USB2 - Enteric and colonic delivery using HPMC capsules - Google Patents

Enteric and colonic delivery using HPMC capsules Download PDF

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Publication number

USB2

USB2 US09/836,627 USA USB2 US B2 US B2 US B2 US A US A US A US B2 US B2 US B2

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Prior art keywords

drug delivery

composition according

coating

delivery composition

capsule

Prior art date

-09-28

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Inventor

Robert A. Scott

Ewart T. Cole

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Warner Lambert Co LLC

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-09-28

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-04-17

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-08-22

-04-17 Application filed by Warner Lambert Co LLC filed Critical Warner Lambert Co LLC

-04-17 Priority to US09/836,627 priority Critical patent/USB2/en

-11-01 Publication of USA1 publication Critical patent/USA1/en

-08-22 Application granted granted Critical

-08-22 Publication of USB2 publication Critical patent/USB2/en

-08-24 Assigned to CAPSUGEL BELGIUM BVBA reassignment CAPSUGEL BELGIUM BVBA ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: WARNER-LAMBERT COMPANY LLC

-08-29 Assigned to UBS AG, STAMFORD BRANCH, AS COLLATERAL AGENT reassignment UBS AG, STAMFORD BRANCH, AS COLLATERAL AGENT SECURITY AGREEMENT Assignors: CAPSUGEL BELGIUM BVBA

-12-23 Assigned to CAPSUGEL BELGIUM reassignment CAPSUGEL BELGIUM CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: CAPSUGEL BELGIUM BVBA

-12-04 Assigned to CAPSUGEL BELGIUM NV reassignment CAPSUGEL BELGIUM NV CORRECTIVE ASSIGNMENT TO CORRECT THE NAME OF ASSIGNEE PREVIOUSLY RECORDED ON REEL FRAME . ASSIGNOR(S) HEREBY CONFIRMS THE CHANGE OF NAME FROM CAPSUGEL BELGIUM TO CAPSUGEL BELGIUM NV. Assignors: CAPSUGEL BELGIUM

-07-10 Assigned to CAPSUGEL BELGIUM BVBA reassignment CAPSUGEL BELGIUM BVBA RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: UBS AG, STAMFORD BRANCH

-09-15 Anticipated expiration legal-status Critical

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• • A&#;HUMAN NECESSITIES
  • A61&#;MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K&#;PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00&#;Medicinal preparations characterised by special physical form
  • A61K9/48&#;Preparations in capsules, e.g. of gelatin, of chocolate
• • A&#;HUMAN NECESSITIES
  • A61&#;MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K&#;PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00&#;Medicinal preparations characterised by special physical form
  • A61K9/48&#;Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/&#;Coated capsules; Multilayered drug free capsule shells
• • A&#;HUMAN NECESSITIES
  • A61&#;MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K&#;PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00&#;Medicinal preparations characterised by special physical form
  • A61K9/48&#;Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/&#;Wall or shell material

Definitions

• Enteric coated products are designed to remain intact in the stomach but to dissolve and release the active substance in the upper intestine. This type of product is termed a delayed release dosage form.
• Enteric coated preparations are usually used for one or more of the following purposes:
• the polymers commonly used to achieve enteric properties are polymethacrylates (copolymerisate of methacrylic acid and either methylmethacrylate or ethyl acrylate (EUDRAGIT®), cellulose based polymers e.g. cellulose acetate phthalate (AQUATERIC®) or polyvinyl derivatives e.g. polyvinyl acetate phthalate (COATERIC®).
• Colonic products are also designed to remain intact in the stomach but to release the active substance further along the gastrointestinal tract, i.e., in the colon.
• the site specific delivery of drugs to the colon has implications in a number of therapeutic areas. These include:
• enteric and colon delivery systems are based on tablets or pellets which are filled into conventional hard gelatin capsules.
• NCE new chemical entities
• enteric or colonic coating of an encapsulated drug formulation would enable the efficacy of the drug to be determined without the complications of gastric instability or irritation.
• the limited amount of drug substance available during the early stage preclude the development of a coated pellet or tablet formulation. Since the coating process is independent of the capsule contents the advantages resulting from the ability to coat a capsule are obvious.
• the oral pharmacological and/or therapeutic efficacy of the NCE can be determined without resorting to extensive formulation development studies which are expensive, time consuming and, in many instances, impossible at this point in the development of the NCE.
• the capsule provides the possibility to deliver liquid or semi-solid formulations to the small or large intestine.
• gelatin The most commonly used material for manufacturing capsules is gelatin. Although it is possible to coat hard gelatin capsules the process is at best very sensitive, especially if an aqueous coating system is used, and can lead to shell embrittlement and poor adhesion of the coat to the smooth gelatin surface. A pre-coating can reduce interactions between the gelatin and the enteric polymer but is time consuming and complicated.
• the invention therefore provides a drug delivery system for delivering a drug to either the small intestine (enteric) or the colon comprising a HPMC capsule containing the drug and wherein the HPMC capsule is provided with a suitable coating such that the drug is released from the capsule either in the small intestine or the colon.
• FIG. 1 depicts the release profile of acetaminophen from HPMC coated capsules.
• FIG. 2 depicts the release profile of acetaminophen front HPMC coated capsules.
• the HPMC capsules are sealed after filling in the overlapping region of capsule body and cap by commonly known sealing techniques like banding or applying a sealing liquid and/or heat to the gap between capsule body and cap.
• a sealing liquid which may include a solfvent applied individually and uniformly to the external edge of the gap of a capsule to be sealed to form a liquid ring around the circumference of the capsule, removing excess sealing liquid from the exterior of the capsule and drying the capsule by applying thermal energy from outside.
• a sealing before coating will prevent problems e.g. with non-uniformity of the coating at the gap or development of fissures during storage under stressing conditions, which can lead to an unwated early leaking of the capsule content into the stomach.
• enteric coated HPMC capsule have superior properties than enteric coated gelatin capsules, especially much higher resistance against acid solutions.
• composition of the coating should ensure a complete disintegration of the coating in the small intestine or the colon while at the same time minimizing the possibility of the coating disintegrating either in the stomach or passing through the gastrointestinal tract intact.
• any coating can be used which ensures that the capsule does not disintegrate until it is emptied from the stomach.
• the coating will usually be one which is pH sensitive and which completely dissolves in the small intestine.
• Typical coating thicknesses will be in the range 5 to 15 mg polymer per cm 2 of capsule surface.
• Preferred coating materials are those which dissolve at a pH of 5&#;6. The coatings therefore only begin to dissolve when they have left the stomach and then rapidly disintegrate once the capsule has entered the small intestine.
• Such a coating can be made from a variety of polymers such as cellulose acetate trimellitiate (CAT), hydroxypropylmethyl cellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP) and shellac.
• Especially preferred materials for aqueous film coating are copolymers of methacrylic acid and ethyl acrylate, Eudragit® L30D-55 (Roehm GmbH, Darmstadt, Germany).
• any coating can be used which ensures that the capsule does not disintegrate until it is emptied from the stomach.
• the coating may be one which is pH-sensitive, redox-sensitive or sensitive to particular enzymes or bacteria, such that the coating only dissolves or finishes dissolving in the colon. Thus the capsules will not release the drug until it is in the terminal ileum or colon.
• Typical coating thicknesses will be in the range 5&#;15 mg polymer per cm 2 of capsule surface. For a capsule of size 1 with a surface area of approx. 4 cm 2 this represents a weight gain of 20 mg to 60 mg per capsule.
• Preferred coating materials are those which dissolve at a pH of 7 or above. The coatings only start to dissolve when they have left the stomach and entered the small intestine. By the time the capsule has reached the terminal ileum or colon the coating will have completely dissolved.
• Such a coating can be made from a variety of polymers such as cellulose acetate trimellitiate (CAT) hydroxypropylmethyl cellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), shellac and copolymers of methacrylic acid and ethyl acrylate.
• CAT cellulose acetate trimellitiate
• HPMCP hydroxypropylmethyl cellulose phthalate
• PVAP polyvinyl acetate phthalate
• CAP cellulose acetate phthalate
• shellac copolymers of methacrylic acid and ethyl acrylate.
• Especially preferred materials for aqueous film coating are copolymers of methacrylic acid and ethyl acrylate to which a monomer of methylacrylate has been added during polymerisation.
• Preparation D as known as Eudragit® FS 30 D from EP-A-704
• preparation D Using preparation D a coating thickness of 5&#;15 mg polymer per square cm of capsule surface is preferred.
• the colonic region is rich in microbial anaerobic organisms providing reducing conditions.
• the coating may suitably comprise a material which is redox-sensitive.
• Such coatings may comprise azopolymers which can for example consist of a random copolymer of styrene and hydroxyethyl methacrylate, cross-linked with divinylazobenzene synthesized by free radical polymerization, the azopolymer being broken down enzymatically and specifically in the colon or may consist of disulphide polymers.
• a coating composition can be prepared by mixing amylose-butan-1-ol complex (glassy amylose) with an aqueous dispersion of Ethocel (Ref. 13) or a coating formulation comprising an inner coating of glassy amylose and an outer coating of cellulose or acrylic polymer material (Ref. 17), calcium pectinate, (Ref. 18) pectin, a polysaccharide which is totally degraded by colonic bacterial enzymes (Ref. 11), chondroitin sulphate (Ref. 19) and resistant starches (Ref. 20), dextran hydrogels (Ref. 12), modified guar gum such as borax modified guar gum (Ref.
• &#; -cyclodextrin, saccharide containing polymers which can include a polymeric construct comprising a synthetic oligosaccharides&#;containing biopolymer including methacrylic polymers covalently couples to oligosaccharides such as cellobiose, lactalose, raffinose, and stachyose, or saccharide&#;containing natural polymers including modified mucopolysaccharides such as cross-linked chondroitin sulphate and metal pectin salts, for example calcium pectate (Ref. 22), methacrylate-galactomannan (Ref. 23) and pH sensitive hydrogels (Ref. 24).
• a synthetic oligosaccharides containing biopolymer including methacrylic polymers covalently couples to oligosaccharides such as cellobiose, lactalose, raffinose, and stachyose
• saccharide&#;containing natural polymers including modified mucopolysaccharides such
• the drug which is contained in the capsule may be any pharmaceutically or therapeutically active agent which is desirable to deliver to the small intestine, for example pancreatin and other proteolytic enzymes, diclofenac, naproxen, aspirin, indomethacin, omeprazole, cardiac glycosides, electrolyte preparations with sodium, potassium and magnesium salts as well as calcium and iron preparations, bisacodyl preparations and valproic acid.
• active agent which is desirable to deliver to the small intestine
• pancreatin and other proteolytic enzymes for example pancreatin and other proteolytic enzymes, diclofenac, naproxen, aspirin, indomethacin, omeprazole, cardiac glycosides, electrolyte preparations with sodium, potassium and magnesium salts as well as calcium and iron preparations, bisacodyl preparations and valproic acid.
• Drugs which are desirable to deliver to the colon include drugs for the treatment of colon disease, for example 5-ASA; steroids such as hydrocortisone, budesonide; laxatives; octreotide; cisapride; anticholinergies; calcium channel blockers, 5HT3-antagonists such as ondansetron and peptides such as insulin.
• HPMC capsules of the present invention are cheap, easy to manufacture and can be readily filled on standard capsule filling machines.
• the coating process is easy to carry out and the adhesion between the film and the HPMC capsule is good.
• Aqueous coating is possible and the resulting capsule is sufficiently robust which is an advantage over gelatin capsules.
• HPMC capsule particularly advantageous for the HPMC capsule is the slower drug release profile in acidic media and the fast release profile at a pH of 5 and above. This can result in lower quantities of polymer coat compared to that required for tablets to achieve the desired release in the small intestine or colon.
• HPMC capsules were filled with a blend comprising (by weight) 85.5% acetaminophen, 8.4% microcrystalline cellulose, 5.8% croscarmellose sodium and 0.3% sterotex.
• the mean capsule fill weight was 250 mg.
• the capsules were coated with a dispersion, the composition of which is given in Table 1.
• the dispersion was sprayed onto the HPMC capsules using an Accela-Cota 10.
• the temperature of the capsule bed during the coating process was 26&#;32° C.
• the mean amounts of polymer applied was from 5 mg/cm 2 to 10 mg/cm 2 .
• the dissolution performance of the capsules was tested using the USP method 2 (rotating paddle at 100 rpm). For the first two hours of the test 0.1N HCl (pH 1.2) was used as the test medium. After two hours the test medium was changed to phosphate buffer pH 6.8. Samples were withdrawn from the dissolution vessel at regular intervals and the concentration of acetaminophen in solution was monitored spectrophotometrically. Results from the dissolution test are presented in FIG. 1 . Capsules coated with &#; 7 mg/cm 2 remained completely intact for a period of two hours in acid and thus were considered to be enteric. After exposure to the pH 6.8 buffer medium, dissolution was rapid and complete thus fulfilling the requirement of an enteric product to deliver the drug in an undiluted form to its absorption site in the small intestine.
• HPMC capsules were filled with a blend comprising (by weight) 85.5% acetaminophen, 8.4% microcrystalline cellulose, 5.8% croscormellose sodium and 0.3% sterotex.
• the mean capsule fill weight was 250 mg.
• the capsules were coated with a dispersion, the composition of which is given in Table 2.
• the dispersion was sprayed onto the HPMC capsules using an Accela-Cota 10.
• the temperature of the capsule bed during the coating process was 26&#;32° C.
• the mean amount of polymer applied was 8 mg/cm 2 .
• the dissolution performance of the capsules was tested using the USP method 2 (rotating paddle at 100 rpm). For the first two hours of the test 0.1 N HCl (pH 1.2) was used as the test medium.

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Abstract

The invention provides a drug delivery system for delivering a drug to either the small intestine (enteric) or the colon comprising a HPMC capsule containing the drug and wherein the HPMC capsule is provided with a suitable coating such that the drug is released from the capsule either in the small intestine or the colon.

Description

This application is a Continuation of Application Ser. No. 09/396,225 filed Sep. 15, , now abandoned, which claims benefit of Provisional Application No. 60/102,017 filed Sep. 28, . Enteric coated products are designed to remain intact in the stomach but to dissolve and release the active substance in the upper intestine. This type of product is termed a delayed release dosage form. Most commercially available products in this category are tablets or pellets filled into hard gelatin capsules. Enteric coated preparations are usually used for one or more of the following purposes:

• • To protect the drug from the destructive action of the enzymes or low pH environment of the stomach.
  • To prevent or reduce nausea associated with a drug's irritation of gastric mucosa.
  • To deliver the drug in an undiluted form to its absorption site in the intestine.

The polymers commonly used to achieve enteric properties are polymethacrylates (copolymerisate of methacrylic acid and either methylmethacrylate or ethyl acrylate (EUDRAGIT®), cellulose based polymers e.g. cellulose acetate phthalate (AQUATERIC®) or polyvinyl derivatives e.g. polyvinyl acetate phthalate (COATERIC®). Colonic products, on the other hand are also designed to remain intact in the stomach but to release the active substance further along the gastrointestinal tract, i.e., in the colon. The site specific delivery of drugs to the colon has implications in a number of therapeutic areas. These include:

• • The local treatment of colonic diseases such as Crohn's disease, irritable bowel syndrome, ulcerative colitis and colon cancer.
  • The ability to deliver a drug into the colon which is susceptible to hydrolysis in the G.I. tract. Advances in biotechnology are producing increasing numbers of proteins and peptides. Protecting these labile compounds during their transit through the hostile environment of the upper G.I. tract and delivering them directly to the colon, a site low in host digestive enzymes and of more favourable pH will increase their chance of being absorbed.
  • The ability to delay systemic absorption in diseases such as asthma, arthritis or inflammation which are affected by circadian rhythmus.

A number of technologies, both marketed and in development, have been described which claim to provide colon specific drug delivery (2&#;24). As previously mentioned, site specific delivery into the upper intestine has been achieved for many years by the use of pH-sensitive coatings. By applying a thicker coating and/or raising the threshold pH at which dissolution of the coating begins colon specific delivery using enteric polymers has been achieved. Tablets containing mesalazine and coated with Eudragit® S100, (Roehm GmbH, Darmstadt, Germany) which dissolves above pH 7, are marketed in a number of countries (Asacol®, SmithKline Beecham, UK), Mesalazine tablets coated with Eudragit® L100, (Roehm GmbH, Darmstadt, Germany) which dissolves above pH 6, are also commercially available (Claversal® available from GlaxoSmithKline, Madrid Spain and Salofalk® Dr. Falk Pharma GmbH, Freiburg, Germany). The majority of the enteric and colon delivery systems are based on tablets or pellets which are filled into conventional hard gelatin capsules. During the early stages of drug development some new chemical entities (NCE's) present a challenge in testing for efficacy due to instability in gastric fluids or because of irritation in the gastrointestinal tract. In these situations, enteric or colonic coating of an encapsulated drug formulation would enable the efficacy of the drug to be determined without the complications of gastric instability or irritation. The limited amount of drug substance available during the early stage preclude the development of a coated pellet or tablet formulation. Since the coating process is independent of the capsule contents the advantages resulting from the ability to coat a capsule are obvious. Thus the oral pharmacological and/or therapeutic efficacy of the NCE can be determined without resorting to extensive formulation development studies which are expensive, time consuming and, in many instances, impossible at this point in the development of the NCE. Additionally, the capsule provides the possibility to deliver liquid or semi-solid formulations to the small or large intestine. The most commonly used material for manufacturing capsules is gelatin. Although it is possible to coat hard gelatin capsules the process is at best very sensitive, especially if an aqueous coating system is used, and can lead to shell embrittlement and poor adhesion of the coat to the smooth gelatin surface. A pre-coating can reduce interactions between the gelatin and the enteric polymer but is time consuming and complicated. Watts (16) has described a colonic drug delivery system based on a starch injection moulded capsule. This system has all the advantages of a capsule described above but suffers from the disadvantage of requiring a specially designed capsule filling and sealing machine, thus narrowing the field of application of the technology. Surprisingly we have found that the disadvantages of the hard gelatin capsule and the general prejudice associated with coating of this dosage form to achieve enteric or colonic delivery can be significantly reduced by the use of capsules made from hydroxypropylmethyl cellulose. This capsule has the same shape as a conventional hard gelatin capsule and can be filled using standard and widely available capsule filling machines. The invention therefore provides a drug delivery system for delivering a drug to either the small intestine (enteric) or the colon comprising a HPMC capsule containing the drug and wherein the HPMC capsule is provided with a suitable coating such that the drug is released from the capsule either in the small intestine or the colon. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 depicts the release profile of acetaminophen from HPMC coated capsules. FIG. 2 depicts the release profile of acetaminophen front HPMC coated capsules. In a preferred embodiement of the invention the HPMC capsules are sealed after filling in the overlapping region of capsule body and cap by commonly known sealing techniques like banding or applying a sealing liquid and/or heat to the gap between capsule body and cap. Preferred is a sealing process, in which a sealing liquid which may include a solfvent applied individually and uniformly to the external edge of the gap of a capsule to be sealed to form a liquid ring around the circumference of the capsule, removing excess sealing liquid from the exterior of the capsule and drying the capsule by applying thermal energy from outside. Such a sealing before coating will prevent problems e.g. with non-uniformity of the coating at the gap or development of fissures during storage under stressing conditions, which can lead to an unwated early leaking of the capsule content into the stomach. Surprisingly it has been found that enteric coated HPMC capsule have superior properties than enteric coated gelatin capsules, especially much higher resistance against acid solutions. In comparative tests 6 from 6 gelatin capsules coated with Eudragit L30D at 10 mg/cm2 opened in a disintegration test after 30 min at pH 1.2, wheras coated HPMC capsules only at 7 mg/cm2 withstood 120 min at pH 1.2. The composition of the coating should ensure a complete disintegration of the coating in the small intestine or the colon while at the same time minimizing the possibility of the coating disintegrating either in the stomach or passing through the gastrointestinal tract intact. For release in the small intestine any coating can be used which ensures that the capsule does not disintegrate until it is emptied from the stomach. The coating will usually be one which is pH sensitive and which completely dissolves in the small intestine. Typical coating thicknesses will be in the range 5 to 15 mg polymer per cm2 of capsule surface. For a capsule of size 1 with a surface area of approx. 4 cm2 this represents a weight gain of 20 mg to 60 mg per capsule (50&#;150 μm). Preferred coating materials are those which dissolve at a pH of 5&#;6. The coatings therefore only begin to dissolve when they have left the stomach and then rapidly disintegrate once the capsule has entered the small intestine. Such a coating can be made from a variety of polymers such as cellulose acetate trimellitiate (CAT), hydroxypropylmethyl cellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP) and shellac. Especially preferred materials for aqueous film coating are copolymers of methacrylic acid and ethyl acrylate, Eudragit® L30D-55 (Roehm GmbH, Darmstadt, Germany). For release in the terminal ileum or colon any coating can be used which ensures that the capsule does not disintegrate until it is emptied from the stomach. The coating may be one which is pH-sensitive, redox-sensitive or sensitive to particular enzymes or bacteria, such that the coating only dissolves or finishes dissolving in the colon. Thus the capsules will not release the drug until it is in the terminal ileum or colon. Typical coating thicknesses will be in the range 5&#;15 mg polymer per cm2 of capsule surface. For a capsule of size 1 with a surface area of approx. 4 cm2 this represents a weight gain of 20 mg to 60 mg per capsule. Preferred coating materials are those which dissolve at a pH of 7 or above. The coatings only start to dissolve when they have left the stomach and entered the small intestine. By the time the capsule has reached the terminal ileum or colon the coating will have completely dissolved. Such a coating can be made from a variety of polymers such as cellulose acetate trimellitiate (CAT) hydroxypropylmethyl cellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), shellac and copolymers of methacrylic acid and ethyl acrylate. Especially preferred materials for aqueous film coating are copolymers of methacrylic acid and ethyl acrylate to which a monomer of methylacrylate has been added during polymerisation. (Preparation D as known as Eudragit® FS 30 D from EP-A-704 208 and EP-A-704 207, Roehm GmbH, Darmstadt, Germany). Due to the free carboxylic acid group the polymer dissolves at pH 7 or above making it particularly suitable for delivery into the colon. Using preparation D a coating thickness of 5&#;15 mg polymer per square cm of capsule surface is preferred. The colonic region is rich in microbial anaerobic organisms providing reducing conditions. Thus the coating may suitably comprise a material which is redox-sensitive. Such coatings may comprise azopolymers which can for example consist of a random copolymer of styrene and hydroxyethyl methacrylate, cross-linked with divinylazobenzene synthesized by free radical polymerization, the azopolymer being broken down enzymatically and specifically in the colon or may consist of disulphide polymers. Other materials providing release in the colon are amylose, for example a coating composition can be prepared by mixing amylose-butan-1-ol complex (glassy amylose) with an aqueous dispersion of Ethocel (Ref. 13) or a coating formulation comprising an inner coating of glassy amylose and an outer coating of cellulose or acrylic polymer material (Ref. 17), calcium pectinate, (Ref. 18) pectin, a polysaccharide which is totally degraded by colonic bacterial enzymes (Ref. 11), chondroitin sulphate (Ref. 19) and resistant starches (Ref. 20), dextran hydrogels (Ref. 12), modified guar gum such as borax modified guar gum (Ref. 21), β-cyclodextrin, saccharide containing polymers, which can include a polymeric construct comprising a synthetic oligosaccharides&#;containing biopolymer including methacrylic polymers covalently couples to oligosaccharides such as cellobiose, lactalose, raffinose, and stachyose, or saccharide&#;containing natural polymers including modified mucopolysaccharides such as cross-linked chondroitin sulphate and metal pectin salts, for example calcium pectate (Ref. 22), methacrylate-galactomannan (Ref. 23) and pH sensitive hydrogels (Ref. 24). The drug which is contained in the capsule may be any pharmaceutically or therapeutically active agent which is desirable to deliver to the small intestine, for example pancreatin and other proteolytic enzymes, diclofenac, naproxen, aspirin, indomethacin, omeprazole, cardiac glycosides, electrolyte preparations with sodium, potassium and magnesium salts as well as calcium and iron preparations, bisacodyl preparations and valproic acid. Drugs which are desirable to deliver to the colon include drugs for the treatment of colon disease, for example 5-ASA; steroids such as hydrocortisone, budesonide; laxatives; octreotide; cisapride; anticholinergies; calcium channel blockers, 5HT3-antagonists such as ondansetron and peptides such as insulin. The HPMC capsules of the present invention are cheap, easy to manufacture and can be readily filled on standard capsule filling machines. The coating process is easy to carry out and the adhesion between the film and the HPMC capsule is good. Aqueous coating is possible and the resulting capsule is sufficiently robust which is an advantage over gelatin capsules. Particularly advantageous for the HPMC capsule is the slower drug release profile in acidic media and the fast release profile at a pH of 5 and above. This can result in lower quantities of polymer coat compared to that required for tablets to achieve the desired release in the small intestine or colon. EXAMPLES Example 1 Enteric Capsules HPMC capsules were filled with a blend comprising (by weight) 85.5% acetaminophen, 8.4% microcrystalline cellulose, 5.8% croscarmellose sodium and 0.3% sterotex. The mean capsule fill weight was 250 mg. The capsules were coated with a dispersion, the composition of which is given in Table 1. TABLE 1 Composition of aqueous Eudragit&#;® dispersion to coat 1.3 kg HPMC capsules g Solids g Eudragit L30D-55 453&#; Triethyl citrate &#;91 91 Tween 80 (33%) &#;20 &#;7 Water &#; The dispersion was sprayed onto the HPMC capsules using an Accela-Cota 10. The temperature of the capsule bed during the coating process was 26&#;32° C. The mean amounts of polymer applied was from 5 mg/cm2 to 10 mg/cm2. The dissolution performance of the capsules was tested using the USP method 2 (rotating paddle at 100 rpm). For the first two hours of the test 0.1N HCl (pH 1.2) was used as the test medium. After two hours the test medium was changed to phosphate buffer pH 6.8. Samples were withdrawn from the dissolution vessel at regular intervals and the concentration of acetaminophen in solution was monitored spectrophotometrically. Results from the dissolution test are presented in FIG. 1. Capsules coated with &#;7 mg/cm2 remained completely intact for a period of two hours in acid and thus were considered to be enteric. After exposure to the pH 6.8 buffer medium, dissolution was rapid and complete thus fulfilling the requirement of an enteric product to deliver the drug in an undiluted form to its absorption site in the small intestine. Example 2 Colonic Capsules HPMC capsules were filled with a blend comprising (by weight) 85.5% acetaminophen, 8.4% microcrystalline cellulose, 5.8% croscormellose sodium and 0.3% sterotex. The mean capsule fill weight was 250 mg. The capsules were coated with a dispersion, the composition of which is given in Table 2. TABLE 2 Composition of aqueous methacrylic acid/methyl methacrylate dispersion (preparation D) to coat 1.3 kg HPMC capsules g Solids g Preparation D &#; 362&#; Triethyl citrate 18 18 Glceryl monostearate 11 11 Tween 80 (33%) 13 &#;4 Water 728&#; &#; The dispersion was sprayed onto the HPMC capsules using an Accela-Cota 10. The temperature of the capsule bed during the coating process was 26&#;32° C. The mean amount of polymer applied was 8 mg/cm2. The dissolution performance of the capsules was tested using the USP method 2 (rotating paddle at 100 rpm). For the first two hours of the test 0.1 N HCl (pH 1.2) was used as the test medium. After two hours the test medium was changed to phosphate buffer pH 6.8 for one/two hours and finally to phosphate buffer pH 7.4. Samples were withdrawn from the dissolution vessel at regular intervals and the concentration of acetaminophen in solution was monitored spectrophotometrically. Results from the dissolution test are presented in FIG. 2

Claims (28)

1. A drug delivery composition consisting essentially of a coated HPMC capsule capable of containing a drug, wherein the HPMC capsule comprises a single aqueous coating such that the drug is not released from the capsule in the stomach. 2. A drug delivery composition according to claim 1, wherein the HPMC capsule is provided with a coating such that the drug is predominately released from the capsule in the small intestine. 3. A drug delivery composition according to claim 1, wherein the HPMC capsule is provided with a coating such that the drug is predominately released from the capsule in the colon and/or terminal ileum. 4. A drug delivery composition according to claim 2 wherein the coating comprises a material which dissolves at a pH of 5.5 or above. 5. A drug delivery composition according to claim 3 wherein the coating comprises a material which dissolves at a pH 7 or above. 6. A drug delivery composition according to claim 2 wherein the coating comprises cellulose acetate trimellitiate (CAT). 7. A drug delivery composition according to claim 2 wherein the coating comprises hydroxypropylmethyl cellulose phthalate (HPMCP). 8. A drug delivery composition according to claim 2 wherein the coating comprises polyvinyl acetate phthalate (PVAP). 9. A drug delivery composition according to claim 2 wherein the coating comprises shellac. 10. A drug delivery composition according to claim 2 wherein the coating comprises a copolymer of methacrylic acid and methylmethacrylate. 11. A drug delivery composition according to claim 3 wherein the coating composition comprises a material which is redox-sensitive. 12. A drug delivery composition according to claim 3 wherein the coating composition comprises an azopolymer or a disulphide polymer. 13. A drug delivery composition according to claim 3 wherein the coating composition comprises a material which is degraded by enzymes or bacteria present in the colon. 14. A drug delivery composition according to claim 3 wherein the coating composition comprises a copolymer of methacrylic acid and methylmethacrylate to which has been added during polymerisation the monomer methyl acrylate. 15. A drug delivery composition according to claim 3 wherein the coating composition comprises a cellulose ester. 16. A drug delivery composition according to claim 3 wherein the coating composition comprises polyvinyl acetate phthalate. 17. A drug delivery composition according to claim 2 wherein the coating is applied in the range of 5&#;15 mg per cm2 of capsule surface. 18. A drug delivery composition according to claim 3 wherein the coating is applied in the range 5&#;20 mg per cm2 of capsule surface. 19. A drug delivery composition according to claim 2 wherein the drug is one which is effective in the small intestine. 20. A drug delivery composition according to claim 1 wherein the drug is one which acts locally in the colon. 21. A drug delivery composition according to claim 1 wherein the coating is applied separately to empty HPMC capsule body and cap. 22. A drug delivery composition according to claim 1 wherein two equal HPMC capsule halves are filled with a caplet. 23. A drug delivery composition according to claim 22 wherein the coating is applied separately to equal empty HPMC capsule halves. 24. A drug delivery composition according to claim 22 wherein one half is coated with an insoluble polymer and the other half is enteric or colonic coated. 25. A drug delivery composition according to claim 1 wherein the HPMC capsule is coated with a film which is non-dissolving at pH<3 to 4 and dissolving at pH>5.5. 26. A drug delivery composition according to claim 1 wherein the HPMC content of the capsule shell is in the range of from 10 to 90% by weight. 27. A drug delivery composition according to claim 1 wherein stomach resistant coating is applied to HPMC capsules having a sealing on the gap between capsule body and cap. 28. A drug delivery composition consisting essentially of an HPMC capsule capable of containing a drug, wherein: (a) drug is not released from the capsule in the stomach; (b) one half of the capsule is enteric coated and the other half is colonic coated; (c) the enteric coating is at least one member selected from the group consisting of cellulose acetate trimellitiate, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate, shellac, and a copolymer of methacrylic acid and ethyl acrylate: and (d) the colonic coating is a member selected from the group consisting of azopolymers, disulphide polymers and amylose. US09/836,627 -09-28 -04-17 Enteric and colonic delivery using HPMC capsules Expired - Fee Related USB2 (en)

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Families Citing this family (54)

* Cited by examiner, &#; Cited by third party Publication number Priority date Publication date Assignee Title SED0 (en) * -03-08 -03-08 Astrazeneca Ab New formulation SED0 (en) -03-08 -03-08 Astrazeneca Ab New formulation USB2 (en) -01-18 -10-03 Pharmacia & Upjohn Company Chemotherapeutic microemulsion compositions of paclitaxel with improved oral bioavailability ATET1 (en) -03-27 -11-15 Pro Pharmaceuticals Inc SIMULTANEOUS ADMINISTRATION OF A POLYSACCHARIDE WITH A CHEMOTHERAPEUTIC AGENT FOR THE TREATMENT OF CANCER USB1 (en) -03-27 -11-11 Pro-Pharmaceuticals, Inc. Delivery of a therapeutic agent in a formulation for reduced toxicity DED1 (en) * -06-01 -09-02 Pozen Inc PHARMACEUTICAL COMPOSITIONS FOR THE COORDINATED DELIVERY OF NSAID SED0 (en) -09-07 -09-07 Astrazeneca Ab New self emulsifying drug delivery system EPA1 (en) * -04-04 -10-08 Applied NanoSystems B.V. Delivery of a substance to a pre-determinated site AUB2 (en) -06-19 -02-14 Intrexon Actobiotics Nv Methods and means to promote gut absorption USB2 (en) * -12-24 -02-03 Lek Pharmaceuticals D.D. Modified release pharmaceutical composition USB2 (en) -09-03 -06-15 Agi Therapeutics Ltd. Formulations and methods of treating inflammatory bowel disease USB2 (en) -09-03 -11-02 Agi Therapeutics Ltd. Modified release formulations and methods of treating inflammatory bowel disease DKT3 (en) -05-18 -10-07 Centre Nat Rech Scient DELIVERY OF ADSORPTIONS TO THE GAS EPB1 (en) -11-29 -01-08 Intrexon Actobiotics NV Induction of mucosal tolerance to gliadin DKT3 (en) * -12-14 -08-26 Oxthera Intellectual Property Ab PHARMACEUTICAL COMPOSITIONS INCLUDING OXALATE-REDUCING BACTERIA AUB2 (en) -12-16 -11-15 Oxthera Intellectual Property Ab Compositions and methods for oxalate reduction USA1 (en) -12-22 -06-28 Banner Pharmacaps, Inc. Gastric reflux resistant dosage forms USB2 (en) -05-17 -11-01 Helene Huguet Site-specific intestinal delivery of adsorbents, alone or in combination with degrading molecules CNB (en) -01-25 -09-28 &#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#; Use the lactobacillus mucosal delivery treatment immunological diseases by antigen of genetic modification WOA2 (en) -04-04 -10-16 Sigmoid Pharma Limited Pharmaceutical cyclosporin compositions ITB1 (en) * -07-24 -04-12 Universita' Degli Studi Di Milano PHARMACEUTICAL FORMS FOR THE TIME-SPECIFIC RELEASE OF DRUGS WOA2 (en) * -09-03 -03-11 New Science Holdings, Llc Compositions and methods for inducing satiety and treating non-insulin dependent diabetes emillitus, pre-diabetic symptoms, insulin resistance and related disease states and conditions USB2 (en) -09-03 -09-12 Volant Holdings Gmbh Compositions and methods for treating insulin resistance and non-insulin dependent diabetes mellitus (type II diabetes) KRB1 (en) * -10-21 -08-02 &#;&#;&#; Method for preparing dissolution time-controlled enteric cleaner composition KRB1 (en) * -09-11 -02-09 &#;&#;&#;&#;&#;&#; &#;&#;&#;&#; Aqueous composition for hard capsule having enteric properties, method of preparing hard capsule having enteric properties and hard capsule prepared by the latter JPB2 (en) -02-25 -09-28 &#;&#;&#;&#;&#; &#;&#;&#; &#;&#;&#;&#;&#;&#;&#; &#;&#;&#; &#;&#;&#;&#;&#;&#;&#;&#; &#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#; &#;&#;&#;&#;&#; &#;&#;&#;&#; Pharmaceutical formulation or nutritional supplement food formulation WOA1 (en) * -08-25 -03-01 Grant Rufus Sparling Ii Improved enteric active substance delivery EPA1 (en) -10-26 -08-01 Capsugel Belgium NV Bulk enteric capsule shells KRB1 (en) * -11-19 -06-14 &#;&#;&#;&#;&#;&#; &#;&#;&#;&#; Composition for enteric hard capsule and enteric hard capsule prepared by using the composition CAC (en) -06-01 -12-14 Actogenix Nv Polycistronic expression system for bacteria WOA2 (en) -09-07 -03-14 JÄNISCH, Melisa Formulation for the controlled release of one or several substances in the digestive tract of a mammal USB2 (en) -09-07 -05-19 Roland SAUR-BROSCH Optimal colon targeting technology CNB (en) * -04-01 -01-20 &#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#; A kind of probiotic microcapsule product and preparation and application thereof EPA3 (en) -05-02 -05-15 Capsugel Belgium NV Aqueous dispersions of controlled release polymers and shells and capsules thereof WOA1 (en) * -07-23 -01-30 Dow Global Technologies Llc Film composition for hard capsule shells USA1 (en) -07-26 -03-06 Ronald L. Moy Skin care compositions and methods EPA4 (en) * -08-29 -03-30 Salix Pharmaceuticals Inc Laxative compositions and methods for treating constipation and related gastrointestinal diseases and conditions WOA1 (en) * -01-30 -08-07 University Of Miami Enteric coated nanoparticles for oral vaccine and drug delivery and methods of production and use thereof WOA1 (en) -11-04 -05-07 Capsugel Belgium Nv Methods and systems for improved bioavailability of active pharmaceutical ingredients including esomeprazole EPB1 (en) -12-02 -07-12 Capsugel Belgium NV Dosage form articles for delayed release AUB2 (en) -01-14 -01-28 Intrexon Actobiotics N.V. Compositions and methods for the treatment of type 1 diabetes CNB (en) * -08-23 -09-28 &#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#; Phthalic acid cellulose acetate CNA (en) -09-02 -06-04 &#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#; Stablize the bacterium of the genetic modification of expression IL-10 and insulin CNB (en) -09-13 -10-20 &#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#; mucoadhesive microorganisms USB2 (en) -10-25 -02-18 Glykon Technologies Group, Llc Hydroxycitric acid compounds and capsule liquid delivery CNA (en) * -05-03 -12-18 &#;&#;&#;&#;&#;&#;&#;&#;&#; Dosage forms for delivering drugs to the lower alimentary canal EPA1 (en) * -08-14 -02-19 Apillet APS Novel oral composition CNB (en) * -12-24 -09-21 &#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#; Enteric slow-release plant capsule and preparation method thereof KRA (en) -09-27 -08-16 &#;&#;&#;&#; &#;&#;&#;&#;&#;&#;&#; &#;.&#;&#;. treatment of celiac disease WOA1 (en) * -07-22 -01-27 &#;&#;&#;&#;&#;&#;&#;&#;&#;&#; Hydroxypropyl methylcellulose hollow capsule WOA1 (en) * -07-22 -01-27 &#;&#;&#;&#;&#;&#;&#;&#;&#;&#; Enteric-coated vacant capsules from hypromellose WOA1 (en) * -10-18 -06-30 Nutra Grace Enteric coated hpmc based herbal oil capsule for treatment of irritable bowel syndrome AUA1 (en) * -04-29 -11-14 Novatek Therapeutics, Llc Black seed oil formulations KRA (en) * -11-30 -06-19 &#;&#;&#;&#; &#;&#;&#;&#;&#;&#;&#;&#;&#; Fecal Microbiota Transplantation double capsule and preparation method thereof

Citations (6)

* Cited by examiner, &#; Cited by third party Publication number Priority date Publication date Assignee Title USA (en) -08-27 -02-06 Parke, Davis & Company Enteric capsules USA (en) * -06-27 -05-24 Paulos Manley A Methods for making and administering a blinded oral dosage form and blinded oral dosage form therefor DEU1 (en) -08-31 -11-03 Röhm GmbH & Co. KG, Darmstadt Thermoplastic plastic for pharmaceutical casings soluble in intestinal juice WOA1 (en) -06-21 -12-28 Danbiosyst Uk Limited Colonic drug delivery composition EPA2 (en) -07-20 -01-22 Tanabe Seiyaku Co., Ltd. Pharmaceutical preparation in form of coated capsule releasable at lower part of digestive tract EPA1 (en) -08-02 -06-02 Hisamitsu Pharmaceutical Co., Inc. Capsules for oral preparations and capsule preparations for oral administration

Family Cites Families (7)

* Cited by examiner, &#; Cited by third party Publication number Priority date Publication date Assignee Title JPSA (en) * -10-23 -05-19 Shin Etsu Chem Co Ltd Hard capsule for drug JPB2 (en) * -10-06 -12-11 &#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#; Hard capsule USA (en) * -02-26 -08-12 The Procter & Gamble Company Bisacodyl dosage form with multiple enteric polymer coatings for colonic delivery DEA1 (en) * -09-01 -03-02 Galenik Labor Freiburg Gmbh Pharmaceutical preparations for the targeted treatment of Crohn's disease and ulcerative colitis JPB2 (en) * -12-01 -10-06 &#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#;&#; Capsule coating composition JPB2 (en) * -07-20 -07-09 &#;&#;&#;&#;&#;&#;&#;&#; Lower digestive tract release coated capsule formulation JPHA (en) * -08-02 -06-09 Hisamitsu Pharmaceut Co Inc Capsule for oral pharmaceutical preparation and oral capsule pharmaceutical preparation

• • -09-23 CA CAA patent/CAC/en not_active Expired - Fee Related
  • -09-23 JP JPA patent/JPB2/en not_active Expired - Fee Related
  • -09-23 EP EPA patent/EPB1/en not_active Expired - Lifetime
  • -09-23 KR KRA patent/KRB1/en not_active IP Right Cessation
  • -09-23 ID IDWA patent/IDA/en unknown
  • -09-23 DE DET patent/DET2/en not_active Expired - Lifetime
  • -09-23 WO PCT/US/ patent/WOA1/en active IP Right Grant
  • -09-23 AU AU/99A patent/AUB2/en not_active Ceased
  • -09-23 PT PTT patent/PTE/en unknown
  • -09-23 ES EST patent/EST3/en not_active Expired - Lifetime
  • -09-23 AT ATT patent/ATET1/en active
  • -09-23 CN CNBA patent/CNC/en not_active Expired - Fee Related
  • -09-23 MX MXPAA patent/MXPAA/en not_active IP Right Cessation
• • -04-17 US US09/836,627 patent/USB2/en not_active Expired - Fee Related

Patent Citations (6)

* Cited by examiner, &#; Cited by third party Publication number Priority date Publication date Assignee Title USA (en) -08-27 -02-06 Parke, Davis & Company Enteric capsules USA (en) * -06-27 -05-24 Paulos Manley A Methods for making and administering a blinded oral dosage form and blinded oral dosage form therefor WOA1 (en) -06-21 -12-28 Danbiosyst Uk Limited Colonic drug delivery composition DEU1 (en) -08-31 -11-03 Röhm GmbH & Co. KG, Darmstadt Thermoplastic plastic for pharmaceutical casings soluble in intestinal juice EPA2 (en) -07-20 -01-22 Tanabe Seiyaku Co., Ltd. Pharmaceutical preparation in form of coated capsule releasable at lower part of digestive tract EPA1 (en) -08-02 -06-02 Hisamitsu Pharmaceutical Co., Inc. Capsules for oral preparations and capsule preparations for oral administration

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* Cited by examiner, &#; Cited by third party Publication number Priority date Publication date Assignee Title USB2 (en) -06-01 -05-24 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs USB2 (en) -06-01 -06-14 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs USB2 (en) -06-01 -10-07 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs USB2 (en) -06-01 -10-15 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs USB2 (en) -06-01 -10-14 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDS USB2 (en) -06-01 -07-18 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs USA1 (en) * -06-01 -11-10 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs USB2 (en) -06-01 -10-21 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs USB2 (en) -06-01 -12-01 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs USB2 (en) -06-01 -10-20 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs USB2 (en) -06-01 -06-26 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs USA1 (en) * -10-11 -05-03 Banner Pharmacaps, Inc. Enteric valproic acid USA1 (en) * -10-11 -04-12 Banner Pharmacaps, Inc. Enteric valproic acid EPA2 (en) * -12-30 -09-10 Cogentus Pharmaceuticals, Inc. Oral pharmaceutical formulations containing non-steroidal anti-inflammatory drugs and acid inhibitors EPA1 (en) -01-18 -02-17 Bows Pharmaceuticals AG Liquid compositions comprising dextran, in situ formed implants obtained thereof USA1 (en) * -10-27 -07-01 Pfizer Products Inc. Hydroxypropyl Methyl Cellulose Hard Capsules and Process of Manufacture USB2 (en) -10-27 -05-23 Capsugel Belgium Nv Hydroxypropyl methyl cellulose hard capsules and process of manufacture USB2 (en) -10-27 -06-26 Capsugel Belgium Nv Hydroxypropyl methyl cellulose hard capsules and process of manufacture USB2 (en) -09-09 -07-19 Pozen Inc. Method for delivering a pharmaceutical composition to patient in need thereof USB2 (en) -09-09 -10-31 Pozen Inc. Method for delivering a pharmaceutical composition to patient in need thereof USB2 (en) -09-09 -12-29 Pozen Inc. Method for delivering a pharmaceutical composition to patient in need thereof USA1 (en) * -03-18 -01-12 Carolin Welz Bleaching Agent Having Delayed Bleaching Action USA1 (en) * -06-25 -01-13 Pozen Inc. Method for Treating a Patient in Need of Aspirin Therapy USB2 (en) -06-25 -02-03 Pozen Inc. Method for treating a patient at risk for developing an NSAID-associated ulcer EPA1 (en) -07-23 -02-16 Actogenix N.V. Aqueous enteric capsule coating WOA1 (en) -09-18 -03-24 Adolor Corporation Use of opioid receptor antagonist for gastrointestinal tract disorders EPA1 (en) -11-09 -11-13 Capsugel Belgium NV Acid resistant banding solution for acid resistant two piece hard capsules USB2 (en) -11-09 -05-29 Capsugel Belgium Nv Acid resistant banding solution for acid resistant two piece hard capsules WOA1 (en) -11-09 -10-10 Capsugel Belgium Nv Acid resistant banding solution for acid resistant two piece hard capsules USB2 (en) -12-28 -01-10 Pozen Inc. Compositions and methods for delivery of omeprazole plus acetylsalicylic acid USB2 (en) -12-28 -06-05 Pozen Inc. Compositions and methods for delivery of omeprazole plus acetylsalicylic acid USB2 (en) -12-28 -03-31 Genus Lifesciences, Inc. Compositions and methods for delivery of omeprazole plus acetylsalicylic acid USB2 (en) -03-29 -03-17 Therabiome, Llc Gastrointestinal site-specific oral vaccination formulations active on the ileum and appendix USB2 (en) -11-21 -06-23 Allergan Pharmaceuticals International Limited 5-aminosalicylic acid capsule formulation USA1 (en) * -11-21 -05-22 Warner Chilcott Company, Llc 5-aminosalicylic acid capsule formulation USB2 (en) -11-21 -04-23 Allergan Pharmaceutical International Limited 5-aminosalicyclic acid capsule formulation USB2 (en) -03-14 -08-06 Therabiome, Llc Targeted gastrointestinal tract delivery of probiotic organisms and/or therapeutic agents USB2 (en) -03-14 -02-28 Therabiome, Llc Targeted gastrointestinal tract delivery of probiotic organisms and/or therapeutic agents USB2 (en) -03-14 -03-06 Therabiome, Llc Targeted gastrointestinal tract delivery of probiotic organisms and/or therapeutic agents USA1 (en) * -05-19 -02-17 Tillotts Pharma Ag Modified release coated capsules USB2 (en) * -05-19 -06-04 Tillotts Pharma Ag Modified release coated capsules USB2 (en) * -05-19 -03-08 Tillotts Pharma Ag Modified release coated capsules EPA1 (en) -11-10 -11-13 Capsugel Belgium NV Acid resistant banding or sealing solution for acid resistant two piece hard capsules EPA1 (en) -11-10 -05-17 Capsugel Belgium NV Acid resistant banding or sealing solution for acid resistant two piece hard capsules USB2 (en) -11-10 -02-15 Capsugel Belgium, NV Acid resistant banding or sealing solution for acid resistant two piece hard capsules WOA1 (en) -07-11 -01-17 &#;&#;&#;&#;&#;&#;&#;&#;&#;&#; Enteric hard capsule KRA (en) -07-11 -03-11 &#;&#;&#;&#;&#;&#; &#;&#;&#;&#;&#;&#;&#; Enteric hard capsules KRA (en) -06-22 -03-03 &#;&#;&#;&#;&#;&#; &#;&#;&#;&#;&#;&#;&#; Enteric hard capsule WOA1 (en) -06-22 -12-26 &#;&#;&#;&#;&#;&#;&#;&#;&#;&#; Enteric hard capsule

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Publication number Publication date AUB2 (en) -02-20 PTE (en) -04-29 IDA (en) -05-10 JPB2 (en) -11-07 DET2 (en) -12-22 KRB1 (en) -03-15 ATET1 (en) -12-15 CNA (en) -11-07 CNC (en) -01-02 JPA (en) -08-13 WOA1 (en) -04-06 USA1 (en) -11-01 KRA (en) -08-09 DED1 (en) -01-05 CAA1 (en) -04-06 EPB1 (en) -12-01 EPA1 (en) -07-25 EST3 (en) -06-16 MXPAA (en) -04-21 CAC (en) -11-25 AUA (en) -04-17

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Polymeric film coating of oral solid dosage forms may generate products that exhibit controlled release of active ingredients, physical and chemical protection of the ingredients from the external environment as well as taste masking properties. Among controlled release products, sustained and delayed release profiles are prominent. For the former, the drug is released gradually over time whereas for the latter, drug release occurs rapidly following a predefined lag-time. Thus, drugs can be delivered to the small intestine as exemplified by pH-sensitive coatings of solid dosage forms.

HPMC (hydroxypropyl methylcellulose) capsules have been available commercially, mainly to the dietary supplement industry as a vegetarian alternative to gelatin, for more than 10 years. Enteric-coated filled HPMC hard capsules are also frequently applied as clinical trial formulations in early stages of clinical investigations since some new chemical entities (NCE&#;s) are prone to instability in gastric fluids or irritate the gastric mucosa. Furthermore, the limited amount of drug substance available at early development stages often precludes the development of other solid dosage forms, such as coated pellets or tablets. Advantages result from the ability to coat a capsule, since the coating process is independent of the capsule contents thus avoiding extensive formulation development.

During capsule coating challenges are generally due to the characteristics of the capsule wall. In particular, for gelatin-based capsules, the shell may soften and become sticky upon spraying of aqueous enteric polymer dispersions or it may become brittle due to water evaporation during drying with consecutive loss of mechanical stability. Furthermore, insufficient adhesion of the film with splintering and peeling of the coat (orange peel effect), especially with organic spray formulations has been reported. In this respect, HPMC capsules offer the advantage of less sensitivity to aqueous coatings if appropriate sealing, i.e. closure of the gap between the capsule body and the cap is obtained to avoid leaking of the capsule content into the stomach or vice versa. Moreover, site-specific delivery of HPMC capsules was claimed by using coating materials with different pH-dependent solubilities, i.e. dissolving at pH &#;5.5 and pH &#;7 for upper GI and colonic delivery, respectively. A comparison between gelatin versus HPMC capsules coated with acrylic polymers Eudragit L and S 12.5 demonstrated that the gelatin capsules resulted in brittle film coats with insufficient adhesion on the smooth capsule surface [6]. Since the surface of HPMC is more ragged compared with gelatin capsules. HPMC materials may lend themselves to better polymer coat adhesion. Download the thesis here: enteric-coated-hpmc-capsules.pdf

Dissertation zur Erlangung des Grades &#;Doktor der Naturwissenschaften&#; am Fachbereich Chemie, Pharmazie und Geowissenschaften der Johannes Gutenberg-Universität Mainz

Maoqi Fu, geb. in Ürümqi , China

Mainz,

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