CN101304752A - Anti-misuse microparticulate oral pharmaceutical form - Google Patents

Abstract

The present invention relates to solid microparticulate oral pharmaceutical forms which have a composition and a structure that prevents the misuse of the active pharmaceutical ingredient (API) contained therein. The aim of the present invention is to prevent the improper use of solid oral drugs for any use other than the therapeutic use(s) officially approved by the appropriate public health authorities. In other words, it is a question of preventing the voluntary or involuntary misuse of solid oral drugs. The invention relates to a solid oral pharmaceutical form, characterized in that it comprises anti-misuse means, in that at least part of the API that it contains is contained in coated microparticles for modified API release, and in that the coated API microparticles comprise a coating layer (Ra), which ensures modified release of the API and which, simultaneously, confers resistance to crushing on the coated API microparticles, so as to prevent misuse.

Description

The microparticulate oral pharmaceutical form of anti-abuse

Technical field

The present invention relates to the solid drugs microparticulate oral pharmaceutical form, its composition and structure make it can avoid its contained medicine or the veterinary drug abuse of active component (AP).

Active component described here (AP) is medicine or veterinary drug AP, for example anaesthetizes product class, analgesic class or anesthetics class.The abuse of these active constituents of medicine can cause the drug dependence behavior.

According to the present invention, the mixture of term " AP " a kind of active component of expression and several active component.

According to the present invention, the drug particles form is interpreted as any form, and wherein said AP is included in the microgranule less than 1000 μ m.These granules that contain described AP can be to be used to improve the coated particle that described AP discharges.In the latter, for example polymeric film coating of microgranule, described polymeric film is controlled the rate of release of described AP behind oral administration.

Background technology

Introduce problem

The objective of the invention is to prevent any inappropriate use of solid drugs, except the treatment of powerful public health care official mission official approval is used.In other words, purpose is to avoid abusing intentionally or unintentionally of Peroral solid dosage form medicine.

Abuse mainly takes place in following situation:

A) addictive behavior (drug dependence, analeptic),

B) criminal behavior (chemistry is obeyed),

C) do not use medicine owing to carelessness or owing to influence patient's deformity according to the mode of medical science suggestion (dosage).

In situation a (or even situation b), the people of attempt abuse Peroral solid dosage form medicine makes great efforts to extract described AP from improving the form that discharges usually, to obtain the form of quick acting, then:

-convert it into powder-form so that suction is obeyed or swallowed by crushing,

-or convert it into the liquid form that maybe can swallow of available injector to inject.

Relate to an intermediate steps from Peroral solid dosage form medication preparation liquid form, i.e. moisture or organic extraction of AP described here.Crushing earlier usually before extraction.

The mode of suction or drug administration by injection is particularly suited for drug dependence person, because these modes can be strengthened the effect of described AP, helps it and absorbs in tissue at short notice.When sucking powder or the water-soluble back injection that obtains through crushing, wish that the described AP excitement or the euphoric effect that obtain very rapidly occur in the mode of aggravating with it.

At present, also have a kind of extremely unwelcome behavioral implications teenager, this behavior relates to analgesia property AP (aAP), especially morphine and opiate derivative class.In fact, teenager are prepared a kind of vodka cocktail that contains oxycodone for their party, and easy water of oxycodone and ethanol extract from tablet.This method is exactly to pour in one glass of Little water. or the water the tablet crushing and with powder, waits time enough with abundant extraction morphine derivatives class then, just can take in then.

Swallow medicine fast and before swallowing, chew the abuse that medicine also may cause the Peroral solid dosage form medicine not according to medication instruction.

The risk relevant with criminal behavior (b) with addictive behavior (a) is conspicuous.Someone points out the worse off by the injection Drug abuse: because excipient may be the reason that causes local tissue necrosis, infection and respiratory system and heart disease.

As for the drug dependence (c) relevant with carelessness and/or patient's deformity, this also may cause serious consequence.For example, the improvement releasing pattern of chewing AP before swallowing makes medicine change into releasing pattern immediately.Therefore, best situation just medicine just lost efficacy after the very short time, and the worst situation is exactly a toxigenicity.

Therefore, drug dependence is a serious public health problem, particularly Peroral solid dosage form medicine beyond doubt, especially based on the abuse of the medicine of analgesic or anesthetics.This phenomenon be on the increase the attention that causes health authority more and more, especially US and European, they more and more need to develop can avoid the medicament forms abused.

Prior art

Patent US-B-6 696 088 relates to the multi-particulate oral medicament forms, points out that it can resist abuse.It comprises the granule of the opiate agonist AP that improves releasing pattern and contains the granule of opiate antagonist.The form that contains antagonist is described as be in the antagonist AP that discharges in the 36h time and is lower than 36%, preferably is lower than 6.2%.Two types granule disperses mutually.

When abuse took place, the crushing microgranule was to discharge described AP and antagonist thereof immediately simultaneously with the result who extracts described opium AP, limits the effect of required abuse opium thus.

In our view, described invention is based on the active substance that uses beyond the described AP, but especially do not advise a kind ofly reducing the influence crushing or reducing the scheme of extracting described AP.

Patent application US-A-2003/0068371 has described a kind of oral drug preparation, contains antagonist (naloxone) and the gellant (as xanthan gum) of opium AP (oxycodone), this AP.Specifically, described US patent application discloses the matrix granule of AP, and it contains lactose, xanthan gum, polyvidone and a kind of based on EUDRAGIT RS

The outer coating of/glyceryl triacetate/antagonist.The existence of gellant makes this preparation have viscosity, thereby can not pass through nasal cavity or parenteral.In our view, this answer is inappropriate, because according to described invention, the use of antagonist is especially necessary.At last, this preparation does not have the resistance to crusing measure, so it can be converted into powder-form, becomes the object of per nasal or per os approach abuse then.

Patent application WO-A-03/013479 has described a kind of oral drug preparation, and it contains the opium kind analgesics and the opioid antagonist (naltrexone) of pharmacy effective dose, and a kind of bitterness promoter.When drug dependence person's tablet of crushing, just discharge opium and antagonist thereof.The effectiveness of opium just has been neutralized thus.In our view, this system especially can not prevent water and optionally not extract opium in the crushing mode.

Antagonist is sought help from all things considered, is difficult to avoid its shortcoming, that is, and and the risk that medical science risk that user may stand and expection therapeutic effect are suppressed.

Patent application WO-A-2004/054542 has described a kind of semiliquid oral pharmaceutical form.It has adopted the form of capsule (as gelatine capsule), contain the described AP in the matrix phase, described matrix phase is made up of water-insoluble high viscosity liquid (Sucrose acetoisobutyrate) and polymer (cellulose acetate-butyrate), and they should form net in liquid phase.Said preparation also can be chosen the chemical compound that contains the described medicament forms rheological characteristic that changes wantonly, and solvent.By changing the concentration of different chemical compound and preparation, the author claims that they can change the curve of blood plasma that the AP of Canis familiaris L. (oxycodone base) given in administration.Because after adding small amount of ethanol, the viscosity of said preparation sharply descends, in our view, this list of references does not provide the scheme that especially stops the injection abuse.

Patent application US-A-2003/0224051 has described and has been used to improve the permeation form that discharges oxycodone.This form is made up of tablet, described tablet contain oxycodone or its salt label, seal to the semipermeable membrane of small part label and film and discharge portalling of oxycodone.In water, soaked for example at least 12 hours, and can easily extract the opium in such tablet.In our view, this tablet also is not to solve the suitable scheme of abuse problem.

Patent application EP-A-1 293 209 discloses a kind of Peroral solid dosage form medicament forms of anti-abuse, and the prolongation that is used for being included in the opiate derivative (AP) of ion exchange resin discharges.Gained AP/ resin complexes can make the misuser be limited in treatment concentration level far below its pursuit by the plasma concentration of chewing, sucking or injecting the back and obtaining.Described AP/ resin complexes adopts matrix form.In our view, according to described prior art document, in medicament forms, do not provide the measure of anti-crushing.And this medicament forms is without any the measure of antagonism solvent extraction AP.Therefore, although normal release time of being longer than described AP time of extracting, it can not stop uses solvent extraction AP.If place one glass of water to reach 24 hours this oral pharmaceutical form, in fact all AP have extracted.

Patent application US-A-2003/0118641 and 2005/0163856 (=WO-A-01/08661) multiple oral drug preparation described, its prolongation that is used for the AP that is made up of opium chemical compound (analgesic) and salt thereof discharges.These preparations should be able to stop the abuse that extracts AP with common solvent.The preparation of this anti-abuse does not comprise antagonist, although have more admonition in order to become, this probability may be noted.These preparations comprise the mixture of following substances:

A kind of hydrophilic matrix reagent (hydroxy alkyl cellulose) of-weight ratio 40-65%;

-a kind of ion exchange resin (granule is less than 50 μ m, weight ratio 5-15%);

-at least a opiates AP.

After adding conventional tabletting additive, mixture changes into tablet.

Therefore, this is a kind of macroscopic matrix system, and it contains the compound ion-exchange resin particles with described AP, and by viscosifier, the anti-extraction measure that preferred hydroxypropyl methylcellulose constitutes.In our view, this system can improve the effect of especially anti-abuse.

The patent documentation WO-A-2005/079760 that inserts discloses a kind of pharmaceutical preparation, and it is made up of the elastomeric AP microgranule that obtains by extruding, and it can make AP prolong the characteristic that discharges and have anti-abuse.These microgranules that squeeze out contain substrate, and described substrate is by poly-(ethyl acrylate/methyl methacrylate) copolymer of non-activity NE 30D or NE 40D form.This substrate contains described AP (oxycodone), another kind

RS PO, a kind of plasticizer and a kind of lubricant.

To prevent abuse, described measure only relates to the rubbery feature that is used to improve the matrix granule that discharges described AP by anti-crushing measure.In our view, do not provide antagonism in solvent medium, to extract the measure of described AP.

In our view, prior art does not also provide satisfied anti-abuse scheme so far, especially prevents water, ethanol or other the potable solvent scheme to the extraction of the AP property abused.

Summary of the invention

In these cases, an object of the present invention is to overcome the deficiencies in the prior art.

Another object of the present invention provides novel Peroral solid dosage form medicine, if possible, it will be difficult abusing this medicine, especially in the above (a) that points out is (b) under the situation of (c), preferred do not use beyond the described AP have pharmaceutical active and therefore to the adventurous material of user, or the AP inhibitor, as the AP antagonist.

Another object of the present invention provides novel Peroral solid dosage form medicine, and if possible, it will be difficult abusing this medicine, and (a) that points out especially in the above is (b) under the situation of (c), even behind the described AP of " length " time liquid extraction (as analgesic).According to the present invention, " length " time liquid extraction is meant the extraction that continues more than 10 minutes.

Another object of the present invention provides novel Peroral solid dosage form medicine, and described medicine prevents abuse by short time liquid extraction and/or crushing.

Another object of the present invention provides novel Peroral solid dosage form medicine, has following feature:

Under-conventional administration the condition, the therapeutic effect of these Peroral solid dosage form medicines reaches for example 12 or 24 hours;

The attempt of-described the AP of any abuse extraction (as analgesic) can cause this medicine to change into a kind of form, makes that absorption back AP can not be by fast Absorption in blood flow.

Another object of the present invention provides novel Peroral solid dosage form medicine, it

-administration is easily given and is difficult to the patient of big tablet that swallows, as the patient who contracts a serious illness, baby or child;

-can be at one or same dosage unit in conjunction with several AP, even these AP compatibility and/or do not have identical release dynamics parameter mutually;

-can be with can be in one day in single or divided doses, and can reach rate of release and the form of time of adjusting different AP independently easily and exist.

Another object of the present invention provides novel Peroral solid dosage form medicine, and its external stripping curve is independent of the dosage of AP.

Another object of the present invention provides novel Peroral solid dosage form medicine, and it can avoid the fraudulence abuse of its contained AP character by preventing from medicine is converted into the form that can take in from mouth, nasal cavity and/or injection (intravenous, subcutaneous, intramuscular etc.) beyond the treatment restriction.This will prevent or at least greatly alleviate the risk relevant with unwelcome behavior.

Another object of the present invention provides novel Peroral solid dosage form medicine, and it can guarantee the patient's that experience is normally followed up a case by regular visits to therapeutic quality when avoiding abusing, especially with the corresponding to dosage of his demand.

Another object of the present invention provides novel Peroral solid dosage form medicine, it can not influence the pharmacological property of described medicine when avoiding abusing, bring extra risk for the patient of normal medication, and when administration, do not reduce patient's comfort at last.

Another object of the present invention provides novel Peroral solid dosage form medicine, and it can be in one day in single or divided doses, and restriction is because the too high risk that causes tissue injury of local concentration of AP.

Another object of the present invention provides novel Peroral solid dosage form medicine, and it can adopt multiple galenical form, as tablet, pockaged powder, capsule etc.

Another object of the present invention provides the Peroral solid dosage form medicine of novel anti-abuse, and its preparation is simple and economical.

Summary of the invention

In order to reach these purposes, the general considerations of reformulating the Drug abuse form is inventor's contribution.

If the different illegal mode of administration of research active component, the normally necessary step of dried forms of in fact as if crushing.

In the situation by the nasal-cavity administration abuse, exsiccant medicament forms at first must change into the powdery that is fit to suction.Therefore, the crushing of medicament forms is undoubtedly necessary step.

In the situation of the dried forms abuse that prolong to discharge by oral administration, be necessary microgranule or tablet fine crushing to quicken the release of active component.

In the abuse situation by parenteral, described AP must at first extract in the liquid phase, and described liquid phase is actually water or organic solvent, to reaching sufficiently high concentration to avoid injection capacity excessive, as surpassing 1ml.The crushing step of carrying out dried forms earlier can be dissolved or suspend active component, the extraction step after helping.And, after the extraction stage, can abuse when having only the viscosity not too high (as being less than or equal to 100mPa.s) when liquid.

Therefore, the crushing of dried forms also is that described medicament forms is by the necessary step of administered in parenteral form abuse.

The problem of reformulating antagonism abuse dry drug form with following feature is applicant's contribution:

-primary problem (a) prevents to crush and contains the system of AP;

-the second problem (b) prevents the abuse of described AP after possible extraction.

This new method makes the applicant find pleasantly surprisedly; in attempting the pharmaceutical composition that prevents to abuse, add the AP that is used to improve the coated particle form that discharges described AP; be suitable; and the pharmaceutically acceptable excipient that can randomly add microgranule or non-particulate form; the physical chemistry pattern of its effect can stop it anyly to have a mind to or abuse unintentionally, even makes it impossible.

Therefore, the present invention relates generally to a kind of Peroral solid dosage form medicament forms, it is characterized in that, it comprises anti-abuse measure, it is characterized in that being included in the microgranule that is used for improving the coating that discharges described AP to its contained described AP of small part, its feature is that also described AP coated particle has a coatings (Ra), and it makes described AP coated particle can resist crushing to avoid abuse when guaranteeing to improve the described AP of release.

Medicament forms of the present invention has especially solved the subject matter that exists, and is aided with the physical chemistry means, satisfies to the small part purpose in effective, simple and economical mode.Described physical chemistry means are fully harmless for normal user.They are chemical compounds of no pharmacological activity, by pharmacopeia and the public health authorities approval of being responsible for authorizing medicine listing permission.

One preferred embodiment in, Peroral solid dosage form medicament forms of the present invention also contains at least a viscosifier (Vb) except anti-crushing coatings (Ra), if possible, described viscosifier make from described AP coated particle and extract the described AP difficulty that becomes very, to avoid the abuse of the described AP after the liquid extraction.

According to the present invention, term " viscosifier " refers to the mixture of a kind of viscosifier and multiple viscosifier simultaneously.

Detailed Description Of The Invention

According to the present invention, be to improve the form that discharges to the described AP of small part, promptly its form is the microgranule that is used to improve the coating that discharges described AP.

The active component (AP) that the present invention considers is medicinal or veterinary drug AP, for example anaesthetizes product class, analgesic class or anesthetics class.The abuse of these AP can cause addictive behavior.

According to the present invention, the mixture of term " AP " a kind of active component of expression and several active component.

According to the present invention, " particulate form " is interpreted as any medicament forms, and wherein said AP is included in the microgranule less than 1000 μ m.These granules that contain described AP can be to improve the microgranule with the independent coating of film that AP discharges.In the latter, microgranule is for example used the film coating based on polymer, and described film is controlled the rate of release of described AP.

Among the present invention, " improvement releasing pattern " refers to a kind of form, and wherein the rate of release of the described AP of at least a portion is lower than the rate of release of releasing pattern immediately.This part can be, 1-100% for example, preferred 10-100%, preferred especially 30-100%.Specifically, it can be that prolong and/or that delay and/or with the form at one or more releases peak (pulse) improve discharging.It is known in the art improving delivery formulations, can reference, and the The science and practice of pharmacy of Remington for example, the 19th edition, Mack publishing company, Pennsylvania, USA.

Among the present invention, " releasing pattern immediately " refers to a kind of form, and the release time of the described AP of its contained major part is short relatively, that is, in external dissolution test, in the pH value 1.4-6.8 scope, at least 70% described AP discharged in preferred 30 minutes in 1 hour.

Whole external dissolution characteristic among the present invention obtains according to the method that is entitled as " dissolution test of solid oral dosage form " in the European Pharmacopoeia the 4th edition: the II type dissolution test that carries out under the SINK condition, 37 ℃ of temperature, mixing speed 75rpm.

Therefore, pharmaceutical preparation of the present invention is to be used to improve the preparation that discharges described AP.

According to the present invention, " pharmaceutical preparation " according to broad understanding, that is, this wording also comprise veterinary drug with and the diet preparation.

This pharmaceutical preparation comprises that also one or more are used for discharging immediately the form of described AP.

Preferably, the structure of pharmaceutical preparation of the present invention, outward appearance and composition all are new, and its existence form can be, for example tablet, pockaged powder, the packed suspendible powder of reconfigurable multiple dose or capsule.

The AP coated particle

Preferably, described to be used to improve the microgranule that discharges described AP be that each microgranule has one deck coating microgranule of (containing for example at least a polymer) at least, the deposition techniques of described coating known to can those skilled in the art.But this problem is reference example such as following works for example, the Formes pharmaceutiques nouvelles:aspects technologique of Buri, Puisieux, Doelker and Benoit, biopharmaceutique et m é dical (novel drugs dosage form: technology, biopharmaceutics and medical science viewpoint), the Lavoisier version, 1985, the 175-227 page or leaf.

In other words, preferred these coated particle, each is all by the kernel that contains AP with contain at least the coating of one deck coatings and forms, and described coatings is sealed kernel (preferably encasing fully) and is arranged the improvement release (preferably constantly) of described AP.This being released in when described AP coated particle contacts with gastro-intestinal Fluid begins.

The not coated particle (before being coating) of described AP can be, for example:

-non-activity kernel is coated with the layer that one deck at least contains AP;

-or the microgranule of pure AP;

-or form, comprise the microgranule of described AP by the substrate of supporting excipient.

Under the situation of supportive microgranule, non-activity kernel or holder can be made up of sucrose and/or sucrose and/or glucose and/or lactose and/or sucrose/starch mixture.Non-activity kernel or holder also can be the granules of cellulose microsphere or any other pharmaceutically acceptable excipient.The granule of xanthan gum, guar gum, calcium phosphate or calcium carbonate can be used as the limiting examples of non-activity holder.Their average diameter can be 10-200 micron, 20-150 micron or 50-100 micron.

The coated particle of these " bank " types (or microgranule of coating) separately can be likened to small intestinal or or even the carrier that is used to transport and discharge at least a AP of big enteral.

Being used for of can mentioning improve the coated particle example that discharges described AP be following patent documentation: EP-B-0 709 087 and WO-A-03/030878 describe those.

The coating of AP microgranule

Preferably, described AP coated particle contains one deck coating (Ra) at least, preferably has only one deck coatings (Ra), and it is guaranteed to improve the described AP of release and makes described AP coated particle can resist crushing to avoid abuse simultaneously.

Particularly preferably, described coatings (Ra) designs in such a way: if crush, it can be maintained until described non-(promptly improved) the immediately release that is used to improve the coated particle that discharges described AP of small part.

Here the crushing of indication can be, for example crushing carried out of the common technology that adopts of misuser, that is, specifically: pestle/mortar, coffee mill, press, crush/chew with two spoons etc.

In a useful embodiment, coatings (Ra) designs in such a way: if crush, it can keep at least 40%, and preferably at least 60%, preferred at least 80% the described improvement that is used to improve the coated particle that discharges described AP discharges especially.

Preferably, anti-crushing coatings (Ra) comprising:

-(A1) at least a in the intestines and stomach liquid undissolved film forming (being total to) polymer (A1);

-(A2) at least a dissolved in the intestines and stomach liquid (being total to) polymer (A2);

-(A3) at least a plasticizer (A3);

-(A4) optional at least a surfactant and/or lubricant and/or mineral and/or organic filler (A4).

Nonrestrictive selection of pure illustrative according to the present invention:

(A1) be selected from down group:

-water-insoluble cellulose derivative class, preferred, ethyl and/or cellulose acetate,

-acrylate copolymer class, copolymer as (methyl) acrylic acid and alkyl (as methyl) ester, acrylic acid and the copolymer (preferred at least a acrylic acid alkyl (methyl) ester and the muriatic copolymer of trimethyl ammonium ethyl-methyl acrylate) that has the methacrylate of at least one quaternary ammonium group, more precisely, the trade mark of this launch is

RS and/or RL,

-polyvinyl acetate esters,

-and composition thereof;

(A2) be selected from down group:

-nitrogenous (being total to) polymer class, preferred group down: polyacrylamide, poly-N-vinyl amide-type, polyvinyl pyrrolidone (PVP) class and poly-N-vinyl lactam class,

-water-soluble cellulose derivative class,

-polyvinyl alcohols (PVA),

-polyalkylene oxide class, preferred poly(ethylene oxide) class (PEO),

-polyethylene glycols (PEG),

-and composition thereof;

Preferred especially PVP;

(A3) be selected from down group:

-cetyl alkoxide,

-glycerol and esters thereof, preferably from following subgroup: acetylizad glyceride type, glyceryl monostearate, glyceryl triacetate and tributyrin,

-phthalate, preferably from following subgroup: dibutyl phthalate, diethyl phthalate, dimethyl phthalate, dioctyl phthalate,

-citric acid ester type, preferably from following subgroup: acetyl tributyl citrate, acetyl triethyl citrate, tributyl citrate, triethyl citrate,

-sebacic acid ester, preferably from following subgroup: ethyl sebacate, dibutyl sebacate,

-adipic acid esters,

-Azelaic Acid esters,

-benzoates,

-plant oil,

-fumaric acid esters, preferred DEF,

-malic acid esters, the preferably apple diethyl phthalate,

-oxalic acid ester, preferred ethyl oxalate,

-succinic acid esters, preferred dibutyl succinate,

-butyric acid ester,

-cetyl alkoxide,

-salicylic acid,

-glyceryl triacetate,

-malonic acid esters, preferred diethyl malonate,

-Oleum Ricini (preferred especially),

-and composition thereof;

(A4) be selected from down group:

-anion surfactant class, preferably from following subgroup: the alkali metal of fatty acid or alkaline-earth metal salt, preferred stearic acid of described fatty acid and/or oleic acid,

-and/or the nonionic surfactant class, preferably from following subgroup:

The oils of-polyethoxylated, the castor oil hydrogenated of preferred polyethoxylated,

-polyoxyethylene/polyoxypropylene copolymer analog,

The Arlacels of-polyethoxylated,

The castor oil derivative class of-polyethoxylated,

-stearates, preferred calcium stearate, magnesium, aluminum or zinc,

-stearoyl-fumarate salt, preferred sodium stearyl fumarate,

-Glyceryl Behenate,

-Pulvis Talci,

-silica sol,

-titanium oxide, magnesium oxide,

-bentonite,

-microcrystalline Cellulose,

-Kaolin,

-aluminium silicate,

-and composition thereof.

Except the qualitative parameter of definition coated particle of the present invention, according to preferred quantitative mode, it is as follows to illustrate that coatings (Ra) accounts for the % weight of coating gross weight:

10≤A1≤90, preferred 15≤A1≤80, and preferred especially 60≤A1≤80;

5≤A2≤50, preferred 10≤A2≤40, and preferred especially 10≤A2≤25;

1≤A3≤30, preferred 2≤A3≤20, and preferred especially 5≤A3≤15;

0≤A4≤40, preferred 0≤A4≤30, and preferred especially 0≤A4≤20,

The summation of percent equals 100.

And, for example adjust rate of release in the following manner:

-control the thickness of described coating (Ra);

Weight ratio between-described coating (Ra) composition A1, A2, A3 and the optional A4.

Preferably, except neccessary composition A1, A2, A3 and optional A4, the described coating that is used to improve the coated particle that discharges described AP can contain other conventional ingredient known to those skilled in the art, for example, especially coloring agent, pigment, antiseptic, flavoring agent etc., and composition thereof.

Another noticeable feature of coating on the coated particle (Ra) is the following fact: represent with the % dry weight, the ratio Tp that coatings (Ra) accounts for the gross weight of coated particle is, Tp 〉=15%, and preferred Tp is 30-60, preferred especially 40-60, very particularly preferably 45-55 or about 50.

Do not want to be bound by theory, this high relatively coating rate makes coatings (Ra) can guarantee improve to discharge described AP and makes the described AP coated particle can be to resistance to crusing to avoid abuse simultaneously.

According to the present invention, the average diameter of preferred AP coated particle is less than or equal to 1000 μ m, preferred 50-800 μ m, and preferred especially 100-600 μ m, and 100-300 μ m very particularly preferably, but this is not restriction the present invention.

Unless point out separately, the mean particle dia of indication of the present invention is a volume mean diameter.

Preparation about described coated particle, be used to deposit that to be used to improve the coating that discharges described AP or deposition be technology known in the art based on the technology of the active layer of described AP, for example spraying packaging technique, the wet granulation technique in the air fluid bed, compress or push/extruding technology.

Outer coating

In a concrete mode of the present invention, the outer coating that is used for improving the described coated particle that discharges described AP designs by this way: in the production of tablet, it helps to be maintained until the improvement that small part is used to improve the AP coated particle that discharges described AP and discharges.Described outer coating is 40 ℃-120 ℃ by at least a fusing point, and preferred 45 ℃-100 ℃ deformable organic principle is formed.

In an optimal way, described outer coating contains the deformable organic principle of at least 10% weight.

Specifically, in a mode of the present invention, the contained deformable organic principle of described outer coating is selected from poly-inferior alkene glycols, and special preferred molecular weight is the polyethylene glycols of 6000-20000 D.

In another mode, the deformable organic principle of described outer coating is the mixture of fat or fats, for example be selected from down group: fats, fatty acid, aliphatic alcohols, fatty acid and/or aliphatic alcohol esters, TPO and the mineral, plant, animal or the synthetic wax class that contain hydrogenated vegetable oil, special preferred fat esters of gallic acid is as diglyceride and triglyceride and composition thereof, Glyceryl Behenate and castor oil hydrogenated, soybean oil, Oleum Gossypii semen and Petiolus Trachycarpi oil.

In another mode, described outer coating contains:

-a kind of mineral filler, for example silicon dioxide or titanium dioxide, or a kind of organic filler, microcrystalline Cellulose for example,

-and/or at least a lubricant, for example magnesium stearate or sodium benzoate,

-and/or at least a hydrophilic polymer, as water-soluble cellulose derivative class, synthetic polymer class, preferably polyethylene base ketopyrrolidine, acrylic acid and methacrylate polymer class or polyvinyl alcohols (PVA),

-and/or at least a surfactant.

Preferably, described outer coating accounts for the described AP 5-50% of coated particle gross weight dry weight again, preferred 10-30%, especially preferred about 20%.

Term " coated particle again " refers to the AP coated particle, and it also comprises previously defined outer coating, promptly in the production of tablet, helps to be maintained until the outer coating that small part is used to improve the improvement release that discharges described APAP coated particle.

The out of Memory of outer coating can be found in disclosed patent application WO-A-03/077888.

Viscosifier (Vb)

Preferably, described viscosifier (Vb) are selected from those that are dissolved at least a following solvent: water, alcohols, ketone and composition thereof, described viscosifier (class) can improve the viscosity of extracting solution to stop abuse, especially the injection abuse.

" water " is interpreted as any aqueous solvent, as proper water or any aqueous solution, and for example aqueous solution, saline, soda water or the beverage of organic solvent (as acetic acid)." alcohols " be interpreted as any alcohols itself or with other pure mixture." ketone " be interpreted as any ketone itself or with the mixture of other ketone.

Particularly preferably, described viscosifier (Vb) are selected from following polymer group:

-polyacrylic and derivant thereof, and/or

-polyolefin diols class (as Polyethylene Glycol), and/or

-polyoxy olefines (as the poly(ethylene oxide) class), and/or

-polyvinylpyrrolidone class, and/or

-gelatin class, and/or

-polysaccharide, preferred following subgroup: sodium alginate, pectin class, guar gum class, xanthan gum class, carrageenan class, gellan gum class and cellulose derivative class (as hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl-cellulose, carboxymethyl cellulose),

-and composition thereof.

According to a mode of the present invention, described viscosifier Vb is a high molecular weight peo, is 1,000,000 g/mol-800, ten thousand g/mol as molecular weight, as 2,000,000,5,000,000 or 7,000,000 g/mol.

Preferably, described viscosifier Vb, as high molecular weight peo with as described in the different mode of AP microgranule be included in the microgranule.

Particularly preferably, described AP microgranule has similar distribution of sizes and density with described viscosifier Vb microgranule, and can't separate by sieve method.

According to an optimal way, described viscosifier Vb can improve the viscosity of the liquid that is used for possible extraction, to catch the AP that is extracted in resisting medium.

These viscosifier Vb can make the viscosity of extracting liq be increased to, more than 100mPa.s, and preferred 200mPa.s, more than the preferred especially 500mPa.s, 1000mPa.s very particularly preferably.

In a mode, proposed aqueous extraction and all effective viscosifier (Vb) of organic solvent extraction, this also is applicant's contribution.Preferably, these viscosifier (Vb) are the mixture of hydrophilic and hydrophobic compound, with the high viscosity (more than 100mPa.s) of guaranteeing extracting solution, no matter it is aqueous or organic extracting solution.

With regard to the consumption of viscosifier (Vb), those skilled in the art can easily determine.Described amount is equivalent to the viscosity value of 2.5ml extracting solution is brought up to the needed minimum more than or equal to 100mPa.s.

In several modes that can make up mutually, at least a viscosifier (Vb) in the medicament forms of the present invention are present in:

In-the microgranule and/or on the microgranule,

-and/or all or part of described AP microgranule on outer coating in,

-and/or exist with free state, that is, neither be included in and also can't help its support in the microgranule.

Preferably, to the form of the described viscosifier of small part be and the coating of described AP or the inseparable particulate form of coated particle not.

The excipient of free state

Described medicament forms can at random contain the pharmaceutically acceptable excipient of one or more free states, that is, neither be included in and can't help also in the AP microgranule that it is supported, described excipient helps to resist the crushing of described AP coated particle.

Preferably, these excipient that help to resist described AP coated particle crushing are selected from down group:

-calcium stearate;

-glyceryl palmitostearate;

-magnesium oxide;

-polyolefin diols class is as polyethylene glycols;

-polyvinyl alcohol;

-sodium benzoate;

-stearic acid;

-corn starch;

-Pulvis Talci;

-silica sol;

-zinc stearate, magnesium stearate;

-stearoyl-fumarate;

-and composition thereof.

In other embodiment of the present invention, to the described viscosifier of small part be:

-free state, that is, neither be included in the coating of AP or also do not can't help its support (option one) in the coated particle, or

-with the coating of described AP or the different particulate form (option 2) of coated particle not.

Preferably, in option 2, described viscosifier microgranule and the coating of described AP or not coated particle can't separate.According to the present invention, " can't separate ", the meaning of this expression way for example was, can't use conventional means such as sieve method or centrifuging to separate.

In option 2, viscosifier for example:

-in microgranule and/or on the microgranule,

-and/or the outer coating on all or part of described AP microgranule in.

Still in option 2, preferably, the microgranule and the AP microgranule that contain described viscosifier are difficult to distinguish physically, therefore all can not easily separate by any suitable physical means.Particularly have identical size and/or identical density and/or identical shape and/or identical color, the microgranule and the described AP microgranule that contain described viscosifier are difficult to differentiate.

In another option, described viscosifier for example:

-in microgranule and/or on the microgranule,

-and/or the outer coating on all or part of described AP microgranule in.

One preferred embodiment in, medicament forms of the present invention is a multiparticulates.If this medicament forms contains AP (as aAP) microgranule and viscosifier (Vb) microgranule, preferred described microgranule has similar distribution of sizes with similar density and preferably can't separate with sieve method.Therefore described viscosifier microgranule can not be from the coating of described AP or is not separated the coated particle.

Another preferred embodiment in, pharmaceutical preparation of the present invention is multiparticulates.If this medicament forms contains AP (as aAP) microgranule and viscosifier (Vb) microgranule, preferred described microgranule has identical distribution of sizes with identical density and preferably can't separate with sieve method.Therefore described viscosifier microgranule can not be from the coating of described AP or is not separated the coated particle.

Sequestering agent Q

Clearly, when the drug particles form contains at least a salt of at least a analgesic bioactive substance, those skilled in the art can add at least a sequestering agent in the described in the past medicament forms, to form sl. sol. complex with described AP in moisture or water alcoholic beverage solution.

Described sequestering agent for example is a kind of salt, and its ionic polarity is opposite with the ion of described AP, preferably a kind of organic ion.Therefore, for cationic active ingredients, this sequestering agent for example is an organic salt, resembles docusate sodium, or anionic polymer.Described sequestering agent also can for example be the salt of ion exchange resin.

According to the present invention, sequestering agent Q is that non-combined state exists with free form in medicament forms of the present invention." non-combined state " refers in described solid drug forms, do not have compound or chemical interaction between the salt of described sequestering agent Q and described active components A P.

If described AP salt and described sequestering agent Q exist in a kind of solvent simultaneously, as attempt is illegal extract as described under the situation of AP, described sequestering agent Q can cause in described solvent and the compound or chemical interaction of described AP salt.According to the present invention, if described sequestering agent Q can cause the compound of described AP salt at least a solvent commonly used, just think described sequestering agent Q " can cause with described AP salt compound ", described solvent commonly used is selected from water and aqueous solution, as water/alcohol mixture, ethanol, alcoholic beverage, soda water, vinegar, hydrogen peroxide and mixing thereof.Preferably, described sequestering agent Q can cause the compound of described AP salt in more than one these common solvent.

Be used to catch described AP, especially the sequestering agent Q of analgesia property AP is harmless, or even often use.From pharmacological point of view, these products are non-activities, and by the approval of the medicine of multi-section pharmacopeia and how tame official registration authorities.

In the medicament forms of the present invention, at least a sequestering agent Q is present in:

-in the microgranule that does not contain AP, and/or

-on microgranule, and/or

-exist with free state, that is, neither be included in and also can't help its support in the microgranule.

Preferably, in a kind of medicament forms of the present invention, described sequestering agent Q is present in first phase of separating mutually with at least a second, and described second contains at least a AP salt mutually.For example, described medicament forms contains the microgranule and the sequestering agent Q microgranule that is different from the former of AP salt.Preferably, described microgranule has similar distribution of sizes, similar density, and can't separate with sieve method.

Preferably, described sequestering agent Q comprises a kind of salt, and described salt comprises the ion that can form complex in solution with described AP.The organic ion that these ions are preferably opposite with the ion polarity of AP described in the solution: if AP described in the solution is an anionic form, described sequestering agent Q just comprises organic cation, metal ion or its mixture.Similarly, if AP described in the solution is a cationic form, described sequestering agent Q just comprises organic anion.

For example, can mention the following salt that contains organic anion:

-organic anion salt is as sodium lauryl sulphate or docusate sodium;

-anionic polymer class, as (methyl) acrylic copolymer class (as

S and

L), cross linked polyacrylate (as Carbopol), carboxymethyl cellulose and derivatives class, cross-linked carboxymethyl cellulose and derivatives class thereof and other polysaccharide (as alginate, xanthan gum or arabic gum) and Polyethylene Glycol alginic acid/(sulfonic acid) ester;

-unit price or multivalence salt are as glucuronic acid salt, citric acid salt, acetic acid salt, carbonate, gluconic acid salt, succinic acid salt, phosphoric acid salt, phosphoglycerol salt, lactates, trisilicate class, fumaric acid salt, adipic acid salt, benzoate, salicylic acid salt, tartrates, sulfonamides and acetyl Sulfonates;

-saponified fatty acid is as acetic acid, succinic acid, citric acid, stearic acid and Palmic acid salt and self emulsifying glyceryl monooleate class;

-polyamino acid class, protein-based or polypeptide class are as albumin class, casein class, globulin class and enzyme;

-and composition thereof.

In another embodiment, the ion opposite with the ion polarity of AP described in the solution is organic metal cation or its mixture.For example, can mention the following salt that contains organic or metal cation:

-cation salt, as the cation salt of metal Ca, Fe, Mg or Zn, form is sulfacetamide Barbiturates, acetic acid salt, adipic acid salt, benzoate, carbonate, chloride-based, citric acid salt, fluoride class, fumaric acid salt, gluconic acid salt, glucuronic acid salt, phosphoglycerol salt, hydroxide class, iodates, iodide class, lactates, oxide-based, phosphoric acid salt, trisilicate class, salicylic acid salt, succinic acid salt, sulfonamides or tartrates;

-organic cation salt is as quaternary ammonium salt, especially trimethyl Tetra-n-decylammonium bromide or benzethonium chloride;

-cationic polymer class, as chitosan and (methyl) acrylic copolymer class (as

RS,

RL or

E);

-polyamino acid class, protein-based or polypeptide class;

-and composition thereof.

Described sequestering agent Q can be an ion exchange resin, and as described AP when being cationic, sequestering agent Q is storng-acid cation exchange resin preferably, or when described AP was anionic, sequestering agent Q is strong-base anion-exchange resin preferably.Preferably, this ion exchange resin be included in first mutually in, described first second is what to separate with what contain described AP mutually.

In an embodiment of the invention, described ion exchange resin for example is the derivant of styrene/divinyl benzene copolymer.

In an embodiment of the invention, described storng-acid cation exchange resin can for example be the derivatives class of sulfonated styrene/divinyl benzene copolymer, as

IRP69,

IR69F (ROHM AND HAAS), Amberlite 200, Amberlite 200C (ROHM AND HAAS) or Dowex 88 (DOW Chemical) etc.

In an embodiment of the invention, described strong-base anion-exchange resin can be selected from the derivatives class of the styrene/divinyl benzene copolymer that for example has quaternary ammonium group, as AP143 (ROHM AND HAAS), Amberlite IRA958, Amberlite IRP67 (ROHM AND HAAS) and DOWEX 22 (DOW Chemical).

The sequestering agent Q of described resin form also can be selected from a kind of of crosslinked methacrylic acid/divinyl benzene copolymer class or its esters, as

IRP88,

IRP64 (ROHM AND HAAS) and DOWEX MAC-3 (DOW Chemical).

The sequestering agent Q of described ion exchange resin form also can be selected from phenol polyamines class, as

IRP58 (ROHM AND HAAS) and composition thereof.

In an embodiment of the invention, the sequestering agent Q of described ion exchange resin form first mutually in, described first and at least a second is what to separate mutually, described second contains described AP salt mutually.For example, the sequestering agent Q of described ion exchange resin form is included in the microgranule, and described microgranule is different with the microgranule that contains described AP salt.The form of the microgranule of the sequestering agent Q of described AP microgranule and described ion exchange resin form can be that the distribution of sizes of the two is similar, density is similar and can't separate by sieve method.

Implement in first optimal way of the present invention, described valency chelating agen Q is selected from:

-organic anion salt is as dodecyl sodium sulfate or docusate sodium;

-organic cation salt, as quaternary ammonium salt, especially trimethyl myristyl ammonium bromide or benzethonium chloride;

-storng-acid cation exchange resin or strong-base anion-exchange resin depend on the polarity of described AP.

Implement in second optimal way of the present invention, described valency chelating agen Q is selected from:

-as described AP when being cationic, be selected from storng-acid cation exchange resin

IRP69, IR69F (ROHM AND HAAS), Amberlite 200, Amberlite 200C (ROHM AND HAAS) or Dowex 88 (DOW Chemical) and composition thereof;

-and when described AP is anionic, be selected from strong-base anion-exchange resin

AP143 (ROHM AND HAAS), Amberlite IRA958, Amberlite IRP67 (ROHM AND HAAS) and DOWEX 22 (DOW Chemical) and composition thereof.

Catch the number of the required ionic charge of the AP of all or part of dosage that contains in the unit dosage forms by calculating, those skilled in the art can adjust the consumption of described reagent Q.The consumption of described sequestering agent Q must can be fully compound with AP, so that the required effect of the quantity not sufficient of remaining free AP when reaching illegal use in the solution.Preferably, the consumption of sequestering agent Q be enough to described unit dosage forms in all AP are compound.

In a kind of mode, described medicament forms also can be a monolithic form (as tablet).

In one embodiment, medicament forms of the present invention comprises viscosifier V microgranule and/or sequestering agent Q microgranule, preferably includes viscosifier V microgranule and sequestering agent Q microgranule.In this embodiment, described viscosifier V microgranule and described sequestering agent Q microgranule are different from described AP microgranule.

In yet another embodiment of the present invention, described medicament forms comprises AP microgranule and viscosifier V microgranule and/or sequestering agent Q microgranule.Preferably, described medicament forms comprises this microgranule of three types,, comprises AP microgranule, viscosifier V microgranule and sequestering agent Q microgranule in one or same unit form that is.Preferably, these microgranules have similar distribution of sizes and similar density, and can't be separated from each other by sieve method.

In first kind of mode, medicament forms of the present invention can not change into can be by the dried forms that discharges described AP immediately of inhalation.

In the second way, medicament forms of the present invention can not change the injectable forms that can discharge described AP immediately into.

In the third mode, medicament forms of the present invention contains AP and the optional AP that discharges immediately that improves release.This mode can make up with first and second kinds of modes of front indication, that is to say, in containing the medicament forms that improves AP that discharges and the AP that discharges immediately, the AP that described improvement discharges can not be converted to can be by the dried forms of inhalation or the injectable forms that discharges immediately.

In the 4th kind of mode, the feature of medicament forms of the present invention is, by chewing and/or crushing that to extract described AP be invalid.

In the 5th kind of mode, the feature of medicament forms of the present invention is not contain the antagonist (class) of AP.

In the 6th kind of mode, the feature of medicament forms of the present invention is that it comprises at least a AP antagonist.According to the knowledge of use AP, those skilled in the art can easily determine appropriate antagonist (class).

Certainly, any at least two kinds of combinations of above-mentioned six kinds of modes are included in the scope of the invention except combinations of the 6th kind of mode (the 5th and).

Active component (class)

Used AP belongs to, for example following active substance family at least a: amphetamine, analgesic class, reduce medicine class, tranquilizer class, antidepressants class, antuepileptic class, migraine material type, Kang Pajinsenshi disease material type, cough medicine class, antianxiety drugs class, barbiturates, benzodiazepines, hypnotic class, cathartic class, antipsychotic drug class, opiates, psychostimulant class, spiritual material type, tranquilizer class and the analeptic class of appetite.When wherein AP was analgesia property AP (aAP), it is opium preferably.

Or rather, employed AP is selected from following chemical compound:

Anileridine; Acetorphine; Acetyl group-alpha-methylfentanyl; The acetyl group Dihydrocodeine; Acetylmethadol; Alfentanil; Allylprodine; The U.S. sand of α-cetyl is many; α-Metro is fixed; Alphaprodine; α-Mei Shaduo; Alpha-methylfentanyl; Alpha-Methyl sulphur fentanyl; Anileridine; Atropine; Butorphanol; Benzethidine; Benzyl morphine; Beta-hydroxyfentanyl; β-methylol-3-fentanyl; The U.S. sand of β-cetyl is many; β-Metro is fixed; β-Mei Shaduo; β-Luoding; Bezitramide; Buprenorphine; Amidalgon; Clonitazene; Cyc; Hemp; Ketobemidone; Coca leaf; Codeine; Coca; Cocaine; Codoxime; Dezocine; Dimenoxadol; Amidalgon; Dipipanone; Desomorphine; Dextromoramide; Dextropropoxyphene; Diampromide; Diethylthiambutene; Difenoxin; Paracodin; DEE; Paramorphane; Dimenoxadol; Dimepheptanol; Dimethylthiambutene; Diphenoxylate; Drotebanol; Eptazocine; Ethoheptazine; Ethylmethylthiambutene; Dionin; Etonitazene; Ecgonine; Ephedrine; Etorphine; Etoxeridine; Fentanyl; Furethidine; Heroin; Hydrocodone; Hydromorphinol; Hydromorphone; Hydroxypethidine; Isomethadone; Ketobemidone; Levallorphan; Lofentanil; Levomethorphan; Levomoramide; Levophenacylmorphan; Levorphanol; Meptazinol; Pethidine; Metazocine; Methadone; Methyldesorphine; Methyldihydromorphine; Methylphenidate; Methyl-3-sulphur fentanyl; Methyl-3-fentanyl; Metopon; Draw amine; Morpheridine; Morphine; Myrophine; Nalbuphine; Papaverine; Nicomorphine; Norlevorphanol; Normethadone; Nalorphine; Normorphine; Nicocodine; Buddhist nun's paracodin; Nicomorphine; Noracymethadol; Norcodeine; Norpipanone; Opium; Oxycodone; Oxymorphone; Narsco; Phenadoxone; Phenoperidine; Promedol; Properidine; Propiram; The third oxygen sweet smell; To the fluorine fentanyl; Pentazocine; Pethidine; Phenampromid; Phenazocine; Phenomorphan; Phenoperidine; Pholcodine; Piminodine; Pirinitramide; Proheptazine; Propranolol; Properidine; Racemethorphan; Racemoramide; Racemorphan; Remifentanil; Sufentanil; Thebacone; Thebaine; The sulphur fentanyl; Tilidine; Trimeperidine; C16H25NO2, its pharmaceutically acceptable salt class; The ester class; The hydrate class; Polymorph class and isomers class and composition thereof.

Medicament forms of the present invention can contain at least a analgesic bioactive substance (aAP) and at least a other the AP that is different from described aAP.The AP of these non-analgesias is preferably from organizing down: antidepressants class, amphetamine, appetite suppressant class, non-analgesia analgesic class, antuepileptic class, migraine material type, Kang Pajinsenshi disease material type, cough medicine class, antianxiety drugs class, barbiturates, benzodiazepines, hypnotic class, cathartic class, antipsychotic drug class, psychostimulant class, antipsychotic material type, tranquilizer class, analeptic class, anti-inflammatory agent class, its pharmaceutically acceptable salt class, esters, hydrate class, polymorph class and isomer class, and composition thereof.

Expect that available anti-inflammatory activity composition is as follows: ibuprofen, acetaminophen, diclofenac, naproxen, Benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pranoprofen, muroprofen, trioxaprofen, suprofen, amineoprofen, tiaprofenic acid, fluprofen, the bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, clofenamic acid, niflumic acid, tolfenamic acid, diflunisal, flufenisal, piroxicam, sudoxicam, isoxicam, its pharmaceutically acceptable salt class, esters, the hydrate class, polymorph class and isomer class, and composition thereof.

Or rather, employed analgesia AP is selected from down group: oxycodone hydrochloride, morphine sulfate, oxymorphone hydrochloride, dihydromorphinone hydrochloride, hydrochloric acid hydrogen are examined ketone and tramadol hydrochloride.

According to the present invention, the statement of " pharmaceutical preparation " promptly, comprises that also particularly veterinary drug is used or edible preparation according to broad understanding.

According to another feature, the present invention relates to a kind of preparation, it is characterized in that it comprises previously defined a large amount of microgranule (coating of AP or coated particle not; The optional viscosifier microgranule that comprises), as at least 500, preferred 1000-1000000, preferred especially 5000-500000 microgranule.

According to another feature, the present invention relates to a kind of pharmaceutical preparation, it contains the coated particle colony of a large amount of AP, and described colony is by its release dynamics and/or its contained AP and the differentiation of other colony.

Yet, it is emphasized that according to pharmaceutical preparation of the present invention extremely have value, its form can be the odd-numbered day oral dose that contains 500-500000 microgranule, it comprises the coated particle of described AP.This is not restriction the present invention.

Preferably, the pharmaceutical preparation that the present invention contains coated particle is the Galenic formula form, is selected from down group: tablet (preferred oral cavity or stomach decentralized), powder, suspending agent, syrup, reconfigurable suspension powder and capsule.

One with identical capsule, one and identical tablet or a kind of and same powder in mix at least two kinds of AP coated particle that release dynamics is different, also in frame feature of the present invention.

The microgranule that the invention still further relates to above-mentioned coating is in producing new pharmaceutical formulation, and especially (unrestricted) is used for the treatment of the application in the pharmaceutical preparation of pain.

The invention still further relates to a kind of Therapeutic Method, it is characterized in that, the previously defined pharmaceutical preparation of patient is given in administration.

The invention still further relates to a kind of Therapeutic Method, it is characterized in that, take in previously defined pharmaceutical preparation according to set dosage.

The invention still further relates to a kind of method for the treatment of pain, it is characterized in that, the previously defined pharmaceutical preparation of patient is given in administration.

The invention still further relates to a kind of method for the treatment of pain, it is characterized in that, take in previously defined pharmaceutical preparation according to set dosage, wherein employed AP comprises a kind of analgesic at least, as analgesic.

The invention still further relates to a kind of method of resisting abuse AP, it is characterized in that, use previously defined medicament forms.

The invention still further relates to a kind of method of resisting abuse AP, it is characterized in that, in medicament forms, use is used to improve the AP coated particle that discharges described AP, and described microgranule has coatings (Ra), and it guarantees to improve the described AP of release and make described AP coated particle can resist crushing simultaneously, to avoid abuse, and randomly contain at least a viscosifier (Vb), it can prevent to extract the described AP that contains in the described AP coated particle, to avoid abuse.

If have described coatings (Ra) and described viscosifier (Vb), they preferred previously defined those.

The present invention will more clearly describe by the following examples, but these embodiment only are illustrative, and it helps to be expressly understood the present invention, and embodiment and/or pattern and different advantages thereof that they are different are described.

Description of drawings

Fig. 1 represent the stripping curve of microgranule in external reference test (stripping D% is as the function of time T) of embodiment 1 :-■-.

Fig. 2 represent the microgranule (■-) of embodiment 1 and the microgranule of embodiment 2 ((a)----, (b)--zero--, (c)---●--, (d)--▲---) stripping curve in external reference test (stripping D% is as the function of time T).

Fig. 3 is the photo with the capsule 's content of the embodiment 3 that observes under bore hole (A) and the optical microscope (B).

Fig. 4 represents the function of the release profiles (aAP weight % as time (hour) of microcapsule among the 0.1 N HCl) (embodiment 8)

Fig. 5 is the photo with the capsule 's content of the embodiment 9 that observes under bore hole (A) and the optical microscope (B).

Fig. 6 represent to crush among the embodiment 9 release profiles of microgranule (black triangle) or complete microgranule (closed square).

The specific embodiment

Reference dissolution test among the embodiment carries out according to the external dissolution test that is entitled as " dissolution test of peroral dosage form " in the European Pharmacopoeia the 5th edition: the II type dissolution test that carries out under the SINK condition, 37 ℃ of temperature, mixing speed 75rpm, medium are the 0.1 N HCl of 900ml.

Embodiment 1: oxycodone hydrochloride microgranule of the present invention

1600g oxycodone hydrochloride, 100g

EF (mixture of hydroxypropyl cellulose/Aqualon) and 12.052g water GPCG1 air fluid bed (

) in peplos on the cellulose bead (Asahi-Kasei) of 300g non-activity.The 450g granule reuse of gained is by 315g ethyl cellulose (Ethocel 20 Premium/DOW), 81g polyvidone (Plasdone PVP K29/32/ISP), 36g Oleum Ricini, 18g Cremophor RH 40 (the mixture coating that hydroxy stearic acid polyethyleneglycol glyceride/BASF) and 12.020g ethanol constitute.

Coating accounts for 50% of microgranule weight, and guarantees that the release of described active component is longer than about 4h, as shown in Figure 1.This release profiles is measured under the condition of reference dissolution test.

Embodiment 2: the oxycodone hydrochloride microgranule that crushing makes according to embodiment 1

200mg microgranule (that is, the dosage of oxycodone hydrochloride is 80mg) with distinct methods crushing embodiment 1 preparation of representing the different modes of may abusing:

(a) acutely press 2 minutes (～120 circle) with pestle and mortar (250ml),

(b) press 8 times with two spoons,

(c) with " LGS flour mill " tablet flour mill (the LGS health promoting product, USA),

(d) ground 30 seconds with coffee mill.

The release profiles of crushing microgranule as shown in Figure 2.This release profiles is measured under the condition of reference dissolution test.

According to f2 similar factors test (f2＞50), (industrial directory SUPAC-MR: improve the solid oral dosage form that discharges, the method for p.32) pointing out is calculated, and embodiment 1 (complete microgranule) is similar with the release profiles of embodiment 2 (crushing microgranule) according to FDA.

Therefore, crushing makes having little effect that oxycodone discharges from microgranule, even does not have effect.

Embodiment 3: the outward appearance of the capsular content of the present invention

The 200mg microgranule (that is, the dosage of oxycodone hydrochloride is 80mg) and the following viscosifier of embodiment 1 preparation mix: prescreening is to the 90mg of 100-600 μ m

HF (hydroxypropyl cellulose/Aqualon), 20mg PolyOx WSR 303 Sentry (poly(ethylene oxide)/Dow) and 20mgXantural 180 (xanthan gum/cpKelco).The gelatine capsule of all packing into then No. 0.

Fig. 3 represents the photo with the capsule 's content of observing under bore hole (A) and the optical microscope (B).

Shown in Fig. 3 (A) that bore hole is observed, the microgranule of active component and the microgranule of viscosifier:

-can't distinguish;

-can't separate by sieve method.

In the photo of Fig. 3 that observes under optical microscope (B), have only two groups of tangible granule colonies: one group is the spherical particle of oxycodone hydrochloride and the microgranule of two kinds of viscosifier, and another group is the rod shaped particles of the 3rd kind of viscosifier.Because these particulate sizes very little (about 0.2mm), they can not be separated from each other.

Embodiment 4: the test of extracting form of the present invention with syringe

The 200mg microgranule (that is, the dosage of oxycodone hydrochloride is 80mg) of embodiment 1 preparation and prescreening are to the 90mg of 100-600 μ m

HF (hydroxypropyl cellulose/Aqualon), 20mgPolyOx WSR 303 Sentry (poly(ethylene oxide)/Dow) and 20mg Xantural 180 (xanthan gum/cpKelco) mix.The gelatine capsule of all packing into then No. 0.

Open described capsule, content is crushed in the mode of embodiment 2 (a) with pestle and mortar, then under room temperature or in the oil bath and 2.5ml extracting solution mixing 10min.By cotton shape hair solution is drawn in the syringe (having the 18G syringe needle) of 2.5ml as filter.Analyze the amount of the oxycodone hydrochloride that extracts with HPLC or UV, as shown in table 1.

Observe extraction ratio low (＜20%), this is enough to stop potential abuse.

Embodiment 5: the test of extracting form of the present invention with syringe

The 200mg microgranule (that is, the dosage of oxycodone hydrochloride is 80mg) of embodiment 1 preparation and 150mg Klucel HXF (hydroxypropyl cellulose/Aqualon), 50mg PolyOx WSR 303 Sentry (poly(ethylene oxide)/Dow) and 30mg Carbopol 971P (carbomer/BF Goodrich) mixing.The gelatine capsule of mixture being packed into No. 00 then.

Open described capsule, content is crushed in the mode of embodiment 2 (a) with pestle and mortar, then under room temperature or in the oil bath and 10ml extracting solution mixing 10min.By cotton shape hair solution is drawn in the syringe (having the 18G syringe needle) of 10ml as filter.Analyze the amount of the oxycodone hydrochloride that extracts with HPLC or UV, as shown in table 2.

Observe extraction ratio low (＜20%), this is enough to stop potential abuse.

Embodiment 6: the test of extracting form of the present invention with syringe

150g Klucel HXF (hydroxypropyl cellulose/Aqualon), 50g PolyOx WSR 303Sentry (polyoxyethylene/Dow), 30g Carbopol 971P (carbomer/BF Goodrich) and 10g polyvidone (Plasdone PVP K29/32/ISP) wet granulation in the MiPro instrument.Granule is by the sieve of 100-600 μ m.

250mg gained granule is joined in the 200mg microgranule that embodiment 1 makes (that is, the dosage of oxycodone hydrochloride is 80mg).All pack into then in No. 0 gelatine capsule.Open described capsule, content is crushed in the mode of embodiment 2 (a) with pestle and mortar, then under room temperature or in the oil bath and 10ml extracting solution mixing 10min.By cotton shape hair solution is drawn in the syringe (having the 18G syringe needle) of 10ml as filter.Analyze the amount of the oxycodone hydrochloride that extracts with HPLC or UV, as shown in table 3.

Observe extraction ratio low (＜20%), this is enough to stop potential abuse.

Embodiment 7: prepare tablet of the present invention

(((xanthan gum/cpKelco), 100g lactose (Tablettose/Meggle GmbH), 10g magnesium stearate (Brenntag AG) and 30g cross-linking sodium carboxymethyl cellulose (Ac-Di-Sol/FMCBipolymer) mix for polyoxyethylene/Dow), 20g Xanthural180 for hydroxypropyl cellulose/Aqualon), 20g PolyOx WSR 303 Sentry for 200g microgranule that embodiment 1 is made and 90g Klucel HF.

Prepare 470mg tablet (that is, the dosage of oxycodone hydrochloride is 80mg) with the reciprocating type tablet machine of Korsch.

The gained tablet is crushed in the mode of embodiment 2 (a) with pestle and mortar, then under room temperature or in the oil bath and 2.5ml extracting solution mixing 10min.By cotton shape hair solution is drawn in the syringe (having the 18G syringe needle) of 2.5ml as filter.Analyze the amount of the oxycodone hydrochloride that extracts with HPLC or UV, as shown in table 4.

Observe extraction ratio low (＜20%), this is enough to stop potential abuse.

Embodiment 8: oxycodone hydrochloride microgranule of the present invention

Step 1: granulate

With 1615g oxycodone and 85g polyvidone ( K29-32/ISP) be scattered in and contain in 2052g water and the alcoholic acid mixture of 1105g.This solution sprays on the 300g cellulose balls (Asahi-Kasei) in Glatt GPCG1 air fluid bed.

Step 2: the microgranule of anti-crushing

315g ethyl cellulose (Ethocel 20 Premium/Dow), 81g polyvidone (PlasdoneK29-32/ISP), 18g hydroxy stearic acid polyethyleneglycol glyceride (Cremophor RH40/BASF) and 36g Oleum Ricini (Garbit huilerie) are dissolved in the mixture of being made up of 3105g acetone and 2070g isopropyl alcohol.This solution spraying is to 450g granule (preparation in the step 1).

Coating accounts for 50% of microgranule weight, and guarantees that described active component is according to release shown in Figure 4.This release profiles is measured under the condition of reference dissolution test.

Embodiment 9: the capsular content of the present invention

The microgranule of 230mg embodiment 8 step 2 gained, 100mg crushing and the AmberliteIR69F (kayexalate) that sieves, Polyox WSR 303 Sentry (polyoxyethylene), 3.8mg magnesium stearate and 1.9mg Aerosil 200 (silica sol) that 70mg sieves be encased in No. 0 the gelatine capsule.

As shown in Figure 5, observe the microgranule of active component and the microgranule of viscosifier down with bore hole (A) with at optical microscope (B):

-can't distinguish;

-can't separate by sieve method.

Embodiment 10: crushing is according to the capsular content of embodiment 9 preparations

The capsule 's content that makes among the embodiment 9 was pressed 2 minutes with pestle and mortar.

The release profiles of crushing back microgranule as shown in Figure 6.This release profiles is measured under the condition of reference dissolution test.

The release profiles of complete sum crushing product is similar.Therefore, crushing makes having little effect that oxycodone discharges from microgranule, even does not have effect.

Embodiment 11: the test of extracting the capsular content for preparing according to embodiment 9 with syringe

Open the capsule according to embodiment 9 preparation, content was pressed 2 minutes with pestle and mortar, then (B) and 2.5ml extracting solution mixing 10min in (A) or the oil bath under room temperature.By cotton shape hair solution is drawn in the syringe (having 18G or 27G syringe needle) of 2.5ml as filter.Analyze the amount of the oxycodone hydrochloride that extracts with HPLC or UV, shown in table 5 and table 6.

Observe extraction ratio low (＜20%), this is enough to stop potential abuse.

Embodiment 12: will extract the test in the beverage according to the capsular content of embodiment 9 preparations

Open the capsule according to embodiment 9 preparations, content was pressed 2 minutes with pestle and mortar, and 100ml non-alcoholic beverages or the 50ml alcoholic beverage with following table mixes then:

Get the solution of gained, analyze the amount of the oxycodone hydrochloride that extracts with HPLC or UV, as shown in table 7.

It is low to observe extraction ratio, even long-time the extraction, extraction ratio is still low, and this is enough to stop potential abuse.

Table 1 (embodiment 4)

Table 2 (embodiment 5)

Table 3 (embodiment 6)

Table 4 (embodiment 7)

Table 5: with 2.5ml AP that syringe extracts amount (%) (embodiment 11) of being furnished with the 27G syringe needle

Table 6: with 2.5ml AP that syringe extracts amount (%) (embodiment 11) of being furnished with the 18G syringe needle

Table 7: AP that different beverage extracts amount (%) is as the function (embodiment 12) of time

Claims (56)

1. Peroral solid dosage form medicament forms is characterized in that:

-it comprises anti-abuse measure,

-be contained in the microgranule of coating to its contained AP of small part, discharge described AP to improve, and

-described AP coated particle has coatings (Ra), and it makes described AP coated particle can resist crushing when guaranteeing to improve the described AP of release, to avoid abuse.

2. medicament forms as claimed in claim 1 is characterized in that, it comprises at least a viscosifier (Vb), and it can prevent to extract and be used for improving the contained AP of described AP coated particle that discharges described AP, to avoid abuse.

3. medicament forms as claimed in claim 1 or 2 is characterized in that, it comprises at least a sequestering agent (Q) that can form complex in solution with described AP.

4. as claim 1,2 or 3 described medicament forms, it is characterized in that the design of described coatings (Ra) is: under the situation of crushing, the improvement that it can be maintained until AP described in the described coated particle of small part discharges.

5. as the described medicament forms of any one claim of front, it is characterized in that, the design of described coatings (Ra) is: under the situation of crushing, it can keep at least 40%, preferably at least 60%, preferred at least 80% improvement that is used to improve the described coated particle that discharges described AP discharges especially.

6. as the described medicament forms of any one claim of front, it is characterized in that described coatings (Ra) comprising:

(A1) at least a in the intestines and stomach liquid undissolvable film forming (being total to) polymer (A1);

(A2) at least a can dissolved (being total to) polymer (A2) in the intestines and stomach liquid;

(A3) at least a plasticizer (A3);

(A4) optional at least a surfactant and/or lubricant and/or mineral and/or organic filler (A4).

7. medicament forms as claimed in claim 6 is characterized in that, described coatings (Ra) comprises (based on the weight % of coating gross weight):

10≤A1≤90, preferred 15≤A1≤80, more preferably 60≤A1≤80;

5≤A2≤50, preferred 10≤A2≤40, more preferably 10≤A2≤25;

1≤A3≤30, preferred 2≤A3≤20, more preferably 5≤A3≤15;

0≤A4≤40, preferred 0≤A4≤30, more preferably 0≤A4≤20.

8. as claim 6 or 7 described medicament forms, wherein,

(A1) be selected from down group:

-water-insoluble cellulose derivative class, preferred, ethyl and/or cellulose acetate,

-acrylate copolymer class, copolymer as (methyl) acrylic acid and alkyl (as methyl) ester, acrylic acid and the copolymer (preferred at least a acrylic acid alkyl (methyl) ester and the muriatic copolymer of trimethyl ammonium ethyl-methyl acrylate) that has the methacrylate of at least one quaternary ammonium group, more precisely, the trade mark of this launch is

RS and/or RL,

-polyvinyl acetate esters,

-and composition thereof;

(A2) be selected from down group:

-nitrogenous (being total to) polymer class, preferably from following subgroup: polyacrylamide, poly-N-vinyl amide-type, polyvinyl pyrrolidone (PVP) class and poly-N-vinyl lactam class,

-water-soluble cellulose derivative class,

-polyvinyl alcohols (PVA),

-polyalkylene oxide class, preferred poly(ethylene oxide) class (PEO),

-polyethylene glycols (PEG),

-and composition thereof;

(A3) be selected from down group:

-cetyl alkoxide,

-glycerol and esters thereof, preferably from following subgroup: acetylizad glyceride type, glyceryl monostearate, glyceryl triacetate and tributyrin,

-phthalate, preferably from following subgroup: dibutyl phthalate, diethyl phthalate, dimethyl phthalate, dioctyl phthalate,

-citric acid ester type, preferably from following subgroup: acetyl tributyl citrate, acetyl triethyl citrate, tributyl citrate, triethyl citrate,

-sebacic acid ester is preferably from following subgroup: ethyl sebacate, dibutyl sebacate

-adipic acid esters,

-Azelaic Acid esters,

-benzoates,

-plant oil,

-fumaric acid esters, preferred DEF,

-malic acid esters, the preferably apple diethyl phthalate,

-oxalic acid ester, preferred ethyl oxalate,

-succinic acid esters, preferred dibutyl succinate,

-butyric acid ester,

-cetyl alkoxide,

-salicylic acid,

-glyceryl triacetate,

-malonic acid esters, preferred diethyl malonate,

-Oleum Ricini (preferred especially),

-and composition thereof;

(A4) be selected from down group:

-anion surfactant class, preferably from following subgroup: the alkali metal of fatty acid or alkaline-earth metal salt, preferred stearic acid of described fatty acid and/or oleic acid,

-and/or the nonionic surfactant class, preferably from following subgroup:

The oils of-polyethoxylated, the castor oil hydrogenated of preferred polyethoxylated,

-polyoxyethylene/polyoxypropylene copolymer analog,

The Arlacels of-polyethoxylated,

The castor oil derivative class of-polyethoxylated,

-stearates, preferred calcium stearate, magnesium, aluminum or zinc,

-stearoyl-fumarate salt, preferred sodium stearyl fumarate,

-Glyceryl Behenate,

-Pulvis Talci,

-silica sol,

-titanium oxide, magnesium oxide,

-bentonite,

-microcrystalline Cellulose,

-Kaolin,

-aluminium silicate,

-and composition thereof.

9. as the described medicament forms of any one claim of front, it is characterized in that, represent with the % dry weight, the ratio Tp that described coatings (Ra) accounts for the coated particle gross weight is: Tp 〉=15, preferred 30-60, preferred especially 40-60, very particularly preferably 45-55 or about 50.

10. as the described medicament forms of any one claim of front, it is characterized in that the average diameter of described AP coated particle is less than or equal to 1000 μ m, preferred 50-800 μ m, more preferably 100-600 μ m, and 100-300 μ m very particularly preferably.

11. as the described medicament forms of any one claim of front, it is characterized in that, the outer coating that is used for improving the coated particle that discharges described AP designs by this way: in the production of tablet, it helps to be maintained until the improvement release that small part is used to improve the described AP coated particle that discharges described AP, described outer coating is 40 ℃-120 ℃ by at least a fusing point, and preferred 45 ℃-100 ℃ deformable organic principle constitutes.

12. medicament forms as claimed in claim 11 is characterized in that, the weight of described outer coating is the AP 5-50% of coated particle gross weight dry weight again, preferred 10-30%, more preferably from about 20%.

13. as claim 2 and optional as the described medicament forms of any one other claim of front, it is characterized in that, described at least a viscosifier (Vb) are selected from those that are dissolved at least a following solvent: water, alcohols, ketone and composition thereof, described viscosifier can improve the viscosity of extracting solution, to stop abuse, especially injection is abused.

14. medicament forms as claimed in claim 13 is characterized in that, described viscosifier (Vb) are selected from following group of polymer class:

-polyacrylic and derivant thereof, and/or

-polyalkylene glycols (as Polyethylene Glycol), and/or

-polyoxy olefines (as the poly(ethylene oxide) class), and/or

-polyvinylpyrrolidone class, and/or

-gelatin class, and/or

-polysaccharide, preferably from following subgroup: sodium alginate, pectin class, guar gum class, xanthan gum class, carrageenan class, gellan gum class and cellulose derivative class (as hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl-cellulose, carboxymethyl cellulose),

-and composition thereof.

15., it is characterized in that described viscosifier (Vb) are high molecular weight peos as claim 13 or 14 described medicament forms, be 1,000,000 g/mol-800, ten thousand g/mol as molecular weight, as 2,000,000,5,000,000 or 7,000,000 g/mol.

16., it is characterized in that at least a viscosifier (Vb) are present in as any one described medicament forms of claim 13-15:

In-the microgranule and/or on the microgranule,

-and/or all or part of described AP microgranule on outer coating in,

-and/or exist with free state, that is, neither be included in and also can't help its support in the microgranule.

17. as any one described medicament forms of claim 13-16, it is characterized in that, the viscosity value of the described liquid that described viscosifier (Vb) can may be used to extract in the extraction volume of 2.5ml increases to more than or equal to 100mPa.s, to catch the AP that is extracted in resisting medium.

18. as any one described medicament forms of claim 13-17, it is characterized in that, to the form of the described viscosifier of small part (Vb) be can not with the described coating or the microgranule of the AP separation of particles of coating not.

19. as claim 3 and optional as the described medicament forms of any one other claim of front, it is characterized in that described sequestering agent Q comprises a kind of salt, described salt contains can be in solution and the ion of the AP salt formation complex of described extraction.

20. medicament forms as claimed in claim 19, wherein, the ion of described sequestering agent Q is the organic ion opposite with the ion polarity of AP described in the solution, and it is in solution and the AP salt formation complex of described extraction.

21. as claim 19 or 20 described medicament forms, wherein, described sequestering agent Q is present in first phase of separating mutually with at least a second, described second contains at least a AP salt mutually.

22. as any one described medicament forms of claim 19-21, it comprises the microgranule of AP salt and the microgranule of sequestering agent Q.

23. medicament forms as claimed in claim 22, wherein, described microgranule has similar distribution of sizes, similar density, and can't separate with sieve method.

24. medicament forms as claimed in claim 20, wherein, the described opposite ion of ion polarity with AP described in the solution is organic anion.

25. as any one described medicament forms of claim 19-23, wherein, described sequestering agent Q contains a kind of salt, is selected from down group:

-organic anion salt is as sodium lauryl sulphate or docusate sodium;

-anionic polymer class, as (methyl) acrylic copolymer class (as

S and

L), cross linked polyacrylate (as Carbopol), carboxymethyl cellulose and derivatives class, cross-linked carboxymethyl cellulose and derivatives class thereof and other polysaccharide (as alginate, xanthan gum or arabic gum) and Polyethylene Glycol alginic acid/(sulfonic acid) ester;

-unit price or multivalence salt are as glucuronic acid salt, citric acid salt, acetic acid salt, carbonate, gluconic acid salt, succinic acid salt, phosphoric acid salt, phosphoglycerol salt, lactates, trisilicate class, fumaric acid salt.Adipic acid salt, benzoate, salicylic acid salt, tartrates, sulfonamides and acetyl Sulfonates;

-saponified fatty acid is as acetic acid, succinic acid, citric acid, stearic acid and Palmic acid salt and self emulsifying glyceryl monooleate class;

-polyamino acid class, protein-based or polypeptide class are as albumin class, casein class, globulin class and enzyme;

-and composition thereof.

26. medicament forms as claimed in claim 20, wherein, the described opposite ion of ion polarity with AP described in the solution is organic metal cation or its mixture.

27. as any one described medicament forms of claim 19-23, wherein, described sequestering agent Q contains a kind of salt, is selected from down group:

-cation salt, as the cation salt of metal Ca, Fe, Mg or Zn, form is sulfacetamide Barbiturates, acetic acid salt, adipic acid salt, benzoate, carbonate, chloride-based, citric acid salt, fluoride class, fumaric acid salt, gluconic acid salt, glucuronic acid salt, phosphoglycerol salt, hydroxide class, iodates, iodide class, lactates, oxide-based, phosphoric acid salt, trisilicate class, salicylic acid salt, succinic acid salt, sulfonamides or tartrates;

-organic cation salt is as quaternary ammonium salt, especially trimethyl Tetra-n-decylammonium bromide or benzethonium chloride;

-cationic polymer class, as chitosan and (methyl) acrylic copolymer class (as

RS,

RL or

E);

-polyamino acid class, protein-based or polypeptide class;

-and composition thereof.

28. as any one described medicament forms of claim 19-23, wherein, described sequestering agent Q is a kind of salt of ion exchange resin, as described AP when being cationic, it is storng-acid cation exchange resin preferably, or when described AP was anionic, it is strong-base anion-exchange resin preferably.

29. medicament forms as claimed in claim 28, wherein, described sequestering agent Q is the derivant of styrene/divinyl benzene copolymer.

30. medicament forms as claimed in claim 28, wherein, described sequestering agent Q is the derivant of sulfonated styrene/divinyl benzene copolymer.

31. medicament forms as claimed in claim 28, wherein, described sequestering agent Q is the derivant that has the styrene/divinyl benzene copolymer of quaternary ammonium group class.

32. medicament forms as claimed in claim 28, wherein, described sequestering agent is a kind of of crosslinked methacrylic acid/divinyl benzene copolymer or its esters.

33. medicament forms as claimed in claim 28, wherein, described ion exchange resin is the phenol polyamines.

34. as any one described medicament forms of claim 19-33, wherein, described sequestering agent Q is selected from:

-organic anion salt is as dodecyl sodium sulfate or docusate sodium;

-organic cation salt, as quaternary ammonium salt, especially trimethyl myristyl ammonium bromide or benzethonium chloride;

-storng-acid cation exchange resin or strong-base anion-exchange resin depend on the polarity of described AP.

35. as any one described medicament forms of claim 19-34, wherein, described sequestering agent Q is selected from:

-as described AP when being cationic, be selected from storng-acid cation exchange resin class and composition thereof class;

-when described AP is anionic, be selected from strong-base anion-exchange resin class and composition thereof class.

36. as any one described medicament forms of claim 19-35, wherein, at least a sequestering agent Q is present in:

-do not contain in the microgranule of AP, and/or

-on microgranule, and/or

-exist with free state, that is, neither be included in and also can't help its support in the microgranule.

37. as any one described medicament forms of claim 19-36, wherein, the amount of sequestering agent is according to the ionic charge adjustment, with unit dosage forms in the AP of all or part of dosage that comprises compound.

38. as any one described medicament forms of claim 19-37, wherein, the form of described sequestering agent (Q) be can not with the described coating or the microgranule of the AP separation of particles of coating not.

39. as any one described medicament forms of claim 19-38, it comprises the microgranule of viscosifier V and/or the microgranule of sequestering agent Q, the microgranule of the microgranule of described viscosifier V and described sequestering agent Q is different from the microgranule of described AP.

40. as any one described medicament forms of claim 19-39, it comprises microgranule and the microgranule of viscosifier V and/or the microgranule of sequestering agent Q of AP, described microgranule has similar distribution of sizes and similar density, and can't be separated from each other by sieve method.

41. as the described medicament forms of any one claim of front, it is characterized in that it contains the excipient of at least a free state, that is, neither be included in and can't help also in the microgranule of AP that it supports that described excipient helps to resist the crushing of described AP coated particle.

42. medicament forms as claimed in claim 41 is characterized in that, the excipient of described free state is selected from down group:

-calcium stearate;

-glyceryl palmitostearate;

-magnesium oxide;

-polyalkylene glycols is as polyethylene glycols;

-polyvinyl alcohol;

-sodium benzoate;

-stearic acid;

-corn starch;

-Pulvis Talci;

-silica sol;

-zinc stearate, magnesium stearate;

-stearoyl-fumarate;

-and composition thereof.

43., it is characterized in that it can not change into can be by the dried forms that discharges described AP immediately of inhalation as the described medicament forms of any one claim of front.

44., it is characterized in that it can not change the injectable forms that discharges described AP immediately into as the described medicament forms of any one claim of front.

45., it is characterized in that it comprises the AP that discharges immediately and/or improves the AP that discharges as the described medicament forms of any one claim of front.

46. as the described medicament forms of any one claim of front, it is characterized in that, by chewing and/or crushing that to extract described AP be invalid.

47. as the described medicament forms of any one claim of front, it is characterized in that employed described AP belongs at least a of following active substance family: amphetamine, analgesic class, reduce medicine class, tranquilizer class, antidepressants class, antuepileptic class, migraine material type, Kang Pajinsenshi disease material type, cough medicine class, antianxiety drugs class, the barbiturates of appetite.Benzodiazepines, hypnotic class, cathartic class, antipsychotic drug class, opiates, psychostimulant class, psychotropic drugs class, tranquilizer class and analeptic class.

48., it is characterized in that employed described AP is selected from following chemical compound as the described medicament forms of any one claim of front:

Anileridine; Acetorphine; Acetyl group-alpha-methylfentanyl; The acetyl group Dihydrocodeine; Acetylmethadol; Alfentanil; Allylprodine; The U.S. sand of α-cetyl is many; α-Metro is fixed; Alphaprodine; α-Mei Shaduo; Alpha-methylfentanyl; Alpha-Methyl sulphur fentanyl; Alphaprodine; Anileridine; Atropine; Butorphanol; Benzethidine; Benzyl morphine; Beta-hydroxyfentanyl; β-methylol-3-fentanyl; The U.S. sand of β-cetyl is many; β-Metro is fixed; β-Mei Shaduo; β-Luoding; Bezitramide; Buprenorphine; Amidalgon; Clonitazene; Cyc; Hemp; Ketobemidone; Coca leaf; Codeine; Coca; Cocaine; Codoxime; Dezocine; Dimenoxadol; Amidalgon; Dipipanone; Desomorphine; Dextromoramide; Dextropropoxyphene; Diampromide; Diethylthiambutene; Difenoxin; Paracodin; DEE; Paramorphane; Dimenoxadol; Dimepheptanol; Dimethylthiambutene; Diphenoxylate; Dipipanone; Drotebanol; Eptazocine; Ethoheptazine; Ethylmethylthiambutene; Dionin; Etonitazene; Ecgonine; Ephedrine; Ethylmethylthiambutene; Dionin; Etonitazene; Etorphine; Etoxeridine; Fentanyl; Furethidine; Heroin; Hydrocodone; Hydromorphinol; Hydromorphone; Hydroxypethidine; Isomethadone; Ketobemidone; Levallorphan; Lofentanil; Levomethorphan; Levomoramide; Levophenacylmorphan; Levorphanol; Meptazinol; Pethidine; Metazocine; Methadone; Methyldesorphine; Methyldihydromorphine; Methylphenidate; Methyl-3-sulphur fentanyl; Methyl-3-fentanyl; Metopon; Draw amine; Morpheridine; Morphine; Myrophine; Nalbuphine; Papaverine; Nicomorphine; Norlevorphanol; Normethadone; Nalorphine; Normorphine; Nicocodine; Buddhist nun's paracodin; Nicomorphine; Noracymethadol; Norcodeine; Norlevorphanol; Normethadone; Normorphine; Norpipanone; Opium; Oxycodone; Oxymorphone; Narsco; Phenadoxone; Phenoperidine; Promedol; Properidine; Propiram; The third oxygen sweet smell; To the fluorine fentanyl; Pentazocine; Pethidine; Phenampromid; Phenazocine; Phenomorphan; Phenoperidine; Pholcodine; Piminodine; Pirinitramide; Proheptazine; Propranolol; Properidine; Propiram; Racemethorphan; Racemoramide; Racemorphan; Remifentanil; Sufentanil; Thebacone; Thebaine; The sulphur fentanyl; Tilidine; Trimeperidine; C16H25NO2, with and the pharmaceutically acceptable salt class; The ester class; The hydrate class; Polymorph class and isomers class and composition thereof class.

49., it is characterized in that employed described AP is selected from down group as the described medicament forms of any one claim of front: oxycodone hydrochloride, morphine sulfate, oxymorphone hydrochloride, dihydromorphinone hydrochloride, hydrochloric acid hydrogen are examined ketone and tramadol hydrochloride.

50., it is characterized in that it does not contain AP antagonist (class) as the described medicament forms of any one claim of front.

51., it is characterized in that it comprises at least a AP antagonist as any one described medicament forms of claim 1-49.

52. as the described medicament forms of any one claim of front, it comprises a large amount of AP coated particle colony, described colony is distinguished by its release dynamics and/or its contained AP and other colony.

53. can improve the application of AP coated particle in the new pharmaceutical preparation of preparation that discharges described AP, the claim of described AP coated particle such as front defines.

54. can improve the application of AP coated particle in the new pharmaceutical preparation that is used for the treatment of pain of preparation that discharges described AP, described AP coated particle such as claim 1-52 define.

55. prevent to abuse the method for AP, it is characterized in that it has used the medicament forms according to any one definition of claim 1-52 basically.

56. the method for antagonism abuse AP, it is characterized in that, this method is to be used to improve the AP coated particle that discharges described AP basically in medicament forms, described microgranule has coatings (Ra), it guarantees to improve release AP and make described AP coated particle can resist crushing simultaneously, to avoid abuse, and randomly use at least a viscosifier (Vb), it can stop and extracts the described AP that contains in the described AP coated particle, avoiding abuse, and randomly uses at least a sequestering agent (Q), it can stop to extract and is used for improving the described AP that the AP coated particle that discharges described AP contains, to avoid abuse, described coatings (Ra), described viscosifier (Vb), if present, and described sequestering agent (Q), if present, its such as among the claim 1-52 definition.

Images