Claims for Patent: 7,659,311

Summary for Patent: 7,659,311

Title:	Disodium salts, monohydrates, and ethanol solvates for delivering active agents
Abstract:	The inventors have discovered that the disodium salt of certain delivery agents has surprisingly greater efficacy for delivering active agents than the corresponding monosodium salt. Furthermore, the inventors have discovered that the disodium salts of these delivery agents form solvates with ethanol and hydrates with water. The delivery agents have the formula ##STR00001## wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently hydrogen, halogen, C.sub.1-C.sub.4 alkyl, or C.sub.1-C.sub.4 alkoxy; and R.sup.5 is a substituted or unsubstituted C.sub.2-C.sub.16 alkylene, substituted or unsubstituted C.sub.2-C.sub.16 alkenylene, substituted or unsubstituted C.sub.1-C.sub.12 alkyl(arylene), or substituted or unsubstituted aryl(C.sub.1-C.sub.12 alkylene). The hydrates and solvates of present invention also have surprisingly greater efficacy for delivering active agents, such as heparin and calcitonin, than their corresponding monosodium salts and free acids. The present invention provides an alcohol solvate, such as ethanol solvate, of a disodium salt of a delivery agent of the formula above. The invention also provides a hydrate of a disodium salt of a delivery agent of the formula above. Preferred delivery agents include, but are not limited to, N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC), N-(10-[2-hydroxybenzoyl]amino)decanoic acid (SNAD), and sodium N-(8-[2-hydroxybenzoyl]amino)caprylate (SNAC). The invention also provides methods of preparing the disodium salt, ethanol solvate, and hydrate and compositions containing the disodium salt, ethanol solvate, and/or hydrate.
Inventor(s):	Bay; William Elliott (Ridgefield, CT), Agarwal; Rajesh K. (San Diego, CA), Chaudhary; Kiran (West Nyack, NY), Majuru; Shingai (Brewster, NY), Goldberg; Michael M. (Englewood, NJ), Corvino; JoAnne P. (Harrison, NY), Azria; Moise (Basel, CH), Ault; Joseph (Blairstown, NJ), Bateman; Simon D. (Randolph, NJ), Patel; Subash (Somerville, NJ), Sikora; Joseph (Succasunna, NJ), Yang; Rebecca F. (Randolph, NJ), Zielinski; Joseph L. (Florham Park, NJ)
Assignee:	Novartis AG (Basel, CH)
Application Number:	12/111,750
Patent Claims:	1. An ethanol solvate of the disodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid. 2. A monohydrate of the disodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid. 3. A solid pharmaceutical composition comprising (a) from about 50% to about 100% by weight of the disodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid, based upon 100% total weight of N-(5-chlorosalicyloyl)-8-aminocaprylic acid and salts thereof in the pharmaceutical composition, and a biologically active agent. 4. The solid pharmaceutical composition of claim 3, wherein the composition comprises from about 90% to about 100% by weight of the disodium salt, based upon 100% total weight of N-(5-chlorosalicyloyl)-8-aminocaprylic acid and salts thereof in the pharmaceutical composition. 5. The solid pharmaceutical composition of claim 3, wherein the composition comprises from about 90% to about 100% by weight of the disodium salt in its monohydrate form, based upon 100% total weight of N-(5-chlorosalicyloyl)-8-aminocaprylic acid in the composition. 6. The solid pharmaceutical composition of claim 3, wherein the biologically active agent is selected from the group consisting of growth hormones; human growth hormones; recombinant human growth hormones; bovine growth hormones; porcine growth hormones; growth hormone-releasing hormones; interferons; .alpha.-interferon; .beta.-interferon; .gamma.-interferon; interleukin-1; interleukin-2; insulin; porcine insulin; bovine insulin; human insulin; human recombinant insulin; insulin-like growth factor; IGF-1; heparin; unfractionated heparin; heparinoids; dermatans; chondroitins; low molecular weight heparin; very low molecular weight heparin; ultra low molecular weight heparin; calcitonin; salmon calcitonin; eel calcitonin; human calcitonin; porcine calcitonin; erythropoietin; atrial naturetic factor; antigens; monoclonal antibodies; somatostatin; protease inhibitors; adrenocorticotropin; gonadotropin releasing hormone; oxytocin; leutinizing-hormone-releasing-hormone; follicle stimulating hormone; glucocerebrosidase; thrombopoietin; filgrastim; prostaglandins; cyclosporin; vasopressin; cromolyn sodium; sodium chromoglycate; disodium chromoglycate; vancomycin; desferrioxamine; parathyroid hormone; fragments of parathyroid hormone; antimicrobials; anti-fungal agents; vitamins; and any combination thereof. 7. The solid pharmaceutical composition of claim 3, wherein the biologically active agent is selected from the group consisting of heparin and calcitonin. 8. A dosage unit form comprising: (a) the solid pharmaceutical composition of claim 3; and (b) (i) an excipient, (ii) a diluent, (iii) a disintegrant, (iv) a lubricant, (v) a plasticizer, (vi) a colorant, (vii) a dosing vehicle, or (viii) any combination thereof. 9. A solid dosage unit form comprising a lyophilized mixture comprising (a) a disodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid; and (b) at least one biologically active agent. 10. A method for preparing a composition comprising mixing: (a) at least one member selected from the group consisting of a disodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid, ethanol solvates thereof, and monohydrates thereof; (b) at least one biologically active agent; and (c) optionally, a dosing vehicle. 11. A method for preparing an anhydrous disodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid comprising drying the ethanol solvate of the disodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid. 12. A method of preparing an ethanol solvate of the disodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid comprising: (a) dissolving N-(5-chlorosalicyloyl)-8-aminocaprylic acid in ethanol to form a solution; and (b) reacting the solution with a molar excess of a sodium containing salt to form the ethanol solvate. 13. The method of claim 12, further comprising the step of recovering the ethanol solvate from the solution containing the ethanol solvate formed in step (b). 14. A method of preparing a monohydrate of a disodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid, the method comprising (a) obtaining an ethanol solvate of the disodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid; (b) drying the solvate to form an anhydrous disodium salt; and (c) hydrating the anhydrous disodium salt to form the hydrate. 15. A pharmaceutical composition comprising calcitonin and from about 90% to about 100% by weight of the disodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid, based upon 100% total weight of N-(5-chlorosalicyloyl)-8-aminocaprylic acid and salts thereof in the composition. 16. A pharmaceutical composition comprising salmon calcitonin and from about 96% to about 100% by weight of the disodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid, based upon 100% total weight of N-(5-chlorosalicyloyl)-8-aminocaprylic acid and salts thereof in the composition.

Details for Patent 7,659,311

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Amgen, Inc.	NEUPOGEN	filgrastim	Injection	103353	02/20/1991		2019-04-05
Amgen, Inc.	NEUPOGEN	filgrastim	Injection	103353	06/28/2000		2019-04-05
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2019-04-05