Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials

• US 20050031693A1
• Filed: 08/03/2004
• Published: 02/10/2005
• Est. Priority Date: 08/04/2003
• Status: Active Grant

• Current Assignee: Lonza Bend Incorporated (Lonza Group AG)
• Original Assignee: Pfizer Inc.
• Inventors: Friesen, Dwayne T., Shanker, Ravi M., Babcock, Walter C., Smithey, Daniel T.
• Granted Patent: US 9,023,393 B2
• Time in Patent Office: Days
• US Class Current: 424/486
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• 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 9/143 with inorganic compounds
• CPC Class Codes: A61K 9/1611 Inorganic compounds
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

A pharmaceutical composition comprises a solid adsorbate comprising a drug adsorbed onto a substrate and a lipophilic microphase-forming material. The solid adsorbate may also be co-administered with a lipophilic microphase-forming material to an in vivo use environment. The compositions of the present invention enhance the concentration of drug in a use environment.

Claims

1. A composition comprising:

(a) a solid adsorbate comprising a drug adsorbed onto a substrate, wherein at least a major portion of said drug in said adsorbate is amorphous;

(b) a lipophilic microphase-forming material, said composition having a mass ratio of said lipophilic microphase-forming material to said drug of from 0.1 to 500;

wherein said lipophilic microphase-forming material is water immiscible and said drug has a partition coefficient K_p between a use environment and said lipophilic microphase-forming material of about 10 or more.

2. The composition of claim 1 wherein said composition further comprises a concentration-enhancing polymer.

3. The composition of claim 2 wherein said solid adsorbate further comprises said concentration-enhancing polymer.

4. The composition of any one of claims 1 and 2 wherein said lipophilic microphase-forming material is present in a sufficient amount so that said composition provides concentration enhancement of said drug in a use environment relative to at least one of a first control composition and a second control composition;

wherein

(i) said first control composition consists essentially of an equivalent amount of said solid adsorbate with no lipophilic microphase-forming material present;

(ii) said second control composition consists essentially of an equivalent amount of said drug in unadsorbed form with an equivalent amount of said lipophilic, microphase-forming material.

5. The composition of any one of claims 1 and 2 wherein said partition coefficient K_p is about 50 or more.

6. The composition of any one of claims 1 and 2 wherein said lipophilic microphase-forming material is present in said composition at a mass of M_lipophile and is measured in grams, and wherein said composition satisfies the equation:

M_lipophile*K_p≧

5.

7. The composition of claim 6 wherein said composition satisfies the equation:

M_lipophile*K_p≧

10.

8. The composition of any one of claims 1 and 2 wherein said lipophilic microphase-forming material forms lipophilic microphases in said use environment having a characteristic diameter of less than about 100 μ

m.

9. The composition of any one of claims 1 and 2 wherein said lipophilic microphase-forming material forms lipophilic microphases in said use environment having a characteristic diameter of less than about 10 μ

m and said drug is a low-solubility drug.

10. The composition of claim 9 wherein said low-solubility drug has a solubility in said use environment of less than about 100 μ

g/ml.

11. The composition of any one of claims 1 and 2 wherein said drug has a dose-to-aqueous solubility ratio greater than about 10 mL.

12. The composition of any one of claims 1 and 2 wherein said lipophilic microphase-forming material is selected from the group consisting of medium-chain glyceryl mono-, di-, and tri-alkylates, sorbitan esters, long-chain fatty alcohols, long-chain fatty-acids, phospholipids, mono and diglycerides of capric and caprylic acid, polyoxyethylene 6 apricot kernel oil, polyoxyethylene corn oil, propylene glycol monolaurate, propylene glycol dicaprylate/caprate, polyglyceryl, sorbitan esters of fatty acids, glyceryl monooleate, medium chain triglycerides and long chain triglycerides, and mixtures of mono-, di-, and triglycerides, or lipophilic derivatives of fatty acids such as esters with alkyl alcohols, fractionated coconut oils, vegetable oils, fatty acid esters of alkyl alcohols, alcohols, polyoxyethylene alkylethers, fatty acids, glycerol fatty acid monoesters, glycerol fatty acid diesters, acetylated glycerol fatty acid monoesters, acetylated glycerol fatty acid diesters, lower alcohol fatty acid esters, polyethylene glycol fatty acid esters, polyethylene glycol glycerol fatty acid esters, polypropylene glycol fatty acid esters, polyoxyethylene glycerides, lactic acid derivatives of monoglycerides, lactic acid derivatives of diglycerides, propylene glycol diglycerides, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, transesterified vegetable oils, sterols, sterol derivatives, sugar esters, sugar ethers, sucroglycerides, polyoxyethylene vegetable oils, polyoxyethylene hydrogenated vegetable oils, reaction products of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols;

and mixtures thereof.

13. The composition of any one of claims 1 and 2 wherein said lipophilic microphase-forming material is selected from the group consisting of sulfonated hydrocarbons and their salts, polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, short-chain glyceryl mono-alkylates, polyglycolized glycerides, mono- and di-alkylate esters of polyols, polyoxyethylene 20 sorbitan monooleate, polyoxyethylene 20 sorbitan monolaurate, polyethylene (40 or 60) hydrogenated castor oil, polyoxyethylene (35) castor oil, polyethylene (60) hydrogenated castor oil, alpha tocopheryl polyethylene glycol 1000 succinate, glyceryl PEG 8 caprylate/caprate, PEG 32 glyceryl laurate, polyoxyethylene fatty acid esters, and polyoxyethylene fatty acid ethers, and mixtures thereof.

14. The composition of any one of claims 1 and 2 wherein said lipophilic microphase-forming material is a mixture of a hydrophobic material and an amphiphilic material.

15. The composition of any one of claims 1 and 2 wherein said lipophilic microphase forming material is selected from the group consisting of mixtures of polyethoxylated castor oils and medium-chain glyceryl mono-, di-, and/or tri-alkylates, mixtures of polyoxyethylene sorbitan fatty acid esters and medium-chain glyceryl mono-, di-, and/or tri-alkylates, mixtures of polyethoxylated castor oils and medium-chain glyceryl mono-, di-, and/or tri-alkylates, mixtures of sodium taurocholic acid and palmitoyl-2-oleyl-sn-glycero-3-phosphocholine and other natural or synthetic phosphatidyl cholines, and mixtures of polyglycolized glycerides and medium-chain glyceryl mono-, di-, and/or tri-alkylates.

16. The composition of any one of claims 1 and 2 wherein said mass ratio of said lipophilic microphase-forming material to said drug is from 0.1 to 100.

17. The composition of any one of claims 1 and 2 wherein said solid adsorbate and said lipophilic microphase-forming material are both present in a single dosage form.

18. The composition of claim 15 wherein said lipophilic-microphase forming material is co-adsorbed with said drug onto said substrate.

19. The composition of any one of claims 1 and 2 wherein said lipophilic microphase-forming material is mixed with said solid adsorbate.

20. The composition of any one of claims 1 and 2 wherein said lipophilic, microphase-forming material is adsorbed onto a second substrate.

21. The composition of any one of claims 1 and 2 wherein said lipophilic, microphase-forming material is dispersed in a matrix.

22. The composition of any one of claims 1 and 2 wherein said composition is solid at 25°

C.

23. The composition of any one of claims 1 and 2 wherein said drug has an absorption rate constant of at least 0.005 min⁻

1.

24. The composition of claim 4 wherein said lipophilic microphase-forming material is present in a sufficient amount so as to provide a concentration of highly mobile drug that is at least 2-fold that provided by at least one of said first control composition and said second control composition.

25. The composition of claim 4 wherein said composition provides a maximum total dissolved drug concentration in said use environment that is at least 1.25-fold that provided by at least one of said first control composition and said second control composition.

26. The composition of claim 4 wherein said composition provides a dissolution area under the curve in a use environment for any 90-minute period between the time of introduction to the use environment and 270 minutes following introduction to the use environment that is at least 1.25-fold that provided by at least one of said first control composition and said second control composition.

27. The composition of claim 4 wherein said composition provides a relative bioavailability of at least 1.25-fold relative to at least one of said first control composition and said second control composition.

28. The composition of claim 4 wherein said composition provides a fed/fasted relative bioavailability ratio of from about 0.5 to about 2.0.

29. The composition of claim 4 wherein said composition provides a precipitate ratio of at least 1.25-fold relative to at least one of said first control composition and said second control composition.

30. The composition of claim 4 wherein said composition provides concentration enhancement of said drug in said use environment relative to both said first control composition and said second control composition.

31. The composition of any one of claims 1 and 2 wherein said composition provides synergistic enhancement.

32. The composition of claim 31 wherein said synergistic enhancement is in relative bioavailability.

33. The composition of any one of claims 1 and 2 wherein said drug is selected from the group consisting of antihypertensives, antianxiety agents, anticlotting agents, anticonvulsants, blood glucose-lowering agents, decongestants, antihistamines, antitussives, antineoplastics, beta blockers, anti-inflammatories, antipsychotic agents, cognitive enhancers, anti-atherosclerotic agents, cholesterol-reducing agents, antiobesity agents, autoimmune disorder agents, anti-impotence agents, antibacterial and antifungal agents, hypnotic agents, anti-Parkinsonism agents, anti-Alzheimer'"'"'s disease agents, antibiotics, anti-depressants, and antiviral agents, glycogen phosphorylase inhibitors, and cholesteryl ester transfer protein inhibitors.

34. The composition of any one of claims 1 and 2 wherein said drug is selected from the group consisting of [2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester, [2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester, and 5-(2-(4-(3-benzisothiazolyl)-piperazinyl)ethyl-6-chlorooxindole.

35. The composition of any one of claims 2 and 3 wherein said concentration-enhancing polymer is selected from the group consisting of hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose, poloxamers, polyvinylpyrrolidone, polyvinyl alcohols that have at least a portion of their repeat units in hydrolyzed form, and mixtures thereof.

36. The composition of claim 3 further comprising a second concentration-enhancing polymer wherein said second concentration-enhancing polymer is not adsorbed to said substrate.

37. The composition of claim 36 wherein said second concentration-enhancing polymer is selected from the group consisting of hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose, poloxamers, polyvinylpyrrolidone, polyvinyl alcohols that have at least a portion of their repeat units in hydrolyzed form, and mixtures thereof.

38. A solid dosage form comprising the composition of any one of claims 1 and 2, wherein said lipophilic, microphase-forming material comprises from 10 wt % to 80 wt % of said solid dosage form, and said dosage form is selected from the group consisting of a tablet and a capsule.

39. A kit comprising a solid adsorbate comprising a drug adsorbed onto a substrate, wherein at least a major portion of said drug in said adsorbate is amorphous and a lipophilic, microphase-forming material.

40. A method for co-administering a solid adsorbate and a lipophilic microphase-forming material in vivo, comprising:

(a) forming a solid adsorbate comprising a drug adsorbed onto a substrate, wherein at least a major portion of said drug in said adsorbate is amorphous;

(b) providing a lipophilic microphase-forming material, wherein a mass ratio of said lipophilic microphase-forming material to said drug is from 0.1 to 500;

(c) administering said solid adsorbate and said lipophilic microphase-forming material in a sufficient amount so as to provide concentration enhancement of said drug in a use environment relative to at least one of a first control composition and a second control composition;

wherein

(i) said first control composition consists essentially of an equivalent amount of said solid adsorbate with no lipophilic microphase-forming material present;

(ii) said second control composition consists essentially of an equivalent amount of said drug in unadsorbed form with an equivalent amount of said lipophilic, microphase-forming material; and

wherein said lipophilic microphase-forming material is water immiscible and said drug has a partition coefficient K_p between said use environment and said lipophilic microphase-forming material of about 10 or more.