Delivery systems for hydrophobic drugs

• US 5,645,856 A
• Filed: 06/06/1995
• Issued: 07/08/1997
• Est. Priority Date: 03/16/1994
• Status: Expired due to Term

• Current Assignee: Catalent Pharma Solutions Incorporated (Catalent, Inc.), Catalent Pharma Solutions Limited (Catalent, Inc.), Catalent USA Packaging LLC (Catalent, Inc.), Catalent USA Paintball, Inc. (Catalent, Inc.), Catalent USA Woodstock, Inc. (Catalent, Inc.)
• Original Assignee: R.P. Scherer Corporation (Cardinal Health, Inc.)
• Inventors: Embleton, Jonathan Kenneth, Lacy, Jonathan Ernest
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Spear, James M.
• Application Number:
  US08/446,874
• Time in Patent Office: 763 Days
• Field of Search: 424/456, 424/455, 514/784, 514/785, 514/786, 514/975, 514/937
• US Class Current: 424/455
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/44 Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14
• CPC Class Codes: A61K 9/4858 Organic compounds

Abstract

There is provided a carrier for hydrophobic drugs, and pharmaceutical compositions based thereon, which carrier comprises a digestible oil and a pharmaceutically acceptable surfactant component for dispersing the oil in vivo upon administration of the carrier, which comprises a hydrophilic surfactant, said surfactant component being such as not to substantially inhibit the in vivo lipolysis of the digestible oil.

Claims

1. A pharmaceutical composition comprising:

(a) a hydrophobic drug comprising progesterone, and

(b) a drug carrier system comprising;

(i) a digestible oil, and

(ii) a pharmaceutically acceptable surfactant for dispersing the oil in vivo upon administration of the carrier system, said surfactant comprising a hydrophilic surfactant component, and being such that it does not substantially inhibit the lipolysis of the digestible oil, said pharmaceutical composition comprising from 0.1% to 50% by weight of said hydrophobic drug and correspondingly from 50% to 99.9% by weight of said drug carrier system.

2. A pharmaceutical composition according to claim 1, wherein said surfactant comprises:

(i) a hydrophilic surfactant component which substantially inhibits the in vivo lipolysis of said digestible oil, and

(ii) a lipophilic surfactant component capable of at least substantially reducing said inhibitory effect of said hydrophilic surfactant component.

3. A pharmaceutical composition according to claim 2, wherein said lipophilic surfactant component comprises one or more lipophilic surfactants selected from fatty acids and mono- and/or di-glycerides of fatty acids.

4. A pharmaceutical composition according to claim 3, wherein said lipophilic surfactant component comprises one or more of oleic acid, a glyceryl mono-/di-caprylate surfactant and a glyceryl mono-/di-caprylate/caprate surfactant.

5. A pharmaceutical composition according to claims 2, 3 or 4 wherein said hydrophilic surfactant component comprises a castor oil or hydrogenated castor ethoxylate having an HLB value greater than 10.

6. A pharmaceutical composition according to claim 5, wherein said hydrophilic surfactant component comprises a polyoxyethylene hydrogenated castor oil.

7. A pharmaceutical composition according to claim 1, wherein said drug carrier system comprises based on the weight thereof:

(a) 10-90% by weight of said digestible oil,

(b) 10-60% by weight of said hydrophilic surfactant component, and

(c) 5-60% by weight of said lipophilic surfactant component.

8. A pharmaceutical composition according to claim 1, wherein said carrier system also includes a hydrophilic solvent.

9. A pharmaceutical composition according to claim 8, wherein said carrier system contains 0.1-20% by weight of said hydrophilic solvent, based on the weight of said carrier system.

10. A pharmaceutical composition according to claim 2, wherein some or all of the digestible oil is replaced by said lipophilic surfactant.

11. A pharmaceutical composition according to claim 2, wherein said hydrophilic surfactant component comprises a transesterification product of polyethylene glycol with glycerol esters of capric and caprylic acids.

13. A pharmaceutical composition according to claim 1, wherein said surfactant also includes a lipophilic surfactant component, and said lipophilic surfactant component is oleic acid.

14. A pharmaceutical composition according to claim 1, wherein said drug carrier system comprises based on the weight thereof:

(a) 25-45% by weight of said digestible oil,

(b) 30-45% by weight of said hydrophilic surfactant component, and

(c) 20-40% by weight of said lipophilic surfactant component.

15. A pharmaceutical composition according to claim 1, wherein said pharmaceutical composition is in a liquid oral unit dosage form.

16. A hard or soft capsule filled with a pharmaceutical composition according to claim 15.

12. A method of preparing a pharmaceutical composition including a hydrophobic drug comprising progesterone and a carrier system for said hydrophobic drug, comprising the steps of forming said carrier system by combining a digestible oil, a hydrophilic surfactant and a lipophilic surfactant, dissolving or dispersing said hydrophobic drug in said carrier system, said hydrophobic drug being rendered bioavailable, at least in part, by in vivo lipolysis of said digestible oil, said hydrophilic surfactant substantially inhibiting lipolysis of said digestible oil and said lipophilic surfactant substantially reducing said inhibitory effect of said hydrophilic surfactant, selecting said surfactants by determining in vitro the relative lipolysis of (a) said digestible oil, (b) said digestible oil and hydrophilic surfactant in combination, and (c) said digestible oil, hydrophilic surfactant and lipophilic surfactant in combination, so that (b) is substantially less than (a) and (c) is substantially more than (b).

17. A method of improving the in vivo bioavailability of a hydrophobic drug comprising progesterone from a pharmaceutical composition comprising the drug dispersed or dissolved in a digestible oil containing a hydrophilic surfactant which substantially inhibits the in vivo lipolysis of said digestible oil, wherein there is added to the composition a lipophilic surfactant capable of at least substantially reducing said inhibitory effect of said hydrophilic surfactant, said hydrophobic drug being rendered bioavailable, at least in part, by in vivo lipolysis of said digestible oil, when said lipophilic surfactant is selected by determining in vitro the relative lipolysis of (a) said digestible oil, (b) said digestible oil and hydrophilic surfactant in combination, and (c) said digestible oil, hydrophilic surfactant and lipophilic surfactant in combination, and (b) is determined to be substantially less than (a) and (c) is determined to be substantially more than (b).

18. A pharmaceutical composition comprising a hydrophobic drug comprising progesterone and a carrier system for said hydrophobic drug, said carrier system comprising a digestible oil, a hydrophilic surfactant and a lipophilic surfactant, said hydrophobic drug being dissolved or dispersed in said carrier system, said hydrophobic drug being rendered bioavailable, at least in part, by in vivo lipolysis of said digestible oil, said hydrophilic surfactant substantially inhibiting lipolysis of said digestible oil and said lipophilic surfactant substantially reducing said inhibitory effect of said hydrophilic surfactant said surfactants being selected by determining in vitro the relative lipolysis of (a) said digestible oil, (b) said digestible oil and hydrophilic surfactant in combination, and (c) said digestible oil, hydrophilic surfactant and lipophilic surfactant in combination, so that (b) is substantially less than (a) and (c) is substantially more than (b).

19. A pharmaceutical composition including a hydrophobic drug comprising progesterone dissolved or dispersed in a carrier system, said carrier system comprising a digestible oil and a hydrophilic surfactant component, said hydrophobic drug being dissolved or dispersed in said carrier system, said hydrophobic drug being rendered bioavailable, at least in part, by in vivo lipolysis of said digestible oil, said carrier system being selected by determining in vitro the relative lipolysis of (a) said digestible oil and (c) said digestible oil and hydrophilic surfactant component in combination so that (c) is 50% or more of (a).

20. A method of preparing a pharmaceutical composition including a hydrophobic drug comprising progesterone dissolved or dispersed in a carrier system, comprising the steps of forming said carrier system by combining a digestible oil and a hydrophilic surfactant component, dissolving or dispersing said hydrophobic drug in said carrier system, said hydrophobic drug being rendered bioavailable, at least in part, by in vivo lipolysis of said digestible oil, selecting said carrier system by determining in vitro the relative lipolysis of (a) said digestible oil and (c) said digestible oil and hydrophilic surfactant component in combination so that (c) is 50% or more of (a).

21. A method according to claim 20, wherein said step of selecting said carrier system includes determining the relative lipolysis of (a) and (c) by comparing the acidity of pancreatin solutions of (a) and (c).

22. A method according to claim 21, wherein said pancreatin solutions comprise simulated intestinal fluids, each containing the same weight of said digestible oil and said hydrophilic surfactant component being present in (c) in the same ratio with said digestible oil as used in said carrier system.

23. A method according to claim 22, wherein said hydrophilic surfactant component includes a hydrophilic surfactant that substantially inhibits the in vivo lipolysis of said digestible oil, and a lipophilic surfactant that substantially reduces said inhibitory effect of said hydrophilic surfactant.