Claims for Patent: 8,779,004

Summary for Patent: 8,779,004

Title:	Stable emulsion formulations
Abstract:	The present invention relates to injectable formulations of irritant agents, such as calcimimetics, that are pharmaceutically stable and demonstrate a reduced incidence of irritation, pain, phlebitis, precipitation and hemolysis upon injection.
Inventor(s):	Gore; Anuradha (Newbury Park, CA), Navratil; Anne (Newbury Park, CA), Neervannan; Seshadri (Irvine, CA), Spancake; Christopher W. (Cary, NC), Zanon; Roger (Carmarillo, CA)
Assignee:	Amgen, Inc. (Thousand Oaks, CA)
Application Number:	11/738,444
Patent Claims:	1. A pharmaceutical formulation comprising: an oil phase from 1 to 30% by weight containing cinacalcet freebase from 0.001 to 5% by weight; a phospholipid emulsifier from 0.1 to 5% by weight; and an aqueous phase containing a charge stabilizer, wherein the formulation is stable and has a protective effect against irritation caused by the cinacalcet freebase. 2. The formulation of claim 1, wherein the phospholipid emulsifier is an egg lecithin, egg yolk phospholipids, soy lecithin or soybean phospholipids. 3. The formulation of claim 1, wherein the charge stabilizer is TRIS buffer in a concentration from 5 to 20 mM. 4. The formulation of claim 1, wherein the charge stabilizer is diethanolamine buffer from 0.05 to 0.3% by weight. 5. The formulation of claim 1, wherein the cinacalcet freebase is present in an amount from 0.001-110 mg/mL. 6. The formulation of claim 1, further comprising glycerol. 7. The formulation of claim 1, wherein pH of the formulation is from 7 to 9.5. 8. The formulation of claim 1, wherein pH of the formulation is from 8.0 to 9.5. 9. The formulation of claim 1 further comprising at least one preservative, antioxidant, buffering agent, acidifying agent, alkalizing agent, antibacterial agent, antifungal agent, solubility enhancing agent, complexation enhancing agent, organic solvent, electrolyte, salt, stabilizer, tonicity modifier, antifoaming agent, or a combination thereof. 10. The formulation of claim 9, wherein the stabilizer is oleic acid, linoleic acid, stearic acid, palmitic acid, decanoic acid, lauric acid, myristic acid, icosanoic acid, behenic acid, myristoleic acid, palmitoleic acid, alpha linolenic acid, arachidonic acid, eicosapentanoic acid, and salts thereof. 11. The formulation of claim 1, wherein the formulation is stable at temperatures from about 5.degree. C. to about 40.degree. C. 12. The formulation of claim 1, wherein the formulation is stable during and after autoclaving. 13. The formulation of claim 1 further comprising one or more local anesthetic agents. 14. The formulation of claim 13, wherein the local anesthetic agent is benzocaine or procaine. 15. A pharmaceutical formulation comprising an oil-in-water emulsion, said emulsion comprises an oil phase from 1 to 30% by weight of said emulsion containing: from 0.001 to 5% by weight of cinacalcet freebase that typically causes irritation at the point of administration compound; from 0.1 to 5% by weight of a phospholipid emulsifier; and an aqueous phase containing a charge stabilizer, wherein said emulsion contains droplets that have an overall negative surface charge. 16. The pharmaceutical formulation of claim 15, wherein said phospholipid emulsifier is an egg lecithin, egg yolk phospholipids, soy lecithin or soybean phospholipids. 17. The pharmaceutical formulation of claim 15, wherein said phospholipids emulsifier comprises a phospholipids agent selected from the group consisting of 1,2-Dilauroyl-sn-glycerol (DLG), 1,2-Dimyristoyl-sn-glycerol (DMG), 1,2-Dipalmitoyl-sn-glycerol (DPG), 1,2-Distearoyl-sn-glycerol (DSG); phosphatidic acids such as 1,2-Dimyristoyl-sn-glycero-3-phosphatidic acid, sodium salt (DMPA,Na), 1,2-Dipalmitoyl-sn-glycero-3-phosphatidic acid, sodium salt (DPPA,Na), 1,2-Distearoyl-sn-glycero-3-phosphatidic acid, sodium salt-(DSPA,Na); phosphatidylcholines such as 1,2-Dilauroyl-sn-glycero-3-phosphocholine (DLPC), 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC); phosphatidylethanolamines such as 1,2-Dilauroyl-sn-glycero-3-phosphoethanolamine (DLPE), 1,2-Dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), 1,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine (DSPE); phosphatidylclyerols such as 1,2-Dilauroyl-sn-glycero-3-phosphoglycerol, sodium salt (DLPG), 1,2-Dimyristoyl-sn-glycero-3-phosphoglycerol, sodium salt (DMPG), 1,2-Dimyristoyl-sn-glycero-3-phospho-sn-1-glycerol, ammonium salt (DMP-sn-1-G,NH4), 1,2-Dipalmitoyl-sn-glycero-3-phosphoglycerol, sodium salt (DPPG,Na), 1,2-Distearoyl-sn-glycero-3-phosphoglycerol, sodium salt (DSPG,Na), 1,2-Distearoyl-sn-glycero-3-phospho-sn-1-glycerol, sodium salt (DSP-sn-1G,Na), phosphatidylserines such as 1,2-Dipalmitoyl-sn-glycero-3-phospho-L-serine, sodium salt (DPPS,Na), 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol, sodium salt (POPG,Na), 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol, ammonium salt (POPG,NH4), 1-Palmitoyl-2-lyso-sn-glycero-3-phosphocholine (P-lyso-PC) and 1-Stearoyl-2-lyso-sn-glycero-3-phosphocholine (S-lyso-PC) and combinations thereof. 18. The pharmaceutical formulation of claim 15, wherein the charge stabilizer is a buffer, an acid or a salt thereof. 19. The pharmaceutical formulation of claim 18, wherein the buffer is selected from the group consisting of diethanolamine, glycine, citrate, acetate, histidine, phosphate, carbonate, meglumine, N-methyl glucamine and tris(hydroxymethyl) aminomethane (TRIS) buffers. 20. The pharmaceutical formulation of claim 18, wherein the acid or the salt thereof is selected from the group consisting of hydrochloric acid, tartaric acid, benzoic acid, citric acid, decanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, icosanoic acid, behenic acid, myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, alpha linolenic acid, arachidonic acid, eicosapentanoic acid, and salts thereof. 21. The pharmaceutical composition of claim 15, wherein the oil phase comprises a vegetable oil or a hydrogenated vegetable oil. 22. The pharmaceutical composition of claim 21, wherein the vegetable or the hydrogenated vegetable oil is selected from the group consisting of peanut oil, corn oil, castor oil, cottonseed oil, soybean oil, olive oil, safflower oil, peppermint oil, coconut oil and palm seed oil. 23. The pharmaceutical formulation of claim 15, wherein the oil phase is selected from the group consisting of beeswax, vitamin E, oleic acid, medium chain monoglycerides, diglycerides, triglycerides, structured triglycerides, and mixtures thereof. 24. The pharmaceutical formulation of claim 15, wherein the formulation is stable at temperatures from about 5.degree. C. to about 40.degree. C. 25. The pharmaceutical formulation of claim 15, wherein the formulation is stable after autoclaving. 26. A method of administering the formulation of claim 1 to a subject in need thereof wherein the administration is intravenous. 27. The method of claim 26, wherein the formulation is administered via infusion. 28. The method of claim 26, wherein the formulation is administered by bolus injection. 29. A method of preparing the formulation of claim 1 comprising the following steps: mixing the aqueous phase and the charge stabilizer; dissolving the cinacalcet freebase in the oil phase at an elevated temperature; mixing the oil phase from step (b) and the aqueous phase from step (a) and said emulsifier; homogenizing the formulation; and optionally adjusting pH. 30. A method of treating a subject in need of a calcimimetic comprising administering a therapeutically effective amount of a formulation of claim 1. 31. The method of claim 30, wherein said subject is suffering from hyperparathyroidism. 32. The method of claim 31 wherein said therapeutically effective amount decreases the levels of parathyroid hormone (PTH) in said subject. 33. The method of claim 30, wherein said subject is suffering from chronic kidney disease associated with elevated PTH levels and said therapeutically effective amount decreases the symptoms of kidney disease in said subject. 34. The method of claim 33, wherein said subject is suffering from hyperparathyroidism. 35. The method of claim 34, wherein said hyperparathyroidism is primary hyperparathyroidism. 36. The method of claim 34, wherein said hyperparathyroidism is secondary hyperparathyroidism. 37. The method of claim 30, wherein said subject is suffering from hypercalcemia. 38. The method of claim 30, wherein said therapeutically effective amount decreases the serum calcium levels of said subject as compared to the serum calcium levels of said subject in the absence of administration of said formulation. 39. The method of claim 30, wherein said therapeutically effective amount decreases the serum phosphorus levels of said subject as compared to the serum phosphorus levels of said subject in the absence of administration of said formulation. 40. The method of claim 30, wherein said subject is suffering from parathyroid carcinoma. 41. The method of claim 30, wherein said formulation is administered at a dose of about 20 mg per day to about 200 mg/day. 42. The method of claim 30, wherein said formulation is administered in combination with a composition comprising vitamin D or a vitamin D analog. 43. The method of claim 30, wherein said formulation is administered in combination with another calcimimetic. 44. The method of claim 30, wherein said formulation is administered in combination with a composition comprising an inhibitor of cytochrome P450 2D6. 45. The method of claim 30, wherein said subject is suffering from vascular calcification and said therapeutically effective amount decreases the formation, growth or deposition of extracellular matrix hydroxyapatite crystal deposits in the blood vessels of said subject. 46. The method of claim 45, wherein said subject is suffering from coronary, valvular, aortic, or other blood vessel calcification.

Details for Patent 8,779,004

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2026-04-20
Aimmune Therapeutics, Inc.	PALFORZIA	peanut (arachis hypogaea) allergen powder	Powder	125696	01/31/2020		2026-04-20