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Last Updated: March 28, 2024

Claims for Patent: 8,920,817


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Summary for Patent: 8,920,817
Title:Formulations for coated microprojections containing non-volatile counterions
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.
Inventor(s): Ameri; Mahmoud (Fremont, CA), Lin; Wei-Qi (Palo Alto, CA), Cormier; Michel J. N. (Mountain View, CA), Maa; Yuh-Fun (Millbrae, CA)
Assignee: Alza Corporation (Vacaville, CA)
Application Number:12/583,761
Patent Litigation and PTAB cases: See patent lawsuits and PTAB cases for patent 8,920,817
Patent Claims:1. A composition comprising a formulation of a pharmaceutically active agent, a volatile counterion and a non-volatile counterion, wherein said formulation has a pH, said biologically active agent has a positive charge at said formulation pH; wherein said volatile counterion comprises a weak acid having at least one pKa higher than about 2 and a melting point lower than about 50.degree. C. or a boiling point lower than about 170.degree. C.; wherein said non-volatile counterion comprises a strong acid having at least one pKa lower than about 2; wherein said pharmaceutically active peptide agent is present as uncharged species and as charged species and wherein said non-volatile counterion is present in an amount sufficient to achieve a molar ratio between said uncharged species and charged species of about 1 uncharged species to at least 100 charged species; wherein said formulation has increased pH stability and solubility when dried, and wherein said composition is applied to a transdermal delivery device having stratum corneum-piercing microprojections; wherein said composition achieves an increase in delivery of the pharmaceutically active agent compared to a composition comprising a formulation without said non-volatile counterion.

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, HGH, HMG, desmopressin acetate, follicle luteoids, .alpha.ANF, growth factors, 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, goserelin, leuprolide, buserelin, triptorelin, gonadorelin, and napfarelin, menotropins, urofollitropin, follicle stimulating hormone (FSH) and luteinizing hormone (LH), oxytocin, streptokinase, tissue plasminogen activator, urokinase, vasopressin, deamino [Va14, D-Arg8] arginine vasopressin, desmopressin, corticotropin (ACTH), ACTH analogs, ACTH (124), 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, 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 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.

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 neutralizes said positive charge of said biologically active agent.

5. The composition of claim 4, 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.

6. 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.

7. A device for transdermally delivering a biologically active agent, comprising at least one stratum-corneum piercing microprojection coated with of a formulation, wherein said formulation comprises said biologically active agent, a volatile counterion and a non-volatile counterion, wherein said volatile counterion comprises a weak acid having at least one pKa higher than about 2 and a melting point lower than about 50.degree. C. or a boiling point lower than about 170.degree. C.; wherein said non-volatile counterion comprise a strong acid having at least one pKa lower than about 2; wherein said pharmaceutically active agent is present as uncharged species and as charged species and wherein said non-volatile counterion is present in an amount sufficient to achieve a molar ratio between said uncharged species and charged species of about 1 uncharged species to at least 100 charged species; and said formulation has increased pH stability and solubility when dried.

8. The device of claim 7, wherein said microprojection is adapted to pierce through the stratum corneum to a depth of less than about 500 micrometers.

9. The device of claim 7 wherein the thickness of the coating is equal to or less than the thickness of said microprojection.

10. A composition for coating a transdermal delivery device having stratum corneum-piercing microprojections, comprising a formulation of a biologically active agent, a volatile counterion, a non-volatile counterion and a formulation adjuvant, wherein said volatile counterion comprises a weak acid having at least one pKa higher than about 2 and a melting point lower than about 50.degree. C. or a boiling point lower than about 170.degree. C.; wherein said non-volatile counterion comprises a strong acid having at least one pKa lower than about 2; wherein said pharmaceutically active agent is present as uncharged species and as charged species and wherein said non-volatile counterion is present in an amount sufficient to achieve a molar ratio between said uncharged species and charged species of about 1 uncharged species to at least 100 charged species; wherein said formulation has increased pH stability and solubility when dried.

11. The composition of claim 10, wherein said formulation adjuvant comprises an antioxidant.

12. The composition of claim 10, wherein said formulation adjuvant comprises a surfactant.

13. The composition of claim 10, wherein said formulation adjuvant comprises an amphiphilic polymer.

14. The composition of claim 10, wherein said formulation adjuvant comprises a hydrophilic polymer.

15. The composition of claim 10, wherein said formulation adjuvant comprises a biocompatible carrier.

16. The composition of claim 10, wherein said formulation adjuvant comprises a stabilizing agent.

17. The composition of claim 10, wherein said formulation adjuvant comprises a vasoconstrictor.

18. The composition of claim 10, wherein said formulation adjuvant comprises a pathway patency modulator.

19. The composition of claim 10, wherein said formulation adjuvant comprises a solubilizing/complexing agent.

20. The composition of claim 10, wherein said formulation adjuvant comprises a non-aqueous solvent.

21. The composition of claim 10, wherein said formulation has a viscosity less than about 500 centipoise and greater than about 3 centipoise.

22. The composition of claim 1, wherein said pharmaceutically active agent is selected from the group consisting of growth hormones, insulin, insultropin, calcitonin, octreotide, endorphin, thyroliberin, N-(((s)-4-oxo-2-azetidinyl)carbonyl)-L-histidyl-L, prolinamide, liprecin, pituitary hormones, follicle luteoids, alpha natriuretic factor, beta-melancoyte-stimulating hormone, somatostatin, bradykinin, somatotropin, asparaginase, bleomyin sulfate, chymopapain, cholecysotokinin, chorionic gonadotropin, erythropoietin, epoprostenol, glucagon, hirulog, hyaluronidase, interferon alpha, interferon beta, interferon gamma, interleukins, granulocyte macrophage colon stimulating factor, granulocyte colony stimulating factor, -leutinizing hormone releasing hormone (LHRH), LHRH analogs, menotropins, oxytocin, steptokinase, tissue plasminogen activator, urokinase, vasopressin, deamina [Va14, D-Arg8] arginine vasopressin, desmopressin, adrenocorticotropic hormone (ACTH), ACTH analogs, atrial natriuretic peptide (ANP), ANP clearance inhibitors, angiotensin II antagonists, antidiuretic hormone agonists, bradykinn antagonists, ceredase, corticostatin analogs, calcitonin gene related peptide, enkephalins, FAB fragments, IgE peptide suppressors, insulin-like growth factor-1, neurotrophic factors, colony stimulating factors, parathyroid hormone, parathyroid hormone agonists, parathyroid hormone antagonists, parathyroid hormone analogs, prostaglandin antagonists, pentigetide protein C, protein S, rennin inhibitors, thymosin alpha-1 thrombolytics, tumor necrosis factor, vasopressin antagonists analogs, alpha-1 antitrypsin, and transforming growth factor-beta.

Details for Patent 8,920,817

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Ferring Pharmaceuticals Inc. NOVAREL chorionic gonadotropin For Injection 017016 01/15/1974 ⤷  Try a Trial 2023-06-30
Ferring Pharmaceuticals Inc. NOVAREL chorionic gonadotropin For Injection 017016 12/27/1984 ⤷  Try a Trial 2023-06-30
Ferring Pharmaceuticals Inc. NOVAREL chorionic gonadotropin For Injection 017016 02/15/1985 ⤷  Try a Trial 2023-06-30
Ferring Pharmaceuticals Inc. NOVAREL chorionic gonadotropin For Injection 017016 02/16/1990 ⤷  Try a Trial 2023-06-30
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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