MXPA06010335A - Pharmaceutical formulations - Google Patents

Abstract

The present invention is directed to novel pharmaceutically acceptable polymeric compositions suitable for melt extrusion and injection molding of single or multi-component pharmaceutical dosage forms comprising a plurality of drug substance containing sub-units, being capsule compartments and/or solid sub-units comprising a solid matrix of a polymer which contains a drug substance, the sub-units being connected together in the assembled dosage form.

Description

PHARMACEUTICAL FORMULATIONS FIELD OF THE INVENTION This invention relates to the preparation of single component or multiple injection molded dosage forms utilizing pharmaceutically acceptable polymer blends.

BACKGROUND OF THE INVENTION Various types of pharmaceutical dosage forms are known for oral dosage. The pharmaceutical capsules are well known, they are generally intended for oral dosing. Such capsules generally comprise a wrapping wall of a pharmaceutically acceptable, for example, orally ingestible polymeric material, such as gelatin, although other materials for the capsule walls, for example, polymers based on starch and celse are also known. Such capsules generally have soft walls made by making a film in a capsule former, which are then allowed to dry. Hard-walled capsules made by injection molding are also known, see, for example, US Patents 4,576,284; US 4,591,475; US 4,655,840; US 4,738,724; US 4,738,817 and US 4,790,881 (all from Warner Lambert). These describe specific constructions of capsules made of gelatin, starch and other polymers, and methods for making them by injection molding mixtures of a hydrophilic-water polymer. The Patent of E.U.A. 4,576,284, specifically describes such capsules, provided with a capsule that closes the capsule, and which is formed in situ in the filled capsule by molding. The Patent of E.U.A. 4,738,724, describes a wide range of shapes and parts for rigid capsules. Capsules with multiple compartments, including those of the type where each compartment has different drug release characteristics, or for example, contain a different active substance or formulation are also known, for example, from US 4,738,724 (Warner-Lambert); US 5,672,359 (University of Kentuc and); US 5,443,461 (Alza Corp.); WO 95/16438 (Cortees Ltd.); WO 90/12567 (Helminthology Inst.); DE-A-3727894, and BE 900950 (Warner Lambert); FR 2524311, and NL 7610038 (Tapanhony NV); FR 1, 454.013 (Pluripharm); US 3,228,789 (Glassman); and US 3,186,910 (Glassman), among others. US 4,738,817 describes a capsule with multiple compartments with a construction similar to that of US 3,228,789 and US 3,186,910, made of a water-laced gelatin. US 4,738,817 ('817), Witter et al., US 4,790, 881 ("881), Wittwer et al., And EP 0 092 908, Wittwer, F., describe all injection-molded capsules prepared with gelatin and Other excipients, Wittwer et al. '817 and' 881, also prepare capsules with other hydrophilic polymers, such as hydroxypropylmethyl celse phthalate (HPMCP), methylcelse, microcrystalline celse, polyethylene glycol, celse acetate phthalate (CAP) and with polyvinyl pyrrolidone. Both US 4,790,881 and EP 0 091 908 propose other polymers having suitable enteric properties to be used, generally including acrylates and methacrylates (Eudragits), although none is shown and no specific details are provided. Also known are pharmaceutical dosage forms comprising a matrix of a solid polymer, in which an active substance is dispersed, included or dissolved as a solid solution. Such dies can be formed by an injection molding process. This technology is described in Cuff G, and Raouf F, Pharmaceutical Technology, June (1998), pages 96-106. Some specific formulations for such dosage forms are described in US 4,678,516; US 4,806,337; US 4,764,378; US 5,004,601; US 5,135,752; US 5,244,668; US 5,139,790; US 5,082,655; US 5,552,159; US 5,939,099; US 5,741,519; US 4,801, 460; US 6,063,821; WO 99/27909; CA 2,227,272; CA 2,188,185; CA 2,211, 671; CA 2,311, 308; CA 2,298,659; CA 2,264,287; CA 2,253,695; CA 2,253,700; and CA 2,257,547, among others. The Patent of E.U.A. 5,705,189, is directed to a group of copolymers of methacrylic acid, methyl methacrylate and methyl acrylate, to be used as thermoplastic agents in the production of drug coatings and capsules. No information is presented about the quality of the capsule formation with respect to deformation or other distortions produced by the injection molding process.

Nor are data of the shear velocity presented for the viscosity / temperature figures of the emulsions presented therein, It would also be desirable to prepare a pharmaceutical dosage form in which a pharmaceutically acceptable polymer mixture is extruded by hot melt in a suitable dosage form, or is injection molded into suitable dosage forms, which can be multi-compartment, such as in a capsule.

This pharmaceutical polymeric composition as the dosage form, can provide different physicochemical characteristics for each segment containing an active agent, so that options for a convenient dosage form can be had, which can include a rapid, immediate, delayed dissolution release, pulsatile or modified, which can be produced by simply selecting the appropriate polymers to be molded for each section.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides new pharmaceutical compositions and their use in melt extrusion technologies, and in the formation of covers for injection molded capsules, binders or separators, caps for injection molded capsules with multiple components, binders or separators, forms of pharmaceutical dosage with multiple components and other aspects as defined in the claims and the description of this application. Another embodiment of the invention is to provide an alternative and improved pharmaceutical dosage form that provides, inter alia, greater flexibility in the dosage form adapted to a specific patient administration requirement, using the novel formulations or compositions of the pharmaceutically acceptable polymers and Suitable excipients in the dosage forms. Another embodiment of the invention is to provide a process for producing the multiple component dosage forms comprising the novel pharmaceutically acceptable polymer blends by injection molding. These multi-component dosage forms are suitable for containing a pharmaceutically acceptable active agent or agents, for the release thereof. According to the invention, there is provided a melt extrusion composition, and an injection molded and / or bonded capsule shell, with a composition, preferably, that includes Eudragit RL 100 or Eudragit RS 100 or a combination thereof. the same. The capsule or binder comprises a solid matrix, and preferably comprises Eudragit RL 100 present in an amount of about 10 to 80% w / w, and a hydroxypropyl cellulose derivative, or a combination of hydroxypropyl celluloses, of about 30. at approximately 70% weight / weight.

The composition may optionally further comprise excipients that modify the solution present in an amount of from about 0% w / w to about 30% w / w; a lubricant present in an amount of up to about 30% w / w; a plasticizer present in an amount of up to about 10% w / w, and a processing agent present in an amount of up to about 10% w / w. In an alternative embodiment, the pharmaceutical dosage form comprises a plurality of subunits, each being a compartment of a capsule containing an active substance. In this case, each compartment is physically separated from at least one adjacent compartment, preferably by means of a wall made of a pharmaceutically acceptable polymeric material. In the case where at least one of the subunits in a compartment of a capsule containing an active substance, its wall thickness is in the range of about 0.1-0.8 mm. In another embodiment, the thickness of the wall is in the range of about 0.3-0.8 mm. The multi-component dosage form of the invention provides a high degree of versatility which can be comprised of various combinations of different dosage forms having different release characteristics. For example, the subunits may be an immediate release subunit, a sustained release subunit or a pulse release subunit.

Other objects and advantages of the invention will be apparent from the following description.

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to novel compositions of a pharmaceutically acceptable polymer and excipients, polymeric composition which can be injection molded into one or more components that can be used together optionally, such as in a stacked or multi-component dosage form. It is recognized that polymer blends can be injection molded into a single component which can also contain the active agent for oral administration. The present invention also relates to the application of a pharmaceutically acceptable film coating on a component comprising the pharmaceutically acceptable polymer blends as described herein. The film coating can be a delayed release formulation, or a formulation for pH control that are well known in the art. A suitable coating is Opradry and / or Eudragit L30D-55. Enteric coatings, represented by the application of L30D-55 for example, can be applied using standard equipment such as an Aerocoater Column Coater GMP The weight gain of the component is nominally from about 3% to about 5% weight / weight. The pharmaceutically acceptable polymer blends herein are designed to provide consistent dissolution profiles. A suitable multi-component dosage form is described in PCT / EP00 / 07295, filed on July 27, 2000, published as WO 01/08666 on February 8, 2001, the content of which is incorporated by reference in the present in its entirety. The parts of the dosage form of this invention, for example, a wall of the capsule compartment, a solid subunit, or a closure or binder, comprise a pharmaceutically acceptable polymer mixture (and adhesive material if adhesive solders are formed), which they are generally considered safe, for example, for oral ingestion and are capable of being formed in the required form of a wall of the capsule compartment, a solid subunit, or a closure or binder as described above. A preferred method for forming the polymeric material in the desired form is injection molding, which can be an injection molding process with a hot or cold wheel. Injection molding machines suitable for such a process are known. The pharmaceutical dosage form may comprise a plurality of compartments of the capsule, each joined and physically separated from at least one adjacent compartment by a wall made of a pharmaceutically acceptable polymeric material, as described herein, the adjacent compartments are connected together in the mounted dosage form, and held together by the connection at least prior to administration to a patient, one or more of the compartments contain an active substance. Suitably, in the assembled dosage form of this first embodiment, there are at least two, for example three, of such compartments of the capsule. Three or more of such compartments can be placed linearly in the mounted dosage form, for example, in an array comprising two end compartments at opposite ends of the line, and one or more intermediate compartments. Suitably, there may be two such compartments of the capsules. Suitably, one of such two compartments of the capsule can be made of a material that is a sustained release component, i.e., in such a way that the wall of the capsule compartment dissolves, explodes or breaks in another way to release its contents after a time delay, when the compartment has reached the intestine. Suitably, the other two such capsule compartments can be made of a material that is an immediate release component, i.e., so that the wall of the capsule compartment dissolves, bursts or otherwise breaks to release its contents immediately or effectively immediately, for example, when the compartment is in the mouth or stomach.

One or more, for example, all of the capsule compartments may, for example, be substantially cylindrical, which term includes shapes having a circular, oval or circular cross section oblate through the longitudinal axis, and shapes that may be parallel or tapered, for example, with side walls tapering conically over at least part of its extension. Such substantially cylindrical capsule compartments may be provided with portions that are connected at one or both of their longitudinally disposed ends, so that the assembled dosage form may also, in general, be substantially cylindrical in shape. Suitably, methacrylic acid copolymers (such as Eudragit E®, Eudragit E100®, Eudragit® L and / or Eudragit® S), poly (meth) acrylate copolymers (such as Eudragit® 4135F and 4155F), and copolymers of ammonium methacrylate (such as Eudragit® RL and / or Eudragit® RS), are used for hot melt extrusion and injection molding. The group of poly (meth) acrylate copolymers, such as Eudragit® RS 100 or RL100 is in one embodiment of this invention. Polymers based on acrylic and / or methacrylic acid which are soluble in intestinal fluids and which can be formed in capsules are described, for example, in US 5,705,189 (Roehm GmbH), the content of which is incorporated herein by reference. reference in its entirety. These poly (meth) acrylate copolymers are extrudable and injection molded into capsule halves, wherein the ratio of acrylic and / or methacrylic acid was generally 20% w / w or more of the copolymer (Examples 1-8). In these Examples, glycerol monostearate was added in a base of 1-6% by weight of the polymer as the sole agent for mold release. The Lehmann patent teaches that unmixed polymers alone are not suitable for injection molding, but must be mixed with a lubricant to produce a capsule shell thereof. In order to produce undistorted, non-deformed, injection molded capsule / subunit components for mounting in single capsule or multi-compartment dosage forms using Eudragit RS 100 or RL 100, it can be determined that at least one lubricant and an agent that modifies the solution are useful to obtain the release of the injection molds. The Eudragit RL100 polymer is described by the manufacturer, Rohm Pharma, as being a highly permeable pH independent polymer whose granules are insoluble in water. The Eudragit RS 100 is also described as being a polymer granule independent of pH with low permeability and insoluble in water. In contrast, Eudragit 4135F / 4155F dissolves only above pH 7, for example, in the colon, therefore, it is suitable for use as a sustained or delayed release component, and the Eudragit E100 polymer dissolves in acid and is suitable for use as an immediate release component. These and other pharmaceutically acceptable polymers are described in detail in the Pharmaceutical Excipients Manual, published jointly by the American Pharmaceutical Association and the Pharmaceutical Society of Brittany. The polymer RL100 is combined with additional excipients which include, but are not limited to, agents for the increase in size, such as HPMC, HPC, etc .; surfactants, such as SDS or the Pluronic agent group; agents that form pores / channels, such as lactose or PEG; additional polymers to be ready, such as RS 100; and additional buffering agents to adjust to the microclimate of the pH conditions. One embodiment of the invention is a RL100 comix with the HPC polymer, such as that marketed by Aqualon, a division of Hercules Incorporated, as Klucel®. Klucel HPC is produced in various grades, determined by its intended use. Suitable Klucel polymers are Klucel EF, Klucel JH, Klucel LF and Klucel GF. The Klucel E has a viscosity in the range of 150-700 (one of 300-6 mPas for EF pharm / EXF Pharm), and a molecular weight of approximately 80,000; J has a viscosity of 150-400 and a molecular weight of about 140,000, L has a viscosity in the range of 75-150, and a molecular weight of about 95,000; and G has a viscosity in the range of 75-400, and a molecular weight of about 370,000. The addition of these thermoplastic polymers to the mixture provides reduced sensitivity for welding conditions, improved tensile properties both pre and post-hydration, and a more robust size increase of the polymer at pH from 1 to 6. It is recognized that the formulations of the comixes still require additional excipients as described herein. One such excipient is a lubricant, such as stearyl alcohol. It has been determined that these blended polymers produce coatings that hydrate and increase in size considerably more than polymeric compositions not mixed under various conditions.

This produces a formulation that has significant improvements in the reproducibility of the solution; the release of the capsule covers is influenced less by the weld settings; an improved hydration profile, resulting in less structural integrity after dissolution; and superior appearances, and tension properties of the resulting covers. Components that have been mixed with Eudragit RL100 have also been found to be stable after prolonged storage conditions. It is recognized that the polymer compositions are first melted in a melt extrusion process, and may also contain additional additives or excipients to aid melt flow, strength, brittleness and other molding characteristics, these additional excipients include, non-exclusive way, plasticizers, absorption enhancers, additional surfactants, flavoring agents, dyes, etc. Therefore, another aspect of the present invention is a pharmaceutical composition for a melt extrusion comprising Eudragit RL100 or RS 100 and a lubricant, such as stearyl alcohol. Although the compositions herein can be molded in a variety of wall thicknesses, it is preferable that the capsules or components have a wall thickness of from about 0.3 to about 0.8 mm, suitably 0.5 mm. However, the performance of the solution will more appropriately adjust the thickness of the wall depending on the desired release profiles. Increases in the thickness of the wall may be necessary to reduce the deformation of the components, or in addition to this, modification of the additional excipients may be necessary. The polymethacrylate polymer, Eudragit RL100 or RS 100 is present in the formulation in an amount of about 10 to about 80% w / w. In another diment, the Eudragit RL100 or RS 100 is present in an amount of about 20 to about 50% w / w. In another diment, the Eudragit RL100 or RS 100 is present in an amount of approximately 20 to 40% w / w. As indicated, the polymeric materials may include other substances to modify their properties and to adapt them to various applications, including, but not limited to, surfactants, absorption enhancers, lubricants, plasticizers, agents that modify the dissolution, processing aids, coloring agents, flavoring agents and sweetening agents. The incorporation of a surfactant into the formulation may be necessary or desired to lower the viscosity and the surface tension of the formulation / mixture, however, in higher amounts, it may adversely affect the quality of the resulting dosage form. The selection of the surfactant can be guided by the HLB values, but it is not necessarily a useful criterion. Although HLB surfactants have been used herein, such as Tween® 80 (HLB = 10), Pluronic F68 (HLB = 28), and SDS (HLB > 40), the surfactants with a lower HLB value, such as Pluronic F92 and F127, can also be used. The Pluronic, made by BASF, USA, has a synonym for POLOXAMERO. Pluronic F68, for example, has a molecular weight of 8,400. Pluronic F127 has a molecular weight of 12,600. Pluronics are polyoxypropylene-polyoxyethylene block copolymers. A surfactant can also be called a modifier of the oligomeric surface, and includes, in a non-exclusive manner: Pluronics® (block copolymers of ethylene oxide and propylene oxide, and also referred to as polyoxypropylene-polyoxyethylene block copolymers); lecithin, Aerosol OT® (sodium dioctyl sulfosuccinate), sodium lauryl sulfate, Poiyoxyl 40®, hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, i.e., polysorbates such as Tween®, such as Tween 20, 60 and 80, the fatty acid esters of sorbitan, ie, monolaurate, monooleate, monopalmitate, monostearate, etc., of sorbitan, such as Span® or Arlacel®, Emsorb®, Capmul® or Sorbester®, Triton X-200, polyethylene glycols, glyceryl monostearate, Vitamin E-TPGS® (polyethylene glycol succinate 1000 of d-alpha-tocopheryl), fatty acid esters of sucrose, such as sucrose stearate, sucrose oleate, sucrose palmitate, sucrose laurate and sucrose acetate butyrate, etc .; and combinations and mixtures thereof. Suitably, the formulation may optionally contain from about 0 to about 10% w / w of surfactants. Suitable surfactants for use herein include, sodium lauryl sulfate, also referred to as sodium dodecyl sulfate (SDS) or a block copolymer of ethylene oxide and propylene oxide, or mixtures thereof. In one embodiment, suitable surfactants are Vitamin E-TPGS®, sodium lauryl sulfate, fatty acid esters of sucrose, lecithin, and Pluronic groups. In another embodiment, if the SDS (Texapon K-12®) or the block copolymers of ethylene oxide and propylene oxide are used in the formulation, they are present in an amount of less than 2% by weight, suitably, less than 1% weight / weight. Polymeric carriers or oligomeric surface modifiers, if appropriately chosen, can by themselves act as absorption enhancers. Suitable absorption enhancers for use herein include, but are not limited to, chitosan, lecithin, lectins, sucrose fatty acid esters such as stearic acid derivatives, oleic acid, palmitic acid, lauric acid and Vitamin E-TPGS, and combinations or mixtures thereof. Suitably, these absorption enhancers are present in a range of from about 0 to about 20% w / w. The plasticizers can be used to assist in the melting characteristics of the composition. Exemplary plasticizers that can be employed in this invention are triethyl citrate (TEC), triacetin, tributyl citrate, acetyl triethyl citrate (ATEC), acetyl tributyl citrate (ATBC), dibutyl phthalate, dibutyl sebacate (DBS), diethyl phthalate, vini triacetate! pyrrolidonglicol, polyethylene glycol, polyoxyethylene sorbitan monolaurate, propylene glycol or castor oil; and combinations or mixtures thereof. The polymeric material will determine which plasticizer is suitable for use. Suitably, the plasticizer is present in an amount of about 0 to about 20% w / w. In one embodiment of the invention, the plasticizers are present in an amount of about 0 to about 5% w / w. One embodiment of the present invention is the ability to form a cover by injection of a formulation of Eudragit RL 100 or RS 100 without the addition of a plasticizer, such as those indicated above. The agents that modify the solution, or substances that help in the modification of the release, alter the characteristics of erosion and / or enlargement of the cover / binder / component of the capsule. Many different kinds of agents can be used, such as the known disintegrants represented by "Explotab" (glycolate starch) sodium), "Kollidon-CL", (cross-linked PVP), Kollidon VA 64 (copovidone) commercially available from BASF, Starch 1500, size-increasing agents, such as polyvinyl pyrrolidone (PVP, also known as POVIDONE, USP), manufactured by ISP-Plasdona or BASF-Kollidon, mainly grades with lower K values (K-15, K-25, but also K-30 to K-90), cellulose derivatives such as hydroxypropyl methyl cellulose (HPMC), wick, such as low molecular weight solutes, for example, mannitol, lactose and starch; inorganic salts such as sodium chloride (typically at 5-10%). The Kollidan VA 64 or copovidone, also known as copolividone, copovidonum, copovidone or copovidon, is a ratio of two monomers, vinylpyrrolidone and vinyl acetate. Another class of solution modifying agent agents for use herein are known as solids that increase in size and include, but are not limited to, poly (ethylene) oxide, cellulose derivatives, such as ethyl cellulose and phthalate. of cellulose acetate; hydroxypropylcellulose (HPC), such as lower molecular weights, for example, grades KLUCEL EF and LF, and mixtures of lower molecular weights with higher molecular weight grades, such as JF or GF; hydroxypropylmethyl cellulose (HPMC), and other hydroxyalkylcellulose derivatives. Suitably, the increasing solids used as excipients that modify the solution are in the range of about 10% to about 70% w / w. In In another embodiment, agents that increase in size are present in an amount of about 20 to about 65% weight / weight, suitably, of about 50% weight / weight. Other suitable excipients that modify the solution include, but are not limited to, the class of non-reducing sugars, such as silitol or mannitol, present in the range of about 2.5 to about 15% w / w. Also included herein, is a class of water-soluble fillers, such as lactose, lactitol, maltitol, sorbitol or alternatively, organic acids such as malic acid, citric acid or succinic acid, suitably present in the range of about 5 to about 70% w / w. In another embodiment of the present invention, water-soluble fillers may be present in an amount of about 5 to about 20% w / w. Another group of suitable modifying excipients are the agents generally referred to as disintegrants, such as sodium starch glycolate, croscarmellose sodium NF (Aci-Di-Sol ®, produced by FMC), copovidone and crospovidone (crosslinked polyvinyl pyrrolidone); and combinations or mixtures thereof. Suitably, the class of disintegrants is present in the range of about 10 to 40%, more preferably about 20 to 30% w / w. It is recognized that one of more classes of excipients that modify the solution can be used alone, or in combination as mixtures of a with the other, resulting in a range of approximately 2.5 to approximately 70% weight / weight. One such combination is hydroxypropylcellulose and lactose. Additional reagents, generally classified as processing aids, include reinforcing agents, such as talcum. Suitably, processing aids are present from about 0 to about 10% w / w. In another embodiment, processing helpers are present from about 0 to about 5% w / w. Lubricants or slides for molding processing suitable for use herein include, but are not limited to, stearyl alcohol, stearic acid, glycerol monostearate (GMS), talc, magnesium stearate, silicon dioxide, amorphous silica and silica. smoker and combinations or mixtures thereof. The lubricant functions mainly as a flow promoter for the composition. One embodiment of the present invention is the use of stearyl alcohol as a suitable lubricant. Suitably, a commercial grade stearyl alcohol, such as Crodacol S95 (Croda Oleochemicals) is used herein. The lubricating material must also be suitable for grinding. The amount of lubricant present in the formulation is from about 0 to about 30% w / w. In another embodiment, the lubricant is present from about 10 to about 25% w / w. In another embodiment, the lubricant is present of approximately 10 to 15% w / w. It has been found that stearyl alcohol acts as a lubricant of the molding process, but that it does not cause distortion in the mold, i.e., crushing of the compartment cover with multiple doses, when the hot soft cover is removed from the mold. Another alternative material useful as a lubricant / flow promoter is lecithin (a natural product). Suitably, the lubricants for use herein, do not introduce any contamination of metal ions. One embodiment of the present invention is the combination of stearyl alcohol, at least one solid that increases in size and the polymer Eudragit RL100. Optionally, the formulation may further comprise a surfactant, such as SDS at 2% w / w or less, or 1% or less. The solid that increases in size can be the hydroxypropylcellulose polymer or a mixture of hydroxypropylcellulose. The final products of this invention, ie, the capsules, and / or the components or subunits, may additionally include materials in the polymeric materials of which they are made to improve the ease with which they can be welded. The subunits can additionally be provided with construction features and / or include materials in the polymeric materials from which they are made, to improve the ease with which they can be attached, either by simple mechanical joints or by welding. A suitable material for such help, are the opacifying materials, such as carbon (for example, 0.2-0.5%), iron oxides or titanium dioxide (for example, 0.5-1.0%) that help the polymer absorb laser energy. Such opacifying materials are generally considered as safe. For example, each of the plurality of subunits, for example, capsule compartments, solid subunits or combinations thereof, may comprise the same or different polymers. For example, each of the plurality of subunits, for example, of compartments of the capsule, solid subunits, or combinations thereof, may comprise the same active substance or a different one. For example, each subunit may contain the same active substance, but release the content in the patient's gastrointestinal tract at a different rate, at different times after administration to the patient or in different places in the patient's gastrointestinal system. Alternatively, each subunit may contain a different active substance, each of which may be released at the same or different rate or time after administration or place in the patient's gastrointestinal system. For example, two or more subunits, for example, two compartments of the capsule, may each contain different active substances, and / or different formulations of active substances, and / or the same drug in different formulations, so that a combination of two or more active substances or formulations can be administered to a patient. The dosage form of this invention allows the assembly of subunits that differ in their drug content and / or release characteristics of the drug content to provide a dosage form designed for specific administration requirements. The dimensions and shape of each of the subunits and therefore of the total mounted dosage form can be determined by the nature and amount of the material to be contained therein, and the intended mode of administration and the intended recipients. For example, a dosage form intended for oral administration may be of a shape and size similar to those of known capsules intended for oral administration. The dosage form is particularly suitable for presentation as an oral dosage form containing one or more active substances suitable for oral administration, and appear to be suitable for all types of active substances. The active substances contained in each compartment of the capsule can be present in any suitable form, for example, as a powder, granules, compact, microcapsules, gel, syrup or liquid with the proviso that the material of the wall of the compartment of the capsule is sufficiently inert to the liquid content of the last three forms. The contents of the compartments, for example, active substances, can introduced into the compartments by standard methods such as those conventionally used to fill capsules, such as dosing or filling terminals with nozzle. The subunits may differ from one another in their release characteristics of the drug content, and this can be achieved in several ways. For example, one or more solid subunits and / or capsule compartments can be of substantially immediate release, ie, release their drug content substantially immediately upon ingestion or withdrawal. reach the stomach. This, for example, can be achieved by means of the matrix polymer or the wall of the capsule compartment which dissolves, disintegrates or otherwise breaks to release the drug content substantially immediately. Generally, immediate release subunits are preferably provided as capsule compartments. For example, one or more solid subunits and / or capsule compartments, can be sustained release subunits. Preferably, these are solid subunits, since a bulk polymer matrix is likely to dissolve or disperse more slowly to release its drug content than a thin-walled capsule. For example, one or more of the solid subunits and / or compartments of the capsule may be pulse release subunits, for example, that release their drug content to a point. predetermined specific in the patient's gastrointestinal system. This can be achieved by the use of polymeric materials that dissolve or disperse only in media at a defined pH, such as the Eudragit® polymers mentioned above. For example, E100 is labile with acids. For example, in the capsule-binder-compartment compartment dosage form described above, one compartment of the capsule can be of effective immediate release and the other can be of sustained, delayed or pulsed release. To achieve this, for example, a capsule compartment can be made of polymeric materials that cause the capsule compartment to release its content of the drug in the stomach or upper part of the digestive tract, and the binder (which acts as a closure). for the second compartment) and the second compartment itself, can be made of materials, for example, the enteric polymers described above, which release their drug content only in the intestinal environment. The determination of the time or location within the gastrointestinal tract in which the subunit releases its content into the active substance can be achieved, for example, by the nature of the subunit material, for example, a solid subunit matrix polymer or a material of the wall of the capsule compartment, or in the case of an end compartment which is closed by a closure, by the nature of the closure material. For example, the wall of different compartments, for example, adjacent, it can be made of polymers that are different or that differ in another way in their dissolution or disintegration characteristics, to provide different compartments with different drug release characteristics. Similarly, for example, the polymer matrix material of different, for example, adjacent solid subunits, may be made of polymers that are different or otherwise differ in their dissolution or disintegration characteristics, to provide different solid subunits with different characteristics of drug release. For example, the matrix, the wall or the closure material can be a polymer that dissolves or disperses in the pH of the stomach to release the substance from the drug in the stomach. Alternatively, the material of the wall of different compartments may differ so that different compartments have different release characteristics. For example, a solid subunit or a compartment of the capsule may have, respectively, a matrix or a wall or a closure comprising an enteric polymer that dissolves or disperses at the pH of the small or large intestine, to release the active substance in the intestine. Such suitable polymers have been described above, for example, with reference to US Pat. No. 5,705,189. Additionally or alternately, the material of the wall may differ in thickness between the compartments, so that the compartments with thicker walls break slowly than thin-walled compartments. Additionally or alternately, the walls of the compartment or closure may have areas or points of weakness that dissolve preferentially and may therefore determine the time of onset and / or the rate of release of the content of the active substance. . For example, such weakness points may include orifices, small holes, for example, laser-drilled holes in the compartment wall or closure, these orifices are closed and / or covered with a film of a polymeric material that dissolves in a predetermined point of the digestive tract, for example, an enteric polymeric material. For example, such weakness points may comprise thinned walls in the wall of the capsule compartment formed during the molding operation in which the capsule compartment is formed. The subunits can, additionally or alternately, having surface characteristics or other construction characteristics that modify its drug release characteristics. For example, solid subunits can be provided with cavities or internal channels to create a large surface area. For example, the solid subunits may be in the form of hollow cylinders, donuts or toroids, with shapes known to tend toward dissolution or first-order erosion in liquid medium, and which correspond by tending toward the release of the first order of the contents of the liquid. drug dispersed in them.

"Pharmaceutically acceptable agents" include, but are not limited to, drugs, proteins, peptides, nucleic acids, nutritional agents, as described herein. This term includes active therapeutic agents, bioactive agents, active agents, therapeutic agents, therapeutic proteins, diagnostic agents, or drugs as defined herein, and follow the guidelines for the European Union Guide to Good Manufacturing Practice. . Such substances are intended to provide the pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of a disease or affect the structure and function of the body. The substance may also include a diagnostic agent, such as an imaging agent and / or a radiolabelled compound. Its use can be in a mammal or it can be in a human. The pharmacological activity can be prophylactic, or for the treatment of a disease state. The agents herein include small molecule therapeutics, as well as peptides and proteins. The pharmaceutical compositions described herein may optionally comprise one or more pharmaceutically acceptable active agents, bioactive agents, active agent, therapeutic agent, therapeutic protein, diagnostic agent, or drugs or ingredients distributed therein. As used herein, the terms "active agent", "drug portion" or "drug" are all used interchangeably.

The solubility in water of an active agent is defined by the Pharmacopoeia of the United States. Therefore, active agents that meet the criteria of highly soluble, freely soluble, soluble and poorly soluble as defined herein, are encompassed by this invention. Suitable active substances can be selected from a variety of known classes of drugs including, but not limited to, analgesics, anti-inflammatory agents, anthelmintics, antiarrhythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents , antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives (hypnotics and neuroleptics), astringents, agents that block the beta adrenoceptor, blood products and substitutes, cardiac inotropic agents, corticosteroids, cough suppressants (expectorants and mucolytics), diagnostic agents, diuretics, dopaminergics (antiparkinsonian agents), hemostats, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calciton ina and bisphosphonates, prostaglandins, radiopharmaceuticals, sex hormones (including steroids), antiallergic agents, stimulants and anorexics, sympathomimetics, thyroid agents, PDE IV inhibitors, NK3 inhibitors, inhibitors of CSBP / RK / p38, antipsychotics, vasodilators and xanthines.

Preferred active substances include those intended for oral administration and intravenous administration. A description of these classes of drugs and a list of the species within each class can be found in Martindale, The Extra Pharmacopoeia, Twenty-ninth Edition, The Pharmaceutical Press, London, 1989, the description of which is incorporated herein by reference In its whole. The active substances are commercially available and / or can be prepared by techniques known in the art. The polymer blends can preferably be selected from known pharmaceutical polymers. The physicochemical characteristics of these polymers, as well as the thickness of the final injection molded component will dictate the design of the dosage form, such as rapid dissolution, immediate release, delayed release, modified release, such as sustained release, controlled release or pulsatile release, etc. The polymer blends are made by well known methods to produce hot melt extrusions, in which the selected ingredients are fed into a feed hopper or into an extrusion machine. Suitable well-known equipment is readily available to produce a hot melt extrusion of the mixtures herein. For the production of a capsule or early release component in a capsule with multiple dosages (such as in a window of 2 hours or less), the Eudragit polymer RL 100 (Rohm), can be extruded into a thin-walled component cover (such as those indicated herein), by mixing with the excipients as indicated herein. As will be seen in the experimental section, the formulation with a lubricant and hydroxypropylcellulose, or an HPC comix has not been shown to produce a stable injection molded component, which can be reliably reproduced and injected from the mold with reduced deformation or without deformation of the mold. cover. The experiments with Kluce! HPC at various percentages, ranging from 30 to 70%, have been formulated and tested for variance in dissolution times. It has been found that formulations containing approximately 26% to 63% Klucel, have similar dissolution times (<2 hours), both in gastric fluid and in simulated intestinal fluids. To ensure consistent release, the pharmaceutical formulations include various hydrophilic excipients. Preferably, the hydrophilic excipient is one that does not melt at the extrusion temperature, for example, lactose, inorganic salts, HPC, HPMC, such as Pharmacoat 603 (an HPMC with a vitreous transition temperature of 175 ° C) . As indicated, these increasing solids are commercially available in various grades by molecular weight, eg, 95K or 80K grades of HPC. A change in the molecular weight of HPC, for example, should retain the ability to hydrate the shell, but the speed of hydration can be slower, that is, the speed of expansion will be reduced. For example, a longer dissolution time of the cover and the release of the components therein may result. Experiments with Klucel® HPC at various percentages have been formulated and tested for variance in dissolution times. It has been found that formulations containing 40 to 70% Klucel® have similar dissolution times. The inclusion of a lubricant, such as stearyl alcohol improves the flow. It has also been found that the higher proportions of stearyl alcohol increase the flowability, to allow the molding of thinner walls. The formulation may optionally include surfactants and disintegrating agents.

EXAMPLES The invention will now be described with reference to the following examples, which are merely illustrative, and should not be construed as limiting the scope of the present invention. All temperatures are given in degrees centigrade; all solvents are of the highest purity available unless otherwise indicated.

EXAMPLE 1 Manufacture of pharmaceutical dosage forms with multiple components with pharmaceutically acceptable polymer compositions as described herein. Example 1 will describe a general procedure used to mold the various capsules with multiple components and the appropriate subunits. Additional pharmaceutical compositions are shown and described below.

Using a suitable mixer, mix: Article 2. Hydroxypropyl Cellulose (Klucel GF) Article 3. Lactose Monohydrate Article 4. Stearyl alcohol, crushed to form a homogeneous powder mixture. Fit an extruder in a hot melt state with a suitable co-rotating double screw with a granule feeder and a powder feeder together with a cooling device for the strand and a granulator. Adjust the selected mold on the injection molding machine. The processing parameters of the example are as follows: Extruder: Screw speed 150 rpm (range of 100-500 rpm) Zone temperature 1 50 ° C (range of 30-75 ° C) (feeding zone) Zone temperature 2 95 ° C (85-85 interval) 130 ° C) Zone temperature 3 100 ° C (range of 90-135 ° C) Zone temperature 4 110 ° C (range 95-140 ° C) Zone temperature 5 115 ° C (inten / alo) 100-145 ° C) Nozzle temperature 120 ° C (105-150 ° C range) of the strand Pellet feeder 0.25 kg / hour (0.2-1.8 kg / hour) Powder feeder 0.75 kg / hour (0.2-1.8 kg / hour) Strand cooling equipment: Suitable for the extrusion speed used Granulator: Suitable for the extrusion speed used Injection molding: Suitable for injection / cooling times , temperature and injection pressure, depending on the type of the machine and the formulation of the granule. Preheat the extruder to the appropriate temperature. Load the granule feeder with the Ammonium methacrylate copolymer (Eudragit RL100) and the powder feeder with the mixture. Start the screws of the extruder so that they turn and then start the two feeders.

Process the extruded strand along the cooling equipment to the granulator and collect the granules formed. Enter the appropriate settings of the machine and preheat the moulder by injection. Preheat the hopper with the granules and mold the units with multiple components. Additional examples or embodiments of this example have been prepared, using the same steps of the procedure, but with various formulations, as shown below. Covers resulting from these examples are welded with a binding unit, as previously described herein, having a composition comprising Eudragit 4135F, 10% hypromellose (HPMC), Pharmacoat 603, Shin-etsu Chemical Company, and Stearyl Alcohol to 12%, using a maximum welding force. Unless stated otherwise, a standard weld for RL100 covers is -2.50 mm, 100% amplitude. With respect to the thickness of the roof, if it does not refer to the wall thickness, the roof is 0.5 mm thick. The welded capsules, when applicable, were tested using a USP2 or USP3 dissolution apparatus.

EXAMPLE 2 Formulation% weight / weight Eudragit RL100 25.00 Klucel GF 50.00 Lactose 13.00 Stearyl alcohol 12.00 Process conditions Extrusion / Injection Molding: Extrusion - 1 kg / hour, nozzle temperature 120 ° C, 150 rpm screw, 46% torque, nozzle pressure 5 bars; Injection Molding - partially filled 2/4 wall section covers of 0.5 mm, full lengths of other terminals; probe temperature 185 ° C. Additional observations of the Deck: many cracked or incompletely molded decks, and a bonded polymer line present on all decks. There was also a high degree of breakage with the welding. Dissolution test using USP 2, 0.5 mm capsule capsules containing an active ingredient, welded at -2.50 mm; a 100% run at 50 rpm at pH 1.2SGF, using Disc immersers demonstrated a fairly reproducible release profile and had a detachment ranging from 34-64 minutes for 6 samples tested.

EXAMPLE 3 Formulation% weight / weight Eudragit RL100 35.00 Klucel EF 40.00 Lactose 13.00 Stearyl alcohol 12.00 Process conditions Extrusion / Injection Molding: Extrusion - 1.1 kg / hour, nozzle temperature 120 ° C, 200 rpm screw, 53% torque, nozzle pressure 2 bars; Injection molding - cracks in 1/4 of the 0.5 mm wall section covers, full lengths of other terminals; probe temperature 175 ° C. Dissolution test using USP 2, 0.5 mm capsule capsules containing an active ingredient, welded at -2.50 mm; a 100% run at 75 rpm at pH 1.2SGF, using Disc submersors demonstrated a release profile that was highly reproducible and had a detachment ranging from 38-58 minutes for 6 samples tested.

EXAMPLE 4 Formulation% weight / weight Eudragit RL 100 25.00 Klucel EF 63.00 Stearyl alcohol 12.00 Process conditions Extrusion / Injection Molding: Extrusion - 1.2 kg / hour, nozzle temperature 110 ° C, screw 200 rpm, 35% torque, nozzle pressure 1 bara; Injection molding - wall section covers 0. 5 mm satisfactory, small line attached in some covers of 0.3 mm, temperature of the probe 180 ° C. Additional observations of the cover: Good molded, very little cracking. Dissolution test using USP 2, 0.5 mm capsules, welded at -2.50 mm; a 100% run at 50 rpm at pH 1.2SGF, using Disc submersers demonstrated variable release times of 58 to 100 minutes. In an alternate mode, using the molded covers of 0. 5 mm from this example, a film coating of Eudragit L30D-55 was added. An Aeromatic Aerocoater was used to apply the coating with standard procedures, to a film coating of 6% per weight gain. The coated covers were not tested for their release profile in a USP2 or USP3 dissolution apparatus.

EXAMPLE 5 Formulation% weight / weight Eudragit RL100 25.00 Klucel EF 31.50 Mucci IF 31.50 Stearyl alcohol 12.00 Process conditions Extrusion / Injection Molding: Extrusion - 1.2 kg / hour; nozzle temperature 115 ° C, screw 200 rpm; 41% torque, nozzle pressure 4 bars; Injection molding - satisfactory wall section covers of 0.5 mm, probe temperature 185 ° C. Additional Observations of the Cover: Very good molded, the covers are completely transparent, without cracks with the welding. Dissolution test using USP 2, 0.5 mm capsules, welded at -2.50 mm; a 100% run at 50 rpm at pH 1.2SGF using Disc submersors demonstrated a very reproducible detachment varying between 36-40 minutes for 6 samples tested.

EXAMPLE 6 Formulation% weight / weight Eudragit RL100 25.00 Klucel EF 50.00 Lactose 13.00 Stearyl alcohol 12.00 Procedure conditions Extrusion / Injection Molding: the film of the 0.5 mm covers was made using the conditions indicated above, and they were coated with a transparent subcoat of Opadry, then coated with an enteric coating of Eudragit L30D-55. The coating was made with an Aeromatic Aerocoater and the weight gain of the film coating was divided into two groups as follows: A = sub-discovery of 1.5% weight / weight; B = enteric coating of 2.5% weight / weight; and C = enteric coating of 6.0% w / w. Dissolution test using USP 3, covers for 0.5 mm capsules with a sub-coating of 1.5% (A) and an enteric coating of 2.5% (B), which contains an active ingredient, welded at -2.60 mm; a 100% run at 10 dpm at pH 1.2SGF, demonstrated a release profile that was very reproducible and had a detachment ranging from 40-55 minutes for 6 samples tested. In an alternative embodiment, the 0.5 mm covers of this example were coated with a film with a transparent undercoat of Opadry. The coating was made with an Aeromatic Aerocoater, and the capsules were divided into two groups with a weight gain of the film coating as follows: A = 3.8% w / w sub-coverage; B = sub-discovery of 7.0% weight / weight. Using the USP3 Dissolution test conditions, the covers coated with Methocel at 7% of group B, ultrasonically welded at -2.60 mm, 100% amplitude, produced very reproducible release profiles between 45-55 minutes for 6 samples tested. In another alternate embodiment, the 0.5 mm covers of this example were coated with a film with a transparent undercoat of Opadry and then coated with an enteric coating of Eudragit L30D-55. An Aeromatic Aerocoater was used, and the capsules were divided into two groups with a weight gain of the film coating as follows: A = 2.5% w / w sub-coverage; B = enteric coating of 7.5% weight / weight; and C = enteric coating of 10.0% w / w. Using the USP3 dissolution test conditions, a sub-discovery of 2.5% and an enteric coating at 10% of L30D55, tested 6 sample covers ultrasonically welded at -2.50 mm, 100% amplitude at 10 dpm. Its release profile was considered good with a reproducible release (1 isolated result) between 80-125 minutes. In another alternate embodiment, the 0.5 mm covers of the films of this example were coated with a transparent undercoating of Opadry using an Aeromatic Aerocoater. The weight gain of the resulting film coating was as follows: A = sub-coating of 1.7% weight / weight; B = enteric coating of 15.3% weight / weight; C = enteric coating of 21.3% weight / weight. Dissolution test using USP 3, caps for 0.5 mm capsules with a sub-coating of 1.7% (A) and an enteric coating of 15.3% (B), containing an active ingredient, welded at -2.60 mm; a 100% run at 10 dpm in pH 1.2SGF, demonstrated a release profile that was very reproducible and had a detachment ranging from 160-190 minutes for 6 samples tested. In another alternate embodiment, the 0.3 mm covers produced using this formulation were film coated with a transparent Opadry subcoat, then coated with an enteric coating of Eudragit L30D-55 (approximately 24 hours between applications). An Aeromatic Aerocoater was used, and the weight gain of the film coating was as follows: A = sub-coating of 2.5% w / w; B = enteric coating of 13.3% weight / weight.

Dissolution test using USP3, covers for 0.3 mm capsules with a sub-coating of 2.5% weight / weight (A) and an enteric coating of 13.3% (B), containing an active ingredient, welded at -2.50 mm; a run at 100% at 10 dpm in pH 1.2SGF (1.5 hours), pH 5.5 SIF (0.5 hours), then pH 6.8 SIF (2 hours), showed a release ranging from 85-130 minutes for 6 samples tested.

EXAMPLE 7 Formulation% weight / weight Eudragit RL 100 25.00 Klucel EF 61.00 Stearyl alcohol 12.00 Titanium dioxide 2.00 Procedure conditions: Extrusion / Injection Molding: Extrusion - 1.00 kg / hour; nozzle temperature 105 ° C, screw 200 rpm, 41% torque, nozzle pressure 1 bara; Injection Molding - satisfactory 0.5 mm wall section covers; probe temperature 180 ° C. Dissolution test using USP 3, covers for 0.5 mm capsules containing an active ingredient, welded at -2.40 mm; a 100% run at 10 dpm at pH 1.2SGF demonstrated a release profile that It was variable and had a detachment that varies from 34-95 minutes for 6 samples tested.

EXAMPLE 8 Formulation% weight / weight Eudragit RL100 24.00 Klucel EF 50.00 Stearyl alcohol 12.00 Succinic acid 13.00 Procedure conditions: Extrusion / Injection Molding: Extrusion 1.00 kg / hour; nozzle temperature 110 ° C, screw 200 rpm, 46% torque, nozzle pressure 1 bara, uniform "glassy" strand. Injection Molding - 0.5 mm; Persistent adhesion in the cavities. A 0.3 mm cover was not attempted.

EXAMPLE 9 Formulation% weight / weight Eudragit RL100 24.00 Klucel EF 50.00 Lactose 13.00 Stearyl alcohol 12.00 SDS 1.00 Procedure conditions: Extrusion / Injection Molding: Extrusion - 0.73 kg / hour; nozzle temperature 110 ° C, screw 200 rpm, 41% torque, nozzle pressure 2 bars; Injection molding - satisfactory 0.5 mm covers with probe at 150 ° C. The covers of this example have not been tested for their release profile in a USP2 or USP3 dissolution apparatus.

EXAMPLE 10 Formulation% weight / weight Eudragit RL100 21.60 Eudragit RS 100 2.40 Klucel EF 32.00 Klucel JF 32.00 Stearyl alcohol 12.00 Procedure conditions: Extrusion / Injection Molding: Extrusion - 1.5 kg / hour; nozzle temperature 120 ° C, 150 rpm screw; 38% of torque; Injection Molding - satisfactory 0.5 mm covers with probe at 180 ° C; Occasional adhesion in the mold. Dissolution test using USP 2, covers for 0.5 mm capsules containing an active ingredient, welded at -2.50 mm; a 100% run at 75 rpm at pH 1.2SGF using Disc submersors demonstrated a release profile that was highly reproducible and had a shedding ranging from 34-48 minutes for 6 samples tested.

EXAMPLE 11 Formulation% weight / weight Eudragit RL 100 2.40 Eudragit RS 100 21.60 Klucel EF 32.00 Klucel JF 32.00 Stearyl alcohol 12.00 Procedure conditions: Extrusion / Injection Molding: Extrusion - 1.5 kg / hour; nozzle temperature of approximately 120 ° C, screw of 153 rpm; 35% torque; Injection Molding - satisfactory 0.5 mm covers with probe at 180 ° C; Occasional adhesion in the mold. Dissolution test using USP 2, covers for 0.5 mm capsules containing an active ingredient, welded at -2.50 mm; a 100% run at 75 rpm at pH 1.2SGF, using Disc submersers demonstrated a release profile that was quite reproducible and had a detachment ranging from 46-50 minutes for 4 samples and 84 and 94 minutes for 2 samples tested. Dissolution test using USP3, cover for 0.5 mm capsules containing an active ingredient, welded at -2.45 mm; a run at 100% at 10 dpm at pH 1.2SGF (1.5 hours), then pH 6.8SIF (4.5 hours), demonstrated a release profile that was very reproducible and had a detachment ranging from 55-80 minutes for 6 samples tested.

EXAMPLE 12 Formulation% weight / weight Eudragit RL100 10.00 Citric acid 20.00 Klucel EF 58.00 Stearyl alcohol 12.00 Procedure conditions: Extrusion: Extrusion - 1.0 kg / hour; with a nozzle temperature of approximately 110 ° C; one screw with 200 rpm; and 35% torque. All publications, including, but not limited to, the patents and patent applications cited in this specification, are incorporated herein by reference as if each individual publication was specifically and individually indicated as being incorporated herein by reference as being disclosed. completely. The foregoing description fully describes the invention, including preferred embodiments thereof. The modifications and improvements of the modalities specifically described herein are within the scope of the following claims. Without further elaboration, it is believed that someone with experience in the area can, using the foregoing description, use the present invention to its fullest extent. Therefore, the Examples herein should be considered as merely illustrative and not a limitation of the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.

Claims (43)

NOVELTY OF THE INVENTION CLAIMS

1. - A capsule having a cover wall, a binder or a subunit of the capsule, composed of a pharmaceutically acceptable composition comprising a copolymer of Type A Ammonium Methacrylate Copolymer (Eudragit RL) or a Type B Copolymer of Ammonium methacrylate (Eudragit RS) present in an amount of about 10 to about 80% w / w; at least one excipient modifying the solution, present in a total amount of from about 20% to about 70% w / w; a lubricant present in an amount of about 5% to about 25% w / w; and optionally a surfactant present in an amount of from 0 to about 10%, a plasticizer present in an amount of from 0 to about 10% w / w and / or a processing agent present in an amount of from 0 to about 10% w / w. , wherein the cover wall, the binder or the subunit are all comprised of the pharmaceutical composition.

2. The cover wall, the binder or the subunit according to claim 1, further characterized in that the copolymer is a Type A Ammonium Methacrylate Copolymer.

3. - The cover wall, binder or subunit according to claim 2, further characterized in that the Type A copolymer is present in an amount of about 15 to about 50% w / w.

4. The wall of the cover, the binder or the subunit according to claim 2, further characterized in that the Type A copolymer is present in an amount of about 20 to about 40% w / w.

5. The wall of the cover, the binder or the subunit according to claim 1, further characterized in that the surfactant is present in an amount of less than 2% w / w.

6. The cover wall, binder or subunit according to claim 5, further characterized in that the surfactant is sodium dodecyl sulfate or is a block copolymer of ethylene oxide and propylene oxide.

7. The cover wall, the binder or subunit according to claim 1 or 5, further characterized in that the lubricant is stearyl alcohol, glycerol monostearate (GMS), talc, magnesium stearate, silicon dioxide, acid amorphous silica or fumed silica; and combinations or mixtures thereof.

8. The cover wall, binder or subunit according to claim 7, further characterized in that lubricant is present in an amount of approximately 10 to 30% w / w.

9. - The cover wall, the binder or the subunit according to claim 8, further characterized in that the lubricant is stearyl alcohol.

10. The wall of the cover, the binder or the subunit according to claim 9, further characterized in that the stearyl alcohol is present from about 10 to about 15% w / w.

11. The wall of the cover, the binder or the subunit according to claim 1, further characterized in that the lubricant is stearyl alcohol.

12. The cover wall, the binder or the subunit according to claim 11, further characterized in that the stearyl alcohol is present from about 10 to about 15% w / w.

13. The cover wall, binder or subunit according to claim 1, further characterized in that the excipient that modifies the solution is a solid that increases in size.

14. The cover wall, binder or subunit according to claim 13, further characterized in that the solid that increases in size is a cellulose derivative of ethyl cellulose, cellulose acetate phthalate; hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate or other hydroxyalkylcellulose derivative, and combinations or mixtures thereof.

15. The cover wall, the binder or the subunit according to claim 13, further characterized in that the solid that increases in size is at least one of hydroxypropyl cellulose, hydroxypropylmethyl cellulose or a combination or mixture thereof.

16. The cover wall, binder or subunit according to claim 1, further characterized in that the excipient that modifies the solution is composed of a mixture of hydroxypropyl cellulose polymers, each having a different molecular weight, present in a total amount of about 30% to about 80% w / w.

17. The cover wall, the binder or subunit according to claim 1, further characterized in that the mixture of polymers of hydroxypropyl cellulose is composed of polymers having a molecular weight averaged of 80,000 and 140,000 (Klucel EF and Klucel JF), or 80,000, 140,000 and 370,000 (Klucel EF, JF and GF), or 140,000 and 370,000 (Klucel JF and GF).

18. The cover wall, binder or subunit according to claim 1, further characterized in that the excipient that modifies the solution is a non-reducing sugar, a low molecular weight solute, or a water-soluble filler.

19. The wall of the cover, the binder or the subunit according to claim 18, further characterized in that the low molecular weight solutes or sugars are xylitol, mannitol, lactose, starch, or sodium chloride, or combinations or mixtures thereof.

20. The wall of the cover, the binder or the subunit according to claim 1, further characterized in that the excipient that modifies the solution is a disintegrant.

21. The cover wall, binder or subunit according to claim 20, further characterized in that the disintegrant is sodium starch glycolate, croscarmellose sodium, crospovidone (crosslinked polyvinyl pyrrolidone), copovidone, polyvinyl pyrrolidone; and combinations or mixtures thereof.

22. The wall of the cover, the binder or the subunit according to claim 1, further characterized in that the plasticizer is triethyl citrate (TEC), tributyl citrate, acetyl triethyl citrate (ATEC), acetyl tributyl citrate (ATBC), dibutyl phthalate, dibutyl sebacate (DBS), diethyl phthalate, vinyl pyrrolidonglicol triacetate, polyethylene glycol, polyoxyethylene sorbitan monolaurate, propylene glycol or castor oil; and combinations or mixtures thereof.

23. The wall of the cover, the binder or the subunit according to claim 1, further characterized in that the processing agent is talc.

24. The wall of the cover, the binder or the subunit according to claim 23, further characterized by the agent of processing is present in an amount of about 1 to about 5% w / w.

25. The wall of the cover, the binder or the subunit according to claim 1, further characterized in that it comprises an absorption enhancer.

26. The cover wall, the binder or the subunit according to claim 25, further characterized in that the absorption enhancer is chitosan, lecithin, lectin, a sucrose fatty acid ester, Vitamin E-TPGS; and combinations or mixtures thereof.

27.- A capsule having a cover wall, a binder, or other subunit of the capsule composed of a pharmaceutically acceptable composition, comprising a copolymer of Ammonium Methacrylate Type A Copolymer (Eudragit RL) present in an amount from about 15 to 50% w / w, a lubricant which is stearyl alcohol, and at least one excipient that modifies the solution which is a hydroxypropyl cellulose derivative, wherein the shell wall, binder or subunit are all comprised of the pharmaceutical composition.

28. The wall of the cover, the binder or the subunit according to claim 27, further characterized in that the hydroxypropyl cellulose is a mixture of hydroxypropyl celluloses having different molecular weights.

29. The cover wall, the binder or the subunit according to claim 28, further characterized in that the mixture of hydroxypropyl cellulose is composed of polymers having a molecular weight averaged of 80,000 and 140,000 (Klucel EF and Klucel JF).

30. The cover wall, the binder or subunit according to claim 1 or 17, further characterized in that the mixture of hydroxypropyl cellulose is composed of polymers having a molecular weight averaged 140,000 and 370,000 (Klucel JF and GF ).

31. The wall of the cover, the binder or the subunit according to claim 1 or 17, further characterized in that the mixture of hydroxypropyl cellulose is composed of polymers having an average molecular weight of 80,000 and 370,000 (Klucel EF and Klucel GF).

32. The wall of the cover, the binder or the subunit according to any of claims 28 to 31, further characterized in that the mixture of hydroxypropyl cellulose is equal to% weight / weight.

33. The cover wall, the binder or the subunit according to any of claims 28 to 32, further characterized in that the mixture of hydroxypropyl cellulose is approximately 32% w / w.

34. The wall of the cover, the binder or the subunit according to claim 27, further characterized in that the HPC is present in an amount of approximately 50% w / w.

35. - The wall of the cover, the binder or the subunit according to claim 27, further characterized in that it comprises a wicking agent.

36. The wall of the cover, the binder or the subunit according to claim 35, further characterized in that the wicking agent is lactose.

37. The wall of the cover, the binder or the subunit according to claim 36, further characterized in that the lactose is present in an amount of approximately 13% w / w.

38.- A capsule having a cover wall, a binder or a subunit of the capsule, comprising a pharmaceutically acceptable (sic) of:

39. - A pharmaceutical dosage form with multiple components comprising a plurality of subunits, each subunit being selected from a) a capsule compartment containing an active substance that is soluble or disintegrable in the gastrointestinal medium of the patient, for the release of the active substance contained in the capsule compartment, and b) a solid matrix; the capsule compartment and / or the solid matrix are comprised of a pharmaceutical composition comprising a copolymer of Ammonium Methacrylate Type A Copolymer or a Type B Copolymer of Ammonium Methacrylate present in an amount of about 15 to 80% weight / weight, less a hydroxypropyl cellulose present in an amount of about 30% to about 70% w / w and containing an active substance, the copolymer is soluble, dispersible or disintegrable in the gastrointestinal medium of a patient to release the active substance contained in the matrix solid, and in which, at least prior to administration to the patient, the subunits are mechanically welded or bonded in a mounted dosage form.

40.- The pharmaceutical dosage form with multiple components according to claim 39, further characterized in that the composition also comprises a lubricant present in an amount of about 10 to about 25% w / w.

41.- The dosage form with multiple components according to claim 39, further characterized in that at least one of the subunits is a compartment of the capsule containing the active substance having a wall with a thickness in the range of approximately 0.1 -0.8 mm.

42. The dosage form with multiple components according to claim 39, further characterized in that at least one of the subunits has a release rate in the gastrointestinal medium that is a substantially immediate release. 43.- A method for making an extruded pharmaceutically acceptable composition, comprising: a) mixing the Ammonium Methacrylate Type A Copolymer or a Type B Ammonium Methacrylate Copolymer present in an amount of about 15 to 80% w / w, at least one hydroxypropyl cellulose present in an amount of about 30% to about 70% w / w; a lubricant present in an amount of about 5% to about 25% w / w; and optionally a surfactant present in an amount of from 0 to about 10%, a plasticizer present in an amount of from 0 to about 10% w / w and / or a processing agent present in an amount of from 0 to about 10% w / w.; and b) introducing the composition of step (a) into a hot melt extruder to form the extruded pharmaceutically acceptable composition.