Formulations for coated microprojections containing non-volatile counterions

• US 20040265354A1
• Filed: 06/29/2004
• Published: 12/30/2004
• Est. Priority Date: 06/30/2003
• Status: Active Grant

• Current Assignee: ALZA Corporation (Johnson & Johnson)
• Original Assignee: ALZA Corporation (Johnson & Johnson)
• Inventors: Ameri, Mahmoud, Cormier, Michel J. N., Maa, Yuh-Fun, Lin, WeiQi
• Granted Patent: US 7,579,013 B2
• Time in Patent Office: Days
• US Class Current: 424/423
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• 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 9/0021 Intradermal administration, e.g. through microneedle arrays, needleless injectors mechanical aspects A61M
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/24 Antidepressants
• 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 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/18 of the parathyroid hormones
• 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

The invention provides for a formulation for coating one or more microprojections which reduces or minimizes the loss of counterions from the coating in order to achieve a pH-stabilized formulation.

Claims

1. A composition for coating a transdermal delivery device having stratum corneum-piercing microprojections comprising a formulation of a biologically active agent and a non-volatile counterion, wherein said formulation has increased pH stability and solubility when dried.

2. The composition of claim 1, wherein said biologically active agent is selected from the group consisting of growth hormone release hormone (GHRH), growth hormone release factor (GHRF), insulin, insultropin, calcitonin, octreotide, endorphin, TRN, NT-36 (chemical name:

N-[[(s)-4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide), liprecin, pituitary hormones (e.g., HGH, HMG, desmopressin acetate, etc), follicle luteoids, aANF, growth factors such as growth factor releasing factor (GFRF), bMSH, GH, somatostatin, bradykinin, somatotropin, platelet-derived growth factor releasing factor, asparaginase, bleomycin sulfate, chymopapain, cholecystokinin, chorionic gonadotropin, erythropoietin, epoprostenol (platelet aggregation inhibitor), glucagon, HCG, hirulog, hyaluronidase, interferon alpha, interferon beta, interferon gamma, interleukins, interleukin-10 (IL-10), erythropoietin (EPO), granulocyte macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), glucagon, leutinizing hormone releasing hormone (LHRH), LHRH analogs (such as goserelin, leuprolide, buserelin, triptorelin, gonadorelin, and napfarelin, menotropins (urofollitropin (FSH) and LH)), oxytocin, streptokinase, tissue plasminogen activator, urokinase, vasopressin, deamino [Val4, D-Arg8] arginine vasopressin, desmopressin, corticotropin (ACTH), ACTH analogs such as ACTHI (1-24), ANP, ANP clearance inhibitors, angiotensin II antagonists, antidiuretic hormone agonists, bradykinn antagonists, ceredase, CSI'"'"'s, calcitonin gene related peptide (CGRP), enkephalins, FAB fragments, IgE peptide suppressors, IGF-1, neurotrophic factors, colony stimulating factors, parathyroid hormone and agonists, parathyroid hormone antagonists, parathyroid hormone (PTH), PTH analogs such as PTH (1-34), prostaglandin antagonists, pentigetide, protein C, protein S, renin inhibitors, thymosin alpha-1, thrombolytics, TNF, vasopressin antagonists analogs, alpha-1 antitrypsin (recombinant), and TGF-beta.

3. The composition of claim 1, wherein said biologically active agent is selected from the group consisting of antigens in the form of proteins, polysaccharide conjugates, oligosaccharides, and lipoproteins. These subunit vaccines in include Bordetella pertussis (recombinant PT accince-acellular), Clostridium tetani (purified, recombinant), Corynebacterium diptheriae (purified, recombinant), Cytomegalovirus (glycoprotein subunit), Group A streptococcus (glycoprotein subunit, glycoconjugate Group A polysaccharide with tetanus toxoid, M protein/peptides linke to toxing subunit carriers, M protein, multivalent type-specific epitopes, cysteine protease, C5a peptidase), Hepatitis B virus (recombinant Pre S1, Pre-S2, S, recombinant core protein), Hepatitis C virus (recombinant-expressed surface proteins and epitopes), Human papillomavirus (Capsid protein, TA-GN recombinant protein L2 and E7 [from HPV-6], MEDI-501 recombinant VLP L1 from HPV-11, Quadrivalent recombinant BLP L1[from HPV-6], HPV-11, HPV-16, and HPV-18, LAMP-E7 [from HPV-16]), Legionella pneumophila (purified bacterial survace protein), Neisseria meningitides (glycoconjugate with tetanus toxoid), Pseudomonas aeruginosa (synthetic peptides), Rubella virus (synthetic peptide), Streptococcus pneumoniae (glyconconjugate [1, 4, 5, 6B, 9N, 14, 18C, 19V, 23F] conjugated to meningococcal B OMP, glycoconjugate [4, 6B, 9V, 14, 18C, 19F, 23F] conjugated to CRM197, glycoconjugate [1, 4, 5, 6B, 9V, 14, 18C, 19F, 23F] conjugated to CRM1970, Treponema pallidum (surface lipoproteins), Varicella zoster virus (subunit, glycoproteins), and Vibrio cholerae (conjugate lipopolysaccharide).

4. The composition of claim 1, wherein said formulation has a pH, said biologically active agent has a positive charge at said formulation pH and said non-volatile counterion comprises a weak acid.

5. The composition of claim 4, wherein said weak acid has at least one acidic pKa and a property selected from the group consisting of a melting point higher than about 50°

C. and a boiling point higher than about 170°

C. at atmospheric pressure.

6. The composition of claim 5, wherein said weak acid is selected from the group consisting of citric acid, succinic acid, glycolic acid, gluconic acid, glucuronic acid, lactic acid, malic acid, pyruvic acid, tartaric acid, tartronic acid, and fumaric acid.

7. The composition of claim 6, wherein said formulation has a pH, said biologically active agent has a positive charge at said formulation pH and said non-volatile counterion comprises a strong acid.

8. The composition of claim 7, wherein said strong acid has at least one pKa lower than about 2.

9. The composition of claim 8, wherein said strong acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, sulfonic acid, sulfuric acid, maleic acid, phosphoric acid, benzene sulfonic acid and methane sulfonic acid.

10. The composition of claim 1, wherein said formulation has a pH, said biologically active agent has a positive charge at said formulation pH and said non-volatile counterion comprises an acidic zwitterion.

11. The composition of claim 10, wherein said acidic zwitterion has at least two acidic pKa'"'"'s and at least one basic pKa, so that there is at least one extra acidic group as compared to the number of basic groups.

12. The composition of claim 11, wherein said acidic zwitterion is selected from the group consisting of glutamic acid and aspartic acid.

13. The composition of claim 1, wherein said formulation has a pH, said biologically active agent has a negative charge at said formulation pH and said non-volatile counterion comprises a weak base.

14. The composition of claim 13, wherein said weak base has at least one basic pKa and a property selected from the group consisting of a melting point higher than about 50°

C. and a boiling point higher than about 170°

C. at atmospheric pressure.

15. The composition of claim 14, wherein said weak base is selected from the group consisting of monoethanolomine, diethanolamine, triethanolamine, tromethamine, methylglucamine, glucosamine.

16. The composition of claim 1, wherein said formulation has a pH, said biologically active agent has a negative charge at said formulation pH and said non-volatile counterion comprises a strong base.

17. The composition of claim 16, wherein said strong base has at least one pKa higher than about 12.

18. The composition of claim 17, wherein said strong base is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, and magnesium hydroxide.

19. The composition of claim 1, wherein said formulation has a pH, said biologically active agent has a negative charge at said formulation pH and said non-volatile counterion comprises a basic zwitterion.

20. The composition of claim 19, wherein said basic zwitterion has at least two basic pKa'"'"'s and at least one acidic pKa, so that there is at least one extra basic group as compared to the number of acidic groups.

21. The composition of claim 20, wherein said basic zwitterion is selected from the group consisting of histidine, lysine, and arginine.

22. The composition of claim 1, wherein said formulation has a pH, said biologically active agent has a positive charge at said formulation pH and said non-volatile counterion comprises a mixture of counterions comprising at least one non-volatile strong acid and at least one non-volatile weak acid.

23. The composition of claim 1, wherein said formulation has a pH, said biologically active agent has a positive charge at said formulation pH and said non-volatile counterion comprises a mixture of counterions comprising at least one non-volatile acid and at least one volatile weak acid.

24. The composition of claim 1, wherein said formulation has a pH, said biologically active agent has a positive charge at said formulation pH and said non-volatile counterion neutralizes said positive charge of said biologically active agent.

25. The composition of claim 24, wherein excess of counterion (as the free acid or as a salt) is further added to the biologically active agent in order to control pH and to provide adequate buffering capacity.

26. The composition of claim 1, wherein said formulation has a pH, said biologically active agent has a negative charge at said formulation pH and said non-volatile counterion comprises a mixture of counterions comprising at least one non-volatile strong base and at least one non-volatile weak base.

27. The composition of claim 1, wherein said formulation has a pH, said biologically active agent has a negative charge at said formulation pH and said non-volatile counterion comprises a mixture of counterions comprising at least one non-volatile base and at least one volatile weak base.

28. The composition of claim 1, wherein said formulation has a pH, said biologically active agent has a negative charge at said formulation pH and said non-volatile counterion neutralizes said negative charge of said biologically active agent.

29. The composition of claim 28, wherein excess of counterion (as the free based or as a salt) is further added to the biologically active agent in order to control pH and to provide adequate buffering capacity.

30. The composition of claim 1, wherein said biologically active agent has a mole ratio between uncharged species and charged species of at least 1 to 100 at a pH between 4 and 10.

31. The composition of claim 28, wherein said non-volatile counterion reduces said mole ratio between uncharged species and charged species of said biologically active agent to less than about 1 to 100.

32. The composition of claim 1, further comprising a transdermal delivery device having at least one microprojection configured to pierce the stratum corneum, wherein said formulation is coated on said microprojection and dried.

33. A device for transdermally delivering a biologically active agen, comprising at least one stratum-corneum piercing microprojection coated with of a formulation, wherein said formulation comprises a biologically active agent and a non-volatile counterion and said formulation has increased pH stability and solubility when dried.

34. The device of claim 33, wherein said microprojection is adapted to pierce through the stratum corneum to a depth of less than about 500 micrometers.

35. The device of claim 33 wherein the thickness of the coating is equal to or less than the thickness of said microprojection.

36. A composition for coating a transdermal delivery device having stratum corneum-piercing microprojections, comprising a formulation of a biologically active agent, a non-volatile counterion and a formulation adjuvant, wherein said formulation has increased pH stability and solubility when dried.

37. The composition of claim 36, wherein said formulation adjuvant comprises an antioxidant.

38. The composition of claim 36, wherein said formulation adjuvant comprises a surfactant.

39. The composition of claim 36, wherein said formulation adjuvant comprises an amphiphilic polymer.

40. The composition of claim 36, wherein said formulation adjuvant comprises a hydrophilic polymer.

41. The composition of claim 36, wherein said formulation adjuvant comprises a biocompatible carrier.

42. The composition of claim 36, wherein said formulation adjuvant comprises a stabilizing agent.

43. The composition of claim 36, wherein said formulation adjuvant comprises a vasoconstrictor.

44. The composition of claim 36, wherein said formulation adjuvant comprises a pathway patency modulator.

45. The composition of claim 36, wherein said formulation adjuvant comprises a solubilizing/complexing agent.

46. The composition of claim 36, wherein said formulation adjuvant comprises a non-aqueous solvent.

47. The composition of claim 36, wherein said formulation has a viscosity less than about 500 centipoise and greater than about 3 centipoise.

48. A method for applying a coating of a biologically active agent to a transdermal delivery device, wherein said transdermal delivery device comprises a plurality of stratum corneum-piercing microprojections, comprising the steps of:

providing a formulation of said biologically active agent;

stabilizing the pH of said formulation by adding a non-volatile counterion; and

applying said formulation to said microprojections.

49. The method of claim 48, wherein the step of stabilizing the pH of said formulation enhances solubility of said formulation when coated and dried on said transdermal delivery device.

50. The method of claim 48, wherein the step of stabilizing the pH of said formulation comprises adding sufficient non-volatile counterion to neutralize a charge on said biologically active agent.

51. The method of claim 50, wherein excess of counterion (as the free acid or as a salt) is added to the biologically active agent in order to control pH and to provide adequate buffering capacity.

52. The method of claim 48, further comprising the step of determining a net charge of said formulation prior to adding said non-volatile counterion and wherein the step of stabilizing said formulation comprises adding sufficient non-volatile counterion to neutralize said determined charge.

53. The method of claim 52, further comprising the step of adding excess of counterion (as the free acid or as a salt) to the biologically active agent in order to control pH and to provide adequate buffering capacity.

54. The method of claim 52, wherein the step of determining a net charge comprises evaluating ionic species distribution based on the pKa'"'"'s of said biologically active agent.

55. The method of claim 54, wherein the step of determining a net charge includes using a recursive algorithm.