Classifications

• • 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
  • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
• • 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
  • A61K47/08—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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the invention relates to a sustained release pharmaceutical formulation adapted for administration by injection containing the compound fulvestrant, 7 ⁇ -[9-(4,4, 5,5,5- 5 pentafluoropentylsulphinyl)nonyl]oestra-l,3,5(10)-triene-3,17 ⁇ -diol, at concentration of at least lOOmg/ml in solution in a ricinoleate vehicle which additionally comprises at least one alcohol and a non-aqueous ester solvent which is miscible in the ricinoleate vehicle.
• Oestrogen deprivation is fundamental to the treatment of many benign and malignant diseases of the breast and reproductive tract. In premenopausal women, this is achieved by 0 the ablation of ovarian function through surgical, radiotherapeutic, or medical means, and, in postmenopausal women, by the use of aromatase inhibitors.
• oestrogen withdrawal is to antagonise oestrogens with antioestrogens.
• drugs that bind to and compete for oestrogen receptors (ER) present in the nuclei of oestrogen-responsive tissue.
• ER oestrogen receptors
• Conventional nonsteroidal antioestrogens, such 5 as tamoxifen, compete efficiently for ER binding but their effectiveness is often limited by the partial agonism they display, which results in an incomplete blockade of oestrogen-mediated activity (Furr and Jordan, Pharmacology & Therapeutics, 25: 127-206, 1984; May and
• Estrogen Receptor-Downregulators E.R.D.
• Steroidal analogues of oestradiol with an alkylsulphinyl side chain in the 7 ⁇ position, provided the first examples of compounds devoid of oestrogenic activity (Bowler et al 1989).
• fulvestrant 7 ⁇ -[9-(4,4,5,5,5-Pentafluoropentylsul ⁇ hinyl)nonyl]oestra-l,3-5(10)-triene-3,17 ⁇ -diol, or ICI 182,780, has been allocated the international non-proprietary name fulvestrant, which is used hereinafter.
• fulvestrant we include pharmaceutically-acceptable salts thereof and any possible solvates of either thereof.
• Fulvestrant binds to ER with an affinity similar to that of oestradiol and completely blocks the growth stimulatory action of oestradiol on human breast cancer cells in vitro; it is more potent and more effective than tamoxifen in this respect. Fulvestrant blocks completely the uterotrophic action of oestradiol in rats, mice and monkeys, and also blocks the uterotrophic activity of tamoxifen.
• fulvestrant Because fulvestrant has none of the oestrogen-like stimulatory activity that is characteristic of clinically available antioestrogens such as tamoxifen or toremifene, it may offer improved therapeutic activity characterised by more rapid, complete, or longer-lasting tumour regression; a lower incidence or rate of development of resistance to treatment; and a reduction of tumour invasiveness.
• fulvestrant In intact adult rats, fulvestrant achieves maximum regression of the uterus at a dose which does not adversely affect bone density or lead to increased gonadotrophin secretion. If also true in humans, these findings could be of extreme importance clinically. Reduced bone density limits the duration of oestrogen-ablative treatment for endometriosis. Fulvestrant does not block hypothalamic ER. Oestrogen ablation also causes or exacerbates hot flushes and other menopausal symptoms; fulvestrant will not cause such effects because it does not cross the blood-brain barrier. European Patent Application No. 0 138 504 discloses that certain steroid derivatives are effective antioestrogenic agents. The disclosure includes information relating to the preparation of the steroid derivatives.
• Example 35 there is the disclosure within Example 35 of the compound 7 ⁇ -[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra- 1,3,5(10)-triene-3 , 17 ⁇ -diol, which compound is specifically named in Claim 4. It is also disclosed that the compounds of that invention may be provided for use in the form of a pharmaceutical composition comprising a steroid derivative of the invention together with a pharmaceutically-acceptable diluent or carrier. It is stated therein that the composition can be in a form suitable for oral or parenteral administration.
• Fulvestrant shows, along with other steroidal based compounds, certain physical properties which make formulation of these compounds difficult. Fulvestrant is a particularly lipophilic molecule, even when compared with other steroidal compounds, and its aqueous solubility is extremely low at around 10 ngml' 1 (this is an estimate from a water/solvent mixture solute since measurements this low could not be achieved in a water only solute).
• sustained release injectable steroidal formulations which have been commercialised. Commonly these formulations use oil as a solvent and wherein additional excipients may be present.
• Example 3 an oil based injection formulation of fulvestrant is described which comprises 50mg of fulvestrant, 400mg of benzyl alcohol and sufficient castor oil to bring the solution to a volume of 1 ml.
• Manufacture at a commercial scale of a formulation as described in US 5,183,814 will be complicated by the high alcohol concentration. Therefore, there is a need to lower the alcohol concentration in fulvestrant formulations whilst preventing precipitation of fulvestrant from the formulation.
• fulvestrant is significantly more soluble in castor oil than any of the other oils tested.
• the greater solvating ability of castor oil for steroidal compounds is known and is attributed to the high number of hydroxy groups of ricinoleic acid, which is the major constituent of the fatty acids within the triglycerides present in castor oil - see (Riffkin et.al. J. Pharm. Sci., (1964), 53, 891).
• a pharmaceutical formulation adapted for intramuscular injection comprising 100 mg/ml or more of fulvestrant, 10 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation vehicle comprises at least 5 % weight of ethanol per volume of formulation vehicle and provided that the following formulation is excluded: fulvestrant up to 102 mg/ml, 15 % weight of ethanol per volume of formulation vehicle, 15 % weight of benzyl alcohol per volume of formulation vehicle, 15 % weight of benzyl benzoate per volume of formulation vehicle and 30 % or more weight of ricinoleate excipient per volume of formulation vehicle.
• a preferred pharmaceutical formulation adapted for intramuscular injection is one comprising 105 mg/ml or more of fulvestrant, 10 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation comprises at least 5 % weight of ethanol per volume of formulation vehicle.
• a more preferred pharmaceutical formulation adapted for intramuscular injection is one comprising 110 mg/ml or more of fulvestrant, 10 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation vehicle comprises at least 5 % weight of ethanol per volume of formulation vehicle.
• a more preferred pharmaceutical formulation adapted for intramuscular injection is one comprising 1 15 mg/ml or more of fulvestrant, 10 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation vehicle comprises at least 5 % weight of ethanol per volume of formulation vehicle.
• a more preferred pharmaceutical formulation adapted for intramuscular injection is one comprising 120 mg/ml or more of fulvestrant, 10 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation vehicle comprises at least 5 % weight of ethanol per volume of formulation vehicle.
• a more preferred pharmaceutical formulation adapted for intramuscular injection is one comprising 130 mg/ml or more of fulvestrant, 15 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation vehicle comprises at least 5 % weight of ethanol per volume of formulation vehicle.
• a more preferred pharmaceutical formulation adapted for intramuscular injection is one comprising 140 mg/ml or more of fulvestrant, 15 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 12.5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle provided the formulation vehicle comprises at least 10 % weight of ethanol per volume of formulation vehicle.
• a more preferred pharmaceutical formulation adapted for intramuscular injection is one comprising 150 mg/ml or more of fulvestrant, 15 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 17.5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and
• a pharmaceutical formulation adapted for intramuscular injection is one comprising 150 mg/ml or more of fulvestrant, 15 % or more weight of a pharmaceutically acceptable alcohol per volume of formulation vehicle, 17.5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of formulation vehicle and 5 % or more weight of ricinoleate excipient per volume of formulation vehicle.
• a pharmaceutical formulation having a solubility for fulvestrant of at least Y mg/ml adapted for intramuscular injection comprising;
• ETOH benzyl alcohol
• BA benzyl benzoate
• a preferred pharmaceutical formulation is one wherein Y is selected from the group consisting of 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 170, 180, 190, and
• a more preferred pharmaceutical formulation is one wherein Y is selected from the group consisting of 120, 125, 130, 135, 140, 145, 150, 155, 160, 170, 180, 190, and 200.
• a more preferred pharmaceutical formulation is one wherein Y is selected from the group consisting of 150, 155, 160, 170, 180, 190 and 200.
• a more preferred pharmaceutical formulation is one wherein Y is selected from 150, 155, 160, 170, 180, 190 and 200 and the formulation comprises at least 150mg/ml of fulvestrant.
• a more preferred pharmaceutical formulation is one wherein Y is 200 and the formulation comprises at least 200mg/ml of fulvestrant.
• a pharmaceutical formulation comprising fulvestrant at a concentration of at least 100 mg/ml in which the formulation is adapted for intra-muscular injection into a human and which is capable after injection of attaining a therapeutically significant blood plasma fulvestrant concentration in a human for at least 2 months and provided that the following formulation is excluded: fulvestrant up to 102 mg/ml, 15 % weight of ethanol per volume of formulation vehicle, 15 % weight of benzyl alcohol per volume of formulation vehicle, 15 % weight of benzyl benzoate per volume of formulation vehicle and 30 % or more weight of ricinoleate excipient per volume of formulation vehicle.
• a pharmaceutical formulation comprising fulvestrant in which the formulation is adapted for intra-muscular injection into a human and which is capable after injection of attaining a therapeutically significant blood plasma fulvestrant concentration in a human for at least 2 months.
• a pharmaceutical formulation comprising fulvestrant at a concentration of at least 100 mg/ml in which the formulation is adapted for intra-muscular injection into a human and which is capable after injection of attaining a therapeutically significant blood plasma fulvestrant concentration in a human for at least 2 months.
• a pharmaceutical formulation comprising fulvestrant at a concentration of at least 150 mg/ml in which the 5 formulation is adapted for intra-muscular injection into a human and which is capable after injection of attaining a therapeutically significant blood plasma fulvestrant concentration in a human for at least 2 months.
• a pharmaceutical formulation comprising fulvestrant at a concentration of at least 200 mg/ml in which the 10 formulation is adapted for intra-muscular injection into a human and which is capable after injection of attaining a therapeutically significant blood plasma fulvestrant concentration in a human for at least 2 months.
• a pharmaceutical formulation comprising fulvestrant at a concentration of at least 300 mg/ml in which the 15 formulation is adapted for intra-muscular injection into a human and which is capable after injection of attaining a therapeutically significant blood plasma fulvestrant concentration in a human for at least 2 months.
• any one of the following pharmaceutical formulations comprising about: 20 i)
• the term "comprising about” in this context means that the numerical value assigned to each component of the formulation may be varied independently to accommodate manufacturing specifications encountered by a skilled person when making up the formulations. Typically this means plus or minus 5%, more preferably plus or minus 4%>, more preferably plus or minus 3%>, more preferably plus or minus 2%, more preferably plus or minus 1%. In a preferred embodiment, more variation in drug level is allowed compared with other components. For example:
• the individual formulations described herein may comprise further excipients commonly used in the formulation field including, for example, an antioxidant preservative, a colorant or a surfactant.
• any one of the following pharmaceutical formulations i)
• a preferred pharmaceutical formulation described herein is one wherein the pharmaceutically-acceptable alcohol is a mixture of ethanol and benzyl alcohol.
• a preferred pharmaceutical formulation described herein is one wherein the pharmaceutically-acceptable non-aqueous ester solvent is selected from benzyl benzoate, ethyl oleate, isopropyl myristate, isopropyl palmitate or a mixture of any thereof. 30
• a preferred pharmaceutical formulation described herein is one wherein the pharmaceutically-acceptable non-aqueous ester solvent is benzyl benzoate.
• a preferred pharmaceutical formulation described herein is one wherein the ricinoleate excipient is castor oil.
• a pharmaceutical formulation adapted for intramuscular injection comprising 100 mg/ml or more of fulvestrant, 10 % > or more weight of a pharmaceutically acceptable alcohol per volume of pharmaceutical formulation, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent 5 per volume of pharmaceutical formulation and 5 %> or more weight of ricinoleate excipient per volume of pharmaceutical formulation provided: a) the pharmaceutical formulation comprises at least 5 % weight of ethanol per volume of pharmaceutical formulation; b) if the pharmaceutically acceptable alcohol is less than or equal to 13%, then the 10 pharmaceutical formulation must comprise at least 50 % non-aqueous ester solvent; and c) if the pharmaceutically acceptable alcohol is greater than 20 % but less than or equal to 25 %, then the pharmaceutical formulation must comprise at least 30 % non-aqueous ester solvent; and also provided that the following pharmaceutical formulation is excluded:
• a preferred pharmaceutical formulation adapted for intramuscular injection is one 20 comprising 100 mg/ml or more of fulvestrant, 20 % or more weight of a pharmaceutically acceptable alcohol per volume of pharmaceutical formulation, 5 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of pharmaceutical formulation and 5 % or more weight of ricinoleate excipient per volume of pharmaceutical formulation provided: 25 a) the pharmaceutical formulation comprises at least 10 % weight of ethanol per volume of pharmaceutical formulation; b) if the pharmaceutically acceptable alcohol is 20%), then the pharmaceutical formulation must comprise at least 22.5 % non-aqueous ester solvent; and c) if the pharmaceutically acceptable alcohol is greater than 20 % but less than or equal to 30 25 %>, then the pharmaceutical formulation must comprise at least 15 % non-aqueous ester solvent; and also provided that the following pharmaceutical formulation is excluded: fulvestrant up to
• a more preferred pharmaceutical formulation adapted for intramuscular injection is one comprising 150 mg/ml or more of fulvestrant, 25 % or more weight of a pharmaceutically acceptable alcohol per volume of pharmaceutical formulation, 30 % or more weight of a pharmaceutically acceptable non-aqueous ester solvent per volume of pharmaceutical formulation and 5 % or more weight of ricinoleate excipient per volume of pharmaceutical formulation provided: a) the pharmaceutical formulation comprises at least 10 % weight of ethanol per volume of pharmaceutical formulation; b) if the pharmaceutically acceptable alcohol is less than 30 %, then the pharmaceutical formulation must comprise at least 35 % non-aqueous ester solvent.
• a particularly preferred pharmaceutical formulation is one which comprises 15% w/v or less of ethanol and in which the solubility of fulvestrant is at least 155mg/ml.
• a unit dose of a pharmaceutical formulation as described herein wherein the total volume of the formulation is 6ml or less.
• a pharmaceutical formulation adapted for intramuscular injection as defined in any preceding claim for use in medical therapy.
• fulvestrant in the preparation of a pharmaceutical formulation, as defined herein for the treatment of a benign or malignant disease of the breast or reproductive tract.
• a sterile syringe or vial comprising a pharmaceutical formulation as defined in any preceding claim.
• pharmaceutical formulation means the combination of drug plus formulation vehicle.
• finished formulation and “finished pharmaceutical formulation” mean the same as “pharmaceutical formulation”.
• formulation vehicle means the combination of all excipients used in the pharmaceutical formulation (and therefore excludes drug per se).
• composition is important for the following reason. For example, if the concentration (y % w/v) of an excipient "A" is measured by its concentration in formulation vehicle and then drug is added, the addition of drug will result in a concentration of excipient A that is lower than concentration y in the finished pharmaceutical formulation.
• concentration expressed in terms of "formulation vehicle” into a concentration of "finished pharmaceutical formulation” it is necessary to use a displacement value.
• the "displacement value” is defined as the number of parts by weight of compound that displaces one part by weight of the formulation vehicle.
• the displacement value allows determination of the amount of formulation vehicle displaced by the compound.
• the displacement value is used to calculate the actual composition of the finished formulation in terms of proportions of excipients.
• the density of the compound affects the amount of formulation vehicle required to make the pharmaceutical formulation to the correct concentration.
• One part by weight of the compound with a density equal to the formulation vehicle will displace an equivalent volume of the formulation vehicle.
• a compound with twice the density of the formulation vehicle will displace half the volume. It is therefore necessary to make allowance for the compound in terms of the particular formulation vehicle, using the displacement value.
• %> weight per volume of formulation for the constituents of the formulation we mean that within a unit volume of the formulation a certain percentage of the constituent by weight will be present, for example a 1% weight per volume formulation will contain within a 100ml volume of formulation lg of the constituent.
• the formulation will be presented in a vial or a prefilled syringe, preferably a prefilled syringe, containing a unit dosage of the formulation as described herein, these being further features of the invention.
• the pharmaceutically-acceptable alcohol may consist of one alcohol or a mixture of two or more alcohols, preferably a mixture of two alcohols.
• Preferred pharmaceutically- acceptable alcohols for parenteral administration are ethanol, benzyl alcohol or a mixture of both ethanol and benzyl alcohol.
• the pharmaceutically-acceptable non-aqueous ester solvent may consist of one or a mixture of two or more pharmaceutically-acceptable non-aqueous ester solvents, preferably just one.
• a preferred pharmaceutically-acceptable non-aqueous ester solvent for parenteral administration is selected from benzyl benzoate, ethyl oleate, isopropyl myristate, isopropyl palmitate or a mixture of any thereof.
• the pharmaceutically-acceptable alcohol will be of a quality such that it will meet pharmacopoeial standards (such as are described in the US, British, European and Japanese pharmacopoeias) and as such will contain some water and possibly other organic solvents, for example ethanol in the US Pharmacopeia contains not less than 94.9% by volume and not more than 96.0% by volume of ethanol when measured at 15.56°C. Dehydrated alcohol in the US Pharmacopeia contains not less than 99.5%) ethanol by volume when measured at 15.56°C.
• the pharmaceutically-acceptable non- aqueous ester solvent will be of a quality that it will meet pharmacopoeial standards (such as described in the US, British, European and Japanese pharmacopoeias).
• ricinoleate excipient we mean an oil which has as a proportion
• the ricinoleate vehicle may be a synthetic oil or conveniently is castor oil, ideally of pharmacopoeial standards, as described above.
• extended release we mean at least 4 weeks, at least 5 weeks, and, preferably at least 8 weeks of continuous release of fulvestrant is achieved. In a preferred feature extended release is achieved for at least 8 weeks or 2 months, more preferably for at least 12 weeks or 3 months.
• Preferably 5ml of the intramuscular injection is administered.
• Additional excipients commonly used in the formulation field including, for example, an antioxidant preservative, a colorant or a surfactant may be used.
• a preferred optional excipient is a surfactant, more preferably an antioxidant.
• fulvestrant is useful in the treatment of oestrogen-dependent indications such as breast cancer and gynaecological conditions, such as endometriosis.
• oestrogen-dependent indications such as breast cancer and gynaecological conditions, such as endometriosis.
• SH-646 l l ⁇ -fluoro- 7 ⁇ -(14,14,15,15,15-pentafluoro-6- methyl-10-thia-6-azapentadecyl)estra-l ,3,5(10)-triene-3,17 ⁇ -diol
• SH-646 l l ⁇ -fluoro- 7 ⁇ -(14,14,15,15,15-pentafluoro-6- methyl-10-thia-6-azapentadecyl)estra-l ,3,5(10)-triene-3,17 ⁇ -diol
• Wakeling AE Therapeutic potential of pure antioestrogens in the treatment of breast cancer. Journal Steroid Biochemistry 1990c; 37: 771-5. 5. Wakeling AE, Bowler J. Steroidal pure antioestrogens. Journal Endocrinology 1987; 1 12: R7-10.
• Figure 1 shows plasma profiles obtained following IM injection (data normalised for rabbit weight, based on 3.2 kg rabbit) in which the y-axis is cone (ng/ml) and the x-axis is time (days);
• Figure 2 shows comparison of plasma profiles in which:
• Figure 2A shows plasma profiles from group A in which the y-axis is cone (ng/ml) and the x-axis is time (days);
• Figure 2B shows plasma profiles from group B in which the y-axis is cone (ng/ml) and the x-axis is time (days);
• Figure 3 shows plasma profiles from formulations 1 , 5 and Control (normalised for rabbit weight, based on 3.2 kg rabbit in which the y-axis is cone (ng/ml) and the x-axis is time (days);
• Figure 4 shows muscle residue data from 3 month PK study in which the y-axis is %> fulvestrant remaining per injection site and the x-axis is formulation number. Each bar represents one injection site (2 sites per animal).
• Figure 5 shows predicted versus actual solubility
• Figure 6 shows a confidence interval for predicted solubility
• Figure 7 shows plasma profiles obtained following IM injection (data normalised for rabbit weight, based on 3.2 kg rabbit) in which the y-axis is cone (ng/ml) and the x- axis is time (days);
• PDP Positive displacement pipette
• 2.1 1ml formulation vehicles were made up in triplicate by adding the appropriate volumes of alcohols and benzyl benzoate, and then adding castor oil by weight 2.2 Fulvestrant was then added to excess, until no more drug was seen to visibly dissolve. The weight of fulvestrant added was noted.
• amber vials were capped, vortex mixed for 10 seconds, sonicated for 10 minutes and then placed in the HPLC autosampler tray.
• Fulvestrant is mixed with ethanol and benzyl alcohol, stirring until completely dissolved. Benzyl benzoate is added and the solution is made to final weight with castor oil and stirred, (for convenience weight is used rather than volume by using the weight to volume ratio).
• the bulk solution is overlaid with nitrogen.
• the solution is sterilised by filtration using one or two filters of 0.2 ⁇ m porosity.
• the sterile filtrate is kept under a nitrogen overlay as it is filled under aseptic conditions into washed and depyrogenised, sterile primary containers, for example vials or pre-filled syringes. An overage is included in the primary pack to 5 facilitate removal of the dose volume.
• the primary packs are overlaid with sterile nitrogen, before aseptically sealing.
• the process flow diagram below depicts the manufacturing process.
• Fulvestrant STAGE 1 DISSOLUTION OF Alcohol ACTIVE AGENT Benzyl Alcohol
• Control Sample refers to the following Pharmaceutical formulation: fulvestrant 50mg/ml, ethanol 10% w/v, benzylalcohol 10% w/v, benzyl benzoate 15% w/v and made to volume with castor oil.
• a matrix of 7 pharmaceutical formulations (samples 3, 4, 5, 9, 12, 14 and 16 - see Example 3 below) was identified for further evaluation from in vitro precipitation and deposition studies.
• Sample 16 was a control.
• the precipitation experiment involved visual inspection of each sample under conditions where evaporation of alcohols led to precipitation of drug.
• Tables below show predicted formulations for various solubilities of fulvestrant; where an "X" means in solution. Note that the Tables include some impractical formulations where the sum of components becomes greater than 100%.
• the principal purpose is to illustrate the wide combinations of ethanol/ benzyl alcohol / benzyl benzoate taught by the invention to achieve different solubilities of fulvestrant.
• Formulations F3 and F6 as described in Example 4 were modified to contain an increased level of fulvestrant to 140mg/ml.
• the modified formulations were named F8 and F9 as described below.
• compositions of the formulations dosed in the PK study are shown in the table below.
• composition of the Control is the same as described in Example 4.
• Compositions F8 and F9 gave similar profiles with improved performance in terms of extended release of higher levels fulvestrant compared with Control.
• compositions analogous or similar to F3, F4, F5 and F6 (see Example 4) but comprising 150mg/ml of fulvestrant are prepared as follows.

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