Mucosal Delivery of Stabilized Formulations of Exendin

• US 20080318861A1
• Filed: 12/07/2006
• Published: 12/25/2008
• Est. Priority Date: 12/08/2005
• Status: Abandoned Application

• Current Assignee: Amylin Pharmaceuticals Incorporated (Bristol-Myers Squibb Company)
• Original Assignee: Nastech Pharmaceutical Company Inc. (Adhera Therapeutics, Inc.)
• Inventors: Quay, Steven C., Costantino, Henry R., Leonard, Alexis Kays
• Application Number:
  US12/096,650
• Publication Number:
  US 20080318861A1
• Time in Patent Office: Days
• US Class Current: 514/12
• CPC Class Codes: A61K 38/2278 Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)
• CPC Class Codes: A61K 47/40 Cyclodextrins; Derivatives thereof
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics

Abstract

What is described is a pharmaceutical formulation for intranasal administration of exendin to a mammal, wherein the formulation comprises a therapeutically effective amount of an exendin, a viscosity enhancer, methyl-β-cyclodextrin, a surfactant, tartrate buffer to control pH and a chelating agent for cations, and wherein such exendin dosage form exhibits at least 95% exenatide recovery after storage for at least 365 days at 5° C.

Claims

1-70. -70. (canceled)

71. An aqueous pharmaceutical formulation for intranasal delivery comprising a therapeutically effective amount of exendin-4 or an exendin-4 agonist analog, a permeation-enhancing solubilizing agent, a permeation-enhancing cation chelator, a permeation-enhancing surfactant and optionally a permeation-enhancing viscosity enhancing agent, wherein

a. the solubilizing agent is selected from at least one of the group consisting of hydroxypropyl-β

-cyclodextrin, sulfobutylether-β

-cyclodextrin, dimethyl-β

-cyclodextrin, methyl-β

-cyclodextrin and Cremophor EL,

b. the viscosity enhancer is selected from at least one of the group consisting of gelatin, methylcellulose and hydroxypropylmethylcellulose, and

c. the surfactant is selected from the group consisting of a least one of phosphotidyl choline, dimyristoly glycero phosphatidylcholine, dilauroyl glycero phosphatidylcholine and L-α

-phosphatidylcholine didecanoyl, and wherein

d. the formulation provides at least 5% permeation of exendin-4 in an in vitro tissue permeation assay, has a viscosity up to 150 cps, has a pH from 2 to 8 and is stable at least two weeks at 5°

C.

72. The formulation of claim 71, wherein the solubilizing agent is methyl-β

-cyclodextrin.

73. The formulation of claim 72, wherein methyl-β

-cyclodextrin is present at a concentration of up to 90 mg/ml.

74. The formulation of claim 71, wherein the chelator is selected from at least one of the group consisting of ethylene diamine tetraacetic acid and ethylene glycol tetraacetic acid.

75. The formulation of claim 74, wherein the chelator is present at a concentration of up to 10 mg/ml.

76. The formulation of claim 71, wherein the surfactant is L-α

-phosphatidylcholine didecanoyl.

77. The formulation of claim 76, wherein L-α

-phosphatidylcholine didecanoyl is present at a concentration of up to 2 mg/ml.

78. The formulation of claim 71, wherein the solubilizing agent concentration is 80 mg/ml, the surfactant concentration is 2 mg/ml and the chelator concentration is 5 mg/ml.

79. The formulation of claim 71, wherein the viscosity enhancing agent is gelatin.

80. The formulation of claim 79, wherein gelatin is present at a concentration of up to 10 mg/ml.

81. The formulation of claim 71, further comprising a tartrate buffer.

82. The formulation of claim 71, further comprising a preservative.

83. The formulation of claim 71, wherein the pH is from 4.5 to 5.5.

84. The formulation of claim 71, wherein the viscosity is from 1.5 to 10.0 cps.

85. The formulation of claims 71, wherein the formulation is stable for at least 4 weeks at 5°

C.

86. A method of treating a subject in need or desirous thereof, comprising administering the aqueous pharmaceutical formulation of claim 71 to the subject by intranasal delivery to treat a metabolic disease selected from the group consisting of hyperglycemia, insulin dependent diabetes mellitus, gestational diabetes, non insulin-dependent diabetes mellitus, obesity or dyslipidemia or to treat a condition benefitted by suppressing appetite, increasing satiety, promoting weight loss, decreasing food intake, slowing astric emptying, lowering plasma glucose or promoting insulin secretion.