Pharmaceutical dosage forms for highly hydrophilic materials

• US 20030104048A1
• Filed: 05/29/2002
• Published: 06/05/2003
• Est. Priority Date: 02/26/1999
• Status: Abandoned Application

• Current Assignee: Lipocine Inc.
• Original Assignee: Lipocine Inc.
• Inventors: Venkateshvaran, Srinivasan, Chen, Feng-Jing, Patel, Mahesh V., Krill, Steven L.
• Application Number:
  US10/158,206
• Publication Number:
  US 20030104048A1
• Time in Patent Office: Days
• US Class Current: 424/451
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 38/13 Cyclosporins
• 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 9/4858 Organic compounds
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

Pharmaceutical dosage forms having a highly hydrophilic fill material and a shell encapsulating the fill material are disclosed and described. Generally, the shell has at least one plasticizing agent therein in order to provide the shell with an effective plasticity. In one aspect, the shell may have included therein an amount of plasticizing agent that is sufficient to provide the shell with an effective plasticity upon migration of a portion of the plasticizing agent into the fill material. In another aspect, the plasticizing agent may have a solubility in the fill material of less than about 10% w/w. In yet another aspect, a combination of a plasticizing agent, and a plasticizing agent having a solubility in the fill material of less than about 10% w/w, may be presented in a total amount sufficient to provide the shell with an effective plasticity upon migration of plasticizing agent into the fill material.

Claims

1. A pharmaceutical dosage form comprising:

a fill material including a carrier of at least about 40% w/w of a hydrophilic surfactant, and at least one pharmaceutically active agent; and

a shell encapsulating the fill material, said shell containing at least one plasticizing agent in an amount sufficient to maintain an effective shell plasticity upon migration of a portion of the plasticizing agent into the fill material.

3. The pharmaceutical dosage form of either claim 1 or 2, further comprising a lipophilic coating on an outer surface of the shell.

4. The pharmaceutical dosage form of either claim 1 or 2, wherein the hydrophilic surfactant is a member selected from the group consisting essentially of:

non-ionic surfactants having an HLB value of equal to or greater than 10, ionic surfactants, and mixtures thereof.

5. The pharmaceutical dosage form of claim 4, wherein the hydrophilic surfactant is a non-ionic surfactant having an HLB value of equal to or greater than 10.

6. The pharmaceutical dosage form of either claim 1 or 2, wherein the carrier further comprises a lipophilic additive selected from the group consisting essentially of:

lipophilic surfactants, triglycerides, and mixtures thereof.

7. The pharmaceutical dosage form of claim 6, wherein the lipophilic additive is a lipophilic surfactant.

8. The pharmaceutical dosage form of claim 7, wherein the lipophilic surfactant is a member selected from the group consisting essentially of:

non-ionic surfactants having an HLB value of equal to or less than 10, unionized ionizable surfactants, and mixtures thereof.

9. The pharmaceutical dosage form of claim 8, wherein the lipophilic surfactant is a non-ionic surfactant having an HLB value of equal to or less than 10.

10. The pharmaceutical dosage form of claim 7, wherein the hydrophilic surfactant and the lipophilic surfactant are presented in the carrier at respective amounts such that upon diluting with an aqueous solution, the carrier forms a clear aqueous dispersion.

11. The pharmaceutical dosage form of claim 10, wherein the surfactants are diluted with an aqueous solution at an aqueous solution to carrier ratio of about 100:

1 by weight, and the clear aqueous dispersion has an absorbance of less than about 0.3 at 400 nm.

12. The pharmaceutical dosage form of either claim 1 or 2, wherein the at least one pharmaceutically active agent is a lipophilic drug.

13. The pharmaceutical dosage form of either claim 1 or 2, wherein the at least one pharmaceutically active agent is a hydrophilic drug.

14. The pharmaceutical dosage form of either claim 1 or 2, wherein the carrier further comprises at least one additive selected from the group consisting of:

antioxidants, bufferants, antifoaming agents, detackifiers, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, stabilizing agents, solubilizers, binders, fillers, plasticizing agents, lubricants, and mixtures thereof.

15. The pharmaceutical dosage form of claim 14, wherein the at least one additive is a solubilizer.

16. The pharmaceutical dosage form of claim 15, wherein the solubilizer is a member selected from the group consisting of alcohols, polyols, amides, esters, propylene glycol ethers, and mixtures thereof.

17. The pharmaceutical dosage form of either claim 1 or 2, wherein the pharmaceutically active agent is at least partially suspended in the carrier.

18. The pharmaceutical dosage form of claim 17, wherein the carrier further includes a stabilizing agent.

19. The pharmaceutical dosage form of claim 18, wherein the stabilizing agent imparts increased viscosity to the fill material and retards sedimentation.

20. The pharmaceutical dosage form of claim 19, wherein the stabilizing agent is a member selected from the group consisting essentially of:

suspending agents, flocculating agents, thickening agents, gelling agents, buffering agents, antioxidants, preservatives, antimicrobial agents, and mixtures thereof.

21. The pharmaceutical dosage form of claim 19, wherein the stabilizing agent is a suspending agent.

22. The pharmaceutical dosage form of claim 20, wherein the suspending agent is a member selected from the group consisting essentially of:

microcrystalline cellulose, sodium carboxymethylcellulose, powdered cellulose, ethymethylcellulose, hydroyxypropyl methylcellulose, methylcellulose, ethylcellulose, ethylhydroxy ethylcellulose, hydroxypropyl cellulose, attapulgite, bentonite, hectorite, montmorillonite, silica gel, fumed silicon dioxide, colloidal silicon dioxide, acacia, agar, carrageenan, guar gum, locust bean gum, pectin, sodium alginate, propylene glycol alginate, tamarind gum, xanthan gum, carbomer, povidone, sodium starch glycolate, starches, tragacanth, magnesium aluminum silicate, aluminum silicate, magnesium silicate, gelatin, and glycyrrhizin, and mixtures thereof.

23. The pharmaceutical dosage form of either claim 1 or 2, wherein the shell further comprises at least one matrix forming material selected from the group consisting of:

gelatin, starch, gum acacia, hydroxypropyl methyl cellulose, and mixtures thereof.

24. The pharmaceutical dosage form of claim 23, wherein the at least one matrix forming material is gelatin.

25. The pharmaceutical dosage form of claim 1, wherein the solubility of the plasticizing agent in the fill material is less than about 10% w/w.

26. The pharmaceutical dosage form of either claim 1 or 25, wherein the solubility of the plasticizing agent in the fill material is less than about 5% w/w.

27. The pharmaceutical dosage form of either claim 1 or 25, wherein the solubility of the plasticizing agent in the fill material is less than about 1% w/w.

28. The pharmaceutical dosage form of either claim 1 or 25, wherein the solubility of the plasticizing agent in the fill material is less than about 0.5% w/w.

29. The pharmaceutical dosage form of either claim 1 or 2, wherein the amount of plasticizing agent in the shell is from about 4% w/w to about 60% w/w of the shell.

32. The pharmaceutical dosage form of either claim 1 or 2, wherein the shell further comprises an additive selected from the group consisting of:

coloring agents, antioxidant, preservatives, surfactants, and mixtures thereof.

33. The pharmaceutical dosage form of claim 32, wherein the shell additive is a surfactant.

34. The pharmaceutical dosage form of either claim 1 or 2, wherein the dosage form is a capsule.

35. The pharmaceutical dosage form of claim 34, wherein the capsule is a hard capsule.

36. The pharmaceutical dosage form of claim 34, wherein the capsule is a soft capsule.

2. A pharmaceutical dosage form comprising:

a fill material including a carrier of at least about 40% w/w of a hydrophilic surfactant, and at least one pharmaceutically active agent; and

a shell encapsulating the fill material, said shell containing an effective amount of a plasticizing agent having a solubility of less than 10% w/w in the fill material.

30. The pharmaceutical dosage form of either claim 2 or 25, wherein the plasticizing agent is a member selected from the group consisting essentially of:

sorbitol, sorbitanes, xylitol, maltitol, maltitol syrup, partially dehydrated hydrogenated glucose syrups, hydrogenated starch hydrolysate, polyhydric alcohols having an equilibrium relative humidity of greater than or equal to 80%, carrageenan, polyglycerol, non-crystallizing solutions of sorbitol, glucose, fructose, glucose syrups, and mixtures and equivalents thereof.

31. The pharmaceutical dosage form of claim 30, wherein the plasticizing agent is a member selected from the group consisting of sorbitol, sorbitanes, maltitol, mannitol, and mixtures thereof.

37. A pharmaceutical dosage form comprising:

a fill material including a carrier of at least about 40% w/w of a hydrophilic surfactant, and at least one pharmaceutically active agent; and

a shell encapsulating the fill material, said shell containing a first plasticizing agent and a second plasticizing agent, said second plasticizing agent having a solubility in the fill material of less than about 10% w/w agent, wherein the first and second plasticizing agents are present in amounts sufficient to maintain an effective shell plasticity upon migration of a portion of either plasticizing agent into the fill material.