Method for stabilizing blood plasma components in a lyophilizate using carbon dioxide and phosphoric acid

• US 8,518,452 B2
• Filed: 02/15/2008
• Issued: 08/27/2013
• Est. Priority Date: 02/15/2007
• Status: Expired due to Fees

• Current Assignee: Octapharma AG (Octapharma Nordic AB)
• Original Assignee: Octapharma AG (Octapharma Nordic AB)
• Inventors: Bjornstrup, Kim, Kern, Martin, Gruber, Gerhard, Roemisch, Juergen, Svae, Tor-Einar, Heger, Andrea, Sachse, Hans, Schuetz, Raimund
• Primary Examiner(s): SAUCIER, SANDRA E
• Application Number:
  US12/449,558
• Publication Number:
  US 20100159023A1
• Time in Patent Office: 2,020 Days
• Field of Search: None
• US Class Current: 424/530
• CPC Class Codes: A61K 35/16 Blood plasma; Blood serum umbilical cord blood A61K35/51
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• 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: A61P 7/08 Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock artificial tears A61P27/04

Abstract

Process for the stabilization of blood plasma components in a lyophilizate, wherein

• • in a freeze-drying process, said blood plasma components were in a solution containing at least two different pH-lowering substances causing a predetermined pH value range to be adjusted in the solution formed upon reconstitution.

Claims

1. In a process of freeze-drying blood plasma components to form a lyophilizate, the improvement wherein, prior to freeze-drying, combining at least different pH-lowering substances carbon dioxide and phosphoric acid with the blood plasma components in aqueous solution, thereby effecting a predetermined pH value range in a reconstituted solution of the components.

2. The process according to claim 1, wherein

freeze-drying occurs in a first container including a sterile material that is impermeable to water but permeable to water vapor and

after freeze-drying uptake of water vapor beyond a predetermined residual moisture content of the lyophilizate is prevented.

3. The process according to claim 2, wherein the sterile material is provided on a support.

4. The process according to claim 3, wherein the support is made of material selected from the group consisting of polypropylene, polyethylene, ethyl vinyl acetate, polyurethane, and block polymers of styrene/butadiene/styrene, styrene/isoprene/styrene, styrene/ethylene/butylene/styrene, styrene/ethylene/propylene/styrene, and combinations thereof.

5. The process according to claim 2, wherein the sterile material is a fluorinated plastic material, polyester, or polyethylene.

6. The process according to claim 2, wherein the first container is disposed in a second container impermeable to water vapor and made of a plastic material or aluminum foil.

7. The process according to claim 2, wherein the first container has walls and connection elements, wherein the walls comprise a sterile material that is impermeable to water but permeable to water vapor.

8. The process according to claim 1, wherein the at least two different pH-lowering substances prevent the pH value from being adjusted into ranges that negatively affect the structure of the blood plasma components in the lyophilizate by an at least partial loss of activity and/or nativity, denaturing, fragmentation, aggregation, or chemical modification.

9. The process according to claim 1, wherein the blood plasma components are selected from the group consisting of proteins, polysaccharides, nucleic acids, lipids, and mixtures thereof.

10. The process according to claim 1, wherein the blood plasma components are proteins from blood, plasma, or serum.

11. The process according to claim 1, wherein the aqueous solution further comprises a stabilizer selected from the group consisting of sugar, polysaccharides, oligosaccharides, polyols, amino acids, and combinations thereof.

12. The process according to claim 1, wherein the blood plasma components are fractions of transgenic or recombinantly prepared proteins.

13. The process according to claim 1, wherein the freeze-drying comprises (i) a first step and (ii) a second step having a lower input of desorption energy than the first step.

14. A process comprising reconstituting a lyophilizate in an aqueous solution containing physiologically acceptable acid-hydrolyzing salts or physiologically acceptable acids, wherein the lyophilizate is obtained by the process of claim 1.

15. A process comprising reconstituting a lyophilizate with neutral water for injection, wherein the lyophilizate is obtained by the process of claim 1.