MXPA06000577A - Pharmaceutical compositions having a swellable coating. - Google Patents

Abstract

A pharmaceutical dosage form containing a pharmaceutical active that is not stable in the presence of acid comprises a core containing the active and a disintegrant, a swellable coating surrounding the core, and an enteric coating surrounding the swellable coating.

Description

PHARMACEUTICAL COMPOSITIONS THAT HAVE A HINCHABLE COATING BACKGROUND OF THE INVENTION "Throughout this application, several patent documents and other documents are mentioned, the contents of these documents are incorporated by reference herein The invention relates to the solid dosage dosage forms that they have coatings that protect the contained pharmaceutical active ingredients against degradation by the gastric acid fluid.In particular, dosage forms have coatings comprising substances that swell after contact with aqueous fluids.A number of pharmaceutical active ingredients do not They are chemically stable in acidic environments For this reason, oral administration can not be effective without some means to protect substances against contact with gastric fluid, however, this also has the generally undesirable effect of delaying availability. of the substance towards the body, since the systemic absorption a will not start until the substance has been released from its dosage form. The procedures for REF: 169395 have been considered to protect pharmaceutical dosage forms from being affected by the contents. stomach acids, and allowing the active ingredients to be made available only after the dosage form enters a more alkaline environment, such as the duodenum, jejunum or ileum. This typically involves coating the dosage form or particles containing an active pharmaceutical agent with a material that resists acid attack, but which dissolves or becomes permeable in a more alkaline environment. Lovgren et al., In the United States Patent No. 4,786,505, describe a pharmaceutically stable preparation of omeprazole that resists acid attack, but dissolves rapidly in neutral or alkaline media. The omeprazole particles are mixed with a water-soluble alkaline reaction substance, and the particles are coated with a "separation layer" which acts as a buffer zone to prevent contact of the drug and the acid groups that are present in it. the final coating material. Finally, the two-layer composition is coated with an enteric polymer coating that does not react with the acids. U.S. Patent No. 5,035,899 to Saeki et al., Relates to acid-labile drug compositions that are protected from contact with gastric acid. A core containing the drug is first coated with fine particles of a material having a low solubility in water, then coated with an enteric film forming material such as ethylcellulose. - .-. .. Mazcr-et-al -.-, - in-the-Patent-of-the-States - United No. 5,160,742, describes a sustained release system for an acid sensitive drug, such as a β-lactam antibiotic. Coated drug particles, suitable for inclusion in syrups or other formulations, are prepared by forming a core containing the drug, coating the core with a prolamine, and applying a final outer coating of an enteric substance such as an acid copolymer methacrylic Optionally, an additional coating of prolamin can be applied on the enteric coating layer. The drug is released over a prolonged time, starting after the coated particles enter a high pH environment. U.S. Patent No. 5,472,712 to Oshlack et al. , teaches the controlled release formulations having a drug-containing core, and a controlled release hydrophobic coating of ethylcellulose, optionally containing a hydrophilic pore-forming substance, such as hydroxypropylmethylcellulose. Optionally, the cores may have an intermediate "barrier" coating of a substance such as hydroxypropylmethylcellulose, which preferably does not affect the rate of dissolution of the final product. In the - Patent-of-the-United-States -No. 5 609-, 909 a Meyer et al. , oral formulations in which the unpleasant taste of a pharmacological substance is masked, but in which the drug is immediately bioavailable after exposure to the acidic fluid in the stomach, are prepared by coating a core particle containing the drug, with a mixture of a prolamine and a non-polymeric plasticizer. U.S. Patent No. 5,811,388 to Friend et al. Teaches the preparation of a dosage form in which the drug is not released into the upper gastrointestinal tract but is released into the lower gastrointestinal tract to directly treat diseases of the colon. The dosage form includes a core tablet containing the drug and a large amount of a hydrocolloid derived from plants, optionally coated with a film of an enteric substance. Lerner et al. , disclose in U.S. Patent No. 5,840,332, a composition that distributes a drug to a particular portion of the gastrointestinal tract, wherein a drug-containing core is coated with a water-insoluble material having embedded particles of insoluble hydrophilic material in water The coated core can optionally be additionally coated with an enteric polymer. . "-" ^ JLa ^ - atente- ... de ^ los ^ .JE &ampados ^ Unidos-No, .- 6 -, - 3 6 ^ 2-6-9- a Hsiao et al. , teach the formulations. Oral for acid-sensitive drugs, where the drug substance is mixed with an alkaline material such as trisodium phosphate, and coated on a core, such as a tablet, then an enteric coating is applied on the layer of the drug substance. Methods for producing films, sheets and articles from zein are taught in U.S. Patent No. 6,635,206 to Padua et al. There is a need for a drug-containing dosage form in which the pharmacological substances will not be exposed to the acid in the stomach, but will be released rapidly when the dosage form enters a more alkaline environment. BRIEF DESCRIPTION OF THE INVENTION In one embodiment, the invention includes a pharmaceutical dosage form comprising: a solid core comprising an active pharmaceutical product and a disintegrator; an inflatable coating that surrounds the core; and an enteric coating surrounding the inflatable coating.

The dosage form can have different modalities, including coated tablets or capsules containing coated pellets or coated pellets. A preferred aspect of the invention is a form of -dose in the -e-ua-1-the-pharmaceutical-active-compound is substantially retained while the dosage form is present in the stomach, but wherein the active pharmaceutical agent is rapidly released after the dosage form enters an environment having a pH value of at least about 5. Also included in the invention is a pharmaceutical dosage form comprising: a solid core comprising an active pharmaceutical agent sensitive to acid, and a disintegrator; an inflatable coating comprising a hydrocolloid-forming component, which surrounds the core; and an enteric coating surrounding the inflatable coating. The invention further includes a pharmaceutical dosage form comprising: a solid core comprising a benzimidazole and a disintegrant; an inflatable coating comprising one or more hydrocolloid formers selected from zein, crospovidone, and a hydroxypropylcellulose, which surrounds the core; and an enteric coating comprising a copolymer of methacrylic acid and ethyl acrylate, surrounding the inflatable coating. Yet another aspect of the invention is a method for treating a medical condition comprising orally administering a pharmaceutical dosage form according to any of the preceding aspects and modalities, in which method: the dosage form remains substantially intact during - e- 1 transit -in-the-stomach, -the enteric-coating is removed in environments of the digestive system that have pH values above about 5; the aqueous fluids penetrate the areas of the dosage form where the enteric coating has been removed, causing the formation of the hydrocolloid in the inflatable coating; the aqueous fluids pass through the hydrocolloid to hydrate the core; . and the hydrated core becomes fragmented, releasing the active pharmaceutical agent from the dosage form. In addition, the invention includes a method for preparing a pharmaceutical dosage form, comprising the steps of: combining the components comprising an active pharmaceutical agent and a disintegrator, and forming a solid core; coating the core with an inflatable coating - · comprising a hydrocolloid-forming component, and applying an outer coating comprising an enteric substance resistant to acid. Preferred swelling agents in the swellable coating include prolamines; vinylpyrrolidone polymers; cellulose derivatives; starches; carboxyvinyl polymers; alginates; pectins; agar; and gums. Zein, crospovidone, or a hydroxypropyl cellulose are more preferred for use as the swelling agent. DETAILED DESCRIPTION OF THE INVENTION The present invention provides a dosage form -pharmaceutical comprising a core- ^ which includes an active pharmaceutical ingredient, and an inflatable coating surrounding the core. The core comprises at least 50%, at least 60%, at least 70%, preferably at least 80%, preferably at least 82.5%, preferably at least 85%, preferably at least 87%, preferably at least 88%, preferably at minus 89% of the total pharmaceutical composition. The core can also comprise at least 90%, at least 91%, at least 92% or at least 93% of the total pharmaceutical composition. In this application, the terms "active pharmaceutical ingredient", "active pharmaceutical agent" and "active" are used interchangeably to refer to a component, of a pharmaceutical dosage form that provides a therapeutic effect after administration to a subject. This invention is particularly applicable to acid sensitive pharmaceutical actives, which exhibit instability in a low pH environment, such as the * benzimidazole derivatives, including their optically active isomers. Specific examples of useful benzimidazole compounds include rabeprazole, omeprazole, esomeprazole, lansoprazole and pantoprazole. Other drugs for which the invention will be useful include, without limitation: pharmaceutical actives that react with the enteric coating components, examples being those which are non-soluble with the enriched coatings, such as fluoxetine and duloxetine; and highly alkaline drugs which can react with the acid groups to reduce the insolubility in acid of the coating, such as diclofenac sodium and piroxicam. As contemplated herein, an "inflatable coating" is a coating that increases in volume after contact with aqueous fluids. This swelling usually occurs through the. water absorption. The inflatable coating adds 0.1-10%, 0.5-8%, 0.7-7%, 1-5%, 15 1.3-3%, 1.5-2%, approximately 2%, or approximately 1.5% by weight of the core. In another modality, the inflatable coating adds 0.1-5%, 0.1-4%, 0.1-3%, 0.1-2%, or 0.1-1% to the weight of the core. In general, the inflatable coating, after 20 the wetting, becomes a hydrocolloid, which is a gelatinous suspension of microscopic particles in water. Preferably, the hydrocolloid is formed from a prolamine, such as gliadan, ordein, or, more preferably, zein. Zein is extracted from corn as an amorphous powder Granular, straw-colored to pale yellow, or as fine flakes and various commercial extracts have molecular weights in the range of 25,000 to 35,000. Zein is insoluble in water and insoluble in alcohols, but soluble in aqueous alcoholic solutions. Chemically, zein is clearly abundant - in glutamine and devoid - of lysine and tryptophan. The zein comprises about 20 to 22% glutamic acid and glutamine, 17 to 20% leucine, 5 to 9% proline, 8 to 10% alanine, 4 to 7% phenylalanine, 3 to 7% isoleucine, 4 to 6% serine, 4 to 5% asparagine and 3 to 5% tyrosine. All the other amino acids in the zein each comprise less than 3%. Zeina has been generally recognized as safe (GRAS) by the United States Food and Drug Administration since March 1985, for use in food and pharmaceutical products. Zein is commercially available from various sources, including Freeman Industries LLC, Tuckahoe, New York USA; among the commercial zeina products sold by this company are those designated as Zeina F4000, Zeina 4400, Zeina F6000, Zeina G-10, Aqua Zein, and Aqua Zelna Neutral. A currently preferred zein for the present invention is Zeina F6000, which has been re-extracted to reduce its color level (from xanthophyll). Zeina F6000 is a very light yellow granular powder, with an approximate molecular weight of 35,000, and a bulk density of 0.125-0.21 g / ml. It contains 90 to 96% of, zein protein, calculated on a dry basis. The hydrocolloid can also be formed from a hydroxypropylmethylcellulose. The viscosity of an aqueous solution at 2 percent by weight of various products of Jaidroxyp-ropymethylcellulose,, and approximately 4,000 mPa-s to approximately 100,000 mPa-s. In one embodiment, hydroxypropylmethylcellulose is Type 2208 Substitution of the United States Pharmacopoeia, also called hypromellose 2208, with a viscosity of 10 about 15,000 mPa-s, which is commercially available as Methocel K15M. In another modality more, the. hydroxypropylmethylcellulose is the Type 2910 Substitution of the United States Pharmacopoeia, also known as hypermellose 2910, with a viscosity of approximately 4,000. 15 mPa-s, which is marketed as Methocel E4M. METHOCEL is a trademark of Dow Chemical Company, Midland, Michigan, USA. Other useful substances to form a. hydrocolloid include, without limitation, crospovidone; croscarmellose 20 sodium; cellulose derivatives such as hydroxyethylcellulose, hydroxypropylcellulose or methylcellulose; gums such as plant extracts, plant exudates, plant seed extracts and microbial fermentation products; starches that include pregelatinized starches and 25 modified; and synthetic materials such as carboxyvinyl polymers, including carbopoles. Additional specific examples include alginates, pectins, low methoxy pectins, agar, carrageenan, gum arabic plus, tragacanth, karaya gum, ghatti gum, locust bean (aigar-reba) T-gua-rv = -dextran, - xanthan,. carrageenan, -tara, - Khaya grandfolia, gelano, Konjac manna, galactomannan, funorano, acetano, welan, ramsan, furceleran, succinoglicano, scieroglicano, schizophilano, crudlan, pullulano, karaya and tamarind. In addition to the pharmaceutical active, the core additionally comprises a disintegrator which, in an aqueous environment, assists in the physical processing of any material with which it is combined. A disintegrator does not promote dissolution or a chemical change in the material that is fragmented. The following are examples of useful disintegrants: starches such as potato or tapioca starch, modified starches (such as sodium starch glycolate) and partially pregelatinized starches (such as Starch 1500); polyvinylpyrrolidones, including modified polyvinylpyrrolidones (such as crospovidone, polymerized under conditions that promote crosslinking); celluloses such as microcrystalline cellulose, modified celluloses (such as low substitution hydroxypropylcellulose, croscarmellose sodium and calcium carboxymethyle cellulose); formaldehyde-casein compounds (such as Esma-Spreng, RTM); resins, such as potassium polacrilin sold by Rohm and Haas Company, Philadelphia, Pennsylvania, USA, using the trademark AMBERLITE IRP88; defatted soybean bean extracts; alginic acid; agar-agar; - calcium carbonate; - Calcium osphate - and - sodium carbonate. U.S. Patent No. 6,696,085 to Rault et al. Teaches that acrylic polymers are useful as tablet disintegrators. In addition to the above, the core may contain any desired components such as binders, lubricants, antioxidants, etc., as are well known in the art and discussed below. The pharmaceutical dosage form further comprises an enteric coating surrounding the inflatable coating. An "enteric coating" is a coating that is substantially insoluble at the acidic pH conditions of the stomach, but is substantially soluble or permeable to water, at the higher pH conditions of the intestines. In this invention, the enteric coating protects the inflatable coating against contact with the acidic environment of the stomach, but allows the contact of the inflatable coating with the more alkaline intestinal fluid. The enteric coating can be chosen to provide objective release to a particular section of the intestine. For example, an enteric coating can provide distribution to the duodenum (pH> 5.5), to the jejunum (pH 6.7), or to the ileum (pH up to 7.5). The intermediate distribution points can be achieved by combining different coating materials or by varying the thickness of the coating. The materials, .. de_. coating of the cellulose-based coatings, such as cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, methacrylate-based coatings, coatings based on polyvinyl acetate phthalate, and shellac-based coatings. . In the present invention, methacrylate-based coatings are preferred and several useful products are commercially available from Rohm GmbH & amp;; Co., Darmstadt, Germany under the trademark EUDRAGIT. Eudragit L100-55 is especially preferred. Eudralgit L 100-55 is a powder, Eudragit L 30 D-55 spray-dried, which can be reconstituted. Eudragit L 30 D-55 is an aqueous dispersion of a pH-dependent polymer, soluble at or above pH 5.5 for targeted distribution in the duodenum. Eudragit L. 100-55 retains the pH dependence of Eudragit L 30 D-55, and is thus soluble at or above pH 5.5 and provides distribution to the duodenum. Eudragit L 100-55 and Eudragit L 30 D-55 are copolymers of methacrylic acid and ethyl acrylate in a 1: 1 ratio. These have the molecular formula: (C2H202-C4H602) x and have been assigned with Register No. 25212-88-8 of Chemical Abstracts. Eudragit L100-55 also complies with the United States Pharmacopeia specification for the Type C Methacrylic Acid Copolymer. In one embodiment, the enteric coating comprises 1-40%, 3_-35%, 5-30%, 6-20. % or 7-10% or 85% of the total composition. In yet another modality, the enteric coating comprises at most 20%, at most 17.5%, at most 15%, at most 12.5%, at most 10%, at most 9%, at most 8% , at most 7%, at most 6%, at most 5%, or at most 4% of the total composition. Optionally, an excipient that modulates the release of the pharmaceutical active is added to the inflatable coating. Modulation can be achieved by facilitating or preventing access of water to the core. Useful excipients include plasticizers such as lactic acid, acetamide of lactic acid, glycerin, glyceryl monostearate, triacetin, sorbitol, triethyl citrate, polyvinylpyrrolidone, triethylene glycol, tricresyl phosphate, dibutyl tartrate, ethylene glycol monooleate, palmitic acid, stearic acid. , oleic acid, dibutyl sebacate, acetylated monoglycerides, and other oils and waxes, as well as polyethylene glycol 300, 400, 600, 1450, 3350 and 8000. Additional excipients that modulate the release rate of the active include water-soluble surfactants, such as such as sodium lauryl sulfate and docusate sodium, and enteric coating materials, such as Eudragit L 100-55, which are mixed in the inflatable coating. Without being limited to any theory of simple operation, it is believed that the enteric coating material incorporated in the inflatable coating dissolves after contact with the intestinal fluid and forms channels in the inflatable coating, which facilitate the entry of intestinal fluids. towards the nucleus. In one embodiment, the enteric coating material constitutes approximately 0.1-30%, 0.5-20%, 1-17.5%, preferably 5-15% or more preferably 5-10% of the swellable coating. In another embodiment, the enteric coating material comprises 10 to 50%, 15 to 40%, preferably 20 to 30% of the swellable coating. Again, without being limited to any theory, it is postulated that the water-soluble surfactant causes rapid wetting of the swellable coating after exposure to intestinal fluids, thereby aiding the entry of fluid into the nucleus. When water-soluble surfactant is present, it constitutes approximately 0.001-30%, 0.005-20%, 0.01-10%, 0.03-8%, 0.05-6%, 0.07-4%, O.OS-2% or 0.1 -1% by weight of the inflatable coating. A preferred range is 0.01 to 10%. For example, when zein is present in the swellable coating, the degree of swelling controls its permeability, and the highest permeation is achieved at the largest swelling volume. See. Y. K. Oh et al., "Swelling and Permeability Characteristics of Zeine Membranes," PDA Journal of Pharmaceutical Science and Technology, Vol. 57, pages _.5- -2-0-8-217- - 20? 3) - for-information-- additional concerning. -a- diffusion through zeina films hydrated. The addition of plasticizers to the zein affects its permeability to water. The combination of zein with hygroscopic plasticizers such as glycerol, 10 Triethylene glycol, and levulinic acid, produces more water absorption than in unplasticized zein. However, by incorporating hydrophobic plasticizers such as dibutyl tartrate and oleic acid into the zein, it results in less water absorption than the zein does not. 15 plasticized. The greater the degree of water permeation, the weaker the tensile force and the coating can simply open the way to provide the complete release of the pharmaceutical active. See J.W. Lawton, "Plasticizers for Zein: Their Effect on Tensile Properties and 20 Water Absorption of Zeina Films, "Cereal Chemistry, Vol. 81, pages 1-5 (2004) for a discussion of the water absorption characteristics of plasticized, voided zein films The modulation of the active release profile 25 Pharmaceutical by an excipient, such as a plasticizer, is not limited to zein In general, when varying the amount and type of plasticizer the tensile strength of the coatings is affected.The use of hygroscopic versus hydrophobic excipients also affects the profile of release of - _J5 = -L = m¿sm-way ^ = that «-s -discute, with respect to the - zei - - - - To form the nuclei of the invention, the pharmaceutical active is mixed. with one or more pharmaceutically acceptable carriers, such as water, saline, sodium citrate or dicalcium phosphate, and / or any one of the following: fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol or silicon acid cico binders, such as carboxymethylcellulose, alginates, gelatin, copolividonum (such as the PLASDONE ™ * S-630 copolymer of N-vinyl-2-pyrrolidone and vinyl acetate, sold by 15 International Specialty Products, Wayne, New Jersey USA), copolymers of ethylene oxide and propylene oxide such as Poloxamer 407, sucrose, or acacia; humectants, such as glycerol; disintegrators, such as starch, polyvinylpyrrolidones, celluloses, formaldehyde-casein compound, defatted soybean extracts, alginic acid, agar-agar, calcium carbonate, calcium phosphate, potato starch or tapioca or sodium carbonate; lubricants such as talc, calcium stearate, magnesium stearate or solid polyethylene glycol; the agents of the solution, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol and glycerol monostearate; surfactants, such as sodium lauryl sulfate or docusate sodium; Absorbents, such as kaolin or benthic-tartaric acid; -and-islets; -s-sta-bilj.-zado is -.- The-active »-pharmaceutical can also be mixed with damping agents such as alkali metal carbonate and oxides of alkaline earth metal. This list is not exhaustive, many other functional components that are known in the art will also be useful in the present invention. The cores of the invention can be in the form of tablets, mini-tablets, granules, particulates or pellets. The tablets and mini-tablets can be manufactured by direct compression or by any other process known to those skilled in the art. Dry granulation, wet granulation, melt granulation, or any other process known to those skilled in the art, can be used to form granules. The particulates and the pellets can be manufactured by any method known to those skilled in the art, such as extrusion or spheronization. The pellets can also be processed by pelletization in molten form or by coating of non-comparable. The wet cores are dried by conventional drying methods such as air drying, or drying under conditions of low pressure and / or heat. The cores of the invention are coated with an inflatable coating, followed by the application of an external enteric coating. In general, the coatings may be made by any techniques known in the art, such as drum coating (including closed or perforated drum coating), coacervation, or coating fluidized bed. The fluidized bed may contain a rotor insert and / or a Wurster column insert. The coatings can be generally plasticized according to their polymeric base such as: those based on cellulose, which include cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylethylcellulose, ethylcellulose, methylcellulose, microcrystalline cellulose; carrageenan; those based on methacrylic acid or methacrylate, such as methacrylic acid, methacrylate, acrylate, methacrylate, ethacrylate, methyl methacrylate, or copolymers thereof; or those based on polyvinyl acetate phthalate. Typically, the polymer is combined with a solvent such as water, and a plasticizer, such as polyethylene glycol, lactic acid, acetamide, glycerin, glyceryl monostearate, triacetin, sorbitol, triethyl citrate, polyvinylpyrrolidone, triethylene glycol, tricresyl phosphate, tartrate dibutyl, ethylene glycol monooleate, palmitic acid, stearic acid, oleic acid, or dibutyl sebacate. Optionally, any of the following elements can also be added: an anti-adhesion agent, an anti-foaming agent, a --reile-nadQi -, - u sur-f-ac-fea-nte, - a dye, - a-flavoring agent, and combinations of any two or more thereof. After application of the enteric coating, the pharmaceutical composition may have identification information printed thereon, using inks and methods known in the art, such as offset printing. Pharmaceutically acceptable inks that can be used with transfer-based printing include Markem "2200, 2202, 2212 and 2222, Markem Corporation, Keene, New Hampshire, USA These inks are typically based on shellac and contain pigments. slimming aggregates are added to any of these inks, to increase or decrease the drying rate and / or to modify the viscosity.After application, these inks are normally air dried.Other pharmaceutically acceptable inks include those products sold as Opacode "and Opacode "15 WB, both of which contain pigments, titanium dioxide, and a solvent, and are sold by Colorcon, West Point, Pennsylvania, USA. Many other printing inks are known to those skilled in the art, and any of these will be useful for the dosage forms of the invention Optionally, the coated dosage forms -entér-ie © --can be-ad-i -ionally- -recubi-ertas- ~ co-a thin film. Frequently, the film will be colored to facilitate the identification of the product and for aesthetic purposes; in this case, any impression of desired information will be made after the film coating has been applied. Many suitable film coating products are commercially available, including those sold by Colorcon, West Point, Pennsylvania, USA, using the trademarks OPADRY and OPAGLOS. These Colorcon products are dry powders, which contain a polymer, plasticizer, and pigment, which are mixed with water or a solvent, such as alcohol, and sprayed onto tablets or other solid dosage forms. This film coating process, and alternative film coating products, are well known in the art. - Coated tablets, pellets, granules or particulates can be enclosed in capsules for ease of administration. The enclosure can be achieved by any method known in the art, such as filling a preformed capsule. Such capsules can be comprised of gelatin or any other material known to those skilled in the art. Without being limited to any theory, it is postulated that after an enteric coating dissolves in the ^ ._. ^ - nt.est oT-ei ^ cu ^ hi-nc able -abso-rbe-intestinal-f-l-uidos and expands outwards. Thus, initially, the inflatable coating expands like a balloon that is inflated and does not explode. As the coating swells, its water permeability increases. The 10 hypothesis that the inflatable coating contains microchannels through which the water enters by diffusion and reaches the nucleus. Water causes the nucleus to begin to fragment. Some of these fragments can sting the inflatable coating, leading to the entry of 15 more water. The additional water produces even more fragmentation of the core, which is thought to cause more fragments to puncture the inflatable coating. It is believed that this cycle continues until the pharmaceutical active is completely released, or until, the inflatable coating is so 20 weakened by the absorption that the coating breaks. Furthermore, without being limited to any theory, it is believed that the release of the active can be modulated by several factors, different from the presence of an enteric coating. One such factor is the selection of a 25 hydrocolloid forming substance, in the inflatable coating. Hydrocolloids vary in their ability to swell and therefore in their permeability to intestinal fluid. It is postulated that the permeability of the hydrocolloid affects the hydration rate of the nucleus and the fragmentation-esu-l-tante-of the nucleus. -The-hydrocolloids-also differ in tensile strength, which is thought to affect the percentage of core fragments that are capable of puncturing the inflatable coating after fragmentation. The number of fragments that are capable of achieving discharge directly affects the release of the pharmaceutical asset. It is also believed that the number of openings created in the inflatable coating further affects the release of the active by allowing more intestinal fluid into the core, producing more fermentation. The tensile strength further affects if and when an inflatable coating breaks due to weakening caused by water absorption, resulting in complete release of the active. In addition, some hydrocolloids are eroded after swelling, which affects the ease with which the core fragments are capable of inflating the inflatable coating. Another factor may be the optional addition of an excipient to the inflatable coating, which modulates the release of the pharmaceutical active. Such agents can increase or decrease the permeability of the hydrocolloid to the intestinal fluid. This permeability affects the. amount of intestinal fluid that makes contact with the nucleus and leads to fragmentation. It is hypothesized that the fragments will puncture the inflatable coating after the fragmentation., -are-l-o ~ Gual- ^ e - a-f-ecta-la-l-i-berae-i p r. It is further believed that the openings created in the inflatable liner provide conduits for the entry of additional intestinal fluid into the core, further accelerating fragmentation. A third factor is, the use of a disintegrator in the nucleus. The use of a disintegrator increases the rate of fragmentation of the core, which is thought to increase the frequency with which the fragments create empty spaces in the inflatable coating. The clear increase in the fragments exiting through the inflatable coating raises the release rate of the pharmaceutical active. In addition, the highest number of empty spaces created in the inflatable coating is believed to allow more water to enter the core, causing an even greater fragmentation of the asset. In addition, the disintegrator can increase the force at which the core fragments impact the inflatable coating, which can result in more fragments successfully creating voids in the inflatable coating. These more forced disintegrations further elevate the release rate of the pharmaceutical active by allowing a greater number of fragments in the core to pass through the inflatable coating. Such disintegrators also produce additional openings for the intestinal fluid to hydrate and fragment the active one, = - | 5 ™ -eendue-i-ende-a-to-lHL-be-ra-eión-adi-eional ~ del-activo -.- - Although the release rate of the pharmaceutical active can be modulated as described above, this invention has no objective of producing sustained release formulations, whereby the active The pharmaceutical is released at a controlled rate over a prolonged period of time, such as 12 or 24 hours. Rather, a feature of this invention is a delayed release of the ingested pharmaceutical active, until the dosage form has reached the intestinal tract, where the Alkaline pH conditions will not affect an acid-sensitive pharmaceutical active, thus facilitating an essentially complete and rapid release of the pharmaceutical active for systemic absorption. The following examples are provided for 20 to help understand the invention, and is not intended, and should not be considered, to limit the invention in any way, as defined in the appended claims. In the examples, the ingredients that are volatile during drying and therefore not present in the final product, are not 25 included in the tabular list of ingredients; such ingredients, however, are mentioned as solvents, etc. in the discussions of the preparation procedure. In addition, the added weight when printing information on a finished dosage form is insignificant and therefore is not included in the final cumulative weights. Percentages are expressed on a weight basis, unless the context clearly indicates otherwise. EXAMPLE 1 Tablets containing either 20 ... or ... 40 mg of pantoprazole were prepared using the following components and procedure: Ingredients Amount (mg) per Amount (mg) per 20 mg tablet 40 mg tablet Dry Mixed Core Tablet Pantoprazole sodium 22.55 45.1 Mannitol (Peariitol SD-200) 110.95 221.9 Crospovidone 8.25 16.5 Sodium carbonate 3.75 7.5 Granulation Anhydrous sodium carbonate 3.75 7.5 Hydroxypropylcellulose (Klucel LF) 4 8 Lubrication Crospovidone 8.25 16.5 Talcum 1.5 3 Calcium stearate 2 4 Total 165 330 Zein F6000 Inflatable coating 2.07 4.13 Methacrylic acid copolymer (Eudragit L 100-55) 0.41 0.82 Total Cumulative 167.48 334.95 Enteric coating Ingredients Quantity (mg) per tablet Quantity (mg) per 20 mg tablet 40 mg Core Tablet Methacrylic Acid Copolymer (Eudragit 9.25 18.49 L 100-55) Triethyl Citrate 0.93 1.85 Titanium Dioxide 1.83 3.65 Talc 1.41 2.81 Total Accumulated 180.83 361.65 Opadry Film Coating Yellow OY-52945 4.52 9.04 Cumulative Total 185.42 370.79 Opacode Black Print S-1-8152 HV As Sufficient Css (css) The tablet cores were prepared by granulating a dry mixture of pantoprazole sodium, mannitol, crospovidone and sodium carbonate with an aqueous solution of hydroxypropylcellulose (Klucel LF) and sodium carbonate. anhydrous. The granulates were dried using conventional drying techniques. The dried granules were then lubricated with crospovidone, talc and calcium stearate. The lubricated granules were compressed into cores. The cores were subcoated with a mixture of zein, Eudragit L 100-55, water, and isopropyl alcohol, and dried. The enteric coating on top of the subcoat was made using Eudragit L 100-55 with isopropyl alcohol as the solvent, and triethyl citrate as the plasticizer. Talc and titanium dioxide were used as the lubricant and the opacifier, respectively. After drying, the enteric coated tablet was film coated using Opadry Yellow OY-52945 and printed with Opacode Black S-1-8152 HV. EXAMPLE 2 Tablets containing either 20 or 40 mg of 5-panfeoprazole were prepared using the following components and procedure. Ingredients Amount (mg) per Amount (mg) per 20 mg tablet 40 mg tablet Dry Mixed Core Tablet Pantoprazole Potassium 22.55 45.1 Mannitol (Pearlitol SD-200) 1 0.95 221.9 10 Crospovidone 8.25 16.5 Sodium Carbonate 3.75 7.5 Carbonate Granulation anhydrous sodium 3.75 7.5 Hydroxypropyl cellulose (iucel LF) 4 8 Lubrication Crospovidone 8.25 16.5 | Talc 1.5 3"15 Calcium stearate 2 4 Total 165 330 Inflatable coating Zeina F6000 2.07 4.13 Methacrylic acid copolymer 0.41 0.82 (Eudragit L 100-55) Total Accumulated 167.48 334.95 Enteric coating Methacrylic acid copolymer 9.25 18.49 20 (Eudragit L 100-55) Triethyl citrate 0.93 1.85 Titanium dioxide 1.83 3.65 Talc 1.41 2.81 Total Cumulative 180.83 361.65 Opadry Film Coating Yellow OY-52945 4.52 9.04 Cumulative Total 185.42 370.79 Printing 25 Opacode black S-1-8152 HV css css The cores of the tablets were prepared by granulating a mixture of ca of pantoprazole sodium, mannitol, crospovidone and sodium carbonate with an aqueous solution of hydroxypropylcellulose (Klucel LF) and anhydrous sodium carbonate. The granulates were dried using conventional drying techniques. The dried granules were then lubricated with crospovidone, talc and calcium stearate. The lubricated granules were compressed into cores. The nuclei were subcoated with a mixture of zein, Eudragit L 100-55, water, and isopropyl alcohol. After drying, an enteric coating on top of the subcoat was performed using Eudragit L 100-55 with isopropyl alcohol as the solvent and triethyl citrate as the plasticizer. Talc and titanium dioxide were used as the lubricant and the opacifier, respectively. Then, the tablet coated with a dry enteric coating was re-coated with film using Opadry Yellow OY-52945 and printed with Opacode Black S-1-8152 HV. EXAMPLE 3 Capsules containing 40 mg of omeprazole were prepared using the following components and procedure.

Ingredients Quantity / capsule (mg) core pellets Omeprazole 40 Mannitol .236 Crospovidone 18 Hydroxypropylmethylcellulose, 5 cps 8 Poloxamer 407 5 Ingredients Quantity / capsule (mg) Meglumine 3 Total 310 Zeta F6000 Inflatable Coating 6.2 Total Cumulative 316.2 Enteric Coating Hydroxypropylmethylcellulose phthalate (HP 55) - - 63.24 Trilethyl Citrate 6.31 Talcum 9.45 Cumulative Total 395.25 The omeprazole core pellets were prepared by mixing omeprazole, mannitol, crospovidone, meglumine and poloxamer, and granulating this mixture with hydroxypropylmethylcellulose as a binder. The granules obtained from. In this way, they were subjected to extrusion and spheronization to produce spherical pellets. The pellets were then dried by conventional drying techniques. The pellets were coated with an inflatable coating containing zein and sodium lauryl sulfate dissolved in a mixture of isopropyl alcohol and water, and then dried. The enteric coating was prepared by dissolving the hydroxypropylmethylcellulose phthalate and triethyl citrate in a mixture of isopropyl alcohol and acetone, and. dispersing the talc in this solution, which was then placed in layers on the intermediate coating. The coated pellets were measured in a gelatin capsule.

EXAMPLE 4 Tablets containing 40 mg of omeprazole were prepared using the following ingredients procedure.

The omeprazole core pellets were prepared by mixing omeprazole, mannitol, crospovidone, meglumine and poloxamer, and granulating this mixture with hydroxypropylmethylcellulose as a binder. The granules were dried in a fluidized bed dryer and the dried granules were compressed into tablets or mini-tablets. These core tablets or mini-tablets were coated with the intermediate coating solution containing zein and sodium lauryl sulphate, dissolved in a mixture of isopropyl alcohol and water, and then dried. The enteric coating was prepared by dissolving phthalate of hydroxypropylmethylcellulose and triethyl citrate in a mixture of "isopropyl alcohol and acetone, and dispersing the talc in --- 5 ~ -e-sta-~ -so-ionion 7 - = - The - then - was then placed in - layers on the intermediate coating EXAMPLE 5 Tablets containing 40 mg of pantoprazole were prepared using the following components and procedure. fifteen twenty 25 Core tablets were prepared by mixing pantoprazole sodium sesquihydrate with mannitol, crospovidone, Plasdone S630, talc and magnesium stearate, and direct compression into tablets. These core tablets were · | - ^ - 5 ---- coated-er-tas --- co-n = -.- &4-uei0n - of-ecovering-h-inc-ha -ble - which contained zein and sodium lauryl sulphate dissolved in a mixture of isopropyl alcohol and water, and then dried. The enteric coating was prepared by dissolving phthalate of hydroxypropylmethylcellulose and triethyl citrate, in a mixture of isopropyl alcohol and acetone, and dispersing the talc in this solution, which was then placed in layers on the intermediate coating. EXAMPLE 6 Capsules containing esomeprazole were prepared using the following components and procedure. 25 Enteric coating Methacrylic acid copolymer Type C 110 Triethium citrate 11 Titanium dioxide 15.29 Talc 16.5 Cumulative total 1410.61 The core was prepared by mixing the esomeprazole magnesium trihydrate, mannitol, crospovidone and sodium lauryl sulfate and granulating this mixture with an aqueous solution of ideal flake. The granules were then subjected to extrusion and spheronization to obtain spherical pellets. The pellets were dried by conventional drying techniques. The dried pellets were coated with the intermediate coating solution containing zein and sodium lauryl sulfate dissolved in a mixture of isopropyl alcohol and water, and then dried. The enteric coating was prepared by dissolving the Methacrylic Acid Copolymer type C and triethium citrate in isopropyl alcohol, and dispersing the talc and titanium dioxide in this solution. The coated pellets are filled into gelatin capsules, giving 4000 capsules each containing 40 mg esomeprazole.

EXAMPLE 7 prepared Esomeprazole Tablets, using the following ingredients and procedure. - - 5 fifteen Esomeprazole magnesium trihydrate,. Magnesium oxide, copovidone, crospovidone, mannitol and silicon dioxide were mixed, then the stearyl fumarate was added 20 of sodium with additional mixing. This mixture was compressed into core tablets. The tablets were coated with an aqueous alcoholic solution of zein, and then dried. Finally, the ingredients of the enteric coating were dispersed in water and coated on the tablets 25 coated with zein, followed by a final drying.

EXAMPLE 8 Tablets containing rabeprazole sodium were prepared, using the following components and procedure.

Sodium rabeprazole, crospovidone, Plasdone S630 and mannitol (Pearlitol SD 200) were mixed with mannitol (Pearlitol DC 400) for 20 minutes. The talc and the magnesium stearate were then added to the mixture and mixed for 5 minutes. This lubricated mixture was then compressed into tablets. The core tablets were subcoated with an aqueous-alcoholic solution of zein (weight increase of 2.5 + 0.5%) and dried. The subcoated tablets were coated with the enteric coating solution - - - (- inereme-nto-in-weight of -8- to -9%) |.- - EXAMPLE 9 Rabeprazole sodium tablets were prepared, using the following components and process. Ingredients Amount / Tablet (mg) Core Tablet Rabeparzole sodium 20 anitol (Pearlitol SD-200) 97.01 Low substitution hydroxypropylcellulose (LH21 ("L-HPC") 14.4 Magnesium oxide 40 Sodium lauryl sulfate 1.8 Hydroxypropylmethylcellulose, 5 mPa-s 3 Talc 1.54 Magnesium stearate 2.25 Total 180 Zein 6000 Inflatable Coating 4.9 Triethyl Citrate 0.49 Total Accumulated 185.39 Coating Eudragit L 100-55 14.46 Triethyl Citrate 1.44 Talc 0.79 Total Accumulated 202.08 Opadry Film Coating Yellow OY-52945 5.05 Total Accumulated 207.13 Opacode Black Printing Css Magnesium Oxide It was siphoned through a 60 mesh screen. Rabeprazole sodium, L-HPC, mannitol (SD 200) and siphoned magnesium oxide were siphoned through a 40 mesh screen. The materials were then mixed for 30 minutes at a mixer-Rapid granulator Sodium lauryl sulfate (SLS) was dissolved in purified water and hydroxypropylmethylcellulose (HPM) was dissolved C) in hot purified water. The rabeprazole sodium mixture was mixed with the SLS and HPMC solutions. The wet mass was dried in a fluid bed dryer and the dried granules were siphoned through a 20 mesh screen. The siphoned granules were mixed with L-HPC in a double cone mixer for 5 minutes. Magnesium stearate was added (siphoned through a 60 mesh screen) into the mixture, and mixed for 5 minutes. The lubricated mixture was then compressed into core tablets. The core tablets were coated with an aqueous-alcoholic coating solution of zein (weight increase of 2.5 + 0.5%) and dried. The coated tablets were additionally coated with the enteric coating solution (increase in weight of 8.0 ± 1.0%). The enteric-coated tablets were further coated with the Opadry solution until the increase in weight was 2.0 ± 0.5%. Then, the film coated tablets were printed with Opacode black ink. EXAMPLE 10 Pantoprazole sodium tablets, prepared according to Example 5, were tested according to Method 724 of the Pharmacopoeia of the United States Pharmacopeia, United States Pharmacopeial Convention, Inc., Rockville, Maryland, USA, pp. 1944-1947, 2000, using Method B and Apparatus 1 (described in Method 711"Dissolution," on page 1942.) One tablet was first subjected to 0.1 N hydrochloric acid with stirring, for two hours at 37 ° C. C. The tablet was then immersed in a phosphate buffer pH 6.8, with shaking, and samples of the buffer were taken at intervals for analysis, to determine the amount of the drug released from the tablet. Next are the data obtained from the six test tablets. The amount of the drug released to the acid is not shown, but it was small. In general, the release of up to 10% of the drug towards the acid is considered acceptable for enteric coated dosage forms. For purposes of this invention, a pharmaceutical active is considered to be substantially retained within the dosage form, if. less - about ten percent by weight is released to 0.1 N hydrochloric acid, under the test conditions of USP.

These results show that the drug was substantially completely released within sixty minutes at pH 6.8. . EXAMPLE 11 As in Example 10, rabeprazole sodium tablets prepared according to Example 9 were tested by Drug Release Method 724 of USP. However, the alkaline solution for the second part of the test was a phosphate buffer adjusted to pH 8.0 and also containing 0.5 weight percent sodium lauryl sulfate. The results were obtained as follows.

These results show that the drug was substantially completely released within sixty minutes at pH 6.8. EXAMPLE 12 Esomeprazole tablets were prepared using the _-5 s-g-ingredients-ingredients and - the-procedure-descri-to - later. 10 fifteen Magnesium esomeprazole trihydrate, magnesium oxide, Plasdone S-630, silicon dioxide and mannitol. They were sieved and mixed, then the sodium stearyl fumarate was added and the mixture was mixed, and finally the tablets were formed by direct compression of the mixture. The zein was dissolved in aqueous alcohol and coated on the tablets. The coated tablets were then dried. Additional tablets were similarly prepared, further including either 7 mg or 10 mg of the crospovidone as a disintegrating ingredient in the core composition, with corresponding decreases in the amount of mannitol to maintain constant tablet weights. The tablets were tested. for-- the - characteristics - of, dissolution. _. a._ pH -6.8, using the procedure of Example 10 (except that the contact step with acid was omitted) and giving the following results.

For this particular formulation, 10 mg of the disintegrator produced the desired rapid release of the drug at pH 6.8. However, other formulations could show the desired release of the drug with different concentrations of the disintegrator, depending on the identity of the various components of the formulation, the physical methods used to prepare the nuclei (such as compression pressure for tablets), and the presence of additional coatings. Therefore, each proposed formulation must be tested using various amounts of the selected disintegrating components, to identify the exact formulation that gives the desired characteristics of drug release. It is noted that in relation to this date, the best known method for carrying out the aforementioned invention is that which is clear from the present description of the invention

Claims (1)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: _; - .. 1. A pharmaceutical dosage form, characterized in that it comprises: a. a solid core comprising a pharmaceutical active agent and a disintegrator; 10 b. an inflatable coating that surrounds the core; and c. an enteric coating surrounding the inflatable coating. 2. The pharmaceutical dosage form according to claim 1, characterized in that the core is a tablet. 3. The pharmaceutical dosage form according to claim 1, characterized in that it comprises multiple coated cores contained in a capsule. 4. The pharmaceutical dosage form according to claim 1, characterized in that the active pharmaceutical agent is unstable in the presence of acid. 5. The pharmaceutical dosage form according to claim 1, characterized in that the agent The active pharmaceutical is reactive with a component in the enteric coating. 6, The pharmaceutical dosage form according to claim 1, characterized in that the active pharmaceutical agent comprises benzimidazole. The pharmaceutical dosage form according to claim 6, characterized in that the benzimidazole is one or more members selected from the group consisting of omeprazole, esomeprazole, lansoprazole, rabeprazole and pantoprazole. 8. The pharmaceutical dosage form according to claim 1, characterized in that the disintegrator comprises one or more members selected from the group consisting of: starches; polyvinyl pyrrolidones; formaldehyde-casein compounds; resins; defatted soybean bean extracts; alginic acid; agar-agar; calcium carbonate; calcium phosphate; sodium carbonate; and acrylic polymers. 9. The pharmaceutical dosage form according to claim 1, characterized in that the incurable coating comprises one or more hydrocolloid-forming members, selected from the group consisting of: prolamines; polyvinylpyrrolidone polymers; cellulose derivatives; starches; carboxyvinyl polymers; alginates, pectins; agar; and gums. 10. The pharmaceutical dosage form according to claim 1, characterized in that the inflatable coating comprises zein. 11. The pharmaceutical dosage form according to claim 1, characterized in that the inflatable coating comprises a hydroxypropylmethylcellulose. 12. The pharmaceutical dosage form of conformity -5-eon-1-a-claim 1, characterized in that the inflatable coating comprises an excipient that modulates the release of the active pharmaceutical agent from the core after hydration. 13. The pharmaceutical dosage form according to claim 12, characterized in that the excipient comprises one or more members selected from the group consisting of: surfactant plasticizers soluble in water; and enteric coating materials. 14. The pharmaceutical dosage form according to claim 1, characterized in that the enteric coating comprises a component that is based on cellulose, based on methacrylate, based on polyvinyl acetate phthalate, or based on shellac. 15. The pharmaceutical dosage form according to claim 1, characterized in that the enteric coating comprises a copolymer. of methacrylic acid and ethyl acrylate. 16. The pharmaceutical dosage form according to claim 1, characterized in that the nucleus 25 comprises at least about 50 weight percent of the dosage form. 17. The pharmaceutical dosage form according to claim 1, characterized in that the inflatable coating comprises about 0.1 to 10 weight percent-of. the form of.-dose. _ _ _-. 18. The pharmaceutical dosage form according to claim 1, characterized in that the enteric coating comprises approximately 0.1 to 30 weight percent of the dosage form. 19. The pharmaceutical dosage form according to claim 1, characterized in that the active pharmaceutical agent is substantially retained in the dosage form, while the dosage formula is. present in the stomach, but is rapidly released after the dosage form enters an environment of the digestive system having a pH value of at least about 5. 20. A pharmaceutical dosage form, characterized in that it comprises: a. a solid core comprising a pharmaceutically active agent sensitive to acid and a disintegrator; b. an inflatable coating comprising a hydrocolloid-forming component, which surrounds the core; and c. an enteric coating surrounding the inflatable coating. 21. The pharmaceutical dosage form according to claim 20, characterized in that the active pharmaceutical agent sensitive to the acid comprises a benzimidazole. 22. The pharmaceutical dosage form of conformity -cn ™ = ^^ - ^ _ ^ r ^ - i d-icaci-ó - = - 20, - -characterized --- because ---- - the disintegrator comprises one or more members selected from the group consisting of: starches; polyvinyl pyrrolidones; formaldehyde-casein compounds; resins; bean, defatted soy extracts; alginic acid; agar-agar; calcium carbonate; calcium phosphate; sodium carbonate; and acrylic polymers. 23. The pharmaceutical dosage form according to claim 20, characterized in that the hydrocolloid-forming component comprises one or more. members selected from the group consisting of: prolamins; vinylpyrrolidone polymers; cellulose derivatives; starches; carboxyvinyl polymers; alginates, pectins; agar; and gums. 2 . The pharmaceutical dosage form according to claim 20, characterized in that the enteric coating comprises a component that is based on cellulose, based on methacrylate, based on polyvinyl acetate phthalate, or based on shellac. 25. The pharmaceutical dosage form according to claim 20, characterized in that the Enteric coating comprises a copolymer of methacrylic acid and ethyl acrylate. 26. A pharmaceutical dosage form, characterized in that it comprises: -5--a. --- a - solid core comprising a benzimidazole and a disintegrator; b. an inflatable coating comprising one or more hydrocolloid formers, selected from zein, crospovidone, and a hydroxypropyl cellulose, surrounding the core; and c. an enteric coating comprising a copolymer of methacrylic acid and ethyl acrylate, which surrounds the inflatable coating. 27. The pharmaceutical dosage form according to claim 26, characterized in that the disintegrator comprises one or more members selected from the group consisting of: starches; polyvinyl pyrrolidones; formaldehyde-casein compounds; resins; defatted soybean bean extracts; alginic acid; agar-agar; 20 calcium carbonate; calcium phosphate; sodium carbonate; and acrylic polymers. 28. The pharmaceutical dosage form according to claim 26, characterized in that the inflatable coating comprises zein. 29. The pharmaceutical dosage form according to claim 26, characterized in that the inflatable coating comprises crospovidone. 30. The pharmaceutical dosage form according to claim 26, characterized in that the inflatable coating comprises a hydroxypropylcellulose. 31. A method of treating a medical condition, comprising orally administering a pharmaceutical dosage form according to claim 1, characterized in that: a. the dosage form remains substantially intact during transit in the stomach; b. the enteric coating is removed in environments of the digestive system that have pH values above about 5; c. the aqueous fluids penetrate the areas of the dosage form where the enteric coating has been removed, causing the formation of hydrocolloid in the inflatable coating; d. the aqueous fluids pass through the hydrocolloid to hydrate the core; and e. the hydrated core becomes fragmented, releasing the active pharmaceutical agent from the dosage form. 32. A method for treating a medical condition, comprising orally administering a pharmaceutical dosage form according to claim 20, characterized in that: a. the dosage form remains substantially intact during transit in the stomach; b. the enteric coating is removed in the areas of the digestive system that have pH values above about 5; c. the aqueous fluids penetrate the areas of the dosage form where the enteric coating has been removed, causing the formation of hydrocolloid in the inflatable coating; d. the aqueous fluids pass through the hydrocolloid to hydrate the core; and e. the hydrated core becomes fragmented, releasing the active pharmaceutical agent from the dosage form. 33. A method for treating a medical condition, comprising orally administering a pharmaceutical dosage form in accordance with claim 26, characterized in that: a. the dosage form remains substantially intact during transit in the stomach; b. the enteric coating is removed in the areas of the digestive system that have pH values above about 5; c. the aqueous fluids penetrate the areas of the dosage form where the enteric coating has been removed, causing the formation of hydrocolloid in the inflatable coating; d. the aqueous fluids pass through the hydrocolloid to hydrate the core; Y -. and. - The ^ - nucleus - hydrated is - arrives - fragment, releasing the active pharmaceutical agent from the dosage form. 34. The method according to claim 33, characterized in that at least about 80 percent of the active pharmaceutical agent is released within about one hour after the dosage form is contacted with an aqueous fluid having a pH of about 6.8. 35. A method of preparing a pharmaceutical dosage form, characterized in that it comprises the steps of: a. combine the components comprising an active pharmaceutical agent and a disintegrator, and forming a solid core; b. coating the core with an inflatable coating comprising a hydrocolloid-forming component; and c. applying an outer coating comprising an enteric substance resistant to acid. 36. The method according to claim 35, characterized in that the solid core is formed as a tablet. 37. The method according to claim 35, further characterized. because it comprises the step of. fill multiple coated cores inside a capsule.