be suitable for the immediate release dosage form described herein include lactose, starch, dextrose, sucrose, fructose, maltose, mannitol, sorbitol, kaolin, microcrystalline cellulose, powder cellulose, calcium sulfate, calcium phosphate, calcium diphosphate, lactitol or any combination of the above. Compared to non-filler ingredients, such as gelling polymers, the molecular weight of the filler is such that when combined with a solvent such as water, it does not significantly increase the viscosity or gel formation, as described herein for a gelling polymer.

Excipient may be present in any part of the dosage form as described, including coated core particles; the excipient may be present in the core, in a layer containing the active pharmaceutical ingredient that is applied to the core, in a solvent-resistant film, in a matrix, or in two or more of these parts of the dosage form. The excipient may be present in any one or more of these parts of the dosage form in such an amount as to provide the desired processing properties or functional properties of part of the dosage form and the entire dosage form. The total amount of excipient in the dosage form may also be as desired to provide the desired functionality, including an immediate release profile, for example, in an amount in the range of 0 to 80% by weight of excipient, based on the total weight of the dosage form, for example, 5 to 50% filler from the total weight of the dosage form.

Examples of binders that can be included in the dosage form as described include polymeric material such as alginic acid, sodium carboxymethyl cellulose, microcrystalline cellulose, dextrin, ethyl cellulose, gelatin, starch, peptized starch, polyvinyl alcohol, polyethylene oxide, polyvinylpyrrolidonidazole, polyvinylpyrrolidonidazole, polyvinylpyrrolidonidazole, polyvinylpyrrolidonidazole, poly polyvinyl alcohols, methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose and any combination of two or more of them. The binder may be a water-soluble material; Compared to non-binding agents, such as a gel-forming polymer, the molecular weight of the binding agent is such that when combined with a small volume of water, it does not form a gel or highly viscous composition. A binder can exhibit a relatively low molecular weight compared to a gelling polymer and a relatively lower viscosity (for example, when measured in a 2% aqueous solution). Typically, the molecular weight of a polymer suitable as a binding agent may be less than 50,000, for example, less than 30,000 or less than 10,000.

A binder may be present in any part of the dosage form as described, including a core or film or coating of a coated core particle, or as part of an excipient for containing or binding particles to a coated core of the core in dosage form. A filler may be incorporated into the core of the coated core particles in combination with an active pharmaceutical ingredient, a gelling polymer, or both; as part of a layer of active pharmaceutical ingredient located above the core, or another layer of coated core particles; as solvent resistant film; or in an excipient suitable for binding particles in a dosage form. A binding agent may be present in any one or more of these parts of the dosage form with immediate release as described herein in such an amount as to provide the desired processing properties or functional properties in each part of the dosage form and in the entire dosage form. The total amount of binding agent in the dosage form may also be as desired to provide the desired functionality, including immediate release functionality, for example, in an amount in the range from 0.1 to 10% by weight of the binding agent of the total weight of the dosage form, for example, 0.5 to 7% by weight of a binding agent of the total weight of the dosage form.

Examples of lubricants include inorganic materials such as talc (hydrated magnesium silicate; polymers such as PEG 4000; fatty acids such as stearic acid; fatty acid esters such as glyceride esters (e.g. glyceryl monostearate, glyceryl tribeneate and glyceryl dibenate) ; sugar esters (e.g., sucrose sorbitan monostearate and monopalmitate); glyceryl dibehenate (Compritol® 888 ATO); and metal salts of fatty acids (e.g., magnesium stearate, calcium stearate and zinc stearate). Braz, conventional lubricants include talc, glyceryl monostearate, calcium stearate, magnesium stearate,

- 16 032013 stearic acid, glyceryl behenate, polyethylene glycol, poloxamer and combinations of the above. The lubricant may be included in the immediate release dosage form as described in any suitable amount, such as an amount in the range from 0.1 to 10% by weight of the lubricant of the total weight of the dosage form, for example, from 0.5 to 7% by weight lubricant of the total weight of the dosage form.

Examples of glidants include colloidal silicon dioxide, untreated colloidal silicon dioxide (for example, as available under the trade name Cabosil (Cab-O-Sil®)) and crystalline or molten quartz. The glidant may be added to the immediate release dosage form as described in any suitable amount.

Examples of colorants include colorants and varnishes of the FD&C type, fruit and vegetable extracts, titanium dioxide, iron oxides, and mixtures thereof. The dye can be introduced into the dosage form by mixing the dye with any other ingredients. Alternatively, the dye can be applied to the outer surface of the dosage form.

In the immediate release dosage form as described herein, any active pharmaceutical ingredient may be included alone or in combination. In the presence of anti-abuse characteristics, as described herein, where some operate on the basis of specific structural or compositional characteristics of coated core particles, APIs that may be particularly suitable may be types of active pharmaceutical ingredients that an individual may abuse which may develop addiction, an overdose or two or more of them; such APIs may be in dosage form in such a position as to provide an anti-abuse effect of the characteristics of the coated particles of the core on the API, for example, in the core or in the inner layer of coated particles of the core.

Drugs that are often abused include sedative-hypnotics, stimulants (e.g., central nervous system (CNS) stimulants), anxiolytics, antipsychotics, dissociative anesthetics and narcotic analgesics, including but not limited to drugs that can cause psychological or physical drug dependency API may include any therapeutically acceptable drug salt derived from the drug Nogo means, analog medicament homologue drug or active pharmaceutical ingredient polymorph.

Sedative hypnotics include, for example, barbiturates, for example, phenobarbital, methobarbital, amobarbital, pentobarbital and secobarbital and their pharmaceutically acceptable salts; benzodiazepines, for example, diazepam, chlordiazepoxide, lorazepam, triazolam, temazepam, alprazolam and flurazepam and their pharmaceutically acceptable salts; phenothiazines, such as, for example, alimemazine, chlorpromazine, thioridazine and their pharmaceutically acceptable salts, and medications for sleep modification, such as, for example, zolpidem, zaleplon and eszopiklon and their pharmaceutically acceptable salts. Anxiolytics include, for example, benzodiazepines, for example, diazepam, chlordiazepoxide, estazolam, lorazepam, triazolam, alprazolam, clonazepam and flurazepam and their pharmaceutically acceptable salts. CNS stimulants include, for example, amphetamines, such as, for example, dextroamphetamine, levoamphetamine (benzadarin), methamphetamine (methadrine), pseudoephedrine and aderal (mixed amphetamine salts) and their pharmaceutically acceptable salts, and non-amphetamine psychostimulants, such as methylphenyl and Armifinidin, modifinidin their pharmaceutically acceptable salts. Narcotic analgesics include opioids, such as, for example, buprenorphine, butorphanol, codeine, dihydrocodeine, dihydromorphine, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, methadone, fentanyl, meperidine, tramadol, propoxyphene salts and their. Antipsychotics may include, for example, phenothiazines, as listed above, butyrophenones, such as, for example, droperidol and haloperidol, dibenzoxazepines, such as loxapine, and atypical antipsychotics, such as aripiprazole, clozapine, olanzapine, queteridone, remoxypride.

Other specific drugs that may be abused include, for example, muscle relaxants, such as, for example, cyclobenzaprine and their pharmaceutically acceptable salts, cannabinols (e.g., Δ-cannabidiol. Δ-cannabidiol, Δ-cannabidiol, Δ ' -cannabidiol, Δ ⁴ -cannabidiol, Δ ⁵ -cannabidiol and Δ ⁶ -cannabidiol); cannabinoids such as dronabinol, delta-9 tetrahydrocannabinol (THC), cannabidiol (CBD), nabilon, dexanabinol, ajulemic acid, cannabinor, rimonabant and taranabant and their pharmaceutically acceptable salts; and dissociative anesthetics such as ketamine and esketamine and their pharmaceutically acceptable salts.

The amount of active pharmaceutical ingredient included in the immediate release dosage form can be any suitable amount, as is known and as can be found in the relevant literature, such as Goodman & Gillman's, The Pharmacological Basis of Therapeutics, 9th ed. pages 219-222, 361-396, 521-535 1996. For example, typical therapeutic

- 17 032013 amounts of oxycodone are 5, 10 or up to 400 mg to the hydrochloride salt. Often when converted to a suitable immediate release dosage form, the active pharmaceutical ingredient may be present in such a dosage form in a generally prescribed amount, typically from 0.5 to 25% based on the dry weight of the total weight of the dosage form. For narcotic analgesics, such as opioids, in a unit dosage form, such as at a level of from about 1 to about 500 mg, or from about 1 to about 250 mg, or from about 1 to about 100 mg; for example, 2.5, 5, 7.5, 10, 15, 20 or 30 mg per unit dosage form. In other embodiments, the dosage form contains any suitable amount of API to provide a therapeutic effect.

The present invention also relates to methods of treatment, comprising oral administration of an effective amount of a dosage form described herein with immediate release and an obstacle to abuse. For example, the present document provides a method for treating or preventing pain or discomfort in an individual in need thereof by administering an effective amount of an immediate release dosage form described herein that prevents an abuse that contains an API that is a narcotic analgesic drug, such as an opioid medicine.

Also provided herein is a method of treating a sleep disorder in an individual in need thereof by administering an effective amount of an immediate release dosage form described herein, and preventing the abuse of an API that is a sedative hypnotic drug, such as barbiturate.

Also provided herein is a method for treating anxiety in an individual in need thereof by administering an effective amount of an immediate release dosage form described herein that prevents an abuse that contains an API that is an anxiolytic drug, such as benzodiazepine.

Also provided herein is a method of treating psychosis in an individual in need thereof by administering an effective amount of an immediate release dosage form described herein that prevents an abuse that contains an API that is an antipsychotic drug such as quetiapine.

When used in relation to the composition described herein, an effective amount is an amount sufficient to produce a therapeutic result in an individual in need thereof. For example, a therapeutic result, by way of non-limiting examples, may include the treatment or prevention of pain, sleep disturbance, anxiety, or psychotic symptoms in an individual.

The dosage form described may optionally contain one or more additional type APIs that are not subject to frequent abuse. These additional APIs may be any suitable or desirable APIs, such as a non-steroidal analgesic drug class API. As used herein, the expression non-steroidal analgesic drugs refers to drugs that include drugs, often referred to as non-steroidal anti-inflammatory drugs or NLVS and acetaminophen, which is non-steroidal but does not act through the inflammation mechanism. Thus, the term non-steroidal analgesic drugs may include acetaminophen and also includes NSAIDs such as aspirin, ibuprofen and naproxen. The dosage form also exhibits immediate release properties in relation to these non-susceptible APIs. And these APIs can be present in the dosage form at any suitable level, typically from 0.5 to 25, for example, from 1 to 10% by weight of the API based on dry weight of the total weight of the dosage form, for example, at 5, 25, 50, 75, 100, 125, 150, 175, 200, 300, 325, 500, 750 or up to or more than 1000 mg per unit of dosage form or between them. In other embodiments, the dosage form comprises an amount of API suitable for providing a therapeutic effect.

The immediate release dosage form as described may include one or more of the described anti-abuse characteristics, alone or in combination; for example, one or more of: a gel-forming polymer as part of a coated particle (eg, in the core of a coated particle); wax as part of the coated particle (for example, in the core of the coated particle); a binding agent or filler as part of the coated particle core (for example, in the core of the coated particle); a film layer, which optionally can be a solvent-resistant film (eg, a pH-sensitive film) as part of a layer of a coated particle core; or a gelling polymer as an excipient or binding component

- 18,032,013 of the agent used to hold together the particles with the coated core as part of the immediate release dosage form. In the presence of these anti-abuse characteristics, other types of known anti-abuse characteristics may be optional and may be specifically excluded from the immediate release dosage form as described. In certain embodiments of the described dosage forms, other types of obstacles to abuse can be specifically excluded.

In particular, some dosage forms include a nasal irritant to counteract or prevent abuse by nasal injection. A nasal irritant may be a mucosal irritant or an irritant to the nasal passages, which when inhaled through the nasal passages when present in a pulverized or powder dosage form can induce pain or irritation of the tissue of the nasal passages of the abusing individual. Examples include surfactants such as sodium lauryl sulfate, poloxamer, sorbitan monosubstituted esters, and glyceryl monooleates. Certain specific embodiments of the dosage forms described herein do not require nasal irritants, such as the nasal irritants described above, and can be specifically excluded.

Alternatively, the dosage forms may include an emetic causing vomiting. Certain specific embodiments of the dosage forms described herein do not require an emetic and can be specifically excluded.

Alternatively, some dosage forms include an effervescent agent that acts as an obstacle to abuse by nasal injection. The effervescent agent includes an acid component and a main component, which when combined in the presence of an aqueous medium, such as after blowing through the nose, release a gas, such as oxygen or carbon dioxide. See, for example, patent publication WO 2013/077851, the entire contents of which are incorporated herein by reference. The acid source can be, for example, citric acid, tartaric acid, malic acid, maleic acid, lactic acid, glycolic acid, ascorbic acid, fumaric acid, adipic acid, succinic acid, salts thereof, and combinations thereof. The base may be, for example, carbonate or bicarbonate. Dosage forms as described herein do not require an effervescent agent in the form of an acid and a base, which can be combined to produce a gas, such as oxygen or carbon dioxide, and can be specifically excluded.

Other dosage forms include a biologically active chemical compound that functions as an antagonist to the active pharmaceutical ingredient. The antagonist can prevent potential abuse of the dosage form by a method comprising taking multiple or more or more units of the dosage form at a time. Antagonists are compounds that block or neutralize the action of the active pharmaceutical ingredient and are available and known for various classes of drugs, including opioids and other pharmaceuticals. Examples of opioid antagonists include compounds such as naltrexone, naloxone, nalmefene, cyclazocine, levallorfan. Specific examples of antagonists and methods for preparing antagonists for addition to a dosage form are provided in US Pat. Nos. 7682633 and 7658939, which are incorporated herein by reference. As described herein, an immediate release dosage form containing an opioid and comprising one or more anti-abuse characteristics as described herein (e.g., a gel-forming polymer, a wax, solvent-resistant film, or a combination thereof) can be formulated so that it does not contain or an API antagonist that is also contained in a dosage form, for example, an opioid antagonist in a dosage form containing an opioid, has been excluded from it.

Turning to FIG. 1A and 1B, the dosage form may contain particles 10A containing an API. The particle (for example, a coated particle or a coated core) may comprise a core 12a (or an uncoated core), which may be coated with one or more layers, films or coatings, for example, 14a, 16a or any additional layer or coating applied over under or in between. In FIG. 1B and 1C, the layer denoted 16a may be an API-containing layer, and the layer denoted 14a may be solvent resistant, for example, a layer of a pH sensitive film. Particle 10A may contain one or more of the ingredients described herein, such as any one or more APIs (especially abusive APIs), a gelling polymer, optionally a wax, optionally a solvent-resistant layer, and one or more additional layers under , above or between these layers or between any of the layers and the core. Each layer may be present in a size or quantity (for example, with a thickness) that allows a suitable immediate release dosage form to be obtained with one or more of the anti-abuse characteristics described herein. Other optional components of the core or layer of particle 10a may be a filler that binds

- 19 032013 agent, another excipient or solvent (not more than a residual amount, if any), such as water or ethanol for use in preparing a coated particle, and which are substantially removed after the core, coating or coated particle is obtained. Examples of core 10A may include any number of different ingredients from: a gelling polymer (e.g., from 0 to 100 percent of the core), a filler as described herein, such as sugar (mannitol) or microcrystalline cellulose (e.g., from 0 to 100% of the core ) binding agent (e.g., from 0 to 100% of the core) and wax (e.g., from 0 to 100% of the core).

Although it is believed that the coated particles of the core 10a are new and patentable, certain process steps suitable for preparing these new coated particles may be known. Available methods include certain methods and processing steps known as suitable for the preparation of particles and coated particles in the pharmaceutical field. The coated core particle 10a can be obtained by initially mixing the ingredients of the core 12a with a solvent such as water or ethanol and forming the mixture into a spherical core particle by known methods. The particles can be dried and separated by size, and then one or more coatings in the form of a continuous film or layer can be applied to the core, optionally sequentially to obtain several layers surrounding the core. A general processing method for producing a multi-layer coated particle may include a number of steps such as composing, mixing, granulating, wet grinding, coating (by any method, such as a fluidized bed coating, spray coating, etc.), and one or more drying steps, such as using a fluidized bed or other drying method. Between the steps of core formation and coating, for example, after the drying step, coated or uncoated particles can be sorted or separated based on size to obtain a composition or set of particles with a desired range and size distribution. Thus, coated granular compositions of the invention can be prepared by a process including:

(i) granulating a wax or gelling polymer or a mixture thereof in the presence of an aqueous alcohol solution or suspension containing a suitable binding agent to form granules;

(ii) layering on the granules formed in step (i) a layer of a solution or suspension containing API; and (iii) coating the coated granules formed in step (ii) with a layer of a solution or suspension containing a film-forming polymer material to form a coated coated granule.

The above method may further include the steps of grinding and drying the granular composition obtained in step (i).

In embodiments where the core contains a sphere of sugar or a sphere of microcrystalline cellulose, the steps of the above method can be modified as follows:

(i) obtaining a sphere from sugar (or a sphere from microcrystalline cellulose);

(ii) layering on a sphere of sugar (or sphere of microcrystalline cellulose) a layer of a solution or suspension containing API; and (iii) coating the coated sphere formed in step (ii) with a solution or suspension containing a film-forming polymer material to form a coated coated sphere.

Compressed tablets of the invention can be prepared by a process comprising:

(i) combining the coated granular composition with a coated layer (or coated sphere with a coated layer) obtained by one of the above methods, a second API (e.g. acetaminophen), a gelling polymer and a disintegrant, and optionally at least one additional excipient selected from a filler, a dye, and a pH adjuster, to form a first mixture, and then mix the first mixture for a suitable time;

(ii) adding a lubricant to the mixed mixture formed in step (i) to form a second mixture, and then mixing the second mixture for a suitable time; (iii) compressing the blended mixture formed in step (ii) to form compressed tablets.

Suitable stirring times in step (i) may be, for example, from about 5 to about 90 minutes, or from about 10 to about 60 minutes, or from about 20 to about 40 minutes, or about 30 minutes. Suitable time for stirring in step (ii) may be, for example, from about 1 to about 30 minutes, or from about 5 to about 20 minutes, or about 10 minutes.

In certain embodiments, as shown in FIGS. 1A, 1B, and 1C, the immediate release dosage form as described may comprise a coated particle core 10A that contains core 12A that contains only a small amount of API or that contains a minor amount of API. The core 12A may contain less than 5% by weight, for example, less than 1 or less than 0.5% by weight of the active pharmaceutical ingredient, based on the total weight of the core of the coated particle. Alternatives

- 20 032013 but, core 12A may contain less than 5% by weight of the total pharmaceutical ingredient in the core coating polymer, for example, less than 5, less than 1, or less than 0.5% by weight of the active pharmaceutical ingredient of the total API mass in particle c coated core. In these embodiments, the bulk of the API may be contained outside the core 12A, for example, in the API layer 16a, which may contain at least 50, at least 75, or at least 90, or at least 95% by weight of the total API in core coating polymer.

The core 12A may include a binder, a gelling polymer (e.g., HPMC), a wax or a filler, optionally separately or in combination, where each is in such an amount as to allow the core materials to function as one or more anti-abuse characteristics, as described herein document. For examples of suitable amounts and ranges of amounts of these ingredients, see the examples included in the present description.

Turning to FIG. 1A, core 12A contains a gelling polymer, wax, binding agent or filler, or any combination thereof, and does not contain an API (i.e., no more than an insignificant amount, such as less than 0.5 or less than 0.1 percent by weight of the core 12A). As shown in FIG. 1B and 1C, an API-free core 12A may be coated with a coating layer that contains an API, for example, an active pharmaceutical ingredient layer or an API 16A layer. As shown in FIG. 1B, a coated core particle 10A includes a core 12A that does not contain any API, and an API layer 16A that contains a certain amount of API, such as the total number of APIs (e.g., an API that is often abused) that must be contained in dosage form obtained from particles 10A. The API layer 16A may contain one or more ingredients, as described herein, suitable for forming the API layer 16A as a layer above the outer surface of the core 12A. (The API in API layer 16A may be an API type that is often prone to abuse, such as an opioid, and may comprise all or most (e.g., at least 70, at least 80, at least 90, or at least 95 percent) of the total amount of this type of API in coated core particles and in dosage form; in this embodiment, the core may contain less than 10, less than 5 or less than 1 percent of the total API in coated particles and less than 10, 5, or 1 percent of the total API amounts in dosage form). Suitable ingredients in the non-API layer API may include a binding agent along with the API. The API and binder can be added to a solvent (for example, water, ethanol, or both) and coated and dried to form a preferably continuous film layer on the outer surface of core 12A, i.e., API layer 16A. For examples of suitable amounts and ranges of amounts of these ingredients, see the examples included in the present description.

The coated core particle 10A may optionally also include a film layer, for example, a solvent resistant layer (e.g., a pH sensitive layer) 14A, as described herein.

In certain alternative embodiments, the dosage form as described may comprise a coated core 10B particle that includes a 12B core that contains a suitable amount of API, such as an amount of API suitable in an immediate release dosage form with one or more anti-abuse characteristics, such as described herein obtained for incorporating 10B particles. See figures 2A and 2B. In such embodiments, the core 12B of particle 10B may comprise a gelling polymer, optionally wax, an optional binding agent or filler, and a certain amount of API.

Turning to FIG. 2A, core 12B contains a gelling polymer, an optional wax, an optional binding agent, and an API. Turning to FIG. 2B, an API containing core 12B may optionally be coated with a solvent resistant layer (e.g., a pH sensitive layer) 14B as described herein for use in an immediate release dosage form. The core 12B can optionally also be coated with a coating layer that contains an API, for example, an active pharmaceutical ingredient layer or an API layer, before applying a solvent resistant layer. Thus, core-containing coated particles of an API, as described herein, may contain an API of a type often abused:

in the API layer surrounding the core, and a significant amount in the core; in the API layer surrounding the core, and in a small amount in the core; only in the API layer surrounding the core; or only at the core.

In certain alternative embodiments, the dosage form as described may comprise a coated core particle 10B, as shown in FIG. 2B, which does not contain an API layer and which does not contain an API at all. Turning to FIG. 2C, such a particle 10B, not

- 21 032013 containing an API may include a core 12B containing a gelling polymer, optionally a wax and optionally a binding agent, where this core 12B may optionally be coated with a solvent resistant layer (e.g., a pH sensitive layer) of 14B as described herein for immediate release dosage formulations.

An API coated coated particle 10a or 10b and optionally an API coated coated particle 10B may be included in any of a number of dosage forms, examples of which are a compressed tablet or compressed capsule, suppository, capsule, droplet, pill, gel, soft gelatin capsule, etc. As one example, dosage form 12 may be prepared as a compressed tablet or compressed capsule. The tablet or capsule 12 may contain particles with a coated core 10 (for example, 10A or 10B) distributed in a matrix 20, compressed to form a compressed tablet or capsule 12. Particles with a coated core 10a or 10B can mainly or specifically be such as described herein, and may contain an amount of API suitable to provide the desired dose when taking a tablet or capsule 12; for example, matrix 20 does not contain any significant amount of API.

Matrix 20 may contain ingredients suitable for combination with coated core particles 10A, 10B to formulate an immediate release dosage form. Examples of suitable immediate release dosage form excipients may include ingredients that permit disintegration or disintegration of the dosage form after administration and facilitate contact with the fluid in the stomach, such as a suitable amount of disintegrant. Examples of such excipients for such a dosage form may also include one or more ingredients that act as anti-abuse characteristics, such as a gelling polymer, as described herein. Other excipients may be suitable for processing to form a compressed dosage form, and may also allow the compressed dosage form to function as an immediate release dosage form with one or more anti-abuse characteristics.

The following non-limiting examples demonstrate various dosage forms as described herein. Described and exemplary dosage forms can be obtained by methods including the steps of granulation, coating and pressing, as described below.

General way

G cancellation.

1. Glyceryl behenate and K100M hypromellose are dry mixed in a granulator with high shear. An aqueous-alcohol solution of ethyl cellulose is added. Alternatively, granulation can be carried out by spraying a water-alcohol solution from above in a fluidized bed granulator. Optionally, a portion of ethyl cellulose, for example, from about 10 to about 50% by weight, or from about 10 to about 40% by weight, or from about 15 to about 30% by weight, before adding an aqueous-alcoholic solution containing the balance of ethyl cellulose, dry mixed with glyceryl behenate and hypromellose K100M.

(Alternatively, when an API is included in the core). Glyceryl behenate and hypromellose K100M and API are dry mixed in a granulator with high shear. Aqueous alcohol solution of ethyl cellulose is added. Alternatively, granulation can be carried out by spraying a water-alcohol solution from above in a fluidized bed granulator. Optionally, a portion of ethyl cellulose, for example, from about 10 to about 50% by weight, or from about 10 to about 40% by weight, or from about 15 to about 30% by weight, before adding an aqueous-alcoholic solution containing the balance of ethyl cellulose, dry mixed with glyceryl behenate and hypromellose K100M.

2. The granules are then wet milled using a grinder (Granumill) and then dried using a fluidized bed and optionally sieved.

Layering.

3. Next, polymer granules are layered using the Wurster API fluidized bed layering method (or alternatively, granulated using high shear granulation or a granulation method by spraying from above onto a fluidized bed).

(Alternatively, when the coated granule does not contain an API). The layering step is skipped and proceed to the coating step 4 below for the granular composition obtained in step 1.

Coating.

4. Then the coated granules after step 3 (or alternatively, when the coated granule should not contain API, the granules obtained in step 1) are coated using a fluidized bed coater equipped with a Wurster insert (lower spray unit) with a suspension a copolymer of Eraudite E100 and magnesium stearate in ethanol. Then covered hour

- 22 032 013 sifters are sieved and mixed.

Mixing and pressing tablets.

The process of mixing, pressing and dispensing vials for hydrocodone and acetaminophen tablets produced using a coated intermediate is as follows:

1. Then, API coated coated granules, APAP, crospovidone, 71G carbopol, sodium bicarbonate, mannitol, optionally coated non-API coated granules, and optionally the desired colorant are added and mixed.

2. Then magnesium stearate (and optionally a colorant) is added to the mixer and mixed. The mixture is compressed into tablets using a rotary tablet press.

Example 1. Obtaining coated granules.

Table 1. Components for the composition of the granules

Component % wt./mass. Hypromellose 60 Glyceryl behenate 26 Ethyl cellulose 14 TOTAL 100

The granules were obtained in a high shear granulator, where hypromellose and glyceryl behenate were dry mixed for 3 minutes. Then, a 10% aqueous-alcoholic solution of ethylcellulose N10 was slowly added, maintaining the speed of the impeller and the granulator grinder at preselected values that provide sufficient shear for the formation and growth of granules. The addition of the solution was continued until the total amount of ethyl cellulose was added. The granules were then wet milled using a grinder (Granumill) and then placed in a fluidized bed for drying.

Table 2. Components for the composition of the granules with a layer

Component % wt./mass. Hydrocodone Bitartrate 10 Polymer Granules (EU, HPMC and Compritol) 85 Hypromellose 2910 5 TOTAL 100

Then, granules were layered on the obtained granules in a device for spray coating from below in a fluidized bed using a 12% aqueous solution of hydrocodone bitartrate and HPMC 2910.

Table 3. Composition Components of Coated Granules

Component % wt./mass. Granules with a layer of hydrocodone bitartrate, 10% fifty Eudrazhit E-100 33 Magnesium stearate 17 TOTAL 100

Then, the pellets coated with a layer of hydrocodone bitartrate were coated in a spray-coating device from below in a fluidized bed using a 25% suspension of Eudragit E-100 copolymer and magnesium stearate in alcohol. Then, the obtained coated granules were used for the further mixing and pressing process.

Example 2. Tablets of hydrocodone / acetaminophen.

Table 4. Composition of hydrocodone / acetaminophen tablets

Component % wt./mass. mg / tablet Granules coated with hydrocodone bitartrate, 5% 20, 0 200 Paracetamol ¹ 33.7 337

- 23,032,013

Mannitol 10.3 103 Carbopol fifty fifty Microcrystalline cellulose 12.0 120 Crospovidone 15, 0 150 Bicarbonate of soda thirty thirty Magnesium stearate 1,0 10 Total 100 1000 [1] Contains 95% acetaminophen (ARAP) and 5% gelatin

Coated granules were prepared according to Example 1 above and mixed with paracetamol and other excipients (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Then magnesium stearate was added to lubricate the mixture, and the mixture was stirred for an additional 5 minutes, followed by compression into hydrocodone / acetaminophen tablets.

Example 3. Hydrocodone bitartrate / acetaminophen.

Table 5. The composition of the granules of hydrocodone / acetaminophen

Coated Core Composition Component Position mg / tablet NRMS K100M Core 51.1 Kompritol Core 21.9 Etotsel Core 12 Hydrocodone Bitartrate API Layer 10 NRMS 2910 API Layer 5 Eudrazhit E-100 Film 66, 7 Magnesium stearate Film 33, 3 Total 200

Table 6. Composition of hydrocodone / acetaminophen tablets

Components mg / tablet Composition with a coated core (above) 200 ARAR 325 Gelatin 12.1 Mannitol 42.9 Carbopol fifty Microcrystalline cellulose 130 Crospovidone 200 Bicarbonate of soda thirty Magnesium stearate 10 Total 1000

Table 7. General composition of tablets of hydrocodone / acetaminophen

- 24,032,013

General composition of tablets Components mg / tablet NRMS K100M 51.1 Kompritol 21.9 Etotsel 12 Hydrocodone Bitartrate 10 NRMS 2910 5 Eudrazhit E-100 66, 7 ARAR * 325 Gelatin 12.1 Mannitol 42.9 Carbopol fifty Microcrystalline cellulose 130 Crospovidone 200 Bicarbonate of soda thirty Magnesium stearate 43.3 Total 1000 * acetaminophen (acetylparaaminophenol).

Coated granules were obtained by the method described in Example 1. Then, the obtained coated granules were mixed with acetaminophen and other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Then magnesium stearate was added to lubricate the mixture, and the mixture was stirred for an additional 5 minutes, followed by compression into hydrocodone / acetaminophen tablets.

Example 4. Hydrocodone bitartrate / acetaminophen.

Table 8. The composition of the granules of hydrocodone / acetaminophen

Coated Core Composition Component Position mg / tablet NRMS cuom Core 25, 5 Kompritol Core 10, 9 Etotsel Core 6 Hydrocodone Bitartrate API Layer 5 NRMS 2910 API Layer 2,5 Eudrazhit E-100 Film 33, 4 Magnesium stearate Film 16, 7 Total 100

Table 9. Hydrocodone / Acetaminophen Tablets

Component mg / tab. Composition with a coated core (above) 100 ARAR 325 Gelatin 12.14 Mannitol 34.88 Carbopol fifty Microcrystalline cellulose 96 Crospovidone 144 Bicarbonate of soda thirty Magnesium stearate 8 Total 800,02

Coated granules were obtained by the method described in example 1. Then, the obtained coated granules were mixed with acetaminophen and other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed in a V-shaped mixer for 30

- 25,032,013 minutes. Then magnesium stearate was added to lubricate the mixture, and the mixture was stirred for an additional 5 minutes, followed by compression into hydrocodone / acetaminophen tablets.

General composition of tablets

Table 10. Composition of gi tablets

Components mg / tablet NRMS cuom 25, 5 Kompritol 10, 9 Etotsel 6 Hydrocodone Bitartrate 5 NRMS 2910 2,5 Eudrazhit E-100 33, 4 ARAR 325 Gelatin 12.14 Mannitol 34.88 Carbopol fifty Microcrystalline cellulose 96 Crospovidone 144 Bicarbonate of soda thirty Magnesium stearate 24.7 Total 800,02

Example 5. Hydrocodone bitartrate / acetaminophen.

Table 11. The composition of the granules of hydrocodone / acetaminophen

Coated Core Composition Component Position mg / tablet NRMS cuom Core 50, 1 Kompritol Core 21.5 Etotsel Core 11, 8 Hydrocodone Bitartrate API Layer 9, 8 NRMS 2910 API Layer 4.9 Eudrazhit E-100 Film 65, 4 Magnesium stearate Film 32,7 Total 196, 2

Table 12. The composition of the tablets of hydrocodone / acetaminophen

Component mg / tab. Composition with a coated core (above) 196, 1 ARAR 325 Gelatin 12.14 Mannitol 46, 2 Carbopol fifty Microcrystalline cellulose 130 Crospovidone 200 Red iron oxide 0, 6 Bicarbonate of soda thirty Magnesium stearate 10 Total 1000

Coated granules were prepared by the method described in Example 1. Then, the obtained coated granules were mixed with acetaminophen and other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, red iron oxide, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Then magnesium stearate was added to lubricate the mixture, and the mixture was stirred for an additional 5 minutes, followed by compression into hydrocodone / acetaminophen tablets.

- 26,032,013

Table 13. The composition of the tablets of hydrocodone / acetaminophen

General composition of tablets Components mg / tablet NRMS K100M 50, 1 Kompritol 21.5 Etotsel 11, 8 Hydrocodone Bitartrate 9, 8 NRMS 2910 4.9 Eudrazhit E-100 65, 4 ARAR 325 Gelatin 12.14 Mannitol 46, 2 Carbopol fifty Microcrystalline cellulose 130 Crospovidone 200 Red iron oxide 0, 6 Bicarbonate of soda thirty Magnesium stearate 42.7 Total 1000.14

Example 6. Oxycodone hydrochloride (single API) (cellel core).

Table 14. The composition of the granules of oxycodone

Coated Core Composition Components Position mg / tablet Celfera (MCC) Core 42 Oxycodone hydrochloride API Layer 5.2 NRMS 2910 API Layer 1.7 Eudrazhit E-100 Film 1.9 Magnesium stearate Film 0, 6 Total 51,4

Microcrystalline cellulose particles were layered in a spray-coating device from below in a fluidized bed using a 12% aqueous solution of oxycodone hydrochloride and HPMC 2910.

The particles with a layer of oxycodone hydrochloride were then coated in a spray bed coating apparatus in a fluidized bed using a 25% suspension of Eudragit E-100 copolymer and magnesium stearate in alcohol. Then, the obtained coated particles were used for the further mixing and pressing process.

Table 15. Composition of oxycodone tablets

Component mg / tab. Composition with a coated core (above) 51.54 Lactose 96.46 Microcrystalline cellulose 40 Crospovidone 10 Magnesium stearate 2 Total 200

The coated particles were mixed with other excipients (crospovidone and lactose) and mixed in a V-shaped mixer for 30 minutes. Then magnesium stearate was added to lubricate the mixture, and the mixture was stirred for an additional 5 minutes, followed by compression into oxycodone tablets.

Table 16. Composition of oxycodone hydrochloride tablets

- 27 032013

General composition of tablets Components mg / tablet Microcrystalline cellulose 82 Oxycodone hydrochloride 5, 2 NRMS 2910 1.7 Eudrazhit E-100 19 Lactose 96.46 Crospovidone 10 Magnesium stearate 2, 6 Total 199.86

Example 7. Hydrocodone bitartrate / acetaminophen (sugar core).

Table 17. The composition of the granules of hydrocodone bitartrate

Coated Core Composition Component Position mg / tablet Sugar Orb Core 47.3 REO Core 24.7 EPO Core 20, 5 Hydrocodone Bitartrate API Layer 5 NRMS 2910 API Layer 2,5 Eudrazhit E-100 Film 75 Magnesium stearate Film 25 Total 200

The particles were layered onto a sphere of sugar in a device for spray coating from below in a fluidized bed using an aqueous solution of hydrocodone bitartrate and HPMC 2910.

The particles with layered hydrocodone bitartrate were then coated in a spray bed coater in a fluidized bed using a 25% suspension of Eudragit E-100 copolymer and magnesium stearate in alcohol. Then, the obtained coated particles were used for the further mixing and pressing process.

Table 18. The composition of the tablets of hydrocodone bitartrate

Composition with a coated core (above) mg / tablet 200 ARAR 325 Binding agent 17.8 Mannitol 192.2 Microcrystalline cellulose 200 Crospovidone fifty Magnesium stearate fifteen Total 1000

The coated spheres were mixed with acetaminophen and other excipients (mannitol, microcrystalline cellulose, a binder, and crospovidone) and mixed in a V-shaped mixer for 30 minutes. Then magnesium stearate was added to lubricate the mixture, and the mixture was stirred for an additional 5 minutes, followed by compression into oxycodone tablets.

Table 19. The composition of the tablets of hydrocodone bitartrate

- 28 032013

General composition of tablets Components mg / tablet Sugar 47.3 REO (polyethylene oxide) 24.7 EPO (E-RO) 20.5 Hydrocodone Bitartrate 5 NRMS 2910 2,5 Eudrazhit E-100 75 ARAR 325 Binding agent 17.8 Mannitol 192.2 Microcrystalline cellulose 200 Crospovidone fifty Magnesium stearate 40 Total 1000

Example 8. Hydrocodone bitartrate / acetaminophen (cellel core).

Table 20. The composition of the granules of hydrocodone bitartrate

Coated Core Composition Component Position mg / tablet Celfera (MCC) Core 117.5 Hydrocodone Bitartrate API Layer 5 NRMS 2910 API Layer 2,5 Eudrazhit E-100 Film 83,4 Magnesium stearate Film 41, 6 Total 250

- 29 032013

Table 21. The composition of the tablets of hydrocodone bitartrate

Component mg / tablet Composition with a coated core (above) 250 ARAR 325 Gelatin 12.14 Mannitol 102.9 Microcrystalline cellulose 120 Xanthan gum thirty Crospovidone 150 Magnesium stearate 10 Total 1000.04

Coated spheres were prepared as in Example 7 and mixed with acetaminophen and other excipients (mannitol, microcrystalline cellulose, xanthan gum and crospovidone) and mixed in a V-shaped mixer for 30 minutes. Then magnesium stearate was added to lubricate the mixture and the mixture was stirred for an additional 5 minutes, followed by compression into hydrocodone tablets. Table 22. The composition of the granules of hydrocodone bitartrate

General composition of tablets Component mg / tablet Microcrystalline cellulose 237.5 Hydrocodone Bitartrate 5 NRMS 2910 2,5 Eudrazhit E-100 83,4 ARAR 325 Gelatin 12, 14 Mannitol 102, 9 Xanthan gum thirty Crospovidone 150 Magnesium stearate 51, 6 Total 1000.04

Example 9. Hydrocodone bitartrate / acetaminophen (cellel core).

Table 23. The composition of the granules of hydrocodone bitartrate

Coated Core Composition Component Position mg / tablet Celfera (MCC) Core 117.5 Hydrocodone Bitartrate API Layer 5 NRMS 2910 API Layer 2,5 Eudrazhit E-100 Film 83, 4 Magnesium stearate Film 41, 6 Total 250

Table 24. The composition of the tablets of hydrocodone bitartrate

Component mg / tablet Composition with a coated core (above) 250 ARAR 325 Gelatin 12, 14 Mannitol 84, 9 Microcrystalline cellulose 120 Carbopol thirty Bicarbonate of soda 18 Crospovidone 150 Magnesium stearate 10 Total 1000.04

- 30,032,013

Coated spheres were prepared as in Example 7 and mixed with acetaminophen and other excipients (mannitol, microcrystalline cellulose, carbopol, sodium bicarbonate and crospovidone) and mixed in a V-shaped mixer for 30 minutes. Then magnesium stearate was added to lubricate the mixture and the mixture was stirred for an additional 5 minutes, followed by compression into tablets.

Table 25. Composition of tablets of hydrocodone bitartrate

General composition of tablets Components mg / tablet Hydrocodone Bitartrate 5 NRMS 2910 2,5 Eudrazhit E-100 83,4 ARAR 325 Gelatin 12.14 Mannitol 84.9 Microcrystalline cellulose 237.5 Carbopol thirty Bicarbonate of soda 18 Crospovidone 150 Magnesium stearate 51.6 Total 1000.04

Example 10. Oxycodone hydrochloride / acetaminophen.

Table 26. The composition of the granules of oxycodone bitartrate

Coated Core Composition Component Position mg / tablet NRMS cuom Core 71 Kompritol Core 30.5 Etotsel Core 16, 8 Oxycodone hydrochloride API Layer 4,5 NRMS 2910 API Layer 2.2 Eudrazhit E-100 Film 83,4 Magnesium stearate Film 41, 6 Total 250

Table 27. Composition of oxycodone tablets

Component mg / tablet Composition with a coated core (above) 250 ARAR 325 Gelatin 12, 14 Lactose 84.9 Carbopol thirty Microcrystalline cellulose 120 Crospovidone 150 Bicarbonate of soda 18 Magnesium stearate 10 Total 1000.04

Granules were prepared and coated as described in Example 1. Then, the coated granules were mixed with acetaminophen and other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Then adding

- 31 032013 Li magnesium stearate to lubricate the mixture and the mixture was stirred for an additional 5 minutes, followed by compression into tablets of oxycodone / acetaminophen.

Table 28. Composition of oxycodone / acetaminophen tablets

General composition of tablets Components mg / tablet NRMS K100M 71 Kompritol 30.5 Etotsel 16, 8 Oxycodone hydrochloride 4,5 NRMS 2910 2.2 Eudrazhit E-100 83,4 ARAR 325 Gelatin 12.14 Lactose 84.9 Carbopol thirty Microcrystalline cellulose 120 Crospovidone 150 Bicarbonate of soda 18 Magnesium stearate 51, 6 Total 1000

Example 11. Oxycodone hydrochloride / acetaminophen.

Table 29. The composition of the granules of oxycodone hydrochloride

Coated Core Composition Component Position mg / tablet NRMS cuom Core 71 Kompritol Core 30.3 Etotsel Core 16, 7 Oxycodone hydrochloride API Layer 5 NRMS 2910 API Layer 2,5 Eudrazhit E-100 Film 83,4 Magnesium stearate Film 41, 6 Total 250, 5

Table 30. Composition of oxycodone / acetaminophen tablets

Component mg / tablet Composition with a coated core (above) 250 ARAR 325 Gelatin 12, 14 Mannitol 82.9 Xanthan gum fifty Microcrystalline cellulose 120 Crospovidone 150 Magnesium stearate 10 Total 1000.04

Granules were prepared and coated as described in Example 1. Then, the coated granules were mixed with acetaminophen and other excipients (xanthan gum, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Then magnesium stearate was added to lubricate the mixture and the mixture was stirred for additional

- 32,032,013 minutes followed by compression into oxycodone / acetaminophen tablets.

Table 31. Composition of oxycodone / acetaminophen tablets

General composition of tablets Components mg / tablet NRMS K100M 71 Kompritol 30.3 Etotsel 16, 7 Oxycodone hydrochloride 5 NRMS 2910 2,5 Eudrazhit E-100 83,4 ARAR 325 Gelatin 12.14 Mannitol 82.9 Xanthan gum fifty Microcrystalline cellulose 120 Crospovidone 150 Magnesium stearate 51, 6 Total 1000,54

Example 12. Oxycodone hydrochloride / acetaminophen.

Table 32. The composition of the granules of oxycodone hydrochloride

Coated Core Composition Component Position mg / tablet NRMS cuom Core 71 Kompritol Core 30, 5 Etotsel Core 16, 8 Oxycodone hydrochloride API Layer 4,5 NRMS 2910 API Layer 2.2 Eudrazhit E-100 Film 83,4 Magnesium stearate Film 41, 6 Total 250

Table 33. Composition of oxycodone / acetaminophen tablets

Component mg / tablet Composition with a coated core (above) 250 ARAR 325 Gelatin 12.14 Mannitol 52.9 Carbopol fifty Microcrystalline cellulose 120 Crospovidone 150 Bicarbonate of soda thirty Magnesium stearate 10 Total 1000.04

Granules were prepared and coated as described in Example 1. Then, the coated granules were mixed with acetaminophen and other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Then magnesium stearate was added to lubricate the mixture, and the mixture was stirred for an additional 5 minutes with

- 33,032,013 following compression into oxycodone / acetaminophen tablets.

Table 34. Composition of oxycodone / acetaminophen tablets

General composition of tablets Components mg / tablet NRMS cuom 71 Kompritol 30.5 Etotsel 16.8 Oxycodone hydrochloride 4,5 NRMS 2910 2.2 Eudrazhit E-100 83,4 ARAR 325 Gelatin 12.14 Mannitol 52.9 Carbopol fifty Microcrystalline cellulose 120 Crospovidone 150 Bicarbonate of soda thirty Magnesium stearate 51, 6 Total 1000

Example 13. Hydrocodone bitartrate / acetaminophen.

Table 35. The composition of the granules of hydrocodone bitartrate

Coated Core Composition Component Position mg / tablet NRMS KYOM Core 51 Kompritol Core 21.9 Etotsel Core 12 Hydrocodone Bitartrate API Layer 10 NRMS 2910 API Layer 5 Eudrazhit E-100 Film 66, 7 Magnesium stearate Film 33.3 Total 199, 9

Table 36. The composition of the tablets of hydrocodone bitartrate / ARAP

Component mg / tab. Composition with a coated core (above) 200 ARAR 325 Gelatin 12.14 Mannitol 74.86 Carbopol 80 Microcrystalline cellulose 100 Crospovidone 150 Bicarbonate of soda 48 Magnesium stearate 10 Total 1000

- 34 032 013

Granules were prepared and coated as described in Example 1. Then, the coated granules were mixed with acetaminophen and other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Then magnesium stearate was added to lubricate the mixture, and the mixture was stirred for an additional 5 minutes, followed by compression into hydrocodone / acetaminophen tablets.

Table 37. The composition of the tablets of hydrocodone bitartrate / ARAP

General composition of tablets Components mg / tablet NRMS K100M 51 Kompritol 21.9 Etotsel 12 Hydrocodone Bitartrate 10 NRMS 2910 5 Eudrazhit E-100 66, 7 ARAR 325 Gelatin 12.14 Mannitol 74.86 Carbopol 80 Microcrystalline cellulose 100 Crospovidone 150 Bicarbonate of soda 48 Magnesium stearate 43.3 Total 999, 9

Example 14. Hydrocodone bitartrate / acetaminophen.

Table 38. The composition of the granules of hydrocodone bitartrate

Coated Core Composition Component Position mg / tablet NRMS K100M Core 42 Kompritol Core 18, 1 Etotsel Core 9, 9 Hydrocodone Bitartrate API Layer 10 NRMS 2910 API Layer 5 Eudrazhit E-100 Film 56, 8 Magnesium stearate Film 28,4 Total 170,2

Table 39. The composition of the tablets of hydrocodone / ARAP

Component mg / tablet Composition with a coated core (above) 170 ARAR 325 Gelatin 12.14 Mannitol 24,905 Carbopol 49, 98 Microcrystalline cellulose 102 Crospovidone 127.5 Bicarbonate of soda 30,005 Magnesium stearate 8.5 Total 850,03

- 35 032 013

Granules were prepared and coated as described in Example 1. Then, the coated granules were mixed with acetaminophen and other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Then magnesium stearate was added to lubricate the mixture, and the mixture was stirred for an additional 5 minutes, followed by compression into hydrocodone / acetaminophen tablets.

Table 40. The composition of the tablets of hydrocodone / ARAP

General composition of tablets Components mg / tablet NRMS cuom 42 Kompritol 18.1 Etotsel 9, 9 Hydrocodone Bitartrate 10 NRMS 2910 5 Eudrazhit E-100 56, 8 ARAR 325 Gelatin 12.14 Mannitol 24,905 Carbopol 49, 98 Microcrystalline cellulose 102 Crospovidone 127.5 Bicarbonate of soda 30,005 Magnesium stearate 36, 9 Total 850,23

Example 15. Hydrocodone bitartrate / acetaminophen.

Table 41. The composition of the granules of hydrocodone bitartrate

Coated Core Composition Component Position mg / tablet NRMS KYOM Core 51 Kompritol Core 21.9 Etotsel Core 12 Hydrocodone Bitartrate API Layer 10 NRMS 2910 API Layer 5 Eudrazhit E-100 Film 66, 7 Magnesium stearate Film 33.3 Total 199, 9

Table 42. The composition of the tablets of hydrocodone / ARAP

Component mg / tablet Composition with a coated core (above) 200 ARAR 325 Gelatin 12.14 Mannitol 134.9 Carbopol thirty Microcrystalline cellulose 120 Crospovidone 150 Bicarbonate of soda 18 Magnesium stearate 10 Total 1000.04

- 36,032,013

Granules were prepared and coated as described in Example 1. Then, the coated granules were mixed with acetaminophen and other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Then magnesium stearate was added to lubricate the mixture, and the mixture was stirred for an additional 5 minutes, followed by compression into hydrocodone / acetaminophen tablets.

Table 43. The composition of the tablets of hydrocodone / ARAP

General composition of tablets Component mg / tablet NRMS K100M 51 Kompritol 21.9 Etotsel 12 Hydrocodone Bitartrate 10 NRMS 2910 5 Eudrazhit E-100 66, 7 ARAR 325 Gelatin 12.14 Mannitol 134.9 Carbopol thirty Microcrystalline cellulose 120 Crospovidone 150 Bicarbonate of soda 18 Magnesium stearate 43.3 Total 999.94

Example 16. Hydrocodone bitartrate / acetaminophen.

Table 44. The composition of the granules of hydrocodone bitartrate

Coated Core Composition Component Position mg / tablet NRMS K100M Core 51 Kompritol Core 21.9 Etotsel Core 12 Hydrocodone Bitartrate API Layer 10 NRMS 2910 API Layer 5 Eudrazhit E-100 Film 66, 7 Magnesium stearate Film 33.3 Total 199, 9

Table 45. The composition of the tablets of hydrocodone / ARAP

Component mg / tablet Coated Core Composition 200 (higher) ARAR 325 Gelatin 12.14 Mannitol 102.9 Carbopol fifty Microcrystalline cellulose 120 Crospovidone 150 Bicarbonate of soda thirty Magnesium stearate 10 Total 1000.04

- 37 032 013

Granules were prepared and coated as described in Example 1. Then, the coated granules were mixed with acetaminophen and other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Then magnesium stearate was added to lubricate the mixture, and the mixture was stirred for an additional 5 minutes, followed by compression into hydrocodone / acetaminophen tablets.

Table 46. The composition of the tablets of hydrocodone / ARAP

General composition of tablets Components mg / tablet NRMS cuom 51 Kompritol 21.9 Etotsel 12 Hydrocodone Bitartrate 10 NRMS 2910 5 Eudrazhit E-100 66, 7 ARAR 325 Gelatin 12, 14 Mannitol 102.9 Carbopol fifty Microcrystalline cellulose 120 Crospovidone 150 Bicarbonate of soda thirty Magnesium stearate 43.3 Total 999.94

17. Hydrocodone bitartrate / acetaminophen.

Example

Table 47. The composition of the tablets of hydrocodone / ARAP

Components (mg / t a b.) 5/325 mg 7.5 / 325 mg 10/325 mg Hypromellose K100M PH 25, 5 38.3 51.1 Kompritol 888 ATO eleven 16, 4 21.9 Ethyl cellulose 6 9 12 Hydrocodone Bitartrate 5 7.5 10 Hypromellose 2910 2,5 3, 8 5 Eudrazhit E-100 33,4 fifty 66, 7 Paracetamol Dc272n ** 342.11 342.11 342.11 Mannitol Ez 29, 89 38.81 37.29 Carbopol 71 g fifty fifty fifty Microcrystalline cellulose 96 108 130 Crospovidone 144 171 200 Sodium bicarbonate No. 1 FD&C aluminum varnish blue No. 2 thirty thirty thirty Ht n /P. 0.54 n /P. Yellow Iron Oxide 5 n /P. 0.54 n /P. Red iron oxide 212р n /P. n /P. 0, 6 Magnesium Stearate, Not Bovine 24, 6 34 43.3 Alcohol SDA-3A, anhydrous * * * to Purified water* * * to Total tablet weight 800 900 1000

* Removed during processing.

- 38 032 013

Granules were prepared and coated as described in Example 1. Then, the coated granules were mixed with paracetamol and other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose and dyes) and mixed in a V-shaped mixer for 30 minutes. Then magnesium stearate was added to lubricate the mixture, and the mixture was stirred for an additional 5 minutes, followed by compression into hydrocodone / acetaminophen tablets.

Table 48. The composition of the granules of hydrocodone bitartrate

5/325 mg Doze 7.5 / 325 mg Doze 10/325 mg Doze Granulation % % % Hypromellose 3.19 4.26 5.11 Kompritol 888 ATO 1.37 1.83 2.19 Ethyl cellulose 0.75 1 1,2 Alcohol SDA-3A, anhydrous * * * Purified water * * * TOTAL 5, 31 7.09 8.5 Layering % % % Hydrocodone Bitartrate Polymer granules (EU, HPMC) 0, 63 0, 83 1 and compromitol) 5, 31 7.09 8.5 Hypromellose 2910 0.31 0.42 0.5 Purified water * * * TOTAL 6, 25 8.34 10 Coating Coated granules % % -b hydrocodone, 10% 6, 25 8.34 10 Eudrazhit E-100 4.17 5, 56 6, 67 Magnesium stearate 2.08 2.77 3, 33 Alcohol, SDA-3A, Anhydrous * * TOTAL 12.5 16, 67 20

* Removed during processing.

Example 18. Armodafinil.

Table 49. Composition of Armodafinil Tablets

Armodafinil: Components (mg / tab.) 50 mg 150 mg 200 mg Hypromellose 64.26 36 48 Kompritol 888 ATO 17.85 10 14 Ethyl cellulose 10.71 10 14 Armodafinil fifty 150 200 Eudrazhit E-100 21 thirty 40 Mannitol Ez 17 25 25 Carbopol 71 g fifty fifty fifty Microcrystalline cellulose 100 125 125 Crospovidone 150 200 200

- 39 032 013

Sodium Bicarbonate # 1 thirty thirty thirty Magnesium Stearate, Not Bovine 71 25 32 Loutrol F68 (1: 5) 150 200 200 Sodium Lauryl Sulfate (3%) 23 thirty 40 Alcohol SDA-3A, anhydrous * * * * Purified water* * * Total tablet weight 754.82 921 1018 * Removed during processing

Granules are prepared and coated as described in Example 1. Then, the coated granules are mixed with other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Then magnesium stearate (non-bovine) is added to lubricate the mixture and the mixture is mixed for an additional 5 minutes, followed by compression into armodafinil tablets.

Table 50. Armodafinil Granule Compositions

Dose 50 mg Dose 150 mg Dose 200 mg Granulation mg / g mg / tab. mg / g mg / tab. mg / g mg / tab. Hypromellose 450 64.26 175 36 175 48 Armodafinil 350 49, 98 725 150 725 200 Kompritol 888 ATO 125 17.85 fifty 10 fifty 14 Ethyl cellulose 75 10.71 fifty 10 fifty 14 Alcohol SDA-3A, anhydrous * 4g * * * * Purified water * 4g * * * 4g TOTAL 1000 142.8 1000 206 1000 276 Coating mg / g mg / tab. mg / g mg / tab. mg / g mg / tab. Armodafinil granules, 35% 820 142.84 820 207 820 276 Eudrazhit E-100 120 20.90 120 thirty 120 40 Magnesium stearate 60 10.45 60 fifteen 60 20 Alcohol, SDA-3A, Anhydrous * 4g 4g * * * TOTAL 1000 174.2 1000 252 1000 336

* Removed during processing

Example 19. Phenobarbital.

Table 51. Phenobarbital Tablet Compositions

Components (mg / tab.) 15 mg 30 mg 60 mg 100 mg Hypromellose 19, 3 38, 6 77,2 128.52 Kompritol 888 ATO 5, 4 10.7 21,4 35, 7 Ethyl cellulose 3.2 6, 4 12.9 21.43 Phenobarbital fifteen thirty 60 100 Eudrazhit E-100 6, 3 15, 5 25, 1 42 Mannitol Ez 20 20 20 20, 1 Carbopol 71 g fifty fifty fifty fifty Microcrystalline cellulose 100 100 100 100 Crospovidone 130 130 130 200 Sodium Bicarbonate # 1 thirty thirty thirty thirty Magnesium Stearate, Not Bovine 9, 1 12.3 19, 1 31 Loutrol F68 (1: 5) 100 100 120 200 Sodium Lauryl Sulfate (3%) 22.8 28 35 fifty Alcohol SDA-3A, anhydrous * * * * * Purified water* * * * * Total tablet weight 511.1 571.5 700,7 1008.75

* Removed during processing.

- 40 032 013

Table 52. Phenobarbital Granule Compositions

Dose 15 mg Dose 30 mg Dose 60 mg Dose 100 mg Granulation mg / g mg / tab. mg / g mg / tab. mg / g mg / tab. mg / g mg / tab. Hypromellose 450 19.31 450 38.57 450 77.18 450 128.57 Phenobarbital 350 15, 02 350 thirty 350 60, 03 350 100 Kompritol 888 ATO 125 5.36 125 10.71 125 21.44 125 35.71 Ethyl cellulose 75 3.22 75 6, 43 75 12.86 75 21.43 Alcohol SDA-3A, 4g 4g 4- 4g 4g 4g 4g 4g anhydrous Purified water 4g 4g * * * 4g 4g * TOTAL 1000 42.91 1000 85.71 1000 171.51 1000 285.71 Coating mg / g mg / tab. mg / g mg / tab. mg / g mg / tab. mg / g mg / tab. Phenobarbital, 35% 820 42.89 820 85, 69 820 171.46 820 285.69 Eudrazhit E-100 120 6.28 120 12.54 120 25.09 120 41.81 Magnesium stearate 60 3.14 60 6.27 60 12.55 60 20.90 Alcohol, SDA-3A, 4g 4g 4g 4g 4g 4g 4g 4g anhydrous TOTAL 1000 52.3 1000 104.5 1000 209.1 1000 348.4

* Removed during processing.

Granules are prepared and coated as described in Example 1. Then, the coated granules are mixed with other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Then magnesium stearate (non-bovine) is added to lubricate the mixture and the mixture is mixed for an additional 5 minutes, followed by compression into phenobarbital tablets.

Example 20. Diazepam.

Table 53. Composition of diazepam tablets

Components 2 mg (mg / tab.) 5 mg (mg / tab.) 10 mg (mg / tab.) Hypromellose Kyuom PH 22.2 55, 6 111.2 Kompritol 888 ATO 9, 5 23, 8 47, 64 Ethyl Cellulose N10 5, 2 13, 1 26, 2 Diazepam 2 5 10 Hypromellose 2910 1 2,5 5 Eudrazhit E-100 26.7 66, 7 133.4 Mannitol Ez 70 70 70 Carbopol 71 g fifty fifty fifty Microcrystalline cellulose 95 95 94 Crospovidone 90 95 150 Sodium bicarbonate No. 1 thirty thirty thirty Magnesium Stearate, Not Bovine 18.1 38, 6 74, 6 Alcohol SDA-3A, anhydrous * A A A Purified water* A A A Total tablet weight 419, 7 545, 3 802.04

* Removed during processing

Granules are prepared and coated as described in Example 1. Then, the coated granules are mixed with other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Then magnesium stearate (non-bovine) is added to lubricate the mixture and the mixture is mixed for an additional 5 minutes, followed by compression into diazepam tablets.

- 41,032,013

Table 54. The composition of the coated granules of diazepam

Dose 2 mg Dose 5 mg Dose 2 mg Granulation mg / g mg / tab. mg / g mg / tab. mg / g mg / tab. Hypromellose 600.86 22.23 600.86 55.58 600.86 111.16 Kompritol 888 AT O 257.51 9, 53 257.51 23.82 257.51 47, 64 Ethyl cellulose 141.63 5, 24 141.63 13.10 141.63 26,20 Alcohol SDA-3A, anhydrous Purified water * 4g 4g 4g 4g 4g TOTAL 1000 37 1000 92.5 1000 185 Layering mg / g mg / tab. mg / g mg / tab. mg / g mg / tab. Diazepam fifty 2 fifty 5 fifty 10 Polymer granules (EU, HPMC and 925 37 925 92.5 925 185 compritol) Hypromellose 2910 25 1 25 2,5 25 5 Purified water * * * * * * TOTAL 1000 40 1000 100 1000 200 Covered 2.5% mg / g mg / tab. mg / g mg / tab. mg / g mg / tab. Granules with inflicted layer 500 40 500 100 500 200 diazepam, 5% Eudrazhit E-100 333, 6 26, 69 333, 6 66, 71 333, 6 133.43 Magnesium stearate 166.4 13, 31 166, 4 33.29 166, 4 66.57 Alcohol, SDA-3A, 4g anhydrous TOTAL 1000 80 1000 200 1000 400

Example 21. Hydrocodone (the only API).

Granules are prepared and coated as described in Example 1. Then, the coated granules are mixed with other excipients (carbopol, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Then magnesium stearate (non-bovine) is added to lubricate the mixture and the mixture is mixed for an additional 5 minutes, followed by compression into hydrocodone tablets.

Example 22. Hydrocodone (the only API) - (continued example 21 above).

Table 55. Composition of tablets of hydrocodone

Components 5 mg (mg / tab.) 10 mg (mg / tab.) Hypromellose K100M pH 25, 5 51.1 Kompritol 888 ATS eleven 21.9 Ethyl Cellulose N10 6 12.04 Hydrocodone Bitartrate 5 10 Hypromellose 2910 2,5 5 Eudrazhit E-100 33,4 66, 7 Mannitol Ez 70 70

- 42 032013

Carbopol 71 g fifty fifty Microcrystalline cellulose 95 95 Crospovidone 100 120 Sodium Bicarbonate # 1 thirty thirty Magnesium Stearate, Not Bovine 21, 6 39, 3 Alcohol SDA-3A, Anhydrous * * * Purified water* * * Total tablet weight 450 571.04

* Removed during processing.

Table 56. The composition of the coated granules of hydrocodone bitartrate

Dose 5 mg Dose 10 mg Granulation mg / g mg / tab. mg / g mg / tab. Hypromellose 600.86 25, 54 600.86 51.07 Kompritol 888 ATO 257.51 10, 94 257.51 21.89 Ethyl cellulose 141.63 6, 02 141.63 12.04 Alcohol SDA-3A, anhydrous * * 4g 4g Purified water * * 4g 4g TOTAL 1000 42.5 1000 85 Layering mg / g mg / tab. mg / g mg / tab. Hydrocodone Bitartrate 100 5 100 10 Polymer Granules (EU, HPMC and Compritol) 850 42.5 850 85 Hypromellose 2910 fifty 2,5 fifty 5 Purified water * 4g 4g 4g TOTAL 1000 fifty 1000 100 Coating mg / g mg / tab. mg / g mg / tab. Granules with a layer of hydrocodone bitartrate, 10% 500 fifty 500 100 Eudrazhit E-100 333, 6 33.36 333, 6 66, 71 Magnesium stearate 166, 4 16, 64 166, 4 33.29 Alcohol, SDA-3A, Anhydrous * 4g 4g 4g TOTAL * (deleted during processing) 1000 100 1000 200

Example 23. Hydrocodone bitartrate / acetaminophen.

Coated granules were obtained in accordance with example 1 above. Then, the obtained coated granules were mixed with paracetamol and other excipients (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose, dyes such as FD and C blue, red iron oxide or yellow iron oxide were pre-mixed and mixed in a hopper mixer for 30 minutes Then, magnesium stearate was added to lubricate the mixture, and the resulting mixture was stirred for an additional 5 minutes, followed by compression into hydrocodone / acetaminophen tablets.

- 43,032,013

Table 57. Composition of tablets of hydrocodone / ARAP

Component (% w / w) 5/325 mg 7.5 / 325 mg 10/325 mg Bitartrate coated granules hydrocodone 12.5 16, 7 20, 0 Paracetamol 42.76 38, 0 34.21 Mannitol 3.74 4.3 3.73 Carbopol 6.25 5, 6 fifty Microcrystalline cellulose 12.0 12.0 13, 0 Crospovidone 18.0 19, 0 20, 0 Bicarbonate of soda 3.75 3.3 thirty Aluminum varnish FD&C blue No. 2 NT n /P. 0.06 n /P. Red iron oxide 212P n /P. n /P. 0.06 Yellow Iron Oxide 510P n /P. 0.06 n /P. Magnesium stearate 10 1,0 10 Total 100 100 100

Example 24. The study of the extraction of the compositions in accordance with example 3.

The dosage form (intact and ground) obtained in accordance with Example 3 above (10/325 mg tablet of hydrocodone / acetaminophen bitartrate) was placed in a small volume of water and extracted to simulate the amount of hydrocodone available to abusing individuals by the intravenous (iv) method introduction. The resulting mixture was evaluated for accessibility by taking the mixture through a filter material into an IV injection syringe. Different needle sizes and extraction volumes were evaluated. The filtrates were evaluated for hydrocodone bitartrate by HPLC.

Table 58. The amount of hydrocodone extracted from two batches of 10/325 mg tablets of hydrocodone / acetaminophen bitartrate at 100 ° C and room temperature (RT)

No. party Intact tablet (mg) Ground tablet (mg) 100 ° C RT 100 ° C RT 1 0 mg 0.09 mg 0 mg 0 mg 2 0 mg 0.07 mg 0 mg 0 mg

Example 25. The study of extracts of the compositions in accordance with example 3 from a simulated nasal fluid.

The dosage form obtained in accordance with example 3 above (tablets 10/325 mg of hydrocodone bitartrate / acetaminophen) was ground using a pestle and mortar and placed in 10 ml of simulated nasal fluid at 37 ° C with gentle stirring to simulate the amount of hydrocodone bitartrate available for abuse by blowing through the nose. After 10 and 30 minutes, aliquots were taken for analysis of hydrocodone bitartrate by HPLC. The amount of hydrocodone bitartrate extracted from ground tablets for simulated nasal injection is shown in the table below.

This method is intended to determine hydrocodone bitartrate released from simulated nasal fluid extracts for extended release hydrocodone bitartrate tablets.

- 44 032 013

A. Parameters of HPLC analysis

Column GL Sciences Inertsil Phenyl-3, 4.6 mm x 50 5 microns Temperature speakers 45 ° C Detection UV at 280 nm Solvent A 0.1% HFBA in water Solvent B Meon Mobile phase Solvent A: Solvent B 70:30 Flushing injector Meon: water 50:50 Flow rate 2.0 ml / min Injection volume 50 μl lead time 4 min Peak response Area Diluent 0.1 N HC1

B. Preparation of a solution for HPLC.

Solvent A (0.1% HFBA in H ₂ O): Combine 1 ml of HFBA and 1 L of water with HPLC purity and mix well. Solvent A is stable for 14 days. You can get proportional volumes.

Mobile phase (Solvent A: MeOH 70:30): Combine 700 ml of solvent A and 300 ml of MeOH and mix well. The resulting solutions are stable for 1 month. You can get proportional volumes. Alternatively, an HPLC pump can be used to mix the mobile phase.

Thinner / Medium (0.1 N HCl): Combine 25 ml of 12 N HCl and 3 L of DI water and mix well. 0.1 N HCl is stable for 4 weeks. You can get proportional volumes.

Injector flushing (MeOH: H ₂ O 50:50): Combine 500 ml of MeOH and 500 ml of water with HPLC purity and mix well. MeOH: H ₂ O 50:50 stable for 1 month. You can get proportional volumes.

C. Obtaining simulated nasal fluid (SNF).

Add 8.7 g of sodium chloride (NaCl), 3.0 g of potassium chloride (KCl), 0.6 g of calcium chloride (CaCl ₂ ), 4.4 g of dibasic sodium phosphate (Na ₂ HPO ₄ ) and 1.1 g monobasic sodium phosphate (NaH ₂ PO ₄ ) in one liter of water. Mix well. Measure and record the pH (should be between 6.0 and 7.0). Store at room temperature. SNF is stable for 2 weeks. You can get proportional volumes.

D. Standard solution of hydrocodone bitartrate.

Concentrated Standard Solution: Dry a portion of the hydrocodone bitartrate standard for 2 hours in vacuo at 105 ° C according to USP. In duplicate, accurately add 30 mg ± 5 mg of hydrocodone bitartrate to separate 100 ml volumetric flasks. Add approximately 50 ml of 0.1 N HCl diluent. Dissolve by sonication for approximately 10 minutes. Dilute to the desired volume with diluent and mix well. They are concentrated standard solutions of approximately 300 μg / ml (as anhydrous hydrocodone bitartrate) and are stable for 29 days under normal laboratory conditions (unprotected from light). You can get proportional volumes.

Working standard solution: pipette 15 ml of each concentrated standard solution into separate 50 ml volumetric flasks. Dilute to the desired volume with 0.1 N HCl diluent and mix well. These working standard solutions are approximately 90 μg / ml (as anhydrous hydrocodone bitartrate) and are stable for 43 days under normal laboratory conditions (unprotected from light). You can get proportional volumes.

E. Obtaining a sample of the extract after simulated nasal injection.

1. Crush one tablet and, accurately hanging, transfer approximately 575 mg of the crushed material to a previously labeled 20 ml glass vial. For drug controls, attach an appropriate mass of material and transfer to a pre-labeled 20 ml glass vial.

2. Heat the water bath and simulated nasal fluid to 37 ° C.

3. Pipette 10 ml of simulated nasal fluid pre-heated to 37 ° C into each of the vials containing the crushed tablet material.

4. Close and turn over twice to wet the powder. Put the bottle on a metal

- 45 032013 pad inside the water bath and mix at 100 rpm.

5. After 10 minutes, pick up the bottle from the site.

6. Open and withdraw 3 ml of solution from each of the vials using a micropipette.

7. Transfer the solution to a 5 ml polypropylene syringe and filter the solution through a 1 μm porous glass filter with a diameter of 25 mm into a test glass tube (16x100 mm).

8. Place the vial back in the water bath and continue stirring.

9. After 30 minutes, stop stirring, open and remove 3 ml of solution from each of the vials using a micropipette.

10. Transfer the solution to a 5 ml polypropylene syringe and filter the solution through a 1 μm porous glass filter with a diameter of 25 mm into a test glass tube (16x100 mm).

11. Pipette 1 ml of the solution from each test tube into separate 50 ml volumetric flasks and dilute to the desired volume of 0.1 N HCl. Stir by turning 10 times.

12. Pass and remove a 1-ml aliquot of the sample solution through a 1-micron porous glass syringe filter with a diameter of 25 mm with the collection of the second aliquot in a glass HPLC vial and cover.

13. Inject each sample once.

Table 59. Extract from simulated nasal liquid for tablets 10/325 mg hydrocodone / acetaminophen bitartrate

The consignment The amount extracted after 10 minutes from crushed tablets containing 10/325 mg of hydrocodone / acetaminophen bitartrate The amount extracted after 30 minutes from crushed tablets containing 10/325 mg of hydrocodone / acetaminophen bitartrate 1 14% 45% 2 60% 66%

Example 26 (a). Assess abuse by taking a few tablets.

The dosage form obtained in accordance with examples 3 and 5 above, was evaluated for resistance to abuse in the form of oral administration of several tablets by mixing the selected number of tablets in 300 ml of 0.1N HCl. Dissolution was carried out using a USP II device at 50 rpm and 37 ° C. One to twelve tablets were simultaneously added to the vessel and aliquots were taken after 5, 10, 15, 30, 60, 120, 240 and 360 minutes of stirring and analyzed for hydrocodone bitartrate (Fig. 4) and APAP (Fig. 5) by HPLC. The results were plotted versus time and are shown in FIG. 4 and 5.

Example 26 (b). Assess abuse by taking a few tablets.

The dosage form obtained in accordance with example 17 above, was evaluated for resistance to abuse in the form of oral administration of several tablets by mixing the selected number of tablets in 300 ml of 0.1N HCl. Dissolution was carried out using a USP II device at 50 rpm and 37 ° C. One to twelve tablets were simultaneously added to the vessel and aliquots were taken after 5, 10, 15, 30, 60, 120, 240 and 360 minutes of stirring and analyzed for hydrocodone bitartrate (Fig. 6) and APAP (Fig. 7) by HPLC. The results were plotted versus time and are shown in FIG. 6 and 7.

Example 26 (c). Assess abuse by taking a few tablets.

The dosage form obtained in accordance with example 17 above, was evaluated for resistance to abuse in the form of oral administration of several tablets by mixing the selected number of tablets in 300 ml of 0.1N HCl. Dissolution was carried out using a USP II device at 50 rpm and 37 ° C. One to twelve tablets were simultaneously added to the vessel and aliquots were taken after 5, 10, 15, 30, 60, 120, 240 and 360 minutes of stirring and analyzed for hydrocodone bitartrate and APAP by HPLC. The results were plotted versus time and are shown in FIG. 8 (hydrocodone bitartrate) and FIG. 9 (ARAP).

Example 27. Coated escetamine granules.

Coated escetamine granules are obtained by the method described in example 1, with a slight difference from example 1 in the components, as illustrated below.

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Table 60. The composition of the granules of esketamine hydrochloride

Granulation % wt./mass. Hypromellose 60 Glyceryl behenate 26 Ethyl cellulose 14 TOTAL 100 Layering % wt./mass. Eschetamine Hydrochloride 5 Polymer Granules (EU, HPMC and Compritol) 92.5 Hypromellose 2910 2,5 TOTAL 100 Coating % wt./mass. Eschetamine-coated granules fifty Eudrazhit E-100 33 Magnesium stearate 17 TOTAL 100

Example 28. Eschetamine HCl tablets.

The coated granules obtained in accordance with Example 27 above are then mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Magnesium stearate is added to lubricate the mixture, and the resulting mixture is stirred for an additional 5 minutes, followed by compression into tablets.

Table 61. Composition of escetamine hydrochloride tablets

Components mg / tab. 1 mg 2 mg 5 mg 10 mg Hypromellose 11.1 22.2 55, 6 111.2 Glyceryl behenate 4, 8 9, 5 23.8 47, 64 Ethyl cellulose 2, 6 5, 2 13.1 26.2 Eschetamine Hydrochloride 1 2 5 10 Hypromellose 2910 0, 5 1 2,5 5 Eudrazhit E-100 13.3 26, 7 66.7 133, 4 Mannitol 70 70 70 70 Carbopol fifty fifty fifty fifty Microcrystalline cellulose 94 95 95 94 Crospovidone 90 90 95 150 Bicarbonate of soda thirty thirty thirty thirty Magnesium stearate eleven 18 38.6 74, 6 Total tablet weight 378.3 419, 6 545, 3 802.04

Example 29. Coated escetamine granules.

Coated escetamine granules are obtained by the method described in example 1 with a slight difference from example 1 in the components, as illustrated in the table below.

Table 62. Composition of coated pellets of escetamine hydrochloride

Granulation % wt./mass. Hypromellose 60 Glyceryl behenate 26 Ethyl cellulose 14

- 47 032013

TOTAL 100 Layering % wt./mass. Eschetamine Hydrochloride 10 Polymer Granules (EU, HPMC and Compritol) 85 Hypromellose 2910 5 TOTAL 100 Coating % wt./mass. Eschetamine-coated granules fifty Eudrazhit E-100 33 Magnesium stearate 17 TOTAL 100

Example 30. Eschetamine HCl tablets.

The coated granules obtained in accordance with Example 29 above are then mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Magnesium stearate is added to lubricate the mixture and the resulting mixture is stirred for an additional 5 minutes, followed by compression into tablets.

Table 63. Composition of escetamine hydrochloride tablets

Components (mg / tab.) 14 mg Hypromellose 71.5 Glyceryl behenate 30, 6 Ethyl cellulose 16, 9 Eschetamine Hydrochloride 14 Hypromellose 2910 7 Eudrazhit E-100 93,4 Mannitol 70 Carbopol fifty Microcrystalline cellulose 130 Crospovidone 150 Bicarbonate of soda thirty Magnesium stearate 55 Total tablet weight 718.4

Example 31. Coated escetamine granules.

Eschetamine granules are obtained in a manner similar to the method described in Example 1 above, with a specific modification of the method. The active ingredient, instead of being layered on the granules, is placed in the core, where it is granulated with other excipients in accordance with the table below, and then coated with E-100.

The granules are obtained in a high shear granulator, where hypromellose, esketamine hydrochloride and glyceryl behenate are dry mixed for 3 minutes. Then, a 10% aqueous-alcoholic solution of ethyl cellulose is slowly added, maintaining the speed of the impeller and the granulator grinder at preselected values that provide sufficient shear for the formation and growth of granules. The addition of the solution is continued until the total amount of ethyl cellulose is added. The granules are then wet milled using a grinder (Granumill) and then placed in a fluidized bed for drying.

Then, the esketamine hydrochloride granules are coated in a spray-coating device from below in a fluidized bed using a 25% suspension of Eudraite E-100 copolymer and magnesium stearate in alcohol (2: 1). The coated granules are then used in a mixing and compression process.

- 48 032013

Table 64. The composition of the granules of esketamine hydrochloride

Granulation % wt./mass. Eschetamine Hydrochloride 35 Hypromellose 45 Glyceryl behenate Ethyl cellulose Total Coating Escetamine Granules 12.5 7.5 100 % wt./mass. 82 Eudrazhit E-100 12 Magnesium stearate 6 TOTAL 100

Example 32. Eschetamine HCl tablets.

Then, the coated granules obtained in accordance with Example 31 above are mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Magnesium stearate is added to lubricate the mixture and the resulting mixture is stirred for an additional 5 minutes, followed by compression into tablets.

Table 65. Composition of Eschetamine Hydrochloride Tablets

Components (mg / tablet) 28 mg 56 mg 84 mg Hypromellose 36 72 108 Glyceryl behenate 10 20 thirty Ethyl cellulose 6 12 18 Eschetamine Hydrochloride 28 56 84 Eudrazhit E-100 11.7 23,4 35, 1 Mannitol 17 17 20, 1 Carbopol fifty fifty fifty Microcrystalline cellulose 100 100 100 Crospovidone 150 150 150 Bicarbonate of soda thirty thirty thirty Magnesium stearate 12 20 thirty Total tablet weight 450.7 550,4 655,2

Example 33. Coated escetamine granules.

Eschetamine granules are obtained in a manner similar to the method described in example 1 and example 32 above, with a specific modification of the method. The active ingredient is granulated with other excipients according to the table below, and then coated with E-100 Eudrajit.

Granules containing eschetamine hydrochloride are prepared in a high shear granulator where hypromellose, escetamine hydrochloride and glyceryl behenate are dry blended for 3 minutes. Then, a 10% aqueous-alcoholic solution of ethyl cellulose is slowly added, maintaining the speed of the impeller and the granulator grinder at preselected values that provide sufficient shear for the formation and growth of granules. The addition of the solution is continued until the total amount of ethyl cellulose is added. The granules are then wet milled using a grinder (Granumill) and then placed in a fluidized bed for drying. The granules are then coated in a spray-coating device from below in a fluidized bed using a 25% suspension of Eudragit E-100 copolymer and magnesium stearate in alcohol (2: 1). The obtained coated granules are used in the method of mixing and pressing.

- 49 032013

Table 66. The composition of the granules of esketamine hydrochloride

Granulation % wt./mass. Eschetamine Hydrochloride 72.5 Hypromellose 17.5 Glyceryl behenate 5 Ethyl cellulose 5 TOTAL 100 Coating % wt./mass. Escetamine Granules 82 Eudrazhit E-100 12 Magnesium stearate 6 Total 100

Example 34. Eschetamine HCl tablets.

The coated granules obtained in accordance with Example 33 above are then mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Magnesium stearate is added to lubricate the mixture and mixed for an additional 5 minutes, followed by compression into tablets.

Table 67. Composition of escetamine hydrochloride tablets

Components (mg / tab.) 200 mg 300 mg 400 mg Hypromellose 48 72 96, 4 Glyceryl behenate 14 21 27, 6 Ethyl cellulose 14 21 27, 6 Eschetamine Hydrochloride 200 300 400 Eudrazhit E-100 40 61 81 Mannitol 25 25 25 Carbopol 75 75 75 Microcrystalline cellulose 125 125 125 Crospovidone 300 300 300 Bicarbonate of soda 45 45 45 Magnesium stearate 140 150 160 Total tablet weight 1026 1195 1362.6

Example 35. Coated Zolpidem Granules.

Coated granules of zolpidem tartrate are obtained by the method described in example 1, in accordance with the composition illustrated in the table below.

T table 68. The composition of the granules of zolpidem tartrate ___________________________

Granulation % wt./mass. Hypromellose 60 Glyceryl behenate 26 Ethyl cellulose 14 TOTAL 100 Layering % wt./mass. Zolpidem Tartrate 10 Polymer Granules (EU, HPMC and Compritol) 85 Hypromellose 2910 5 TOTAL 100 Coating % wt./mass. Zolpidem-coated granules fifty Eudrazhit E-100 33 Magnesium stearate 17 TOTAL 100

- 50 032013

Example 36. Tablets of zolpidem tartrate.

Coated zolpidem granules are prepared by the method described in Example 35 above. The coated granules are mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose and mixed in a V-shaped mixer for 30 minutes. Magnesium stearate is added to lubricate the mixture and mixed for an additional 5 minutes, followed by compression into tablets.

Table 69. Composition of Zolpidem Tartrate Tablets

Components (mg / tab.) 5 mg 10 mg Hypromellose 25, 5 51.1 Glyceryl behenate eleven 21.9 Ethyl cellulose 6 12 Zolpidem Tartrate 5 10 Hypromellose 2910 2,5 5 Eudrazhit E-100 33,4 66, 7 Mannitol 70 70 Carbopol fifty fifty Microcrystalline cellulose 95 94 Crospovidone 100 100 Bicarbonate of soda thirty thirty Magnesium stearate 21, 6 39, 3 Total tablet weight 450 550

Example 37. Coated granules of quetiapine fumarate.

Quetiapine granules are obtained by a method similar to the method described in example 1 above, with a specific modification of the method. Quetiapine fumarate, instead of layering on the granules, is placed in the core, where it is granulated together with other excipients in accordance with table 70 (granulation), and then coated with E-100 eraudite and magnesium stearate.

The granules are obtained in a high shear granulator, where hypromellose, quetiapine fumarate, part of lutrol, sodium lauryl sulfate and glyceryl behenate are dry mixed for 3 minutes. Then, a 10% aqueous-alcoholic solution of ethyl cellulose is slowly added, maintaining the speed of the impeller and the granulator grinder at preselected values that provide sufficient shear for the formation and growth of granules. The addition of the solution is continued until the total amount of ethyl cellulose is added. The granules are then wet milled using a grinder (Granumill) and then placed in a fluidized bed for drying.

Then, the quetiapine fumarate granules are coated in a spray-coating device from below in a fluidized bed using a suspension of Eudragit E-100 copolymer and magnesium stearate in alcohol. Then, the obtained coated granules are used in the method of mixing and pressing.

Table 70. The composition of the coated granules of quetiapine fumarate

Granulation % wt./mass. Quetiapine Fumarate 23.7 Hypromellose 37, 6 Glyceryl behenate 13,4 Ethyl cellulose 8.1 Sodium lauryl sulfate 9, 1 Loutrol 8.1 TOTAL 100 Coating % wt./mass. Quetiapine Granules 62.5 Eudrazhit E-100 25 Magnesium stearate 12.5 TOTAL 100

Example 38. Tablets of quetiapine fumarate.

Coated granules obtained in accordance with example 37 above, then mixed with other

- 51 032013 components (carbomer, crospovidone, the remaining part of lutrol, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Magnesium stearate is added to lubricate the mixture and mixed for an additional 5 minutes, followed by compression into tablets.

Table 71. Composition of Quetiapine Fumarate Tablets

Components (mg / tablet) 25 mg 50 mg 100 mg (mg / tablet) (mg / tablet) (mg / tablet) Hypromellose 16 32 63 Glyceryl behenate 9 18 36 Ethyl cellulose 5 eleven 22 Quetiapine Fumarate 25 fifty 100 Eudrazhit E-100 27 53 107 Mannitol 17 17 20.1 Carbopol fifty fifty fifty Microcrystalline cellulose 100 100 100 Crospovidone 150 150 200 Bicarbonate of soda thirty thirty thirty Magnesium stearate 18 31 63 Loutrol 45 51 62 Sodium lauryl sulfate 6 12 24 Total tablet weight 498 605 877.1

Example 39. Coated Quetiapine Granules.

Quetiapine is obtained in a manner similar to the method described in example 1 and with a specific modification of the method. Quetiapine fumarate, instead of layering on granules, is placed in the core, where it is granulated together with other excipients in accordance with table 72, and then coated with E-100 eudrazhit.

Granules are obtained in a granulator with high shear, where hypromellose, quetiapine fumarate, sodium lauryl sulfate, part of lutrol and glyceryl behenate are dry mixed for 3 minutes. Then, a 10% aqueous-alcoholic solution of ethyl cellulose is slowly added, maintaining the speed of the impeller and the granulator grinder at preselected values that provide sufficient shear for the formation and growth of granules. The addition of the solution is continued until the total amount of ethyl cellulose is added. The granules are then wet milled using a grinder (Granumill) and then placed in a fluidized bed for drying. Then, the quetiapine fumarate granules are coated in a spray-coating device from below in a fluidized bed using a suspension of Eudragit E-100 copolymer and magnesium stearate in alcohol. Then, the obtained coated granules are used in the method of mixing and pressing.

Table 72. Composition of quetiapine fumarate granules

Granulation % wt./mass. Quetiapine Fumarate 14.3 Hypromellose 59, 2 Glyceryl behenate 4, 1 Ethyl cellulose 4.1 Sodium lauryl sulfate 10, 1 Loutrol 8.2 TOTAL 100 Coating % wt./mass. Quetiapine Granules 82 Eudrazhit E-100 12 Magnesium stearate 6 TOTAL 100

Example 40. Tablets of quetiapine fumarate.

The coated granules obtained as in Example 39 above are then mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose and the remaining

- 52 032013 part of lutrol) and mixed in a V-shaped mixer for 30 minutes. Magnesium stearate is added to lubricate the mixture and mixed for an additional 5 minutes, followed by compression into tablets.

Table 73. Composition of Quetiapine Fumarate Tablets

Components (mg / tab.) 200 mg 300 mg 4 00 mg Hypromellose 48 72.5 97 Glyceryl behenate 14 20.8 28 Ethyl cellulose 14 20.8 28 Quetiapine Fumarate 200 300 400 Eudrazhit E-100 40 74 99 Mannitol 25 25 25 Carbopol fifty 65 65 Microcrystalline cellulose 125 125 125 Crospovidone 200 275 275 Bicarbonate of soda 45 45 45 Magnesium stearate 36 48 64 Loutrol 78 91, 6 105 Sodium lauryl sulfate 34 51,2 69 Total tablet weight 909 1213.9 1425

Example 41. Covered hydromorphone granules.

The coated hydromorphone granules are prepared by the method described in Example 1 with a slight difference from Example 1 in the components, as illustrated below.

Table 74. The composition of the granules of hydromorphone hydrochloride

Granulation % wt./mass. Hypromellose 60 Glyceryl behenate 26 Ethyl cellulose 14 TOTAL 100 Layering % wt./mass. Hydromorphone hydrochloride 5 Polymer Granules (EU, HPMC and Compritol) 92.5 Hypromellose 2910 2,5 TOTAL 100 Coating % wt./mass. Hydromorphone Pellets fifty Eudrazhit E-100 33 Magnesium stearate 17 TOTAL 100

Example 42. Tablets of hydromorphone hydrochloride.

The coated hydromorphone granules are prepared by the method described in Example 1 and Example 41 above. Then, the coated granules are mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Magnesium stearate is added to lubricate the mixture and mixed for an additional 5 minutes, followed by compression into tablets.

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Table 75. Composition of tablets of hydromorphone hydrochloride

Components (mg / tablet) 2 mg 4 mg 8 mg Hypromellose 22.2 44,4 88.9 Glyceryl behenate 9, 5 19, 1 38.1 Ethyl cellulose 5, 2 10.5 21 Hydromorphone hydrochloride 2 4 8 Hypromellose 2910 1 2 4 Eudrazhit E-100 26.7 53,4 106, 7 Mannitol 70 70 70 Carbopol fifty fifty fifty Microcrystalline cellulose 95 95 94 Crospovidone 90 95 150 Bicarbonate of soda thirty thirty thirty Magnesium stearate 18, 1 58.3 60,4 Total tablet weight 419, 7 531.7 721.1

Example 43. Coated granules of methamphetamine.

Coated methamphetamine granules were prepared by the method described in Example 1.

Table 76. The composition of the granules of methamphetamine hydrochloride

Granulation % wt./mass. Hypromellose 60 Glyceryl behenate 26 Ethyl cellulose 14 TOTAL 100 Layering % wt./mass. methamphetamine hydrochloride 5 Polymer Granules (EU, HPMC and Compritol) 92.5 Hypromellose 2910 2,5 TOTAL 100 Coating % wt./mass. Methamphetamine Pellets fifty Eudrazhit E-100 33 Magnesium stearate 17 TOTAL 100

Example 44. Methamphetamine hydrochloride tablets.

Coated methamphetamine granules are prepared by the method described in Example 1 and Example 43 above. Then, the coated granules are mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Magnesium stearate is added to lubricate the mixture and mixed for an additional 5 minutes, followed by compression into tablets.

Table 77. Composition of methamphetamine hydrochloride tablets

Components (mg / tablet) 5 mg Hypromellose 55, 6 Glyceryl behenate 23, 8 Ethyl cellulose 13, 1 methamphetamine hydrochloride 5 Hypromellose 2910 2,5

- 54 032 013

Eudrazhit E-100 66, 7 Mannitol 70 Carbopol fifty Microcrystalline cellulose 95 Crospovidone 100 Bicarbonate of soda thirty Magnesium stearate 39 Total tablet weight 550.7

Example 45. Coated granules of oxymorphone.

Coated oxymorphone granules are prepared by the method described in Example 1.

Table 78. The composition of the granules of oxymorphone hydrochloride

Granulation % wt./mass. Hypromellose 60 Glyceryl behenate 26 Ethyl cellulose 14 TOTAL 100 Layering % wt./mass. Oxymorphone hydrochloride 10 Polymer Granules (EU, HPMC and Compritol) 85 Hypromellose 2910 5 TOTAL 100 Coating % wt./mass. Oxymorphone Pellets fifty Eudrazhit E-100 33 Magnesium stearate 17 TOTAL 100

Example 46. Oxymorphone hydrochloride tablets.

Coated oxymorphone granules are prepared by the method described in Example 1 and Example 45 above. Then, the coated granules are mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Magnesium stearate is added to lubricate the mixture and mixed for an additional 5 minutes, followed by

Table 79 by compression into tablets.

. Oxymorphone Hydrochloride Tablet Compositions

Components (mg / tablet) 5 mg 10 mg Hypromellose 25, 5 51.1 Glyceryl behenate eleven 21.9 Ethyl cellulose 6 12 Oxymorphone hydrochloride 5 10 Hypromellose 2910 2,5 5 Eudrazhit E-100 33,4 66, 7 Mannitol 70 70 Carbopol 45 45 Microcrystalline cellulose 95 94 Crospovidone 100 100 Bicarbonate of soda 27 27 Magnesium stearate 21, 6 39, 3 Total tablet weight 442 542

Example 47

Coated oxycodone granules are prepared by the method described in Example 1.

Coated oxycodone granules.

- 55 032013

Table 80. The composition of the granules of oxycodone hydrochloride

Granulation % wt./mass. Hypromellose 60 Glyceryl behenate 26 Ethyl cellulose 14 TOTAL 100 Layering % wt./mass. Oxycodone hydrochloride 10 Polymer Granules (EU, HPMC and Compritol) 85 Hypromellose 2910 5 TOTAL 100 Coating % wt./mass. Oxycodone Coated Granules fifty Eudrazhit E-100 33 Magnesium stearate 17 TOTAL 100

Example 48. Tablets of oxycodone hydrochloride.

Coated oxycodone granules are prepared by the method described in Example 1 and Example 47 above. Then, the coated granules are mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Magnesium stearate is added to lubricate the mixture and mixed for an additional 5 minutes, followed by compression into tablets.

Table 81. Composition of oxycodone hydrochloride tablets

Components (mg / tablet) 5 mg 15 mg 30 mg Hypromellose 25, 5 76, 6 153, 3 Glyceryl behenate eleven 32.8 65, 7 Ethyl cellulose 6 18.1 36, 1 Oxycodone hydrochloride 5 fifteen thirty Hypromellose 2910 2,5 7.5 fifteen Eudrazhit E-100 33,4 100, 1 200, 1 Mannitol 70 37.29 70 Carbopol 45 fifty fifty Microcrystalline cellulose 95 130 94 Crospovidone 100 150 200 Bicarbonate of soda 27 thirty thirty Magnesium stearate 21, 6 57 110 Total tablet weight 442 704.39 1054.2

Example 49. Coated granules of morphine sulfate.

Coated morphine granules are prepared by the method described in Example 1. Table 82. Compositions of morphine sulfate tablets

Granulation % wt./mass. Hypromellose 60 Glyceryl behenate 26 Ethyl cellulose 14 TOTAL 100 Layering % wt./mass. Morphine sulfate 10 Polymer Granules (EU, HPMC and Compritol) 85 Hypromellose 2910 5 TOTAL 100 Coating % wt./mass. Morphine coated granules fifty Eudrazhit E-100 33 Magnesium stearate 17 TOTAL 100

- 56 032013

Example 50. Morphine sulfate tablets.

Coated morphine granules are prepared by the method described in Example 1 and Example 49 above. Then, the coated granules are mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Magnesium stearate is added to lubricate the mixture and mixed for an additional 5 minutes, followed by compression into tablets.

Table 83. Composition of morphine sulfate tablets

Components (mg / tablet) 6 mg 15 mg 30 mg Hypromellose 30, 6 76, 6 153.3 Glyceryl behenate 13, 1 32.8 65, 7 Ethyl cellulose 7.2 18.1 36, 1 Morphine sulfate 6 fifteen thirty Hypromellose 2910 3 7.5 fifteen Eudrazhit E-100 Mannitol Carbopol Microcrystalline cellulose Crospovidone 40, 02 70 45 95 100 100, 1 70 fifty 130 150 200, 1 70 fifty 94 200 Bicarbonate of soda 27 thirty thirty Magnesium stearate 24.5 57 110 Total tablet weight 461.42 737.1 1054.2

Coated granules of mixed amphetamine salts.

Example 51

Coated granules containing mixed amphetamine salts (dextroamphetamine sugar, amphetamine aspartate, dextroamphetamine sulfate, amphetamine sulfate) are prepared by the method described in Example 1.

Table 84. The composition of the granules of mixed amphetamine salts

Granulation % wt./mass. Hypromellose 60 Glyceryl behenate 26 Ethyl cellulose 14 TOTAL 100 Layering % wt./mass. Amphetamine Mixed Salts (* Sugar dextroamphetamine, amphetamine aspartate) 10 Polymer Granules (EU, HPMC and Compritol) 85 Hypromellose 2910 5 TOTAL 100 Coating % wt./mass. Amphetamine mixed salt granules fifty Eudrazhit E-100 33 Magnesium stearate 17 TOTAL 100

Example 52. Tablets of mixed amphetamine salts.

Coated granules containing mixed amphetamine salts are prepared by the method described in Example 1 and Example 51 above.

Then, the coated granules are mixed with other components, such as carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose, and mixed in a V-shaped mixer for 30 minutes. Magnesium stearate is added to lubricate the mixture and mixed for an additional 5 minutes, followed by compression into tablets.

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Table. 85. Composition of tablets of mixed amphetamine salts

The total equivalent of ampho amine / base 3.13 mg 5 mg 4.7 mg 7.5 mg 6.3 mg 10 mg 7.8 mg 12.5 mg 9.4 mg 15 mg 12.6 mg 2 0 mg 18.8 mg 3 0 mg Components (mg / tablet) Hypromellose 25, 5 38.3 51.1 63, 8 76, 6 102.15 153.3 Glyceryl behenate 10, 9 16, 4 21.9 27.4 32.8 43, 8 65, 7 Ethyl cellulose 6, 02 9, 03 12.04 15, 05 18, 1 24.1 36, 1 Amphetamine Mixed Salts * 5 7.5 10 12.5 fifteen 20 thirty Hypromellose 2910 2,5 3.75 5 6, 25 7.5 10 fifteen Eudrazhit E-100 33,4 50, 04 66, 7 83,4 100, 1 133.4 200, 1 Mannitol 70 70 70 70 70 70 70 Carbopol 45 45 45 fifty fifty fifty fifty Microcrystalline cellulose 95 95 95 130 130 130 150 Crospovidone 100 100 100 150 150 160 200 Bicarbonate of soda 27 27 27 thirty thirty thirty thirty Magnesium stearate 21.5 thirty 38, 6 48 57 75 110 Total tablet weight 441.82 492.02 542.34 686, 4 737.1 848.45 1110.2

* dextroamphetamine sugar, equivalent of amphetamine aspartate monohydrate, dextroamphetamine sulfate, amphetamine sulfate.

Example 53. Granules of codeine phosphate.

Coated granules containing codeine phosphate, obtained by the method described in example 1, with certain modifications in the composition, as described below.

Table 86. Composition of Codeine Phosphate Granules

Granulation % wt./mass. Hypromellose 60 Glyceryl behenate 26 Ethyl cellulose 14 TOTAL 100 Layering % wt./mass. Codeine Phosphate. 20 Polymer Granules (EU, HPMC and Compritol) 70 Hypromellose 2910 10 TOTAL 100 Coating % wt./mass. Codeine Phosphate Coated Granules 70 Eudrazhit E-100 20 Magnesium stearate 10 TOTAL 100

Example 54. Tablets of codeine phosphate.

Coated granules containing codeine phosphate are prepared by the method described in Example 1 and Example 53 above. Then, the coated granules are mixed with another active ingredient (paracetamol) and other components (carbomer, crospovidone, sodium bicarbonate, mannitol, dye, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Magnesium stearate is added to lubricate the mixture and mixed for an additional 5 minutes, followed by compression into tablets.

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Table 87. Composition of codeine phosphate / ARAP tablets

Components (mg / tablet) 30/300 mg 60/300 mg Hypromellose 63, 1 126, 2 Glyceryl behenate 27 54.1 Ethyl cellulose 14.9 29, 7 Codeine Phosphate thirty 60 Hypromellose 2910 fifteen thirty Eudrazhit E-100 42.9 85, 7 Paracetamol* 315, 8 315, 8 Mannitol 29, 4 29, 4 Carbopol fifty fifty Microcrystalline cellulose 180 180 Crospovidone 200 200 Bicarbonate of soda thirty thirty FD&C Blue No. 2 n /P. 0, 6 Yellow Iron Oxide 510P 0.5 n /P. Magnesium stearate 31.5 57 Total tablet weight 1030.1 1248.5 * Paracetamol contains 300 mg of APAP and 15.8 mg of gelatin

Example 55. Granules of methylphenidate hydrochloride.

Coated granules containing methylphenidate hydrochloride are prepared by the method described in Example 1.

Table 88. The composition of the granules of methylphenidate hydrochloride

Granulation % wt./mass. Hypromellose 60 Glyceryl behenate 26 Ethyl cellulose 14 TOTAL 100 Layering % wt./mass. Methylphenidate hydrochloride 10 Polymer Granules (EU, HPMC and Compritol) 85

Hypromellose 2910 5 TOTAL 100 Coating % wt./mass. Methylphenidate Hydrochloride Pellets fifty Eudrazhit E-100 33 Magnesium stearate 17 TOTAL 100

Example 56. Tablets of methylphenidate hydrochloride.

Coated granules containing methylphenidate hydrochloride are prepared by the method described in Example 1 and Example 55 above. Then, the coated granules are mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Magnesium stearate is added to lubricate the mixture and mixed for an additional 5 minutes, followed by compression into tablets.

Table 89. Composition of tablets of methylphenidate hydrochloride.

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Components (mg / tablet) 5 mg 20 mg Hypromellose 25, 5 102.15 Glyceryl behenate 10, 9 43, 8 Ethyl cellulose 6, 02 24.1 Methylphenidate hydrochloride 5 20 Hypromellose 2910 2,5 10 Eudrazhit E-100 33,4 133.4 Mannitol 70 70 Carbopol 45 fifty Microcrystalline cellulose 95 150 Crospovidone 100 160 Bicarbonate of soda 27 thirty Magnesium stearate 21.5 75 Total tablet weight 441.82 868.45

Example 57. Granules of oxycodone hydrochloride.

Coated granules containing oxycodone hydrochloride were prepared and coated by the method described in Example 1.

Table 90. The composition of the granules of oxycodone hydrochloride

Granulation % wt./mass. Hypromellose 60 Glyceryl behenate 26 Ethyl cellulose 14 TOTAL 100 Layering % wt./mass. Oxycodone hydrochloride 10 Polymer Granules (EU, HPMC and Compritol) 85 Hypromellose 2910 5 TOTAL 100 Coating % wt./mass. Granules with a layer of oxycodone, 10% fifty Eudrazhit E-100 33 Magnesium stearate 17 TOTAL 100

The granules were obtained in a high shear granulator, where hypromellose and glyceryl behenate were dry mixed for 3 minutes. Then, a 10% aqueous-alcoholic solution of ethylcellulose N10 was slowly added, maintaining the speed of the impeller and the granulator grinder at preselected values that provide sufficient shear for the formation and growth of granules. The addition of the solution was continued until the total amount of ethyl cellulose was added. The granules were then wet milled using a grinder (Granumill) and then placed in a fluidized bed for drying. Then, layering was carried out on the obtained granules in a device for spray coating from below in a fluidized bed using a 12% aqueous solution of oxycodone hydrochloride and HPMC 2 910 (2: 1).

Then, the granules coated with a layer of oxycodone hydrochloride were coated in a spray-coating device from below in a fluidized bed using a 25% suspension of Eudragit E-100 copolymer and magnesium stearate in alcohol (2: 1). Then, the obtained coated granules were used for the further mixing and pressing process.

Example 58. Oxycodone / acetaminophen tablets. The coated granules obtained in accordance with Example 57 above were mixed with another active agent, paracetamol, and other excipients (carbomer, crospovidone, sodium bicarbonate, mannitol, FD&C blue, microcrystalline cellulose) and mixed in V- shaped mixer for 30 minutes Then, magnesium stearate was added to lubricate the mixture and mixed for an additional 5 minutes, followed by compression into oxycodone / APAP tablets.

- 60 032013

Table 91. Composition of oxycodone hydrochloride tablets

Component % wt./mass. Oxycodone Coated Granules 20, 0 Paracetamol* 33.7 Mannitol 4.2 Carbopol fifty Microcrystalline cellulose 13, 0 Crospovidone 20, 0 Bicarbonate of soda thirty FD&C blue 0.06 Magnesium stearate 1,0 Total 100 * Contains 95% acetaminophen and 5% gelatin

Example 59. Oxycodone / acetaminophen tablets.

The coated granules obtained in accordance with Example 57 above were mixed with another active agent, paracetamol, and other excipients (carbomer, crospovidone, sodium bicarbonate, mannitol, FD&C blue, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Then, magnesium stearate was added to lubricate the mixture and mixed for an additional 5 minutes, followed by compression into oxycodone / APAP tablets.

Table 92. The compositions of the oxycodone / acetaminophen tablets

Component (% w / w) 5/325 mg 7.5 / 325 mg 10/325 mg Oxycodone Coated Granules 12.5 16, 7 20, 0 Paracetamol* 42, 8 38, 0 34.2 Mannitol 3,7 4.37 3.79 Carbopol 6.25 5, 6 5 Microcrystalline cellulose 12 12 thirteen Crospovidone 18 19 20 Bicarbonate of soda 3.75 3.3 3 Yellow iron oxide 0.06 n /P. n /P. FD&C Blue No. 2 n /P. 0.06 n /P. Magnesium stearate 10 1,0 1,0 Total 100 100 100 * Contains 95% acetaminophen and 5% gelatin

60. Granules of armodafinil.

Example

Armodafinil granules are obtained by a method similar to the method described in example 1, and with a specific modification of the method. The active ingredient, armodafinil, instead of layering on the granules, is placed in the core, where it is granulated with other excipients in accordance with table 93, and then coated with E-100 Eudrazhit.

Granules are produced in a high shear granulator, where hypromellose, armodafinil, povidone and glyceryl behenate are dry mixed for 3 minutes. Then, a 10% aqueous-alcoholic solution of ethyl cellulose is slowly added, maintaining the speed of the impeller and the granulator grinder at preselected values that provide sufficient shear for the formation and growth of granules. The addition of the solution is continued until the total amount of ethyl cellulose is added. The granules are then wet milled using a grinder (Granumill) and then placed in a fluidized bed for drying.

The granules of armodafinil are then coated in a spray-coating device from below in a fluidized bed using a suspension of Eudragit E-100 copolymer and magnesium stearate in alcohol. Then, the obtained coated granules are used in the method of mixing and pressing.

Table 93. Composition of granules of armodafinil.

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Granulation % wt./mass. Armodafinil 66, 99 Hypromellose 16, 75 Glyceryl behenate 3, 83 Ethyl cellulose 3, 83 Povidone 8, 61 TOTAL 100 Coating % wt./mass. Armodafinil Granules 70 Eudrazhit E-100 20 Magnesium stearate 10 TOTAL 100

Example 61. Armodafinil tablets.

The coated granules obtained as in Example 60 above are then mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Magnesium stearate is added to lubricate the mixture and mixed for an additional 5 minutes, followed by compression into tablets.

Table 94. Compositions of Armodafinil Tablets

Components (mg / tablet) 50 mg 150 mg 200 mg (mg / tablet) (mg / tablet) (mg / tablet) Hypromellose 12.5 37.5 fifty Glyceryl behenate 2.9 8, 6 eleven Ethyl cellulose 2.9 8, 6 eleven Armodafinil fifty 150 200 Eudrazhit E-100 21.3 64 85 Mannitol 17 25 25 Carbopol fifty fifty fifty Microcrystalline cellulose 100 125 125 Crospovidone 150 200 200 Bicarbonate of soda thirty thirty thirty Magnesium stearate 16 40 52 Povidone 6, 4 19.3 26 Total tablet weight 459 758 865

Example 62. Phenobarbital granules.

Phenobarbital granules are obtained by a method similar to the method described in example 1 and with a specific modification of the method. The active ingredient, phenobarbital, instead of layering on the granules, is placed in the core, where it is granulated with other excipients in accordance with the table below, and then coated with E-100 Eudrazhit.

Granules are obtained in a granulator with a high shear, where hypromellose, phenobarbital, povidone and glyceryl behenate are dry mixed for 3 minutes. Then, a 10% aqueous-alcoholic solution of ethyl cellulose is slowly added, maintaining the speed of the impeller and the granulator grinder at preselected values that provide sufficient shear for the formation and growth of granules. The addition of the solution is continued until the total amount of ethyl cellulose is added. The granules are then wet milled using a grinder (Granumill) and then placed in a fluidized bed for drying.

Phenobarbital granules are then coated in a spray-coating device from below in a fluidized bed using a suspension of Eudragit E-100 copolymer and magnesium stearate in alcohol. Then, the obtained coated granules are used in the method of mixing and pressing.

- 62 032013

Table 95. The composition of the granules of phenobarbital

Granulation % wt./mass. Phenobarbital 66, 99 Gipromello s a 16, 75 Glyceryl behenate 3, 83 Ethyl cellulose 3, 83 Povidone 8, 61 TOTAL 100 Layering % wt./mass. Phenobarbital Granules fifty Eudrazhit E-100 33 Magnesium stearate 17 TOTAL 100

Phenobarbital tablets.

Example 63

The coated granules obtained as in Example 62 above are then mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Magnesium stearate is added to lubricate the mixture and mixed for an additional 5 minutes, followed by compression into tablets.

Table 96. The compositions of the phenobarbital tablets

Components 15 mg 30 mg 60 mg 100 mg (mg / tablet) (mg / tablet) (mg / tablet) (mg / tablet) Hypromellose 3, 8 7.5 fifteen 25, 01 Glyceryl behenate 1 2 3.4 5, 72 Ethyl cellulose 1 2 3.4 5, 72 Phenobarbital fifteen thirty 60 100 Eudrazhit E-100 fifteen thirty 59 98.5 Mannitol 20 20 20 20 Carbopol fifty fifty fifty fifty Microcrystalline cellulose 75 100 100 100 Crospovidone 130 130 200 200 Bicarbonate of soda thirty thirty thirty thirty Magnesium stearate 12 20 36 59 Povidone 2 4 7.7 12.9 Total tablet weight 354.8 425, 5 584.5 706.85

Example 64. Granules of diazepam.

Coated diazepam granules are obtained by the method described in example 1, with a slight difference from example 1 in the components, as illustrated in the table below.

Table 97. The composition of the granules of diazepam

Granulation % wt./mass. Hypromellose 60 Glyceryl behenate 26 Ethyl cellulose 14 TOTAL 100 Layering % wt./mass. Diazepam 5 Polymer Granules (EU, HPMC and Compritol) 92.5 Hypromellose 2910 2,5 TOTAL 100 Coating % wt./mass. Diazepam coated granules fifty Eudrazhit E-100 33 Magnesium stearate 17 TOTAL 100

- 63 032 013

Example 65. Diazepam tablets.

Coated diazepam granules are prepared by the method described in Example 1 and Example 64 above. Then, the coated granules are mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Magnesium stearate is added to lubricate the mixture and mixed for an additional 5 minutes, followed by compression into tablets.

Table 98. The composition of the diazepam tablets

Components (mg / tablet) 2 mg 5 mg 10 mg Hypromellose 22.2 55, 6 111.2 Glyceryl behenate 9, 5 23, 8 47, 64 Ethyl cellulose 5.2 13, 1 26.2 Diazepam 2 5 10 Hypromellose 2910 1 2,5 5 Eudrazhit E-100 26, 7 66, 7 133.4 Mannitol 70 70 70 Carbopol fifty fifty fifty Microcrystalline cellulose 95 95 94 Crospovidone 120 120 150 Bicarbonate of soda thirty thirty thirty Magnesium stearate 18.1 38, 6 74, 6 Total tablet weight 449,7 570.3 802.04

Example 66. Granules of hydrocodone bitartrate.

Coated granules containing hydrocodone bitartrate are prepared by the method described in Example 1.

Table 99. The composition of the granules of hydrocodone bitartrate

Granulation % wt./mass. Hypromellose 60 Glyceryl behenate 26 Ethyl cellulose 14 TOTAL 100 Layering % wt./mass. Hydrocodone Bitartrate 10 Polymer Granules (EU, HPMC and Compritol) 85 Hypromellose 2910 5 TOTAL 100 Coating % wt./mass. Bitartrate-coated granules hydrocodone fifty Eudrazhit E-100 33 Magnesium stearate 17 TOTAL 100

Example 67. Tablets of hydrocodone bitartrate.

Coated granules containing hydrocodone bitartrate are prepared by the method described in Example 1 and Example 66 above. Then, the coated granules are mixed with other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed in a V-shaped mixer for 30 minutes. Magnesium stearate is added to lubricate the mixture and mixed for an additional 5 minutes, followed by compression into tablets.

- 64 032 013

Table 100. The compositions of the tablets of hydrocodone

Components 5 mg 10 mg (mg / tablet) (mg / tablet) Hypromellose 25, 5 51.1 Glyceryl behenate eleven 21.9 Ethyl cellulose 6 12.04 Hydrocodone Bitartrate 5 10 Hypromellose 2910 2,5 5 Eudrazhit E-100 33,4 66, 7 Mannitol 70 70 Carbopol fifty fifty Microcrystalline cellulose 95 95 Crospovidone 100 120 Bicarbonate of soda thirty thirty Magnesium stearate 21, 6 39, 3 Total tablet weight 450 571.04

Example 68. Coated granules of oxycodone hydrochloride

Table 101. The composition of the granules Component % wt./mass. Hypromellose K100M 60 Glyceryl behenate 26 Ethyl Cellulose (10 cP) 14 TOTAL 100

Table 102. Composition of coated granules

Component % wt./mass. Oxycodone hydrochloride 10 Polymer Granules (EU, HPMC and Compritol) 85 Hypromellose 2910 EZ 5 TOTAL 100

Table 103. The composition of the coated granules

Component % wt./mass. Hydrochloride Coated Granules oxycodone, 10% fifty Eudrazhit E-100 33 Magnesium stearate 17 TOTAL 100

Granules were obtained in a high shear granulator, where hypromellose, glyceryl behenate and part (67%) of ethyl cellulose were dry mixed for 3 minutes. Then, a water-alcohol solution (~ 28 parts water and ~ 72 parts alcohol) of ethyl cellulose solution (10% w / w) was slowly added, maintaining the speed of the impeller and the granulator grinder at preselected values that provide sufficient shear for the formation and growth of granules . The addition of the solution was continued until the total amount of ethyl cellulose was added. The granules were then wet milled using a grinder (Granumill) and then placed in a fluidized bed for drying.

Then, layering was carried out on the obtained granules in a spray coating apparatus from below in a fluidized bed using 12% w / w. oxycodone hydrochloride aqueous solution and HPMC.

Then, granules with a layer of oxycodone bitartrate were coated in a spray-coating device from below in a fluidized bed using a 25% suspension of Eudragit E-100 copolymer and magnesium stearate in alcohol. Then, the obtained coated granules were mixed to give homogeneity and used for the further mixing and pressing process.

- 65 032013

Example 69. Composition of oxycodone / acetaminophen tablets.

Coated granules were prepared in accordance with Example 68 above, and mixed with paracetamol (prepared using acetaminophen and gelatin) and other excipients (as listed in table 104 below) and mixed for approximately 270 rpm. Then magnesium stearate was added to lubricate the mixture and mixed for an additional 45 revolutions. The mixture was then compressed into oxycodone / acetaminophen tablets.

Table 104. Composition of tablets

Component % wt./mass. mg / tablet Coated Hydrochloride Granules oxycodone, 5% 20, 0 200 Paracetamol 33.7 337 * Mannitol 10.3 103 Carbopol fifty fifty Microcrystalline cellulose 12.0 120 Crospovidone 15, 0 150 Bicarbonate of soda thirty thirty Magnesium stearate 1,0 10 Total 100 1000

* contains 325 mg of acetaminophen.

Example 70. Coated granules of oxycodone, 5%.

Granules were obtained, layered API and then coated. Then, these coated particles were mixed with other components and compressed into tablets.

Table 105. The composition of the granules

Component % wt./mass. Hypromellose K10 0M 60 Glyceryl behenate 26 Ethyl Cellulose (10 cP) 14 TOTAL 100

Table 106. Composition of coated granules

Component % wt./mass. Oxycodone hydrochloride 10 Polymer Granules (EU, HPMC and Compritol) 85 Hypromellose 2910 (HPMC 2910 EZ) 5 TOTAL 100

Table 107. The composition of the coated granules

Component % wt./mass. Hydrochloride Coated Granules oxycodone, 10% fifty Eudrazhit E-100 33 Magnesium stearate 17 TOTAL 100

Granules were obtained in a high shear granulator, where hypromellose, part of ethyl cellulose and glyceryl behenate were dry mixed for 3 minutes. Then slowly added 10% wt./mass. water-alcohol (~ 28 parts of water and ~ 72 parts of ethanol) solution of ethyl cellulose 10 cps, maintaining the speed of the impeller and grinder of the granulator at pre-selected values that provide sufficient shear for the formation and growth of granules. The addition of the solution was continued until the total amount of ethyl cellulose was added. The granules were then wet milled using a grinder (Granumill) and then placed in a fluidized bed for drying.

Then, layering was carried out on the obtained granules in a spray coating apparatus from below in a fluidized bed using 12% w / w. hydrochloric acid solution

- 66 032013 oxycodone reed and HPMC 2910 E3.

Then, the granules coated with a layer of oxycodone hydrochloride were coated in a spray bed coating apparatus in a fluidized bed using a 25% suspension of Eudragit E-100 copolymer and magnesium stearate in alcohol. Then, the obtained coated granules were mixed to give homogeneity and used for the further mixing and pressing process.

Example 71. Coated polymer granules.

Granules were obtained in a high shear granulator, where hypromellose, part of ethyl cellulose and glyceryl behenate were dry mixed for 3 minutes. Then, 10% w / w was slowly added. water-alcohol (~ 28 parts of water and ~ 72 parts of ethanol) solution of ethyl cellulose 10 cps, maintaining the speed of the impeller and grinder of the granulator at pre-selected values that provide sufficient shear for the formation and growth of granules. The addition of the solution was continued until the total amount of ethyl cellulose was added. The granules were then wet milled using a grinder (Granumill) and then placed in a fluidized bed for drying.

Then, the granules were coated in a spray-coating device from below in a fluidized bed using a 25% suspension of Eudragit E-100 copolymer and magnesium stearate in alcohol.

Table 108. The composition of the granules Component % wt./mass. Hypromellose K100M 60 Glyceryl behenate 26 Ethyl Cellulose (10 cP) 14 TOTAL 100

Table 109. Composition of coated polymer granules

Component % wt./mass. Polymer granules fifty Eudrazhit E-100 33 Magnesium stearate 17 TOTAL 100

Example 72A and example 72B.

Coated oxycodone hydrochloride granules were prepared according to Example 70 and mixed with coated polymer granules obtained according to Example 71. Another active agent was added, i.e. paracetamol (prepared using acetaminophen and gelatin), and other excipients, such as carbomer, crospovidone, sodium bicarbonate, mannitol and microcrystalline cellulose, and mixed for approximately 270 rpm. Then magnesium stearate was added to lubricate the mixture and mixed for an additional 45 turns, followed by compression into oxycodone / acetaminophen tablets.

Table 110. Composition of tablets

Component Example 7 2A Example 72B % wt./mass. mg / tablet % wt./mass. mg / tablet Coated granules of oxycodone hydrochloride, 5% 10, 87 108.7 16, 3 163 Coated Polymer Granules 9, 13 91.3 3,7 37 Paracetamol 33.7 337 * 33.71 337.1 * Mannitol 4.29 42.9 4.29 42.9 Carbopol fifty 50, 0 fifty fifty Microcrystalline cellulose 13, 0 130, 0 13, 0 130 Crospovidone 20, 0 200. 20, 0 200 Bicarbonate of soda thirty thirty thirty thirty Magnesium stearate 1,0 10 1,0 10 Total 100 1000 100 1000

* contains 325 mg of acetaminophen.

Example 73. The analysis of resistance to abuse in the form of oral administration of several tablets in vitro.

The dosage form obtained in accordance with example 72A and example 72B, was evaluated for resistance to abuse in the form of oral administration of several tablets in vitro by mixing the selected number of tablets in 300 ml of 0.1N HCl. Dissolution was carried out using a USP II device at 50 rpm and 37 ° C. From one to twelve tablets were simultaneously added to the vessel and aliquots were periodically taken and analyzed for oxycodone hydrochloride (FIG. 10) and

- 67 032013 acetaminophen (ARAP) [Fig. 11] by HPLC. The results were plotted versus time and are shown in FIG. 10 and FIG. eleven.

Example 74. Polymer granules.

Table 111. The composition of the granules

Component % wt./mass. Hypromellose K100M 60 Glyceryl behenate 26 Ethyl Cellulose (10 cP) 14 TOTAL 100

Granules were obtained in a high shear granulator, where hypromellose, part of ethyl cellulose and glyceryl behenate were dry mixed for 3 minutes. Then, 10% w / w was slowly added. water-alcohol (~ 28 parts of water and ~ 72 parts of ethanol) solution of ethyl cellulose 10 cps, maintaining the speed of the impeller and grinder of the granulator at pre-selected values that provide sufficient shear for the formation and growth of granules. The addition of the solution was continued until the total amount of ethyl cellulose was added. The granules were then wet milled using a grinder (Granumill) and then placed in a fluidized bed for drying.

Example 75. Granules coated with hydrocodone bitartrate, 5%.

Then, the granules obtained in accordance with example 74 were layered in a spray coating apparatus from below in a fluidized bed using 12% w / w. aqueous solution of hydrocodone bitartrate and HPMC 2910 E3. Then, the pellets coated with a layer of hydrocodone bitartrate were coated in a spray-coating device from below in a fluidized bed using a 25% suspension of Eudragit E-100 copolymer and magnesium stearate in alcohol.

Table 112. Composition of coated granules.

Component % wt./mass. Hydrocodone Bitartrate 10 Polymer Granules (EU, HPMC and Compritol) 85 Hypromellose 2910 5 TOTAL 100

Table 113. The composition of the coated granules

Component % wt./mass. Granules with a layer of hydrocodone bitartrate, 10% fifty Eudrazhit E-100 33 Magnesium stearate 17 TOTAL 100

Example 76. Tablets of hydrocodone bitartrate.

Hydrocodone bitartrate granules were prepared according to Example 75 above and mixed with polymer granules obtained according to Example 74. Another active agent was added, i.e. paracetamol (obtained using acetaminophen and gelatin), and other excipients such as carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose, and mixed for approximately 270 revolutions. Then magnesium stearate was added to lubricate the mixture and mixed for an additional 45 turns, followed by compression of hydrocodone / acetaminophen into tablets.

Table 114. Composition of tablets

Component % mass./mass. mg / tablet Granules coated with hydrocodone bitartrate, 5% 9, 62 96, 2 Polymer granules 5, 38 53, 8 Paracetamol 33.71 337.1 * Mannitol 9.29 92.9 Carbopol fifty fifty Microcrystalline cellulose 13, 0 130 Crospovidone 20, 0 200 Bicarbonate of soda thirty thirty Magnesium stearate 10 10 Total 100 1000

^ contains 325 mg of acetaminophen.

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Example 77A and example 77B. Hydrocodone bitartrate tablets.

Hydrocodone bitartrate coated granules, 5%, were prepared according to Example 75 above and mixed with coated polymer granules prepared according to Example 71. Another active agent was added to the mixer, i.e. paracetamol (prepared using acetaminophen and gelatin), and other excipients such as carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose and mixed for approximately 270 revolutions. Then magnesium stearate was added to lubricate the mixture and mixed for an additional 45 turns, followed by compression of hydrocodone / acetaminophen into tablets.

Table 115. Composition of tablets

Component Example 7 7A Example 77B % mass./mass. mg / tab. % mass./mass. mg / tab. Granules coated with hydrocodone bitartrate, 5% 9, 62 96.2 14.42 96, 2 Coated Polymer granules 10.38 103.8 5.58 103, 8 Paracetamol 33.71 337.1 * 33.71 337.1 * Mannitol 4.29 42.9 4.29 42, 9 Carbopol 5,0 fifty 5,0 fifty Microcrystalline cellulose 13, 0 130 13.0 130 Crospovidone 20, 0 200 20,0 200 Bicarbonate of soda thirty thirty 3.0 thirty Magnesium stearate 10 10 1,0 10 Total 100 1000 100 1000

* contains 325 mg of acetaminophen.

Example 78. The analysis of resistance to abuse in the form of oral administration of several tablets in vitro.

The dosage form obtained in accordance with example 76, and example 77A, and example 77B, was evaluated for resistance to abuse in the form of oral administration of several tablets in vitro by mixing the selected number of tablets in 300 ml of 0.1N HCl. Dissolution was carried out using a USP II device at 50 rpm and 37 ° C. One to twelve tablets were simultaneously added to the vessel and aliquots were periodically taken and analyzed for hydrocodone bitartrate (FIG. 12) and APAP (FIG. 13) by HPLC. The results were plotted versus time and are shown in FIG. 12 and FIG. thirteen.

Example 79. Coated granules of oxycodone, 5%.

Granules are obtained and then coated. These coated particles are then mixed with other components and compressed into tablets.

The granules are obtained in a high shear granulator, where oxycodone hydrochloride, hypromellose, part of ethyl cellulose and glyceryl behenate are dry mixed for 3 minutes.

- 69 032013

Then, an aqueous-alcoholic solution of ethyl cellulose 10 cps is slowly added, maintaining the speed of the impeller and the granulator grinder at preselected values that provide sufficient shear for the formation and growth of granules. The addition of the solution is continued until the total amount of ethyl cellulose is added. The granules are then wet milled using a grinder (Granumill) and then placed in a fluidized bed for drying. Then, the oxycodone hydrochloride granules are coated in a spray-coating device from below in a fluidized bed using a 25% suspension of Eudragit E-100 copolymer and magnesium stearate in alcohol.

Example 80. Oxycodone / acetaminophen tablets.

Coated oxycodone hydrochloride granules, 5%, are prepared according to Example 79 above and mixed with another active agent, i.e. paracetamol (obtained using acetaminophen and gelatin), and other excipients such as carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose, and stirred for approximately 270 revolutions. Then magnesium stearate is added to lubricate the mixture and mixed for an additional 45 turns, followed by compression into oxycodone / acetaminophen tablets.

Table 118. Composition of tablets

Component % wt./mass. mg / tablet Coated Hydrochloride Granules oxycodone, 5% 20 200 Paracetamol 34.2 342 * Mannitol 3, 8 38 Carbopol fifty fifty Microcrystalline cellulose 13, 0 130 Crospovidone 20, 0 200 Bicarbonate of soda thirty thirty Magnesium stearate 10 10 Total 100 1000

* contains 325 mg of acetaminophen.

Example 81. Coated granules of oxycodone.

Oxycodone hydrochloride granules are prepared and then coated. Then these coated particles are mixed with other components and compressed into tablets.

Table 119. The composition of the granules

Component % wt./mass. Hypromellose K100M 56 Glyceryl behenate 25 Ethyl Cellulose (10 cP) 14 Oxycodone hydrochloride 5 TOTAL 100

Table 120. The composition of the coated granules

Component % wt./mass. Oxycodone hydrochloride granules, 5% fifty Eudrazhit E-100 33 Magnesium stearate 17 TOTAL 100

The granules are obtained in a high shear granulator, where oxycodone hydrochloride, hypromellose, part of ethyl cellulose and glyceryl behenate are dry mixed for 3 minutes. Then, an aqueous-alcoholic solution of ethyl cellulose 10 cps is slowly added, maintaining the speed of the impeller and the granulator grinder at preselected values that provide sufficient shear for the formation and growth of granules. The addition of the solution is continued until the total amount of ethyl cellulose is added. The granules are then wet milled using a grinder (Granumill) and then placed in a fluidized bed for drying. Then, the oxycodone hydrochloride granules are coated in a spray-coating device from below in a fluidized bed using a 25% suspension of Eudragit E-100 copolymer and magnesium stearate in alcohol.

- 70 032013

Example 82. Oxycodone / acetaminophen tablets. Coated oxycodone hydrochloride granules, 2.5%, are prepared according to Example 81 above and mixed with another active agent, i.e. paracetamol (obtained using acetaminophen and gelatin), and other excipients such as carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose, and stirred for approximately 270 revolutions. Then magnesium stearate is added to lubricate the mixture and mixed for an additional 45 turns, followed by compression into oxycodone / acetaminophen tablets.

Table 121. Composition of tablets

Component % mass./mass. mg / tablet Coated Hydrochloride Granules oxycodone, 2.5% 20 200 Paracetamol 34.2 342 Mannitol 3, 8 38 Carbopol fifty fifty Microcrystalline cellulose 13, 0 130 Crospovidone 20, 0 200 Bicarbonate of soda thirty thirty Magnesium stearate 1,0 10 Total 100 1000

^ contains 325 mg of acetaminophen.

Example 83. Coated granules of oxycodone.

Oxycodone hydrochloride granules are prepared and then coated. Then these coated particles are mixed with other components and compressed into tablets.

Table 122. The composition of the granules

Component % wt./mass. Hypromellose K100M 54.5 Glyceryl behenate 24 Ethyl Cellulose (10 cP) 14 Oxycodone hydrochloride 7.5 TOTAL 100

Table 123. The composition of the coated granules

Component % wt./mass. Oxycodone hydrochloride granules, 7.5% fifty Eudrazhit E-100 33 Magnesium stearate 17 TOTAL 100

The granules are obtained in a high shear granulator, where oxycodone hydrochloride, hypromellose, part of ethyl cellulose and glyceryl behenate are dry mixed for 3 minutes. Then, an aqueous-alcoholic solution of ethyl cellulose 10 cps is slowly added, maintaining the speed of the impeller and the granulator grinder at preselected values that provide sufficient shear for the formation and growth of granules. The addition of the solution is continued until the total amount of ethyl cellulose is added. The granules are then wet milled using a grinder (Granumill) and then placed in a fluidized bed for drying. Then, the oxycodone hydrochloride granules are coated in a spray-coating device from below in a fluidized bed using a 25% suspension of Eudragit E-100 copolymer and magnesium stearate in alcohol.

Example 84. Oxycodone / acetaminophen tablets.

Coated oxycodone hydrochloride granules, 3.75%, are prepared according to Example 83 above and mixed with another active agent, i.e. paracetamol (obtained using acetaminophen and gelatin), and other excipients such as carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose, and stirred for about 270 rpm

- 71 032 013 goods Then magnesium stearate is added to lubricate the mixture and mixed for an additional 45 turns, followed by compression into oxycodone / acetaminophen tablets.

Table 124. Composition of tablets

Component % wt./mass. mg / tablet Coated Hydrochloride Granules 20 200 oxycodone 3.75% Paracetamol 34.2 342 * Mannitol 3, 8 38 Carbopol fifty fifty Microcrystalline cellulose 13, 0 130 Crospovidone 20, 0 200 Bicarbonate of soda thirty thirty Magnesium stearate 1,0 10 Total 100 1000

^ contains 325 mg of acetaminophen.

Example 85. Coated granules of oxycodone hydrochloride.

Oxycodone hydrochloride granules are prepared and then coated. Then these coated particles are mixed with other components and compressed into tablets.

Table 125. The composition of the granules

Component % wt./mass. Hypromellose KYOM 54 Glyceryl behenate 23 Ethyl Cellulose (10 cP) thirteen Oxycodone hydrochloride 10 TOTAL 100

Table 126. The composition of the coated granules

Component % wt./mass. Oxycodone hydrochloride granules, 10% 40 Eudrazhit E-100 40 Magnesium stearate 20 TOTAL 100

The granules are obtained in a high shear granulator, where oxycodone hydrochloride, hypromellose, part of ethyl cellulose and glyceryl behenate are dry mixed for 3 minutes. Then, an aqueous-alcoholic solution of ethyl cellulose 10 cps is slowly added, maintaining the speed of the impeller and the granulator grinder at preselected values that provide sufficient shear for the formation and growth of granules. The addition of the solution is continued until the total amount of ethyl cellulose is added. The granules are then wet milled using a grinder (Granumill) and then placed in a fluidized bed for drying. Then, the oxycodone hydrochloride granules are coated in a spray-coating device from below in a fluidized bed using a 25% suspension of Eudragit E-100 copolymer and magnesium stearate in alcohol.

Example 86. Oxycodone / acetaminophen tablets.

Coated oxycodone hydrochloride granules, 4%, are prepared according to Example 85 above and mixed with another active agent, i.e. paracetamol (obtained using acetaminophen and gelatin), and other excipients such as carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose, and stirred for approximately 270 revolutions. Then magnesium stearate is added to lubricate the mixture and mixed for an additional 45 turns, followed by compression into oxycodone / acetaminophen tablets.

- 72 032013

Table 127. Composition of tablets

Component % wt./mass. mg / tablet Coated Hydrochloride Granules oxycodone, 4% 18.8 188 Paracetamol 34.2 342 * Mannitol 5 fifty Carbopol fifty fifty Microcrystalline cellulose 13, 0 130 Crospovidone 20, 0 200 Bicarbonate of soda thirty thirty Magnesium stearate 10 10 Total 100 1000

^ contains 325 mg of acetaminophen.

Example 87. Coated granules of oxycodone.

Oxycodone is obtained and then coated. Then these coated particles are mixed with other components and compressed into tablets.

Table 128. The composition of the granules

Component % wt./mass. Hypromellose KYOM 54 Glyceryl behenate 23 Ethyl Cellulose (10 cP) thirteen Oxycodone hydrochloride 10 TOTAL 100

Table 129. The composition of the coated granules

Component % wt./mass. Oxycodone hydrochloride granules, 10% thirty Eudrazhit E-100 47 Magnesium stearate 23 TOTAL 100

The granules are obtained in a high shear granulator, where oxycodone hydrochloride, hypromellose, part of ethyl cellulose and glyceryl behenate are dry mixed for 3 minutes. Then, an aqueous-alcoholic solution of ethyl cellulose 10 cps is slowly added, maintaining the speed of the impeller and the granulator grinder at preselected values that provide sufficient shear for the formation and growth of granules. The addition of the solution is continued until the total amount of ethyl cellulose is added. The granules are then wet milled using a grinder (Granumill) and then placed in a fluidized bed for drying. Then, the oxycodone hydrochloride granules are coated in a spray-coating device from below in a fluidized bed using a 25% suspension of Eudragit E-100 copolymer and magnesium stearate in alcohol.

Example 88. Oxycodone / acetaminophen tablets.

Coated oxycodone hydrochloride granules (3%) are prepared according to Example 87 above and mixed with another active agent, i.e. paracetamol (obtained using acetaminophen and gelatin), and other excipients such as carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose, and stirred for approximately 270 revolutions. Then magnesium stearate is added to lubricate the mixture and mixed for an additional 45 turns, followed by compression into oxycodone / acetaminophen tablets.

- 73 032 013

Table 130. Composition of tablets

Component % wt./mass. mg / tablet Coated Hydrochloride Granules oxycodone, 3% 16, 7 167 Paracetamol 34.2 342 * Mannitol 7.1 71 Carbopol fifty fifty Microcrystalline cellulose 13, 0 130 Crospovidone 20, 0 200 Bicarbonate of soda thirty thirty Magnesium stearate 1,0 10 Total 100 1000

* contains 325 mg of acetaminophen.

Example 89. Coated oxycodone granules.

Oxycodone is obtained and then coated. Then these coated particles are mixed with other components and compressed into tablets.

Table 131. The composition of the granules

Component % wt./mass. Hypromellose K100M 56 Glyceryl behenate 25 Ethyl Cellulose (10 cP) 14 Oxycodone hydrochloride 5 TOTAL 100

Table 132. The composition of the coated granules

Component % wt./mass. Oxycodone hydrochloride granules, 5% 70 Eudrazhit E-100 20 Magnesium stearate 10 TOTAL 100

The granules are obtained in a high shear granulator, where oxycodone hydrochloride, hypromellose, part of ethyl cellulose and glyceryl behenate are dry mixed for 3 minutes. Then, an aqueous-alcoholic solution of ethyl cellulose 10 cps is slowly added, maintaining the speed of the impeller and the granulator grinder at preselected values that provide sufficient shear for the formation and growth of granules. The addition of the solution is continued until the total amount of ethyl cellulose is added. The granules are then wet milled using a grinder (Granumill) and then placed in a fluidized bed for drying. Then, the oxycodone hydrochloride granules are coated in a spray-coating device from below in a fluidized bed using a 25% suspension of Eudragit E-100 copolymer and magnesium stearate in alcohol.

Example 90. Oxycodone / acetaminophen tablets.

Coated oxycodone hydrochloride granules, 3.5%, are prepared according to Example 89 above and mixed with another active agent, i.e. paracetamol (obtained using acetaminophen and gelatin), and other excipients such as carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose, and stirred for approximately 270 revolutions. Then magnesium stearate is added to lubricate the mixture and mixed for an additional 45 turns, followed by compression into oxycodone / acetaminophen tablets.

- 74 032013

Table 133. Composition of tablets

Component % wt./mass. mg / tab. Coated Hydrochloride Granules oxycodone, 3.5% 21,4 214 Paracetamol 34.2 342 * Mannitol 2,4 24 Carbopol fifty fifty Microcrystalline cellulose 13, 0 130 Crospovidone 20, 0 200 Bicarbonate of soda thirty thirty Magnesium stearate 1,0 10 Total 100 1000

* contains 325 mg of acetaminophen.

Example 91. Coated granules of oxycodone.

Oxycodone hydrochloride granules are prepared and then coated. Then these coated particles are mixed with other components and compressed into tablets.

Table 134. The composition of the granules

Component % wt./mass. Hypromellose K100M 54.5 Glyceryl behenate 24 Ethyl Cellulose (10 cP) 14 Oxycodone hydrochloride 7.5 TOTAL 100

Table 135. The composition of the coated granules

Component % wt./mass. Oxycodone hydrochloride granules, 7.5% 70 Eudrazhit E-100 20 Magnesium stearate 10 TOTAL 100

The granules are obtained in a high shear granulator, where oxycodone hydrochloride, hypromellose, part of ethyl cellulose and glyceryl behenate are dry mixed for 3 minutes. Then, an aqueous-alcoholic solution of ethyl cellulose 10 cps is slowly added, maintaining the speed of the impeller and the granulator grinder at preselected values that provide sufficient shear for the formation and growth of granules. The addition of the solution is continued until the total amount of ethyl cellulose is added. The granules are then wet milled using a grinder (Granumill) and then placed in a fluidized bed for drying. Then, the oxycodone hydrochloride granules are coated in a spray-coating device from below in a fluidized bed using a 25% suspension of Eudragit E-100 copolymer and magnesium stearate in alcohol.

Example 92. Oxycodone / acetaminophen tablets.

Coated oxycodone hydrochloride granules, 5.25%, are prepared according to Example 91 above and mixed with another active agent, i.e. paracetamol (obtained using acetaminophen and gelatin), and other excipients such as carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose, and stirred for approximately 270 revolutions. Magnesium stearate is then added to lubricate the mixture and mixed for an additional 45 turns, followed by compression into tablets of oxycodone / acetaminophen.

Table 136. Composition of tablets

Component % wt./mass. mg / tablet Coated Hydrochloride Granules oxycodone, 5.25% 19.05 190.5 Paracetamol 34.2 342 * Mannitol 4.75 47.5 Carbopol fifty fifty Microcrystalline cellulose 13, 0 130 Crospovidone 20, 0 200

- 75 032013

Bicarbonate of soda thirty thirty Magnesium stearate 1,0 10 Total 100 1000

* contains 325 mg of acetaminophen.

Example 93. Hydrocodone / acetaminophen tablets.

Hydrocodone bitartrate pellets were prepared according to Example 75 and mixed with another active agent, i.e. paracetamol (obtained using acetaminophen and gelatin), together with other excipients such as carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose (stirred for approximately 270 revolutions). Then magnesium stearate was added to lubricate the mixture and mixed for an additional 45 turns, followed by compression of hydrocodone / acetaminophen into tablets.

Table 137. Composition of tablets

Component % wt./mass. mg / tablet Granules coated with hydrocodone bitartrate, 5% 20, 0 200 Paracetamol 34.21 342.1 * Mannitol 3.73 37.3 Carbopol fifty fifty Microcrystalline cellulose 13, 0 130 Crospovidone 20, 0 200 Bicarbonate of soda thirty thirty Magnesium stearate 1,0 10 Red iron oxide 0.06 0, 6 Total 100 1000

* contains 325 mg of acetaminophen

Example 94. The analysis of resistance to abuse in the form of oral administration of several tablets in vitro - crushed and intact tablets.

The dosage form (ground or intact) obtained in accordance with Example 93 was evaluated for abuse resistance by oral administration of several tablets in vitro, by conducting dissolution experiments in 300 ml or 900 ml of 0.1 N HCl. Dissolution was carried out using a USP II device at 50 rpm and 37 ° C. Twelve tablets (crushed or intact) were added to the vessel simultaneously or sequentially and periodically, aliquots were taken and analyzed for hydrocodone bitartrate and APAP by HPLC. Grinding the tablets was carried out using a mortar and pestle (twelve movements). The results were plotted versus time and are shown in FIG. 14 and 15.

Example 95. Eschetamine HCl tablets.

The coated granules obtained in accordance with Example 31 are then mixed with the coated polymer granules obtained in accordance with Example 71 and other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed for 270 revolutions. Magnesium stearate is added to lubricate the mixture and the resulting mixture is stirred for an additional 45 turns, followed by compression into tablets.

Table 138. Composition of tablets

Components mg / tablet mg / tablet mg / tablet mg / tablet Coated granules escetamine hydrochloride, 28.7% 87.1 87.1 348.4 348.4 Coated Polymer granules fifty 31 fifty 31 Mannitol 37 37 37 37 Carbopol fifty fifty fifty fifty Microcrystalline cellulose 130 130 130 130 Crospovidone 200 200 200 200 Bicarbonate of soda thirty thirty thirty thirty Magnesium stearate 6 6 9 8.5 Total 590.1 571.1 854.4 834.9

- 76 032013

Example 96. Eschetamine HCl tablets.

The coated granules obtained in accordance with Example 31 are then mixed with the polymer granules obtained in accordance with Example 74 and other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed for 270 revolutions. Magnesium stearate is added to lubricate the mixture and the resulting mixture is stirred for an additional 45 turns, followed by compression into tablets.

Table 139. Composition of tablets

Components mg / tablet mg / tablet mg / tablet mg / tablet Coated granules escetamine hydrochloride, 28.7% 87.1 87.1 348.4 348.4 Polymer granules fifty 27 fifty 27 Mannitol 37 37 37 37 Carbopol fifty fifty fifty fifty Microcrystalline cellulose 130 130 130 130 Crospovidone 200 200 200 200 Bicarbonate of soda thirty thirty thirty thirty Magnesium stearate 6 6 9 8.5 Total 590, 1 567.1 854.4 830, 9

Example 97. Eschetamine HCl tablets.

The coated granules obtained in accordance with Example 27 are then mixed with the coated polymer granules obtained in accordance with Example 71 and other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed for 270 revolutions. Magnesium stearate is added to lubricate the mixture and the resulting mixture is stirred for an additional 45 turns, followed by compression into tablets.

Table 140. Composition of Eschetamine Hydrochloride Tablets

Components mg / tab. 1 mg 2 mg Eschetamine hydrochloride coated granules, 2.5% 40 80 Coated Polymer Granules 160 120 Mannitol 70 70 Carbopol fifty fifty Microcrystalline cellulose 94 95 Crospovidone 200 200 Bicarbonate of soda thirty thirty Magnesium stearate eleven 18 Total tablet weight 655 663

Example 98. Eschetamine HCl tablets.

The coated granules obtained in accordance with Example 27 above are then mixed with the polymer granules obtained in accordance with Example 74 and other components (carbomer, crospovidone, sodium bicarbonate, mannitol, microcrystalline cellulose) and mixed for 270 revolutions. Magnesium stearate is added to lubricate the mixture and the resulting mixture is stirred for an additional 45 turns, followed by compression into tablets.

Table 141. Composition of Eschetamine Hydrochloride Tablets

Components mg / tab. 1 mg 2 mg Eschetamine hydrochloride coated granules, 2.5% 40 80 Polymer granules 80 60 Mannitol 70 70 Carbopol fifty fifty Microcrystalline cellulose 94 95 Crospovidone 150 150 Bicarbonate of soda thirty thirty Magnesium stearate eleven 18 Total tablet weight 525 553

Claims (32)

CLAIM 1. A dosage form with immediate release and an obstacle to abuse, containing: a) coated core particles comprising a core containing a gelling polymer selected from natural starch, synthetic starch, natural cellulose, synthetic cellulose, acrylate, polyalkylene oxide, carbomer, and combinations thereof; an active pharmaceutical ingredient layer surrounding the core containing the active pharmaceutical ingredient selected from sedative-hypnotics, stimulants, anxiolytics, antipsychotics, dissociative anesthetics and narcotic analgesics, and the active pharmaceutical ingredient layer further comprises one or more excipients, binders, excipients or solvents; at least one layer surrounding the active pharmaceutical ingredient layer, which contains a pH-sensitive film containing a pH-sensitive polymer, insoluble in water at pH greater than 5 and soluble in water at pH less than 5; and b) a matrix containing a disintegrant and a gelling polymer; where the gelling polymer is selected from natural starch, synthetic starch, natural cellulose, synthetic cellulose, acrylate, polyalkylene oxide, carbomer and combinations thereof, where the dosage form shows the profile of the immediate release of the active pharmaceutical ingredient when administered to humans in therapeutic doses and the profile of the extended release of the active pharmaceutical ingredient when administration to humans in doses exceeding therapeutic doses. 2. The dosage form of claim 1, where less than 5% of the total amount of active pharmaceutical ingredient in the coated particles of the core is contained in the core. 3. The dosage form according to claim 1, where at least 90% of the total amount of the active pharmaceutical ingredient in the coated particles of the core is contained in the layer of the active pharmaceutical ingredient. 4. The dosage form according to any one of claims 1 to 3, additionally containing a second type of coated core particles that do not contain a layer of active pharmaceutical ingredient, where the second type of particles comprises a core containing a gelling polymer selected from natural starch, synthetic starch, natural cellulose, synthetic cellulose, acrylate, polyalkylene oxide, carbomer, and combinations thereof; and at least one layer surrounding the core containing a pH-sensitive film containing a pH-sensitive polymer, insoluble at pH greater than 5 and soluble at pH less 5. 5. The dosage form according to claim 1, where the layer of the active pharmaceutical ingredient contains a narcotic analgesic, which is an opioid. 6. The dosage form according to claim 5, additionally containing a non-steroidal analgesic drug. 7. The dosage form according to claim 5, where the opioid is selected from buprenorphine, codeine, dihydrocodeine, dihydromorphine, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone and their pharmaceutically acceptable salts. 8. The dosage form according to claim 6, where the non-steroidal analgesic drug is selected from acetaminophen, aspirin, ibuprofen and naproxen. 9. The dosage form according to claim 1, where the layer of the active pharmaceutical ingredient contains a dissociative anesthetic. 10. The dosage form of claim 9, wherein the dissociative anesthetic is ketamine, esketamine, or pharmaceutically acceptable salts thereof. 11. The dosage form according to claim 1, where the layer of the active pharmaceutical ingredient contains hydroxypropylmethyl cellulose. 12. A dosage form according to any one of claims 1 to 11, wherein the gelling polymer in the core is selected from ethyl cellulose, cellulose acetate, cellulose propionate acetate, cellulose butyrate acetate, cellulose acetate, cellulose triacetate, cellulose ether, cellulose ether, cellulose ether with ester groups, cellulose, a copolymer of acrylic acid and methacrylic acid, a copolymer of methyl methacrylate, ethoxyethyl methacrylate and cyanoethyl methacrylate, polyacrylic acid, polymethacrylic acid, copolymer a methacrylic acid alkylamide, polymethyl methacrylate, polymethyl methacrylate, polymethacrylate, polymethyl methacrylate copolymer, methacrylic anhydride copolymer, glycidyl methacrylate copolymer, gum arabic, karaya, tragacanth, algin, guar, cellulose, hydroxymethylmethyl hydroxymethyl hydroxymethyl hydroxymethyl hydroxymethyl hydroxymethyl hydroxymethyl hydroxymethyl - 78 032013 vines, sodium carboxymethyl cellulose, carbomer polymer, polyethylene oxide, polyvinyl alcohol, and combinations thereof. 13. The dosage form of claim 12, wherein the gelling polymer in the core is selected from hydroxypropyl methyl cellulose, hydroxymethyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, sodium carboxymethyl cellulose, carbomer polymer, polyethylene oxide, polyvinyl alcohol, and combinations thereof. 14. The dosage form according to claim 1, where the gel-forming polymer in the core is present in an amount of from 0.5 to 15 wt.% Of the total weight of the dosage form. 15. The dosage form according to any one of claims 1 to 11, wherein the gel-forming polymer in the matrix is selected from ethyl cellulose, cellulose acetate, cellulose propionate acetate, cellulose butyl acetate, cellulose acetate, cellulose triacetate, cellulose ether, cellulose ether, cellulose ether with ester groups, cellulose, a copolymer of acrylic acid and methacrylic acid, a copolymer of methyl methacrylate, ethoxyethyl methacrylate and cyanoethyl methacrylate, polyacrylic acid, polymethacrylic acid, alk copolymer amylamide methacrylic acid, polymethyl methacrylate, polymethacrylate, copolymer of polymethyl methacrylate, polyacrylamide, copolymer of aminoalkyl methacrylate, polymer of anhydride of methacrylic acid, copolymer of glycidyl methacrylate, agar, gum arabylamide, polyhydroxymethyl amide hydrochloride, alginine, polyamide , methyl cellulose, hydroxyethyl methyl cellulose, sodium carboxymethyl cellulose, carbomer polymer, polyethylene oxide, water yl alcohol and combinations thereof. 16. The dosage form of claim 15, wherein the gel-forming polymer in the matrix is selected from hydroxypropyl methyl cellulose, hydroxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl methyl cellulose, sodium carboxymethyl cellulose, carbomer polymer, and combinations thereof. 17. The dosage form according to claim 1, where the gel-forming polymer in the matrix is present in an amount of from 0.5 to 15% of the total weight of the dosage form. 18. The dosage form according to any one of claims 1 to 11, wherein the disintegrant in the matrix is selected from croscarmellose sodium, crospovidone, sodium starch glycolate and combinations thereof. 19. The dosage form according to claim 18, which contains from 0.5 to 50% of the disintegrant of the total weight of the dosage form. 20. The dosage form according to any one of claims 1 to 11, where the pH-sensitive polymer is a copolymer of dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate. 21. The dosage form according to any one of claims 1 to 11, in which emetic, nasal irritant, opioid antagonist and effervescent agent are excluded. 22. The dosage form according to any one of claims 1 to 11, where the dosage form, if it is ground and combined with a small volume of solvent selected from ethanol, methanol, water or mixtures thereof, forms a composition with a viscosity that prevents the composition from being set with a hypodermic syringe injection. 23. A dosage form according to any one of claims 1 to 11, wherein the dosage form reduces the risk of overdose of the active pharmaceutical ingredient while taking several units of the oral dosage form orally. 24. The dosage form according to any one of claims 1 to 11, which reduces the possibility of abuse while taking orally several units of the oral dosage form. 25. A dosage form according to any one of claims 1 to 11, which is capable of releasing at least 75 wt.% Of the active pharmaceutical ingredient in an aqueous solution of hydrochloric acid within 240 minutes, where the pH of the solution is from 1 to 2 and the temperature is approximately 37 ° FROM. 26. The dosage form according to any one of claims 1 to 11, wherein the immediate release profile corresponds to a release of at least 90% API in 60 minutes, and the extended release profile corresponds to a release of not more than 95% in 60 minutes, where the release profiles can be estimated by dissolving in 300 ml of 0.1 N HCl medium using a USP II device at a stirrer speed of 50 rpm and 37 ° C. 27. A dosage form according to any one of claims 1 to 11, wherein the exceeding therapeutic dose is five or more tablets. 28. The dosage form according to any one of claims 1 to 11, which is in the form of a suppository, capsule, caplet, pill, gel, soft gelatin capsule or compressed tablet. 29. The dosage form of claim 28, which is in the form of a compressed tablet. 30. A method of preventing, reducing or decreasing the intensity of a level of pain in an individual, comprising administering to the individual a dosage form with immediate release and an obstacle to abuse according to any one of paragraphs. 1-11. 31. A method of preventing abuse of an active pharmaceutical ingredient, comprising providing a dosage form with immediate release and a barrier to abuse according to any one of claims 1 to 11. 32. A way to prevent overdose through inadvertent or intentional - 79 032013 th administration of a higher than therapeutic dose of the active pharmaceutical ingredient, including the provision of a dosage form with abuse according to any one of claims 1 to 11.