Dry powder fibrin sealant

• US 9,827,205 B2
• Filed: 12/12/2009
• Issued: 11/28/2017
• Est. Priority Date: 12/12/2008
• Status: Expired due to Fees

• Current Assignee: Mallinckrodt Pharma Ip Trading DAC (Mallinckrodt plc), Quadrant Drug Delivery Limited (Vectura Group Ltd.)
• Original Assignee: Mallinckrodt Pharma Ip Trading DAC (Mallinckrodt plc), Quadrant Drug Delivery Limited (Vectura Group Ltd.)
• Inventors: Whitfield, Nicola, Koopman, Jaap, Grimbergen, Jos
• Primary Examiner(s): Steadman, David J
• Application Number:
  US12/636,718
• Publication Number:
  US 20100150900A1
• Time in Patent Office: 2,908 Days
• Field of Search: None
• CPC Class Codes: A61K 38/363 Fibrinogen
• CPC Class Codes: A61K 38/4833 Thrombin (3.4.21.5)
• CPC Class Codes: A61K 41/17 by ultraviolet [UV] or infrared [IR] light, X-rays or gamma rays
• 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 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: C12Y 304/21005 Thrombin (3.4.21.5)

Abstract

The invention provides a composition comprising a mixture of first microparticles that comprise fibrinogen and trehalose, and second microparticles that comprise thrombin and trehalose. The invention further provides methods for treating wounds by administering the novel microparticle composition.

Claims

1. A dry powder fibrin sealant composition, comprising:

a mixture of first microparticles that comprise fibrinogen and trehalose, and

second microparticles that comprise thrombin and trehalose,

wherein trehalose is the only stabilizing sugar in the first microparticles and second microparticles, and

wherein the concentration of trehalose in the first microparticles is sufficient to preserve at least 70% of fibrinogen activity after exposure of the first microparticles to a 25 kGy dose of gamma irradiation delivered at a rate of 8 kGy/hour.

2. The composition of claim 1, wherein fibrinogen activity is measured by ELISA.

3. The composition of claim 1, wherein fibrinogen activity is measured by clot strength assay.

4. The composition of claim 1, wherein fibrinogen activity is measured by ELISA and clot strength assay.

5. The composition of claim 1, wherein the concentration of trehalose in the first microparticles and second microparticles is sufficient to preserve at least 70% of expected clot strength after exposure of the mixture of microparticles to a 25 kGy dose of gamma irradiation delivered at a rate of 8 kGy/hour.

6. The composition according to claim 1 or claim 5, wherein said first microparticles contain 0.5 to 20% w/w fibrinogen.

7. The composition of claim 6, wherein said second microparticles comprise 10 to 20,000 IU/g thrombin.

8. The composition of claim 7, wherein said second microparticles comprise 25 to 1,000 IU/g thrombin.

9. The composition of claim 1 or 5, wherein said microparticles are spray-dried microparticles.

10. The composition of claim 9, wherein the composition has a residual moisture content no greater than 5% (w/w).

11. The composition of claim 10, wherein the residual content is no great than 3% (w/w).

12. The composition of claim 1 or claim 5, wherein said first and second microparticles are mixed in a weight ratio of 1:

1.

13. A method of treating a wound, comprising administering to the wound an effective amount of the composition as defined in claim 1.

14. The method, as claimed in claim 13, further comprising the step of applying pressure immediately after said administering.

15. The dry powder fibrin sealant composition of claim 1, wherein the composition is sterilizable.

16. A method for preparing a dry powder fibrin sealant composition comprising a mixture of first microparticles that comprise fibrinogen and trehalose and second microparticles that comprise thrombin and trehalose, wherein trehalose is the only stabilizing sugar in the first microparticles and second microparticles, the method comprising:

(i) spray-drying a first aqueous solution comprising fibrinogen and trehalose to produce said first microparticles, wherein said first aqueous solution does not include a second stabilizing sugar and the concentration of trehalose in the first microparticles is sufficient to preserve at least 70% of fibrinogen activity after exposure of the first microparticles to a 25 kGy dose of gamma irradiation delivered at a rate of 8 kGy/hour;

(ii) spray-drying a second aqueous solution comprising thrombin and trehalose to produce said second microparticles, wherein said second aqueous solution does not include a second stabilizing sugar; and

(iii) mixing the first and second microparticles.

17. The method of claim 16, wherein the concentration of trehalose in each of the first and second microparticles is sufficient to preserve at least 70% of expected clot strength after exposure of the mixture of microparticles to a 25 kGy dose of gamma irradiation delivered at a rate of 8 kGy/hour.

18. The method of claim 16 or claim 17, wherein said first microparticles contain 0.5 to 20% w/w fibrinogen.

19. The method of claim 16 or claim 17, wherein said second microparticles comprise 10 to 20,000 IU/g thrombin.

20. The method of claim 19, wherein said second microparticles comprise 25 to 1,000 IU/g thrombin.

21. The method of claim 16 or claim 17, wherein each of the first and second aqueous solutions is spray-dried with an outlet temperature of at least about 80°

C.

22. The method of claim 21, wherein the dry powder fibrin sealant composition has a residual moisture content no greater than 5% (w/w).

23. The method of claim 22, wherein each of the first and second aqueous solutions is spray-dried with an outlet temperature of at least about 83°

C.

24. The method of claim 22, wherein the residual moisture content is no greater than 3% (w/w).

25. The method of claim 16 or claim 17, wherein step (iii) comprises mixing the first and second microparticles in a weight ratio of 1:

1.