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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• • 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
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • 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
  • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• • 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
  • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• • 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
  • A61K9/08—Solutions
• • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
  • A61P5/32—Antioestrogens
• • 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
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions

Definitions

• the present invention relates to fulvestrant formulations, especially to injectable formulations of fulvestrant, and particularly to intramuscular injectable formulations.
• the invention also related to the solvents glycofurol, poloxamer, reverse poloxamer, polyethylene glycol, propylene glycol, and dihydrolipoic acid.
• Fulvestrant Injection for intramuscular administration is an estrogen receptor antagonist without known agonist effects and is marketed by Astra-Zeneca under trade name Faslodex®.
• the chemical name is 7-alpha-[9-(4,4,5,5,5-penta fluoropentylsulphinyl) nonyl]estra-l,3,5-(10)- triene-3,17-beta-diol.
• the molecular formula is C 32 H 47 F 5 O 3 S and its structural formula is:
• Fulvestrant is a white powder with a molecular weight of 606.77.
• the solution for injection (as currently marketed) is a clear, colorless to yellow, viscous liquid.
• Each injection of the currently marketed FASLODEX contains as inactive ingredients: Alcohol, USP; Benzyl Alcohol, NF; and Benzyl Benzoate, USP, as co-solvents; and Castor Oil, USP as a co-solvent and release rate modifier. Its manufacture and general use are disclosed in US 4,659,516, which is incorporated herein by reference in its entirety.
• FASLODEX is supplied in sterile single patient pre-filled syringes containing 50 mg/ml fulvestrant either as a single 5 ml or two concurrent 2.5 ml injections to deliver the required monthly dose. Fulvestrant is currently labeled in the currently marketed FASLODEX product to be administered as an intramuscular injection of 250 mg once monthly.
• a formulation of fulvestrant for intramuscular injection is disclosed in US 6,774,122, which is incorporated herein by reference in its entirety.
• the formulation claimed in that patent is a fulvestrant solution in a ricinoleate vehicle that additionally has at least one alcohol and a non-aqueous solvent which is miscible with the ricinoleate vehicle.
• the currently marketed FASLODEX injection product contains, in addition to the fulvestrant; alcohol USP; benzyl alcohol; benzyl benzoate; and castor oil. Castor oil administration by injection has been associated with potential side effects. In fulvestrant formulations having castor oil, injection site irritation is one of the most common side effects.
• Ricinoleate (the major component of castor oil) is an intestinal secretogogue.
• Zinc ricinoleate has been found to be a sensitizer in deodorants in which it has been incorporated.
• Sodium ricinoleate has been found to have membrane disruptive effects.
• Type IV dermal sensitization response in those previously sensitized to ricinoleate have been attributed to ricinoleate administration.
• US 5,462,726 is directed to a method of reducing, inhibiting, or treating the unwanted side effects of castor oil in a solvent in a drug formulation by administering a thromboxane A 2 receptor antagonist.
• It is a further object of the invention is to provide a method of administering fulvestrant by injection that is substantially free of, if not totally free of, injection site irritation.
• It is yet another object of the invention is to provide an intramuscular injection formulation of fulvestrant being substantially free, if not totally free of, castor oil and castor oil derivatives.
• Still another object of the invention is to provide a method of administering fulvestrant by intramuscular injection that is substantially free of, if not totally free of, injection site irritation.
• Still an additional object of the invention is to provide a method of administering the recommended dose of fulvestrant with reduced volume (i.e., 1-4 ml relative to currently marketed Faslodex of 5 ml) at the injection site.
• Yet another object of the invention is to provide an injectable formulation of fulvestrant that can deliver dosages of up to 1 gram of fulvestrant in volumes of less than 5 ml of formulation.
• a further object of the invention is to provide a transdermal administrate formulation of fulvestrant that is substantially free, if not totally free of, castor oil and castor oil derivatives.
• An even further object of the invention is to provide a method of administering a fulvestrant formulation transdermally that is substantially free of side effects associated with castor oil and castor oil derivatives.
• a still further object of the invention is the provision of a fulvestrant formulation for injection or transdermal administration in which the fulvestrant is present in a vehicle containing at least one solvent selected from polyethylene glycol, propylene glycol, glycofurol, poloxamer, reverse poloxamer, dihydrolipoic acid, mixtures thereof, and non-aqueous solutions of the foregoing.
• An even further object of the invention is to provide an intramuscular injection dosage form of fulvestrant that is capable of delivering a therapeutically effective amount of fulvestrant in less than 5 ml of formulation.
• Still another object of the invention is to provide a fulvestrant intramuscular injection dosage form that can deliver a therapeutically effective amount of fulvestrant in a single injection of about or less than 2.5 ml of formulation.
• Still another object of the invention is to provide a fulvestrant intramuscular injection dosage form that can deliver a therapeutically effective amount of fulvestrant in a single injection of about or less than 1.5 ml of formulation.
• Yet another object of the invention is the provision of an intramuscular injection dosage form of fulvestrant capable of delivering up to and/or in excess of 500 mg of fulvestrant in a single injection of less than or about 5 ml of formulation.
• An even further object of the invention is the provision of an intramuscular injection dosage form of fulvestrant capable of delivering up to and/or in excess of 500 mg of fulvestrant in a single injection of less than or about 2 ml of formulation.
• a composition comprising (1) fulvestrant in a concentration of at least 40 mg/ml in (2) a solvent or solvent system, wherein said solvent or solvent system is selected from the group consisting of glycofurol, polyethylene glycol, poloxamer, reverse poloxamer, propylene glycol, dihydrolipoic acid and mixtures thereof as well as substantially non-aqueous solutions thereof provided that (a) glycofurol or dihydrolipoic acid be a constituent of the solvent system or (b) if neither glycofurol nor dihydrolipoic acid is a component of the solvent system then the solvent system contain at least polyethylene glycol in combination with at least one of a poloxamer, a reverse poloxamer, or propylene glycol; and (3) optionally containing other
• a second embodiment of the invention the foregoing and other objects of the invention can be achieved by substantially higher concentrations of fulvestrant in a solvent or solvent system selected from the same group as set forth above for the first embodiment except that propylene glycol can only be present if at least one of glycofurol or dihydrolipoic acid is present or if the solvent system is polyethylene glycol/propylene glycol in the absence of a substantial amount of poloxamer or reverse poloxamer.
• castor oils and castor oil derivatives such as partially and fully hydrogenated versions of castor oil or polyethoxylated versions of either are substantially absent, if not totally absent, as defined further herein below.
• the present invention is directed to formulations of fulvestrant that are primarily designed for intramuscular injection, although other injection routes that are compatible with fulvestrant and the excipients are also contemplated as within the invention.
• administration by transdermal or topical administration where desired are also within the scope of the invention.
• fulvestrant is contained within the formulation in a concentration of at least 40 mg/ml, preferably in a first embodiment at a concentration of about 45 to about 60 mg/ml, more preferably about 50 mg/ml and in a second embodiment in excess of 50 mg/ml generally up to about 500mg/ml (although even higher concentrations are achievable), preferably about 75 mg/ml or more, more preferably about 100 mg/ml or more, other preferred amounts including about 150 mg/ml or more, about 200 mg/ml or more, about 250 mg/ml, about 300 mg/ml or more, about 375 mg/ml or more, about 400 mg/ml or more, about 450 mg/ml or more, and about 500 mg/ml or more, although concentrations greater than about 300 mg/ml are generally too viscous for intramuscular injection, such formulations remain suitable for topical and transdermal administration of fulvestrant; (2) the formulation contains a solvent or mixed solvent system selected from the group consisting of
• glycofurol/poloxamer/reverse poloxamer/propylene glycol [0044] glycofurol/poloxamer/reverse poloxamer/propylene glycol, [0045] glycofurol/poloxamer/reverse poloxamer/polyethylene glycol/propylene glycol,
• dihydrolipoic acid reverse poloxamer/polyethylene glycol [0056] dihydrolipoic acid reverse poloxamer/polyethylene glycol
• glycofurol/dihydrolipoic acid/poloxamer/propylene glycol [0068] glycofurol/dihydrolipoic acid/reverse poloxamer
• glycofurol/dihydrolipoic acid/poloxamer/polyethylene glycol/propylene glycol [0071] glycofurol/dihydrolipoic acid/poloxamer/polyethylene glycol/propylene glycol,
• glycofurol/dihydrolipoic acid reverse poloxamer/polyethylene glycol
• formulations are substantially non-aqueous solutions thereof and optionally containing other compatible excipients with the proviso that the formulations are substantially free of, preferably completely free of, castor oil and castor oil derivatives.
• These formulations are preferably administered intramuscularly, but can be administered by other suitable injection routes that are suitable for the fulvestrant active agent, or via transdermal or topical administration.
• the foregoing and other objects of the invention can be achieved by substantially higher concentrations of fulvestrant in a solvent or solvent system selected from the foregoing group of solvent systems except that if propylene glycol is used, it is only used when glycofurol or dihydrolipoic acid is also present, preferably for this embodiment, propylene glycol is not used at all.
• the solvent or solvent system is selected from
• glycofurol/polyethylene glycol/propylene glycol [0090] glycofurol/polyethylene glycol/propylene glycol
• glycofurol reverse poloxamer/polyethylene glycol [0097] glycofurol reverse poloxamer/polyethylene glycol
• glycofurol/poloxamer/reverse poloxamer/propylene glycol [0101] glycofurol/poloxamer/reverse poloxamer/polyethylene glycol/propylene glycol, [0102] glycofurol/poloxamer/reverse poloxamer/polyethylene glycol/propylene glycol,
• glycofurol/dihydrolipoic acid/poloxamer/propylene glycol [0125] glycofurol/dihydrolipoic acid/reverse poloxamer
• glycofurol/dihydrolipoic acid reverse poloxamer/polyethylene glycol
• formulations are substantially non-aqueous solutions thereof and optionally containing other compatible excipients with the proviso that the formulations are substantially free of, preferably completely free of, castor oil and castor oil derivatives.
• These formulations are preferably administered intramuscularly, but can be administered by other suitable injection routes that are suitable for the fulvestrant active agent, or via transdermal or topical administration.
• substantially free when referencing the amount of a component of a formulation means not more than about 5%, preferably not more than about 4.5%, more preferably not more than about 4%, even more preferably not more than about 3%, still more preferably not more than about 2%, yet more preferably not more than about 1%, still more preferably not more than about 0.5%, even still more preferably not more than about 0.1%, still more preferably not more than about 0.01% (100 ppm), most preferably undetectable amounts with the use of Standard analytic equipment as of the filing date of the present specification, (i.e., zero), each of the %s being with reference to the complete formulation.
• the term "substantially free of means that the present invention has a significantly lesser rate of incidence of that side effect in test populations as compared to formulations having the same percentage of castor oil as present in the FASLODEX marketed product as sold in the US as of the filing date of the present invention and/or (preferably and) an absolute rate of incidence of such side effect of not more than about 10% of the test population, preferably not more than about 5% of the test population, even more preferably not more than about 2% of the test population, still more preferably not more than about 1% of the test population, even more preferably not more than about 0.5% of the test population.
• substantially free with respect to the avoidance of side effects also means a reduction in or avoidance of such side effect with respect to the degree of such side effect seen in patients given the present invention as compared to that degree seen in patients generally given similar formulations having castor oil or castor oil derivatives in amounts present in the FASLODEX marketed product as sold in the US as of the filing date of the present invention.
• both absolute rate of side effect presentation (described in the previous paragraph) and degree of reduction of that side effect independently can be the basis for "substantial free" when speaking of side effect issues, preferably both incidence and degree of side effect reduction meet these limitations simultaneously.
• substantially free means less than 20% of that seen with the current marked FASLODEX product (independently with respect to rate of side effect presentation and/or side effect level), preferably less than about 10%, more preferably less than about 7.5%, still more preferably less than about 5%, even more preferably less than about 2.5%, still more preferably less than about 1%, most preferably 0% of that seen with the FASLODEX product.
• the products of the present invention meet each of (1) the absolute amount "substantially free” limitation on castor oil and castor oil derivative and (2) at least one of the "substantially free” limitations (a) on side effect per se or (b) rate of side effect in test populations.
• a solvent or solvent system that is (a) capable of solubilizing fulvestrant to the appropriate degree; (b) be a solvent that is administrable via injection, especially intramuscularly, or via the transdermal or topical route; and (c) that is substantially free of or completely free of the side effects typically attributable to castor oil or castor oil derivatives upon injection.
• the typical side effects of castor oil and its derivatives are (a) skin and other irritation at the administration site; (b) allergic reaction; and (c) gastrointestinal disturbances even though the product is not administered to the Gl tract.
• the primary (but not exclusive) measure of whether the invention product is "substantially free" of the "castor oil associated side effects" is skin or injection site irritation.
• solubility of fulvestrant in 1 : 1 PEG 400 and propylene glycol is quite surprising as solubility in neat (100%) propylene glycol was only 4 mg/ml, and in neat (100%) PEG-400 was only 22.5 mg/ml, while in 1 :1 PEG-400 and propylene glycol system, the solubility is 50 mg/ml. It is equally surprising that solubility in the Lutrol/PEG400/propylene glycol blends was 50 mg/ml as it was insoluble in the neat 2% Lutrol solution, 4mg/ml in the neat propylene glycol, and 22.5mg/ml in the neat PEG 400. It is still additionally surprising that fulvestrant was soluble at 66.7 mg/ml in 2% Lutrol in PEG 400 without the propylene glycol.
• N-methylpyrrolidone and 1.4-dioxane are excellant solubilizers for fulvestrant, each of these have their own significant side effects that make them unsuitable for use in injectable formulations.
• the present invention permits fulvestrant containing formulations containing up to and in excess of 250 mg/ml fulvestrant.
• Preferably embodiments contain fulvestrant in amounts of about 45 mg/ml, about 50 mg/ml, about 55 mg/ml, about 60 mg/ml, about 65 mg/ml, about 70 mg/ml, about 75 mg/ml, about 80 mg/ml, about 85 mg/ml, about 90 mg/ml, about 95 mg/ml, about 100 mg/ml, about 105 mg/ml, about 1 10 mg/ml, about 115 mg/ml, about 120 mg/ml, about 125 mg/ml, about 130 mg/ml, about 135 mg/ml, about 140 mg/ml, about 145 mg/ml, about 150 mg/ml, about 155 mg/ml, about 160 mg/ml, about 165 mg/ml, about 170 mg/ml, about 175 mg/ml, about 180 mg/ml, about 185 mg/ml, about 190 mg/ml, about 195 mg/ml, about 200 mg/ml, about 205 mg
• Fulvestrant dissolved in 100% glycofurol or in mixtures of glycofurol with PEG or mixtures of glycofurol with poloxamer or fulvestrant dissolved in 100% dihydrolipoic acid or mixtures of poloxamer and dihydrolipoic acid, or mixtures having both glycofurol and dihydrolipoic acid are preferred for concentrations in excess of about 95 mg fulvestrant/ml of formulation.
• the mixtures may be in any proportion, but is preferred where the glycofurol (for glycofurol containing formulations) or dihydrolipoic acid (for formulations containing dihydrolipoic acid as the solvent) makes up at least 20% of the mixture of solvents.
• 1 :1 mixtures of glycofurol with either polyethylene glycol or propylene glycol are mixtures of 20-50 mg of poloxamer/ml of dihydrolipoic acid and 20-50 mg ploxamer per ml of 1 :1 mixture of dihydrolipoic acid and lipoic acid.
• Other preferred solutions, especially when a solubility of about 50 mg/ml or less is necessary include PEG/propylene glycol (1 : 1), 2%poloxamer in PEG in combination with propylene glycol (with the propylene glycol making up 20-30% of the solvent system), and 2% poloxamer in PEG.
• polyethylene glycol When polyethylene glycol (PEG) is used, it is preferably PEG-200-800, more preferably PEG-400.
• Another preferred solvent system is poloxamer generally about up to 4%, preferably about 1 to about 3%, more preferably about 2% in polyethyleneglycol, preferably in polyethylene glycol 400, glycofurol, or dihydrolipoic acid or mixtures thereof.
• Preferred poloxamers include, without limitation poloxamer 188 and poloxamer 421 and the commercial material known as LUTROL (which is poloxamer 188, aka Pluronic F-68).
• Poloxamers are block copolymers having a central block of polypropyleneoxide bounded on each side by a block of polyethylene oxide.
• Reverse poloxamers are block copolymers having a central block of polyethyleneoxide bounded on each side by polypropyleneoxide.
• the reverse poloxamers can generally be used in place of poloxamers in the same proportions as set forth for the poloxamers.
• the reverse poloxamers and the poloxamers differ slightly in their hydrophilic/hydrophobic nature and those of ordinary skill in the art would be able to make appropriate substitutions between poloxamers and reverse poloxamers for use in the instant invention in light of this specification.
• a rat paw lick test was conducted to further evaluate the irritation issue and the results are shown in the table below.
• 0.1 ml of the solvent system is injected on the subplanar paw of the rat and the irritation is measured by the number of time that rat licks its paw over 15 minutes. This is quite quantitative and the number licks correlate to the irritation of the system.
• a stable product is one which when stored under the directed conditions retains at least 80% of label potency, preferably at least about 90% of labeled potency at a designated date, which is generally at least one year, preferably at least about 18 months, more preferably at least about 2 years, and most preferably even longer.
• label potency preferably at least about 90% of labeled potency at a designated date, which is generally at least one year, preferably at least about 18 months, more preferably at least about 2 years, and most preferably even longer.
• a stable product is one which has not more than a total of area % of degradants of 3% and any one degradant area % of not more than 1%, preferably both total degradant and any one degradant limitations are simultaneously met.
• both potency and degredant area % limitations are met.
• Suitable non-limiting antioxidants include, without limitation, lipoic acid and its structural analogs such as dihydrolipoic acid, methionine and other sulfur-containing amino acids, acetone sodium bisulfate, propyl gallate, BHT, BHA and sodium formaldehyde sulfoxylate.
• the antioxidant is lipoic acid or its structural analogs such as dihydrolipoic acid, and preferably the antioxidant is present in an amount ranging up to about 75 mg/ml, more preferably about 25-75 mg/ml, still more preferably about 50 mg/ml.
• dihydrolipoic acid can also be used as a solubilizing agent as well as a carrier solvent, which can further aid to prolong the release of drug as well as reducing the injection volume. Because of these additional uses of dihydrolipoic acid, it may further be used beyond these "antioxidant" limitation amounts all the way up to the amounts indicated as suitable earlier for use as a solvent.
• the storage condition for the current commercial FASLODEX formulation is 2-8°C which means that the marketed product needs to be stored under refrigerated conditions.
• stability of fulvestrant in strongly acidic, basic and peroxide media at 60 0 C.
• acid we stored the samples for 7 days, in base for 5 days and in peroxide for 48 hour.
• the degradation profile is tabulated below:
• Example 1 [0155] Fulvestrant : lOOmg/ml In a solvent system of Labrofac 50% PG 25% PEG 400 25%
• the formulation showed a better degradation profile compare to the simulated innovator formulation.
• Fulvestrant 25mg/ml in Glycofurol 100%
• Example 4 & Example 5 [0160] Example 4 & Example 5:
• the 75 mg/ml and 50 mg/ml formulations show better stability than the concentrated 150 mg/ml formulation.
• Fulvestrant showed outstanding stability in this system.
• the accelerated stability data indicate that this formulation is stable for 2 years at room temperature storage. Also, we did not find any significant levels of oxidative degradation this system, suggesting that the combination of propylene glycol and glycofurol surprisingly prevents the oxidative degradation. This is quite unusual as both these solvents are known to promote the oxidation.
• the stability of fulvestrant in this system is comparable to glycofurol/PG containing system.
• composition of the formulation we tested is as follows:
• a 50 mg/ml fulvestrant formulation using dihydrolipoic acid as a solvent is prepared having the following components and amounts:
• Example 10 [0171] A 100 mg/ml fulvestrant formulation using dihydrolipoic acid as a solvent is prepared having the following components and amounts:
• fulvestrant 100 mg is weighed into a ImI volumetric flask and dissolved by adding 0.5ml of dihydrolipoic acid. After complete dissolution, the content of the flask is made to the volume by adding dihydrolipoic acid.
• a 150 mg/ml fulvestrant formulation using dihydrolipoic acid as a solvent is prepared having the following components and amounts:
• 150 mg of fulvestrant is weighed into a ImI volumetric flask and dissolved by adding 0.5ml of dihydrolipoic acid. After complete dissolution, the content of the flask is made to the volume by adding dihydrolipoic acid.
• a 250 mg/ml fulvestrant formulation using dihydrolipoic acid as a solvent is prepared having the following components and amounts: Fulvestrant : 250mg
• 250 mg of fulvestrant is weighed into a ImI volumetric flask and dissolved by adding 0.5ml of dihydrolipoic acid and sonicating the contents of flask for 2 minutes. After complete dissolution, the content of the flask is made to the volume by adding dihydrolipoic acid.
• a 350 mg/ml fulvestrant formulation using dihydrolipoic acid as a solvent is prepared having the following components and amounts:
• fulvestrant 350 mg is weighed into a ImI volumetric flask and dissolved by adding 0.5ml of dihydrolipoic acid and sonicating the contents of flask for 5 minutes and heating to 60 0 C for 10 minutes. After complete dissolution, the content of the flask is made to the volume by adding dihydrolipoic acid.
• a 500 mg/ml fulvestrant formulation using dihydrolipoic acid as a solvent is prepared having the following components and amounts: Fulvestrant : 500mg
• fulvestrant 500 mg isweighed into a ImI volumetric flask and dissolved by adding 0.5ml of dihydrolipoic acid and sonicating the contents of flask for 10 minutes and heating to 6O 0 C for 30 minutes. After complete dissolution, the content of the flask is made to the volume by adding dihydrolipoic acid.
• a 250 mg/ml fulvestrant formulation using dihydrolipoic acid/poloxamer as a solvent is prepared having the following components and amounts:
• Example 16 A 250 mg/ml fulvestrant formulation using dihydrolipoic acid/poloxamer as a solvent with additional lipoic acid as antioxidant is prepared having the following components and amounts:
• a 250 mg/ml fulvestrant formulation using dihydrolipoic acid/polyethylene glycol as a solvent is prepared having the following components and amounts:
• Dihydrolipoic acid quantity sufficient to make ⁇ lml 250 mg of fulvestrant is weighed into a ImI volumetric flask and dispersed by adding 0.5 ml of PEG 400. The contents of the flask are dissolved by adding 0.3ml of dihydrolipoic acid and sonicating the contents of flask for 2minutes. After complete dissolution, the content of the flask is made to the volume by adding dihydrolipoic acid.
• a 250 mg/ml fulvestrant formulation using dihydrolipoic acid/poloxamer/polyethylene glycol as a solvent is prepared having the following components and amounts:
• 250 mg of Fulvestrant and 20 mg of lutrol are weighed into a ImI volumetric flask and dispersed by adding 0.5 ml of PEG 400.
• the contents of the flask are dissolved by adding 0.3ml of dihydrolipoic acid and sonicating the contents of flask for 2 minutes. After complete dissolution, the content of the flask is made up to volume by adding dihydrolipoic acid.

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• 2009
  • 2009-03-05 JP JP2010549670A patent/JP2011514349A/ja active Pending
  • 2009-03-05 US US12/380,968 patent/US9180088B2/en active Active
  • 2009-03-05 CN CN2009801081573A patent/CN102014925B/zh not_active Expired - Fee Related
  • 2009-03-05 CA CA2716576A patent/CA2716576A1/en not_active Abandoned
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