Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
  • C07D225/04—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• This invention relates to new 17-allylamino- 17-demethoxygeldanamycin ("17- AAG”) polymorphs, methods for making such new polymorphs, pharmaceutical formulations containing 17- AAG (especially formulations containing such new polymorphs), and methods for making and using such pharmaceutical formulations.
• 17- AAG 17-allylamino- 17-demethoxygeldanamycin
• Geldanamycin belongs to the ansamycin natural product family, whose members are characterized by a macrolactam ring spanning two positions meta to each other on a benzenoid nucleus.
• the ansamycins include the macbecins, the herbimycins, the TAN-420s, and reblastatin.
• Hsp90 heat shock protein-90
• client proteins proteins
• the binding of geldanamycin to Hsp90 disrupts Hsp90-client protein interactions, preventing the client proteins from being folded correctly and rendering them susceptible to proteasome- mediated destruction.
• Hsp90 client proteins are many mutated or overexpressed proteins implicated in cancer: p53, Bcr-Abl kinase, Raf-1 kinase, Akt ldnase, Npm-Alk kinase, Cdk4, Cdk6, Weel, HER2/Neu (ErbB2), and hypoxia inducible factor- l ⁇ (HIF- l ⁇ ).
• p53 Bcr-Abl kinase
• Raf-1 kinase Akt ldnase
• Npm-Alk kinase Npm-Alk kinase
• Cdk4 Cdk4
• Cdk6 Weel
• HER2/Neu ErbB2
• hypoxia inducible factor- l ⁇ HIF- l ⁇
• Sasaki et al US 4,261,989 (1981) (hereinafter "Sasaki”); Schnur et al, US 5,932,566 (1999); Schnur et al, J. Med. Chem. 1995, 38 (19), 3806-3812; Schnur et a!., J. Med. Chem. 1995 38 (19), 3813-3820; and Santi et al, US 6,872,715 B2 (2005); the disclosures of which are incorporated by reference.
• the SAR inferences are supported by the X-ray crystal co- structure of the complex between Hsp90 and a geldanamycin derivative, showing that the 17-substituent juts out from the binding pocket and into the solvent (Jez et al, Chemistry & Biology 2003, 10, 361-368).
• the best-known 17-substituted geldanamycin derivative is 17-AAG, first disclosed in Sasaki and currently undergoing clinical trials.
• Another noteworthy derivative is 17-(2-dimethylaminoethyl)amino-17-demethoxygeldanamycin ("17-DMAG", Snader et al, 6,890,917 B2 (2005)), also in clinical trials.
• polymorphs of the drug being formulated may differ in their pharmaceutically relevant properties, including solubility, storage stability, hygroscopicity, density, and bioavailability.
• One polymorph may more or less spontaneously convert to another polymorph during storage.
• a formulation designed to deliver a particular polymorph may end up containing a different polymorph that is incompatible with the formulation.
• a hygroscopic polymorph may pick up water during storage, introducing errors into weighing operations and affecting handleability.
• a preparation procedure designed for use with a particular polymorph may be unsuitable for use with a different polymorph.
• polymorph includes amorphous forms and non-solvated and solvated crystalline forms, as specified in guideline Q6A(2) of the ICH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use).) [0006] It is now known that 17-AAG is polymorphic. Sasaki originally disclosed a single form of 17-AAG melting at 212-214 °C.
• Mansfield includes X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) data for both forms and discloses oral pharmaceutical formulations made with them. Mansfield further discloses that the low melt form is actually a mixture of two polymorphs and that it is his preferred form for use in pharmaceutical formulations.
• XRPD X-ray powder diffraction
• DSC differential scanning calorimetry
• the water miscible solvent can be dimethylsulfoxide (DMSO), dimethylformamide, ethanol, glycerin, propylene glycol, or polyethylene glycol.
• the surfactant can be egg phospholipid.
• Mansfield discloses a pharmaceutical formulation for oral administration, comprising an ansamycin and one or more pharmaceutically acceptable solubilizers, with the proviso that when the solubilizer is a phospholipid, it is present in a concentration of at least 5% w/w of the formulation.
• solubilizers disclosed include polyethylene glycols of various molecular weights, ethanol, sodium lauryl sulfate, Tween 80, Solutol® HS 15, propylene carbonate, and so forth. Both dispersion and solution embodiments are disclosed.
• the present invention provides new polymorphs of 17-AAG and pharma- ceutical formulations made therefrom, in particular an especially desirable polymorph that is superior for the preparation of dispersion-based pharmaceutical formulations.
• This invention provides novel polymorphs of 17- AAG, including some that are especially suitable for use in suspension formulations.
• Two such suitable polymorphs are designated Polymorph C and Polymorph G, especially when used in their purified forms. Their preparation and characteristics are described in greater detail hereinbelow.
• a pharmaceutical suspension formulation comprising (a) 17-AAG comprising a polymorph selected from purified Polymorph C, purified Polymorph G, and combinations thereof and (b) at least one pharmaceutically acceptable excipient.
• the 17-AAG is present in an amount of between about 2.5 to about 75 weight percent as particles suspended in an aqueous medium, the 17-AAG having a particle size distribution between about 50 nm and about 3.0 microns with a median (volume distribution) particle size of between about
• the at least one pharmaceutically acceptable excipient comprises a surface active agent selected from the group consisting of (i) an ester of poly- oxyethylenesorbitan and a C 12 -C 20 fatty acid, the weight ratio of the ester to 17-AAG being between about 0.20 and about 1.0, (ii) a polyoxyethylene-polyoxypropylene block copolymer, the weight ratio of the block copolymer to 17-AAG being between about 0.5 and about 1.0, (iii) a phosphatidylcholine, the weight ratio of the phosphatidylcholine to the 17-AAG being between about 0.04 and about 0.1; and (iv) combinations thereof.
• a surface active agent selected from the group consisting of (i) an ester of poly- oxyethylenesorbitan and a C 12 -C 20 fatty acid, the weight ratio of the ester to 17-AAG being between about 0.20 and about 1.0, (ii) a polyoxyethylene-polyoxypropylene block
• a method for making a pharmaceutical suspension formulation comprising homogenizing a mixture of (a) 17-AAG comprising a polymorph selected from purified Polymorph C, purified G, and combinations thereof, in an amount of between about 2.5 and about 10 weight percent and
• a surface active agent selected from the group consisting of (i) an ester of polyoxyethylenesorbitan and a C 12 -C 20 fatty acid, the weight ratio of the ester to 17-AAG being between about 0.20 and about 1.0, (ii) a polyoxyethylene-polyoxypropylene block copolymer, the weight ratio of the block copolymer to 17-AAG being between about 0.5 and about 1.0,
• a phosphatidylcholine (iii) a phosphatidylcholine, the weight ratio of the phosphatidylcholine to the 17-AAG being between about 0.04 and about 0.1; and (iv) combinations thereof, until the particle size of the 17-AAG is reduced to a particle size distribution between about 50 nm and about 3.0 microns with a median (volume distribution) particle size of between about 200 and about 400 nm.
• a method for making a sterile pharmaceutical formulation comprising the steps of (a) providing a sterile composition comprising 17-AAG; (b) aseptically combining the sterile composition comprising 17-AAG with a sterile solution of a surface active agent selected from the group consisting of (i) an ester of polyoxyethylenesorbitan and a C 12 -C 20 fatty acid, (ii) a polyoxyethylene-polyoxypropylene block copolymer, (iii) a phosphatidylcholine, and (iv) combinations thereof to form a sterile mixture; and
• the amount of 17-AAG is preferably is between about 2.5 and 20, more preferably between about 2.5 and 10, and most preferably between about 4 and about 6 weight percent, based on total formulation weight.
• a method of administering 17- AAG to a subject in need of treatment with 17- AAG comprising administering intravenously to such subject a pharmaceutical formulation of this invention.
• a method for preparing purified 17-AAG comprising the steps of (a) preparing a solution of 17-AAG in refluxing acetone; (b) cooling the solution to a temperature in the range between about 18 and about 30 0 C; (c) precipitating the 17-AAG by the addition of an antisolvent portionwise; and (d) collecting the precipitated 17-AAG.
• 17-AAG so purified will have been significantly purged of non-17-AAG impurities and can be used for preparing Polymorphs C or G.
• Figs. 1, and 2 are an XRPD pattern and an infrared spectrum, respectively, of purified Polymorph C of 17-AAG.
• Figs. 3a and 3b are DSC scans of two different samples of purified Polymorph C of 17-AAG.
• Figs. 4, 5, and 6 are an XRPD pattern, an IR spectrum, and a DSC scan, respectively, of purified Polymorph G of 17-AAG.
• Fig. 7 is a scanning electron microscope (SEM) picture of 17-AAG nanoparticles in a formulation of this invention.
• Fig. 8 is plot of particle size as a function of the number of passes for a homogenization batch containing 200 mg/g 17-AAG. DETAILED DESCRIPTION OF THE INVENTION 17- AAG Polymorphs
• Geldanamycin is a well-known natural product, obtainable by culturing Streptomyces hygroscopicus var. geldanus NRRL 3602. 17-AAG is made semi- synthetically, by the reaction of allylamine with geldanamycin, as described in Sasaki. Both geldanamycin and 17-AAG also are available commercially.
• 17-AAG is polymorphic and exists in multiple forms, many of which are solvates.
• the polymorphs were characterized by techniques such as XRPD, DSC, infrared spectroscopy, gravimetric vapor sorption (GVS), 1 H-NMR, polarized light microscopy (PLM), and thermogravimetric analysis (TGA).
• XRPD XRPD
• DSC infrared spectroscopy
• VMS gravimetric vapor sorption
• PLM polarized light microscopy
• TGA thermogravimetric analysis
• VT-XRPD shows that, upon heating, Polymorph B is converted to Polymorph C.
• Group C Polymorph C is a non-solvated polymorph. Of the 17-AAG polymorphs identified by us, it is the most stable to moisture and heat. It has characteristic XRPD peaks at about 6.4, 8.3, 9.6, 13.3, 14.9, 15.7, 19.1, and 20.8 degrees 20. The DSC thermograms of Polymorph C show an endotherm with an onset temperature of about 188 to about 205 °C, without any thermal events noticeable at lower temperatures. Polymorph C does not convert to any other polymorph upon heating.
• Group D Polymorph D (dichloromethane solvate) has XRPD peaks at about 3.9, 4.6, 5.7, and 7.9 degrees 2 ⁇ , the first three being its lowest angle peaks. Upon heating, it converts to Polymorph C.
• Polymorph G group has characteristic XRPD peaks at about 5.4, 6.8, 7.7, 8.9, 9.6, 10.7, and 13.6 degrees 2 ⁇ , with the first six being its lowest angle peaks. Heating converts Polymorph G to Polymorph C.
• Polymorph C is the most stable to heat and humidity. Many of the other ones are unstable or are converted to Polymorph C by heat and/or humidity. For these reasons, Polymorph C is an especially preferred polymorph for pharmaceutical formulations. Further, we have discovered that Polymorph C produces the most stable nanoparticulate suspension formulations, as shown hereinbelow. As shown by the data below, Polymorph G also produces stable nanoparticulate suspension formulations and thus is also a preferred polymorph.
• Highly pure 17-AAG usually more than 95% pure and preferably more than 97% pure (free of chemical impurities, i.e., components that are not 17-AAG) and suitable for conversion into purified Polymorph C or purified Polymorph G, can be prepared by first making a solution of 17-AAG in refluxing acetone, cooling the solution to approximately ambient temperature (i.e., about 18 to about 30 °C), precipitating the 17-AAG by the addition of an antisolvent such as water over a period of about 1 h (though a shorter or longer period can be used, e.g., 15 min to 24 h), and collecting the precipitated 17-AAG.
• an antisolvent such as water
• 17-AAG in acetone is prepared.
• a volume of water approximately equal to the volume of the solution is added, at a temperature between about 18 and about 30 °C.
• the purified 17- AAG is allowed to precipitate out of solution, with stirring, and collected. The stirring can be maintained for a period from about 15 min to about 24 h.
• a preferred method for making purified Polymorph C comprises the steps of: (a) providing a solution of 17-AAG in acetone, at reflux;
• the refluxing acetone solution of 17-AAG can be prepared by dissolving the 17-AAG in a volume of refluxing acetone or by dissolving the 17-AAG in a volume of acetone at room temperature and bringing the solution up to reflux. After an approximately equal volume of water is added, the acetone is removed by distillation at atmospheric pressure. Distillation is continued until the pot and vapor temperatures are both at about the boiling point for water (i.e., about 100 °C for operations conducted at sea level) or just below it (e.g., about 95 0 C), at which point substantially all the acetone will have been removed.
• 17-AAG phase separates (precipitates or crystallizes) out of solution as suspended Polymorph C.
• the Polymorph C crystals can be collected by cooling the suspension to ambient (room) temperature, filtering, and washing with 1 : 1 acetone water.
• the collected crystals can be dried in vacuo, for example in a vacuum oven at 40 0 C for 12 h.
• Another method for making Polymorph C — albeit not as desirable because the crystallinity of the product is lower - comprises heating 17-AAG at a temperature between about 70 and about 100 0 C for a period of between 1 and 18 h.
• FIG. 1 A representative XRPD pattern for purified Polymorph C is shown in Fig. 1, this particular pattern being that of a highly crystalline and pure sample.
• Table I numerically summarizes data from the XRPD of Fig. 1, including its three lowest 2 ⁇ angle peaks and several additional peaks useful for characterizing Polymorph C.
• Polymorph C can be defined by its XRPD peaks at 6.4*0.3, 8.3 ⁇ 0.3, 9.6 ⁇ 0.3, 13.3 ⁇ 0.3, 14.9 ⁇ 0.3, 15.7 ⁇ 0.3, 19.1 ⁇ 0.3, and 20.8 ⁇ 0.3 degrees 20, with the first three being its lowest angle peaks and the remaining ones being the next few most intense peaks, such peaks being the most relevant ones for defining Polymorph C.
• the peak at 21.3 ⁇ 0.3 degrees 2 ⁇ can be used as a further diagnostic peak.
• Fig. 2 shows the infrared spectrum of a highly crystalline and pure sample of Polymorph C.
• FIG. 3a A representative DSC trace for purified Polymorph C is reproduced in Fig. 3a, showing an endothermic transition (melting point) with an onset temperature at about 193 °C, without any desolvation transitions at a lower temperature, consistent with its identification as an unsolvated polymorph.
• Fig. 3b shows the DSC scan for a exceptionally highly pure sample (both in terms of being free of non-17-AAG materials and of other polymorphs of 17-AAG) of Polymorph C, with an endothermic transition having an onset temperature of about 205 0 C.
• Polymorph C can be characterized DSC-wise by an endothermic transition having an onset temperature in the range between about 188 and about 205 0 C, without the occurrence of any other DSC thermal events (e.g., desolvation) at a lower temperature.
• DSC thermal events e.g., desolvation
• Mansfield reported DSC melt transitions at 156 and 172 °C for his low melt form and at 204 0 C for his high melt form, indicating that his forms are distinguishable from polymorphs of this invention.
• Purified Polymorph G can be prepared by several different routes. In one route, a solution of 17-AAG in acetone is poured into water with stirring, and stirring is continued for a few minutes. The crystals are harvested by filtration and vacuum dried, hi another method, water is added gradually over a period of time such as 50 min. The crystals are similarly harvested and dried.
• Fig. 4 shows an XRPD pattern for purified Polymorph G, which can be defined by its six lowest angle peaks at 5.4 ⁇ 0.3, 6.8 ⁇ 0.3, 7.7 ⁇ 0.3, 8.9 ⁇ 0.3, 9.6 ⁇ 0.3, and 10.7 ⁇ 0.3 degrees 20 and by apeak at 13.6 ⁇ 0.3 degrees 20.
• Fig. 5 is an infrared spectrum of purified Polymorph G
• Fig. 6 is a DSC scan of purified Polymorph G, showing an endothermic transition with an onset temperature of about 196 °C, but with several transitions at lower temperatures.
• Table II juxtaposes XRPD data for Polymorphs C and G against XRPD data reported by Mansfield for his high melt and low melt forms, listing the first ten significant peaks of each.
• Polymorphs C and G and Mansfield's forms have distinctly different XRPD patterns, showing that Polymorphs C and G are novel.
• Particularly noteworthy are the differences in the first several lowest angle peaks, which are generally regarded in the art as the most diagnostically useful peaks.
• Polymorphs C or G can be purified as a result of a preparation pro- cedure that converts another polymorph of 17-AAG into them or as a result of a separation process to remove other polymorphs of 17-AAG. Additionally, other impurities may have been removed as a result of such purification.
• purified Polymorph C contains a predominant amount of Polymorph C, to the exclusion of other 17-AAG polymorphs.
• purified Polymorph G preferably contains a predominant amount of Polymorph G 5 to the exclusion of other polymorphs of 17-AAG.
• purified Polymorph C is substantially free of other polymorphs of 17-AAG, meaning that little or none of the other polymorphs are detectable by XRPD.
• purified Polymorph C or Polymorph G are substantially chemically pure, meaning that they contain 5% or less of chemical impurities (components that are not 17-AAG).
• purified Polymorph C is a composition comprising 17- AAG, the composition being characterized by an XRPD pattern having its three lowest angle peaks at 6.4 ⁇ 0.3, 8.3 ⁇ 0.3, and 9.6 ⁇ 0.3 degrees 20 and further having peaks at 13.3 ⁇ 0.3, 14.9 ⁇ 0.3, 15.7 ⁇ 0.3, 19.1 ⁇ 0.3, and 20.8 ⁇ 0.3 degrees 2 ⁇ .
• purified Polymorph C is a composition comprising 17-AAG, wherein the 17-AAG is present in the composition predominantly in the form of Polymorph C characterized by an XRPD pattern having its three lowest angle peaks at 6.4 ⁇ 0.3, 8.3 ⁇ 0.3, and 9.6 ⁇ 0.3 degrees 2 ⁇ and further having peaks at 13.3 ⁇ 0.3, 14.9 ⁇ 0.3, 15.7 ⁇ 0.3, 19.1 ⁇ 0.3, and 20.8 ⁇ 0.3 degrees 2 ⁇ .
• purified Polymorph G is a composition comprising 17- AAG, the composition being characterized by an XRPD pattern having its six lowest angle peaks at 5.4 ⁇ 0.3, 6.8 ⁇ 0.3, 7.7 ⁇ 0.3, 8.9 ⁇ 0.3, 9.6 ⁇ 0.3, and 10.7 ⁇ 0.3 degrees 2 ⁇ and further having a peak at 13.6 ⁇ 0.3 degrees 20.
• purified Polymorph G is a composition comprising 17-AAG, wherein the 17-AAG is present in the composition predominantly in the form of Polymorph G characterized by an XRPD pattern having its six lowest angle peaks at 5.4 ⁇ 0.3, 6.8 ⁇ 0.3, 7.7 ⁇ 0.3, 8.9 ⁇ 0.3, 9.6 ⁇ 0.3, and 10.7 ⁇ 0.3 degrees 20 and further having a peak at 13.6 ⁇ 0.3 degrees 2 ⁇ .
• Formulations [0043] Generally, we have found that the ability to prepare a successful nanoparticulate formulation employing purified Polymorph C or G is not dependent on the initial particle size - that is, it is not necessary to pre-reduce the particle size of the 17- AAG by micronization or other similar process before homogenization.
• the 17- AAG particles simply must be sufficiently small to pass through the narrowest point of the homogenization flow path, typically on the order of less than about 500 ⁇ m.
• Nanoparticulate formulations of this invention have a 17-AAG particle size distribution between about 50 nm and about 3.0 microns, preferably between about 50 nm and about 2.0 microns, more preferably between about 50 nm and about 1.2 micron.
• the median (volume distribution) particle size is between about 200 and about 400 nm, preferably between about 250 and about 350 nm.
• Particle size distributions can be measured by a suitable particle size analyzer such as Nanotrac 250 (Microtrac, Inc., Montgomeryville, PA, USA) or Zetasizer Nano (Malvern Instruments Ltd., Worcestershire, UK).
• the surface active agent is an ester of polyoxyethylenesorbitan and a Ci 2 -C 20 fatty acid
• the latter can be saturated or unsaturated.
• suitable fatty acids include lauric, linoleic, linolenic, oleic, palmitic, pahnitoleic, and stearic acids.
• the polyoxyethylenesorbitan can be singly or multiply esterified with the Ci 2 -C 20 fatty acid.
• Suitable esters of polyoxyethylenesorbitan with a C 12 -C 20 fatty acid include: polyoxyethylenesorbitan monooleate (polyethylene glycol sorbitan monooleate, polysorbate 80 or TWEEN® 80); polyoxyethylenesorbitan monolaurate (polyethylene glycol sorbitan monolaurate or TWEEN® 20); polyoxyethylenesorbitan monopalmitate (polyethylene glycol sorbitan monopalmitate or TWEEN® 40); polyoxyethylenesorbitan monostearate (polyethylene glycol sorbitan monostearate or TWEEN® 60); polyoxyethylenesorbitan trioleate (polyethylene glycol trioleate or TWEEN® 85); and polyoxyethylenesorbitan tristearate (polyethylene glycol sorbitan tristearate or TWEEN® 65); with the first two being preferred and the first one being especially preferred.
• the weight ratio of the ester to 17-AAG preferably is between about 0.20 and about 1.0, more preferably between about
• the surface active agent is polyoxyethylene-polyoxypropylene block copolymer
• a commercially available version is Pluronic® F-68.
• the weight ratio of the copolymer to 17-AAG preferably is between about 0.5 to about 1.0.
• the surface active agent is phosphatidylcholine (also known as lecithin), it can be derived from sources such as soybean or egg, with the former being preferred.
• the weight ratio of phosphatidylcholine to 17-AAG preferably is between about 0.04 and about 0.1, more preferably between about 0.04 and about 0.06.
• a specific phosphatidylcholine that can be used is Phospholipon® 9OG, which is phosphatidylcholine of soybean provenance.
• Combinations of two or more different surface active agents can be used, for example two different esters of polyoxyethylenesorbitan and a C 12 -C 20 fatty acid or one such ester and a polyoxyethylene-polyoxypropylene block copolymer.
• a preferred combination of surface active agents is (A) a polyoxyethylenesorbitan and a C 12 -C 20 fatty acid or polyoxyethylene-polyoxypropylene block copolymer and (B) a phosphatidylcholine.
• the homogenizing step is effected by high-pressure homogenization under high shear conditions, such as by forcing the mixture through a small orifice (e.g., 50 to 125, preferably 80 to 100, microns in diameter) at pressures between 1,000 and 45,000 psi, preferably pressures of about 18,000 to about 23,000 psi), using multiple passes as needed.
• a small orifice e.g., 50 to 125, preferably 80 to 100, microns in diameter
• pressures between 1,000 and 45,000 psi, preferably pressures of about 18,000 to about 23,000 psi
• Any number of apparatuses can be used, including microfluidizers, mills, and the like.
• formulations of this invention further comprise a carbohydrate, such as a mono- and/or disaccharide or combinations thereof.
• the final formulation preferably contains by weight between about 5 and about 15 weight % of total carbohydrate.
• the final formulation can contain 10 weight % sucrose or a combination of 4 weight % mannitol and 1 weight % sucrose (for a total carbohydrate content of 5 weight %).
• the carbohydrate can be selected from the group consisting of sucrose, mannitol, lactose, trehalose, dextrose, and combinations thereof, with sucrose being preferred.
• the formulations of this invention can be lyophilized (rreeze-dried) and stored as a lyophilate for later reconstitution.
• the use of a carbohydrate is preferred, to serve as a cryoprotectant and/or lyoprotectant.
• Exemplary disclosures relating to lyophilization of pharmaceutical formulations include Konan et ah, Int. J. Pharm. 2002 233 (1-2), 293-52; Quintanar-Guerreo et ah, J. Microencapsulation 1998 15 (1), 107-119; Johnson et ah, J. Pharmaceutical ScL 2002, 91 (4), 914-922; and Tang et ah, Pharmaceutical Res.
• a formulation of this invention can be stored frozen and then thawed, reconstituted, and diluted before administration.
• a carbohydrate such as sucrose as a cryoprotectant is preferred.
• the formulation is diluted shortly before administration - for example by about 1OX to 20X into a suitable vehicle such as water for injection (WFI) or 5% dextrose in water (D5W) — and administered, typically within 12 to 24 h of dilution.
• WFI water for injection
• D5W dextrose in water
• the formulation can be prepared directly at the final administration concentration.
• the formulation can be administered to a subject by an appropriate method, such as parenterally (especially intravenously). Alternatively, oral administration is also contemplated.
• a diluted formulation ready for infusion (approximately 260 mmol/kg) is similar to physiological conditions. Because the formulation contains a higher concentration of 17-AAG a smaller volume is administered, with a concomitant shorter administration time.
• 17-AAG can be used to treat a variety of proliferative disorders, 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, neurofibrosarcoma, osteosarcoma, synovial sarcoma, liposarcoma, and alveolar soft part sarcoma; ne
• cancers that can be targeted for treatment by 17- AAG include breast cancer, multiple myeloma, melanoma, colon cancer, lung cancer (especially non-small cell lung cancer (NSCLC)), prostate cancer, thyroid cancer, ovarian cancer, lymphoma, pancreatic cancer, and leukemia (especially chronic myelogenous leukemia (CML) and chronic lymphocytic leukemia or (CLL)).
• NSCLC non-small cell lung cancer
• CML chronic myelogenous leukemia
• CLL chronic lymphocytic leukemia
• 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 monatitis, allergic dermatitis), periodontal disease (i.e., periodontitis), polycystic kidney disease, and type I diabetes.
• atrophic gastritis inflammatory hemolytic anemia, graft rejection
• 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.g., ide
• 17-AAG can be administered in combination with another active pharmaceutical ingredient (API), such as other anti-cancer or cytotoxic agents including alkylating agents, angiogenesis inhibitors, antimetabolites, DNA cleavers, DNA crosslinkers, DNA intercalators, DNA minor groove binders, enediynes, heat shock protein 90 inhibitors, histone deacetylase inhibitors, microtubule stabilizers, nucleoside (purine or pyrimidine) analogs, nuclear export inhibitors, proteasome inhibitors, topoisomerase (I or II) inhibitors, tyrosine kinase inhibitors.
• API active pharmaceutical ingredient
• Specific anti-cancer or cytotoxic agents include ⁇ -lapachone, ansamitocin P3, auristatin, bicalutamide, bleomycin, bortezomib, busulfan, callistatin A, camptothecin, capecitabine, CC-1065, cisplatin, cryptophycins, daunorubicin, disorazole, docetaxel, doxorubicin, duocarmycin, dynemycin A, epothilones, etoposide, floxuridine, floxuridine, fludarabine, fluoruracil, gefitinib, geldanamycin, 17-DMAG, gemcitabine, hydroxyurea, imatinib, interferons, interleukins, irinotecan, maytansine, methotrexate, mitomycin C, oxaliplatin, paclitaxel, suberoylanilide hydroxamic acid (SA
• Preferred combinations are with gefitinib (Iressa®), bortezomib (Velcade®), paclitaxel (Taxol®), docetaxel, thalidomide (Thalomid®), lenalidomide (Revlimid®), and Herceptin®.
• a course of treatment entails a combination treatment involving 17-AAG and another API
• such other API can be administered separately, in its own formulation, or, where amenable, can be administered as an additional component added to a formulation of this invention.
• 17-AAG can 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 dose of about 308 mg/m 2 weekly can be administered. See Goetz et al, Eur. J. Cancer 38 (Supp. 7), S54-S55 (2002).
• Another dosage regimen is twice weekly, with doses ranging from 220 mg/m 2 to 340 mg/m 2 (preferably either 220 mg/m 2 or 340 mg/m 2 ).
• a dosage regimen that can be used for combination treatments with another drug, such as docetaxel, is to administer the two drags every three weeks, with the dose of 17-AAG being up to 650 mg/m 2 at each administration.
• Formulations of this invention may contain additional excipients.
• Suitable excipients include carriers, surface active agents, thickening or emulsifying agents, solid binders, dispersion or suspension aids, solubilizers, colorants, flavoring agents, coatings, cryoprotectants, lyoprotectants, disintegrating agents, lubricants, sweeteners, preservatives, isotonic agents, and combinations thereof.
• the selection and use of suitable excipients is taught in Gennaro, ed., Remington: The Science and Practice of Pharmacy, 20th Ed. (Lippincott Williams & Wilkins 2003), the disclosure of which is incorporated herein by reference.
• the subject is typically a human, although the methods of the invention can be practiced for veterinary purposes, with suitable adjustment of the unit dose for the particular mammal of interest (including cats, cattle, dogs, horses, and the like).
• 17-AAG 1.0 g was dissolved in acetone (117 mL) and stirred at room temperature. Water (117 mL) was added at a rate of 15 mL/min. The mixture was stirred for an additional 50 min and the Polymorph G crystals were harvested by filtration and dried at 70 °C for 44 h.
• Example 4 Analysis and Characterization of 17-AAG Polymorphs
• XRPD patterns were obtained by Pharmorphix Ltd. (Cambridge, United Kingdom). XRPD patterns of pure 17-AAG Polymorph C and 17-AAG Polymorph C mixed with silicon powder (Aldrich, 60 mesh, Cat. No. 267414-5G) were acquired under identical conditions on a Siemens D5000 diffractometer: CuKa radiation (4OkV, 4OmA), ⁇ - ⁇ goniometer, automatic divergence and receiving slits, a graphite secondary monochrorhator and a scintillation counter. The data were collected over an angular range of 2° to 42° in 2 ⁇ in continuous scan mode using a step size of 0.02° 2 ⁇ and a step time of 1 second.
• Infrared spectra were obtained with a Perkin-Elmer Model 1600 fitted with an ATR accessory. Exemplary infrared spectra are shown in Figs. 2 and 5, previously discussed in this specification.
• DSC data was collected on a TA instruments QlOO or QlOOO machine.
• the 0 energy and temperature calibration standard was indium. Samples were heated at a rate of 10 °C/min between 20 and 250 °C under a nitrogen purge. All samples were scanned in a non-hermetically sealed aluminum pan. Exemplary scans are presented in Figs. 3 and 6, previously discussed in this specification.
• Example 5 Formulation with Polysorbate 80 5
• 17-AAG (purified Polymorph C, 1.25 g) crystals were mixed with WFI (13 g) and a solution of polysorbate 80 in WFI (3.75 g of a 10 weight % solution in WFI).
• the mixture was loaded into the reservoir of a Microfluidics Model HOS microfluidizer containing 7 g of WFI and set up with a GlOZ interaction chamber equipped with a cooling coil immersed in an ice water bath and processed in recirculation mode for 13 0 min (640 strokes) at 23 kpsi, with compressed air supplied at a pressure of 100 psi.
• This procedure yielded a formulation having a 17-AAG concentration of about 50 mg/niL (more exactly, 52.6 mg/mL) in an aqueous medium having approximately 1.5 weight % polysorbate 80, with a 17-AAG particle size distribution (volume distribution) of below 1 micron with median particle size of 300 nm (volume distribution).
• Particle size distribution was determined by dynamic light scattering with a Nanotract 250 particle size analyzer (Microtrac Inc., Montgomeryville, Pennsylvania). The Nanotrac 250 settings were configured for measuring the PSD (volume distribution) of "Irregular" Shaped particles of "Absorbing" Transparency in a fluid with characteristics of water (Refractive Index: 1.333, Viscosity at 20°C: 0.797 cP, Viscosity at 30°C: 1.002 cP). A background signal was measured using 5% Dextrose for Injection (D5W). Then, the nanoparticle formulation was diluted 10 to 20-fold into D5W and mixed well.
• PSD volume distribution
• D5W Dextrose for Injection
• the PSD of the diluted sample was measured as the average of five replicate 5-minute analyses and reported in histogram format as a function of particle size. While the PSD reflects the range and frequency of particle sizes, other characteristics of the PSD were used for quantitation.
• the D50 is the volume percentile corresponding to the particle size larger than 50% of the total particle volume (i.e. the median particle size).
• the D90 is the volume percentile corresponding to the particle size larger than 90% of the total particle volume and is a measure of the largest particles in the dispersion.
• the particle size distribution measured by dynamic light scattering techniques was supplemented with SEM images, acquired by techniques established in the art. The particle sizes determined via the SEM images were in general agreement with those determined by light scattering.
• Fig. 7 shows a representative SEM image of 17-AAG nanoparticles in one of our formulations.
• the processing time was chosen to correspond to approximately 150 passes, using the following relationship:
• Vbatch volume of formulation batch r — rate (piston strokes/time)
• y stroke volume of piston stroke displacement [0077]
• the number of passes is between about 50 and 200 passes, preferably between about 100 and about 150 passes. A greater number of passes in non- detrimental, but unnecessarily prolongs processing time.
• processing time can be determined by assessing particle size distribution at intermediate time points and processing until the desired particle size distribution is attained.
• Example 6 Formulation with Polysorbate 80 and Phosphatidylcholine
• 17- AAG purified Polymorph C, 1.25 g
• WFI 13.62 g
• a solution of polysorbate 80 solution in WFI 2.5 g of a 10 weight % solution in WFI
• an aqueous suspension of soybean phosphatidylcholine 0.63 g of a 10 weight % suspension in WFI
• HOS micro fluidizer containing 7 g WFI HOS micro fluidizer containing 7 g WFI
• This procedure yielded a formulation having a 17-AAG concentration of approximately 50 mg/mL in an aqueous medium having approximately 1.0 weight % polysorbate 80 and 0.25 weight % soy phosphatidylcholine, with a 17-AAG particle size distribution of below 1 micron with median particle size of 300 nm (volume distribution).
• Example 7 Formulation with Polysorbate 80, Phosphatidylcholine and Sucrose
• 17-AAG (purified Polymorph C, 1.25 g) was mixed with WFI (3.62 g) and a solution of polysorbate 80 (2.5 g of a 10 weight % solution in WFI), an aqueous suspension of soybean phosphatidylcholine (0.63 g of a 10 weight % suspension in WFI), and a solution of sucrose (10 g of a 25 weight % solution in WFI).
• WFI 3.62 g
• a solution of polysorbate 80 2.5 g of a 10 weight % solution in WFI
• an aqueous suspension of soybean phosphatidylcholine (0.63 g of a 10 weight % suspension in WFI
• sucrose 10 g of a 25 weight % solution in WFI
• This procedure yielded a formulation having a 17-AAG concentration of approximately 50 mg/mL in an aqueous medium having approximately 1.0 weight % polysorbate 80, 0.25 weight % soy phosphatidylcholine, and 10 weight % sucrose, with a 17-AAG particle size distribution of below 1 micron with median particle size of 300 nm volume distribution.
• the polysorbate 80 and sucrose solutions were prepared using WFI and filter sterilized, either as separate solutions or as a solution of the two combined.
• the phosphatidylcholine suspension was prepared and then autoclaved.
• the 17-AAG was mixed with a portion of the WFI and autoclaved.
• the phosphatidylcholine suspension and 17-AAG slurry were autoclaved as separate mixtures or combined as a single mixture. After sterilization, the 17-AAG, the polysorbate® 80 and sucrose solutions, and the phosphatidylcholine mixture were combined aseptically to achieve the desired final composition.
• the microfluidizer was sterilized (e.g., by autoclaving) and the transfer and processing steps were performed aseptically but otherwise as described in Example 5.
• centrifugation is the recommended technique.
• centrifugation can cause a corresponding shift in particle size distribution and a loss of up of 40% of the 17-AAG.
• Filtration can be used to remove outliers - big but infrequent particles - such filtration not affecting perceptibly 17-AAG particle size distribution or assay.
• Processing time in a homogenizer is a function of batch volume and the number of passes.
• a given particle should see the same number of passes independent of the particulate concentration, raising the possibility that homogenizer throughput can be increased by using the same number of passes, but with a more concentrated 17-AAG starting suspension.
• Fig. 8 shows the particle size distribution (both based on D50 and D90) as a function of the number of passes for a batch containing 200 mg/mL 17-AAG. The data show that, after 50 passes, the particle size distribution has leveled out and that, by using batches having a 17-AAG concentration of 200 mg/mL, the homogenizer throughput can be quadrupled.
• the polysorbate 80 is filter sterilized as a 25% w/w solution into the sterilized 17-AAG mixture.
• the homogenization equipment (Microfluidics MSl 10) is sterilized by autoclaving for 60 min.
• Nanoparticulate formulations of 17-AAG with Pluronic® F68 polyoxyethylene-polyoxypropylene block copolymer were prepared as described in Example 5 except comprising 5 weight % 17-AAG and between 1.25 and 5 weight % Pluronic® F68 The formulations comprising 2.5 and 5 weight % Pluronic® F68 yielded formulations containing about 50 mg/mL 17-AAG with particle size distributions below 1.2 microns. Both formulations exhibited stable median particle sizes, albeit with possible growth of the largest particles (inconsistent fluctuations in D90 over 24 h).
• Non-sterile formulations of 17-AAG were made with other polymorphs using the procedure of Example 7 and compared against formulations made with purified Polymorph C.
• the results provided in Table III show that other forms of 17-AAG lead to inferior formulations, with the exception of purified Polymorph G (albeit resulting in a formulation with a higher D50).
• Example 11 - Lvophilization For the preparation of formulations that are to be lyophilized, a portion of the WFI was replaced with a corresponding amount of a carbohydrate cryoprotectant solution, as described in the preceding example. For instance, a portion of the WFI can be replaced with an aqueous solution of sucrose to yield final formulations as in the preceding examples, but further containing 10 weight % sucrose. Alternatively, formulations otherwise identical to those described in Examples 4 and 5 but further containing 4 weight % mannitol and 1 weight % sucrose can be prepared by replacing a portion of the WFI with a corresponding amount of a mannitol-sucrose solution.
• Nanoparticulate formulations of this invention were stored over a period of months at either 5 °C or 25 0 C, to evaluate their stability.
• the stability of the formulations was evaluated by comparing PSD measured at production to PSD after storage. No significant change in the PSD was observed over a period of several months at either storage condition. Furthermore, no significant change in chemical composition (17- AAG assay and impurity profile) was observed under either storage condition. Ongoing studies show physical and chemical stability over at least nine months.
• the stability of the nanoparticle formulation was also tested under conditions of clinical use.
• the formulation was diluted 10-fold in D5W, maintained under ambient light and temperature conditions, and sampled over a period of 72 h. No significant change was observed in the diluted formulation in terms of appearance, chemical composition, particle size distribution, osmolality, and pH. These stability studies indicate that the diluted material was completely stable under typical conditions of clinical use.
• This example compares the photostability of a dispersion formulation of 17- AAG according to Example 7 compared to a formulation made using Cremophor® (Zhong et al, US 2005/0256097 Al (2005)).
• Each formulation (20 mL) was placed in a vial under separate lamps equipped with a 60 watt soft-white light bulb. The vials were laid horizontally at a distance from the lamps such that the light intensity falling on each was 1,080 light candles, as measured by a calibrated light meter. Each formulation was exposed to light for three days. An aliquot (1 mL) of each formulation was removed each day for analysis, with the 17-AAG content assayed by HPLC. Table IV compares the photostability of the two formulations.
• This example compares the pharmacokinetic parameters for two formulations, a nanosuspension formulation according to this invention (Formulation A) and a Cremophor®-based formulation (Formulation B).
• the composition of Formulation A was: 17-AAG (50 mg/mL) aqueous nanosuspension containing additionally polysorbate 80 (1%), lecithin (0.25%), and sucrose (10%).
• the composition of Formulation B was: 17-AAG in Cremophor® EL (20%), propylene glycol (30%), and ethanol (50%).
• Each formulation was diluted 1OX (Formulation A into D5W; Formulation B into saline) and administered to male beagle dogs by 60 min intravenous infusions or oral gavage, in each instance at a dose of 1.0 mg/kg.

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