Claims for Patent: 8,337,817

Summary for Patent: 8,337,817

Title:	Preparation for transnasal application
Abstract:	Disclosed is a preparation for transnasal application, which has improved fluidability. Specifically disclosed is a preparation for transnasal application, which comprises at least a complex comprising: a fluidability-improving component comprising a first crystalline cellulose (A) having specified powder properties, tricalcium phosphate (B) having specified powder properties, and a second crystalline cellulose (C) having specified powder properties or a starch (D) having specified powder properties; and a physiologically active substance.
Inventor(s):	Nagata; Ryoichi (Kagoshima, JP), Haruta; Shunji (Kagoshima, JP)
Assignee:	Shin Nippon Biomedical Laboratories, Ltd. (Kagoshima, JP)
Application Number:	12/521,116
Patent Claims:	1. A powdery nasal preparation comprising: a) a physiologically active substance; and b) a carrier, comprising a first crystalline cellulose, wherein the first crystalline cellulose has an average particle diameter of 30 .mu.m or less and wherein the angle of repose of the powdery preparation is 53.degree. or less. 2. The carrier formulation of claim 1, wherein the angle of repose of the carrier is 40.degree. to 53.degree.. 3. The nasal preparation of claim 1, wherein the carrier further comprises a second crystalline cellulose or a starch. 4. The nasal preparation of claim 3, wherein the second crystalline cellulose or starch has an average particle diameter of 30 to 100 .mu.m. 5. The nasal preparation of claim 3, wherein the second crystalline cellulose or starch is present from 5.0 to 30 (W/W) % of the carrier composition. 6. The nasal preparation of claim 1, wherein the carrier further comprises tribasic calcium phosphate. 7. The nasal preparation of claim 6, wherein the tribasic calcium phosphate has an average particle diameter of 100 .mu.m or less. 8. The nasal preparation of claim 6, wherein the tribasic calcium phosphate is present from 0.5 to 5 (W/W) % of the carrier composition. 9. The nasal preparation of claim 1, wherein the first crystalline cellulose is present from 60 to 94.9 (W/W) % of the carrier composition. 10. The nasal preparation of claim 1, wherein the physiologically active substance is present at a weight ratio of 0.0001 to 1.2 to the total weight of the carrier in its free form without being converted to the salt form, when the total weight of the carrier is taken as 1. 11. The nasal preparation of claim 1, wherein the physiologically active substance is a peptide/protein drug. 12. The nasal preparation of claim 11, wherein the peptide/protein drug is selected from the group consisting of insulin, growth hormone, growth hormone releasing peptide, ghrelin, glucagon, calcitonin, interferon, erythropoietin, interleukin, PTH(1-84), PTH(1-34), PTH-related peptide, GLP-1, vasopressin, leuprorelin, granulocyte-colony stimulating factor, prolactin, human menopausal gonadotropin, chorionic gonadotropin, follicle stimulating hormone, luteinizing hormone, leptin, nerve growth factor (NGF), stem cell growth factor (SCGF), keratinocyte growth factor (KGF), thioredoxin, cyclosporin, and influenza vaccine. 13. The nasal preparation of claim 11, wherein the peptide/protein drug is selected from growth hormone, glucagon, calcitonin, parathyroid hormone(1-84), parathyroid hormone (1-34) and PTH-related peptide. 14. The nasal preparation of claim 1, wherein the physiologically active substance is a non-peptide/non-protein drug. 15. The nasal preparation of claim 14, wherein the non-peptide/non-protein drug is selected from the group consisting of morphine, fentanyl, oxycodone, butorphanol, tramadol, granisetron, ondansetron, tropisetron, palonosetron, indisetron, sumatriptan, zolmitriptan, rizatriptan, naratriptan, ergotamine, triazolam, melatonin, carbamazepine, midazolam, donepezil, tiapride, cefaclor, enoxacin, aciclovir, zidvudine, didanosine, nevirapine, indinavir, dantrolene, digoxin, trihexyphenidyl, biperiden, dextromethorphan, naloxone, betahistine, naphazoline, diltiazem, tranilast, loperamide, diclofenac, beclomethasone, chlorpheniramine, sildenafil, vardenafil, cyanocobalamin, finasteride, epinephrine, 5-fluorouracil (5-FU), low-molecular-weight heparin, tacrolimus, RNA, RNAi, siRNA, antisense DNA, and allergen extract powder. 16. The nasal preparation of claim 14, wherein the non-peptide/non-protein drug is selected from fentanyl, oxycodone, granisetron, ondansetron, sumatriptan and zolmitriptan. 17. The nasal preparation of claim 1, further comprising a pH adjustor, preservative, stabilizer, flavor, absorbefacient, or substance that captures a divalent calcium ion. 18. A powdery carrier formulation for nasal administration wherein the angle of repose of the carrier formulation is 35.degree. to 55.degree., wherein the carrier comprises a first crystalline cellulose having an average particle diameter of 30 .mu.m or less. 19. The carrier formulation of claim 18, wherein the angle of repose of the carrier formulation is 40.degree. to 53.degree.. 20. The carrier formulation of claim 18, wherein the carrier further comprises a second crystalline cellulose or a starch. 21. The carrier formulation of claim 20, wherein the second crystalline cellulose or starch has an average particle diameter of 30 to 100 .mu.m. 22. The carrier formulation of claim 20, wherein the second crystalline cellulose or starch is present from 5.0 to 30 (W/W) % of the total composition. 23. The carrier formulation of claim 18, wherein the carrier further comprises tribasic calcium phosphate. 24. The carrier formulation of claim 23, wherein the tribasic calcium phosphate has an average particle diameter of 100 .mu.m or less. 25. The carrier formulation of claim 23, wherein the tribasic calcium phosphate is present from 0.1 to 10 (W/W) % of the total composition. 26. The carrier formulation of claim 18, wherein the first crystalline cellulose is present from 60 to 94.9 (W/W) % of the total composition. 27. A nasal preparation, which comprises at least a complex of a physiologically active substance and a powder flowability-improving component comprising: (i) crystalline cellulose (A), which is a first crystalline cellulose with an untapped bulk density of 0.13 to 0.29 g/cm.sup.3, a specific surface area of 1.3 m.sup.2/g or more, an average particle diameter of 30 .mu.m or less, and an angle of repose of 55.degree. or more; (ii) tribasic calcium phosphate (B); and (iii) crystalline cellulose (C), which is a second crystalline cellulose with an untapped bulk density of 0.26 to 0.48 g/cm.sup.3, a specific surface area of 1.3 m.sup.2/g or less, an angle of repose of 50.degree. or less, and an average particle diameter of 150 .mu.m or less, or starch (D) with an untapped bulk density of 0.35 to 0.65 g/cm.sup.3, a specific surface area of 1.3 m.sup.2/g or less, an angle of repose of 55.degree. or less, and an average particle diameter of 150 .mu.m or less; wherein the flowability-improving component comprises 0.1 to 10 (W/W) % tribasic calcium phosphate (B), 5.0 to 30 (W/W) % second crystalline cellulose (C) and/or starch (D), and the remainder is the first crystalline cellulose (A); and the nasal preparation comprises the physiologically active substance at a weight ratio of 0.0001 to 1.2 to the total weight of the powder flowability-improving component in its free form without being converted to the salt form, when the total weight of the flowability-improving component is taken as 1. 28. The nasal preparation of claim 27, wherein the angle of repose of the nasal preparation is 53.degree. or less. 29. The nasal preparation of claim 27, wherein the physiologically active substance is a peptide/protein drug. 30. The nasal preparation of claim 29, wherein the peptide/protein drug is selected from the group consisting of insulin, growth hormone, growth hormone releasing peptide, ghrelin, glucagon, calcitonin, interferon, erythropoietin, interleukin, PTH(1-84), PTH(1-34), PTH-related peptide, GLP-1, vasopressin, leuprorelin, granulocyte-colony stimulating factor, prolactin, human menopausal gonadotropin, chorionic gonadotropin, follicle stimulating hormone, luteinizing hormone, leptin, nerve growth factor (NGF), stem cell growth factor (SCGF), keratinocyte growth factor (KGF), thioredoxin, cyclosporin, and influenza vaccine. 31. The nasal preparation of claim 29, wherein the peptide/protein drug is selected from growth hormone, glucagon, calcitonin, parathyroid hormone(1-84), parathyroid hormone (1-34) and PTH-related peptides. 32. The nasal preparation of claim 27, wherein the physiologically active substance is a non-peptide/non-protein drug. 33. The nasal preparation of claim 32, wherein the non-peptide/non-protein drug is selected from the group consisting of morphine, fentanyl, oxycodone, butorphanol, tramadol, granisetron, ondansetron, tropisetron, palonosetron, indisetron, sumatriptan, zolmitriptan, rizatriptan, naratriptan, ergotamine, triazolam, melatonin, carbamazepine, etizolam, midazolam, donepezil, tiapride, cefaclor, enoxacin, aciclovir, zidvudine, didanosine, nevirapine, indinavir, dantrolene, digoxin, trihexyphenidyl, biperiden, dextromethorphan, naloxone, betahistine, naphazoline, diltiazem, tranilast, loperamide, diclofenac, beclomethasone, chlorpheniramine, sildenafil, vardenafil, cyanocobalamin, finasteride, epinephrine, 5-FU, low-molecular-weight heparin, tacrolimus, RNA, RNAi, siRNA, antisense DNA, allergen extract powder, therapeutic agents for Parkinson's disease, and non-steroidal anti-inflammatory drugs (NSAIDs). 34. The nasal preparation of claim 32, wherein the non-peptide/non-protein drug is selected from fentanyl, oxycodone, granisetron, ondansetron, sumatriptan and zolmitriptan.

Details for Patent 8,337,817

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	01/15/1974		2026-12-26
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	12/27/1984		2026-12-26
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	02/15/1985		2026-12-26
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	02/16/1990		2026-12-26
Bel-mar Laboratories, Inc.	CHORIONIC GONADOTROPIN	chorionic gonadotropin	Injection	017054	03/26/1974		2026-12-26
Ferring Pharmaceuticals Inc.	A.P.L.	chorionic gonadotropin	For Injection	017055	12/13/1974		2026-12-26