Pharmaceutical composition

• US 20050192260A1
• Filed: 04/21/2003
• Published: 09/01/2005
• Est. Priority Date: 04/19/2002
• Status: Active Grant

• Current Assignee: FCB I LLC (Xstelos Holdings)
• Original Assignee: CPEX Pharmaceuticals Incorporated
• Inventors: Gyurik, Robert J
• Granted Patent: US 7,320,968 B2
• Time in Patent Office: Days
• US Class Current: 514/171
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/568 substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
• 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 47/08 containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
• 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 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 21/06 Anabolic agents androgens A61P5/26
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 5/24 of the sex hormones
• CPC Class Codes: A61P 5/26 Androgens

Abstract

A pharmaceutical composition comprising: (A) an androgen; (B) a cyclic enhancer of the type used in the compositions and methods claimed by U.S. Pat. No. 5,023,252 to Hsieh; and (C) a thickening agent; including, for example, a composition in which the cyclic enhancer is a macrocyclic ester or a macrocyclic ketone; the use of the composition to treat a condition, for example, male hypogonadism, in a patient by applying the composition to the membrane of the patient; and a method for making the composition.

Claims

1. A pharmaceutical composition comprising:

(A) an androgen;

(B) a Hsieh enhancer; and

(C) a thickening agent.

6. A composition according to claim 1 wherein said androgen is testosterone.

7. A composition according to claim 1 wherein said androgen is dihydrotestosterone.

8. A composition according to claim 1 wherein said androgen is an ester of testosterone

13. A composition according to claim 1 in which said enhancer is a macrocyclic enhancer.

14. A composition according to claim 1 in which said enhancer is a cyclic ketone or a cyclic ester.

16. A composition according to claim 1 in which said enhancer is oxacyclohexadecan-2-one.

17. A composition according to claim 1 wherein said thickening agent produces a low level of irritability or no irritability to the target membrane.

18. A composition according to claim 1 wherein said thickening agent is selected from the group consisting of:

cellulosic thickening agents and acrylic thickening agents.

21. A composition according to claim 1 wherein said thickening agent is a carbomer.

23. A composition according to claim 1 wherein said thickening agent is carboxypolymethylene.

24. A composition according to claim 1 in the form of a topical gel.

25. A composition according to claim 1 wherein said thickening agent has bioadhesive properties.

28. A composition according to claim 1 which comprises also a solvent.

29. A composition according to claim 1 which comprises also a crystallization inhibitor.

30. A composition according to claim 1 which comprises also a neutralizing agent.

31. A composition according to claim 1 which comprises a neutralizing agent which is tromethamine.

33. A composition according to claim 1 which comprises also a carrier in which said androgen and/or said enhancer is/are miscible in one fluid and less miscible or immiscible in another fluid.

34. A composition according to claim 1 which comprises also ethanol and water.

37. A composition according to claim 1 wherein said composition has a viscosity of about 2,800 cps to about 4,600 cps.

39. A composition according to claim 1 which produces a low level of irritability or no irritability to a target membrane.

40. A method for treating a condition in a patient comprising the step of delivering to said patient a composition according to claim 1.

41. A method according to claim 40 in which said composition is applied topically.

42. A method according to claim 40 wherein said composition is maintained on a membrane of the patient for a period of time sufficient for delivery of testosterone to the body through said membrane.

49. A composition according to claim 1 comprising also a lower alkanol comprising at least about 40% by weight of the composition.

2. A unit dose formulation which is effective in supplying testosterone transdermally to the blood of a male patient such that, following a single application of the unit dose to the patient, the amount of circulating testosterone (AUC_0-24) in the blood serum of the patient achieved in the 24-hour period following the application is about 100 to about 35,000 ng.h/dL greater than the amount of circulating testosterone (AUC_0-24) in the blood serum of the patient that would have been achieved in the same 24-hour period had the dose not been administered, said unit dose comprising up to about 1% by weight testosterone, about 0.01 to about 25% by weight of a Hsieh enhancer, and about 0.1 to about 10% by weight of thickening agent, said testosterone being present in said unit dose in an amount of about 1 to about 300 mg.

43. A method for treating a condition in a patient comprising the step of applying a unit dose according to claim 2 to the shoulder or upper arm of a patient.

44. A method according to claim 43 wherein said step of applying a unit dose to the shoulder or upper arm of a patient is accomplished by rubbing the content of the unit dose until dry.

45. A method for treating a condition in a patient comprising the step of applying, once daily, a unit dose according to claim 2 to the shoulder or upper arm of a patient.

46. A method for treating a condition in a patient comprising the step of applying, once daily, a unit dose according to claim 2 to the shoulder or upper arm of a patient and if, after 7 to 14 days, the testosterone concentration in the blood serum of said patient is below the normal testosterone concentration in the blood serum of an adult, increasing the number of said unit doses applied daily.

47. A method for treating a condition in a patient comprising the step of applying, once daily, more than one unit dose according to claim 2 to the shoulder or upper arm of a patient and if, after 7 to 14 days, the testosterone concentration in the blood serum of said patient is above normal testosterone concentration in the blood serum of an adult, lowering the number of said unit doses applied daily.

3. A unit dose formulation which is effective in supplying testosterone transdermally to the blood of a female patient such that, following a single application of the unit dose to the patient, the amount of circulating testosterone (AUC_0-24) in the blood serum of the patient achieved in the 24-hour period following the application is about 0.10 to about 11,700 ng.h/dL greater than the amount of circulating testosterone (AUC_0-24) in the blood serum of the patient that would have been achieved in the same 24-hour period had the dose not been administered, said unit dose comprising up to about 1% by weight testosterone, about 0.01 to about 25% by weight of a Hsieh enhancer, and about 0.1 to about 10% by weight of thickening agent, said testosterone being present in said unit dose in an amount of about 0.01 to about 100 mg.

4. A unit dose formulation which is effective in supplying dihydrotestosterone transdermally to the blood of a male patient such that, following a single application of the unit dose to the patient, the amount of circulating dihydrotestosterone (AUC_0-24) in the blood serum of the patient achieved in the 24-hour period following the application is about 11,625 to about 465,000 pg.h/mL greater than the amount of circulating dihydrotestosterone (AUC_0-24) in the blood serum of the patient that would have been achieved in the same 24-hour period had the dose not been administered, said unit dose comprising up to about 1% by weight dihydrotestosterone, about 0.01 to about 25% by weight of a Hsieh enhancer, and about 0.1 to about 10% by weight of thickening agent, said dihydrotestosterone being present in said unit dose in an amount of about 5 to about 200 mg.

5. A unit dose formulation which is effective in supplying dihydrotestosterone transdermally to the blood of a female patient such that, following a single application of the unit dose to the patient, the average dihydrotestosterone concentration (AUC_0-24) in the blood serum of the patient achieved in the 24-hour period following the application is about 11.6 about 232,500 pg.h/mL greater than the average dihydrotestosterone concentration (AUC_0-24) in the blood serum of the patient that would have been achieved in the same 24-hour period had the dose not been administered, said unit dose comprising up to about 1% by weight dihydrotestosterone, about 0.01 to about 25% by weight of a Hsieh enhancer, and about 0.1 to about 10% by weight of thickening agent, said dihydrotestosterone being present in said unit dose in an amount of about 0.005 to about 100 mg.

9-12. -12. (canceled)

15. (canceled)

19-20. -20. (canceled)

22. (canceled)

26-27. -27. (canceled)

32. (canceled)

35-36. -36. (canceled)

38. A pharmaceutical composition comprising:

(A) about 0.01 to about 15% by weight androgen;

(B) about 1 to about 15% by weight of a Hsieh enhancer; and

(C) about 1 to about 6% by weight of thickening agent.

53. A composition according to claim 38 wherein said composition is in the form of a homogenous topical gel and has a pH of about 3 to about 9 and a viscosity of about 2,800 cps to about 4,600 cps, said androgen is testosterone, said enhancer is oxacyclohexadecan-2-one, and said thickening agent comprises carboxypolymethylene and acrylic acid/methacrylate copolymer, said composition comprising also about 40 to about 98 wt. % of a carrier comprising ethanol and water and about 0.001 to about 5 wt. % of a crystallization inhibitor.

48. A method for making a composition useful for treating a condition in a patient comprising the step of mixing an androgen, a Hsieh enhancer, and a thickening agent.

50-52. -52. (canceled)