Gastrointestinal drug delivery system

• US 5,840,332 A
• Filed: 01/18/1996
• Issued: 11/24/1998
• Est. Priority Date: 01/18/1996
• Status: Expired due to Term

• Current Assignee: Dexcel Pharma Technologies (Dexcel Limited)
• Original Assignee: Perio Products, Ltd.
• Inventors: Penhasi, Adel, Lerner, E. Itzhak, Flashner, Moshe
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Benston, Jr., William E.
• Application Number:
  US08/588,247
• Time in Patent Office: 1,041 Days
• Field of Search: 424/464, 424/489, 424/480, 424/457, 424/468, 424/495, 128/260
• US Class Current: 424/464
• CPC Class Codes: A61K 9/205 Polysaccharides, e.g. alginate, gums; Cyclodextrin
• CPC Class Codes: A61K 9/2846 Poly(meth)acrylates
• CPC Class Codes: A61K 9/286 Polysaccharides, e.g. gums; Cyclodextrin
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system

Abstract

A gastrointestinal delivery system is provided. The system comprises a drug in combination with a core material, the core being surrounded by a water-insoluble or relatively water-insoluble coating material in which particulate water-insoluble material is embedded. When the delivery device enters the gastrointestinal tract, the particulate matter takes up liquid, thus forming channels interconnecting the drug-containing core with the outside of the delivery device. These channels allow the release of drug from the core into the gastrointestinal tract. By controlling parameters in the device, such as the core material, carrier material in the coating, and particulate matter, the location of release of the drug can be carefully controlled. Thus, the invention is also directed to a method of using the device for the treatment of disease by the release of drugs in the gastrointestinal tract in a location- and time- dependent manner.

Claims

1. A drug delivery formulation for localized drug release in the gastrointestinal tract of an animal comprising:

a. a core comprising a drug and core material; and

b. a coating surrounding said core, said coating having an outer surface,

wherein said coating comprises water-insoluble hydrophilic particulate matter embedded in a water-insoluble carrier, such that when said formulation enters the gastrointestinal tract, said particulate matter absorbs liquid, thus forming channels that interconnect said core with said outer surface of said coating, and through which channels, said drug from said core is released into the gastrointestinal tract.

2. The formulation of claim 1 wherein said core is selected from the group consisting of tablets, capsules, and pellets.

3. The formulation of claim 1 wherein said water-insoluble carrier of said coating is selected from the group consisting of a dimethylaminoethylacrylate/ethylmethacrylate copolymer, said copolymer based on acrylic and methacrylic acid esters with a low content of quaternary ammonium groups, wherein the molar ratio of the ammonium groups to the remaining neutral (meth)acrylic acid esters is approximately 1:

20, said polymer corresponding to USP/NF "Ammonio Methacrylate Copolymer Type A", an ethylmethacrylate/chlorotrimethylammoniumethyl methacrylate copolymer, said copolymer based on acrylic and methacrylic acid esters with a low content of quaternary ammonium groups wherein the molar ratio of the ammonium groups to the remaining neutral (meth)acrylic acid esters is 1;

40, said polymer corresponding to USP/NF "Ammonio Methacrylate Copolymer Type B", a dimethylaminoethylmethacrylate/methylmethacrylate and butylmethacrylate copolymer, a copolymer based on neutral methacrylic acid esters and dimethylaminoethyl methacrylate esters wherein the polymer is cationic in the presence of acids, an ethylacrylate and methylacrylate/ethylmethacrylate and methyl methylacrylate copolymer, said copolymer being a neutral copolymer based on neutral methacrylic acid and acrylic acid esters, ethylcellulose, shellac, zein, and waxes.

4. The formulation of claim 1 wherein said coating (b) is further coated with an enteric coating.

5. The formulation of claim 1 wherein said core comprises a swellable material.

6. The formulation of claim 5 wherein said swellable material is selected from the group consisting of polysaccharide, cross-linked polyacrylic acid, and modified cellulose.

7. The formulation of claim 6 wherein said polysaccharide is selected from the group consisting of alginate, pectin, xantham gum, guar gum, carrageenan, tragacanth gum, locust bean gum, starch, microcrystalline starch, microcrystalline cellulose, metal salts thereof, and covalently crosslinked derivatives thereof.

8. The formulation of claim 6 wherein said modified cellulose is selected from the group consisting of hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose and carboxymethylcellulose.

9. The formulation of claim 1 wherein said particulate matter comprises a polymer selected from the group consisting of a water-insoluble polysaccharide, a water-insoluble cross-linked polysaccharide, a water-insoluble polysaccharide metal salt, a water-insoluble cross-linked protein, a water-insoluble cross-linked peptide, water insoluble protein:

polysaccharide complex, a water insoluble peptide;

polysaccharide complex, a polysaccharide or a protein or peptide rendered insoluble by interaction with a poly-cation or poly-anion and a water-insoluble cross-linked hydrophilic polymer in dried powder form.

10. The formulation of claim 9 wherein said polysaccharide is selected from the group consisting of an insoluble metal salt of pectin, xantham gum, carrageenan, tragacanth gum, locust bean gum, and alginic acid;

an insoluble crosslinked derivative of xantham gum, guar gum, dextran, carrageenan, tragacanth gum, locust bean gum, pectin, starch, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and alginic acid, cellulose, microcrystalline cellulose, insoluble starch and microcrystalline starch.

11. The formulation of claim 10 wherein said insoluble metal salt of alginic acid is selected from the group consisting of calcium alginate, zinc alginate, aluminum alginate, ferric alginate, and ferrous alginate.

12. The formulation of claim 10 wherein said insoluble metal salt of pectin is selected from the group consisting of calcium pectinate, zinc pectinate, aluminum pectinate, ferric pectinate, and ferrous pectinate.

13. The formulation of claim 9 wherein said cross-linking is by a cross-linking agent selected from the group consisting of formaldehyde, glutaraldehyde, epichlorhydrin, diacid chloride, diacid anhydride, diisocyanates, diamines and borax.

14. The formulation of claim 9 wherein said water insoluble cross-linked protein is selected from the group consisting of glutaraldehyde-cross-linked hydrolyzed gelatin, formaldehyde-cross-linked hydrolyzed gelatin, glutaraldehyde-cross-linked gelatin, formaldehyde-cross-linked gelatin, glutaraldehyde-cross-linked collagen and formaldehyde-cross-linked collagen.

15. The formulation of claim 9 wherein said water-insoluble cross-linked hydrophilic polymer is selected from the group consisting of carbomers.

16. The formulation of claim 9 wherein said water-insoluble cross-linked hydrophilic polymer is selected from the group consisting of Crospovidone.

17. The device of claim 1 wherein said water-insoluble carrier is a dimethylaminoethylmethacrylate/methylmethacrylate and butylmethacrylate copolymer, said copolymer based on neutral methacrylic acid esters and dimethylaminoethyl methacrylate esters, wherein said polymer is cationic in the presence of acids, said water-insoluble hydrophilic particulate is calcium pectinate, and said enteric coating is an anionic copolymer based on methacrylic acid and methylmethacrylate wherein the ratio of free carboxyl groups to the ester groups is approximately 1:

1.

18. A method of delivering an agent to the gastrointestinal tract of a patient in need of such drug, wherein said method comprises oral administration of the drug delivery formulation of any of one of claims 1-17.

19. The method of claim 18 wherein said agent is selected from the group consisting of diagnostic and therapeutic agents.

20. The method of claim 18 wherein the portion of the gastrointestinal tract wherein said drug is released is selected from the group consisting of the stomach, the small intestine, the colon, and the rectum.

21. The method of claim 18 wherein said patient is treated for a disease selected from the group consisting of colitis, Crohn'"'"'s disease, irritable bowel syndrome, gastritis, pancreatitis, hypertension, angina, arthritis, rheumatoid arthritis, asthma, arrythmia, local spasmolytic action, ulceration of the mucosa, diarrhea, constipation, polyps, carcinoma, cysts, infectious disorders, and parasitic disorders.