Injection vehicle for polymer-based formulations

• US 7,582,311 B1
• Filed: 10/13/2000
• Issued: 09/01/2009
• Est. Priority Date: 10/15/1999
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Okumu, Franklin, Lam, Xanthe M., Cleland, Jeffrey L.
• Primary Examiner(s): KAM, CHIH MIN
• Application Number:
  US09/687,951
• Time in Patent Office: 3,245 Days
• Field of Search: 424/488, 424/489, 424/490, 424/497, 514/2, 514/8, 514/12, 514/54, 536/551, 530/324
• US Class Current: 424/489
• CPC Class Codes: A61K 31/728 Hyaluronic acid
• CPC Class Codes: A61K 38/185 Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
• CPC Class Codes: A61K 38/1866 Vascular endothelial growth factor [VEGF]
• CPC Class Codes: A61K 38/27 Growth hormone [GH], i.e. somatotropin
• CPC Class Codes: A61K 39/39591 Stabilisation, fragmentation
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• 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 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61P 23/00 Anaesthetics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• 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 5/06 of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
• CPC Class Codes: C07K 16/22 against growth factors ; against growth regulators

Abstract

The invention provides injection vehicles suitable for administering particulate suspensions, such as polymer-based formulations, as well as associated pharmaceutical formulations, articles of manufacture, and kits. Other aspects of the invention included methods for producing and administering pharmaceutical formulations. The injection vehicles of the invention are superior to conventional injection vehicles in that they include a pseudoplastic composition that improves injectability, which facilitates delivery of the desired dose. The injection vehicles of the invention also allow the use of smaller-bore needles than are usually necessary to inject polymer-based formulations, reducing the pain associated with injection of such formulations.

Claims

1. A method for administering a biologically active agent, the method comprising:

injecting to an animal a formulation comprising;

(a) an injection vehicle comprising hyaluronic acid or sodium hyaluronate dissolved in a physiological buffer at a concentration of about 0.01 to about 3 percent weight per volume; and

(b) particles comprising;

(i) a first component that is the biologically active agent; and

(ii) a second component that is a biocompatible polymeric matrix,

wherein the concentration of the particles is about 100 mg/mL to about 500 mg/mL of the formulation, and further wherein the hyaluronic acid or sodium hyaluronate is at a concentration sufficient to inject the formulation through a 23-gauge or smaller bore needle.

2. The method of claim 1, wherein the concentration of hyaluronic acid or sodium hyaluronate is about 0.01 to about 1 percent weight per volume.

3. The method of claim 2, wherein the concentration of hyaluronic acid or sodium hyaluronate is about 0.01 to about 0.8 percent weight per volume.

4. The method of claim 1, wherein the injection vehicle comprises hyaluronic acid.

5. The method of claim 1, wherein the hyaluronic acid or sodium hyaluronate is at a concentration sufficient to inject the formulation through a 24-gauge needle.

6. The method of claim 1, wherein the hyaluronic acid or sodium hyaluronate is at a concentration sufficient to inject the formulation through a 25-gauge needle.

7. The method of claim 1, wherein the hyaluronic acid or sodium hyaluronate is at a concentration sufficient to inject the formulation through a 26-gauge needle.

8. The method of claim 1, wherein the hyaluronic acid or sodium hyaluronate is at a concentration sufficient to inject the formulation through a 27-gauge needle.

9. The method of claim 1, wherein the hyaluronic acid or sodium hyaluronate is at a concentration sufficient to inject the formulation through a 28-gauge needle.

10. The method of claim 1, wherein the hyaluronic acid or sodium hyaluronate is at a concentration sufficient to inject the formulation through a 30-gauge needle.

11. An injectable formulation, comprising:

(a) an injection vehicle comprising hyaluronic acid or sodium hyaluronate dissolved in a physiological buffer at a concentration of about 0.01 to about 3 percent weight by volume; and

(b) particles, comprising;

(i) a first component that is a biologically active agent, and

(ii) a second component that is a biocompatible polymeric matrix,

wherein the concentration of the particles is about 100 mg/mL to about 500 mg/mL of the formulation,

and further wherein the hyaluronic acid or sodium hyaluronate is at a concentration sufficient to inject the particles through a 23-gauge or smaller bore needle.

12. The injectable formulation of claim 11, wherein the physiological buffer comprises physiological saline.

13. The injectable formulation of claim 11, wherein the polymeric matrix comprises a blocked polymer.

14. The injectable formulation of claim 11, wherein the polymeric matrix comprises an unblocked polymer.

15. The injectable formulation of claim 11, wherein the polymeric matrix comprises poly(lactide-co-glycolide).

16. The injectable formulation of claim 11, wherein the biologically active agent is a polypeptide.

17. The injectable formulation of claim 16, wherein the polypeptide is selected from the group consisting of a growth hormone, a cytokine;

a cytokine receptor;

a chimeric protein comprising a cytokine or its receptor;

a tumor necrosis factor;

a tumor necrosis factor receptor;

a lipoprotein;

a clotting factor;

an anti-clotting factor;

a serum albumin;

a microbial protein;

a receptor for a hormone;

a receptor for a growth factor;

a rheumatoid factor;

a neurotrophic factor;

a nerve growth factor;

a fibroblast growth factor;

a transforming growth factor (TGF);

a CD protein;

an osteoinductive factor;

an immunotoxin;

a bone morphogenetic protein (BMP);

an interferon;

a colony stimulating factor (CSF);

an interleukin (IL);

a viral antigen;

a transport protein;

a homing receptor;

a regulatory protein;

an antibody;

a chimeric protein, a plasminogen activator;

a tissue-type plasminogen activator;

a urokinase;

an insulin-like growth factor binding protein;

a T-cell receptor;

a surface membrane protein;

an HIV-1 envelope glycoprotein; and

an immunoadhesin.

18. The injectable formulation of claim 16, wherein the polypeptide is an anti-vascular endothelial growth factor Fab (anti-VEGF Fab).

19. The injectable formulation of claim 16, wherein the polypeptide is selected from the group consisting of tumor necrosis factor-alpha (TNF-alpha);

tumor necrosis factor-beta (TNF-beta);

tumor necrosis factor receptor-1 (TNFR-1);

tumor necrosis factor receptor-2 (TNFR-2);

renin;

human growth hormone;

bovine growth hormone;

growth hormone releasing factor;

parathyroid hormone;

thyroid stimulating hormone;

alpha-1-antitrypsin;

insulin A-chain;

insulin B-chain;

proinsulin;

follicle stimulating hormone;

calcitonin;

luteinizing hormone;

glucagon;

factor VIIIC;

factor IX;

tissue factor;

von Willebrand'"'"'s factor;

Protein C;

atrial natriuretic factor;

lung surfactant;

bombesin;

thrombin;

hemopoietic growth factor;

enkephalinase;

RANTES;

human macrophage inflammatory protein (MIP- 1-alpha);

human serum albumin;

mullerian-inhibiting substance;

relaxin A-chain;

relaxin B-chain;

prorelaxin;

mouse gonadotropin-associated peptide;

beta-lactamase;

DNase;

inhibin;

activin;

vascular endothelial growth factor (VEGF);

anti-VEGF Fab;

glucagon-like peptide I (GLP-I);

hepatocyte growth factor (HGF);

integrin;

protein A;

protein D;

bone-derived neurotrophic factor (BDNF);

neurotrophin-3, -4, -5, and -6 (NT-3, NT-4, NT-5, NT-6);

NGF-beta;

platelet-derived growth factor (PDGF);

aFGF;

bFGF;

epidermal growth factor (EGF);

TGF-alpha;

TGF-beta, including TGF-beta1, TGF-beta2, TGF-beta3, TGF-beta4, and TGF- beta5;

insulin-like growth factor-I (IGF-I);

insulin-like growth factor-Il (IGF-II);

des (1-3)-IGF-I (brain IGF-I);

CD-3;

CD-4;

CD-8;

CD-19;

erythropoietin;

interferon-alpha;

interferon-beta;

interferon-gamma;

M-CSF;

GM-CSF;

G-CSF;

IL-1;

IL-2;

IL-3;

IL-4;

IL-5;

IL-6;

IL-7;

IL-8;

IL-9;

IL-10;

superoxide dismutase;

decay accelerating factor;

gp120;

gp160; and

addressin.

20. The injectable formulation of claim 11, wherein the concentration of the particles in the formulation is about 100 mg/mL to about 300 mg/mL.

21. The injectable formulation of claim 11, wherein the injection vehicle comprises hyaluronic acid.

22. The injectable formulation of claim 11, wherein the injection vehicle comprises sodium hyaluronate.

23. The injectable formulation of claim 11, wherein the concentration of hyaluronic acid or sodium hyaluronate is about 0.01 to about 1 percent weight per volume.

24. The injectable formulation of claim 23, wherein the concentration of hyaluronic acid or sodium hyaluronate is about 0.01 to about 0.8 percent weight per volume.

25. The injectable formulation of claim 23, wherein the concentration of hyaluronic acid or sodium hyaluronate is between about 0.05 and about 1 percent weight per volume.

26. The injectable formulation of claim 23, wherein the concentration of hyaluronic acid or sodium hyaluronate is between about 0.05 and about 0.8 percent weight per volume.

27. The injectable formulation of claim 11, wherein the polymeric matrix comprises a polymer selected from a biodegradable polymer, a non-biodegradable polymer, a mixture of biodegradable and non-biodegradable polymers, and a copolymer comprising biodegradable and non-biodegradable units.

28. The injectable formulation of claim 11, wherein the polymeric matrix comprises a polymer selected from blocked polymers, unblocked polymers, and mixtures of blocked and unblocked polymers.

29. The injectable formulation of claim 11, wherein the polymeric matrix comprises a polymer selected from a poly (glycolide);

a poly (lactide-co-glycolide);

a poly (lactic acid);

a poly (glycolic acid);

a poly (lactic acid-co-glycolic acid);

a polyanhydride;

a polyorthoester;

a polyetherester;

a polycaprolactone;

a polyesteramide;

a block copolymer of polyethylene glycol and lactide;

a block copolymer of polyethylene glycol and glycolide; and

blends or copolymers thereof.

30. A method for administering the injectable formulation of claim 11, the method comprising injecting the injectable formulation through a 23-gauge or smaller bore needle.

31. The injectable formulation of claim 11, wherein the biologically active agent is dispersed within, coated on, or dispersed within and coated on the particles.

32. The injectable formulation of claim 31, wherein the biologically active agent is dispersed within the particles.

33. The injectable formulation of claim 11, wherein the particles are microparticles.

34. The injectable formulation of claim 11, wherein the particles are microspheres.

35. The injectable formulation of claim 11, wherein the particles have an average diameter of between about 5 and about 200 microns.

36. The injectable formulation of claim 11, wherein the concentration of particles in the formulation is between about 125 mg/mL to about 250 mg/mL.

37. The injectable formulation of claim 11, wherein the concentration of particles in the formulation is between about 200 mg/mL to about 250 mg/mL.

38. The injectable formulation of claim 11, wherein the hyaluronic acid or sodium hyaluronate is at a concentration sufficient to inject the formulation through a 24-gauge needle.

39. The injectable formulation of claim 11, wherein the hyaluronic acid or sodium hyaluronate is at a concentration sufficient to inject the formulation through a 25-gauge needle.

40. The injectable formulation of claim 11, wherein the hyaluronic acid or sodium hyaluronate is at a concentration sufficient to inject the formulation through a 26-gauge needle.

41. The injectable formulation of claim 11, wherein the hyaluronic acid or sodium hyaluronate is at a concentration sufficient to inject the formulation through a 27-gauge needle.

42. The injectable formulation of claim 11, wherein the hyaluronic acid or sodium hyaluronate is at a concentration sufficient to inject the formulation through a 28-gauge needle.

43. The injectable formulation of claim 11, wherein the hyaluronic acid or sodium hyaluronate is at a concentration sufficient to inject the formulation through a 30-gauge needle.

44. A method for making a pharmaceutical formulation, comprising:

adding an effective amount of a biologically active agent coated on, dispersed within, or coated on and dispersed within polymeric particles to an aqueous injection vehicle comprising hyaluronic acid or sodium hyaluronate at a concentration of about 0.01 to about 3% (w/v);

wherein the concentration of particles in the formulation is between about 100 and 500 mg/mL (w/v); and

further wherein the hyaluronic acid or sodium hyaluronate is at a concentration sufficient to inject the particles through a 23-gauge or smaller bore needle.