Transdermal System for the Delivery of Sufentanil and Its Analogs

• US 20090130190A1
• Filed: 10/21/2008
• Published: 05/21/2009
• Est. Priority Date: 04/21/2006
• Status: Abandoned Application

• Current Assignee: Labtec Gmbh (Maxingvest AG)
• Original Assignee: Labtec Gmbh (Maxingvest AG)
• Inventors: Vollmer, Ulrike, Klaffenbach, Peter, Breitenbach, Armin, Lehrke, Ingo
• Application Number:
  US12/255,466
• Publication Number:
  US 20090130190A1
• Time in Patent Office: Days
• US Class Current: 424/449
• CPC Class Codes: A61L 15/44 Medicaments
• CPC Class Codes: A61L 15/58 Adhesives
• CPC Class Codes: A61L 2300/402 Anaestetics, analgesics, e.g. lidocaine
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow

Abstract

Methods and systems for the transdermal delivery of sufentanil and its analogs are described, from patches having a unique pharmacodynamic profile that can be used to treat persistent pain over extended periods and acute pain episodes of limited duration.

Claims

1. ) A method of treatment comprising:

a) adhering a first sufentanil patch system having a first sufentanil load to a first location on the skin of a patient in need of treatment for pain, for a first period of at least three days; and

b) delivering sufentanil from said first sufentanil patch system to said patient at a defined rate in which either

(1) said first patch system demonstrates a normalized C_max of greater than 12 ng/(ml·

(mg/hr)),

(2) said first patch system achieves a mean plasma concentration divided by said defined rate of greater than 1.4*10<sup>−

5</sup> hr/ml,

(3) said first patch system demonstrates an 80% T_max of 18 hours or less,

(4) said first patch system demonstrates a load relative C_max of 0.12 ng/ml·

mg or greater, or combinations thereof.

2. ) The method of claim 1, wherein said first period is three days.

3. ) The method of claim 1, wherein said defined rate constitutes the steady state rate of flux when said patch system is sequentially removed and replaced by successive patch systems each having said first sufentanil load.

4. ) The method of claim 1, wherein said first sufentanil patch system achieves a mean plasma concentration divided by nominal flux of greater than 1.0*10⁻

5 hr/ml.

5. ) The method of claim 1, wherein said first sufentanil patch system is the first in sequence patch system, said patient has an existing opioid demand equipotent to n·

90 mg/d of oral morphine, and said first patch system delivers n·

(3.5±

0.5) mcg/hr of sufentanil, wherein n is an integer of from 1 to 5.

6. ) The method of claim 1, wherein said first patch system demonstrates a normalized C_max of greater than 14, 16 or 18 ng/(ml·

(mg/hr)).

7. ) The method of claim 1, wherein said first patch system demonstrates an 80% T_max of 16, 14 or 12 hours or less.

8. ) The method of claim 1, wherein said first patch system demonstrates a T_max of 24, 22, 20, or 18 hours or less.

9. ) The method of claim 1, wherein said first patch system comprises a 50% T_max of less than 10 hours, and a t_1/2 after patch removal of less than 10 hours.

10. ) The method of claim 1, wherein said first patch system demonstrates a load relative C_max of 0.14, 0.16, 0.18, or 0.20 ng/ml·

mg or greater.

11. ) The method of claim 1, wherein said first patch system, after reaching C_max and before the end of said first period, produces sufentanil plasma concentrations of 65%, 60%, 55% or 50% less than said C_max.

12. ) The method of claim 1, wherein said first patch system delivers 65, 70 or 75 wt. % or greater of said initial sufentanil loading to said patient during said first period.

13. ) The method of claim 1, wherein said first patch system demonstrates a standardized C_max of 0.01, 0.02, 0.03 ng/ml·

cm² or greater.

14. ) The method of claim 1, wherein said first patch system has an in vivo flux rate of n·

(3.5±

0.5) mcg/hr, wherein n is 1, 2, 3, 4 or 5.

15. ) The method of claim 1, wherein said first patch system has a standardized in vivo flux rate of 2.0±

0.5 mcg/hr·

cm².

16. ) The method of claim 1, wherein said pain is persistent moderate to severe chronic pain.

17. ) The method of claim 1, wherein said pain is acute.

18. ) The method of claim 1, wherein said patient is opioid tolerant.

19. ) The method of claim 1, wherein said sufentanil is present in said first patch system in a concentration of from about 0.1 to about 0.5 mg/cm².

20. ) The method of claim 1, wherein said first patch system comprises a matrix, and said matrix comprises from about 2 to about 4 wt. % sufentanil base.

21. ) The method of claim 1, wherein said first patch system comprises a matrix, and said sufentanil is present below its solubility limit in said matrix.

22. ) The method of claim 1, wherein said first period is said initial period, said patient experiences inadequate pain control during said initial period, further comprising adhering a second sufentanil patch system to the skin of said patient after said first period, for a second period of at least three days, wherein said first and second patch systems are defined by an identical composition and size.

23. ) The method of claim 1, wherein said first period is said initial period, said patient experiences inadequate pain control during said initial period, further comprising adhering a second sufentanil patch system to the skin of said patient after said first period, for a second period of at least three days, wherein said first and second patch systems are defined by an identical composition and a different size.

24. ) The method of claim 1, wherein said first sufentanil patch system demonstrates a C_max having a coefficient of variation of 50%, 40%, 30%, 20% or less.

25. ) The method of claim 1, wherein said first sufentanil patch system comprises one or more sufentanil patches having a surface area of 1.75, 3.5, 5.25, 7.0 or 8.75.

26. ) The method of claim 1, wherein said sufentanil patch system comprises calcium glycerophosphate.

27. ) A transdermal patch comprising sufentanil or an analog thereof, wherein:

a) said patch comprises a protective flexible cover, an intermediate active layer having an adhesive surface opposite said protective cover, and a removable cover adjacent said adhesive surface, and

b) said patch system either

(1) demonstrates a normalized C_max of greater than 12 ng/(ml·

(mg/hr)),

(2) achieves a mean steady state plasma concentration and a mean steady state in vivo flux, said mean steady state plasma concentration divided by said mean steady state in vivo flux is greater than 1.4*10<sup>−

5</sup> hr/ml,

(3) demonstrates an 80% T_max of 18 hours or less,

(4) demonstrates a load relative C_max of 0.12 ng/ml·

mg or greater, or

(5) combinations thereof.

28. ) A transdermal patch comprising:

a) a protective flexible cover,

b) an intermediate active layer comprising;

i) sufentanil or an analog thereof;

ii) a non-saccharide polyhydric alcohol phosphate ester, or a pharmaceutically acceptable salt thereof; and

iii) an adhesive surface opposite said protective cover, and

c) a removable cover adjacent said adhesive surface.

29. ) The transdermal patch of claim 28, wherein said non-saccharide polyhydric alcohol phosphate ester is calcium glycerophosphate.

30. ) A transdermal patch comprising:

a) a protective flexible cover,

b) an intermediate active layer comprising;

i) sufentanil or an analog thereof;

ii) greater than 50 wt. % polyisobutylene; and

iii) an adhesive surface opposite said protective cover, and

c) a removable cover adjacent said adhesive surface.

31. ) The transdermal patch of claim 30 wherein said polyisobutylene comprises:

a) low molecular weight polyisobutylene, having a molecular weight less than 100,000 g/mol; and

b) high molecular weight polyisobutylene, having a molecular weight of greater than 650,000 g/mol.

32. ) The transdermal patch of claim 30, wherein said intermediate layer further comprises polybutene, wherein the weight ratio of polyisobutylene to polybutene is from about 2:

1 to about 5;

1.

33. ) A transdermal patch that is bioequivalent to a reference patch, wherein said reference patch is a matrix patch made by a process comprising:

a) dissolving in hexane 1.0 weight parts of a high molecular weight polybutene, 5.0 weight parts of a low molecular weight polyisobutylene, and 2.0 weight parts polybutene to form an adhesive mixture;

b) dissolving 0.25 weight parts of sufentanil base in ethyl acetate to form a drug mixture;

c) mixing 0.25 weight parts of calcium glycerophosphate in said drug mixture to form a CGP mixture;

d) mixing said adhesive mixture and said CGP mixture to form a mixed liquid, and stirring said mixed liquid for one hour;

e) coating said mixed liquid onto a release liner at a sufentanil concentration of about 0.25 mg/cm²;

f) drying said coated liner; and

g) applying a backing foil to said dried coated liner.