Apparatus for transdermal delivery of parathyroid hormone agents

• US 8,361,022 B2
• Filed: 07/01/2009
• Issued: 01/29/2013
• Est. Priority Date: 05/13/2004
• 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, Daddona, Peter E., Kamberl, Marika
• Primary Examiner(s): Skowronek, Karlheinz R
• Assistant Examiner(s): GUDIBANDE, SATYANARAYAN R
• Application Number:
  US12/459,499
• Publication Number:
  US 20100152649A1
• Time in Patent Office: 1,308 Days
• Field of Search: None
• US Class Current: 604/123
• CPC Class Codes: A61K 38/29 Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 9/0021 Intradermal administration, e.g. through microneedle arrays, needleless injectors mechanical aspects A61M
• CPC Class Codes: A61M 2037/0023 Drug applicators using microneedles
• CPC Class Codes: A61M 2037/0046 Solid microneedles
• CPC Class Codes: A61M 2037/0061 Methods for using microneedles
• CPC Class Codes: A61M 37/0015 by using microneedles
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 5/18 of the parathyroid hormones

Abstract

An apparatus and method for transdermally delivering a biologically active agent comprising a delivery system having a microprojection member (or system) that includes a plurality of microprojections (or array thereof) that are adapted to pierce through the stratum corneum into the underlying epidermis layer, or epidermis and dermis layers. In one embodiment, the PTH-based agent is contained in a biocompatible coating that is applied to the microprojection member.

Claims

1. A device for transdermally delivering a PTH-based agent to a patient, comprising:

a microprojection member having a plurality of microprojections that are adapted for pulsatile delivery of a PTH based agent and to pierce the stratum corneum of the patient; and

a biocompatible coating disposed on said microprojection member, said coating being formed from a coating formulation comprising at least one PTH-based agent, wherein said PTH based agent is hPTH(1-34) or salts thereof and is at a dose of 10-1000 μ

g that results in a plasma C_max of at least 50 pg/ml after a single application, wherein said coating formulation includes a biocompatible carrier selected from the group consisting of bioengineered human albumin, polyglutamic acid, polyaspartic acid, polyhistidine, pentosan polysulfate, polyamino acids, sucrose, trehalose, melezitose, raffinose, stachyose and mannitol, and wherein said biocompatible carrier is in the range of 2-70 wt. % of said coating formulation.

2. The device of claim 1, wherein said coating is disposed on at least one of said plurality of microprojections.

3. The device of claim 1, wherein said microprojection member has a microprojection density of at least 10 microprojections/cm².

4. The device of claim 1, wherein said microprojection member has a microprojection density in the range of 200-2000 microprojections/cm².

5. The device of claim 1, wherein said microprojection member is constructed out of a material selected from the group consisting of stainless steel, titanium and nickel titanium alloys.

6. The device of claim 5, wherein said microprojection member is coated with a non-conductive material.

7. The device of claim 6, wherein said non-conductive material is selected from the group consisting of Dichloro-[2.2]-paracyclophane, [2.2]-paracyclophane, poly(di-chloro-para-xylylene), polytetrafluoroethylene, and silicon.

8. The device of claim 1, wherein said microprojection member is constructed out of a non-conductive material.

9. The device of claim 1, wherein said coating formulation comprises an aqueous formulation.

10. The device of claim 1, wherein said coating formulation comprises a non-aqueous formulation.

11. The device of claim 1, wherein said hPTH salt is selected from group consisting of acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, levulinate, chloride, bromide, citrate, succinate, maleate, glycolate, gluconate, glucuronate, 3-hydroxyisobutyrate, tricarballylicate, malonate, adipate, citraconate, glutarate, itaconate, mesaconate, citramalate, dimethylolpropinate, tiglicate, glycerate, methacrylate, isocrotonate, beta-hydroxibutyrate, crotonate, angelate, hydracrylate, ascorbate, aspartate, glutamate, 2-hydroxyisobutyrate, lactate, malate, pyruvate, fumarate, tartarate, nitrate, phosphate, benzene sulfonate, methane sulfonate, sulfate and sulfonate.

12. The device of claim 1, wherein said PTH-based agent comprises in the range of 1-30 wt. % of said coating formulation.

13. The device of claim 1, wherein said PTH-based agent comprises in the range of 10 μ

g-100 μ

g of said biocompatible coating.

14. The device of claim 1, wherein said pH of said coating formulation is in the range of pH 2-6.

15. The device of claim 1, wherein said coating formulation includes at least one low volatility counterion.

16. The device of claim 15, wherein said coating formulation includes a plurality of low volatility counterions.

17. The device of claim 15, wherein said PTH-based agent has a positive charge at said coating formulation pH and said low volatility counterion comprises a first acid having at least one acidic pKa.

18. The device of claim 17, wherein said first acid is selected from the group consisting of maleic acid, malic acid, malonic acid, tartaric acid, adipic acid, citraconic acid, fumaric acid, glutaric acid, itaconic acid, meglutol, mesaconic acid, succinic acid, citramalic acid, tartronic acid, citric acid, tricarballylic acid, ethylenediaminetetraacetic acid, aspartic acid, glutamic acid, carbonic acid, sulfuric acid and phosphoric acid.

19. The device of claim 17, wherein said PTH-based agent has a positive charge at said coating formulation pH and wherein said coating formulation includes at least a second counterion comprising a second acid with one or more pKas.

20. The device of claim 19, wherein said second acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, maleic acid, phosphoric acid, benzene sulfonic acid, methane sulfonic acid, citric acid, succinic acid, glycolic acid, gluconic acid, glucuronic acid, lactic acid, malic acid, pyruvic acid, tartaric acid, tartronic acid, fumaric acid, acetic acid, propionic acid, petanoic acid, carbonic acid, malonic acid, adipic acid, citraconic acid, levulinic acid, glutaric acid, itaconic acid, meglutol, mesaconic acid, citramalic acid, citric acid, aspartic acid, glutamic acid, tricarballylic acid and ethylenediaminetetraacetic acid.

21. The device of claim 15, wherein the amount of said low volatility counterion present in said coating formulation is sufficient to balance the charge of said PTH-based agent.

22. The device of claim 1, wherein said PTH-based agent comprises hPTH (1-34) and wherein said coating formulation comprises at least one viscosity-enhancing counterion.

23. The device of claim 22, wherein said viscosity-enhancing counterion is selected from the group consisting of citric acid, tartaric acid, malic acid, hydrochloric acid, glycolic acid and acetic acid.

24. The device of claim 22, wherein said coating formulation has a viscosity in the range of 20-200 cp.

25. The device of claim 1, wherein said coating formulation includes a viscosity-enhancing counterion comprising an acidic counterion.

26. The device of claim 25, wherein said acidic counterion comprises a low volatility weak acid that exhibits at least one acidic pKa.

27. The device of claim 26, wherein said low volatility weak acid has a melting point higher than 50°

C.

28. The device of claim 26, wherein said low volatility weak acid has a boiling point higher than 170°

C. at P_atm.

29. The device of claim 26, wherein said low volatility 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.

30. The device of claim 25, wherein said acidic counterion comprises a first strong acid that exhibits at least one pKa lower than 2.

31. The device of claim 30, wherein said first 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.

32. The device of claim 25, further comprising a plurality of acidic counterions, wherein at least a first counterion comprises a strong acid and at least a second counterion comprises a low volatility weak acid.

33. The device of claim 25, further comprising a plurality of acidic counterions wherein at least a first counterion comprises a strong acid and at least a second counterion comprises a high volatility weak acid with at least one pKa higher than 2.

34. The device of claim 33, wherein said high volatility weak acid has a melting point lower than 50°

C.

35. The device of claim 33, wherein said high volatility weak acid has a boiling point lower than 170°

C. at P_atm.

36. The device of claim 33, wherein said high volatility weak acid is selected from the group consisting of acetic acid, propionic acid and pentatonic acid.

37. The device of claim 1, wherein said coating formulation includes at least one buffer selected from the group consisting of ascorbic acid, citric acid, succinic acid, glycolic acid, gluconic acid, glucuronic acid, lactic acid, malic acid, pyruvic acid, tartaric acid, tartronic acid, fumaric acid, maleic acid, phosphoric acid, tricarballylic acid, malonic acid, adipic acid, citraconic acid, glutaratic acid, itaconic acid, mesaconic acid, citramalic acid, dimethylopropionic acid, tiglic acid, glyceric acid, methacrylic acid, isocrotonic acid, β

-hydroxybutyric acid, crotonic acid, angelic acid, hydracrylic acid, aspartic acid, glutamic acid, glycine, and mixtures thereof.

38. The device of claim 1, wherein said coating formulation includes at least one antioxidant selected from the group consisting of sequestering agents and free radical scavengers.

39. The device of claim 38, wherein said sequestering agent is selected from the group consisting of sodium citrate, citric acid and ethylene dinitrilo-tetraacetic acid.

40. The device of claim 38, wherein said free radical scavenger is selected from the group consisting of ascorbic acid, methionine and sodium ascorbate.

41. The device of claim 38, wherein the concentration of said antioxidant is in the range of 0.01-20 wt. % of said coating formulation.

42. The device of claim 38, wherein the concentration of said antioxidant is in the range of 0.03-10 wt. % of said coating formulation.

43. The device of claim 1, wherein said coating formulation includes at least one surfactant selected from the group consisting of sodium lauroamphoacetate, sodium dodecyl sulfate (SDS), cetylpyridinium chloride (CPC), dodecyltrimethyl ammonium chloride (TMAC), benzalkonium, chloride, polysorbates, sorbitan derivatives, sorbitan lauratealkoxylated alcohols, polyoxyethylene castor oil derivatives and mixtures thereof.

44. The device of claim 43, wherein the concentration of said surfactant is in the range of −

0.01-20 wt. % of said coating formulation.

45. The device of claim 1, wherein said coating formulation includes at least one polymeric material having amphiphilic properties.

46. The device of claim 45, wherein said polymeric material comprises a cellulose derivative.

47. The device of claim 46, wherein said cellulose derivative is selected from the group consisting of hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC), hydroxypropycellulose (HPC), methylcellulose (MC), hydroxyethyl-methycellulose (NEMC), or ethylhdroxy-ethylcellulose (EHEC), and pluronics.

48. The device of claim 45, wherein the concentration of said polymeric material is in the range of 0.01-20 wt. % of said coating formulation.

49. The device of claim 1, wherein said coating formulation includes a hydrophilic polymer selected from the following group consisting of hydroxyethyl starch, carboxymethyl cellulose and salts of, dextran, poly(vinyl alcohol), poly(ethylene oxide), poly(2-hydroxyethyl-methacrylate), poly(n-vinyl pyrolidone), polyethylene glycol and mixtures thereof.

50. The device of claim 49, wherein the concentration of said hydrophilic polymer is in the range of −

1-30 wt. % of said coating formulation.

51. The device of claim 1, wherein said coating formulation includes a stabilizing agent selected from the group consisting of a non-reducing sugar, a polysaccharide and a reducing sugar.

52. The device of claim 51, wherein said non-reducing sugar is selected from the group consisting of sucrose, trehalose, stachyose and raffinose.

53. The device of claim 51, wherein said polysaccharide is selected from the group consisting of dextran, soluble starch, and dextrin.

54. The device of claim 51, wherein said reducing sugar is selected from group consisting of monosaccharides and disaccharides.

55. The device of claim 54, wherein said monosaccharide is selected from the group consisting of apiose, arabinose, lyxose, ribose, xylose, digitoxose, fucose, quercitol, quinovose, rhamnose, allose, altrose, fructose, galactose, gulose, hamamelose, idose, mannose and tagatose.

56. The device of claim 54, wherein said disaccharide is selected from the group consisting of primeverose, vicianose, rutinose, scillabiose, cellobiose, gentiobiose, lactose, lactulose, maltose, melibiose, sophorose and turanose.

57. The device of claim 51, wherein the concentration of said stabilizing agent in said coating formulation is at a ratio of 0.01-2.0:

1 wt % with respect to said PTH-based agent.

58. The device of claim 1, wherein said coating formulation includes at least one vasoconstrictor selected from the group consisting of amidephrine, cafaminol, cyclopentaimine, deoxyepinephrine, epinephrine, felypressin, indanzoline, metizoline, midodrine, naphazoline, nordefrin, octodrine, ornipressin, oxymethazoline, phenylephrine, phenylethanolamine, phenylpropanolamine, propylhexedrine, pseudoephedrine, tetrahydrozoline, tramazoline, tuaminoheptane, tymazoline, vasopressin, xylometazoline, and mixtures thereof.

59. The device of claim 58, wherein the concentration of said vasoconstrictor is in the range of 0.1-10 wt. % of said coating formulation.

60. The device of claim 1, wherein said coating formulation includes at least one pathway patency modulator selected from the group consisting of osmotic agents, zwitterionic compounds, anti-inflammatory agents and anticoagulants.

61. The device of claim 60, wherein said anti-inflammatory agent is selected from the group consisting of betamethasone 21-phosphate disodium salt, triamcinolone acetonide 21-disodium phosphate, hydrocortamate hydrochloride, hydrocortisone 21-phosphate disodium salt, methylprednisolone 21-phosphate disodium salt, methylprednisolone 21-succinaate sodium salt, paramethasone disodium phosphate and prednisolone 21-succinate sodium salt.

62. The device of claim 60, wherein said anticoagulant is selected from the group consisting of citric acid, citrate salts, dextrin sulfate sodium, aspirin and EDTA.

63. The device of claim 1, wherein said coating formulation includes a solubilising/complexing agent selected from the group consisting of Alpha-Cyclodextrin, Beta-Cyclodextrin, Gamma-Cyclodextrin, glucosyl-alpha-Cyclodextrin, maltosyl-alpha-Cyclodextrin, hydroxyethyl-beta-Cyclodextrin, methyl-beta-Cyclodextrin, sulfobutylether-alpha-Cyclodextrin, sulfobutylether-beta-Cyclodextrin, and sulfobutylether-gamma-Cyclodextrin.

64. The device of claim 63, wherein the concentration of said solubilising/complexing agent is in the range of 1-20 wt. % of said coating formulation.

65. The device of claim 1, wherein said coating formulation has a viscosity in the range of 3-500 centipose.

66. The device of claim 1, wherein the thickness of said biocompatible coating is less than 25 microns.

67. The device of claim 1, wherein said PTH-based agent is recombinant h PTH(1-34) or synthetic hPTH(1-34).

71. The device of claim 1, wherein the coating allows for a pulsatile delivery profile having an increase in baseline blood concentration in the range of 50-10000 pg/ml in a period from 1 minute to 4 hours.

72. The device of claim 71, wherein the coating allows for a decrease in blood serum concentration from C_max to the baseline concentration in a period ranging from 1-8 hours after C_max is achieved.

73. The device of claim 72, wherein the C_max is 0.10-0.72 ng/mL.

68. A device for transdermally delivering a PTH-based agent to a patient, comprising:

a microprojection member having a plurality of microprojections that are adapted for pulsatile delivery of a PTH based agent and to pierce the stratum corneum of the patient; and

a biocompatible coating disposed on said microprojection member, said coating comprising said PTH-based agent, a low volatility counterion, a surfactant, a stabilizing agent, and an antioxidant, wherein said PTH-based agent is recombinant hPTH(1-34) or synthetic hPTH(1-34) or salts thereof.

69. The device of claim 68, wherein said stabilizing agent is a non-reducing sugar.

70. The device of claim 68, wherein said PTH-based agent is hPTH(1-34) acetate and said counterion is an acid.

74. The device of claim 68, wherein the low volatility counterion is an acid.

75. The device of claim 74, wherein the low volatility counterion is selected from the group consisting of:

hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, maleic acid, phosphoric acid, benzene sulfonic acid, methane sulfonic acid, citric acid, succinic acid, glycolic acid, gluconic acid, glucuronic acid, lactic acid, malic acid, pyruvic acid, tartaric acid, tartronic acid, fumaric acid, acetic acid, propionic acid, petanoic acid, carbonic acid, malonic acid, adipic acid, citraconic acid, levulinic acid, glutaric acid, itaconic acid, meglutol, mesaconic acid, citramalic acid, citric acid, aspartic acid, glutamic acid, tricarballylic acid and ethylenediaminetetraacetic acid.

76. The device of claim 74, wherein the low volatility counterion is hydrochloric acid, glycolic acid or tartaric acid.