Stable protein and nucleic acid formulations using non-aqueous, anhydrous, aprotic, hydrophobic, non-polar vehicles with low reactivity

• US 6,730,328 B2
• Filed: 05/04/2001
• Issued: 05/04/2004
• Est. Priority Date: 10/16/1996
• Status: Expired due to Term

• Current Assignee: DURECT Corporation
• Original Assignee: Jessica G. Smith, Manley T. Huang, Steven Joseph Prestrelski, Victoria Knepp Maskiewicz
• Inventors: Prestrelski, Steven Joseph, Huang, Manley T., Maskiewicz, Victoria Knepp, Smith, Jessica G.
• Primary Examiner(s): NGUYEN, DAVE TRONG
• Application Number:
  US09/849,402
• Publication Number:
  US 20010038859A1
• Time in Patent Office: 1,096 Days
• Field of Search: 424/499, 424/489, 424/422, 424/425, 514/2, 435/320.1
• US Class Current: 424/499
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61K 38/38 Albumins
• CPC Class Codes: A61K 38/4826 Trypsin (3.4.21.4) Chymotrypsin (3.4.21.1)
• CPC Class Codes: A61K 38/4846 Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)
• CPC Class Codes: A61K 47/06 Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• 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 9/0019 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 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/0026 Blood substitute; Oxygen transporting formulations; Plasma extender
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Abstract

This invention relates to stable non-aqueous formulations which are suspensions of proteinaceous substances or nucleic acids in non-aqueous, anhydrous, aprotic, hydrophobic, non-polar vehicles with low reactivity. More specifically, the present invention relates to stable protein or nucleic acid formulations wherein the compound remains in stable, dry powder form, yet the formulation is flowable and, therefore amenable to delivery to an animal via injection, transdermal administration, oral delivery or using an implantable device for sustained delivery. These stable formulations may be stored at elevated temperatures (e.g., 37° C.) for long periods of time and are especially useful as flowable formulations which can be shipped and/or stored at high temperatures or in implantable delivery devices for long term delivery (e.g., 1-12 months or longer) of drug.

Claims

1. A stable non-aqueous composition of a biologically active agent comprising:

a) a biologically active agent containing powder wherein the biologically active agent hydration in said powder is less than 10%; and

b) at least one anhydrous, aprotic, hydrophobic, non-polar, low-reactivity vehicle, wherein at least one said vehicle is selected from the group consisting of perfluorodecalin, methoxyflurane, and perfluorotributylamine, and wherein said biologically active agent is selected from the group consisting of beta- and gamma-interferon.

2. The composition of claim 1 wherein at least about 80% of the biologically active agent remains stable for at least one month at 37°

C.

3. The composition of claim 1 wherein said biologically active agent hydration is less than about 5%.

4. The composition of claim 1 wherein said biologically active agent containing powder comprises up to about 30% (w/w) of said composition.

5. The composition of claim 1 wherein said biologically active agent is pharmaceutically useful.

6. A method for preparing the composition of claim 1 comprising suspending the biologically active agent-containing powder of claim 1 in at least one anhydrous, aprotic, hydrophobic, non-polar, low-reactivity vehicle, wherein at least one said vehicle is selected from the group consisting of perfluorodecalin, methoxyflurane, and perfluorotributylamine.

7. A method for administering the biologically active agent according to claim 1, said method comprising administering to said subject an effective amount of the composition of claim 1.

8. The composition of claim 1 wherein said biologically active agent containing powder comprises about 10 to about 30% (w/w) of said composition.

9. The method of claim 7 wherein the administration of the composition is via a route selected from the group consisting of parenteral, transdermal, mucosal, oral and enteral.

10. The method of claim 7 wherein the administration of the composition is via an implantable delivery device.

11. The method of claim 7 wherein the administration of the composition is long-term continuous administration.