Heparain-bulking agent compositions and methods thereof

• US 9,357,765 B2
• Filed: 03/14/2013
• Issued: 06/07/2016
• Est. Priority Date: 04/03/2012
• Status: Active Grant

• Current Assignee: Smiths Medical ASD, Inc. (Smiths Group International Holdings Ltd.)
• Original Assignee: Smiths Medical ASD, Inc. (Smiths Group International Holdings Ltd.)
• Inventors: Schalhoub, Kenneth G., Tyler, Joseph E., Farrar, Quinton
• Primary Examiner(s): Singh, Satyendra K
• Application Number:
  US13/827,658
• Publication Number:
  US 20130260363A1
• Time in Patent Office: 1,181 Days
• US Class Current: 1/1
• CPC Class Codes: A01N 1/0226 Physiologically active agents, i.e. substances affecting physiological processes of cells and tissue to be preserved, e.g. anti-oxidants or nutrients
• CPC Class Codes: A61K 31/727 Heparin; Heparan
• 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 9/145 with organic compounds
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61L 33/0011 Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate

Abstract

A free-flowing anti-coagulant powder composition, the anti-coagulant composition containing heparin and a bulking agent that is lyophilized or spray dried and ground into a powder. The powdered anti-coagulant composition can be dry filled into syringes and other blood collections systems for rapid dissolution and mixing with collected blood sample without agitation of the container. The formulation may also retain a portion of the initial moisture, which may improve the shelf life and stability of the composition.

Claims

1. A method of preparing a heparin-bulking agent composition, the method comprising:

providing a heparin component and at least one bulking agent;

dissolving the heparin component and the at least one bulking agent in a solution to form a heparin-bulking agent formulation;

drying the heparin-bulking agent formulation to form a heparin-bulking agent composition having a solid mass, the heparin component comprising about 3% to about 40% by weight of the solid mass and intermixed with the bulking agent comprising about 60% to about 97% by weight of the solid mass; and

grinding the solid mass of the heparin-bulking agent composition to a particulate size having an X₁₀ and X₉₀ value particle size distribution range between about 35 microns and about 400 microns such that the heparin-bulking agent composition comprises a free-flowing powder that is readily dissolvable upon contact with a blood sample in under 10 seconds.

2. The method of claim 1, wherein the heparin component is a heparin salt chosen from lithium, sodium, calcium, zinc or combinations thereof.

3. The method of claim 2, wherein the heparin component is provided as a solution, an aqueous solution, a solid material, or a lyophilized heparin salt.

4. The method of claim 2, wherein the bulking agent is a water soluble material chosen from a sugar alcohol, a carbohydrate, a water-soluble polymer, or combinations thereof.

5. The method of claim 4, wherein the water soluble material is selected from the group consisting of mannitol, trehalose, raffinose, sorbitol, sucrose, lactose, polyvinylpyrollidone, and combinations thereof.

6. The method of claim 5, wherein the water soluble bulking agent is provided as an aqueous solution or a solid material.

7. The method of claim 4, further comprising mixing the heparin component and the bulking agent component in an aqueous solution until dissolved to form the heparin-bulking agent formulation.

8. The method of claim 4, wherein the heparin-bulking agent formulation is lyophilized to form the heparin-bulking agent composition.

9. The method of claim 8, further comprising freezing the heparin-bulking agent formulation to form a solidified heparin-bulking agent formulation prior to lyophilizing the heparin-bulking agent formulation.

10. The method of claim 9, wherein the solidified heparin-bulking agent formulation is lyophilized at a temperature below about −

32°

C.

11. The method of claim 4, wherein the heparin-bulking agent formulation is spray dried to form the heparin-bulking agent composition.

12. The method of claim 1, wherein the heparin-bulking agent formulation is spray dried to form the heparin-bulking agent composition.

13. The method of claim 12, wherein a sprayer inlet temperature is in the range of about 115°

C. to about 175°

C. and a sprayer outlet temperature is in the range of about 50°

C. to about 65°

C.

14. The method of claim 1, wherein a moisture content of the heparin bulking agent composition is less than about 10%.

15. The method of claim 1, wherein a sterilization stability of the free-flowing powder of the heparin-bulking agent composition is substantially unchanged over a period of about 5 years.

16. The method of claim 1 further comprising filling a blood collection container with a predetermined amount of the free-flowing powder of said heparin-bulking agent composition.

17. An anti-coagulant comprising:

a plurality of particles of a heparin-bulking agent composition, each of the plurality of particles of the heparin-bulking agent composition having a heparin component intermixed with a bulking agent component, wherein the plurality of particles of the heparin-bulking agent composition are ground into a free-flowing powder adapted for use with a powder filling apparatus;

wherein the plurality of particles of the heparin-bulking agent composition have an X₁₀ and X₉₀ value particle size distribution range between about 35 microns and about 400 microns;

wherein a predetermined amount of the free-flowing powder is readily dissolvable within a blood sample in under 10 seconds; and

wherein the heparin component comprises about 3% to about 40% by weight of a solid content of each of the plurality of particles of the heparin-bulking agent composition and the bulking agent comprises about 60% to about 97% by weight of the solid content of each of the plurality of particles of the heparin-bulking agent composition.

18. The anti-coagulant of claim 17, wherein the heparin component is a heparin salt selected from the group consisting of lithium, sodium, calcium, zinc and combinations thereof.

19. The anti-coagulant of claim 18, wherein the bulking agent is a water soluble material selected from the group consisting of a sugar alcohol, a carbohydrate, a water-soluble polymer, and combinations thereof.

20. The anti-coagulant of claim 19, wherein the water soluble material is selected from the group consisting of mannitol, trehalose, raffinose, sorbitol, sucrose, lactose, polyvinylpyrollidone, and combinations thereof.

21. The anti-coagulant of claim 17, wherein the range of particle size distribution between the X₁₀ and X₉₀ value for each of the plurality of particles of the heparin-bulking agent composition is between about 40 microns and about 380 microns.

22. The anti-coagulant of claim 17, wherein a moisture content of the heparin-bulking agent composition is less than about 10%.

23. The anti-coagulant of claim 18, wherein the heparin-bulking agent composition is a lyophilized heparin-bulking agent composition or a spray dried heparin-bulking agent composition.

24. The anti-coagulant of claim 18, wherein said anti-coagulant is pre-loaded into a blood collection container.

25. A blood collection container comprising the anti-coagulant as set forth in claim 18 pre-loaded into said container, wherein the anti-coagulant has a dissolution of less than about 10 seconds upon a blood sample being added to the blood collection container.

26. A blood collection container comprising the anti-coagulant as set forth in claim 18 pre-loaded into said container, wherein the anti-coagulant has a dissolution of less than about 10 seconds upon a blood sample being added to the blood collection container without the need of agitating the blood collection container to dissolve the anti-coagulant within the blood sample.

27. A blood collection device, comprising:

a container having an internal volume capable of receiving a blood sample; and

a predetermined amount of a free-flowing powder of an anti-coagulant loaded into the internal volume of the container, the anti-coagulant comprising a heparin-bulking agent composition, the heparin-bulking agent composition having a heparin component intermixed with a bulking agent component, wherein the free-flowing powder comprises a plurality of particles having an X₁₀ and X₉₀ value particle size distribution range between about 35 microns and about 400 microns, wherein the predetermined amount of the free-flowing powder is readily dissolvable within a blood sample in under 10 seconds, and wherein the heparin component comprises about 3% to about 40% by weight of a solid content of each of the plurality of particles of the heparin-bulking agent composition and the bulking agent comprises about 60% to about 97% by weight of the solid content of each of the plurality of particles of the heparin-bulking agent composition.

28. The blood collection device of claim 27, wherein the heparin-bulking agent composition is dissolvable within the blood sample received within the internal volume.

29. The blood collection device of claim 27, wherein the heparin component is a heparin salt chosen from lithium, sodium, calcium, zinc or combinations thereof.

30. The blood collection device of claim 27, wherein the bulking agent is a water soluble material chosen from a sugar alcohol, a carbohydrate, a water-soluble polymer, or combinations thereof.

31. The blood collection device of claim 30, wherein the water soluble material is selected from the group consisting of mannitol, trehalose, raffinose, sorbitol, sucrose, lactose, polyvinylpyrollidone, and combinations thereof.

32. The blood collection device of claim 27, wherein a moisture content of the heparin-bulking agent composition is less than about 10%.

33. The blood collection device of claim 27, wherein the container is a blood sample collection tube, a syringe, or a vacuum tube.

34. The blood collection device of claim 27, wherein internal volume of the container between about 0.5 mg to about 5.0 mg of the heparin-bulking agent composition.

35. The blood collection device of claim 27, wherein the anti-coagulant is capable of being dissolved within a blood sample of a patient in less than about 10 seconds upon the blood sample being added to the internal volume of the blood collection container without the need of agitating the blood collection container to dissolve the anti-coagulant within the blood sample.

36. The blood collection device of claim 27, wherein a sterilization stability of the free-flowing powder of the heparin-bulking agent composition is substantially unchanged over a period of about 5 years.

37. A method of collecting a blood sample from a patient, the method comprising:

providing a container having an internal volume capable of receiving a blood sample;

loading a predetermined amount of an anti-coagulant powder into the internal volume of the container, the anti-coagulant powder comprising a heparin-bulking agent composition having a heparin component intermixed with at least one bulking agent component, wherein the free-flowing powder comprises a plurality of particles having an X₁₀ and X₉₀ value particle size distribution range between about 35 microns and about 400 microns, and wherein the heparin component comprises about 3% to about 40% by weight of a solid content of each of the plurality of particles of the heparin-bulking agent composition and the bulking agent comprises about 60% to about 97% by weight of the solid content of each of the plurality of particles of the heparin-bulking agent composition;

drawing the blood sample from the patient into the internal volume of the container; and

allowing the anti-coagulant powder to dissolve within the blood sample, wherein the predetermined amount of the free-flowing powder is readily dissolvable within the blood sample in under 10 seconds.

38. The method of claim 37, wherein the heparin component is a heparin salt chosen from lithium, sodium, calcium, zinc or combinations thereof.

39. The method of claim 38, wherein the bulking agent is a water soluble material selected from the group consisting of mannitol, trehalose, raffinose, sorbitol, sucrose, lactose, polyvinylpyrollidone, and combinations thereof.

40. The method of claim 39, wherein the container is a blood sample collection tube, a syringe, or a vacuum tube.

41. The method of claim 37, wherein the anti-coagulant powder is capable of being dissolved within the blood sample without agitation of the container.

42. The method of claim 37 further comprising inserting at least a portion of the blood sample collected into a blood analyzer for a blood gas analysis.