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WO2004082676A1 - Preparations medicamenteuses contenant des triglycerides a longue chaine et a chaine moyenne - Google Patents

Preparations medicamenteuses contenant des triglycerides a longue chaine et a chaine moyenne Download PDF

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Publication number
WO2004082676A1
WO2004082676A1 PCT/US2003/031667 US0331667W WO2004082676A1 WO 2004082676 A1 WO2004082676 A1 WO 2004082676A1 US 0331667 W US0331667 W US 0331667W WO 2004082676 A1 WO2004082676 A1 WO 2004082676A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
chain triglycerides
aag
oil
long chain
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Ceased
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PCT/US2003/031667
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English (en)
Inventor
Edgar H. Ulm
Robert Mansfield
Marcus Boehm
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Conforma Therapeutics Corp
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Conforma Therapeutics Corp
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Priority claimed from PCT/US2003/010533 external-priority patent/WO2003086381A1/fr
Application filed by Conforma Therapeutics Corp filed Critical Conforma Therapeutics Corp
Priority to JP2005513578A priority Critical patent/JP2006514994A/ja
Priority to EP03816401A priority patent/EP1605931A4/fr
Priority to AU2003277299A priority patent/AU2003277299B2/en
Priority to CA002518836A priority patent/CA2518836A1/fr
Priority to US10/548,968 priority patent/US20060148776A1/en
Publication of WO2004082676A1 publication Critical patent/WO2004082676A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates in general to pharmaceutical formulations and methods, and in more specific embodiments to emulsified formulations of ansamycins, e.g., 17-AAG. BACKGROUND
  • 17-allylamino-geldanamycin (17-AAG) is a synthetic analog of geldanamycin
  • GDM GDM
  • SBP90s heat shock protein 90s
  • HSP90s are ubiquitous chaperone proteins that are involved in folding, activation and assembly of a wide range of proteins, including key proteins involved in signal transduction, cell cycle control and transcriptional regulation.
  • HSP90 chaperone proteins are associated with important signaling proteins, such as steroid hormone receptors and protein kinases, including, e.g., Raf-1, EGFR, v-Src family kinases, Cdk4, and ErbB-2 ( Buchner J., 1999, TIBS, 24:136-141; Stepanova, L.
  • Hsp70 e.g., Hsp70, p60/Hop/Stil, Hip, Bagl, HSP40/Hdj2/Hsj l, immunophilins, p23, and p50
  • HSP90 may assist HSP90 in its function (see, e.g., Caplan, A., , Trends in Cell Biol, 9: 262-68 (1999).
  • Ansamycin antibiotics e.g., herbimycin A (HA), geldanamycin (GM), and 17-AAG are thought to exert their anticancerous effects by tight binding of the N-terminus ATP- binding pocket of HSP90 (Stebbins, C. et al, 1997, Cell, 89:239-250). This pocket is highly conserved and has weak homology to the ATP-binding site of DNA gyrase (Stebbins, C. et al, supra; Grenert, J.P. et al, 1997, J. Biol Chem., 272:23843-50).
  • ATP and ADP have both been shown to bind this pocket with low affinity and to have weak ATPase activity (Proromou, C. et al, 1997, Cell, 90: 65-75; Panaretou, B. et al, 1998, EMBO J., 17: 4829- 36).
  • occupancy of this N-terminal pocket by ansamycins and other HSP90 inhibitors alters HSP90 function and inhibits protein folding.
  • ansamycins and other HSP90 inhibitors have been shown to prevent binding of protein substrates to HSP90 (Scheibel, T., H. et al, 1999, Proc. Natl. Acad. Sci.
  • the substrates are degraded by a ubiquitin-dependent process in the proteasome (Schneider, C, L., supra; Sepp- Lorenzino, L., et al, 1995, J. Biol Chem., 270:16580-16587; Whitesell, L. et al, 1994, Proc. Natl Acad. Sci. USA, 91: 8324-8328).
  • This substrate destabilization occurs in tumor and non-transformed cells alike and has been shown to be especially effective on a subset of signaling regulators, e.g., Raf (Schulte, T. W. et al, 1997, Biochem. Biophys. Res. Commun.
  • EGF receptor EGFR
  • Her2/Neu Her2/Neu
  • HSP90 inhibitors have also been implicated in a wide variety of other utilities, including use as anti-inflammation agents, anti-infectious disease agents, agents for treating autoimmunity, agents for treating stroke, ischemia, cardiac disorders and agents useful in promoting nerve regeneration (See, e.g., Rosen et al., WO 02/09696 (PCT/USOl/23640); Degranco et al., WO 99/51223 (PCT/US99/07242); Gold, U.S. Patent 6,210,974 Bl; DeFranco et al., US Patent 6,174,875).
  • PCT/USOO/09512 PCT/USO 1/09512
  • PCT/US01/23640 PCT/US01/46303
  • PCT/USOl/46304 PCT/US02/06518, PCT/US02/29715, PCT/US02/35069,
  • PCT/US02/35938 PCT US02/39993, 60/293,246, 60/371,668, 60/331,893, 60/335,391, 06/128,593, 60/337,919, 60/340,762, and 60/359,484.
  • the lipid phase constitutes 5-30% by weight of the total formulation, more preferably 5-20%.
  • the overall w/w percent of long chain triglycerides does not exceed 10%, more preferably ranges at 7% or below, and more preferably still ranges at 6% or below to comport with viscosity constraints.
  • medium chain triglycerides are present in a w/w ratio of from 10:0.0001 to 0.0001:10, and more preferably 10:1 to 1:10 relative to long chain triglycerides.
  • the phospholipids are present in a range of from 3-10% w/w of the total. In some embodiments, the triglycerides constitute 5-20% w/w of the total.
  • the composition further comprises one or more of water, a preservative (e.g., sodium edentate), cryoprotectant, buffer, chelating agent, and tonicifier.
  • a preservative e.g., sodium edentate
  • cryoprotectant e.g., sodium edentate
  • buffer e.g., sodium edentate
  • tonicifier e.g., sodium edentate
  • 17-AAG 17-allylaminogeldanamycin 17-allylamino-17- demethoxy-geldanamycin
  • 17-AAG 17-allylaminogeldanamycin 17-allylamino-17- demethoxy-geldanamycin
  • is the drug and . is present in an amount of 0.5 mg/ml to 4 mg/ml or 0.05% w/w to 0.4% w/w relative to the total formulation weight.
  • AAG 7.5% lecithin, 15% Miglyol 812N, 10% sucrose, and water.
  • 17-AAG is 17-allylaminogeldanamycin and has structure:
  • composition of the invention also comprises small chain triglyerides.
  • the composition comprises long chain triglycerides in an amount sufficient to lessen or negate the incidence of medium chain triglyceride-mediated central nervous system (CNS) effects, especially if medium chain triglycerides are also present in the same composition.
  • CNS effects are typically negative, undesirable effects, and include but are not limited to one or more of somnolence, nausea, drowsiness, and changes in EEG. In some embodiments, however, such effect(s) may be desirable in a given context, such that the relative amount of medium chain triglycerides is increased relative to long chain triglycerides.
  • the composition is frozen and/or lyophilized, e.g., as generally described in PCT/US03/10533.
  • the weight percents of the individual triglycerides, phospholipids, drug, and non-volatile components necessarily increases over and above the ranges described above to comport with their relative fractional increase upon loss of water and any other volatile agents that may initially be present and lost thereafter upon lyophilization.
  • the invention features a method of lessening the incidence of medium chain triglyceride-mediated central nervous system effects in a patient comprising providing a drug formulation comprising a pharmacologically active drug and long chain triglycerides, said long chain triglycerides present in an amount sufficient to reduce or negate the incidence of medium-chain fatty acid mediated central nervous system effects, and administering the product of step a) to a patient.
  • a drug formulation comprising a pharmacologically active drug and long chain triglycerides, said long chain triglycerides present in an amount sufficient to reduce or negate the incidence of medium-chain fatty acid mediated central nervous system effects, and administering the product of step a) to a patient.
  • Embodiments for this aspect may track any of the composition embodiments for the foregoing aspect and combinations thereof.
  • the invention features methods of using the pharmaceutical compositions, formulations, methods and products described above for treating or preventing a disorder in an organism, e.g., a mammal, by administering to the organism a pharmaceutically effective amount of product.
  • the disorder at least in the instance of mammalian treatment, is preferably selected from the group of disorders consisting of ischemia, proliferative disorders and neural damage, and includes an HSP90 inhibitor, e.g, one or more ansamycins, as the pharmacologically active drug.
  • Proliferative disorders include but are not limited to tumors and cancers, inflammatory diseases, fungal infections, yeast infections, and viral infections.
  • the mammal is human.
  • the administration mode is intravenous, although as described in more detail, below, other modes of administration are also contemplated.
  • Advantages of the invention include, depending on the specific embodiment, one or more of ease of manufacture, the use of clinically acceptable reagents (e.g., having reduced environmental and/or patient toxicity), enhanced formulation stability, uncomplicated shipment and warehousing, simple pharmacy and bed-side handling, IV and systemic tolerance upon administration, and the negation of certain undesirable side-effects that often accompany medium chain fatty acids and triglyceride loads in the body.
  • the term "pharmacologically active compound” is synonymous with "drug” and means any compound that exerts, directly or indirectly, a biological effect, in vitro or in vivo when administered to cultured cells or to an organism.
  • the drug is preferably capable of encasement in liposomes and/or emulsification, and will typically, although not necessarily, be lipophilic.
  • inert atmospheric condition is one that is relatively less reactive than the air of standard atmospheric conditions.
  • pure or substantially pure nitrogen gas during formulation is one example of such an inert atmospheric condition. Persons of ordinary skill in the art are familiar with others.
  • hydrating or rehydrating means adding an aqueous solution, e.g., water or a physiologically compatible buffer such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • aqueous solution e.g., water or a physiologically compatible buffer such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • ansa structure which comprises any one of benzoquinone, benzohydroquinone, naphthoquinone or naphthohydroquinone moities bridged by a long chain.
  • Compounds of the naphthoquinone or naphthohydroquinone class are exemplified by the clinically important agents rifampicin and rifamycin, respectively.
  • geldanamycin including its synthetic derivatives 17-allylamino-17- demothoxy geldanamycin (17-AAG) and 17-N,N-dimethylamino-ethylamino-17- demethoxygeldanamycin (DMAG)), dihydrogeldanamycin and herbamycin.
  • the benzohydroquinone class is exemplified by macbecin. Ansamycins and benzoquinone ansamycins according to this invention.
  • Ansamycins and benzoquinone ansamycins according to the invention may be synthetic, naturally-occurring, or a combination of the two, i.e., "semi-synthetic", and may include dimers and conjugated variant and prodrug froms.
  • Some exemplary benzoquinone ansamycins useful in the processes of the invention and their methods of preparation include but are not limited to those described, e.g., in U.S. Patents 3,595,955 (describing the preparation of geldanamycin), 4,261,989, 5,387,584, and 5,932,566.
  • Geldanamycin is also commercially available, e.g., from CN Biosciences, an affiliate of Merck KGaA, Darmstadt, Germany, headquartered in San Diego, California, USA (cat. no. 345805).
  • the biochemical purification of the geldanamycin derivative, 4,5- Dihydrogeldanamycin and its hydroquinone from cultures of Streptomyces hygroscopicus (ATCC 55256) are described in International Application Number PCT/US92/10189, assigned to Pfizer Inc., published as WO 93/14215 on July 22, 1993, and listing Cullen et al. as inventors; an alternative method of synthesis for 4,5-Dihydrogeldanamycin by catalytic hydrogenation of geldanamycin is also known.
  • Oils include fatty acids and glycerides containing the same, e.g., mono-, di- and triglycerides as known in the art.
  • the fatty acids and glycerides for use in the invention can be saturated and/or unsaturated, natural and/or synthetic, charged or neutral.
  • Synthetic may be entirely synthetic or semisynthetic as those terms are known in the art.
  • the oils may also be homogenous or heterogeneous in their constituents and/or origin.
  • Medium chain triglycerides as used herein are triglyceride compositions having fatty acids ranging in size from 8-12 linear carbon atoms in length, and more preferably 8-10 carbon atoms in length.
  • Various embodiments of the invention include the use of Miglyol®
  • Miglyol® 812 contains roughly
  • Caprylic acid 8 carbons
  • Capric acid 10 carbons
  • Caproic acid (6 carbon atoms) is also present, up to a maximum of about 2%, as is Costume Acid (12 carbons). Present in still a lesser amount (1% max) is Myristic acid (14 carbons). Condea also offers
  • Miglyol® 810, 818, 829, and 840 are examples of these other organic compounds.
  • Miglyol® solutions as well as other medium chain triglyceride solutions can also be used more or less successfully in connection with various aspects and embodiments of the invention. As to the latter, one of ordinary skill in the art knows their identity, source and/or manner of preparation, and can acquire or prepare them without undue investigation or experimentation. Miglyol 812N has monographs in the European Pharmacopeia as Medium
  • Short chain triglycerides are triglyceride compositions having fatty acids less than 8 linear carbon atoms in length.
  • Long chain triglycerides are triglyceride compositions having fatty acids greater than 12 linear carbon atoms in length.
  • a common source of these is vegetable oil, for example, soy oil, which typically contains 55-60% linoleic acid (9,12-octadecadienoic acid), 22%) oleic acid (cis-9-octadecenoic acid), and lesser amounts of palmitic and stearic acid.
  • short, medium and long can also be used with respect to a fatty acid alone, in which case the definitions of such include, respectively, less than 8 linear carbon atoms, 8 to 12 linear carbon atoms, and greater than 12 linear carbon atoms.
  • Phospholipon 90G has previously been used in parenteral nutritional products such as Intralipid® at a concentration of about 1.2%, Doxil® (doxorubicin) at about 1%, Ambisome® (amphotericin B) at about 2%, and Propofol® at about 1.2%. In the case of the latter, see, e.g., US Patent 6,140,374.
  • the surfactant/emulsifying agent is typically present in a concentration of about 0.5-25% w/v based on the amount of the water and/or other components into which the surfactant is dissolved.
  • the surfactant is present in a concentration of about 0.5-10%) w/v, most preferably about 1-8% w/v.
  • anionic surfactants include sodium lauryl sulfate, lauryl sulfate triethanolamine, sodium polyoxyethylene lauryl ether sulfate, sodium polyoxyethylene nonylphenyl ether sulfate, polyoxyethylene lauryl ether sulfate triethanolamine, sodium cocoylsarcosine, sodium N-cocoylmethyltaurine, sodium polyoxyethylene (coconut)alkyl ether sulfate, sodium diether hexylsulfosuccinate, sodium a-olefin sulfonate, sodium lauryl phosphate, sodium polyoxyethylene lauryl ether phosphate, perfluoroalkyl carboxylate salt (manufactured by Daikin Industries Ltd.
  • cationic surfactants include dialkyl(C 12 -C 22 )dimethylammonium chloride, alkyl(coconut)dimethylbenzylammonium chloride, octadecylamine acetate salt, tetradecylamine acetate salt, tallow alkylpropylenediamine acetate salt, octadecyltrimethylammonium chloride, alkyl(tallow) trimethylammonium chloride, dodecyltrimethylammonium chloride, alkyl(coconut) trimethylammonium chloride, hexadecyltrimethylammonium chloride, biphenyltrimethylammonium chloride, alkyl(tallow)- imidazoline quaternary salt, tetradecylmethylbenzylammonium chloride, octadecyidimethylbenzylammonium chloride, dio
  • nonionic surfactants include polyoxyethylene lauryl ether, polyoxyethylene tridecyl ether, polyoxyethylene cetyl ether, polyoxyethylene polyoxypropylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene octylphenyl ether, polyoxyethylene monolaurate, polyoxyethylene monostearate, polyoxyethylene monooleate, sorbitan monolaurate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene polyoxypropylene block
  • a “physiologically acceptable carrier” refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • An “excipient” refers to a substance added to a pharmacological composition to further facilitate administration of a compound. Examples of excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose and cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. These can also be physiologically acceptable carriers, as described above, e.g., sucrose. Further falling within the definition of excipient are bulking agents.
  • sucrose is thought to form an amorphous glass upon freezing and subsequent lyophilization, allowing for potential stability enhancement of the formulation by forming a dispersion of the oil droplets containing the active ingredient in a rigid glass. Stability may also be enhanced by virtue of the sugar acting as a replacement for the water lost upon lyophilization. The sugar molecules, rather than the water molecules, become bonded to the interfacial phospholipid through hydrogen bonds.
  • Lyophilization is the removal or substantial removal of liquid from a sample, e.g., by sublimation, and as described in the section above entitled “solvent removal.” .
  • Lipids can be detected in the region of 203-205 nm. Unsaturated fatty acids exhibit high absorbance while the saturated fatty acids exhibit lower absorbance in the 200 nm wavelength region of the UV spectrum.
  • Vemuri and Rhodes, supra described the separation of egg yolk PC and PG on Licrosorb Diol and Licrosorb SI -60. The separations used a mobile phase of acetonitrile- methanol with 1% hexane- water (74:16:10 v/v/v). In 8 minutes, separation of PG from PC was observed. Retention times were approximately 1.1 and 3.2 min, respectively.
  • Emulsion droplet size distribution can be determined, e.g., using a particle size distribution analyzer such as the CAPA-500 made by Horiba Limited (Am Arbor, MI, USA), a Coulter counter (Beckman Coulter Inc., Brea, CA, USA), or a Zetasizer (Malvern Instruments, Southborough, MA, USA). Stability Determination Using HPLC
  • the chemical stability of the therapeutically active ingredient can be assessed by HPLC after extraction of the emulsion.
  • Specific assay procedures can be developed that allow for the separation of the therapeutically active ansamycin from its degradation products.
  • the extent of degradation can be assessed either from the decrease in signal in the HPLC peak associated with the therapeutically active ansamycins and/or by the increase in signal in the HPLC peak(s) associated with degradation products.
  • Ansamycins, relative to other components of the emulsion components are easily and quite specifically detected at their absorbance maximum of 345 nm.
  • compositions may be manufactured utilizing conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • Table illustrates a 4000 gm batch preparation of 17-AAG made according to one embodiment of the invention.
  • the skilled artisan will recognize that the procedure can be scaled up or down, that variations can be made with respect to the amounts of individual components, etc., and that additional components not listed may also be added.
  • the emulsion pH is adjusted to 6.0 +/- 0.2 with 0.2N NaOH.
  • Tlie primary emulsion is then passed through a Model 110S microfluidizer (Microfluidics Inc., Newton, MA, USA) operating at static pressure of about 110 psi (operating pressure of 60-95 psi) with a 75- micron emulsion interaction chamber (F20Y) for 6-8 passages until the average droplet size is ⁇ 190 nm.
  • LLS may be used following the individual passages to evaluate progress.
  • the solution may further be checked for the presence of crystals using polarized light under an optical microscope.
  • the emulsion is then passed across a 0.45 micron Gelman mini capsule filter (Pall Corp., East Hills, NY, USA), and then across a sterile 0.2 micron Sartorius Sartobran P capsule filter (500 cm 2 ) (Sartorius AG, Goettingen, Germany). Pressure up to 60 PSI is used to maintain a smooth and continuous flow. Filtrate is collected in one or more polypropylene bottles and immediately placed in a -20°C freezer. A 1-ml aliquot may be set aside for testing using laser light scattering (LLS) and/or high performance liquid chromatography (HPLC).
  • LLC laser light scattering
  • HPLC high performance liquid chromatography
  • 17-AAG can be brought into solution in the oil phase without ethanol being present by heating a preformed emulsifying agent in triglyceride solution, e.g., Phospholipon in Miglyol® 812, preferably to 65° C or more, adding to this the drug, e.g., 17- AAG, and mixing, e.g., by stirring and/or sonication. It has also been discovered that a lower melting point form of 17-AAG from example 2 prepared through crystallization of 17-AAG from isopropanol rather than ethanol more readily can be dissolved into the Phospholipon in Miglyol solution at room temperature.
  • a preformed emulsifying agent in triglyceride solution e.g., Phospholipon in Miglyol® 812
  • Emulsification can be accomplished by mechanical mixing, by treating with ultrasonic irradiation, and finally by passage through a microfluidizer, although it will be understood that the terms "emulsify” and “emulsification” should not be limited to such processing events and that other emulsification techniques exist and can be used alternatively or in tandem with one or more of the preceding techniques.
  • a variation of the processes described above includes the addition of long chain triglycerides, e.g., in the form of soya oil.
  • a source of long chain triglycerides (soya oil) is mixed with Miglyol 812N (a source of medium chain triglycerides) and an emulsifying agent (Phospholipon 90G (PL90G)), in the following respective w/w proportions: 16.7%:50.0%:33.3%. This is homogenized until the PL90G is completely dissolved (-20,000 rpm for about 20 minutes).
  • This "primary" emulsion is then microfluidized by passage through an F12Y interaction chamber and filter sterilized using a 0.2 ⁇ m polyethersulfone (PES) filter membrane.
  • PES polyethersulfone
  • Lyophilization of the emulsions from Examples 5 and 6 may be accomplished according to a scheme similar to that in the following Table.
  • the stability profile for the lyophilized 17-AAG emulsion was as follows when stored at 2-8 °C, and following reconstitution:
  • Example 8 Long Chain Triglycerides Inhibit Somnolence Miglyol 812N, when administered rapidly, can cause sedation due to the metabolic release of octanoate.
  • sedation was observed at infusion rates greater than 1.1 gm total lipid/Kg/hr. See Figure 2. Sedation was also noted in dogs given intravenous iinfusions of the 17-AAG emulsion formulation at rates greater than 1.13 gm total lipid/kg/hr.
  • soybean oil was added as described above to compete with the metabolism of Miglyol 812N in- vivo to reduce octanoate fatty acid produced during intravenous infusions.
  • soybean oil/Miglyol 812N CF237 emulsions no sedation was observed acutely in rats at infusion rates of up to about 40 gm total lipid/kg/hr.
  • the combination of soybean oil with Miglyol 812N greatly improves tolerability of the CF237 emulsion formulation with regard to sedation.
  • no sedation was observed in monkeys administered six doses of the CF237 emulsion formulation as an intravenous infusion of 12 mL formulation/kg/hr, and no vein irritation was observed.
  • Ansmaycins Other Than 17-AAG Essentially any ansamycin can be substituted for 17-AAG and formulated as described in the above examples. Various such ansamycins and their preparation are detailed in PCT/US03/04283. The preparation of two of these are described below.
  • Compound 237 A dimer. 3,3'-diamino-dipropylamine (1.32g, 9.1mmol) was added dropwise to a solution of Geldanamycin (lOg, 17.83mmol) in DMSO (200ml) in a flame- dried flask under N 2 and stirred at room temperature. The reaction mixture was diluted with water after 12 hours. A precipitate was formed and filtered to give the crude product. The crude product was chromatographed by silica chromatography (5% CH 3 0H/CH 2 C1 2 ) to afford the desired dimer as a pu ⁇ le solid.
  • the corresponding HC1 salt was prepared by the following method: an HC1 solution in EtOH (5 ml, 0.123N) was added to a solution of compound #237 (1 gm as prepared above) in THF (15 ml) and EtOH (50 ml) at room temperature. The reaction mixture was stirred for

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Abstract

L'invention a trait à des préparations médicamenteuses contenant des émulsifiants et à la fois des triglycérides à chaîne moyenne et des triglycérides à longue chaîne. Dans des modes de réalisation préférés, les triglycérides à longue chaîne éliminent ou réduisent les effets néfastes pour le système nerveux central des triglycérides à chaîne moyenne.
PCT/US2003/031667 2002-04-10 2003-10-04 Preparations medicamenteuses contenant des triglycerides a longue chaine et a chaine moyenne Ceased WO2004082676A1 (fr)

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JP2005513578A JP2006514994A (ja) 2003-03-13 2003-10-04 長鎖および中鎖トリグリセリドを有する医薬製剤
EP03816401A EP1605931A4 (fr) 2003-03-13 2003-10-04 Preparations medicamenteuses contenant des triglycerides a longue chaine et a chaine moyenne
AU2003277299A AU2003277299B2 (en) 2002-04-10 2003-10-04 Drug formulations having long and medium chain triglycerides
CA002518836A CA2518836A1 (fr) 2003-03-13 2003-10-04 Preparations medicamenteuses contenant des triglycerides a longue chaine et a chaine moyenne
US10/548,968 US20060148776A1 (en) 2003-03-13 2003-10-04 Drug formulations having long and medium chain triglycerides

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US45481203P 2003-03-13 2003-03-13
US60/454,812 2003-03-13
USPCT/US03/10533 2003-04-04
PCT/US2003/010533 WO2003086381A1 (fr) 2002-04-10 2003-04-04 Formulations d'ansamycine et procedes de production et d'utilisation de celles-ci
US47843003P 2003-06-12 2003-06-12
US60/478,430 2003-06-12
US49105003P 2003-07-29 2003-07-29
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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006094029A3 (fr) * 2005-02-28 2007-04-12 Kosan Biosciences Incoporated Preparations pharmaceutiques contenant 17-allylamino-17-demethoxygeldanamycine
WO2007064926A3 (fr) * 2005-12-01 2007-12-13 Conforma Therapeutics Corp Compositions contenant de l'ansamycine
JP2008535844A (ja) * 2005-04-07 2008-09-04 コンフォーマ・セラピューティクス・コーポレイション リン脂質をベースとする医薬製剤およびその製造および使用方法
US7662813B2 (en) 2005-08-18 2010-02-16 Synta Pharmaceuticals Corp. Triazole compounds that modulate HSP90 activity
US7691392B2 (en) 2005-04-29 2010-04-06 Kosan Biosciences Incorporated Method of treating multiple myeloma using 17-AAG or 17-AG or a prodrug of either
US7825148B2 (en) 2004-11-18 2010-11-02 Synta Pharmaceuticals Corp. Triazole compounds that modulate Hsp90 activity
US7947670B2 (en) 2006-12-12 2011-05-24 Infinity Pharmaceuticals Inc. Ansamycin formulations and methods of use thereof
US8252779B2 (en) 2003-12-23 2012-08-28 Infinity Pharmaceuticals, Inc. Analogs of benzoquinone-containing ansamycins and methods of use thereof
US8778921B2 (en) 2008-10-15 2014-07-15 Infinity Pharmaceuticals, Inc. Ansamycin hydroquinone compositions
US9101615B2 (en) 2009-08-14 2015-08-11 Opko Health, Inc. Intravenous formulations of neurokinin-1 antagonists
US9205086B2 (en) 2010-04-19 2015-12-08 Synta Pharmaceuticals Corp. Cancer therapy using a combination of a Hsp90 inhibitory compounds and a EGFR inhibitor
US9402831B2 (en) 2011-11-14 2016-08-02 Synta Pharmaceutical Corp. Combination therapy of HSP90 inhibitors with BRAF inhibitors
US9439899B2 (en) 2011-11-02 2016-09-13 Synta Pharmaceuticals Corp. Cancer therapy using a combination of HSP90 inhibitors with topoisomerase I inhibitors
US10500193B2 (en) 2011-11-02 2019-12-10 Synta Pharmaceuticals Corporation Combination therapy of HSP90 inhibitors with platinum-containing agents

Families Citing this family (1)

* Cited by examiner, † Cited by third party
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CN106018611B (zh) * 2016-06-21 2018-08-24 广州白云山汉方现代药业有限公司 一种气相色谱内标法检测中链甘油三酯含量的测定方法

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US5932566A (en) * 1994-06-16 1999-08-03 Pfizer Inc. Ansamycin derivatives as antioncogene and anticancer agents
US6140374A (en) * 1998-10-23 2000-10-31 Abbott Laboratories Propofol composition

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EP0706516A1 (fr) * 1993-06-29 1996-04-17 Pfizer Inc. Derives de l'ansamycine utilises comme agents anti-oncogenes et anticancereux
DE10036871A1 (de) * 2000-07-28 2002-02-14 Pharmasol Gmbh Dispersionen zur Formulierung wenig oder schwer löslicher Wirkstoffe
JP2005528390A (ja) * 2002-04-10 2005-09-22 コンフォーマ・セラピューティクス・コーポレイション アンサマイシン製剤およびその製造ならびに使用方法

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US5932566A (en) * 1994-06-16 1999-08-03 Pfizer Inc. Ansamycin derivatives as antioncogene and anticancer agents
US6140374A (en) * 1998-10-23 2000-10-31 Abbott Laboratories Propofol composition

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
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See also references of EP1605931A4 *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8252779B2 (en) 2003-12-23 2012-08-28 Infinity Pharmaceuticals, Inc. Analogs of benzoquinone-containing ansamycins and methods of use thereof
US8703755B2 (en) 2003-12-23 2014-04-22 Infinity Pharmaceuticals, Inc. Analogs of benzoquinone-containing ansamycins and methods of use thereof
US8901308B2 (en) 2004-11-18 2014-12-02 Synta Pharmaceuticals Corp. Triazole compounds that modulate Hsp90 activity
US7825148B2 (en) 2004-11-18 2010-11-02 Synta Pharmaceuticals Corp. Triazole compounds that modulate Hsp90 activity
US8362055B2 (en) 2004-11-18 2013-01-29 Synta Pharmaceuticals, Inc. Triazole compounds that modulate HSP90 activity
EP1853238A4 (fr) * 2005-02-28 2008-07-23 Kosan Biosciences Inc Preparations pharmaceutiques contenant 17-allylamino-17-demethoxygeldanamycine
WO2006094029A3 (fr) * 2005-02-28 2007-04-12 Kosan Biosciences Incoporated Preparations pharmaceutiques contenant 17-allylamino-17-demethoxygeldanamycine
JP2008535844A (ja) * 2005-04-07 2008-09-04 コンフォーマ・セラピューティクス・コーポレイション リン脂質をベースとする医薬製剤およびその製造および使用方法
US7691392B2 (en) 2005-04-29 2010-04-06 Kosan Biosciences Incorporated Method of treating multiple myeloma using 17-AAG or 17-AG or a prodrug of either
US7662813B2 (en) 2005-08-18 2010-02-16 Synta Pharmaceuticals Corp. Triazole compounds that modulate HSP90 activity
JP2009518302A (ja) * 2005-12-01 2009-05-07 コンフォーマ・セラピューティクス・コーポレイション アンサマイシン含有組成物
WO2007064926A3 (fr) * 2005-12-01 2007-12-13 Conforma Therapeutics Corp Compositions contenant de l'ansamycine
US8283343B2 (en) 2006-12-12 2012-10-09 Infinity Pharmaceuticals Inc. Ansamycin formulations and methods of use thereof
US8357676B2 (en) 2006-12-12 2013-01-22 Infinity Discovery, Inc. Ansamycin formulations and methods of use thereof
US7947670B2 (en) 2006-12-12 2011-05-24 Infinity Pharmaceuticals Inc. Ansamycin formulations and methods of use thereof
US8778921B2 (en) 2008-10-15 2014-07-15 Infinity Pharmaceuticals, Inc. Ansamycin hydroquinone compositions
US9101615B2 (en) 2009-08-14 2015-08-11 Opko Health, Inc. Intravenous formulations of neurokinin-1 antagonists
US9205086B2 (en) 2010-04-19 2015-12-08 Synta Pharmaceuticals Corp. Cancer therapy using a combination of a Hsp90 inhibitory compounds and a EGFR inhibitor
US9439899B2 (en) 2011-11-02 2016-09-13 Synta Pharmaceuticals Corp. Cancer therapy using a combination of HSP90 inhibitors with topoisomerase I inhibitors
US10500193B2 (en) 2011-11-02 2019-12-10 Synta Pharmaceuticals Corporation Combination therapy of HSP90 inhibitors with platinum-containing agents
US9402831B2 (en) 2011-11-14 2016-08-02 Synta Pharmaceutical Corp. Combination therapy of HSP90 inhibitors with BRAF inhibitors

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AU2003277299A1 (en) 2004-10-11
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EP1605931A1 (fr) 2005-12-21
CA2518836A1 (fr) 2004-09-30
EP1605931A4 (fr) 2009-04-29
AU2003277299B2 (en) 2009-12-10

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