Pharmaceutical dosage form with multiple enteric polymer coatings for colonic delivery

• US 5,686,105 A
• Filed: 05/17/1995
• Issued: 11/11/1997
• Est. Priority Date: 10/19/1993
• Status: Expired due to Term

• Current Assignee: Mayo Foundation For Medical Education And Research (Mayo Clinic)
• Original Assignee: The Procter & Gamble Company
• Inventors: Kelm, Gary Robert, Manring, Gary Lee
• Primary Examiner(s): Nutter, Nathan M.
• Application Number:
  US08/442,920
• Time in Patent Office: 909 Days
• Field of Search: 424/452, 424/457, 424/458, 424/461, 424/462, 424/465, 424/468, 424/494, 424/497, 424/528, 424/769, 424/781, 424/782, 424/783, 424/877, 424/195.1, 514/33, 514/25, 514/892, 536/4.1, 536/18.1
• US Class Current: 424/452
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 9/2846 Poly(meth)acrylates
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/4891 Coated capsules; Multilayered drug free capsule shells with drug coating for immediate release A61K9/4808; osmotic devices A61K9/0004
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

The present invention relates to a pharmaceutical composition in a unit dosage form for peroral administration in a human or lower animal, having a gastrointestinal tract comprising a small intestine and a colon with a lumen therethrough having an inlet to the colon from the small intestine, comprising:

a. a safe and effective amount of a therapeutically active agent incorporated into or coated on the surface of a dosage form selected from the group consisting of a spherical substrate, an elliptical substrate, a hard capsule, or a compressed tablet, with a maximum diameter of about 3 mm to about 10 mm; and

b. an enteric polymer coating material comprising at least one inner coating layer and one outer coating layer;

wherein the dosage form has a smooth surface free from edges or sharp curves; the elliptical substrate and the hard capsule have a ratio of the long to short diameters of no greater than about 1.5; the therapeutically active agent is released at a point near the inlet to, or within the colon; each of the inner coating layer(s) is an enteric polymer that begins to dissolve in an aqueous media at a pH between about 5 to about 6.3; and the outer coating layer is an enteric polymer that begins to dissolve in an aqueous media at a pH between about 6.8 to about 7.2.

Claims

1. A pharmaceutical composition in a unit dosage form for peroral administration in a human or lower animal, having a gastrointestinal tract comprising a small intestine and a colon with a lumen therethrough having an inlet to the colon from the small intestine, comprising:

a. a safe and effective amount of a therapeutically active agent incorporated into or coated on the surface of a dosage form selected from the group consisting of a spherical substrate, an elliptical substrate, a hard capsule, or a compressed tablet, with a maximum diameter of about 3 mm to about 10 mm;

b. at least one inner enteric polymer coating material selected from the group consisting of cellulose acetate phthalate;

cellulose acetate trimellitate;

hydroxypropyl methylcellulose phthalate;

hydroxypropyl methylcellulose acetate succinate;

polyvinyl acetate phthalate;

poly(methacrylic acid, methyl methacrylate) 1;

1;

poly(methacrylic acid, ethyl acrylate) 1;

1; and

compatible mixtures thereof; and

c. an outer enteric polymer coating material;

wherein the dosage form has a smooth surface free from edges or sharp curves;

the elliptical substrate and the hard capsule have a ratio of the long to short diameters of no greater than about 1.5;

the therapeutically active agent is released at a point near the inlet to, or within the colon;

each of the inner coating layer(s) is an enteric polymer that begins to dissolve in an aqueous media at a pH between about 5 to about 6.3; and

the outer coating layer is an enteric polymer that begins to dissolve in an aqueous media at a pH between about 6.8 to about 7.2.

2. The composition of claim 1 wherein the therapeutically active agent is selected from the group consisting of picosulfate, sennosides, anti-diarrheals, nonsteriodal anti-inflammatory agents, glucocorticoids, antimicrobials, immunosupressants, chemotherapeutics, peptides, proteins, beta blockers, calcium channel blockers, ACE inhibitors, H2-blockers, antiasthmatic agents, and antihistamines.

3. The compositon of claim 1 wherein the dosage form is selected from the group consisting of a soft elastic gelatin capsule;

a molded spherical substrate or elliptical substrate made from any pharmaceutically acceptable excipient that can be melted or molded; and

a spherical substrate or elliptical substrate prepared by coating or layering a substrate onto a seed crystal made of any inert pharmaceutically acceptable excipient.

4. The composition of claim 3 wherein the dosage form is a soft elastic gelatin capsule or a sugar sphere.

5. The composition of claim 1 wherein the enteric polymer coating material comprises one inner coating layer.

6. The composition of claim 5 wherein the inner coating layer is selected from the group consisting of poly(methacrylic acid, methyl methacrylate) 1:

1;

poly(methacrylic acid, ethyl acrylate) 1;

1; and

compatable mixtures thereof.

7. The composition of claim 6 wherein the inner coating layer is poly(methacrylic acid, ethyl acrylate) 1:

1, which has a coating thickness of about 120 μ

m to about 350 μ

m when the diameter is about 4 mm.

8. The composition of claim 6 wherein the inner coating layer is poly(methacrylic acid, ethyl acrylate) 1:

1, which has a coating thickness of about 100 μ

m to about 300 μ

m when the diameter is about 7 mm.

9. The composition of claim 6 wherein the inner coating layer is poly(methacrylic acid, methyl methacrylate) 1:

1, which has a coating thickness of about 110 μ

m to about 300 μ

m when the diameter is about 4 mm.

10. The composition of claim 6 wherein the inner coating layer is poly(methacrylic acid, methyl methacrylate) 1:

1, which has a coating thickness of about 90 μ

m to about 250 μ

m when the diameter is about 7 mm.

11. The composition of claim 5 wherein the outer coating layer is selected from the group consisting of poly(methacrylic acid, methyl methacrylate) 1:

2, and a mixture of poly(methacrylic acid, methyl methacrylate) 1;

1 and poly(methacrylic acid, methyl methacrylate) 1;

2 in a ratio of about 1;

10 to about 1;

2.

12. The composition of claim 11 wherein the outer coating layer is poly(methacrylic acid, methyl methacrylate) 1:

2.

13. The composition of claim 12 wherein the outer coating layer has a coating thickness of about 20 μ

m to about 50 μ

m.

14. A pharmaceutical composition in a unit dosage form for peroral administration in a human or lower animal, having a gastrointestinal tract comprising a small intestine and a colon with a lumen therethrough having an inlet to the colon from the small intestine, comprising:

a. a therapeutically active agent incorporated into a soft elastic gelatin capsule with a maximum diameter of about 3 mm to about 10 mm;

b. an inner enteric polymer coating material comprising poly(methacrylic acid, ethyl acrylate) 1;

1 or poly(methacrylic acid, methyl methacrylate) 1;

1; and

c. an outer enteric polymer coating material comprising poly(methacrylic acid, methyl methacrylate) 1;

2;

wherein the soft elastic gelatin capsule has a smooth surface free from edges or sharp curves; and

the therapeutically active agent is released to a point near the inlet to, or within the colon.

15. The composition of claim 14 wherein the inner coating layer is poly(methacrylic acid, ethyl acrylate) 1:

1 which has a coating thickness of about 120 μ

m to about 350 μ

m when the diameter is about 4 mm.

16. The composition of claim 14 wherein the inner coating layer is poly(methacrylic acid, ethyl acrylate) 1:

1 which has a coating thickness of about 100 μ

m to about 300 μ

m when the diameter is about 7 mm.

17. The composition of claim 14 wherein the inner coating layer is poly(methacrylic acid, methyl methacrylate) 1:

1 which has a coating thickness of about 110 μ

m to about 300 μ

m when the diameter is about 4 mm.

18. The composition of claim 14 wherein the inner coating layer is poly(methacrylic acid, methyl methacrylate) 1:

1 which has a coating thickness of about 90 μ

m to about 250 μ

m when the diameter is about 7 mm.

19. A pharmaceutical composition in a unit dosage form for peroral administration in a human or lower animal, having a gastrointestinal tract comprising a small intestine and a colon with a lumen therethrough having an inlet to the colon from the small intestine, comprising:

a. a safe and effective amount of a therapeutically active agent coated on the surface of a sugar spherical substrate with a maximum diameter of about 3 mm to about 10 mm;

b. an inner enteric polymer coating material comprising poly(methacrylic acid, ethyl acrylate) 1;

1 or poly(methacrylic acid, methyl methacrylate) 1;

1;

c. an outer enteric polymer coating material comprising poly(methacrylic acid, methyl methacrylate) 1;

2; and

d. optionally, a barrier coating which coats the sugar spherical substrate after coating with the therapeutically active agent;

wherein the sugar spherical substrate has a smooth surface free from edges or sharp curves; and

the therapeutically active agent is released to a point near the inlet to, or within the colon.

20. The composition of claim 19 wherein the diameters of substantially all of the sugar spherical substrates are within about 5% of the mean diameter.

21. The composition of claim 20 wherein the inner coating layer is poly(methacrylic acid, ethyl acrylate) 1:

1 which has a coating thickness of about 120 μ

m to about 350 μ

m when the diameter is about 4 mm.

22. The composition of claim 20 wherein the inner coating layer is poly(methacrylic acid, ethyl acrylate) 1:

1 which has a coating thickness of about 100 μ

m to about 300 μ

m when the diameter is about 7 mm.

23. The composition of claim 20 wherein the inner coating layer is poly(methacrylic acid, methyl methacrylate) 1:

1 which has a coating thickness of about 110 μ

m to about 300 μ

m when the diameter is about 4 mm.

24. The composition of claim 20 wherein the inner coating layer is poly(methacrylic acid, methyl methacrylate) 1:

1 which has a coating thickness of about 90 μ

m to about 250 μ

m when the diameter is about 7 mm.

25. The composition of claim 20 wherein the barrier coating is hydroxypropyl methylcellulose.