KR20060065632A - 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 HAVING A SWELLABLE COATING}

A number of patents and other documents are mentioned herein. The contents of these documents are incorporated herein by reference.

The present invention relates to a solid pharmaceutical dosage form having a coating protecting the pharmaceutically active ingredient contained therein against degradation by acidic gastric fluid. In particular, the formulations have a coating containing a substance that expands upon contact with the aqueous liquid.

Many pharmaceutically active ingredients are not chemically stable under acidic environments. For this reason, oral administration can be ineffective without methods to protect the substance against contact with gastric juice. However, this generally has an undesirable effect by delaying the delivery of substance efficacy to the body because systemic absorption does not occur until the substance is released from its formulation.

Prevents pharmaceutical formulations from being affected by acidic gastric contents and is only used after active ingredients enter the more alkaline environment such as duodenum, jejunum or ileum Much research has been done to make this possible. This typically involves the application of a formulation or particle containing the active agent with a substance that can protect against acid attack but that can dissolve or permeate in a more alkaline environment.

In US Pat. No. 4,786,505, Lovgren et al describes a stable pharmaceutical preparation of omeprazole that defends against acid attack but dissolves rapidly in neutral or alkaline media. The omeprazole particles are mixed with a water soluble alkali reactant and the particles are applied with a "separation layer" which serves as a pH buffering area to prevent contact of the acid groups present in the drug and the final coating material. Finally, the bilayer composition is applied with an enteric polymer coating that does not react with the acid.

In US Pat. No. 5,035,899, Saeki et al discloses acid-stable drug compositions that prevent contact with gastric acid. The drug-containing core is first applied with fine particles of low water solubility material followed by an enteric film forming material such as ethylcellulose.

In US Pat. No. 5,160,742 Mazer et al discloses a sustained release system for acid-sensitive drugs such as β-lactam antibiotics. Drug particles applied to be suitable for insertion into syrups or other formulations form a core containing the drug, the core is coated with prolamin, and an enteric material such as methacrylic acid copolymer It is prepared by carrying out a final outer coating. Optionally, an additional prolamin coating can be formed over the enteric coating layer. The drug is released for a long time starting after the coated particles enter a high pH environment.

In US Pat. No. 5,472,712, Oshlack et al have a controlled release hydrophobic coating consisting of a drug-containing core and ethylcellulose, and a controlled release formulation optionally containing a hydrophilic pore forming material such as hydroxypropyl methylcellulose. Teaching formal. Optionally, the cores may have a mediated "barrier" coating of a material, such as hydroxypropyl methylcellulose, which preferably does not affect the dissolution rate of the final product.

In US Pat. No. 5,609,909, Meyer et al. Prolase drug-containing core particles that block the unpleasant taste of the drug but which is immediately bioavailable when the drug is exposed to acidic fluid in the stomach. It is disclosed that it can be prepared by applying with a mixture of a min and non-polymerizable plasticizer.

In US Pat. No. 5,811,388 Friend et al teaches a formulation in which the drug is not released in the upper gastrointestinal tract but is released in the lower colon to directly treat diseases of the colon. The formulation comprises a core tablet containing the drug and a large amount of plant-derived hydrocolloid and is optionally applied as a film of enteric material.

In U.S. Patent No. 5,840,332, Lerner et al describe a composition in which the drug-containing core is coated with a water-insoluble substance in which particles of water-insoluble hydrophilic matter are embedded, and the drug is delivered to a specific site of the gastrointestinal tract. Is starting. The coated core may optionally be further applied with an enteric polymer.

In US Pat. No. 6,346,269, Hsiao et al teaches oral formulations for acid-sensitive drugs, which are mixed with an alkaline substance such as trisodium phosphate and applied onto a core such as a tablet. An enteric coating material is applied over the drug substance layer.

Methods for making films, sheets and articles from zeins are taught by Padua et al in US Pat. No. 6,635,206.

There is a constant need for drug-containing dosage forms in which the drug is not exposed to acids in the stomach but is released quickly when the drug enters a more alkaline environment.

Summary of the Invention

In one embodiment, the invention provides a solid core comprising a pharmaceutical active and a disintegrant; An intumescent coating surrounding the core; And a pharmaceutical formulation comprising an enteric coating surrounding the swellable coating. The formulation may have other embodiments, including coated tablets or capsules containing coated pellets or coated minitablets.

A preferred aspect of the invention is that the pharmaceutically active substance is substantially maintained while the formulation is present in the stomach, but the pharmaceutically active substance is rapidly released after the formulation enters an environment having a pH value of at least about 5. Formulation.

The present invention also provides a solid core comprising an acid-sensitive pharmaceutical active and a disintegrant; An intumescent coating comprising a hydrocolloid-forming component surrounding the core; And a pharmaceutical formulation comprising an enteric coating surrounding the intumescent coating.

The present invention also relates to a solid core comprising benzimidazole and a disintegrant; An intumescent coating comprising at least one hydrocolloid-formers selected from the group consisting of zein, crospovidone and hydroxypropyl cellulose surrounding the core; And an enteric coating comprising a copolymer of methacrylic acid and ethylacrylate surrounding the intumescent coating.

Another aspect of the invention is a method of treating a medical condition comprising orally administering a pharmaceutical formulation according to any one of the above embodiments and aspects, the method comprising: the formulation substantially comprises Intact during gastric transit; The enteric coating is removed in a digestive system environment having a pH value of about 5 or greater; When the enteric coating is removed, the aqueous liquid penetrates into the formulation site to form hydrocolloids in the intumescent coating; The aqueous liquid passes through the hydrocolloid to hydrate the core; And the hydrated core is degraded to release the pharmaceutical active from the formulation.

In addition, the present invention comprises the steps of combining a component and a disintegrant comprising a pharmaceutically active agent; Forming a solid core; Applying the core with an intumescent coating comprising a hydrocolloid-forming component; And applying an outer coating comprising an acid-resistant enteric material.

Preferred swelling agents in the intumescent coating include prolamines; Vinylpyrrolidone polymers; Cellulose derivatives; Starch; Carboxyvinyl polymers; Alginates; Pectins; Agar; And gums. Zein, crospovidone or hydroxypropyl cellulose are more preferred for use as the swelling agent.

The present invention provides a pharmaceutical formulation comprising a core comprising a pharmaceutically active ingredient and an intumescent coating surrounding the core. The core is 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 of the total pharmaceutical composition Comprises at least 88%, preferably at least 89%. The core also comprises at least 90%, at least 91%, at least 92%, at least 93% of the total pharmaceutical composition.

As used herein, the terms "pharmaceutical active ingredient" "pharmaceutical active" and "active" are both pharmaceutical formulations that provide a therapeutic effect when administered to a therapeutic subject. Used to mean the component of. The present invention is particularly useful for acid-sensitive pharmaceutical actives that exist unstable in low pH environments, such as benzimidazole derivatives including their optically active isomers. Specific examples of useful benzimidazole compounds include rabeprazole, omeprazole, esomeprazole, lansoprazole and pantoprazole. Other drugs useful in the present invention include, but are not limited to the following: A pharmaceutical active that reacts with an enteric coating component, ie, a drug that forms an insoluble complex with an enteric coating, such as fluoxetine ( fluoxetine) and duloxetine; And highly alkaline drugs that can react with acidic groups to reduce acid-insolubility of the coating, such as diclofenac sodium and piroxicam.

As used herein, a "swellable coating" is a coating that increases in volume when in contact with aqueous fluids. This expansion is usually caused by the imbibition of water. The intumescent coating increases the weight of the core by 0.1-10%, 0.5-8%, 0.7-7%, 1-5%, 1.3-3%, 1.5-2%, about 2%, or about 1.5%. In another embodiment, the intumescent coating increases the weight of the core by 0.1-5%, 0.1-4%, 0.1-3%, 0.1-2%, or 0.1-1%.

Generally, the intumescent coating is in a hydrocolloidal state where microscopic particles are gelatinically suspended in water when wet. Preferably, the hydrocolloid is formed from prolamin such as gliadan, hordein or more preferably zein. Jane is extracted from corn in the form of granular, pale yellow to pale yellow amorphous powder or fine flakes, and various commercial extracts have a molecular weight in the range of 25,000-35,000. Jane is insoluble in water and alcohol but soluble in aqueous alcohol solution. Chemically, Jane is very rich in glutamine and lacks lysine and tryptophan. Jane is about 20-22% glutamic acid and glutamine, 17-20% leucine, 5-9% proline, 8-10% alanine, 4-7% phenylalanine, 3-7% isoleucine, 4-6% serine, 4-5 %% asparagine and 3-5% tyrosine. All other amino acids in zein contain less than 3% each. Jane has been generally considered safe (GRAS) for use in food and medicine by the US Food and Drug Administration since March 1985. Jane is commercially available from several sources including Freeman Industries LLC, Tuckahoe, New York USA; The commercial names of the zein products available from the manufacturer are Zein F4000, Zein 4400, Zein F6000, Zein G-10, Aqua Zein, and Aqua Zein Neutral.

A preferred zein for use in the present invention is Zein F6000, which is reextracted to reduce its color (xanthophyll) level. Jane F6000 is a very pale yellow granular with a molecular weight of about 35,000 and a bulk density of 0.125-0.21 g / ml. It contains 90-96% zein protein, calculated on a dry basis.

The hydrocolloid may also be formed from hydroxypropyl methylcellulose. The viscosity of the 2 wt% aqueous solution of the various hydroxypropyl methylcellulose products ranges from about 4,000 mPa · s to about 100,000 mPa · s. In one embodiment, the hydroxypropyl methylcellulose is commercially available as Methocel K15M as United States Pharmacopeia Substitution Type 2208, aka hypromellose 2208, and having a viscosity of about 15,000 mPa · s. In another embodiment, the hydroxypropyl methylcellulose is a United States Pharmacopeia Substitution Type 2910, aka hypermellose 2910, having a viscosity of about 4,000 mPa · s, sold as Methocel E4M. METHOCEL is a trademark of Dow Chemical Company, Midland, Michigan U. S. A.

Other useful materials that form hydrocolloids include, but are not limited to: crospovidone; Croscarmellose sodium; Cellulose derivatives such as hydroxyethyl cellulose, hydroxypropyl cellulose or methylcellulose; Gums such as seaweed extracts, plant extracts, plant exudates, plant seed extracts and microbial fermentation products; Starch, such as pregelatinized and modified starch; And carboxyvinyl polymers including carbopols. Additional specific examples include alginates, pectins, low methoxy pectins, agar, carrageenan, plus arabic, tragacanth, Karaya, ghatti, locust bean (carob), guar, dextran, xanthan, carrageenan, tara , Khaya grandfolia, gellan, Konjac mannan, galactomannan, funoran, acetan, welan, raham (rhamsan), percelleran, succinoglycan, scieroglycan, schizophylan, curdlan, pullulan, pulaya and karaya ) And tamarind gums.

In addition to the pharmaceutically active agent, the core further comprises a disintegrant which assists in physical degradation with any substance bound in an aqueous environment. Disintegrants do not promote dissolution or chemical change as the material decomposes. The following are examples of useful disintegrants: starch such as potatoes or tapioca starch, modified starch (eg sodium starch glycolat, sodium starch glycolat) and partially pregelatinized starch (eg Starch 1500); Polyvinylpyrrolidone, including modified polyvinylpyrrolidone (eg crospovidone, polymerized under conditions that promote crosslinking); Celluloses such as microcrystalline cellulose, modified celluloses (eg, less substituted hydroxypropyl cellulose, croscarmellose sodium and calcium carboxymethyl cellulose); Formaldehyde-casein compounds (eg, Esma-Spreng.RTM); Resins such as polacrilin potassium available under the trade name AMBERLITE IRP88 from the manufacturer Rohm and Haas Company, Philadelphia, Pennsylvania U.S.A .; Nonfat soy extract; Alginic acid; Agar-agar; Calcium carbonate; Calcium phosphate; And sodium carbonate. In US Pat. No. 6,696,085 Rault et al teaches acrylic polymers useful as tablet disintegrants.

In addition to the foregoing, the core may contain other preferred components such as binders, lubricants, antioxidants, and the like, which will be apparent to those skilled in the art, as described below.

The pharmaceutical formulation further comprises an enteric coating surrounding the intumescent coating. An "enteric coating" is a coating that is substantially insoluble in acidic pH conditions of the stomach, but is substantially soluble or water-permeable at high pH conditions of the intestines. In the present invention, the enteric coating protects the intumescent coating against contact with an acidic gastric environment but allows the intumescent coating to come into contact with more alkaline intestinal fluid. The enteric coating may be selected to allow targeted release at specific sites of the intestinal. For example, the enteric coating can be delivered to the duodenum (pH> 5.5), jejunum (pH 6-7), or ileum (7.5 below pH). Intermediate delivery points can be obtained by combining different coating materials or modifying the thickness of the coating. Enteric coating materials include cellulose based coatings such as cellulose acetate phthalate and hydroxypropylmethyl cellulose phthalate, methacrylate based coatings, polyvinyl acetate phthalate based coatings and shellac-based coatings.

Methacrylic based coatings are preferred in the present invention, and some useful products are available under the trade name EUDRAGIT from the manufacturer Rohm GmbH & Co., Darmstadt, Germany. Eudragit L 100-55 is particularly preferred. Eudragit L 100-55 is a powdery spray-dried Eudragit L 30 D-55 that can be reconstituted. Eudragit L 30 D-55 is an aqueous dispersion that is pH dependent polymer soluble above pH 5.5 for targeted delivery to the duodenum. Eudragit L 100-55 maintains the pH dependence of Eudragit L 30 D-55 and is soluble at pH 5.5 and above and can be delivered up to the duodenum. Eudragit L 100-55 and Eudragit L 30 D-55 are copolymers of methacrylic acid and methyl acrylate in a 1: 1 ratio. They have the molecular formula (C ₅ H ₂ 0 ₂ · C ₄ H ₆ 0 ₂ ) _x , and the Chemical Abstracts Registry No. Designated as 25212-88-8. Eudragit L100-55 also meets the United States Pharmacopeia specificiation for Methacrylic Acid Copolymer Type C.

In one embodiment, the enteric coating comprises 1-40%, 3-35%, 5-30%, 6-20% or 7-10% or 8% of the total composition. In other embodiments, the enteric coating can be up to 20%, up to 17.5%, up to 15%, up to 12.5%, up to 10%, up to 9%, up to 8%, up to 7%, up to 6%, up to 5% of the total composition. , Or up to 4%.

Optionally, excipients that control the release of the pharmaceutical active are added to the intumescent coating. Regulation can be accomplished by facilitating or disrupting water access to the core. Useful excipients are lactic acid, lactic acetamide, glycerine, glyceryl monosterate, triacetin, sorbitol, triethyl citrate, polyvinylpyrrolidone, triethylene glycol, tricresyl phosphate, dibutyl tartrate, ethylene glycol Plasticizers such as monooleate, palmitic acid, stearic acid, oleic acid, dibutyl sebacate, acetylated monoglycerides and other oils and waxes, in addition to polyethylene glycol 300, 400, 600, 1450, 3350 and 8000 . Additional excipients that control the rate of active release may include enteric coating materials such as Eudragit L 100-55 mixed into the intumescent coating and water-soluble surfactants such as sodium lauryl sulfate and docusate sodium mixed with the intumescent coating. Include.

Although not limited to this theory, it is believed that the enteric coating material incorporated into the intumescent coating dissolves in contact with the intestinal fluid to form channels in the intumescent coating, which promotes entry of the intestinal fluid into the core. In one embodiment, the enteric coating material constitutes about 0.1-30%, 0.5-20%, 1-17.5%, preferably 5-15%, or more preferably 5-10% of the intumescent coating. In another embodiment, the enteric coating material comprises 10-50%, 15-40%, preferably 20-30% of the intumescent coating.

In addition, although not limited to this theory, it is believed that water soluble surfactants help the liquid enter the core by causing rapid wetting when the intumescent coating is exposed to intestinal fluid. If a water soluble surfactant is present, it is about 0.001-30%, 0.005-20%, 0.01-10%, 0.03-8%, 0.05-6%, 0.07-4%, 0.09-2%, or Constitute 0.1-1%. The preferred range is 0.01-10%.

For example, if Jane is present in the intumescent coating, its expansion size controls its permeability and the maximum transmission is obtained at the maximum expansion volume. PDA Journal of Pharmaceutical Science and Technology, Vol. 57, pages 208-217 (2003), by YK Oh et al, for further information regarding diffusion through hydrated zein films "Swelling and Permeability Characteristics of Zein Membranes).

Adding a plasticizer to Jane affects its permeability to water. Incorporating the zein with hygroscopic plasticizers such as glycerol, triethylene glycol and levulinic acid results in greater water hygroscopicity than the unplasticized zein. However, the incorporation of hygroscopic plasticizers such as dibutyl tartrate and oleic acid into the zener results in less water hygroscopicity than the unplasticized zein. As the water permeability increases, the tension becomes weaker, and the coating may simply provide a way to provide sufficient release of the pharmaceutical active. For a discussion of the water hygroscopicity of cast plasticized zein films, see "The Plasticizers for Zein: Their Effect on Tensile Properties and Water Absorption of" by JW Lawton. Zein Films) "Cereal Chemistry, Vol. 81, pages 1-5 (2004).

Controlling the release profile of the pharmaceutically active agent by excipients such as plasticizers is not limited to zein. In general, changing the amount and type of plasticizer affects the tension of the coating. Employing hygroscopicity against hydrophobic excipients also affects the release profile in the same way as mentioned for Jane.

To form the core of the present invention, the pharmaceutically active agent may be admixed with one or more pharmaceutically acceptable carriers such as water, saline, sodium citrate or dicalcium phosphate and / or the following materials: filler Or extenders such as starch, lactose, sucrose, glucose, mannitol or salicylic acid; Binders such as carboxymethylcellulose, alginates, gelatin, copolyvidonum (e.g. copolymers of N-vinyl-2-pyrrolidone and vinyl acetate PLASDONE ^™ S-630, 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; Excipients such as starch, polyvinyl pyrrolidone, cellulose, formaldehyde-casein compounds, fat free soybean extracts, alginic acid, agar-agar, calcium carbonate, calcium phosphate, potato or tapioca starch or sodium carbonate; Glidants such as talc, calcium stearate, magnesium stearate, or solid polyethylene glycols; Solution retarding agents 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 bentonite clay; And stabilizers. The pharmaceutical active may also be combined with buffers such as alkali metal carbonates and alkaline earth metal oxides. Such materials are not consumed and other functional ingredients well known to those skilled in the art can also be used in the present invention.

The core of the present invention may be formed in the form of tablets, minitablets, granules, particulates or pellets. The tablets and minitablets can be prepared by direct compression or by other processes well known to those skilled in the art. Dry granulation, wet granulation, melt granulation or other processes known to those skilled in the art can be used to form the granules. The particulates and pellets can be prepared by methods known to those skilled in the art, for example by extrusion or spheroonization. Pallets can also be prepared by melt pelletization or by coating non-pareil seeds. The wet core can be dried by conventional drying processes such as air drying or drying under heating and / or low pressure conditions.

The core of the present invention is then applied with an intumescent coating followed by an external enteric coating. In general, the coating is a technique known in the art, such as pan coating (including perforated closed system pan coating), coacervation or liquefied bed coating ( fluidized bed coating). The liquefied bed may contain a rotor insert and / or a Worster column insert. The coating can generally be classified according to its polymer base. For example: cellulose-based, including cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxypropylethyl cellulose, ethyl cellulose, methyl cellulose, microcrystalline cellulose ( cellulose-based); Carrageenan; Methacrylates or acrylates such as methacrylic acid, methacrylate, acrylate, methacrylate, acrylate, methyl methacrylate, or copolymers thereof; Or polyvinyl acetate phthalate system. Typically, the polymer is a solvent such as water and polyethylene glycol, lactic acid, lactic acid, acetamide, glycerin, glyceryl monostearate, triacetin, sorbitol, triethyl citrate, polyvinylpyrrolidone, triethylene glycol, tri Compounding agents such as cresyl phosphate, dibutyl tartrate, ethylene glycol monooleate, palmitic acid, stearic acid, oleic acid or dibutyl sebacate. Optionally, any of the following elements may be added: anti-tack agent, anti-foam agent, filler, surfactant, colorant, flavoring agent and these Of two or more combinations.

After application of the enteric coating, the pharmaceutical composition may have identifying information printed thereon using methods known in the art such as ink and offset gravure printing. Pharmaceutically acceptable inks that may be used for offset grabber printing include Markem ^™ 2200, 2202, 2212 and 2222, available from Markem Corporation, Keene, New Hampshire USA. Such inks are typically shellc-based and contain pigments. Diluents may be added to these inks to increase or decrease the rate of drying and / or to control the viscosity. This ink is then usually dried in air. Other pharmaceutically acceptable inks include products such as Opacode ^™ and Opacode ^™ WB containing pigments, titanium dioxide and solvents, respectively, which are available from Colorcon, West Point, Pennsylvania USA. Other printing inks are known to those skilled in the art and they will be usefully employed in the formulation of the present invention.

Optionally, the enteric coated formulation may be further applied in a thin film. Often, the film will be colored for identification and aesthetic purposes of the product: in this case, printing of the desired information will be carried out after the film coating is carried out. Many suitable film coating products are commercially available and include the trade names OPADRY and OPAGLOS available from Colorcon, West Point, Pennsylvania USA. Such products purchased from Colorcon are dry powders comprising polymers, plasticizers and pigments, which are mixed with solvents such as water or alcohols and sprayed into tablets or other solid formulations. Such film coating processes and alternative film coating products are known in the art.

 Coated tablets, pallets, granules or particulates can be packaged in capsules to facilitate administration. Such packaging can be carried out by methods known in the art, such as by filling pre-formed capsules. Such capsules consist of gelatin or other materials known in the art.

Without being bound by this theory, it is assumed that after the enteric coating is dissolved in the intestine, the expandable coating absorbs the intestinal fluids and expands outward. Thus, initially the intumescent coating expands like a balloon and does not suddenly expand. As the coating expands, the permeability to water also increases. The intumescent coating is assumed to contain microchannels where water enters by diffusion and reaches the core. The water causes the core to begin to degrade. Some of these degradants can puncture the intumescent coating, which allows more water to enter. Additional water causes more degradation of the core and more decomposition products perforate the intumescent coating. This cycle lasts until sufficient release of the pharmaceutically active or the intumescent coating becomes too weak by absorption leading to coating ruptures.

Also, without being limited to this theory, the release of the active can be controlled by several other factors besides the presence of an enteric coating. One such element is the selection of hydrocolloid-forming materials for intumescent coatings. Hydrocolloids change their swelling ability to change their permeability to intestinal fluids. The permeability of the hydrocolloid will affect the rate of hydration of the core and thus the degradation of the core. In addition, hydrocolloids have different tensions and this affects the percentage of core degradants that can puncture the intumescent coating upon decomposition. The number of degradants that can be directly released affects the release of the pharmaceutical actives. In addition, the number of openings created in the intumescent coating further affects the release of the actives by allowing more intestinal fluid to enter the core, causing more degradation. Tension additionally affects when the intumescent coating ruptures due to softening caused by the absorption of water to allow the active to be released completely. In addition, some hydrocolloids corrode upon expansion, making it easier for the core decomposition products to perforate the intumescent coating.

As another element, excipients may optionally be added to the intumescent coating that controls the release of the pharmaceutical active. Such reagents may increase or decrease the permeability of hydrocolloids to the intestinal fluid. This permeability affects the amount of intestinal fluid that contacts and degrades the core. The degradation products are assumed to affect the release of the pharmaceutical active by puncturing the intumescent coating upon degradation. It is also believed that openings formed in the intumescent coating allow additional bowel fluid to enter the core to accelerate further degradation.

A third element is the use of disintegrants in the core. The use of such disintegrants increases the rate of degradation of the core, thereby increasing the frequency of degradation products forming voids in the intumescent coating. Increasing the sheer of the degradation product present through the intumescent coating increases the release rate of the pharmaceutical active. In addition, the more voids formed in the intumescent coating, the more water enters the core allowing the decomposition of more active material. In addition, the disintegrant increases the force of the core degradant to impact the intumescent coating, allowing more degradants to successfully form voids in the intumescent coating. Many of these powerful disintegrants further increase the release rate of the pharmaceutical active by allowing a greater number of core degradation products to pass through the intumescent coating. Such disintegrants also create additional openings in the intestinal fluid to hydrate and decompose the actives, resulting in additional release of the actives.

While the release rate of the pharmaceutically active agent can be controlled as described above, the present invention produces sustained release formulations so that the pharmaceutically active agent is controlled at extended rates for extended periods of time, such as 12 or 24 hours. It is not intended to be released. Rather, aspects of the present invention are directed to delayed release of the collected pharmaceutical active until systemic ingestion is reached in the intestinal tract where alkaline pH conditions do not affect the acid-sensitive pharmaceutical active and systemic absorption. to promote rapid and complete pharmaceutical release for systemic absorption.

The following examples are provided to aid the understanding of the present invention and should not be construed as limiting the invention to the appended claims. In this embodiment, components which volatilize during drying and are not present in the final product are not included in the tabular listings; However, such components are referred to herein as solvents and the like. In addition, the weight added by printing information to the final formulation is insignificant and therefore not included in the final cumulative weights. Percentages are expressed by weight unless otherwise indicated.

Example  One

Tablets containing 20 or 40 mg of pantoprazole were prepared using the following ingredients and processes:

ingredient Amount (mg) for 20 mg tablets Amount (mg) for 40 mg tablets Core tablets Dry mix Pantoprazole Sodium 22.55 45.1 Mannitol (Pearlitol SD-200) 110.95 221.9 Crospovidone 8.25 16.5 Sodium carbonate 3.75 7.5 Granulation Sodium carbonate anhydride 3.75 7.5 Hydroxypropyl Cellulose (Klucel LF) 4 8 Lubrication Crospovidone 8.25 16.5 talc 1.5 3 Calcium stearate 2 4 Total 165 330 Intumescent coating Jane F6000 2.07 4.13 Methacrylic acid copolymer (Eudragit L 100-55) 0.41 0.82 Cum. Total 167.48 334.95 Enteric  coating Methacrylic acid copolymer (Eudragit L 100-55) 9.25 18.49 Triethyl citrate 0.93 1.85 Titanium dioxide 1.83 3.65 talc 1.41 2.81 Cum. Total 180.83 361.65 Film coating Opadry Yellow OY-52945 4.52 9.04 Cum. Total 185.42 370.79 Printing Opacode Black S-1-8152 HV q.s. q.s.

A dry mix of pantoprazole sodium, mannitol, crospovidone and sodium carbonate was added to an aqueous solution of hydroxypropyl cellulose (Klucel LF) and sodium carbonate anhydrous. And granulation to prepare a core tablet. The granules were dried using conventional drying techniques. The dried granules were then lubricated using crospovidone, talc and calcium stearate as lubricants. The glidant granules were pressed into the core. The cores were dried by subcoating with a mixture of zein, Eudragit L 100-55, water and isopropyl alcohol. An enteric coating was performed using Eudragit L 100-55 with isopropyl alcohol as a solvent and triethyl citrate as a plasticizer on top of the subcoating. Talc and titanium dioxide were used as lubricants and opaquents, respectively. After drying, the enteric coated tablets were film-coated with Opadry Yellow OY-52945 and printed with Opacode Black S-1-8152 HV.

Example  2

Tablets containing 20 or 40 mg pantoprazole were prepared using the following ingredients and processes.

ingredient Amount (mg) for 20 mg tablets Amount (mg) for 40 mg tablets Core tablets Dry mix Pantoprazole Potassium 22.55 45.1 Mannitol (Pearlitol SD-200) 110.95 221.9 Crospovidone 8.25 16.5 Sodium carbonate 3.75 7.5 Granulation Sodium carbonate anhydride 3.75 7.5 Hydroxypropyl Cellulose (Klucel LF) 4 8 Lubrication Crospovidone 8.25 16.5 talc 1.5 3 Calcium stearate 2 4 Total 165 330 Intumescent coating Jane F6000 2.07 4.13 Methacrylic acid copolymer (Eudragit L 100-55) 0.41 0.82 Cum. Total 167.48 334.95 Enteric  coating Methacrylic acid copolymer (Eudragit L 100-55) 9.25 18.49 Triethyl citrate 0.93 1.85 Titanium dioxide 1.83 3.65 talc 1.41 2.81 Cum. Total 180.83 361.65 Film coating Opadry Yellow OY-52945 4.52 9.04 Cum. Total 185.42 370.79 Printing Opacode Black S-1-8152 HV q.s. q.s.

A core mix was prepared by granulating a dry mix of pantoprazole sodium, mannitol, crospovidone and sodium carbonate with an aqueous solution of hydroxypropyl cellulose (Klucel LF) and sodium carbonate anhydride. The granules were dried using conventional drying techniques. The dried granules were then lubricated using crospovidone, talc and calcium stearate as lubricants. The glidant granules were pressed into the core. The core was subcoated with a mixture of zein, Eudragit L 100-55, water and isopropyl alcohol. After drying, an enteric coating was carried out using Eudragit L 100-55 with isopropyl alcohol as solvent and triethyl citrate as plasticizer on top of the subcoating. Talc and titanium dioxide were used as lubricants and opaquents, respectively. The dried enteric coated tablets were then film-coated 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 ingredients and processes.

ingredient Volume / Capsule (mg) core Pallet Omeprazole 40 Mannitol 236 Crospovidone 18 Hydroxypropyl methylcellulose, 5cps 8 Poloxamer 407 5 Meglumine 3 Total 310 Intumescent coating Jane F 6000 6.2 Cum. Total 316.2 Enteric  coating Hydroxypropyl methylcellulose phthalate (HP 55) 63.24 Triethyl citrate 6.31 talc 9.45 Cum. Total 395.25

Omeprazole, mannitol, crospovidone, meglumine and poloxamer were mixed and this mixture was granulated with hydroxypropyl methylcellulose as a binder to prepare an omeprazole core pallet. The granules were then extruded and spheronized to make spherical pallets. The pallet was then dried by conventional drying techniques. The pallet was coated with an expandable coating 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 hydroxypropyl methylcellulose phthalate and triethyl citrate in a mixture of isopropyl alcohol and acetone, dispersing talc in this solution and then laminating on an intermediate coating.

The coated pallet was placed in gelatin capsules.

Example  4

Tablets containing 40 mg of omeprazole were prepared using the following ingredients and processes.

ingredient Amount / tablet (mg) Core tablets Omeprazole 40 Mannitol (Pearlitol SD-200) 231.3 Crospovidone 6 Meglumine 3 Poloxamer 407 5 Hydroxypropyl methylcellulose, 5 mPas 8 Magnesium stearate 3.8 talc 3 Total 300 Intumescent coating Jane F 6000 2.73 Sodium Lauryl Sulfate 0.27 Cum. Total 303 Enteric  coating Hydroxypropyl methylcellulose phthalate (HP 55) 24 Triethyl citrate 2.4 talc 3.6 Cum. Total 333

Omeprazole core tablets were prepared by mixing with omeprazole, mannitol, crospovidone, meglumine and poloxamer, and granulating the mixture with hydroxypropyl methylcellulose as a binder. The granules were dried in a fluid bed drier and the dried granules were compressed into tablets or minitablets. This core tablet or minitablet was coated with an 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 hydroxypropyl methylcellulose phthalate and triethyl citrate in a mixture of isopropyl alcohol and acetone, dispersing talc in this solution and then laminating it on a mediated coating.

Example  5

Tablets containing 40 mg of pantoprazole were prepared using the following ingredients and processes.

ingredient Amount / tablet (mg) Core tablets Pantoprazole Sodium Sesquihydrate 45 Mannitol (Pearlitol SD-200) 143.18 Mannitol (Pearlitol DC-400) 47.72 Crospovidone 16.5 Plasdon S-630 30 Sodium Lauryl Sulfate 2.5 Meglumine 3 Calcium stearate 6 talc 6 Total 300 Intumescent coating Jane 4.5 Cum. Total 304.5 Enteric  coating Methacrylic acid copolymer (Eudragit L100-55) 16.81 Triethyl citrate 1.68 Titanium dioxide 3.39 talc 2.51 Cum. Total 328.89

Core tablets were prepared by combining pantoprazole sodium sesquihydrate with mannitol, crospovidone, Plasdone S630, talc, and magnesium stearate and pressing directly into tablets. These core tablets were coated with an intumescent 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 hydroxypropyl methylcellulose phthalate and triethyl citrate in a mixture of isopropyl alcohol and acetone, dispersing talc in this solution and then laminating it on a mediated coating.

Example  6

Capsules containing esomeprazole were prepared using the following ingredients and processes.

ingredient Volume (g) Pallet Esomeprazole Magnesium Trihydrate 178 Mannitol 938 Crospovidone 72 Sodium Lauryl Sulfate 20 Copovidone 32 Total 1240 Intumescent coating Jane 16.2 Sodium Lauryl Sulfate 1.62 Cum. Total 1257.82 Enteric  coating Methacrylic Acid Copolymer Type C 110 Triethyl citrate 11 Titanium dioxide 15.29 talc 16.5 Cum. Total 1410.61

The core was prepared by mixing esomeprazole magnesium trihydrate, mannitol, crospovidone and sodium lauryl sulfate and granulating the mixture with an aqueous solution of copovidone. The granules were then extruded and spheroonized to give spherical pellets. The pellets were dried by conventional drying techniques. The dried pellets were coated with a mediated coating solution containing zein and sodium lauryl sulfate dissolved in a mixture of isopropyl alcohol and water and dried. The enteric coating was prepared by dissolving methacrylic acid copolymer Type C and triethyl citrate in isopropyl alcohol and dispersing talc and titanium dioxide in this solution. The coated pellets were filled into gelatin capsules to give 4000 capsules each containing 40 mg of esomeprazole.

Example  7

Esomeprazole tablets were prepared using the following ingredients and processes.

ingredient Amount (mg / tablet) Core tablets Esomeprazole Magnesium Trihydrate 44.5 Magnesium oxide 20 Plasdon S-630 17.5 Crospovidone 10 Mannitol (Pearlitol SD 200) 227 Colloidal silicon dioxide 3.5 Sodium stearyl fumarate 17.5 Total 340 Intumescent coating Jane F6000 6.8 Cum. Total 346.8 Enteric  coating Eudragit L100-55 19.1 Triethyl citrate 1.9 Titanium dioxide 3.8 talc 2.9 Cum. Total 374.5

Esomeprazole magnesium trihydrate, magnesium oxide, copovidone, crospovidone, mannitol and silicon dioxide were combined, followed by further addition of sodium stearyl fumarate. This mixture was compressed into core tablets. The tablets were coated with an aqueous alcohol solution with zein and then dried. Finally, the enteric coating component was dispersed in water, coated on the zein-coated tablets and finally dried.

Example  8

Tablets containing rabeprazole sodium were prepared using the following ingredients and processes.

ingredient Amount / tablet (mg) Core tablets Rabeprazole Sodium 20 Mannitol (Pearlitol SD 200) 97.2 Mannitol (Pearlitol DC 400) 28 Meglumine 5.1 Crospovidone 3.4 Plasdone S-630 10.5 talc 3.4 Magnesium stearate 2.4 Total 170 Intumescent coating Jane F6000 4.25 Triethyl citrate 0.2 Cum. Total 174.45 Enteric  coating Methacrylic acid copolymer (Eudragit L 100-55) 12.26 Triethyl citrate 1.224 talc 0.68 Cum. Total 188.614

Rabeprazole sodium, crospovidone, Plasdone S630 and mannitol (Pearlitol SD 200) were mixed with mannitol (Pearlitol DC 400) for 20 minutes. Talc and magnesium stearate were then added to this mixture and mixed for 5 minutes. This glidant formulation was then compressed into tablets. The core tablets were subcoated with a water-alcohol solution with zein (weight gain 2.5 ± 0.5%) and dried. The subcoated tablets were coated with an enteric coating solution (weight gain 8-9%).

Example  9

Rabeprazole sodium tablets were prepared using the following ingredients and processes.

ingredient Amount / tablet (mg) Core tablets Rabeprazole Sodium 20 Mannitol (Pearlitol SD 200) 97.01 Low Substituted Hydroxypropyl Cellulose, LH21 (“L-HPC”) 14.4 Magnesium oxide 40 Sodium Lauryl Sulfate 1.8 Hydroxypropyl methylcellulose, 5 mPas 3 talc 1.54 Magnesium stearate 2.25 Total 180 Intumescent coating Jane 6000 4.9 Triethyl citrate 0.49 Cum. Total 185.39 Enteric  coating Eudragit L100-55 14.46 Triethyl citrate 1.44 talc 0.79 Cum. Total 202.08 Film coating Opadry Yellow OY-52945 5.05 Cum. Total 207.13 Printing Opacode black q.s.

Magnesium oxide was sieved through 10 mesh sieves. Rabeprazole sodium, L-HPC, mannitol (SD 200) and sieved magnesium oxide were sieved through 40 mesh sieves. The material was then mixed for 30 minutes in a Rapid mixer granulator. Sodium lauryl sulfate (SLS) was dissolved in purified water and hydroxypropylmethylcellulose (HPMC) was dissolved in warm purified water. The rabeprazole sodium mixture was mixed with SLS and HPMC solution. The wet mass was dried in a fluid bed drier, and the dried granules were sieved through 20 mesh sieves. The sieved granules were combined with L-HPC for 5 minutes in a double cone blender. Magnesium stearate (passed through 60 mesh sieves) was added to the formulation and mixed for 5 minutes. The glidized formulation was then compressed into core tablets. The core tablets were coated with a water-alchhol zein coating solution (weight gain 2.5 ± 0.5%) and dried. The coated tablets were further coated with an enteric coating solution (weight gain 8.0 ± 1.0%). The enteric coated tablets were additionally coated using an Opadry solution until the weight gain was 2.0 ± 0.5%. The film coated tablets were then printed with Opacode black ink.

Example  10

Pantoprazole sodium tablets were prepared according to Example 5 and using Method B and Apparatus 1 (described in Method 711 “Dissolution,” page 1942). Tested according to Method 724 (Method 724) “Drug Release” of United States Pharmacopeia 24, United States Pharmacopeial Convention, Inc., Rockville, Maryland USA, pp.1944-1947, 2000. The tablet was first immersed in 0.1 N hydrochloric acid at 37 ° C. for 2 hours with stirring. The tablets were then immersed in a phosphate buffer at pH 6.8 with stirring, and a sample of the buffer solution was intermittently taken for analysis to determine the amount of drug released from the tablets.

The following is data obtained from testing six tablets. The amount of drug released as acid is not disclosed but very small. In general, it is believed that less than 10% of the drug is released as an acid in an enteric coated formulation. For the purposes of the present invention, it is believed that the pharmaceutically active substance remains substantially in the formulation when less than 10% by weight is released into 0.1N hydrochloric acid under USP test conditions.

Minutes Drug release percent Tablets 1 Tablets 2 Tablets 3 Tablets 4 Tablets 5 Tablets 6 Average 0 0 0 0 0 0 0 0 15 29 18 22 21 18 17 21 30 61 62 65 57 55 58 60 45 82 86 84 84 81 79 83 60 92 94 91 92 89 88 91

These results indicate that the drug is substantially completely released within 60 minutes at pH 6.8.

Example  11

As in Example 10, rabeprazole sodium tablets prepared according to Example 9 were tested by USP Drug Release Method 724. However, the alkaline solution for the second part of the test was a phosphate buffer with a pH adjusted to 8.0 and also containing 0.5% by weight sodium lauryl sulfate. The results obtained are shown below.

Minutes Drug release percent Tablets 1 Tablets 2 Tablets 3 Tablets 4 Tablets 5 Tablets 6 Average 0 0 0 0 0 0 0 0 10 0 0 0 0 0 0 0 20 0 0 0 0 0 0 0 30 18 37 12 43 0 28 23 45 82 94 74 94 93 92 88 60 91 91 92 90 92 92 91

This result indicates that the drug is released substantially completely within 60 minutes at pH 6.8.

Example  12

Esomeprazole tablets were prepared using the following ingredients and processes.

ingredient Amount / tablet (mg) Core tablets Esomeprazole Magnesium Trihydrate 44.5 Magnesium oxide 20 Plasdone S-630 17.5 Mannitol (Pearlitol SD 200) 237 Colloidal silicon dioxide 3.5 Sodium stearyl fumarate 17.5 Total 340 Intumescent coating Jane F6000 6.8 Cum. Total 346.8

After sieving and blending Esomeprazole magnesium trihydrate, magnesium oxide, Plasdone S-630, silicon dioxide and mannitol, the mixture was formulated by adding sodium stearyl fumarate. Finally, the mixture was compressed directly to form a tablet. Jane was dissolved in an aqueous alcohol solution and coated onto tablets. The coated tablets were then dried.

Additional tablets were prepared in a similar manner, further comprising 7 mg or 10 mg of disintegrant component crospovidone in the core composition and correspondingly reducing the amount of mannitol to maintain the same tablet weight. The tablets were tested for dissolution properties at pH 6.8 using the method of Example 10 (except that the acid contact step was omitted) and the following results were obtained.

Minutes Drug release percent No disintegrant Disintegrant 7mg Disintegrant 10mg 15 0 0 61 30 0 One 80 45 0 3 86 60 0 6 89 90 0 - 88 120 One - -

For this particular formulation 10 mg of disintegrant provided rapid drug release at pH 6.8. However, other formulations are desired to have different disintegrant concentrations depending on the identity of the various formulation components, the method used to prepare the core (eg, press compression for tablets), and the presence of additional coatings. Drug release. Therefore, each provided formulation should be tested by varying the amount of disintegrant component selected to identify the correct formulation that provides the desired drug release properties.

Claims (37)

Solid cores comprising pharmaceutically active and disintegrants; A swellable coating surrounding the core; And A pharmaceutical form comprising an enteric coating surrounding the intumescent coating. The pharmaceutical formulation of claim 1, wherein the core is a tablet. The pharmaceutical formulation of claim 1 comprising multiple coated cores contained in a capsule. The pharmaceutical formulation of claim 1, wherein the pharmaceutically active agent is unstable in the presence of an acid. The pharmaceutical formulation of claim 1, wherein the pharmaceutically active agent reacts with an enteric coating component. The pharmaceutical formulation of claim 1, wherein the pharmaceutically active agent comprises benzimidazole. The method according to claim 6, wherein the benzimidazole is at least one selected from the group consisting of omeprazole, esomeprazole, lansoprazole, rabeprazole and pantoprazole Pharmaceutical formulation, characterized in that the member (member). The method of claim 1, wherein the disintegrant is starches, polyvinyl pyrrolidone, formaldehyde-casein compound, resin, fat free soybean extract, alginic acid, agar-agar, calcium carbonate, calcium phosphate Pharmaceutical composition, characterized in that at least one member selected from the group consisting of sodium carbonate and acrylic polymer. The method of claim 1 wherein the intumescent coating is in the group consisting of prolamines, vinylpyrrolidone polymers, cellulose derivatives, starches, carboxyvinyl polymers, alginates, pectins, agars and gums A pharmaceutical formulation comprising at least one hydrocolloid-forming member selected. The pharmaceutical formulation of claim 1, wherein the intumescent coating comprises zein. The pharmaceutical formulation of claim 1, wherein the intumescent coating comprises hydroxypropylmethyl cellulose. The pharmaceutical formulation of claim 1, wherein the intumescent coating comprises an excipient that controls the release of the pharmaceutical active from the core upon hydration. 13. The pharmaceutical formulation of claim 12, wherein the excipient comprises at least one member selected from the group consisting of plasticizers, water soluble surfactants and enteric coating materials. The method of claim 1, wherein the enteric coating comprises a cellulose-based, methacrylate-based, polyvinyl acetate phthalate-based or shellac-based component. Pharmaceutical formulations comprising a. The pharmaceutical formulation of claim 1, wherein the enteric coating comprises a copolymer of methacrylic acid and ethylacrylate. The pharmaceutical formulation of claim 1, wherein the core comprises at least about 50% of the formulation weight. The pharmaceutical formulation of claim 1, wherein the intumescent coating comprises about 0.1 to 10% of the formulation weight. The pharmaceutical formulation of claim 1, wherein the enteric coating comprises about 0.1-30% of the formulation weight. The method of claim 1, wherein the pharmaceutically active substance remains substantially in the formulation while the formulation is present in the stomach, but is released rapidly after the formulation enters the digestive environment having a pH value of at least about 5. 5. Pharmaceutical formulations characterized in that. Solid cores including acid-sensitive pharmaceutical actives and disintegrants; An intumescent coating comprising a hydrocolloid-forming component surrounding the core; And A pharmaceutical formulation comprising an enteric coating surrounding the intumescent coating. The pharmaceutical formulation of claim 20, wherein said acid-sensitive pharmaceutical active comprises benzimidazole. 21. The method of claim 20 wherein the disintegrant is starch, polyvinyl pyrrolidone, formaldehyde-casein compound, resin, fat free soybean extract, alginic acid, agar-agar, calcium carbonate, calcium phosphate, sodium carbonate And at least one member selected from the group consisting of acrylic polymers. The hydrocolloid-forming component of claim 20 wherein the hydrocolloid-forming component comprises at least one member selected from the group consisting of prolamin, vinyl pyrrolidone polymer, cellulose derivative, starch, carboxyvinyl polymer, alginate, pectin, agar and gum. Pharmaceutical formulations characterized in that. The pharmaceutical formulation of claim 20, wherein the enteric coating comprises components that are cellulose based, methacrylate based, polyvinyl acetate phthalate based, or shellac based. The pharmaceutical formulation of claim 20, wherein the enteric coating comprises a copolymer of methacrylic acid and ethyl acrylate. Solid cores including benzimidazole and disintegrants; An intumescent coating comprising at least one hydrocolloid-formers selected from zein, crospovidone and hydroxypropyl cellulose surrounding the core; And A pharmaceutical formulation comprising an enteric coating comprising a copolymer of methacrylic acid and ethylacrylate surrounding the intumescent coating. 27. The method of claim 26, wherein the disintegrant is starch, polyvinyl pyrrolidone, formaldehyde-casein compound, resin, fat free soybean extract, alginic acid, agar-agar, calcium carbonate, calcium phosphate, sodium carbonate And at least one member selected from the group consisting of acrylic polymers. 27. The pharmaceutical formulation of claim 26, wherein the intumescent coating comprises zein. 27. The pharmaceutical formulation of claim 26, wherein the intumescent coating comprises crospovidone. 27. The pharmaceutical formulation of claim 26, wherein the intumescent coating comprises hydroxypropyl cellulose. A method of treating a medical condition comprising orally administering a pharmaceutical formulation according to claim 1, The formulation remains substantially undamaged for the duration of the stomach transit; The enteric coating is removed in a digestive system environment having a pH value of about 5 or greater; When the enteric coating is removed, aqueous fluids penetrate the formulation site to form hydrocolloids in the intumescent coating; The aqueous liquid passes through the hydrocolloid to hydrate the core; And Wherein the hydrated core breaks down to release the pharmaceutically active agent from the formulation. A method of treating a medical condition comprising orally administering a pharmaceutical formulation according to claim 20, The formulation remains substantially undamaged for the duration of the stomach transit; The enteric coating is removed from the digestive system region having a pH value of about 5 or greater; When the enteric coating is removed, aqueous fluids penetrate the formulation site to form hydrocolloids in the intumescent coating; The aqueous liquid passes through the hydrocolloid to hydrate the core; And Wherein the hydrated core breaks down to release the pharmaceutically active agent from the formulation. A method of treating a medical condition comprising orally administering a pharmaceutical formulation according to claim 26, The formulation remains substantially undamaged for the duration of the stomach transit; The enteric coating is removed from the digestive system region having a pH value of about 5 or greater; When the enteric coating is removed, the aqueous liquid penetrates through the formulation site to form a hydrocolloid in the expandable coating; The aqueous liquid passes through the hydrocolloid to hydrate the core; And Wherein the hydrated core breaks down to release the pharmaceutically active agent from the formulation. The method of claim 33, wherein at least about 80% of the pharmaceutically active agent is released within about 1 hour after the formulation is contacted with an aqueous liquid having a pH of about 6.6. Combining a component comprising a pharmaceutically active agent and a disintegrant to form a solid core; Applying the core with an intumescent coating comprising a hydrocolloid forming component; And A method of making a pharmaceutical formulation comprising applying an outer coating comprising an acid-resistant enteric material. 36. The method of claim 35, wherein said solid core is formed into a tablet. 36. The method of claim 35, further comprising filling the multiple coated cores into a capsule.