Stable Therapeutic Formulations

Abstract

Compositions of and methods for formulating and delivering biologically active agent formulations having enhanced physical stability, and wherein deterioration from the presence of oxygen and/or water is minimized and/or controlled, to yield a stable formulation. The compositions of and methods for formulating and delivering biologically active agents of the present invention further facilitate their incorporation into a biocompatible coating which can be employed to coat a stratum-corneum piercing microprojection, or a plurality of stratum-corneum piercing microprojections of a delivery device, for delivery of the biocompatible coating through the skin of a subject, thus providing an effective means of delivering the biologically active agents.

1 - 24 . (canceled) 
     
     
         25 . A method for delivering biologically active agent formulations comprising:
 (i) providing a microprojection member having a plurality of microprojections;   (ii) providing a formulation of biologically active agent;   (iii) forming a biocompatible coating formulation that includes the formulation of biologically active agent;   (iv) coating the microprojection member with the biocompatible coating formulation to form a biocompatible coating;   (v) packaging the biocompatible coating under dry inert atmospheric conditions and/or a partial vacuum in a chamber; and   (vi) applying the coated microprojection member to the skin of a subject;   wherein the formulation of biologically active agent is optionally a stable biologically active agent formulation.   
     
     
         26 . The method of  claim 25 , wherein packaging the biocompatible coating comprises providing a desiccant. 
     
     
         27 . The method of  claim 26 , wherein the desiccant comprises calcium oxide, clay desiccant, calcium sulfate, silica gel, or a mixture thereof. 
     
     
         28 . The method of  claim 25 , wherein the dry inert atmosphere comprises nitrogen, argon, helium, neon, krypton, carbon dioxide, or a mixture thereof. 
     
     
         29 . The method of  claim 25 , wherein the dry inert atmosphere has essentially zero water content. 
     
     
         30 . The method of  claim 25 , further comprising purging the chamber with dry nitrogen to reduce moisture or oxygen content during packaging prior to sealing the chamber. 
     
     
         31 . The method of  claim 25 , wherein the packaging is carried out under partial vacuum. 
     
     
         32 . The method of  claim 31 , wherein partial vacuum is from about 0.01 to about 0.3 atmospheres. 
     
     
         33 . The method of  claim 25 , wherein packaging comprises providing a foil-lined chamber. 
     
     
         34 . The method of  claim 33 , wherein said biocompatible coating is enclosed in said foil-lined chamber. 
     
     
         35 . The method of  claim 34 , wherein the chamber comprises a foil lid, and a desiccant and/or oxygen absorber is attached to the foil lid wherein said chamber is sealed by the foil lid. 
     
     
         36 . The method of  claim 35 , wherein the chamber is purged with dry nitrogen prior to sealing the chamber. 
     
     
         37 . The method of  claim 25 , wherein the biologically active agent comprises hBNP, hPTH or an analog thereof. 
     
     
         38 . The method of  claim 25 , wherein the biologically active agent comprises hBNP(1-32), hPTH(1-34) and analogs thereof. 
     
     
         39 . The method of  claim 25 , wherein said packaging comprises sterilizing said biocompatible coating. 
     
     
         40 . The method of  claim 25 , wherein the biologically active agent is selected from the group consisting of anti-infectives, analgesics, analgesic combinations, anesthetics, anorexics, antiarthritics, antiasthmatic agents, anticonvulsants, antidepressants, antidiabetic agents, antidiarrheals, antihistamines, anti-inflammatory agents, antimigraine preparations, antimotion sickness preparations, antinauseants, antineoplastics, antiparkinsonism drugs, antipruritics, antipsychotics, antipyretics, antispasmodics, anticholinergics, sympathomimetrics, xanthine derivatives, cardiovascular preparations, beta blockers, beta-agonists, antiarrythmics, antihypertensives, ACE inhibitors, diuretics, vasodilators, central nervous system stimulants, cough and cold preparations, decongestants, diagnostics, hormones, hypnotics, immunosuppressants, muscle relaxants, parasympatholytics, parasympathomimetrics, prostaglandins, proteins, peptides, psychostimulants, sedatives, tranquilizers, vasoconstrictors, anti-healing agents, vaccines, antigens and pathway patency modulators. 
     
     
         41 . The method of  claim 25 , wherein the biologically active agent is selected from the group consisting of antibiotics, antiviral agents, fentanyl, sufentanil, remifentanil, buprenorphine, terbutaline, scopolamine, ondansetron, nifedipine, dobutamine, ritodrine, atenolol, ranitidine, parathyroid hormone; 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, follicle luteoids, aANF, growth factors, bMSH, GH, somatostatin, bradykinin, somatotropin, platelet-derived growth factor releasing factor, asparaginase, bleomycin sulfate, chymopapain, cholecystokinin, chorionic gonadotropin, erythropoietin, epoprostenol, 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, oxytocin, streptokinase, tissue plasminogen activator, urokinase, vasopressin, deamino [Val4, D-Arg8] arginine vasopressin, desmopressin, corticotropin (ACTH), ACTH analogs such as ACTH (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), bacteria, protein-based vaccines, polysaccharide-based vaccine, nucleic acid-based vaccines, antigenic agents and TGF-beta. 
     
     
         42 . The method of  claim 40 , wherein the biologically active agent further comprises:
 (a) one or more augmenting adjuvants with the vaccine or antigen; or   (b) one or more counterions to further improve the stability of the formulation.   
     
     
         43 . The method of  claim 25 , wherein the biologically active agent is applied to the microprojections homogeneously and wherein the homogeneous coating provides for greater mechanical stability both during storage and during insertion into the skin. 
     
     
         44 . The method of  claim 25 , wherein the coating microprojection member is maintained in piercing relation with the skin for extended periods of time.