Classifications

• • 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
• • 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 invention features a pharmaceutical composition
• a pharmaceutical composition comprising a pharmacologically active compound, e.g., an ansamycin such as 17-AAG, in combination with an emulsifying agent (e.g., phospholipids such as found in lecithin) and oil.
• a pharmacologically active compound e.g., an ansamycin such as 17-AAG
• an emulsifying agent e.g., phospholipids such as found in lecithin
• the oil may and preferably does contain long chain triglycerides.
• the composition can also contain medium chain triglycerides.
• the emulsifying agent and oil together constitute a lipid phase.
• 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.
• triglycerides are present, at least in part, in the form of naturally existing oils, e.g., plant oils such as soy, sesame, safflower and corn.
• 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.
• the composition has the following components: 2 mg/ml 17- AAG, 3.3% soy oil, 6.6% lecithin, 9.9% Miglyol 812N, 7.5% sucrose, and water. In another embodiment, the composition has the following components: 2 mg/ml 17-
• 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.
• compositions are also formulated and/or stored in an inert atmospheric conditions, e.g., in the case of the latter a dark and/or light impervious bottle, vial, or ampoule.
• 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.
• Figure 1 illustrates reduced somnolence in rats attributable to inclusion of long chain fatty acids in formulations that contain medium chain triglycerides.
• the formulations of the invention have particular merit in rendering water-insoluble drugs suitable for intravenous and other types of administration to a patient.
• the method of formulation is relatively simple, typically utilizes clinically acceptable reagents, and results in a product that affords storage, stability, and biotolerability advantages over existing methods and products.
• 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.
• Emsifying agents are synonymous with “surfactants” and include but are not limited to phospholipids such as lecithins.
• “Lecithins” are naturally occurring mixtures of diglycerides of stearic, palmitic, and oleic acids, linked to the choline ester of phosphoric acid.
• the term surfactant or emulsifying agent also embraces phosphatidylcholine, which distinct compound is well known.
• Preferred emulsifying agents for use with the invention are soya lecithin, e.g., Phospholipon 90G as supplied by American Lecithin Company (Oxford, CT, USA).
• 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.
• a “bulking agent” generally provides mechanical support for a lyophile formulation by allowing the dry formulation matrix to maintain its conformation.
• Sugars as used herein include but are not limited to monosaccharides, disaccharides, oligosaccharides and polysaccharides. Specific examples include but are not limited to fructose, glucose, mannose, trehalose, sorbose, xylose, maltose, lactose, sucrose, dextrose, and dextran.
• Sugar also includes sugar alcohols, such as mannitol, sorbitol, inositol, dulcitol, xylitol and arabitol. Mixtures of sugars may also be used in accordance with this invention.
• bulking agents e.g., glycerol, sugars, sugar alcohols, and mono and disaccharides may also serve the function of isotonizing agents, as described above. It is preferred that the bulking agents be chemically inert to drug(s) and have no or extremely limited detrimental side effects or toxicity under the conditions of use.
• other carriers that may or may not serve the purpose of bulking agents include, e.g., adjuvants and diluents as well known and readily available in the art.
• a prefe ⁇ -ed bulking agent for the invention is sucrose.
• 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.
• cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl- cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
• disintegrating agents may also be added, e.g., cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
• an amount that lessens or negates the incidence of medium chain triglyceride-mediated central nervous system effects can be empirically determined by one or ordinary skill without undue experimentation using the starting points described herein.
• Emulsification Emulsions comprising an oil phase and an aqueous phase are widely known in the art as carriers of therapeutically active ingredients or as sources of parenteral nutrition.
• Emulsions can exist as either oil-in-water or water-in-oil forms. If, as is the case in the current instance, the therapeutic ingredient is particularly soluble in the oil phase the oil-in- water type is the preferred embodiment.
• Simple emulsions are thermodynamically unstable systems from which the oil and aqueous phases separate (coalescence of oil droplets). Incorporation of emulsifying agent(s) into the emulsion is critical to reduce the process of coalescence to insignificant levels.
• antioxidants e.g., alpha-tocopherol and butylated hydroxytoluene
• preservatives such as edentate
• oxygen deprivation e.g., formulation in the presence of inert gases such as nitrogen and argon, and/or the use of light resistant containers.
• Emulsification can be effected by a variety of well known techniques, e.g., mechanical mixing, homogenization (e.g., using a polytron or Gaulin high-energy-type instrument), vortexing, and sonication. Sonication can be effected using a bath-type or probe-type instrument.
• Microfluidizers are commercially available, e.g., from Microfluidics Corp., Newton, Mass., are further described in U.S. Patent 4,533,254, and make use of pressure-assisted passage across narrow orifices. Pressure assisted extrusion through various commercially available polycarbonate membranes may also be employed.
• Low pressure devices also exist that can be used. These high and low pressure devices can be used to select for and/or modulate vesicle size.
• Filtration can include a pre-filtration through a larger diameter filter, e.g., a 0.45 micron filter, and then through smaller filter, e.g., a 0.2 micron filter.
• the preferred filter medium is cellulose acetate (Sartorius- SartobranTM). Lyophilization
• 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.” .
• Phospholipids and degradation products may be determined after being extracted from emulsions.
• the lipid mixture can then be separated in a two-dimensional thin-layer chromatographic (TLC) system or in a high performance liquid chromatographic (HPLC) system.
• TLC thin-layer chromatographic
• HPLC high performance liquid chromatographic
• spots corresponding to single constituents can be removed and assayed for phosphorus.
• Total phosphorous in a sample can be quantitatively determined, e.g., by a procedure using a spectrophotometer to measure the intensity of blue color developed at 825 nm against water.
• HPLC phosphatidylcholine (PC) and phosphotidylglycerol (PG) can be separated and quantified with accuracy and precision.
• PC phosphatidylcholine
• PG phosphotidylglycerol
• 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 visual appearance, average droplet size, and size distribution can be important parameters to observe and maintain. There are a number of methods to evaluate these parameters. For example, dynamic light scattering and electron microscopy are two techniques that can be used. See, e.g., Szoka and Papahadjopoulos, Annu. Rev. Biophys. Bioeng., 9:467-508 (1980). Morphological characterization, in particular, can be accomplished using freeze fracture electron microscopy. Less powerful light microscopes can also be used.
• 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.
• intravenous administration is preferred in various aspects and embodiments of the invention
• one of ordinary skill will appreciate that the methods can be modified or readily adapted to accommodate other administration modes, e.g., oral, aerosol, parenteral, subcutaneous, intramuscular, intraperitoneal, rectal, vaginal, intratumoral, or peritumoral.
• administration modes e.g., oral, aerosol, parenteral, subcutaneous, intramuscular, intraperitoneal, rectal, vaginal, intratumoral, or peritumoral.
• administration modes e.g., oral, aerosol, parenteral, subcutaneous, intramuscular, intraperitoneal, rectal, vaginal, intratumoral, or peritumoral.
• compositions may be manufactured utilizing conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
• compositions may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Some excipients and their use in the preparation of formulations have already been described. Others are known in the art, e.g., as described in PCT/US99/30631, Remmington's Pharmaceutical Sciences, Meade Publishing Co., Easton, PA (most recent edition), and Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Pergamon Press, New York, N.Y. (most recent edition).
• the agents may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer, as each are well-known in the art.
• physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer, as each are well-known in the art.
• penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
• Formulations of the invention are well suited for immediate or near-immediate parenteral administration by injection, e.g., by bolus injection or continuous infusion.
• Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative, e.g., edetate.
• the pharmaceutical compositions of the invention can be stored in an inert environment, e.g., in ampoules or other packaging that are light-resistant or oxygen-free.
• a phase I pharmacologic study of 17-AAG in adult patients with advanced solid tumors determined a maximum tolerated dose (MTD) of 40 mg/m 2 when administered daily by 1-hour infusion for 5 days every three weeks.
• MTD maximum tolerated dose
• Wilson et al Am. Soc. Clin. Oncol., abstract, Phase I Pharmacologic Study of 17-(Allylamino)-17-Demethoxygeldanamycin (AAG) in Adult Patients with Advanced Solid Tumors (2001).
• mean +/- SD values for terminal half-life, clearance and steady-state volume were determined to be 2.5+/- 0.5 hours, 41.0+/-13.5 L/hour, and 86.6 +/-34.6 L/m 2 .
• Plasma Cmax levels were determined to be 1860+/-660 nM and 3170+/-1310 nM at 40 and 56 mg/m2. Using these values as guidance, it is anticipated that the range of useful patient dosages for formulations of the present invention will include between about 0.40 mg/m 2 and 4000 mg/m 2 of active ingredient. M 2 represents surface area. Standard algorithms exist to convert mg/m 2 to mg drug/kg bodyweight.
• the 17-AAG obtained from any one of Examples 1-4, above, is dissolved in ethanol.
• 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.
• 17-AAG (CNF-101) is weighed in a 5L polypropylene beaker. Ethanol is added in an amount approximately 50x the drug weight and the solution sonicated in a water bath to disperse the drug. Miglyol 812 (Sasol North America Inc; Houston, TX, USA) and Phospholipon 90G (American Lecithen Co., Oxford, CT, USA) are then added to the dispersion and the mixture placed on a stir plate and stirred until the solids are more or less completely dissolved. A sonicator bath and/or heat to approximately 45°C may be used to help dissolve the solids. The solution may be checked using an optical microscope to ensure desired dissolution.
• a stream of dry air or nitrogen (National Formulary) gas is forced over the liquid surface in combination with vigorous stirring to evaporate the ethanol until the ethanol content is reduced, preferably to less than 50%) of its initial presence, more preferably to less than 10%, and most preferably to about 5%o or less, w/w.
• the solution can be checked under an optical microscope equipped with polarizing filters to ensure the desired level of dissolution, preferably complete dissolution (no crystals or precipitate).
• EDTA sodium, dihydrate, USP
• sucrose sucrose
• water for injection WFI
• EDTA sodium, dihydrate, USP
• WFI water for injection
• the aqueous phase is then added to the oil phase and thorough mixing effected using a high-speed emulsifier equipped with an emulsion head at 5000 RPM until the oil adhering to the surface is "stripped off.” Shearing rate is then increased to 10000 RPM for 2-5 minutes to obtain a uniform primary emulsion.
• Laser light scattering LLS may be used to measure the average droplet size, and the solution may further be checked , e.g.,. under an optical microscope to determine the relative presence or absence of crystals and solids.
• 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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