Drug delivery system

• US 5,814,338 A
• Filed: 01/09/1997
• Issued: 09/29/1998
• Est. Priority Date: 07/11/1994
• Status: Expired due to Fees

• Current Assignee: Therapicon S.R.L.
• Original Assignee: Therapicon S.R.L.
• Inventors: Veronesi, Paolo Alberto
• Primary Examiner(s): Schofer, Joseph L.
• Assistant Examiner(s): Shelborne, Kathryne E.
• Application Number:
  US08/765,952
• Time in Patent Office: 628 Days
• Field of Search: 424/472, 424/451, 424/456, 424/463, 424/488
• US Class Current: 424/472
• CPC Class Codes: A61K 9/4816 Wall or shell material
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• 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: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention deals with a pharmaceutical product in unit dosage form and a unit dosage drug delivery system which comprises a multiple layer capsule or housing having two or more layers, the layers being of materials, wherein the outer layer possesses a hydrophilic character and the inner layer possesses a hydrophobic character, and a capsule filling wherein one or more drug substances are admixed, dissolved, suspended or agglomerated in a hydrophobic support.

Claims

1. A unit dosage drug delivery system which comprises:

a) a multiple layer capsule housing, comprising at least two coupled layers, sheaths or films from different materials, the first outer layer or sheath with hydrophilic character and the inner sheaths or films with hydrophobic character; and

b) a capsule filling, embodying one or more active drug substances, with conventional or extended drug release properties, with a remarkable hydrophobic character.

2. The unit dosage drug delivery system of claim 1 wherein said multiple layer capsule housing comprises:

a) a first outer hydrophilic layer, consisting either of a mixture of gelatin, glycerin and/or modified sorbitol solution, water or alternatively of other suitable compounds, alike polyphenyl compounds;

b) a second inner hydrophobic film or sheath from silicone, silicone mixture or other pharmaceutically acceptable silicone polymers; and

c) an optional inner third or additional films or sheaths, made from silicone polymers or waxes or alternatively from jaluronic acid polymers.

3. The unit dosage drug delivery system of claim 1 wherein said capsule filling, confined within the capsule housing, contains:

a) one or more active drug substances which are admixed, dissolved, suspended or agglomerated in an hydrophobic support;

b) silicone resin having a viscosity in the range of from 100 to 1,100 cSt and specific gravity in the range of from 0.96 to 1.02;

c) optional components, particularly sodium laurylsarcosinate in the range from 0.1% to 2.0% and absolute ethanol in the range from 1.0% to 30.0% of the capsule filling; and

d) optional release modifying substances providing an extended release of the active medicinal drug, said modifying substances selected from the group consisting of;

beeswax, silicone waxes and natural or modified stearic acid, palmitic acid, myristic acid, lauric acid, stearyl alcohol, cetyl alcohol, glyceryl stearate, ethyl oleate, arachids oils, cotton seed oil, rape seed oil, liquid paraffin and polyethylene glycol from 400 to 20,000.

4. The unit dosage drug delivery system of claim 1 having size, shape and color of a conventional capsule for oral, rectal or vaginal administration.

5. The unit dosage drug delivery system of claim 1 wherein the capsule housing has conventional or enteric release dissolution.

6. The unit dosage drug delivery system of claim 2 wherein the first outer hydrophilic layer of the capsule housing presents a thickness at the wet state comprised between 0.50 mm and 1 mm.

7. The unit dosage drug delivery system of claim 2 wherein a second inner hydrophobic film or sheath of the capsule housing is made from silicone, having a low-medium viscosity comprised between 10 and 200,00 cSt.

8. The unit dosage drug delivery system of claim 2 wherein the second inner hydrophobic film or sheath of the capsule housing presents a thickness comprised between 0.1 and 100 μ

m.

9. The unit dosage drug delivery system of claim 2 having an optional inner third or multiple films or sheaths of the capsule housing, with a thickness comprised between 0.1 and 100 μ

m, and a melting range of about 39°

C.-40°

C.

10. The unit dosage drug delivery system of claim 2 having a third inner hydrophobic film or sheath of the capsule housing optionally covered with pores of suitable size, comprised between 10 and 100 μ

m, and a pore distribution from 2,500 to 25 pores/mm², in order to achieve a retarded diffusion of the active drug substance.

11. The unit dosage drug delivery system of claim 2 wherein the second inner hydrophobic sheath or film of the capsule housing has an intrinsic viscosity lower than that of the third inner film or sheath.

12. The unit dosage drug delivery system of claim 2 wherein the first outer hydrophilic layer represents from 83.33% to 99.96% by weight of the entire capsule housing.

13. The unit dosage drug delivery system of claim 2 wherein the sum of the second inner hydrophobic film or sheath and of the optional inner third or multiple films or sheaths, is further comprising of from 0.04% to 16.67% by weight of the entire capsule housing.

14. The unit dosage drug delivery system of claim 3 wherein the capsule filling contains one or more active drug substances, selected among the groups of oligopeptides, peptides, proteins, prostaglandins, cholesterol lowering agents, gastric antisecretories, antiacids, antiallergic agents, antiasthmatic agents, ACE inhibitors, diuretic agents, antineoplastic agents, antiviral nucleosides agents, antifungal agents, antiparkinson agents, antiepileptic agents, analgesics, non-steroidal antiinflammatories, antitussives, decongestionants, narcotics, antibiotics, cardiovasculars, their organic and inorganic salts, liophylized yeasts and vitamins.

15. The unit dosage drug delivery system of claim 3 wherein the capsule filling contains one or more pharmaceutical active drug substances in the range of from 0.0001% to 45% by weight.

16. The unit dosage drug delivery system of claim 3 wherein the release modifying substances are further comprising of from 15% to 60%, by weight of the silicone resin of the capsule filling.

17. The unit dosage drug delivery system of claim 2 wherein the multiple layer capsule housing presents an enteric release coating, obtained by conventional gastroenteric coating methods, preferably by immersion in a solution of formaldehyde dispersed in acetone in a ratio 1:

60.

18. The unit dosage drug delivery system of claim 2 wherein the first outer layer of the capsule housing is made from polyphenyl compounds, and wherein the gastroenteric release coating is obtained by applying a suitable conventional coating composition.

19. The unit dosage drug delivery system of claim 14 wherein the capsule filling contains cyclosporines.

20. The unit dosage drug delivery system of claim 14 wherein the capsule filling contains omeprazole.

21. The unit dosage drug delivery system of claim 14 wherein the capsule filling contains ranitidine or its salts.

22. The unit dosage drug delivery system of claim 1 particularly suitable and convenient for delivering active drug substances, selected among the groups of oligopeptides, peptides, proteins, prostaglandins, cholesterol lowering agents, gastric antisecretories, antiacids, antiallergic agents, antiasthmatic agents, ACE inhibitors, diuretic agents, antineoplastic agents, antiviral nucleosides agents, antifungal agents, antiparkinson agents, antiepileptic agents, analgesics, non-steroidal antiinflammatories, antitussives, decongestionants, narcotics, antibiotics, cardiovasculars, their organic and inorganic salts, liophylized yeasts and vitamins, sensitive to moisture, oxidation or easily degradable from the atmosphere.

23. The unit dosage drug delivery system of claim 1 which advantageously prevents the diffusion of the water soluble active drug substances or of their pharmaceutically acceptable salts, selected among the groups of oligopeptides, peptides, proteins, prostaglandins, cholesterol lowering agents, gastric antisecretories, antiacids, antiallergic agents, antiasthmatic agents, ACE inhibitors, diuretic agents, antineoplastic agents, antiviral nucleosides agents, antifungal agents, antiparkinson agents, antiepileptic agents, analgesics, non-steroidal antiinflammatories, antitussives, decongestionants, narcotics, antibiotics, cardiovasculars, their organic and inorganic salts, liophylized yeasts and vitamins, from the capsule filling to the first outer hydrophilic layer of the capsule housing.

24. A method of preparing a unit dosage drug delivery system, which comprises the steps of:

a) providing a capsule housing comprising the following ingredients;

i) a first outer hydrophilic layer, consisting either of a mixture or gelatin, glycerin and/or modified sorbitol solution, water or alternatively of other suitable compounds, alike polyphenyl compounds;

ii) a second inner hydrophobic film or sheath from silicone, silicone mixture or other pharmaceutically acceptable silicone polymers; and

iii) an optional inner third or additional films or sheaths, made from silicone polymers or waxes or alternatively from jaluronic acid polymers; and

b) providing a capsule filling comprising the following ingredients;

i) one or more active drug substances which are admixed, dissolved, suspended or agglomerated in an hydrophobic support;

ii) silicone resin having a viscosity in the range of from 100 to 1,100 cSt and specific gravity in the range of from 0.96 to 1.02;

iii) optional components particularly sodium lauryl-sarcosinate in the range from 0.1% to 2.0% and absolute ethanol in the range from 1.0% to 30.0% of the capsule filling; and

iv) optional release modifying substances providing an extended release of the active medicinal drug, said modifying substances selected from the group consisting of;

beeswax, silicone waxes and natural or modified stearic acid, palmitic acid, myristic acid, lauric acid, stearyl alcohol, cetyl alcohol, glyceryl stearate, ethyl oleate, arachids oil, cotton seed oil, rape seed oil, liquid paraffin and polyethylene glycol from 400 to 20,000.

25. The method of claim 24 wherein the capsule housing has conventional or enteric release dissolution.

26. The method of claim 24 wherein the first outer hydrophilic layer of the capsule housing presents a thickness at the wet state comprised between 0.50 mm and 1 mm.

27. The method of claim 24 wherein a second hydrophobic inner film or sheath of the capsule housing is made from silicone, having a low-medium viscosity comprised between 10 and 200,000 cSt.

28. The method of claim 24 wherein the second inner hydrophobic film or sheath of the capsule housing presents a thickness comprised between 0.1 and 100 μ

m.

29. The method of claim 24 having an optional inner third or multiple films or sheaths of the capsule housing, with a thickness comprised between 0.1 and 100 μ

m and a melting range of about 39°

C.-40°

C.

30. The method of claim 24 wherein the third film or sheath of the capsule housing is optionally covered with pores of suitable size, comprised between 10 and 100 μ

m, and a pore distribution from 2,500 to 25 pores/mm², in order to achieve a retarded diffusion of the drug substance.

31. The method of claim 24 wherein the second inner hydrophobic sheath or film of the capsule housing has an intrinsic viscosity lower than that of the optional third inner film or sheath.

32. The method of claim 24 wherein the first hydrophilic outer layer represents from 83.33% to 99.69% by weight of the entire capsule housing.

33. The method of claim 24 wherein the sum of the second inner hydrophobic film or sheath and of the optional inner third or multiple film or sheath, is further comprising from 0.04% to 16.67% by weight of the entire capsule housing.

34. The method of claim 24 wherein the capsule filling contains one or more active drug substances, selected among the groups of oligopeptides, peptides, proteins, prostaglandins, cholesterol lowering agents, gastric antisecretories, antiacids, antiallergic agents, antiasthmatic agents, ACE inhibitors, diuretic agents, antineoplastic agents, antiviral nucleosides agents, antifungal agents, antiparkinson agents, antiepileptic agents, analgesics, non-steroidal antiinflammatories, antitussives, decongestionants, narcotics, antibiotics, cardiovasculars, their organic and inorganic salts, liophylized yeasts and vitamins.

35. The method of claim 24 wherein the capsule filling contains one or more pharmaceutical drug substances, in the range of from 0.0001% to 45% by weight.

36. The method of claim 24 wherein the capsule filling contains the release modifying substances further comprising of from 15% to 60% by weight of the silicon resin, excluding the active drug substance.

37. The method of claim 24 wherein the multiple layer capsule housing presents an enteric release coating, obtained by conventional gastroenteric coating methods, preferably by immersion in a solution of formaldehyde dispersed in acetone in a ratio 1:

60.

38. The method of claim 24 wherein the first outer layer of the capsule housing is made from polyphenyl compounds, wherein the gastroenteric release coating is obtained by applying a suitable conventional coating composition.

39. A medicated composition which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a unit dosage drug delivery system comprising:

a) a first outer hydrophilic layer, consisting either of a mixture or gelatin, glycerin and/or modified sorbitol solution, water or alternatively or other suitable compounds, alike polyphenyl compounds;

b) a second inner hydrophobic film or sheath from silicone, silicone mixture or other pharmaceutically acceptable silicone polymers;

c) an optional inner third or additional films or sheaths, made from silicone polymers or waxes or alternatively from jaluronic acid polymers; and

d) a capsule filling comprising;

i) one or more active drug substances which are admixed, dissolved, suspended or agglomerated in an hydrophobic support;

ii) silicone resin having a viscosity in the range of from 100 to 1,100 cSt and specific gravity in the range of from 0.96 to 1.02;

iii) optional components particularly sodium lauryl-sarcosinate in the range from 0.1% to 2.0% and absolute ethanol in the range from 1.0% to 30.0% of the capsule filling; and

iv) optional release modifying substances, providing an extended release of the active medicinal drug, said modifying substances selected from the group consisting of;

beeswax, silicone waxes and natural or modified stearic acid, palmitic acid, myristic acid, lauric acid, stearyl alcohol, cetyl alcohol, glyceryl stearate, ethyl oleate, arachids oil, cotton seed oil, rape seed oil, liquid paraffin and polyethylene glycol from 400 to 20,000.

40. The medicated composition of claim 39 adapted for oral, rectal or vaginal administration.

41. The medicated composition of claim 39 wherein the active drug substances are advantageously protected from atmosphere, from oxidation, and from moisture-induced hydrolytic or degradation processes.

42. The medicated composition of claim 39 wherein the total moisture of the capsule filling is less the 1.

43. The medicated composition of claim 39 wherein the active drug substance is conveniently protected from moisture, oxidation and atmospheric degradation processes.

44. The medicated composition of claim 39 wherein the diffusion of the active drug substance, from the capsule filling to the hydrophilic first outer layer of the capsule housing, is advantageously prevented by the hydrophobic second inner layer.

45. The medicated composition of claim 39 wherein the possible unpleasant taste or odor of the active drug substance is suitably masked, improving the administration compliance.

46. The medicated composition of claim 39 adapted to extend the delivery of the active drug substance thereof, as to maintain a therapeutically plasma level thereof for a desired interval.

47. The medicated composition of claim 39 for eliciting a therapeutic response in a mammalian organism in need of such treatment, comprising administering to such organism a therapeutically effective amount of the unit dosage drug delivery system.

48. A pharmaceutical product in unit dosage form which comprises:

a) a multiple layer capsule housing having two or more layers, said layers being of different materials, wherein the outer layer possesses a hydrophilic character and the inner layer possesses a hydrophobic character; and

b) a filling comprising one or more drug substances which are admixed, dissolved, suspended or agglomerated in an hydrophobic support.