EP1853238A2 - Preparations pharmaceutiques contenant 17-allylamino-17-demethoxygeldanamycine - Google Patents

Preparations pharmaceutiques contenant 17-allylamino-17-demethoxygeldanamycine

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Publication number
EP1853238A2
EP1853238A2 EP06736517A EP06736517A EP1853238A2 EP 1853238 A2 EP1853238 A2 EP 1853238A2 EP 06736517 A EP06736517 A EP 06736517A EP 06736517 A EP06736517 A EP 06736517A EP 1853238 A2 EP1853238 A2 EP 1853238A2
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Prior art keywords
aag
volume
amount
component
formulation
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EP06736517A
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German (de)
English (en)
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EP1853238A4 (fr
Inventor
Indu Isaacs
John G. Augustine
Usha Srinivasula
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Kosan Biosciences Inc
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Kosan Biosciences Inc
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Publication of EP1853238A2 publication Critical patent/EP1853238A2/fr
Publication of EP1853238A4 publication Critical patent/EP1853238A4/fr
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Definitions

  • This invention relates to pharmaceutical formulations containing 17-allylamino-17- demethoxygeldanamycin ("17-AAG”) and methods for their preparation and use.
  • Geldanamycin belongs to the ansamycin family of natural products, whose members are characterized by a benzenoid nucleus (typically a benzoquinone or hydroquinone nucleus) connected at two meta positions to form a macrolactam. Besides geldanamycin, the ansamycins include the macbecins, the herbimycins, the TAN-420s, and reblastatin. [0003] Geldanamycin and its derivatives are the most extensively studied of the ansamycins. Although geldanamycin was originally identified as a result of screening for antibiotic activity, current interest in it is based primarily on its cytotoxicity towards tumor cells and, therefore, its potential as an anticancer agent.
  • a benzenoid nucleus typically a benzoquinone or hydroquinone nucleus
  • Hsp90 heat shock protein-90
  • client proteins proteins
  • Hsp90 client proteins are many mutated or overexpressed proteins implicated in cancer: p53, Bcr-Abl lcinase, Raf-1 kinase, Akt kinase, Npm-Alk kinase pl85 ErB2 transmembrane kinase, Cdk4, Cdk6, Weel (a cell cycle-dependent lcinase), Her2/Neu (ErbB2), and hypoxia inducible factor- l ⁇ (HIF-l ⁇ ).
  • p53 Bcr-Abl lcinase
  • Raf-1 kinase Akt kinase
  • Npm-Alk kinase Npm-Alk kinase pl85 ErB2 transmembrane kinase
  • Cdk4 Cdk4
  • Cdk6 a cell cycle-dependent lcinase
  • Her2/Neu ErbB2
  • hypoxia inducible factor- l ⁇ HIF-
  • position 17 is an attractive one for the introduction of property-modulating substituents, such as a solubilizing group.
  • the best-known 17-substituted geldanamycin derivative is 17-AAG, first disclosed in Sasaki et at., cited supra, and currently undergoing clinical trials.
  • geldanamycin compound is 17-(2-dimethylaminoethyl)amino-17- demethoxygeldanamycin (("17-DMAG”) (Snader et al., WO 02/079167 Al (2002), incorporated by reference), also undergoing clinical trials.
  • geldanamycin compounds such as geldanamycin itself and 17-AAG, especially for parenteral administration, is their very poor water solubility, only about 0.1 mg/mL at neutral pH for 17- AAG.
  • WO 03/086381 discloses a method for preparing pharmaceutical formulations for ansamycins by (a) providing the ansamycin dissolved in ethanol; (b) mixing the product of step (a) with a medium chain triglyceride to form a first mixture; (c) substantially removing the ethanol from the first mixture; (d) combining the product of step (c) with an emulsifying agent and a stabilizer to form a second mixture; and (e) emulsifying the second mixture.
  • the emulsified second mixture optionally can be lyophilized and then re-hydrated.
  • the medium chain triglyceride comprises caprylic and/or caproic acid
  • the emulsifying agent comprises phosphotidylcholine
  • stabilizer comprises sucrose
  • the present invention provides a pharmaceutical formulation for 17-AAG, a method for administering 17-AAG to a patient in need thereof, and a method for preparing a pharmaceutical formulation comprising 17-AAG.
  • the present invention provides a formulation including 17-AAG that is suitable for intravenous administration.
  • the formulation comprises 17-AAG in a concentration of between about 1.0 mg/mL and about 5.0 mg/mL dissolved in a vehicle comprising (i) a first component that is an aprotic, polar solvent in an amount between about 0.1 and about 10 volume %; and, (ii) a second component that is an aqueous mixture comprising between about 5.0 and about 55 volume % long chain triglycerides, in an amount between about 90.0 and 99.9 volume %.
  • the present invention provides a method for administering 17-AAG to a patient in need thereof, comprising the steps of:
  • a pharmaceutical formulation comprising 17-AAG in a concentration of between about 1.0 mg/mL and about 5.0 mg/mL dissolved in a vehicle comprising (i) a first component that is an aprotic, polar solvent in an amount between about 0.1 and about 10 volume %; and, (ii) a second component that is an aqueous mixture comprising between about 5.0 and about 55 volume % long chain triglycerides, in an amount between about 90.0 and 99.9 volume %.
  • the present invention provides a method for preparing a pharmaceutical formulation comprising 17-AAG, comprising the steps of:
  • Aprotic, polar solvents are solvents that do not contain an O-H group but still possess a fairly large dipole.
  • aprotic, polar solvents include, without limitation, dimethylsulfoxide (i.e., DMSO), N,N-dimethylacetamide (i.e., DMA), N,N- dimethylformamide (i.e., DMF), and N-methylpyrrolidone (i.e., NMP).
  • Intralipid either 10% or 20%, includes soybean oil, phospholipids (lecithin), glycerin and water for injection.
  • One liter of Intralipid 10% contains the following: 100 g of purified soybean oil; 12 g of purified egg phospholipids, 22 g anhydrous glycerin, and water to a volume of 1 liter. The pH is adjusted with sodium hydroxide to approximately 8.
  • One liter of Intralipid 20% contains the following: 200 g of purified soybean oil; 12 g of purified egg phospholipids, 22 g anhydrous glycerol, and water to a volume of 1 liter. The pH is adjusted with sodium hydroxide to approximately 8.
  • the Intralipids are typically stored at a controlled temperature below 25 0 C.
  • Liposyn II either 10% or 20%, includes safflower oil, soybean oil, phospholipids
  • Liposyn II 10% contains 5 weight % safflower oil, 5 weight % soybean oil, up to 1.2 weight % egg phosphatides added as an emulsifier, and
  • Liposyn II 20% contains 10 weight % safflower oil, 10 weight % soybean oil, 1.2 weight % egg phosphatides, and 2.5 weight % glycerin in water for injection..
  • the pH may be adjusted with sodium hydroxide to between 6 and 9.
  • Lecithin is a mixture of the diglycerides of stearic, palmitic, and oleic acids, linked to the choline ester of phosphoric acid.
  • Commercial lecithin is typically soybean lecithin, which contains 11.7% palmitic acid, 4.0% stearic acid, 8.6% palmitoleic acid, 9.8% oleic acid,
  • Egg lecithins are one suitable type of lecithin.
  • Linoleic acid is a fatty acid of the formula C 18 H 32 O 2 .
  • Linolenic acid is a fatty acid of the formula C 18 Hs 0 O 2 .
  • Long chain triglycerides are triglyceride compositions that include fatty acids ranging from 12 to 22 carbons in length as the predominant constituent, preferably 16 to 20 carbons in length.
  • Medium chain triglycerides are triglyceride compositions that include fatty acids ranging from 7 to 11 carbons in length as the predominant constituent, preferably 8 to 10 carbons in length.
  • Oleic acid is a fatty acid of the formula C 18 H 34 O 2 .
  • Palmitic acid is a fatty acid of the formula C 16 H 32 O 2 .
  • Safflower oil is a mixture of triglycerides of palmitic acid (6.4%), stearic acid (3.1%), arachidic (0.2%), oleic acid (13.4%), linoleic acid (76.6-79.0%), and linolenic acid (0.04-
  • Sesame oil comprises primarily triglycerides of oleic and linoleic acids. However, it appeal's to adversely affect the stability of 17-AAG and is not as desirable for this reason.
  • Stearic acid is a fatty acid of the formula C 18 H 36 O 2 .
  • Soybean oil is a mixture of triglycerides of oleic acid (26%), linoleic acid (49%) linolenic acid (11%), and saturated acids (14%).
  • Soybean oil/safflower oil in a 50/50 mixture includes triglycerides composed of approximately 65.8% linoleic acid, 17.7% oleic acid, 8.8% palmitic acid, 3.4% stearic acid, and 4.2% linolenic acid.
  • the pharmaceutical formulation of the present invention includes 17-AAG and is suitable for intravenous administration.
  • the formulation comprises 17-AAG in a concentration of between about 1.0 mg/mL and about 5.0 mg/mL dissolved in a vehicle comprising (i) a first component that is an aprotic, polar solvent in an amount between about
  • a second component that is an aqueous mixture comprising between about 5.0 and about 55.0 volume % long chain triglycerides, in an amount between about 90.0 and 99.9 volume %.
  • the concentration of 17-AAG in the formulation is typically between about 1.25 mg/mL and 4.0 mg/mL.
  • the concentration of 17-AAG oftentimes ranges from about 2.0 mg/mL to about 3.0 mg/mL; where the aprotic, polar solvent is DMA, the concentration oftentimes ranges from about 1.50 mg/mL to about 3.0 mg/mL.
  • Aprotic, polar solvents are typically present in the formulation in an amount between about 0.5 and about 5.0 volume %. The concentration of such solvents is maintained within
  • the tolerated dose for DMA is approximately 14.8 g/m 2 .
  • the concentration of aprotic, polar solvent ranges from about 1.0 to about 4.0 volume %.
  • the second component of the vehicle is typically an aqueous mixture comprising between about 5.0 and about 55.0 volume % long chain triglycerides.
  • suitable second components include, without limitation, the following: Intralipid 10%; Intralipid 20%; Liposyn II 10%; and Liposyn II 20%.
  • the triglyceride content oftentimes ranges from about 7.5 to about 30 volume %.
  • Phospholipids preferably egg phospholipids
  • the phospholipid concentration oftentimes ranges from about 0.8 to about 3.0 volume percent, with 1.0 to 2.0 volume percent being preferred.
  • Examples of suitable 17-AAG of the present invention include, without limitation, the following:
  • Formulation 1 comprising a) concentration of 17-AAG of between about 1 mg/mL and about 3 mg/mL; b) first component is DMSO present in an amount between about 1.0 to about 4.0 volume %; and, c) second component is an aqueous mixture comprising between about 7.5 and 30.0 volume % long chain triglycerides.
  • Formulation 2 comprising a) concentration of 17-AAG of between about 2.0 mg/mL and about 3.0 mg/mL; b) first component is DMSO present in an amount between about 1.0 to about 4.0 volume %; and, c) second component is an aqueous mixture comprising between about 7.5 and 30.0 volume % long chain triglycerides.
  • Formulation 3 comprising a) concentration of 17-AAG of between about 2.25 mg/mL to about 2.75 mg/mL; b) first component is DMSO present in an amount between about 1.0 to about 4.0 volume %; and, c) second component is an aqueous mixture comprising between about 7.5 and 30.0 volume % long chain triglycerides.
  • Formulation 4 comprising a) concentration of 17-AAG of between about 2.25 mg/mL to about 2.75 mg/mL; b) first component is DMSO present in an amount between about 2.0 to about 3.5 volume %; and, c) second component is an aqueous mixture comprising between about 7.5 and 30.0 volume % long chain triglycerides.
  • Formulation 5 comprising a) concentration of 17-AAG of between about 2.25 mg/mL to about 2.75 mg/mL; b) first component is DMSO present in an amount between about 2.0 to about 3.5 volume %; and, c) second component is an aqueous mixture comprising between about 15.0 and 30.0 volume % long chain triglycerides.
  • Formulation 6 comprising a) concentration of 17-AAG of between about 2.25 mg/mL to about 2.75 mg/mL; b) first component is DMSO present in an amount between about 2.0 to about 3.5 volume %; and, c) second component is an aqueous mixture comprising between about 15.0 and 30.0 volume % long chain triglycerides, wherein the fatty acid component of the triglycerides comprises linoleic acid, oleic acid and palmitic acid.
  • Formulation 7 comprising a) concentration of 17-AAG of between about 2.25 mg/mL to about 2.75 mg/mL; b) first component is DMSO present in an amount between about 2.0 to about 3.5 volume %; and, c) second component is an aqueous mixture comprising between about 15.0 and 30.0 volume % long chain triglycerides, wherein the fatty acid component of the triglycerides comprises linoleic acid (50% to 75% of fatty acids) , oleic acid (15% to 25% fatty acids) and palmitic acid (7% to 10% fatty acids).
  • Formulation 8 comprising a) concentration of 17-AAG of between about 2.25 mg/mL to about 2.75 mg/mL; b) first component is DMSO present in an amount between about 2.0 to about 3.5 volume %; c) second component is an aqueous mixture comprising between about 15.0 and 30.0 volume % long chain triglycerides, wherein the fatty acid component of the triglycerides comprises linoleic acid (50% to 75% of fatty acids) , oleic acid (15% to 25% fatty acids) and palmitic acid (7% to 10% fatty acids); and, d) third component — phospholipids — present in an amount between about 1.0 percent and 2.0 volume percent.
  • Formulation 9 comprising a) concentration of 17-AAG of between about 2.25 mg/mL to about 2.75 mg/mL; b) first component is DMSO present in an amount between about 2.0 to about 3.5 volume %; c) second component is an aqueous mixture comprising between about 15.0 and 30.0 volume % long chain triglycerides, wherein the fatty acid component of the triglycerides comprises linoleic acid (50% to 75% of fatty acids) , oleic acid (15% to 25% fatty acids) and palmitic acid (7% to 10% fatty acids); d) third component — egg phospholipids — present in an amount between about 1.0 w and 2.0 volume percent; and, e) glycerin in an amount between about 2.0 and 3.0 volume %.
  • Formulation 10 comprising a) concentration of 17-AAG of between about 1.0 mg/mL and about 3.0 mg/mL; b) first component is DMA present in an amount between about 1.0 to about 4.0 volume %; and, c) second component is an aqueous mixture comprising between about 7.5 and 30.0 volume % long chain triglycerides.
  • Formulation 11 comprising a) concentration of 17-AAG of between about 1.5 mg/mL and about 3 mg/mL; b) first component is DMA present in an amount between about 1.0 to about 4.0 volume %; and, c) second component is an aqueous mixture comprising between about 7.5 and 30.0 volume % long chain triglycerides.
  • Formulation 12 comprising a) concentration of 17-AAG of between about 1.65 mg/mL to about 2.50 mg/mL; b) first component is DMA present in an amount between about 1.0 to about 4.0 volume %; and, c) second component is an aqueous mixture comprising between about 7.5 and 30.0 volume % long chain triglycerides.
  • Formulation 13 comprising a) concentration of 17-AAG of between about 1.65 mg/mL to about 2.50 mg/mL; b) first component is DMA present in an amount between about 2.0 to about 3.5 volume %; and, c) second component is an aqueous mixture comprising between about 7.5 and 30.0 volume % long chain triglycerides.
  • Formulation 14 comprising a) concentration of 17-AAG of between about 1.65 mg/mL to about 2.50 mg/mL; b) first component is DMA present in an amount between about 2.0 to about 3.5 volume %; and, c) second component is an aqueous mixture comprising between about 15.0 and 30.0 volume % long chain triglycerides.
  • Formulation 15 comprising a) concentration of 17-AAG of between about 1.65 mg/mL to about 2.50 mg/mL; b) first component is DMA present in an amount between about 2.0 to about 3.5 volume %; and, c) second component is an aqueous mixture comprising between about 15.0 and 30.0 volume % long chain triglycerides, wherein the fatty acid component of the triglycerides comprises linoleic acid, oleic acid and palmitic acid.
  • Formulation 16 comprising a) concentration of 17-AAG of between about 1.65 mg/mL to about 2.50 mg/mL; b) first component is DMA present in an amount between about 2.0 to about 3.5 volume %; and, c) second component is an aqueous mixture comprising between about 15.0 and 30.0 volume % long chain triglycerides, wherein the fatty acid component of the triglycerides comprises linoleic acid (50% to 75% of fatty acids) , oleic acid (15% to 25% fatty acids) and palmitic acid (7% to 10% fatty acids).
  • Formulation 17 comprising a) concentration of 17-AAG of between about 1.65 mg/mL to about 2.50 mg/mL; b) first component is DMA present in an amount between about 2.0 to about 3.5 volume %; c) second component is an aqueous mixture comprising between about 15.0 and 30.0 volume % long chain triglycerides, wherein the fatty acid component of the triglycerides comprises linoleic acid (50% to 75% of fatty acids) , oleic acid (15% to 25% fatty acids) and palmitic acid (7% to 10% fatty acids); and, d) third component — phospholipids — present in an amount between about 1.0 and 2.0 volume percent.
  • Formulation 18 comprising a) concentration of 17-AAG of between about 1.65 mg/mL to about 2.50 mg/mL; b) first component is DMA present in an amount between about 2.0 to about 3.5 volume %; c) second component is an aqueous mixture comprising between about 15.0 and 30.0 volume % long chain triglycerides, wherein the fatty acid component of the triglycerides comprises linoleic acid (50% to 75% of fatty acids) , oleic acid (15% to 25% fatty acids) and palmitic acid (7% to 10% fatty acids); d) third component — egg phospholipids — present in an amount between about 1.0 and 2.0 volume percent; and, e) glycerin in an amount between about 2.0 and 3.0 volume %.
  • the formulations of the present invention exhibit stability for a period of hours at a variety of temperatures.
  • the 17-AAG of Formulations 1, 2, 3, 4, 5, 6, 7, 8, and 9 — at room temperature, 4 0 C, and -20 0 C — degrades less than 5% over a period of 7 hours, preferably less than 2.5%, and more preferably less than 1%;
  • the 17-AAG of Formulations 10, 11, 12, 13, 14, 15, 16, 17, and 18 exhibits the same stability.
  • the 17-AAG of Formulations 1 through 18 — at room temperature, 4 0 C, and -20 °C — degrades less than 5% over a period of 14 hours, preferably less than 2.5%, and more preferably less than 1%.
  • the present formulation offers a number of advantages. It is easily prepared and stored, and it avoids the use of excessive amounts of DMSO, which can have poor patient acceptance due to its odor.
  • the present formulation furthermore allows the delivery of a requisite amount of 17-AAG within an acceptable infusion time (e.g., 90 min.).
  • the present invention also provides a method for administering 17-AAG to a patient in need thereof, comprising the steps of:
  • a pharmaceutical formulation comprising 17-AAG in a concentration of between about 1 mg/mL and about 5 mg/mL dissolved in a vehicle comprising (i) a first component that is an aprotic, polar solvent in an amount between about 0.1 and about 10 volume %; and, (ii) a second component comprising between about 5.0 and about 55.0 volume % long chain triglycerides in an amount between 90.0 and 99.9 volume %;
  • Examples of 17-AAG formulations administered to patients include, without limitation, Formulations 1 through 18 discussed above. Any suitable apparatus may be used to delivery the formulation intravenously, including an IV bag with attached medical tubing. Finally, the rate of intravenous delivery can be readily determined by one of ordinary skill in the art using well-known methods.
  • the present invention further provides a method for preparing a pharmaceutical formulation comprising 17-AAG, comprising the steps of:
  • the amount of 17-AAG provided is typically such that a concentration between about
  • 1.0 mg/mL and 5 mg/mL results in the formulation.
  • the first component is DMSO
  • an amount is oftentimes provided that results in a formulation concentration from about 2.0 mg/mL to about 3.0 mg/mL
  • the first component is DMA
  • an amount is oftentimes provided that results in a formulation concentration from about 1.50 mg/mL to about 3.0 mg/mL.
  • the 17-AAG is dissolved in the first component — an aprotic, polar solvent such as DMSO or DMA — to provide a solution.
  • the solution is combined with components that typically include a substantial amount of water, along with long chain triglycerides and phospholipids.
  • suitable components include, without limitation, Mralipid 10%; Intralipid 20%; Liposyn II 10%; and, Liposyn II 20%. Should some degree of precipitation occur upon combining the solution with the vehicle, the resulting formulation is usually filtered.
  • formulations prepared through this method include, without limitation, Formulations 1 through 18 discussed above.
  • Geldanamycin is a well-known natural product, obtainable by culturing the producing organism, Streptomyces hygroscopicus var. geldanus NRRL 3602. 17-AAG is made semi- synthetically from geldanamycin, by reaction of geldanamycin with allylamine, as described in Sasaki et al, US 4,261,989 (1981), the disclosure of which is incorporated herein by reference.
  • 17-AAG administered via a pharmaceutical solution formulation of this invention can be used for treating diseases such as, but not limited to, hyperproliferative diseases, including: cancers of the head and neck which include tumors of the head, neck, nasal cavity, paranasal sinuses, nasopharynx, oral cavity, oropharynx, larynx, hypopharynx, salivary glands, and paragangliomas; cancers of the liver and biliary tree, particularly hepatocellular carcinoma; intestinal cancers, particularly colorectal cancer; treat ovarian cancer; small cell and non-small cell lung cancer; breast cancer sarcomas, such as fibrosarcoma, malignant fibrous histiocytoma, embryonal rhabdomysocarcoma, leiomysosarcoma, neuioflbrosarcoma, osteosarcoma, synovial sarcoma, liposarcoma, and alveolar soft part sarcoma
  • compositions described herein will result in a reduction in the size or number of the cancerous growth and/or a reduction in associated symptoms (where applicable).
  • Pathologically practice of the method and use of compositions described herein will produce a pathologically relevant response, such as: inhibition of cancer cell proliferation, reduction in the size of the cancer or tumor, prevention of further metastasis, and inhibition of tumor angiogenesis.
  • the method of treating such diseases comprises administering a therapeutically effective amount of an inventive combination to a subject. The method may be repeated as necessary.
  • Non-cancer disorders that are characterized by cellular hyperproliferation can also be treated by 17-AAG administered in accordance with this invention.
  • Illustrative examples of such disorders include but are not limited to: atrophic gastritis, inflammatory hemolytic anemia, graft rejection, inflammatory neutropenia, bullous pemphigoid, coeliac disease, demyelinating neuropathies, dermatomyositis, inflammatory bowel disease (ulcerative colitis and Crohn's disease), multiple sclerosis, myocarditis, myositis, nasal polyps, chronic sinusitis, pemphigus vulgaris, primary glomerulonephritis, psoriasis, surgical adhesions, stenosis or restenosis, scleritis, scleroderma, eczema (including atopic dermatitis, irritant dermatitis, allergic dermatitis), periodontal disease ( periodontitis), polycy
  • vasculitis e.g., Giant cell arteritis (temporal arteritis, Takayasu's arteritis), polyarteritis nodosa, allergic angiitis and granulomatosis (Churg- Strauss disease), polyangitis overlap syndrome, hypersensitivity vasculitis (Henoch- Schonlein purpura), serum sickness, drug-induced vasculitis, infectious vasculitis, neoplastic vasculitis, vasculitis associated with connective tissue disorders, vasculitis associated with congenital deficiencies of the complement system, Wegener's granulomatosis, Kawasaki's disease, vasculitis of the central nervous system, Buerger's disease and systemic sclerosis); gastrointestinal tract diseases (e.g., pancreatitis, Crohn's disease, ulcerative colitis, ulcerative proctitis, primary sclerosing cholangitis, benign strictures of any cause including ideopathic (e.
  • ideopathic
  • 17-AAG can be administered in combination with other anti-cancer or cytotoxic agents, including alkylating agents, angiogenesis inhibitors, antimetabolites, DNA cleavers, DNA crosslinkers, DNA intercalators, DNA minor groove binders, heat shock protein 90 inhibitors, histone deacetylase inhibitors, microtubule stabilizers, nucleoside (purine or pyrimidine) analogs, proteasome inhibitors, topoisomerase (I or II) inhibitors, tyrosine kinase inhibitors.
  • other anti-cancer or cytotoxic agents including alkylating agents, angiogenesis inhibitors, antimetabolites, DNA cleavers, DNA crosslinkers, DNA intercalators, DNA minor groove binders, heat shock protein 90 inhibitors, histone deacetylase inhibitors, microtubule stabilizers, nucleoside (purine or pyrimidine) analogs, proteasome inhibitors, topoisomerase (I or II) inhibitors, tyrosine kina
  • Specific anti-cancer or cytotoxic agents include ⁇ -lapachone, 17- DMAG, bicalutamide, bleomycin, bortezomib, bisulfan, calicheamycin, camptothecin, capecitabine, callistatin A, CC-1065, cisplatin, cryptophycins, daunorubicin, discodermolide, docetaxel, doxorubicin, duocarmycin, dynemycin A, epothilones, etoposide, floxuridine, fludarabine, fluoruracil, gefitinib, geldanamycin, gemcitabine, hydroxyurea, imatinib, interferons, interleukins, irinotecan, leptomycin B, methotrexate, mitomycin C, oxaliplatin, paclitaxel, spongistatins, suberoylanilide hydroxamic acid (SAHA), thio
  • the co-administered anti-cancer or cytotoxic agent can be a protein kinase inhibitor, including: quinazolines, particularly 4-anilinoquinazolines such as Iressa (AstraZeneca; N- (3- chloro-4-fluorophenyl)-7-methoxy-6-[3(4- quinazolinamine) and Tarceva (Roche/Genentech; N-(3-ethynylphenyl)-6,7- bis(2-methoxyethoxy)-4-quinazolinamine monohydrochloride); phenylamino-pyrimidines such as Gleevec (Novartis; 4-[(4-methyl-l- piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2- pyrimidinyl]amino]phenyl]benzamide); pyrrolo- and pyrazolopyrimidines such as BEBX 13
  • 17-AAG may be administered in a dose ranging from about 4 mg/m 2 to about 4000 mg/m 2 depending on the frequency of administration.
  • a preferred dosage regimen for 17-AAG is about 450 mg/m 2 weekly (Banerji et al, Proc. Am, Soc. Clin. Oncol. , 22, 199 (2003, abstract 797), "A Pharmacokinetically (PK)-pharmacodynamically (PD) Guided Phase I Trial of the Heat Shock Protein 90 (HSP90) Inhibitor 17-Allyl-17-demethoxygeldanamycin (17AAG)").
  • PK Pharmacokinetically
  • PD pharmacodynamically
  • HSP90 Heat Shock Protein 90
  • a dose of about 308 mg/m 2 weekly can be administered. See Goetz et al, Eur. J. Cancer, 38 (Supp. 7), S54-S55 (2002), "A phase I trial of 17-Allyl-Amino-Geldanamycin (17-AAG) in patients with
  • 17-AAG reference standard 1 mg was initially dissolved in 1 mL of 100% methanol. The sample was diluted to 0.4 mg/mL concentration with methanol and used as a reference standard. 17-AAG was dissolved in various organic solvents or oils. The formulations were lightly vortexed to ensure homogeneity and subsequently filtered through 0.2 ⁇ m PVDF syringe filters. The 17-AAG stock formulations were diluted in their respective solvents to determine the initial concentration and purity as well as the recovery of 17-AAG by RP-HPLC analysis. [0067] 20 mg of 17-AAG was taken in different vials and 0.2 niL of various oils was added as listed in Table 1. The samples were vortexed to dissolve 17-AAG. Upon preparation, the samples showed varying degrees of precipitation and were subsequently filtered through 0.2 ⁇ m PVDF filters and analyzed by RP-HPLC.
  • Table 1 Visual appearance, solubility and purity of 17-AAG/oil formulations.
  • 17-AAG stocks were prepared in 100% DMA (50 mg/mL or 120 mg/mL).
  • the formulations listed in Tables 2 to 5 were prepared by two different methods. Either the 17- AAG/solvent stock was slowly added to excess oil (Method I), or the oil was added to an aliquot of the 17-AAG/solvent stock (Method II).
  • solvent to oil Methodhod I
  • a 20 ⁇ L or 50 mg/mL 17-AAG/DMA stock was added to vial containing 500 ⁇ L of the Safflower oil under sti ⁇ ing conditions.
  • Oil to solvent (Method II) was prepared by adding 500 ⁇ L of oil dropwise to a vial containing 20 ⁇ L of 50 mg/mL 17- AAG/DMA stock over a period of 5 minutes. The sample was stirred on a magnetic stir plate for a period of 30 minutes. Upon preparation, the DMA samples showed varying degrees of precipitation. The formulations were subsequently filtered using 0.2 ⁇ m PVDF filters and analyzed by RP-HPLC. There was no change in appearance observed in any of the formulations tested after 24 hours of incubation at room temperature. [0069] Table 2 provides data regarding an evaluation of 17-AAG solubility using DMA in combination with various oils.
  • Table 3 provides data regarding an evaluation of 17-AAG solubility using DMA in combination with various oils.
  • the combinations were prepared in accordance with Method II, where a 50 mg/mL stock solution of 17-AAG/DMA was used. Percent recovery was calculated by dividing the solubility of 17-AAG by the targeted concentration (2 mg/mL).
  • Table 4 provides data regarding an evaluation of 17-AAG solubility using DMA in combination with various oils.
  • the combinations were prepared in accordance with Method I, where a 120 mg/mL stock solution of 17-AAG/DMA was used. Percent recovery was calculated by dividing the solubility of 17-AAG by the targeted concentration (4.8 mg/mL).
  • Table 5 provides data regarding an evaluation of 17- AAG solubility using DMA in combination with various oils.
  • the combinations were prepared in accordance with Method II where a 120 mg/mL stock solution of 17-AAG/DMA was used. Percent recovery was calculated by dividing the solubility of 17-AAG by the targeted concentration (4.8 mg/mL).
  • 17-AAG stocks were prepared in 100% DMSO (50 mg/mL or 200 mg/mL).
  • the formulations listed below in Tables 6 to 9 were prepared by two different methods. Either the 17-AAG solvent stock was slowly added to excess oil (Method I), or the oil was added to an aliquot of the 17-AAG/solvent stock (Method II).
  • solvent to oil (Method I) was prepared as follows: A 20 ⁇ L of 50 mg/mL 17-AAG/DMSO stock was added to a vial containing 500 ⁇ L of the Safflower oil under stirring conditions.
  • Oil to solvent (Method II) was prepared by adding 500 ⁇ L of oils dropwise to a vial containing 20 ⁇ L of 50 mg/mL 17- AAG/DMSO stock over a period of 5 minutes. The sample was stirred on a magnetic stir plate for a period of 30 minutes. Upon preparation, the formulations formed tiny oil droplets initially and precipitated after 10 minutes. The formulations were subsequently filtered using 0.2 ⁇ m PVDF filters and analyzed by RP-HPLC. The DMSO containing formulations showed oil droplet formation even after filtering; thus supernatant without the oil droplets was loaded on the RP-HPLC. There was no change in the appearance observed in any of the formulations tested after 24 hours of incubation at room temperature.
  • Table 6 provides data regarding an evaluation of 17-AAG solubility using DMSO in combination with various oils.
  • the combinations were prepared in accordance with Method I, where a 50 mg/mL stock solution of 17-AAG/DMSO was used. Percent recovery was calculated by dividing the solubility of 17-AAG by the targeted concentration (2 mg/mL).
  • Table 7 provides data regarding an evaluation of 17-AAG solubility using DMSO in combination with various oils.
  • the combinations were prepared in accordance with Method ⁇ , where a 50 mg/mL stock solution of 17-AAG/DMSO was used. Percent recovery was calculated by dividing the solubility of 17-AAG by the targeted concentration (2 mg/mL).
  • Table 8 provides data regarding an evaluation of 17-AAG solubility using DMSO in combination with various oils.
  • the combinations were prepared in accordance with Method I, where a 200 mg/mL stock solution of 17-AAG/DMSO was used. Percent recovery was calculated by dividing the solubility of 17-AAG by the targeted concentration (8 mg/mL).
  • Table 9 provides data regarding an evaluation of 17-AAG solubility using DMSO in combination with various oils.
  • the combinations were prepared in accordance with Method II, where a 200 mg/mL stock solution of 17-AAG/DMSO was used. Percent recovery was calculated by dividing the solubility of 17-AAG by the targeted concentration (8 mg/mL).
  • 17-AAG stocks were prepared in either 100% DMA (50 mg/mL or 120 mg/mL) or DMSO (50 mg/mL or 200 mg/mL). The formulations were prepared as follows: A 10 or 20 ⁇ L aliquot of 17-AAG/solvent stock was added to a vial containing 500 ⁇ L of the oil and gently swirled for 20 seconds to ensure complete homogeneity. The samples were subsequently incubated at room temperature and monitored over the course of 2 hours. [0079] Table 10 presents the visual appearance and solubility profiles of 17-AAG formulations containing a combination of DMA and oils prepared with no mechanical stress. Upon preparation, the DMA samples showed either little or no evidence of precipitation.
  • Table 11 presents the visual appearance and solubility profiles of 17-AAG formulations containing combinations of DMSO and oils prepared with no mechanical shearing. Upon preparation, the DMSO samples showed tiny oil droplets. After 2 hours of incubation at room temperature, there was a large amount of particles settled on the bottom of the vial containing DMSO/oil combinations in comparison to the DMA/oil formulations, irrespective of the stock concentrations used.
  • 17-AAG/DMA 50, 55, 60, and 65 mg/mL
  • 17-AAG/DMSO 50, 55, 60, and 65 mg/mL.
  • the formulations listed below in Tables 12 to 15 were prepared by mixing different aliquots of each 17-AAG/solvent stock in 1 mL of 10% Intralipid.
  • a 50/25 of 17-AAG/DMA/10% Intralipid combination was prepared as follows: 25 ⁇ L of 50 mg/ML 17-AAG/ DMA stock was slowly added to vial containing 1 mL of the 10% Intralipid. The sample was mixed by inverting the vials continuously for 20 seconds. All of the formulations were incubated at room temperature for a period of 24 hours to monitor the stability of 17- AAG in the lipid emulsions.
  • Table 12 below presents the visual observation for 17-AAG/DMA or DMSO emulsions prepared from a 50 mg/mL 17-AAG stock and formulated with 10% Intralipid.
  • Table 13 below presents the visual observation for 17-AAG/DMA or DMSO emulsions prepared from a 55 mg/rnL 17-AAG stock and formulated with 10% Intralipid.
  • Table 13 Stability of 17-AAG in 10% Intralipid by visual appearance.
  • Table 14 below presents the visual observation for 17-AAG/DMA or DMSO emulsions prepared from a 60 mg/mL 17-AAG stock and formulated with 10% Intralipid.
  • Table 14 Stability of 17-AAG in 10% Intralipid by visual appearance.
  • Table 15 below presents the visual observation for 17-AAG/DMA or DMSO emulsions prepared from a 65 mg/mL 17-AAG stock and formulated with 10% Intralipid.
  • Table 15 Stability of 17-AAG in 10% Intralipid by visual appearance.
  • 17-AAG/DMA Different stock concentrations of 17-AAG were prepared either in 100% DMA or DMSO as follows: 17-AAG/DMA— 55, 60, and 65 mg/mL; 17-AAG/DMSO— 55, 60 and 65 mg/mL.
  • the formulations listed below in Tables 16 to 18 were prepared by mixing different aliquots of each 17-AAG/solvent stock in 1 mL of 10% Liposyn II.
  • a 55/25 of 17-AAG/DMA/10% Liposyn II combination was prepared as follows: 25 ⁇ L of 55 mg/mL 17-AAG/DMA stock was slowly added to a vial containing 1 mL of the 10% Liposyn II. The sample was mixed by inverting the vials continuously for 20 seconds. AU of the formulations were incubated at room temperature for a period of 24 hours to monitor the stability of 17-AAG in the lipid emulsions.
  • Table 16 below presents the visual observation for 17-AAG/DMA or DMSO emulsions prepared from a 55 mg/mL 17-AAG stock and formulated with 10% Liposyn II.
  • Table 16 Stability of 17-AAG in 10% Liposyn II by visual appearance.
  • Table 17 below presents the visual observation for 17-AAG/DMA or DMSO emulsions prepared from a 60 mg/mL 17-AAG stock and formulated with 10% Liposyn II.
  • Table 17 Stability of 17-AAG in 10% Liposyn II by visual appearance.
  • Table 18 presents the visual observation for 17-AAG/DMA or DMSO emulsions prepared from a 65 mg/mL 17-AAG stock and formulated with 10% Liposyn II.
  • Table 18 Stability of 17-AAG in 10% Liposyn II by visual appearance.
  • 17-AAG/DMSO— 70, 80 90, 95 and 100 mg/mL The formulations listed below in Tables 19 to 20 were prepared by mixing different aliquots of each 17-AAG/solvent stock in 1 mL of 10 or 20% Intralipid.
  • a 70/25 of 17-AAG/DMA/Intralipid combination was prepared as follows: 25 ⁇ L of 70 mg/mL 17-AAG/DMA stock was slowly added to a vial containing 1 mL of Intralipid. The sample was mixed by inverting the vials continuously for 40 seconds. AU of the formulations were incubated at room temperature for a period of 24 hours to monitor the stability of 17-AAG in the lipid emulsions.
  • Table 19 below presents the visual observation for 17-AAG/DMA or DMSO emulsions prepared from a 70 mg/mL 17-AAG stock and formulated with 10% Intralipid.
  • Table 19 Stability of 17-AAG in 10% Intralipid by visual appearance following dilution in 10% Intralipid.
  • Table 20 below presents the visual observation for 17-AAG/DMA or DMSO emulsions prepared from a 70-80 mg/mL 17-AAG stock and formulated with 20% Intralipid.
  • Table 20 Stability of 17-AAG in 20% Intralipid by visual appearance.
  • 17-AAG/DMSO— 70, 80, 90, 95 and 100 mg/mL The formulations listed below in Tables 21 to 23 were prepared by mixing different aliquots of each 17-AAG/solvent stock in 1 mL of 10 or 20% Liposyn II.
  • a 70/25 of 17-AAG/DMA/Liposyn II combination was prepared as follows: 25 ⁇ L of 70 mg/mL 17-AAG/DMA stock was slowly added to vial containing 1 mL of Liposyn ⁇ . The sample was mixed by inverting the vials continuously for 40 seconds. All of the formulations were incubated at room temperature for a period of 24 hours to monitor the stability of 17-AAG in the lipid emulsions.
  • Table 21 below presents the visual observation for 17-AAG/DMA or DMSO emulsions prepared from a 70 or 80 mg/mL 17-AAG stocks and 10% Liposyn II.
  • Table 21 Stability of 17-AAG in 10% Liposyn II by visual appearance.
  • Table 22 below presents the visual observation for 17-AAG/DMA or DMSO emulsions prepared from a 70-80 mg/rnL 17-AAG stocks and 20% Liposyn II.
  • Table 22 Stability of 17-AAG in 20% Liposyn II by visual appearance following dilution in 20% Liposyn II.
  • Table 23 below presents the visual observation for 17-AAG/DMA or DMSO emulsions prepared from a 90-100 mg/mL 17-AAG stock and 20% Liposyn II.
  • Table 23 Stability of 17-AAG in 20% Liposyn II by visual appearance.
  • Emulsion particle size was measured after adding 17-AAG to the fat emulsions using a light microscope. 10 ⁇ L aliquots of 17-AAG emulsions were loaded onto a RP-HPLC. Osmolality was determined by removing 10 ⁇ L aliquots of the 17-AAG emulsions and measuring the quantity using a Wescor VaproTM Vapor Pressure Osmometer. [0099] Table 24 below presents the microscopic observations of lipid emulsions before and after the addition of 17-AAG.
  • the oil droplet of the emulsion was categorized into 3 different sizes: small ( ⁇ 200 nm); medium (200-400 nm) or large droplets (> 400 nm).
  • Table 24 Stability of 17-AAG in lipid emulsions by microscopic observation.
  • Table 25 below presents the stability of 17-AAG/DMA or DMSO emulsions prepared from a 55, 70 or 100 mg/mL 17-AAG stocks and 20% Liposyn II.
  • Table 25 Stability of 17-AAG in 20% Liposyn II by visual appearance following dilution in 20% Liposyn II.
  • Table 26 below presents the osmolality of the commercially available lipid emulsions with no drug.
  • Table 26 Osmolality of commercially available lipid emulsions with no drug.
  • Table 27 Osmolality of 17-AAG/DMSO emulsions.
  • Table 28 Osmolality of 17-AAG/DMA emulsions.
  • Tables 29 and 30 below present various 17-AAG formulations/emulsions with the final dosage/ volume of active and inactive ingredients to be infused.
  • Table 29 Final 17-AAG and DMSO concentrations in various 17-AAG formulations/ emulsions in fat emulsions.
  • Table 30 Final 17-AAG and DMA concentrations in various 17-AAG formulations/ emulsions in fat emulsions
  • a 100 mg/mL stock of 17-AAG was prepared either in 100% DMA or
  • Table 31 Short-term stability on 17-AAG formulations by RP-HPLC analysis.
  • Table 32 below presents 24 hour stability data of 17-AAG stock in either DMA or DMSO at 100 mg/mL 17-AAG concentration incubated at 4 0 C, room temperature, or -20 0 C.
  • Table 32 17-AAG Lipid Emulsion Stability after 24 hours of incubation at RT in 20% Liposyn II.
  • Table 33 17-AAG Lipid Emulsion Stability after 24 hours of incubation at RT in 20% Liposyn II.

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Abstract

L'invention concerne une préparation pharmaceutique contenant 17-AAG dans une quantité comprise entre environ 1 mg/mL et environ 5 mg/mL dissoute dans un excipient qui renferme (i) un premier composé constituant un solvant polaire aprotique dans une quantité allant d'environ 0,1 à 10 % en volume et (ii) un second composé constituant un mélange aqueux qui renferme entre environ 5,0 et environ 55,0 % en volume de triglycérides à chaîne longue, dans une quantité allant d'environ 90,0 à 99,9 % en volume.
EP06736517A 2005-02-28 2006-02-28 Preparations pharmaceutiques contenant 17-allylamino-17-demethoxygeldanamycine Withdrawn EP1853238A4 (fr)

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US7648976B2 (en) 2005-11-23 2010-01-19 Bristol-Myers Squibb Company 17-allylamino-17-demethoxygeldanamycin polymorphs and formulations
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WO2006094029A3 (fr) 2007-04-12
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CA2596867A1 (fr) 2006-09-08
WO2006094029A2 (fr) 2006-09-08

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