MXPA95004645A - Delivery of system (s) of release control - Google Patents

Abstract

The present invention relates to a method of preparing fast-dissolving edible units having a controlled release system, comprising: subjecting a feedstock containing a carrier material or flow-by-run processing to provide a stress-shaped matrix uncured shear; shredding said matrix in an uncured shear form; mixing said untreated, shredded shear form matrix and a controlled release system comprising a composition for making an active ingredient available to a host biological system with components selected from the group consisting of an instant release component, a delayed release component, a sustained release component, and their combinations, molding the matrix mixture in an uncured shear form, and the controlled release system resulting from step prior to providing a dosage form unit that has bridging between the crystallized matrix material when curing, and curing said matrix in a shear form to produce a stable structure.

Description

DELIVERY OF CONTROLLED RELEASE SYSTEM (S) INVENTORS: GARRY. MYERS, GERALD E. BATTIST and RICHARD C. FUISZ, all citizens of the United States, residing respectively at 1353 Heritage Oak, Reston, Virginia 22091; 1588 North Village, Reston, Virginia 22094; and 9320 Cornwell Farm Road, Great Falls, Virginia 22066, all in the United States.

APPLICANT: FUISZ TECHNOLOGIES, LTD., A company of the United States, with address at 3810 Concorde Parkway, Suite 100, Chantilly, Virginia 22021, United States.

BACKGROUND OF THE INVENTION The present invention relates to controlled release systems and, in particular, to improved delivery of controlled release systems or systems. The convenience of administering a single dose of a drug that releases active ingredients in a controlled manner over a prolonged period of time, unlike the administration of several single doses at regular intervals, has long been recognized in the field of Pharmaceutical The advantage for the patient and the doctor of having consistent and uniform levels of medication in blood for a prolonged period of time is also recognized. The advantages of a variety of controlled release dosage forms are well known. Among the most important advantages are: (1) increased contact time for the drug to allow local activity in the stomach, intestine or other activity focus; (2) increased and more efficient absorption of drugs that have specific absorption sites; (3) the ability to reduce the number of doses per period of time; (4) the use of less total medication; (5) the minimization or elimination of local and / or systemic side effects; (6) the minimization of drug accumulation associated with chronic dosing; (7) increased efficiency and safety of treatment; (8) reduced fluctuation of the drug level; and (9) better compliance of the patient with respect to the overall administration of the condition. Additionally, many experts believe that the delivery of controlled-release drugs has many important non-therapeutic ramifications as well, including financial savings for the patient in terms of fewer days of lost work, reduced hospitalization and fewer doctor visits. It is known that certain design parameters are critical for the proper delivery of medicines. Typically, they are: (1) deliver the medication to the target tissue; (2) supplying the medication in the correct time pattern for a predetermined period of time; and (3) manufacture a delivery system that provides medication in the desired spatial and temporal pattern. Delivery systems of controlled release medications are intended to use these parameters to achieve the aforementioned advantages compared to conventional pharmaceutical dosage. It is used in the present "controlled release" to describe a method and composition for making an active ingredient available to the biological system of a host. Controlled release includes the use of instant release, delayed release, and sustained release. "Instant release" is a self-explanatory term in the sense that it refers to immediate release to the host's biosystem. "Delayed release" means that the active ingredient is not available to the host until a certain time delay after administration. (Doses are usually administered by oral ingestion in the context of the present invention, although other forms of administration are not excluded from the scope of the present invention.) "Sustained release" generally refers to the release of active ingredient with which the level of active ingredient available to the host is maintained at a certain level for a period of time. The method of performing each type of release can be varied. For example, the active ingredient can be physically and / or chemically associated with a surfactant, chelating agent, etc. Alternatively, the active ingredient can be masked by means of a coating, a laminate, etc. Regardless of the method of providing the desired release pattern, the present invention contemplates the delivery of a controlled release system utilizing one or more of the "release" methods and compositions. Moreover, the present invention can be an element of the method and / or the release composition, especially with respect to the instant release system (s). The patent and scientific literature is replete with various methods and formulations of sustained release (SR). For common methods of obtaining SR systems, see Sustained and Controlled Relay Drug Delivery Systems, Robinson, Joseph R., ed., Pp. 138-171, 1978, Marcel Dekker Inc., New York, New York. For example, it is known to carry polymeric capsules with a solid, liquid, suspension or gel containing a therapeutic agent that is slowly released by diffusion through the capsule walls. Heterogeneous matrices, for example compressed tablets, control the release of their therapeutic agents by diffusion, erosion of the matrix or a combination of both. Other SR systems focus on the manufacture of laminates of polymeric material and therapeutic agent that are then formed into a sandwich, based on diffusion or erosion to control the release of the therapeutic agent. A liquid-liquid system encapsulated in a viscous solution of syrup-type polymer has also been known to be useful for controlling the release of the therapeutic agent. Additionally, it is generally known that heterogeneous dispersions or solution of therapeutic agents in water-swellable hydrogel matrices are useful for controlling the release of the agent by slow swelling of the surface to the center of the matrix and subsequent diffusion of the agent from the swollen in water from the matrix. During the dissolution of a controlled release matrix tablet, the dosage form generally remains as a non-disintegrating, slowly eroding entity, from which it leaches the therapeutic agent, through a diffusion-controlled process . Conventional SR formulations are generally designed to release their activities for a prolonged period of time, usually 8 to 24 hours. Conventional SR formulations use paraffins or hydrophilic gums as the primary carriers of drug to prolong the release of the active ingredients. In conventional formulations of paraffin matrix tablets, the medicament is dispersed in the paraffin matrix in the melted state. Conventional paraffin and paraffin materials used in pharmaceutical formulations are carnauba wax, spermaceti wax, candelilla wax, cocoa butter, cetosteryl alcohol, beeswax, partially hydrogenated vegetable oils, ceresin, paraffin, myristyl alcohol, stearyl alcohol, cetyl alcohol and stearic acid. They are generally used in amounts of from about 10 to about 50% by weight of the total formulation. It has also been known that hydrophilic gums are reasonably effective as SR carriers for both high and low dose medications. Typical hydrophilic gums used as SR carrier materials are acacia, gelatin, tragacanth, V-gum, xanthan gum, carboxymethyl cellulose (CMC), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), and hydroxyethyl cellulose (HEC). Generally, these materials are present in amounts of about 10 to 50% by weight of the final formulation. USP (corn or potato) starch is commonly used as a component of conventional formulations of hard cap tablets or capsules. It generally works in conventional applications as a diluent or as a disintegrant in oral dosage forms. Starch paste is also often used as a binder in these products. Modified modified starches, such as the carboxymethyl starch currently marketed under the brand name Explotab or Primojel, are used both in tablets and in capsules as disintegrating agents. The literature discloses that native and modified starches are useful to promote the rapid release of drugs from solid oral dosage forms.

Additionally, native starch has been used in some cases as a binder to produce granulations of drug active substances. More recently, pre-gelatinized starch has been reported as useful as an SR matrix for theophylline formulations by Herman and Remon, "Modified Starches as Hydrophilic Matrices for Controlled Oral Delivery; III Evaluation of Sustained-Release Theophylline Formulations Based on Thermal Modified Starch Matrices in Dogs ", in International Journal of Pharmaceutics, 63 (1990) 201-205. In sustained release applications, various types of modified starch were mixed with anhydrous theophylline (60:40, weight / weight) as well as with silicon dioxide (Aerosil 200) and sodium benzoate. In previous publications, (International Journal of Pharmaceutics, vol 56 (1988) 145-153; 56 (1989) 51-63; and 56 (1989) 65-70), the authors discussed the use of both drum drying and extrusion. of native starches to obtain partial or total pre-gelatinization. Existing sustained release technologies generally involve relatively complicated formulations and manufacturing processes that are difficult and expensive to control accurately. For example, a well-known SR delivery system, Oros, marketed by Alza Corporation, involves laser punching through a tablet to create a passage for drug release from the tablet core. In all controlled release technologies it is desirable to be able to incorporate the active ingredient in its controlled release pattern into a single dosage unit without deterioration of the active ingredient. Moreover, the dosage unit must be able to deliver the system without interfering with its release pattern. Various methods have been designed to allow delivery of controlled release systems to a host without destruction of the delivery system during manufacturing, handling and sales. For example, controlled release systems have been provided in the form of beads or particles that are packaged in a gelatin capsule for oral dosing. This delivery method of the controlled release system prevents damage to the coating on the beads. In many cases it may be desirable to provide an oral dosage form as a tablet. However, when controlled release systems are incorporated in a chewable tablet, chewing the tablet can often break the coatings on the active ingredient. This results in unpredictable release and delivery rates to the host biosystem. Moreover, when controlled release components are incorporated into compression tablets, the extremely high pressure required to form the tablet can be expected to break the coatings. Consequently, the compression tablet delivery form is not usable, or extremely tough elastic linings are required to withstand the tablet's normal pressures. Furthermore, when controlled release active ingredients are incorporated into compression tablets, it can be difficult for many people to swallow such tablets. In addition, the dissolution of the high compression tablets is often small and erratic, resulting in localized hot spots of irritation in the digestive tract, where ultimately disintegration and release of the active ingredient occurs. The present invention overcomes the disadvantages of the prior art by offering simple and inexpensive means of incorporating a controlled release system into a dosage unit form that avoids the limitations normally associated with unit dosage delivery systems. SUMMARY OF THE INVENTION In a first embodiment of the present invention, there is provided a method of preparing a fast dissolving edible unit by mixing untreated shear form matrix and a controlled release system., molding the mixture to form a unit dosage form, and curing the matrix in shear form. Preferably, the shear-form matrix includes a crystallization enhancer and / or a coagulation aid. As used herein, the controlled release system may include a component selected from the group consisting of the instant release component (s), delayed release component (s), sustained release component (s), and combinations thereof. The instant release components may be provided by the simple inclusion of the active ingredient as an ingredient in the shear form matrix or may include a dispersion improver such as a surfactant, etc. A delayed release component is a component that has been treated by coating or otherwise to provide delayed bioavailability in the host. Such systems include, but are not limited to, polymer coatings, biodegradable coatings, etc. The sustained release components are components that have been designed to provide a constant release of dosage to the biosystem over a period of time. The present invention also includes their combinations. The shearing form matrix used to form dosage units according to the invention can be made with flavors and / or sweeteners included in the feedstock used to make the matrix. Flavors of natural and synthetic flavor liquids can be selected. Sweeteners are those materials that provide sweetness to the matrix in addition to the sweetness that is provided by the carrier material used to form the matrix, for example sucrose. The mixture can be molded by introducing it into a unit dosage cavity and plugging the mixture into it. The clogged mixture is then cured by subjecting it to ambient conditions of heat, humidity and pressure, which induce crystallization. For example, the unit can be cured by increasing the heat under substantially constant humidity conditions. The heat can be increased by subjecting the covered unit to microwave energy. Another type of additive that can be used in the present invention is an effervescent disintegrating agent. The term "disintegrating effervescent agent (s)" includes gas releasing compounds. Preferred effervescent agents release gas by means of chemical reactions that take place upon exposure of the effervescent agent of disintegration to saliva in the mouth. The agent or agents can be included in various forms in the units of the present invention. First, the agents can be incorporated into the matrix by mixing with the feedstock before processing by flow-through. Alternatively, all of the effervescent agent can be mixed with the matrix in a shear form after it has been produced by flow-through techniques. As still a third alternative, a part of the agent can be included in the feedstock which is processed by runoff while the other part of the agent can be incorporated after flow-by-run processing. In any case, the effervescent agent of disintegration provides controlled and rapid disintegration of the tablet when it is placed in the mouth and provides a positive organoleptic sensation by the effervescent action in the mouth. The texture, speed and disintegration sensation can be adapted especially for use by children in combination with the taking of one or more medicaments contemplated for use in the present invention. It is used herein to "plug or cap" to mean that the mixture is subjected to compression pressure of less than about 500 psi, preferably less than 250 psi, and most preferably from about 20 to about 100 psi. . Another method of identifying the compression force required to mold uncured matrix according to the present invention is by identifying the density resulting from the tamponade. The product of the present invention should be compressed in its uncured condition at a density no greater than about 1.2., preferably not greater than about 0.8, and most preferably not greater than about 0.65. In a more preferred embodiment, the density of the finished product is between 0.25 and 0.40. The product prepared according to the aforementioned method can be dissolved in the mouth of the consumer in less than 10 seconds. Usually, a product well made according to this process will dissolve in less than five seconds and, most preferably, less than three seconds. The most highly dissolvable units have been described as literally "exploding" in the mouth. In this first embodiment, the present invention also includes a composition for delivering a controlled release system where the controlled release system is incorporated into a crystal structure molded from saccharides. The composition also includes the "saccharide-based structure having a crystalline sugar, bi-dimensionally stabilized." Sugar is produced by forming a crystalline sugar framework from an external portion of an amorphous sugar mass in the form of shear stress, and subsequently converting the remaining portion of the mass into a substantially complete crystalline structure The product is preferably monodisperse and is also preferably microcris-talin For definitions related to "monodisperse" and "microcrystalline", as well as other relative definitions to the composition aspects of the present invention, reference is made to U.S. patent application Serial No. 08 / 133,669, filed October 7, 1993, which is incorporated herein by reference. The shear force can also include an additive that is co-crystallized in a crystalline product. The shear force is substantially in the form of a bar, and has two dimensions that lie in a plane in the cross section of the bar. The dimension that remains alone extends along a linear axis of the bar. Preferably, the monodisperse, structurally stabilized cross section does not exceed 50 μm, and preferably does not exceed 15 μm. Yet another manifestation of the first embodiment of the present invention is a method of administering an active ingredient to a human host. The method includes ingesting a rapidly dissolving edible unit prepared by the method of the present invention, i.e. mixing uncured matrix in shear form and an active ingredient, followed by casting a unit dosage and curing the matrix in shear form in the unit dosage form. The next step requires the host to retain the rapid dissolution unit in the oral cavity for a sufficient time to contact the unit with water while it is in the oral cavity. Finally, the human host introduces water into the oral cavity while the unit is retained there to improve the dissolution of the dosage unit. As a result of the process of the embodiment described herein, a rapidly dissolving dosage unit can be manufactured on a continuous basis and even prepared for shipping to the consumer in a single manufacturing line. The product can be made to provide the surprising sensation of exploding in the oral cavity when ingested by the consumer.

In a second embodiment of the present invention, there is provided a method of preparing an edible unit that rapidly disperses in the consumer's mouth. The method includes initiating the matrix crystallization in a shear form either before or after combining the matrix in the form of shear with a delivery system, as defined above, to form compact micro-particulates, capable of flowing . The combination, which includes at least partially crystallized shear form matrix, is then compacted to form the edible unit. Preferably, a crystallization / agglutination promoter is used to enhance the formation of flowable, compactable microparticles. The crystallization / agglutination promoter can be selected from the group consisting of an alcohol, such as ethanol, polyvinylpyrrolidone and a combination thereof. The promoter can also be a surfactant. Surfactants may be added to the feed material used to form the matrix. Alternatively, polydextrose can be used as a promoter by inclusion in the feed material. The shear-form matrix can be prepared by flow-through processing of feed material including a saccharide-based material as a carrier component. Sucrose is a preferred carrier, and can be combined with other carrier components based on saccharides, such as dextrose, and sugar alcohols, such as sorbitol, mannitol, etc. The feedstock may also include a crystallization improver such as a surfactant, for example Tweens, Spans, etc. In order to form the edible unit, an average compression force can be used without fear of affecting the disintegration capacity of the unit. The compression force does not need to exceed ten strong Cobb units ("SCU") and preferably does not exceed average compression forces of between six (6) and eight (8) SCUs. In some embodiments, a low compression force may also be used. In any case, the tablets produced according to the invention can be made of low density and easily disintegrated. Another method of identifying the compression force required to mold the uncured matrix according to the present invention is by identifying the density resulting from the compaction. The product of the present invention must be compacted at a density no greater than about 1.2, and preferably no greater than about 0.8. It has been found that the components of the delivery system are not "tied" with the components of the dosage unit. Consequently, pharmaceutical active ingredients are made available to biosystems to which they have been administered. Another type of additive that can be used in the present invention is an effervescent disintegrating agent. The term "disintegrating effervescent agent (s)" includes gases releasing compounds. Preferred effervescent agents give off gases by means of chemical reactions that take place when the effervescent agent of disintegration is exposed to saliva in the mouth. The agent or agents can be included in various forms in the units of the present invention. First, the agents can be incorporated into the matrix by mixing with the feedstock before processing by flow-through. Alternatively, all of the effervescent agent can be mixed with the matrix in a shear form after it has been produced by flow-through techniques. As yet a third possibility, a part of the agent can be included in the feedstock that is processed by runoff flow while the other part of the agent can be incorporated after the runoff flow processing. In any case, the effervescent disintegration agent provides rapid and controlled disintegration of the tablet when placed in the mouth and provides a positive organoleptic sensation by effervescent action in the mouth. The texture, speed and disintegration sensation may be adapted especially for use by children in combination with taking one or more of the medicaments contemplated for use in the present invention.

The present invention also includes a composition for delivering a controlled release delivery system where the active ingredient is incorporated into a crystal structure molded from saccharides. The composition also includes the saccharide-based structure having a bi-dimensionally stabilized crystalline sugar, as defined hereinbefore. Yet another manifestation of this embodiment is a method of administering an active ingredient to a human host. The method includes ingesting a rapidly dissolving edible unit prepared by the method of the present invention. The next step requires the host to retain the rapid dissolution unit in the oral cavity for a sufficient time to contact the unit with water while it is in the oral cavity. Finally, the human host introduces water into the oral cavity, while the unit is retained in it, to increase the dissolution of the dosage unit. In all embodiments of the present invention, another aspect includes reinforcing particles that inhibit the destruction of components of the controlled release system. The reinforcing particles have a size, a shape, and a hardness that are intended to withstand the destructive pressure of an accidental bite by the consumer. For example, the reinforcing particles may have a size that is up to 100 times larger than the controlled release components. The hardness is preferably greater than the hardness of the components of the controlled release system. The shape is preferably a shape that does not deviate from the texture and mouthfeel of the dosage unit during ingestion. As a result of the present invention, a rapidly dispersible edible unit can be manufactured for shipment and sale to consumers. The method of the present invention is such that manufacturing can proceed on a continuous commercial scale. A unit that is durable and can withstand handling associated with packaging and distribution can be formed. Moreover, the dispersion capacity of the unit is perceived as almost instantaneous. Consequently, the consumer does not experience unpleasant effects of unpleasant ingredients that remain in the oral cavity. Further, the component or components of the controlled release system can be made available to the host virtually without interference with the ingredients therein. These and other advantages of the present invention will be appreciated from the detailed description and examples set forth herein. The detailed description and the examples improve the understanding of the invention, but are not intended to limit the scope of the invention. Detailed Description of the Invention The present invention is a method of making edible units that rapidly disintegrate in the mouth of the consumer. The units produced according to the present invention disintegrate almost instantaneously. However, these units or tablets are capable of being manufactured so that they can be handled for packaging and distribution without deterioration of the integrity of the edible units. In the past, edible units such as tablets have been made primarily by compressing feed material under extremely high pressure in order to provide the necessary hardness for handling required during packing and dispensing. Accordingly, the prior art tablets thus produced are limited since their high density reduces the ability to cause them to be rapidly disintegrable in the mouth. The high density packing resulting from the high compression prevents disintegration and wetting of the inner portion of the tablet. This aspect of the prior art has been improved by the technology described in the United States patent application Serial No. 194, 682, filed on February 10, 1994. However, as a result of the present invention, a significant step forward has been taken in the field of the preparation of edible units that disintegrate very quickly in the mouth and that can deliver a controlled release system. In fact, the tablets produced by the present invention disintegrate in seconds. The product is prepared by a unique combination of processing steps. The present invention also includes products that are produced by the new process. The first step of the process of the first embodiment is to mix a matrix of uncured shear form and a controlled release system including an active ingredient, preparing to mold a unit dosage. "Cutting force form matrix" means in the present invention a matrix produced by subjecting a feed material containing a carrier material to flow-by-run processing. Flow-by-run processing can be accomplished in several ways. Heat due to runoff and shear stress are two processes that can be used. In the process of heat by runoff, the feed material is heated sufficiently to create an internal flow condition that allows part of the feed material to move at the sub-particle level with respect to the rest of the mass and exit with openings provided on the perimeter of a spinning head. The centrifugal force created in the spinning head expels the feed material that flows out of the head so that it is reformed with a changed structure. The force required to separate and discharge feed material capable of flowing is the centrifugal force that is produced by the spinning head. A preferred apparatus for implementing a heat runoff process is a "cotton candy" type manufacturing machine. The spinning machine used to achieve a run-off heat condition is a cotton candy machine such as the Econo-Floss model 3017, manufactured by Gold Medal Products Company of Cincinnati, Ohio, United States. Any other apparatus or physical process that provides similar conditions of force and temperature gradient can also be used. In the shear shear process, a shear force form matrix is formed by raising the temperature of the feed material including a non-solubilized carrier, such as a saccharide-based material until the carrier undergoes internal flow upon application of a shear force of fluids. The feedstock is advanced and ejected while in the condition of internal flow, and subjected to disruptive force of fluid shear to form multiple parts or masses having a morphology different from that of the original feedstock. The multiple masses are cooled substantially uniformly after contact with the shear force of fluid and allowed to continue in a free-flowing condition until solidified. The shear shear process can be carried out in an apparatus having means for increasing the temperature of an unsolubilized feed material and means for advancing it simultaneously for ejection. A twin-screw, multi-zone heating extruder can be used to increase the temperature of the non-solubilized feed material. A second element of the apparatus is an ejector that provides the feed material in a condition for shear stress. The ejector is in fluid communication with the means for increasing the temperature and is disposed at a point to receive the feed material while in the condition of internal flow. The ejector is preferably a nozzle that provides high pressure ejection of the feed material. See United States patent application Serial No. 965, 804, filed on October 23, 1992, entitled "Process for Making Shearform Matrix", of the same assignee as the present one, which is incorporated herein by reference. The feed material for producing a shear-form matrix includes a carrier material. The carrier material can be selected from materials capable of undergoing both physical and chemical changes associated with run-off flow processing. The materials useful as matrices can be selected from those carbohydrates that are capable of forming free-form agglomerates when processed. Preferred materials useful as matrices can be selected from classes such as "sugars". "Sugars" are those substances that are based on simple crystal structures of mono and disaccharides, that is, based on structures of sugars C5 and C6. "Sugars" include sucrose, fructose, lactose, maltose, and sugar alcohols such as sorbitol, mannitol, maltitol, etc. The preferred sugar option in the present invention is sucrose. Preferred combinations of sugars include sugars such as those used herein in combination with other mono, di, tri and polysaccharides up to 50% of the total amount, preferably up to 30%, and most preferably up to 20%. A shear-form product is used in the art of the present invention to obtain a new sugar product. A shear-shaped sugar product is a substantially amorphous sugar that results from subjecting sugar to sufficient heat and shear to transform crystalline sugar (usually granulated) into amorphous sugar without the use of a solution. Thus, in the sense of the present invention, a sugar product of shear stress is characterized as a sugar product that is the result of a non-solubilized sugar. It is the initial material to form the unique crystalline product of the present invention. Other carrier materials may be used, but preferably in combination with sugar, not as a total replacement. Maltodextrins are an example of other carrier materials. Maltodextrins include those carbohydrate mixtures that result from the hydrolysis of a saccharide feedstock that are described as solids having a dextrose equivalent (DE) up to and including 65. The feedstock may also include maltooligosaccharides produced by hydrolysis Selective corn starch followed by removal of high and low molecular weight compounds. The general description of maltooligosaccharides, as contemplated herein, appears in U.S. Patent Application Serial No. 07 / 847,595, filed March 5, 1992, also pending. Polydextrose is also contemplated for use as a carrier. Polydextrose is an essentially non-nutritive carbohydrate substitute, not sucrose. It can be prepared by means of glucose polymerization in the presence of polycarboxylic acid catalyst and polyols. Generally, it is known that polydextrose is commercially available in three forms: polydextrose A and polydextrose K, which are solid powders, and polydextrose N supplied as a 70% solution. Each of these products also contains some low molecular weight components, such as glucose, sorbitol and certain oligomers. With respect to polydextrose, the content of U.S. Patent Application Serial No. 07 / 881,612, filed May 12, 1992, is incorporated herein. As previously mentioned, each of the carriers is primarily used. in combination with sugars, and not as a total replacement. Other materials that can be incorporated into the feedstock to improve the shear-form matrix include flavors and sweeteners (other than the carrier itself). The flavors can be selected from natural and synthetic flavor liquids. An illustrative list of such agents includes volatile oils, synthetic flavor oils, aromatic flavors, oils, liquids, oleorese-sinas or extracts derived from plants, leaves, flowers, fruits, stems and their combinations. A non-limiting representative list of examples includes citrus oils such as lemon, orange, grape, lime and grapefruit and fruit essences that include apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot or other flavors of fruits. Other useful flavorings include aldehydes and esters such as benzaldehyde (cherry, almond), citral, ie alpha-citral (lemon, lime), neral, ie beta-citral (lemon, lime), decanal (orange, lemon), aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehyde C-12 (citrus fruits), tolyl aldehyde (cherry, almond), 2,6-dimethyloctanal (green fruits) and 2-dodecenal (citrus fruits, mandarin), their mixtures and the like. Sweeteners can be selected from the following non-limiting list: glucose (corn syrup), dextrose, invert sugar, fructose and their mixtures (when not used as carrier); saccharin and its various salts such as sodium salt; dipeptide sweeteners such as aspartame; compounds of dihydrochalcone, glycyrrhizin; Stevia Rebaudiana (stevioside); chlorinated derivatives of sucrose, such as sucralose; sugar alcohols such as sorbitol, mannitol, xylitol and the like. Also contemplated are hydrogenated starch hydrolysates and the synthetic sweetener 3,6-dihydro-6-methyl-1-1-1-, 2, 3-oxathiacin-4-one-2,2-bioxide, particularly the potassium salt (acesulfama). -K), and its sodium and calcium salts. Other sweeteners can also be used. Other ingredients in the present invention may also be used either during the mixing step, during the agglomeration step, or after the agglomeration step. Such ingredients are ingredients that are useful for tabletting such as glidants that adhere to the cohesive material and improve flow properties. The flow property is improved by reducing the interparticle friction that exists in another way. Glidants that can be used include starch, talc, magnesium and calcium stearate, zinc stearate, calcium dibasic phosphate, magnesium carbonate, magnesium oxide, calcium silicate and silica aerogels. Color additives can also be used in the preparation of tablets. Such color additives include colors for food, drugs and cosmetics (FD &C), colors for drugs and cosmetics (D &C), or external colors for drugs and cosmetics (Ext. D &C). These colors are pigments, their corresponding dyes, and certain natural dyes and derivatives. The dyes are absorbed in aluminum hydroxide. Still another embodiment of the present invention includes the use of an effervescent disintegrating agent. Its action can help to mask the objectionable taste of active ingredients such as vitamins, medicines and / or minerals, etc. It is generally believed that the positive organoleptic sensation achieved by effervescent action in the mouth, texture, speed and the sensation of disintegration, helps to mask undesirable flavor notes in the mouth. In preferred embodiments of the present invention, the effervescent disintegrating agent may include at least one acid selected from the group consisting of citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, acid anhydrides and acid salts and mixtures thereof, and at least one base selected from the group consisting of carbonate salts, bicarbonate salts and mixtures thereof. The term "effervescent" refers to those agents that give off gases, and the bubble or gas that generates the action is very often the result of the reaction of a source of soluble acid and the source of carbonate of alkali metal or carbonate. The reaction of these two general classes of compounds produces gaseous carbon dioxide upon contact with the water included in the saliva. Carbonate sources include dry solid carbonate and bicarbonate salts such as sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, magnesium carbonate and sodium sesquicarbonate, glycine sodium carbonate, L-lysine carbonate, carbonate arginine, and amorphous calcium carbonate. Although the food acids may be those indicated above, the acid anhydrides of the acids described above may also be used. The acid salts may also include sodium dihydrogen phosphate, disodium dihydrogen pyrophosphate, citrate acid salts and sodium acid sulfite. Another source of effervescence may be included and the present invention is not specifically limited to those specifically noted herein. Also as previously mentioned, the effervescent agent ingredients can be included in one of at least three ways. The first method includes incorporating all the effervescent agent into the feedstock that is used to form the product in the form of shear. The second way to incorporate an effervescent disintegrating agent is to include all of the agent as an additive that is mixed with a shear-form matrix after it is formed. The third method contemplates incorporating one portion of the disintegrating agent in the matrix in the form of shear and another portion of the disintegrating agent as an additive after the formation of the matrix material in the form of shear. The person skilled in the art will determine the best way to preserve the agent by its disintegrating and effervescent properties when ingested by the host. The shear force form matrix used in the process of the invention must be uncured before being molded. "Not cured" means amorphous or having a degree of amorphism that allows the formation of a dosage unit when curing. "Cure" means to transform the amorphous matrix into crystalline while it is bound enough to produce a stable structure. Curing can be improved by crystallization modifiers. Crystallization modifiers can be added to the feed material before processing by runoff flow, such modifiers including, but not limited to, surfactants (Spans and Tweens), dextrose, polyethylene glycol (PEG), polypropylene glycol (PPG), etc. These modifiers generally provide controlled acceleration of crystallization while the matrix is linked.

Crystallization modifiers improve the formation of a crystalline framework and the conversion of the remaining mass. "Improvement", as used with respect to the process of the present invention, primarily means acceleration of the process. The improvement also includes contribution to the strength of the crystal structure, and the predictability of the results. Other benefits, such as product of reduced size, are also achieved through the use of crystallization modifiers. Crystallization modifiers, which are preferably added to sugars before being processed to amorphous mass in a shear (or can be coated on sugar), are used to affect the rate or rate of crystallization. The water itself is a crystallization modifier, and is preferably included in the amorphous mass of sugar in the form of shear in an amount between about 0.5 and about 2.0%. Hydrophilic non-saccharide organic materials (NSHMs) are also used as crystallization modifiers. Although some NSHMs are surfactants, other materials may be used. The materials found to be the most effective have a hydrophilic to lipid balance (HLB) of 6 or greater, that is, they have the same degree of hydrophilicity as the surfactants characterized by the degree of HLB. Such materials include, but are not limited to, anionic, cationic, zwitterionic surfactants as well as neutral materials having an HLB of 6 or greater. Preferred NSHMs are hydrophilic materials having polyethylene oxide bonds. Also, preferred NSHMs have a molecular weight of at least 200, and preferably at least 400. Lecithin is a surfactant for use in the present invention. The lecithin can be included in the feed material in an amount of from about 0.25 to about 2.00% by weight. Other surfactants include, but are not limited to, Spans and Tweens, which are commercially available from ICI Americas Inc. Carbowax is still another crystallization modifier which is very useful in the present invention. Preferably, Tweens or combinations of surfactants are used to achieve the desired HLB. By using a surfactant, the process and the product of the present invention can be reproduced with a high degree of predictability. As additional crystallization modifiers that improve the process and the product of the present invention, all those additional crystallization modifiers within the scope of the claimed invention are identified herein. The process of the present invention requires mixing an additive with a matrix of uncured shearing form. When the shearing form matrix is in the form of a yarn, it is preferably first cut to reduce the volume of the product without compressing it. The additive may be any ingredient or ingredients necessary to supply the dosage unit with the required characteristics. The primary ingredients are medicinal substances. In a second embodiment of the present invention, the controlled delivery system is combined before or after initiating crystallization. "Initiating crystallization" means inducing crystallization in the present invention. The shear form matrix used in the present invention contains a substantial amount of amorphous sugar. Crystallization can be initiated in several ways. For example, crystallization promoters can be included in the feedstock used to make the matrix in shear form. Crystallization promoters include surfactants such as Tweens, Spans and polydextrose, and mixtures thereof. Crystallization can also be initiated by adding a crystallization agent to the matrix before or after combining with an additive. Therefore, initiating the crystallization in the present invention can occur before or after combining with the additive. "Combine" an additive with a shear-form matrix to form compactable micro-particulates, capable of flowing, means adding and mixing an additive before or after initiating the crystallization to form a medium consisting of micro-particulates. Micro-particulates are discrete entities that seem to "roll" easily or "flow" in response to the force of gravity and / or agitation. On a macroscopic scale, the micro-particulates appear as a mass or a medium capable of flowing. Consequently, the medium can be easily used in tabletting machinery without clogging and / or creating undue dust in the ambient atmosphere. The shear force form of the present invention is removed from processing and generally "cut" before being combined with the additive. The additive may be any ingredient or ingredients necessary to supply the edible unit with the required characteristics. Preferably, the primary ingredient of the additive is one or more medicinal substances. The medicinal substances that can be used in the present invention are varied. The medicinal substances can be encapsulated for controlled release. A non-limiting list of medicinal substances is as follows: antitussives, anti-histamines, decongestants, alkaloids, mineral supplements, laxatives, vitamins, anti-acids, ion-exchange resins, anti-cholesterol, anti-lipid agents, anti- arrhythmic, anti-pyretic, analgesic, appetite suppressants, expectorants, anti-anxiety agents, anti-ulcer agents, anti-inflammatory substances, coronary dilators, cerebral dilators, peripheral vasodilators, anti-infective, psychotropic, anti-manic, stimulants, gastrointestinal agents , sedatives, anti-diarrheal preparations, anti-anginal drugs, vasodilators, anti-hypertensive drugs, vasoconstrictors, migraine treatments, antibiotics, tranquilizers, anti-psychotics, anti-tumor drugs, anti-coagulants, anti-thrombotic, hypnotic, anti-emetics, anti-nauseants, anti-convulsants, neuromuscular drugs, hipe agents re hypoglycemics, thyroid and anti-thyroid preparations, diuretics, anti-spasms, uterine relaxants, mineral and nutritional additives, anti-obesity drugs, anabolic medications, erythropoietic drugs, anti-asthmatics, cough suppressants, mucolytics, anti-drugs -uricémicos, and their mixtures. Especially preferred active ingredients contemplated for use in the present invention are antacids, H2 antagonists and analgesics. For example, antacid dosages can be prepared using the calcium carbonate ingredients alone or in combination with magnesium hydroxide and / or aluminum hydroxide. Moreover, anti-acids can be used in combination with H2 antagonists. Analgesics include aspirin, acetaminophen and acetaminophen plus caffeine. Other preferred medicaments or other preferred active ingredients for use in the present invention include anti-diarrheals such as imodium AD, anti-histamines, anti-tresses, decongestants, vitamins and breath fresheners.

Also contemplated for use herein are anxiolytics such as Xanax; anti-psychotics such as Clozaril and Haldol; non-steroidal anti-inflammatories (NSAIDs) such as Voltaren and Lodine; anti-histamines such as Seldane, Hismanal, Relafen and Tavist; anti-emetics such as Kytril and Cesamet; bronchodilators such as Bentolin, Proventil; anti-depressants such as Prozac, Zoloft, and Paxil; anti-migraine agents such as Imigran; ACE inhibitors such as Vasotec, Capoten and Zeztril; anti-Alzheimer agents such as Nicergoline; and CaH antagonists such as Procardia, Adalat and Calan. Popular H2 antagonists contemplated for use in the present invention include cimetidine, ranitidine hydrochloride, famotidine, nizatidine, ebrotidine, mifentidine, roxatidine, pisatidine and aceroxatidine. Other ingredients that may be included are fragrances, tinctures, artificial and natural sweeteners, and other additives. For example, fillers may be used to increase the volume of the tablet. Some of the commonly used fillers are calcium sulfate, both di and tribasic, starch, calcium carbonate, microcrystalline cellulose, modified starches, lactose, sucrose, mannitol and sorbitol. Other ingredients include binders that contribute to the ease of training and overall quality of the tablet. The binders include starches, pre-gelatinized starches, gelatin, polyvinylpyrrolidone, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, pliviniloxazozolidone and polyvinyl alcohols. Lubricants can also be used to aid in packing and compaction. Lubricants may include, but are not limited to the following: magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, polyoxyethylene, monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, lauryl magnesium sulfate and light mineral oil. Further, disintegrants can be used to improve the dispersibility of the compressed tablet in an aqueous environment. Dispersants may include starch, alginic acid, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorph silicate, and microcrystalline cellulose. In view of the highly soluble nature of the product of the present invention, there is little need for disintegrants. Another useful ingredient for tabletting is the gliders that adhere to the cohesive material in order to improve the flow properties by reducing interparticle friction. Glidants that may be used include starch, talc, magnesium and calcium stearate, zinc stearate, calcium dibasic phosphate, magnesium carbonate, magnesium oxide, calcium silicate and silica aerogels.

Further, dispersion improvers can be used to improve the breaking capacity of the compressed tablet in an aqueous environment. Dispersants may include starch, alginic acid, polyvinyl pyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorph silicate, and microcrystalline cellulose as high HLB emulsifying surfactants. In view of the ease with which the product of the present invention disintegrates, there is little need for disintegrants. Color additives useful in the preparation of tablets include colors for food, medicine and cosmetics (FD &C), colors for medicines and cosmetics (D &C), or external colors for medicines and cosmetics (Ext. D &C). These colors are pigments, their corresponding dyes, and certain natural dyes and derivatives. The dyes are absorbed in aluminum hydroxide. In a preferred embodiment, the present invention is particularly useful in the preparation of antacid tablets. Antacids are conveniently provided in the form of a tablet capable of sucking to provide a convenient method of delivering the antacid to the consumer. The shape capable of sucking provides an advantage as the tablet is disintegrated into granules during the action of sucking and mixed with saliva before swallowing. This makes the antacid formulation of the tablet a suspension. One of the disadvantages of the antacid tablets of the prior art is that the mass of ingredients that reside in the mouth during and after sucking has an objectionable texture and taste. The present invention overcomes these disadvantages because the ingredients explode virtually in a solution. The texture is also significantly improved and the residence time is substantially reduced. The active ingredients antacids include, but are not limited to the following: aluminum hydroxide, dihydroxyaluminium aminoacetate, aminoacetic acid, aluminum phosphate, sodium dihydroxyaluminium carbonate, bicarbonate, bismuth aluminate, bismuth carbonate, bismuth subcarbonate, bismuth subgalate, bismuth subnitrate , calcium carbonate, calcium phosphate, citrate ion (acid or salt), aminoacetic acid, hydrous magnesium aluminate sulfate, magaldrate, magnesium aluminosilicate, magnesium carbonate, magnesium glycinate, magnesium hydroxide, magnesium oxide, trisilicate magnesium, milk solids, aluminum calcium phosphate pono-ordibase, tricalcium phosphate, potassium bicarbonate, sodium tartrate, sodium bicarbonate, magnesium aluminosilicates, acids and tartaric salts. After the controlled release system has been mixed with the matrix in an uncured shear form, the result of the mixture must be "molded" as a unit dosage form.

It is used herein to "mold" to mean to associate matrix material in an uncured (i.e., non-crystallized) shear form in a sufficiently narrow manner to provide bridging between the crystallized matrix material upon cure. Generally, this requires a sufficient source to provide intimate contact of the fibers before curing, followed by crystallization to form a continuous crystalline structure, bound through the entire tablet. Unlike conventional tableting that relies primarily on compression to provide the structure, the present process uses the curing process to help form the final product. Consequently, weak compressive forces can be used to mold the product. In a preferred embodiment, the compression required to mold uncured matrix material is referred to as "plugging". "Plugging" means compressing with less force than that required in compression tabletting, which is generally in the order of thousands of pounds per square inch (psi). The maximum pressure used in the present invention is only 500 psi, but in most cases it will never exceed about 250 psi, and in the most preferred embodiments, no more than 80 psi (ie, 40 to 80). psi). These lower pressures are called tamponade. Another method of measuring the compression force required to "mold" uncured matrix is by product density. The product of the present invention must be compressed in an uncured condition at a density not greater than about 1.20, preferably not greater than 0.8 and, most preferably, not greater than 0.65. While a method of the present invention requires extremely low pressures for molding, it is possible to mold directly into plastic product cavities that can be used as packaging for sales. Accordingly, the present invention includes the concept of molding matrix materials not clearly cured in product cavities such as plastic blister packing depressions. In the second embodiment, the present invention requires compacting the combination resulting from "combining" the controllable delivery delivery system and the shear force form matrix. "Compacting" means, in the present invention, pressing into an edible unit, i.e. a tablet, at a pressure generally greater than about 500 psi, but not necessarily as large as the normal tableting pressure, which is of the order of magnitude of thousands of psi (that is, at least about 1,000 psi). In a preferred embodiment where polydextrose (especially Poly Dex brand polydextrose, provided by A.E. Staley &Co.) has been included as a crystallization promoter, it has been found that a compaction pressure as low as 50 psi is effective. In all of the present cases, the micro-particulate medium that is being compacted includes a shear-shape matrix that has been at least partially crystallized. The combination of the shear force form matrix and the additive should be provided as compact micro-particulates, capable of flow. The micro-particulates are agglomerates of a type that includes the ingredients of the mixture, but which are relatively low density. The "micro-particulates" of the present invention are capable of withstanding a relatively high compaction force without experiencing an increase in density. The microparticles can then be compacted under a comparatively high compaction force to form a low density dosing unit having high structural integrity, high strength and excellent appearance. The microparticles are preferably formed by combining the mixture with a crystallization / agglutination promoter such as ethanol (preferably 200 degrees), polyvinylpyrrolidone, a combination thereof, as well as other agents that improve the formation of micro-particulates without increasing the density of the mixture. The micro-particulates that result from the previous step can then be compacted, for example to 6-8 SCUs (strong Cobb units), whereby a structurally resistant tablet can be formed that has an excellent appearance and can be handled without deterioration. of the surface or structure. After preparing the matrix in the form of shear stress and molding the uncured matrix, the product must be cured. "Cure" means to agglutinate and crystallize the matrix material substantially simultaneously. Curing is carried out by subjecting the product to sufficient heat and moisture to provide controlled crystallization. Controlled crystallization occurs when contact points of uncured matrix material become crystalline development points and crystallization of the material proceeds to provide crystalline structures. Agglutination occurs at the contact points, and the simultaneous crystalline development is such that the structural integrity is maintained. The "curing" process of the present invention involves a transformation from amorphous to crystalline state. The transformation must take place while the amorphous matrix of shear force remains linked. Moreover, curing requires the transformation to take place without collapsing the structural integrity of the matrix in its "shaped" condition. As the amorphous shear-form product is hygroscopic, this transformation can be difficult. When the points of contact between pieces of the matrix can become points of crystalline development during the curing, the structural integrity is established and maintained. One way to promote the occurrence of this phenomenon is to include crystallization enhancers, for example surfactants, any alcohol, polyethylene glycol, polypropylene glycol, etc. Without being limited by theory, it is believed that control of the propagation of crystalline development, as outlined above, is significantly improved by the use of crystallization enhancers. Prior to curing, the mixture of the shear-form matrix and the active ingredient is maintained at temperature and humidity below the glass transition temperature of the matrix material in shear form. Suitable conditions for curing may include environmental conditions of heat and humidity or modified environmental conditions. For example, it has been found that curing can be conducted at a temperature of 0 to 90 ° C at a relative humidity of 25 to 90%. In one case, it has been found that the curing will take place in 15 minutes at 40 ° C and 85% relative humidity. In other cases, it has been found that the optimum temperature range is 20 to 50 ° C. Microwave energy can be used to accelerate curing in a controlled manner. Generally, the crystallization is carried out in an environment where the tableting material is cured at a water content of less than 5% by weight, and preferably less than 1% by weight based on the weight of the tablet. In this way, the curing environment, for example chamber or enclosure, is maintained at a relative humidity that allows the admission of water to no more than 5%, and preferably less than 1%. It has been found that curing the product in a package cavity results in shrinkage of the tablet from the walls of the cavity. This aspect is particularly advantageous for the purposes of manufacturing individual dosage units since molding and curing can be carried out in the packaging used for commercial sales. As a result, several transfer steps can be eliminated. It has been found that the products prepared according to the present invention have densities from about 0.20 to about 0.90 g / cc2, and some preferred embodiments have densities from about 0.40 to about 0.65 g / cc2. Another ingredient that can be included in the matrix in the form of shear is a coadjuvant or agglutination agent. A binding agent is used to assist in the molding step and, in some cases, contributes to the dissolution capabilities of the finished product. The binding agents useful herein include some low transition glass materials. Some agents found to be useful include, but are not limited to, sorbitol, mannitol, lactose, etc. The binding agents are processed by flow-through with the carrier. The binding agents also help to keep the matrix material in place for curing. In some cases, portions of the binder become part of the matrix material. In the second embodiment of the present invention, a method of measuring the results of the present invention is the ability to make a low density product. The microparticles are capable of undergoing high pressure without reducing the density of the resulting product. Accordingly, the product prepared in accordance with the present invention, even after compaction under high pressure, will remain below 1.2 g / cc, and preferably below 0.8 g / cc. The pressure required to prepare tablets according to the present invention exceeds that generally required in the first embodiment described herein, but is less than that previously required with normal tabletting procedures (although some embodiments do not require compaction pressure. greater than the one indicated in the United States patent application Serial No. 08 / 259,258). As a result of the increase in pressure that can be used to form tablets according to the present invention, the strength of the product is increased, and the hardness of the surface is also increased. This results in a dosage unit that is capable of being manually handled and machine processed without surface degradation or structural integrity. The microparticles retain their individual integrity and disintegration lines are provided throughout the entire unit. Moreover, since the mass can be subjected to relatively high pressure compaction, the surface of the resulting dosage unit is smooth, and the strength of the tablet is relatively high. Therefore, the resulting units can be handled easily without deterioration of the surface appearance or destruction of the edible units. In the formation of the micro-particulates, the material preferably contains up to 5% water, and most preferably up to 1% water. The water can be provided by the water contained in the ingredients such as that carried in the sugars or binders. The water can also be provided in small amounts in the alcohol, such as in 200 degree alcohol which absorbs moisture rapidly and generally contains small amounts of moisture, for example up to 1% by weight. Additional moisture can be provided by the surrounding environment, such as the humidity of the air. It has been found that the present invention is suitable for the preparation of antacid tablets and tablets in which antacids are used as an ingredient to attenuate the acidic conditions of the body in order to help drugs that do not tolerate acidic conditions. In the case of the antacids themselves, the instant dispersion of the tablet in the mouth prevents the earthy residual taste of a conventional antacid tablet. In the case of ingredients that do not tolerate acidic conditions, it is desirable to include the antacids plus the "acid sensitive" pharmaceutical product in a dosage unit prepared according to the invention. For example, didanosine is an anti-viral agent that does not tolerate an acidic environment well. Accordingly, the use of didanosine in combination with an antacid such as calcium carbonate in the same drug delivery system is an ideal method of introducing the drug into the body. The present invention includes the combination of an "acid sensitive" ingredient and an antacid in a dosage unit. The shear force matrix material used in the following examples is an amorphous sugar. The "amorphous sugar", as used herein, means a sugar material that contains a high degree of amorphism, ie more than 50% by weight, and preferably more than 70% by weight of the sugar material is amorphous. EXAMPLE A controlled release system according to the present invention was prepared by preparing a shear-form matrix using a combination of 49.75% sucrose, 0.025% Tween 80 as a surfactant, 40% Cantab (a crystalline form of a product corn syrup with high DE, dextrose equivalent, from Penwest Foods Co., Cedar Rapids, Iowa, United States), and 10% D-xylose. The shear force form matrix was collected and shredded to a small consistent size and stored in an air-proof container and subsequently formulated for tableting.

The tablet formulation was prepared with 60% of yarn, as indicated above, 37% of medicine for the Contact brand catarrh, 0.55% aspartame, 0.5% of dye, 1% of Comprital HD5 (a product of polyethylene glycol behenate glycerol, from Gattefossé, Westwood, New Jersey, United States) and 0.50% flow agent Syloid 244 FP. The combination was mixed in a way that ensured that the drug was mixed substantially homogeneously with the other ingredients. The combination was then weighed in samples of 0.7 g and loaded in a press and tabletted by plugging at a pressure of 40 psi for approximately five seconds. The resulting tablets had a very uniform and attractive surface, and maintained good physical integrity. The tablets were sealed in a blister pack. The tablets crystallized in the package in a period of 24 hours. The tablets produced by the aforementioned process were rapidly dispersible in the oral cavity. The drug was also rapidly dispersed and it is believed that the process can be easily adapted to existing commercial tabletting drug facilities. Thus, although those currently considered to be the preferred embodiments of the present invention have been described, those skilled in the art will appreciate that other and additional modifications may be made without departing from the true spirit of the invention, and are intended to include all other modifications and changes as they fall within the scope of the invention, as indicated in the appended claims.

Claims (33)

1. CLAIMS 1. A method of preparing fast dissolving edible units having a controlled release system, comprising: mixing uncured shear form matrix and a controlled release system; molding a unit dosage form; and curing said matrix in the form of shear stress.
2. 2. The method of preparing fast-dissolving edible units according to claim 1, wherein said shear-shaped form matrix further comprises a crystallization improver or a binding agent.
3. The method of preparing fast dissolving edible units according to claim 1, wherein said molding comprises introducing the mixture resulting from the mixing step into a unit dosage cavity and plugging said mixture; optionally, wherein said plugging is carried out at a pressure of less than about 500 psi; and optionally, wherein said pressure is less than about 250 psi, preferably from about 20 to about 100 psi.
4. 4. The method of preparing fast dissolving edible units according to claim 1, wherein the curing comprises subjecting to environmental conditions of heat, humidity and pressure that induce crystallization; and optionally, wherein said heat is increased under substantially constant humidity conditions or by subjecting to microwave energy.
5. The method of preparing fast dissolving edible units according to claim 1, wherein said controlled release system comprises a component selected from the group consisting of an instant release component, a delayed release component, a sustained release component , and their combinations.
6. 6. The method of preparing fast dissolving edible units according to claim 5, wherein said controlled release system includes an active ingredient selected from the group consisting of anti-tussocks, anti-histamines, decongestants, alkaloids, mineral supplements, laxatives , vitamins, anti-acids, ion exchange resins, anti-cholesterol, anti-lipid agents, antiarrhythmics, anti-pyretics, analgesics, appetite suppressants, expectorants, anti-anxiety agents, anti-ulcer agents, anti-inflammatory substances , coronary dilators, cerebral dilators, peripheral vasodilators, anti-infective, psychotropic, anti-manic, stimulants, gastrointestinal agents, sedatives, anti-diarrheal preparations, anti-anginal drugs, vasodilators, anti-hypertensive drugs, vasoconstrictors, migraine, antibiotics, tranquilizers, anti-psychotic, anti-tumor drugs, anti icoagulants, anti-thrombotic, hypnotic, antiemetic, anti-nauseating, anti-convulsive, neuromuscular, hyperglycemic agents, thyroid and anti-thyroid preparations, diuretics, anti-spasms, uterine relaxants, mineral and nutritional additives, anti-drugs -obesity, anabolic medications, erythropoietic drugs, anti-asthmatics, cough suppressants, mucolytics, anti-uricémics, and their mixtures.
7. 7. A rapidly dissolving dosage unit having a controlled release system, said unit prepared by the method comprising: mixing matrix in an uncured shear form and a controlled release system; molding a unit dosage form; and curing said die in the form of shear stress; and optionally, wherein said controlled release system further comprises reinforcing particles having the size, shape and hardness which inhibit the destruction of components of said controlled release system in the presence of accidental chewing by a host.
8. The unit of claim 7, wherein said shear-shaped form matrix further comprises a crystallization enhancer or binder.
9. The unit of claim 7, wherein said molding comprises introducing the mixture resulting from the mixing step into a unit dosage cavity and plugging said mixture therein.; and optionally, wherein said plugging is carried out at a pressure of less than about 500 psi, preferably less than about 250 psi, and most preferably from about 20 to about 100 psi.
10. The unit of claim 7, wherein the curing comprises subjecting to environmental conditions of heat, humidity and pressure that induce crystallization; and optionally, wherein said heat is increased under substantially constant humidity conditions or by subjecting to microwave energy.
11. The unit of claim 7, wherein said controlled release system comprises a component selected from the group consisting of an instant release component, a sustained release component, a delayed release component, and combinations thereof.
12. The unit of claim 11, wherein said controlled release system includes an active ingredient selected from the group consisting of anti-tresses, anti-histamines, decongestants, alkaloids, mineral supplements, laxatives, vitamins, anti-acids, resins of ion exchange, anti-cholesterol, anti-lipid, anti-arrhythmic, anti-pyretic, analgesic, appetite suppressant, expectorant, anti-anxiety agents, anti-ulcer agents, anti-inflammatory substances, coronary dilators, dilators cerebral, peripheral vasodilators, anti-infective, psychotropic, anti-manic, stimulants, gastrointes-tíñales agents, sedatives, anti-diarrheal preparations, anti-anginal drugs, vasodilators, anti-hypertensive drugs, vasoconstrictors, migraine treatments, antibiotics, tranquilizers , anti-psychotic, anti-tumor drugs, anticoagulants, anti-thrombotic, hypnotic, anti -emetic, anti-nauseating, anti-convulsive, neuromuscular drugs, hyper and hypoglycemic agents, thyroid and anti-thyroid preparations, diuretics, anti-spasmodics, uterine relaxants, mineral and nutritional additives, anti-obesity drugs, anabolic medications, erythropoietic drugs , anti-asthmatics, cough suppressants, mucolytics, anti-uricémics, and their mixtures; and optionally, wherein said active ingredient comprises an antacid and a pharmaceutical ingredient that is adversely affected by an acidic environment.
13. 13. A composition for delivering a controlled release delivery system, comprising: a controlled release system; and a crystalline structure based on saccharides comprising a crystalline sugar stabilized and continuously bound in two-dimensional form, produced by means of i) forming a crystalline sugar framework from an external portion of amorphous sugar masses in the form of shear stress, ii) molding said masses to form a unit dosage, and iii) subsequently converting the remaining portion of said masses into a substantially complete crystalline structure which is continuously bound and stabilized, said active ingredient mixed with said masses before molding, whereby said active ingredient is incorporated into said crystalline structure based on saccharides.
14. The composition of claim 13, wherein said masses are bi-dimensionally monodisperse.
15. 15. The composition of claim 13, wherein said shear-form masses further comprise an additive, whereby said additive is co-crystallized in said crystalline product.
16. 16. The composition of claim 15, wherein said monodisperse stabilized masses are microcrystalline.
17. The composition of claim 15, wherein said amorphous shear-shaped product is substantially rod-shaped, said two dimensions lying in a cross-sectional plane of said bar and said third dimension extending along the linear axis of said bar; and optionally, wherein said structurally stabilized, monodisperse cross section does not exceed 50 μm, preferably does not exceed 10 μm.
18. 18. A method of administering a controlled release system to a human host, comprising: ingesting a rapidly dissolving edible unit prepared by the method comprising: i) mixing uncured matrix in shear form and a controlled release system , ii) molding a unit dosage form, and iii) curing said matrix in shear form; retaining said unit in the oral cavity for a sufficient time for said unit to make contact with water introduced into said oral cavity; and introducing water into said oral cavity while said unit is retained therein, thereby speeding up the dissolution of said unit significantly.
19. 19. A method of preparing rapidly dissolving edible units having a controlled release delivery system, comprising: a) initiating the crystallization of the matrix in a shear form; b) before or after initiating crystallization, combining a controlled release delivery system with said matrix in the form of shear to form micro-particle-two compactables, capable of flow; c) compacting the combination resulting from step "b", which includes at least one at least partially crystallized shear form, to form said unit; and optionally, d) incorporating an effervescent disintegrating agent into said unit.
20. The method of preparing fast dissolving edible units according to claim 19, wherein said combination further comprises subjecting said additive and said matrix to treatment with a crystallization / binder promoter; and optionally, wherein said promoter comprises an ingredient selected from the group consisting of an alcohol, polyvinyl pyrrolidone, and a combination thereof.
21. The method of preparing fast dissolving edible units according to claim 19, wherein a crystallization / binder promoter is incorporated in said matrix in shear form including said promoter in feedstock from which said matrix is formed; and optionally, wherein said promoter is a surfactant or a polydextrose.
22. The method of preparing fast dissolving edible units according to claim 19, wherein said controlled release system comprises a component selected from the group consisting of an instant release component, a delayed release component, a sustained release component , and their combinations; and optionally, wherein said controlled release system includes an active ingredient selected from the group consisting of anti-tresses, anti-histamines, decongestants, alkaloids, mineral supplements, laxatives, vitamins, antacids, ion-exchange resins, anti-cholelemy, anti-lipid, anti-arrhythmic, anti-pyretic, analgesic, appetite suppressant, expectorant, antianxiety agents, anti-ulcer agents, anti-inflammatory substances, coronary dilators, cerebral dilators, peripheral vasodilators, anti-infective, psychotropic , anti-manic, stimulants, gastrointestinal agents, sedatives, anti-diarrheal preparations, anti-anginal drugs, vasodilators, anti-hypertensive drugs, vasoconstrictors, migraine treatments, antibiotics, tranquilizers, anti-psychotics, anti-tumor drugs, anti- coagulants, antithrombotic, hypnotic, anti-emetic, anti-nauseant, anti-convulsants, neuromuscular drugs, hyper and hypoglycemic agents, thyroid and anti-thyroid preparations, diuretics, anti-spasms, uterine relaxants, mineral and nutritional additives, anti-obesity drugs, anabolic drugs, erythropoietic drugs, anti-asthmatics, suppressants cough, mucolytics, anti-uricémicos medicines, and their mixtures.
23. 23. The method of preparing fast dissolving edible units according to claim 19, wherein said compaction is carried out under a pressure not greater than 10 SCUs; and optionally, where said pressure is not greater than 8 SCUs.
24. 24. An edible unit, which has a controlled release system, which disperses rapidly in the mouth, prepared from the process comprising: a) initiating matrix crystallization in the form of shear; b) before or after initiating the crystallization, combining a controlled release system with said matrix in a shear form to form compact, flowable microparticles; and c) compacting the combination resulting from step "b", which includes at least at least partially crystallized shear form, to form said unit.
25. 25. The unit according to claim 24, wherein said combination further comprises subjecting said additive and said matrix to treatment with a crystallization / binder promoter; and optionally, wherein said promoter comprises an ingredient selected from the group consisting of an alcohol, polyvinylpyrrolidone, and a mixture thereof.
26. 26. The unit according to claim 24, wherein a crystallization / binder promoter is incorporated in said matrix in a shear-force manner including said promoter in the feedstock from which said matrix is formed; and optionally, wherein said promoter is a surfactant or a polydextrose.
27. 27. The unit according to claim 24, wherein said controlled release system comprises a component selected from the group consisting of an instant release component, a delayed release component, a sustained release component, and combinations thereof.
28. The unit according to claim 27, wherein said controlled release system comprises an active ingredient selected from the group consisting of antitussives, anti-histamines, decongestants, alkaloids, mineral supplements, laxatives, vitamins, anti-acids, resins of ion exchange, anti-cholesterol, anti-lipid, anti-arrhythmic, anti-pyretic, analgesic, appetite suppressant, expectorant, anti-anxiety agents, anti-ulcer agents, anti-inflammatory substances, coronary dilators, cerebral dilators, peripheral vasodilators , antiinfectants, psychotropic, anti-manic, stimulants, gastrointestinal agents, sedatives, anti-diarrheal preparations, anti-anginal drugs, vasodilators, anti-hypertensive drugs, vasoconstrictors, migraine treatments, antibiotics, tranquilizers, anti-psychotics, anti- tumor, anti-coagulants, anti-thrombotic, hypnotic os, anti-emetics, anti-nauseants, anti-convulsants, neuromuscular drugs, hyper and hypoglycemic agents, thyroid and anti-thyroid preparations, diuretics, anti-spasms, uterine relaxants, mineral and nutritional additives, anti-obesity drugs, anabolic medications, erythropoietic drugs, anti-asthmatics, cough suppressants, mucolytics, anti-uricémics, and their mixtures; and optionally, wherein said active is ibuprofen, acetaminophen, aspirin, a H2 antagonist, antacid, or a breath freshener.
29. 29. The unit according to claim 24, wherein said combination further comprises subjecting said controlled release system and said matrix to treatment with a crystallization / binder promoter; optionally, wherein said controlled release system further comprises incorporating an effervescent disintegrating agent into said unit; and optionally, wherein said controlled release system further comprises reinforcing particles having a size, a shape and a hardness that inhibit the destruction of components of said controlled release system in the presence of accidental chewing by a host.
30. 30. A composition for delivering a controlled release system, comprising: a controlled release system; and a crystalline structure based on saccharides comprising a crystal sugar bound and continuously stabilized in two-dimensional form produced by means of i) initiating the formation of a crystalline sugar framework from an external portion of amorphous sugar masses in an effort form cutting, ii) before or after initiating the formation of said crystalline framework combine said controlled release system with said matrix in the form of shear to form compact, capable micro-particulates to flow; iii) compacting said masses to form a unit dosage; and iv) subsequently converting the remaining portion of said masses into a substantially complete crystalline structure which is continuously bound and stabilized, whereby said controlled release system is incorporated into said crystalline structure based on saccharides.
31. 31. The composition of claim 30, wherein said masses are bi-dimensionally monodisperse; optionally, wherein said monodisperse stabilized masses are microcrystalline; optionally, wherein said amorphous shear-shaped product is substantially in the form of a bar, said two dimensions lying in a cross-sectional plane of said bar and said third dimension extending along the linear axis of said bar; and optionally, wherein said structurally stabilized, monodisperse cross section does not exceed 50 μm, preferably does not exceed 10 μm.
32. 32. The composition of claim 30, wherein said shear force masses further comprise an additive, whereby said additive is co-crystallized in said crystalline product.
33. 33. A method of administering a controlled-release system to a human host, comprising: ingesting a rapidly dissolving edible unit prepared by the method comprising: i) initiating matrix crystallization in shear form, ii) before or after after initiating the crystallization, combine a controlled release system with said matrix in a shear form to form compact, flowable microparticles; and iii) compacting the combination resulting from step "ii", which includes at least partially crystallized shear form matrix; retaining said unit in the oral cavity for a sufficient time to contact said unit with water introduced into said oral cavity; and introducing water into said oral cavity while said unit is retained in it, thereby speeding up the dispersion of said unit significantly.