Source: https://patents.google.com/patent/US8026276B2/en
Timestamp: 2018-08-15 04:27:33
Document Index: 417351438

Matched Legal Cases: ['Application No. 1490', 'Application No. 1490', 'Application No. 1490', 'Application No. 05', 'Application No. 2005105301', 'Application No. 05', 'Application No. 2005105301', 'Application No. 1', 'Application No. 2003254168', 'Application No. 03771828', 'Application No. 03771828', 'Application No. 03771828', 'Application No. 03771828', 'Application No. 03771828', 'Application No. 03771828']

US8026276B2 - Parenteral CCI-779 formulations containing cosolvents, an antioxidant, and a surfactant - Google Patents
Parenteral CCI-779 formulations containing cosolvents, an antioxidant, and a surfactant Download PDF
US8026276B2
US8026276B2 US10626943 US62694303A US8026276B2 US 8026276 B2 US8026276 B2 US 8026276B2 US 10626943 US10626943 US 10626943 US 62694303 A US62694303 A US 62694303A US 8026276 B2 US8026276 B2 US 8026276B2
US10626943
US20040167152A1 (en )
Parenteral formulations of rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl) -2-methylpropionic acid (CCI-779) are provided. One parenteral formulation contains CCI-779, an alcoholic co-solvent, and an antioxidant. Another parenteral formulation contains CCI-779, an alcoholic solvent, an antioxidant, a diluent solvent, and a surfactant. Processes for preparing parenteral CCI-779 formulations using a co-solvent concentrate are also provided.
This is a non-provisional of U.S. patent application Ser. No. 60/399,526, filed Jul. 30, 2002 and claims the benefit of the priority thereof.
Any given formulation of this invention may contain multiple ingredients of each class of component. For example, a parenterally acceptable solvent can include a non-alcoholic solvent, an alcoholic solvent, or mixtures thereof. Examples of suitable non-alcoholic solvents include, e.g., dimethylacetamide, dimethylsulfoxide or acetonitrile, or mixtures thereof. “An alcoholic solvent,” may contain one or more alcohols as the alcoholic solvent component of the formulation. Examples of solvents useful in the formulations invention include, without limitation, ethanol, propylene glycol, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000, or mixtures thereof. These cosolvents are particularly desirable because degradation via oxidation and lactone cleavage occurs to a lower extent for these cosolvents. Further, ethanol and propylene glycol can be combined to produce a less flammable product, but larger amounts of ethanol in the mixture generally result in better chemical stability. A concentration of 30 to 100% v/v of ethanol in the mixture is preferred.
In some embodiments, components with chelating activity are included in the formulations of the invention as the sole “antioxidant component”. Typically, such metal-binding components, when acting as chelating agents are used in the lower end of the range of concentrations for the antioxidant component provided herein. In one example, citric acid enhanced the stability of CCI-779 when used at a concentration of less than 0.01% w/v. Higher concentrations are less stable solutions and thus, less desirable for products to be subject to long-term storage in liquid form. Additionally, such chelating agents may be used in combination with other antioxidants as part of the antioxidant component of the invention. For example, an acceptable formulation may contain both citric acid and d,l-α-tocopherol. Optimal concentrations for the selected antioxidant(s) can be readily determined by one of skill in the art, based upon the information provided herein.
Advantageously, in the formulations of the invention, precipitation of CCI-779 upon dilution with aqueous infusion solutions or blood is prevented through the use of a surfactant contained in the diluent solution. The most important component of the diluent is a parenterally acceptable surfactant. One particularly desirable surfactant is polysorbate 20 or polysorbate 80. However, one of skill in the art may readily select other suitable surfactants from among salts of bile acids (taurocholate, glycocholate, cholate, deoxycholate, etc.) which are optionally combined with lecithin. Alternatively, ethoxylated vegetable oils, such as a pegylated castor oil [e.g., such as PEG-35 castor oil which is sold, e.g., under the name CREMOPHOR® EL polyethyleneglycerol triricinoleat 35 (polyethoxy 35 castor oil), BASF], vitamin E tocopherol propylene glycol succinate (Vitamin E TGPS), and polyoxyethylene-polyoxypropylene block copolymers can be used in the diluent as a surfactant, as well as other members of the polysorbate family such as polysorbate 20 or 60 Other components of the diluent may include water, ethanol, polyethylene glycol 300, polyethylene 400, polyethylene 600, polyethylene 1000, or blends containing one or more of these polyethylene glycols, propylene glycol and other parenterally acceptable cosolvents or agents to adjust solution osmolarity such as sodium chloride, lactose, mannitol or other parenterally acceptable sugars, polyols and electrolytes. It is expected that the surfactant will comprise 2 to 100% w/v of the diluent solution, 5 to 80% w/v, 10 to 75% w/v, 15 to 60% w/v, and preferably, at least 5% w/v, or at least 10% w/v, of the diluent solution.
CCI-779 25 mg
Citric acid, anhydrous 0.005% w/v
Dehydrated ethanol, USP q.s. 1.0 ml
The above formulation was packaged in a glass ampoule with a nitrogen/air headspace and had a shelf-life of 18 -30 months when stored at 2-8° C.
dehydrated ethanol, USP 0.395 g
citric acid, anhydrous, USP 0.025 mg [0.0025% w/v]
d,l-α-tocopherol, USP 0.75 mg [0.075% w/v]
The above formulation was packaged in a vial with a nitrogen/air headspace. It has demonstrated good stability after 24 months storage at 2-8° C. and room temperature. No significant degradation had been observed after 24 months at 5° C. Both formulations presented in Examples 1 and 2 can be sterilized by aseptic filtration.
Citric acid, anhydrous 0.025 mg
D,L-α-tocopherol, USP 0.75 mg
N,N-dimethylacetamide q.s 1.0 mL
Exposure to short-term temperature stress indicated that the above formula was stable(greater than 97% potency was retained after exposure to stress temperature conditions (e.g. 70° C.) for at least 24 hours).
Polysorbate 80, NF 5% w/v
Polyethylene glycol 400 NF 5% w/v
Water for injection, USP q.s. 100%
CREMOPHOR ® EL polyethoxy 35 castor oil 10 w/v %
Water for Injection q.s. 100 w/v %
Vitamin E TPGS NF 10 w/v %
Water for Injection, USP q.s 100 w/v %
Polysorbate 20 10% w/v
Water for Injection, USP q.s. 100% w/v
Polysorbate 80, NF 40% w/v
Dehydrated ethanol, USP 19.9% w/v
Polyethylene glycol 400, NF q.s. 100%
Polysorbate 20 20% w/v
Polyethylene glycol 400 q.s 100% w/v
US10626943 2002-07-30 2003-07-25 Parenteral CCI-779 formulations containing cosolvents, an antioxidant, and a surfactant Active 2026-01-20 US8026276B2 (en)
US10626943 US8026276B2 (en) 2002-07-30 2003-07-25 Parenteral CCI-779 formulations containing cosolvents, an antioxidant, and a surfactant
US13206641 US8299116B2 (en) 2002-07-30 2011-08-10 CCI-779 concentrate formulations
US13651623 US8455539B2 (en) 2002-07-30 2012-10-15 CCI-779 concentrate formulations
US13892389 US8722700B2 (en) 2002-07-30 2013-05-13 CCI-779 formulations for parenteral administration
US13206641 Division US8299116B2 (en) 2002-07-30 2011-08-10 CCI-779 concentrate formulations
US20040167152A1 true US20040167152A1 (en) 2004-08-26
US8026276B2 true US8026276B2 (en) 2011-09-27
US10626943 Active 2026-01-20 US8026276B2 (en) 2002-07-30 2003-07-25 Parenteral CCI-779 formulations containing cosolvents, an antioxidant, and a surfactant
US13206641 Active US8299116B2 (en) 2002-07-30 2011-08-10 CCI-779 concentrate formulations
US13651623 Active US8455539B2 (en) 2002-07-30 2012-10-15 CCI-779 concentrate formulations
US13892389 Active US8722700B2 (en) 2002-07-30 2013-05-13 CCI-779 formulations for parenteral administration
US20110184010A1 (en) * 2003-11-04 2011-07-28 Mayo Foundation For Medical Education And Research Method of treating mantle cell lymphoma
WO1993019763A1 (en) 1992-03-30 1993-10-14 American Home Products Corporation Rapamycin formulation for iv injection
DE4418115A1 (en) 1993-05-27 1994-12-01 Sandoz Ag Pharmaceutical preparations contg macrolide antibiotics
EP0650730A1 (en) 1993-09-30 1995-05-03 American Home Products Corporation Rapamycin formulations for oral administration
GB2327611A (en) 1994-10-26 1999-02-03 Novartis Ag Stabilisation of Macrolide Compositions
US6358969B1 (en) 1991-02-19 2002-03-19 Smithkline Beecham P.L.C. 3-desmethylrapamycin or derivatives thereof, processes for their preparation and their use as antifungal agents and immunosuppressants
US6605613B2 (en) 1998-12-07 2003-08-12 Novartis Ag Macrolides
WO2003077915A1 (en) 2002-03-13 2003-09-25 Wyeth Use of rapamycin for inhibiting of cell death
US6670168B1 (en) 1999-10-29 2003-12-30 Kosan Bioscience, Inc. Recombinant Streptomyces hygroscopicus host cells that produce 17-desmethylrapamycin
US20050020615A1 (en) 2003-07-25 2005-01-27 Wyeth CCI-779 lyophilized formulations
US20050234234A1 (en) 2004-04-14 2005-10-20 Wyeth Regiospecific synthesis of rapamycin 42-ester derivatives
US20050234087A1 (en) 2004-04-14 2005-10-20 Wyeth Process for preparing rapamycin 42-esters and FK-506 32-esters with dicarboxylic acid, precursors for rapamycin conjugates and antibodies
US20060183766A1 (en) 2005-02-15 2006-08-17 Wyeth Orally bioavailable CCI-779 formulations
US20070129541A1 (en) 2005-12-07 2007-06-07 Wyeth Scalable process for the preparation of a rapamycin 42-ester from a rapamycin 42-ester boronate
US20070142422A1 (en) 2005-12-20 2007-06-21 Wyeth Control of CCI-779 dosage form stability through control of drug substance impurities
US7384953B2 (en) 2005-03-02 2008-06-10 Wyeth Purification of rapamycin
CA2133180A1 (en) 1993-09-30 1995-03-31 Wyeth Rapamycin formulation for iv injection
US6455543B1 (en) * 1999-07-30 2002-09-24 University Of Kentucky Research Foundation Cis-2,6-disubstituted piperidines for the treatment of psychostimulant abuse and withdrawal, eating disorders, and central nervous system diseases and pathologies
DE60136200D1 (en) * 2000-09-19 2008-11-27 Wyeth Corp Water-soluble rapamycin ester
WO1995028406A1 (en) 1994-04-18 1995-10-26 American Home Products Corporation Rapamycin hydroxyesters, process for their preparation and pharmaceutical compositions containing them
US6852729B2 (en) 1998-12-07 2005-02-08 Novartis Ag Macrolides
US20030100577A1 (en) 2001-08-22 2003-05-29 Wyeth Rapamycin dialdehydes
US20030114477A1 (en) 2001-08-22 2003-06-19 Wyeth Rapamycin 29-Enols
"Added Substances (Excipients) in Parenteral Formulations" in Modern Pharmaceutics, 4th Ed., Banker & Rhodes, Eds., Marcel Dekker Inc.: New York, NY, Jul. 4, 2002, pp. 388-393.
"Added Substances" in Pharmaceutical Dosage forms and Drug Delivery Systems, 7th Ed., Ansel et al., Eds., Lippincott Williams and Wilkins: Philadelphia, PA, 1999, pp. 405-406.
"Butylated Hydroxyanisole" in Handbook of Pharmaceutical Excipients, 3rd Ed., Kibbe, Ed., American Pharmaceutical Association: Washington, DC, 2000, pp. 49-50.
"Butylated Hydroxyanisole" in Römpp Lexikon Chemie, 10th Ed., Falbe and Regitz, Eds., Georg Theime Verlag, Stuttgart, Germany: 1996, p. 423.
"Butylated Hydroxytoluene" in "Handbook of Pharmaceutical Excipients", 3rd Ed., Kibbe, Ed., American Pharmaceutical Association: Washington, DC, 2000, pp. 51-52.
"Citric Acid Monohydrate" in Handbook of Pharmaceutical Excipients, 3rd Ed., Kibbe, Ed., American Pharmaceutical Association: Washington, DC, 2000, pp. 140-141.
"Citric Acid" in Römpp Lexikon Chemie, 10th Ed., Falbe and Regitz, Eds., Georg Theime Verlag, Stuttgart, Germany: 1996, p. 759-760.
"Oxidation Inhibitor" in Römpp Lexikon Chemie, 10th Ed., Falbe and Regitz, Eds., Georg Theime Verlag, Stuttgart, Germany: 1996, p. 229.
"Solution Formulations" in Pharmaceutical Preformulation and Formulation, 2001, pp. 196-210.
"Tocopherol" in Römpp Lexikon Chemie, 10th Ed., Falbe and Regitz, Eds., Georg Theime Verlag, Stuttgart, Germany: 1996, p. 4572-4573.
Baker et al, Rapamycin (AY-22,989), A New Antifungal Antibiotic, III. In Vitro and In Vivo Evaluation, The Journal of Antibiotics, vol. XXXI, No. 6, pp. 539-545, (Jun. 1978).
Calne et al, Prolonged Survival of Pig Orthotopic Heart Grafts Treated with Cyclosporin A, The Lancet, pp. 1183-1185 (Jun. 3, 1978).
Correspondence from the Chilean associate with an informal English translation of a first Office Action issued in Chilean Patent Application No. 1490-2003 in 2006.
Correspondence from the Chilean associate with an informal English translation of a second Office Action issued in Chilean Patent Application No. 1490-2003 in 2008.
Correspondence from the Chilean associate with an informal English translation of a third Office Action issued in Chilean Patent Application No. 1490-2003 in 2009.
Dudkin, Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition, Clinical Cancer Research, vol. 7, pp. 1758-1764, Jun. 2001.
English translation of a first Office Action issued in Colombian Patent Application No. 05-017.056 on Aug. 26, 2009.
English translation of a first Office Action issued in Russian Federation Patent Application No. 2005105301 on May 23, 2007.
English translation of a second Office Action issued in Colombian Patent Application No. 05-017.056 on Feb. 4, 2009.
English translation of a second Office Action issued in Russian Federation Patent Application No. 2005105301 on Oct. 30, 2007.
English translation of a second Office Action issued in Vietnam Patent Application No. 1-2005-00241 on Jan. 11, 2007.
English translation of an Opposition filed by the Association of Pharmaceutical Laboratories in Ecuador Patent Application No. SP-05-5628 in 2005.
Fiedler, H.Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik and angrenzende Gebiete, vol. 2, No. 4, Auglage, pp. 1210-1217, Cantor-Verlag, Aulendorf, Deutchland, 1996.
Garber, K., Rapamycin's Resurrection: A new way to target the cancer cell cycle, J. National Cancer Institute, vol. 93, No. 20, pp. 1517-1519, Oct. 2001.
Georger, Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination therapy, Cancer Research, vol. 61, pp. 1527-1532, Feb. 2001.
Grunwald, V., et al, Inhibitors of mTOR reverse doxorubicin resistance conferred by PTEN status in prostate cancer cells, Cancer Research, vol. 62, pp. 6141-6145, Nov. 2002.
Hidalgo et al, A Phase I and Pharmacological Study of CCI-779, a Rapamycin Ester Cell Cycle Inhibitor, Annals of Oncology, vol. 11, Suppl. 4, pp. 133, (Oct. 2000).
Hidalgo et al, The Rapamycin-Sensitive Signal Transduction Pathway as a Target for Cancer Therapy, Oncogene, 19, pp. 6680-6686, (Dec. 2000).
Injection the basis, preparation and application, Nanzando Edition 1, pp. 21-23, (1995).
Machine translation of "Butylated Hydroxytoluene" in Römpp Lexikon Chemie, 10th Ed., Falbe and Regitz, Eds., Georg Theime Verlag, Stuttgart, Germany: 1996, p. 423.
Machine translation of "Citric Acid" in Römpp Lexikon Chemie, 10th Ed., Falbe and Regitz, Eds., Georg Theime Verlag, Stuttgart, Germany: 1996, p. 759-760.
Machine translation of "Oxidation Inhibitor" in Römpp Lexikon Chemie, 10th Ed., Falbe and Regitz, Eds., Georg Theime Verlag, Stuttgart, Germany: 1996, p. 229.
Machine translation of "Tocopherol" in Römpp Lexikon Chemie, 10th Ed., Falbe and Regitz, Eds., Georg Theime Verlag, Stuttgart, Germany: 1996, p. 4572-4573.
Martel et al, Inhibition of the Immune Response by Rapamycin, a New Antifungal Antibiotic, Can. J. Physiol. Pharmacol. vol. 55, pp. 48-51 (1977).
Mendenhall, Stability of Parenterals, Drug Development and Industrial Pharmacy, vol. 10, No. 8-9, pp. 1297-1342, Oct. 1984.
Oellerich et al, Immunosuppressive Drug Monitoring of Sirolimus and cyclosporine in Pediatric Patients, Clinical Biochemistry, 37, pp. 424-428, (Jun. 2004).
Office Action issued in Australian Patent Application No. 2003254168 on Jun. 2, 2008.
Official Communication of Revocation of Patent issued in European Patent Application No. 03771828.5 on dated Mar. 1, 2011.
Pharmaceutical Additive Dictionary, Yakuji Nippou Limited, pp. 2, 3, 6, 38, 39, 63, 90, 91, 117, 214, (1994).
Podsypanina, K, An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/−mice, PNAS, vol. 98, No. 18, pp. 10320-10325, Aug. 2001.
Podsypanina, K, An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/-mice, PNAS, vol. 98, No. 18, pp. 10320-10325, Aug. 2001.
Powell, M., Compendium of Excipients for Parenteral Formulations, PDA Journal of Pharmaceutical Science and Technology, vol. 52, No. 5, pp. 238-311, Nov. 1999.
Response to Oppositions filed in European Patent Application No. 03771828.5 on Jun. 30, 2009.
Sehgal et al, Rapamycin (AY-22, 989), A New Antifungal Antibiotic, II. Fermentation, Isolation and Characterization, The Journal of Antibiotics, vol. XXVIII No. 10, pp. 727-732 (Oct. 1975).
Sorbera, L.A., et al, CCI-779 Oncolytic mTOR inhibitor, Drugs of the Future, vol. 27, No. 1, pp. 7-13, Jan. 2002.
Strickley, R., Parenteral forumulations of small molecules therapeutics marketed in the United States (1999) Part I, Journal of Pharmaceutical Science and Technology, vol. 53, No. 6, pp. 324-349, Nov. 1999.
Summons to Attend Oral Proceedings issued in European Patent Application No. 03771828.5 on Sep. 17, 2010.
Sweetana, S. and Akers, M., Solubility principles and practices for parenteral drug dosage form development, PDA Journal of Pharmaceutical Science and Technology, vol. 50, No. 5, pp. 330-342, Sep. 1996.
Teva's Response dated Nov. 23, 2010 to the Summons to Attend Oral Proceedings issued in Europe Patent Application No. 03771828.5 on Sep. 17, 2010.
Vezina et al, Rapamycin (AY-22,989) A new Antifungal Antibiotic, I. Taxonomy of the Producing Streptomycete and Isolation of the Active Principle, The Journal of Antibiotics, pp. 721-726 (Oct. 1975).
Wichmann's Response dated Nov. 24, 2010 to the Summons to Attend Oral Proceedings issued in Europe Patent Application No. 03771828.5 on Sep. 17, 2010 and English translation thereof.
Written Submissions for Oral Proceedings filed by Applicant in European Patent Application No. 03771828.5 on Dec. 13, 2010.
Wyeth Pharmaceuticals Inc, Highlights of Prescribing Information, (Torisel, temsirolimus), Philadelphia, USA, May 2007.
Yu, mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer, Endocrine-Related Cancer, vol. 8, pp. 249-258, Sep. 2001.
US8507518B2 (en) 2003-11-04 2013-08-13 Mayo Foundation For Medical Education And Research Method of treating mantle cell lymphoma
CA2493878C (en) 2013-07-23 grant
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:SISKAVICH, VICTORIA;REEL/FRAME:014355/0966
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:RUBINO, JOSEPH T.;HARRISON, MAUREEN M.;GANDHI, POOJA;REEL/FRAME:014355/0977;SIGNING DATES FROM 20030721 TO 20030722
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:RUBINO, JOSEPH T.;HARRISON, MAUREEN M.;GANDHI, POOJA;SIGNING DATES FROM 20030721 TO 20030722;REEL/FRAME:014355/0977
Free format text: CHANGE OF ADDRESS FOR ASSIGNEE;ASSIGNOR:WYETH LLC;REEL/FRAME:039743/0965