Stable co-formulation of hyaluronidase and immunoglobulin, and methods of use thereof

• US 9,084,743 B2
• Filed: 09/16/2010
• Issued: 07/21/2015
• Est. Priority Date: 09/17/2009
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Baxter Healthcare SA (Baxter International Inc.), Baxter International Inc.
• Inventors: Teschner, Wolfgang, Svatos, Sonja, Bruckschwaiger, Leopold, Weber, Alfred, Schwarz, Hans-Peter, Lei, Laura
• Primary Examiner(s): Kim, Yunsoo
• Application Number:
  US12/807,991
• Publication Number:
  US 20110066111A1
• Time in Patent Office: 1,769 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61K 39/39591 Stabilisation, fragmentation
• CPC Class Codes: A61K 47/42 Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein oligopeptides having up to five amino acids A61K47/183; polyamino acids A61K47/34
• CPC Class Codes: A61K 9/0021 Intradermal administration, e.g. through microneedle arrays, needleless injectors mechanical aspects A61M
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07K 16/00 Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C07K 16/06 from serum
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C12N 9/2474 : Hyaluronoglucosaminidase (3.2.1.35), i.e. hyaluronidase
• CPC Class Codes: C12Y 302/01035 : Hyaluronoglucosaminidase (3.2.1.35), i.e. hyaluronidase
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Provided herein are stable co-formulations of immunoglobulin and hyaluronidase that are stable to storage in liquid form at room temperature for at least 6 months and at standard refrigerator temperatures for 1-2 years. Such co-formulations can be used in methods of treating IG-treatable diseases or conditions by subcutaneous administration.

Claims

1. A stable composition formulated for subcutaneous administration, wherein:

the stable composition contains hyaluronidase and immune globulin (IG);

the stable composition is a liquid co-formulation;

the composition has a pH of between 4 or about 4 to 5 or about 5, inclusive; and

the composition comprises;

(a) immune globulin (IG) at a concentration that is at least 10% w/v;

a soluble hyaluronidase at a concentration that is at least 50 U/mL and is present in an amount sufficient to allow for the subcutaneous administration of the composition at a single injection site at an infusion rate equal to or greater than the intravenous infusion rate for intravenous immunoglobulin; and

an alkali metal chloride salt at a concentration of 0.05 M to 0.25 M, whereby the co-formulated composition is stable at temperatures of 28°

C. to 32°

C. for at least 6 months;

or

(b) immune globulin (IG) at a concentration that is at least 10% w/v;

a soluble hyaluronidase at a concentration that is at least 50 U/mL and is present at a ratio of at least 100 Units (U) of hyaluronidase per gram (g) of the IG; and

an alkali metal chloride salt at a concentration of 0.05 M to 0.25 M, whereby the co-formulated composition is stable at temperatures of 28°

C. to 32°

C. for at least 6 months.

2. The stable composition of claim 1, further comprising an amino acid stabilizer at a concentration that is at least 0.1 M.

3. The stable composition of claim 2, wherein the amino acid stabilizer is selected from among alanine, histidine, arginine, lysine, ornithine, isoleucine, valine, methionine, glycine and proline.

4. The stable composition of claim 2, wherein the amino acid stabilizer is at a concentration that is 0.25 M or at least 0.25 M.

5. The stable composition of claim 1, wherein the concentration of IG is at least 20% w/v.

6. The stable composition of claim 1, wherein the concentration of IG is between at or about 10% w/v to at or about 20% w/v.

7. The stable composition of claim 1, wherein the IG is from human plasma.

8. The stable composition of claim 1, wherein the IG is purified from human plasma by a purification method comprising alcohol fractionation.

9. The stable composition of claim 8, wherein the IG is further purified by any one or more of a polyethylene glycol (PEG) precipitation, ion-exchange chromatography, enzymatic cleavage, diafiltration or ultrafiltration.

10. The stable composition of claim 1, wherein the IG contains greater than 95% IgG.

11. The stable composition of claim 1, wherein the alkali metal chloride salt is KCl or NaCl.

12. The stable composition of claim 1, wherein the concentration of NaCl is at least 0.15 M.

13. The stable composition of claim 1, wherein the soluble hyaluronidase is a PH20, or a truncated form thereof.

14. The stable composition of claim 13, wherein the PH20 is selected from an ovine, bovine or truncated human PH20.

15. The stable composition of claim 14, wherein PH20 is a truncated human PH20 and the truncated human PH20 is selected from among polypeptides having a sequence of amino acids set forth in any of SEQ ID NOS:

4-9, or variants thereof having at least 91% sequence identity to any of SEQ ID NOS;

4-9.

16. The stable composition of claim 1, wherein the soluble hyaluronidase is a composition designated rHuPH20.

17. The stable composition of claim 1, wherein the soluble hyaluronidase is at a concentration that is 50 U/mL to 500 U/mL.

18. The stable composition of claim 1, wherein the soluble hyaluronidase is at a ratio of 100 U of hyaluronidase per gram of the IG to 3000 U of hyaluronidase per gram of the IG.

19. The stable composition of claim 1 that in concentrated form has a pH of 4.4 to 4.9, inclusive.

20. The stable composition of claim 1, wherein the co-formulation is formulated for multiple dosage administration or for single dosage administration.

21. The stable composition of claim 1 that is formulated for single dosage administration in an amount sufficient to treat an IG-treatable disease or condition when administered daily, weekly, biweekly, every 2-3 weeks, every 3-4 weeks or monthly.

22. The stable composition of claim 1, wherein the amount of IG in the co-formulation is substantially the same as the amount in a single dosage administration when administered intravenously for treatment of an IG-treatable disease or condition.

23. The stable composition of claim 1, wherein the co-formulation is formulated for single dosage administration and the amount of IG is or is about at least 1 gram (g) to 200 g.

24. The stable composition of claim 1, wherein the co-formulation is formulated for single dosage administration and the amount of hyaluronidase in the composition is or is about at least 500 Units, 1000 Units, 2000 Units, 5000 Units, 10,000 Units, 30,000 Units, 40,000 Units, 50,000 Units, 60,000 Units, 70,000 Units, 80,000 Units, 90,000 Units, 100,000 Units or more.

25. A container, comprising a stable composition of claim 1.

26. A container of claim 25 that is a tube, bottle, vial or syringe and optionally includes a needle for injection.

27. A kit, comprising the container of claim 25, and a means for infusing the composition.

28. The stable composition of claim 1 that comprises:

immune globulin (IG) at a concentration that is at least 10% w/v;

a soluble hyaluronidase at a concentration that is 50 U/mL to 500 U/mL and is present at a ratio of at least 100 Units (U) of hyaluronidase per gram (g) of the IG; and

an alkali metal chloride salt at a concentration of 0.05 M to 0.25 M, whereby the co-formulated composition is stable at temperatures of 28°

C. to 32°

C. for at least 6 months.

29. The stable composition of claim 1 that comprises:

immune globulin (IG) at a concentration that is at least 10% w/v;

a soluble hyaluronidase at a concentration that is 50 U/mL to 500 U/mL and is present in an amount sufficient to allow for the subcutaneous administration of the composition at a single injection site at an infusion rate equal to or greater than the intravenous infusion rate for intravenous immunoglobulin; and

an alkali metal chloride salt at a concentration of 0.05 M to 0.25 M, whereby the co-formulated composition is stable at temperatures of 28°

C. to 32°

C. for at least 6 months.