TEPZZ_ 5Z_¥8B T (19) (11) EP 1 250 138 B2 NEW EUROPEAN PATENT SPECIFICATION (12) After opposition procedure (45) Date of publication and mention of the opposition decision: 08.07.2015 Bulletin 2015/28 (51) Int Cl.: A61K 31/565 (2006.01) A61K 47/14 (2006.01) (45) Mention of the grant of the patent: 19.10.2005 Bulletin 2005/42 (86) International application number: PCT/GB2001/000049 (21) Application number: 01900186.6 (87) International publication number: WO 2001/051056 (19.07.2001 Gazette 2001/29) A61P 35/00 (2006.01) A61K 47/44 (2006.01) (22) Date of filing: 08.01.2001 (54) FULVESTRANT FORMULATION FULVESTRANT FORMULIERUNG PREPARATION DE FULVESTRANT (84) Designated Contracting States: AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR Designated Extension States: AL LT LV MK RO SI (30) Priority: 10.01.2000 GB 0000313 12.04.2000 GB 0008837 (43) Date of publication of application: 23.10.2002 Bulletin 2002/43 (60) Divisional application: 05016921.8 / 1 669 073 10180661.0 / 2 286 818 10180667.7 / 2 266 573 (73) Proprietor: AstraZeneca AB 151 85 Södertälje (SE) EP 1 250 138 B2 (72) Inventors: • EVANS, John, Raymond Macclesfield, Cheshire SK10 4TG (GB) • GRUNDY, Rosalind, Ursula Macclesfield, Cheshire SK10 4TG (GB) (74) Representative: Hoffmann Eitle Patent- und Rechtsanwälte PartmbB Arabellastraße 30 81925 München (DE) (56) References cited: EP-A- 0 346 014 EP-A1- 0 346 014 WO-A-97/21440 • JOHN C. WATERTON; ET AL.: "A Case of Adenomyosis in a Pigtailed Monkey Diagnosed by Magnetic Resonance Imaging and treated with the Novel Pure Antiestrogen, ICI 182,780" LABORATORY ANIMAL SCIENCE, vol. 43, no. 3, 1993, pages 247-251, XP000998289 • C. RIFFKIN ET AL.: ’Castor Oil as a Vehicle for Parenteral Administration of Steroid Hormones’ JOURNAL OF PHARMACEUTICAL SCIENCES vol. 53, no. 8, 1964, pages 891 - 895 • J.F.R. ROBERTSON ET AL.: ’Pharmacokinetic Profile of Intramuscular Fulvestrant in Advanced Breast Cancer’ CLIN. PHARMACOKINET vol. 43, no. 8, 2004, pages 529 - 538 • S. MCLESKEY ET AL.: ’Tamoxifen-resistant Fibroblast Growth Factor-transfered MCF-7 Cells Are Cross-Resistant in Vivo to the Antiestrogen ICI 182,780 and Two Aromatase Inhibitors’ CLINICAL CANCER RESEARCH vol. 4, March 1998, pages 697 - 711 • A. HOWELL ET AL.: ’Pharmacokinetics, pharmacological and anti-tumour effects of the specific anti-oestrogen ICI 182780 in women with advanced breast cancer’ BRITISH JOURNAL OF CANCER vol. 74, 1996, pages 300 - 308 • A. HOWELL ET AL.: ’Response to a specific antioestrogen (ICI 182780) in tamoxifen-resistant breast cancer’ THE LANCET vol. 345, 07 January 1995, pages 29 - 30 • M. DUKES ET AL.: ’Antiuterotrophic effects of a pure antioestrogen, ICI 182,780: magnetic resonance imaging of the uterus in ovariectomized monkeys’ JOURNAL OF ENDOCRINOLOGY vol. 135, 1992, pages 239 - 247 EP-A1- 0 310 542 WO-A-96/19997 US-A- 3 164 520 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 1 250 138 B2 • A. HOWELL ET AL.: ’ICI 182,780 (Faslodex TM) Development of a Novel, "Pure" Antiestrogen’ AMERICAN CANCER SOCIETY vol. 89, 2000, pages 817 - 825 • J. ROBERTSON ET AL.: ’The anti-tumor effects of single dose, long acting Faslodex TM (ICI182780) compared with Tamoxifen in postmenopausal primary breast cancer patients treated before surgery, Breast Cancer Research and Treatment 59, 2000, 99’ BREAST CANCER RESEARCH AND TREATMENT vol. 57, no. 1, 2000, • M. DUKES ET AL.: ’Antiuterotrophic effects of the pure antioestrogen ICI 182,780 in adult female monkeys (Macaca nemestrina): quantitative magnetic resonance imaging’ JOURNAL OF ENDOCRINOLOGY vol. 138, 1993, pages 203 - 209 • R. M. O’REGAN ET AL.: ’Effects of the Antiestrogens Tamoxifen, Toremifene, and ICI 182,780 on Endometrial Cancer Growth’ JOURNAL OF THE NATIONAL CANCER INSTITUTE vol. 90, no. 20, 21 October 1998, pages 1552 - 1558 • Third party observation filed 24 January 2013 with letter dated 22 January 2013 2 EP 1 250 138 B2 Description 5 10 15 20 25 30 35 40 45 50 55 [0001] The invention relates to the use of 7α-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3,5(10)-triene3,17β-di-ol in the preparation of a formulation for administration byl intramuscular injection containing the compound 7α-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3,5(10)-triene-3,17β-diol 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, for the treatment of a benign or malignant disease of the breast or reproductive tract. [0002] 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 the ablation of ovarian function through surgical, radiotherapeutic, or medical means, and, in postmenopausal women, by the use of aromatase inhibitors. [0003] An alternative approach to oestrogen withdrawal is to antagonise oestrogens with antioestrogens. These are drugs that bind to and compete for oestrogen receptors (ER) present in the nuclei of oestrogen-responsive tissue. Conventional nonsteroidal antioestrogens, such 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 1984, May and Westley 1987). [0004] The potential for nonsteroidal antioestrogens to display agonistic properties prompted the search for novel compounds that would bind ER with high affinity without activating any of the normal transcriptional hormone responses and consequent manifestations of oestrogens. Such molecules would be "pure" antioestrogens, clearly distinguished from tamoxifen-like ligands and capable of eliciting complete ablation of the trophic effects of oestrogens. Such compounds are referred to as Estrogen Receptor-Downregulators (E.R.D.). The rationale for the design and testing of novel, pure antioestrogens has been described in: Bowler et al 1989, Wakeling 1990a, 1990b, 1990c. Wakeling and Bowler 1987, 1988. [0005] Steroidal analogues of oestradiol, with an alkylsulphinyl side chain in the 7α position, provided the first examples of compounds devoid of oestrogenic activity (Bowler et al 1989). One of these, 7α-[9-(4,4,5,5,5-pentafluoropentyl sulphinyl)nonyl]oestra-1,3,5-(10)triene-3,17β-diol was selected for intensive study on the basis of its pure oestrogen antagonist activity and significantly increased antioestrogenic potency over other available antioestrogens. In vitro findings and early clinical experience with 7α-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra-1,3-5(10)-triene-3,17β-diol have promoted interest in the development of the drug as a therapeutic agent for oestrogen-dependent indications such as breast cancer and certain benign gynaecological conditions. [0006] 7α-[9-(4,4,5,5,5-Pentafluoropentylsulphinyl)nonyl]oestra-1,3-5(10)-triene-3,17β-diol, or ICI 182,780, has been allocated the international non-proprietary name fulvestrant, which is used hereinafter. When referring to fulvestrant we include pharmaceutically-acceptable salts thereof and any possible solvates of either thereof. [0007] 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. [0008] 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. [0009] 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. [0010] 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. In particular there is the disclosure within Example 35 of the compound 7α-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra1,3,5(10)-triene-3,17β-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. [0011] 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). [0012] Currently there are a number of sustained release injectable steroidal formulations which have been commercialised. Commonly these formulations use oil as a solvent and wherein additional excipients may be present. Below in 3 EP 1 250 138 B2 Table 1 are described a few commercialised sustained release injectable formulations. [0013] In the formulations within Table 1 a number of different oils are used to solubilise the compound and additional excipients such as benzyl benzoate, benzyl alcohol and ethanol have been used. Volumes of oil needed to solubilise the steroid active ingredient are low. Extended release is achievable for periods from 1 to 8 weeks. 5 10 15 20 25 30 35 40 45 50 55 4 50 55 5 PROGESTERONE RETARD GRAVIBINAN Estradiol hexahydrobenzoate Hydroxy progesterone caproate Estradiol 17-β-valerate Hydroxyprogesterone caproate Hydroxy progesterone enantate Progesterone α-Tocopherol Estrapronicate Nandrolone undecanoate Hydroxyprogesterone heptanoate Norethisterone oenanthoate Testosterone proprionate Testosterone phenylproprionate Testosterone isocaproate Testosterone decanoate Hydroxy progesterone hexanoate 45 BENZO-GYNOESTRYL 40 NORJSTERAT 35 TROPHOBOLENE 30 TOCOGESTAN 25 SUSTANON 100 Pharlon Schering HC 5mgml-1 Mixed 250mgml-1 Roussel Schering HC Theramax Theramax Schering HC Organon 250mgml-1 Progestogen 5mg Estradiol 200mg Contraceptive 80mg 50mg 250mg 1.3mg Mixed 50mg 200mg Progestogen 250mgml-1 Progestogen 100mg 60mg 60mg 30mg Androgen ABPI Data Sheet Comp.1999 Dict. Vidal 1998 Diet. Vidal 1999 Dict. Vidal 1995 Dict. Vidal 1997 ABPI Data Sheet Comp.1999 Dict. Vidal 1999 Sheet Comp.1999 ABPI Data Castor Castor Arachis Castor Olive Ethyl oleate Castor Arachis YES YES YES 45% *40% up to 46% 15 PROLUTON DEPOT 20 Table 1- OIL BASED LONG-ACTING INTRAMUSCULAR INJECTIONS DOSE TYPE COMP’. SOURCE OIL BzBz 0.1ml BzQH EtOH 10 STEROID 3 weeks DOSING 1 week 8 weeks 15 to 30 days < 1 week 1 or 2ml 1- 2 weeks 1 or 2ml 1 week 1ml 1ml 1ml 2ml 1 or 2ml 1 week 1ml DOSE 5 PRODUCT NAME EP 1 250 138 B2 50 55 30 35 45 J.Pharm. Sci (1964) 53(8) 891 Dict.Vidal 1997 Castor Arachis 78% 58% YES 15 BMS Negma 20% 40% YES 75mg 45mg 1.5ml 5 2 weeks DELESTROGEN Estradiol valerate 2% 2% Progestrogen DMS J.Pharm. Sci.(1964) Castor up to DELALUTIN 17-Hydroxy 53(8) 891 2% progesterone BzBz = benzylbenzoate BzOH = benzylalcohol ETOH - ethanol Dict. Vidal = Dictionnaire Vidal % are w/v and * approximate as measured directly from a single sample Estradiol 20mgml-1 40mgml-1 250mgml-1 40 Androgen 25 76mg 20 Trenbolone 10 PARABOLAN EP 1 250 138 B2 6 EP 1 250 138 B2 5 [0014] In US 5,183,814 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. [0015] Table 2 shows the solubility of fulvestrant in a number of different solvents. Table 2 - 10 SOLUBILITY OF FULVESTRANT SOLVENT SOLUBILITY (mgml-1 at 25°C) 15 20 25 30 35 40 45 50 55 Water Arachis oil Sesame oil Castor oil Miglyol 810 Miglyol 812 Ethyl oleate Benzyl benzoate Isopropyl myristate Span 85 (surfactant) Ethanol Benzyl Alcohol 0.001 0.45 0.58 20 3.06 2.72 1.25 6.15 0.80 3.79 >200 >200 [0016] As can be seen 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). [0017] However, even when using the best oil based solvent, castor oil, we have found that it is not possible to dissolve fulvestrant in an oil based solvent alone so as to achieve a high enough concentration to dose a patient in a low volume injection and achieve a therapeutically significant release rate. To achieve a therapeutically significant release rate the amount of fulvestrant needed would require the formulation volume to be large, at least 10 ml. This requires the doctor to inject an excessively large volume of formulation to administer a dose significantly high enough for human therapy. [0018] Currently guidelines recommend that no more than 5mls of liquid is injected intramuscularly in a single injection. Pharmacologically active doses required for a 1 month long acting depot formulation of fulvestrant is around 250mg. Therefore, when dissolved in just castor oil, fulvestrant would need to be administered in at least 10ml of castor oil. [0019] The addition of organic solvents in which fulvestrant is freely soluble, and which are miscible with castor oil, may be used, such as an alcohol. With the addition of high concentrations of an alcohol concentrations of >50mgml-1 of fulvestrant in a castor oil formulation is achievable, thereby giving an injection volumes of <5ml - see Table 3 below. We have surprisingly found that the introduction of a non-aqueous ester solvent which is miscible in the castor oil and an alcohol surprisingly eases the solubilisation of fulvestrant into a concentration of at least 50 mgml-1 - see Table 3 below. The finding is surprising since the solubility of fulvestrant in non-aqueous ester solvents - see Table 2 above - is significantly lower than the solubility of fulvestrant in an alcohol. The solubility of fulvestrant is also lower in non-aqueous ester solvents than is the solubility of fulvestrant in castor oil. [0020] Therefore, we present as a feature of the invention a pharmaceutical formulation comprising fulvestrant (preferably fulvestrant is present at 3-10%w/v, 4-9%w/v, 4-8%w/v, 4-7%w/v, 4-6%w/v and most preferably at about 5%w/v) in a ricinoleate vehicle, a pharmaceutically acceptable non-aqueous ester solvent, and a pharmaceutically acceptable alcohol wherein the formulation is adapted for intramuscular administration and attaining a therapeutically significant blood plasma fulvestrant concentration for at least 2 weeks. [0021] Another feature of the invention is 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 for at least 2 weeks. [0022] Further features of the invention include a pharmaceutical formulation adapted for intra-muscular injection comprising fulvestrant, 30% or less weight of a pharmaceutically-acceptable alcohol per volume of formulation, at least 7 EP 1 250 138 B2 5 10 1% weight of a pharmaceutically-acceptable non-aqueous ester solvent miscible in a ricinoleate vehicle per volume of formulation and a sufficient amount of a ricinoleate vehicle so as to prepare a formulation which is capable after injection of attaining a therapeutically significant blood plasma fulvestrant concentration for at least 2 weeks. [0023] Further features of the invention include a pharmaceutical formulation adapted for intra-muscular injection comprising fulvestrant; 35% (preferably 30% and ideally 25%) or less weight of a pharmaceutically-acceptable alcohol per volume of formulation, at least 1% (preferably at least 5% or ideally 10%) weight of a pharmaceutically-acceptable non-aqueous ester solvent miscible within a ricinoleate vehicle per volume of formulation and a sufficient amount of a ricinoleate vehicle so as to prepare a formulation of at least 45mgml-1 of fulvestrant. [0024] For the avoidance of any doubt when using the term % 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 1g of the constituent. By way of further illustration 15 20 [0025] 25 30 35 40 45 50 55 % of x by weight per volume of formulation weight of x in 1ml of formulation 30% 20% 10% 5% 1% 300mg 200mg 100mg 50mg 10mg Preferred pharmaceutical formulations of the invention are as described above wherein: 1. The total volume of the formulation is 6ml, or less, and the concentration of fulvestrant is at least 45mgml-1. 2. The total amount of fulvestrant in the formulation is 250mg, or more, and the total volume of the formulation is 6ml, or less. 3. The total amount of fulvestrant in the formulation is 250mg and the total volume of the formulation is 5-5.25ml. [0026] It is appreciated that in the formulation an excess of formulation may be included to allow the attendant physician or care giver to be able to deliver the required dose. Therefore, when a 5ml dose is required it would be appreciated that an excess of up to 0.25ml, preferably up to 0.15ml will also be present in the formulation. Typically 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. [0027] Preferred concentrations of a pharmaceutically-acceptable alcohol present in any of the above formulations are; at least 3%w/v, at least 5%w/v, at least 7%w/v, at least 10% w/v, at least 11% w/v, at least 12% w/v, at least 13% w/v, at least 14% w/v, at least 15% w/v and, preferably, at least 16% w/v. Preferred maximal concentrations of pharmaceutically-acceptable alcohol present in the formulation are ;28% w/v or less, 22% w/v or less and 20% w/v or less.. Preferred ranges of pharmaceutically-acceptable alcohol present in any of the above formulations are selected from any minimum or maximum value described above and preferably are; 3-35%w/v, 4-35%w/v, 5-35%w/v, 5-32%w/v, 7-32%w/v, 10-30%w/v, 12-28%w/v, 15-25%w/v, 17-23%w/v, 18-22%w/v and ideally 19-21%w/v. [0028] 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, preferably the ethanol and benzyl alcohol are present in the formulation in the same w/v amounts. Preferably the formulation alcohol contains 10% w/v ethanol and 10% w/v benzyl alcohol. [0029] 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. [0030] The ricinoleate vehicle should preferably be present in the formulation in a proportion of at least 30% weight per volume of the formulation, ideally at least 40% or at least 50% weight per volume of formulation. [0031] It will be understood by the skilled person that 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, tor 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. 8 EP 1 250 138 B2 5 10 15 [0032] Preferred concentrations of the pharmaceutically-acceptable non-aqueous ester solvent present in any of the above formulations are; at least 5% w/v, at least 8% w/v, at least 10% w/v, at least 11% w/v, at least 12% w/v, at least 13% w/v, at least 15% w/v, at least 16% w/v, at least 17% w/v, at least 18% w/v, at least 19% w/v and at least 20% w/v. Preferred maximal concentrations of the pharmaceutically-acceptable non-aqueous ester solvent are; 60% w/v or less, 50%w/v or less, 45% w/v or less, 40% w/v or less, 35% w/v or less, 30% w/v or less and 25% w/v or less. A preferred concentration is 15% w/v. Preferred ranges of pharmaceutically-acceptable non-aqueous ester solvent present in any of the above formulations are selected from any minimum or maximum value described above and preferably are; 5-60%w/v, 7-55%w/v, 8-50%w/v, 10-50%w/v, 10-45%w/v, 10-40%w/v, 10-35%w/v, 10-30%w/v, 10-25%w/v, 12-25%w/v, 12-22%w/v, 12-20%w/v, 12-18%w/v, 13-17%w/v and ideally 14-16%w/v. Preferably the ester solvent is benzyl benzoate, most preferably at about 15%w/v. [0033] It will be understood by the skilled person that 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). [0034] Preferred combinations of pharmaceutically-acceptable alcohol and pharmaceutically-acceptable non-aqueous ester solvent in the formulation are set out below: Pharmaceutically-acceptable alcohol(%w/v) Pharmaceutically-acceptable non-aqueous ester (%w/v) 10-30 5-60, 7-55, 8-50, 10-50, 10-45, 10-40, 10-35, 10-30, 10-25, 12-25, 12-22, 12-20, 12-18, 13-17 and ideally 14-16. 17-23 5-60, 7-55, 8-50, 10-50, 10-45, 10-40, 10-35, 10-30, 10-25, 12-25, 12-22, 12-20, 12-18, 13-17 and ideally 14-16. 3-35, 4-35, 5-35, 5-32, 7-32, 10-30, 12-28, 15-25, 17-23, 18-22 and ideally 19- 10-35 3-35, 4-35, 5-35, 5-32, 7-32, 10-30, 12-28, 15-25, 17-23, 18-22 and ideally 19-21. 12-18 ethanol and benzyl alcohol, most preferably each at about 10% benzyl benzoate, most preferably at about 15% 20 25 30 35 40 45 50 55 [0035] By the use of the term ricinoleate vehicle we mean an oil which has as a proportion (at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% w/v) of its composition as triglycerides of ricinoleic acid. The ricinoleate vehicle may be a synthetic oil or conveniently is castor oil, ideally of pharmacopoeial standards, as described above. [0036] We have surprisingly found that the above formulations used in the invention provide, after intra-muscular injection, satisfactory release of fulvestrant over an extended period of time. [0037] This finding is indeed surprising for the following reasons. 1. Previously tested by the applicants have been intra-muscular injections of fulvestrant in the form of an aqueous suspension. We have found extensive local tissue irritation at the injection site as well as a poor release profile. It is believed that the tissue irritation/inflammation was due to the presence of fulvestrant in the form of solid particles. The release profile appeared to be determined by the extent of inflammation/irritation present at the injection site and this was variable and diffcult to control. Also the fulvestrant release rate was not sufficiently high to be clinically significant. 2. Our findings from studies using 14C labelled benzyl alcohol show that it dissipates rapidly from the injection site and is removed from the body within 24 hours of administration. [0038] It would be expected that ethanol will dissipate at least as quickly, if not more rapidly, from the injection site. [0039] It is known that benzyl benzoate is metabolised by conjugation to glycine to form hippuric acid by the human liver and excreted into the urine - Martindale: The Extra Pharmacopoeia 32nd edition page 1103, and, therefore, it is unlikely that benzyl benzoate, when used, is present at the injection site during the whole of the extended release period. [0040] We have found that despite the rapid elimination of the additional solubilising excipients, i.e. the alcohol and pharmaceutically-acceptable non-aqueous ester solvent, from the formulation vehicle and the site of injection after injection of the formulation, extended release at therapeutically significant levels of fulvestrant over an extended period can still achieved by the formulation of the invention. [0041] By use of the term "therapeutically significant levels" we mean that blood plasma concentrations of at least 2.5 ngml-1, ideally at least 3 ngml-1, at least 8.5 ngml-1, and up to 12 ngml-1 of fulvestrant are achieved in the patient. Preferably blood plasma levels should be less than 15 ngml-1. 9 EP 1 250 138 B2 5 10 15 20 [0042] By use of the term "extended release" we mean at least two weeks, at least three weeks, and, preferably at least four weeks of continuous release of fulvestrant is achieved. In a preferred feature extended release is achieved for 36 days. Preferably extended release of fulvestrant is for at least 2- 5 weeks and more preferably for the following periods (weeks) 2.5-5, 2.5-4, 3-4, 3.5-4 and most preferably for at least about 4 weeks. [0043] It will be understood that the attendant physician may wish to administer the intramuscular injection as a divided dose, i.e. a 5ml formulation is sequentially administered in two separate injections of 2.5ml, this is a further feature of the invention [0044] Simply solubilising fulvestrant in an oil based liquid formulation is not predictive of a good release profile or lack of precipitation of drug after injection at the injection site. [0045] Table 3 shows the solubility of fulvestrant in a castor oil vehicle additionally containing alcohols ethanol and benzyl alcohol with or without benzyl benzoate. The results clearly show the positive effect of benzyl benzoate on fulvestrant solubility in castor oil, despite fulvestrant having a lower solubility in benzyl benzoate than in either alcohol or castor oil. Table 3 Table 3 - EFFECT OF BENZYL BENZOATE ON FULVESTRANT SOLUBILITY IN CASTOR OIL AT 25°C Ethanol (96%) Benzyl Alcohol Benzyl Benzoate Castor Oil Fulvestrant Solubility [mgml-1] 5 5 to 100 27 5 5 15 to 100 36 % w/v 10 5 10 5 15 to 100 54 to 100 46 10 10 10 10 15 to 100 65 to 100 45 15 15 to 100 76 15 15 15 to 100 102 25 [0046] The following Table 4 shows the solubility of fulvestrant in a range of oil based formulations which contain the same amounts of alcohol and benzyl benzoate but in which the oil is changed. The data also shows solubility of fulvestrant after removal of the alcohols. 30 Table 4 Solubility comparisons of fulvestrant in oil based formulations with and without alcohols Fulvestrant Solubility mg ml-1 @ 25°C 35 40 Formulation (a) Complete vehicle Vehicle minus alcohols Castor oil based Miglyol 812-N based Sesame seed/Castor oil (1:1) based Sesame seed oil based Arachis oil based 81.2 86.8 70.1 45.7 40.2 12.6 1.7 4.4 0.7 < 0.2 (a) Complete Vehicle Formulations comprised ethanol [96%](10%), benzyl alcohol (10%) and benzyl benzoate (15%) made to volume with the stated oil. Excess fulvestrant was added to each solvent mixture and solubility determined. 45 Effect of formulation on precipitation of fulvestrant at the injection site Days 50 55 Formulation a 2 3 4 7 10 30 51 Formulation F1 castor oil based Formulation F2 Miglyol 812-N based Formulation F3 sesame seed oil/castor oil based 0 ++ b +c 0 +++ ++ 0 +++ ++ 0 +++ +++ 0 +++ ++ 0 ++ + 0 0 + 0, + , ++, +++ = Degree of precipitation (None detected, Mild, Moderate, Severe) 10 EP 1 250 138 B2 (continued) Effect of formulation on precipitation of fulvestrant at the injection site Days 5 Formulation a 2 3 4 7 10 30 51 a 10 15 20 25 30 35 40 45 Formulations comprised fulvestrant (5%), ethanol [96%] (10%), benzyl alcohol (10%) and benzyl benzoate (15%) made to volume with the stated oil. b Mainly large needle shaped crystals c Small needles and/or sheafs of crystals [0047] Precipitation of fulvestrant and the release profile was determined with the above formulations In an in vivo rabbit study. [0048] Figure 1 shows the release profile in vivo of the four formulations from the second part of Table 4 and shows the effect of the fixed oil component on fulvestrant plasma profile over five days following Intramuscular administration in rabbits (data normalised to 50mg per 3kg; mean given; number of animals per timepoint=8, plasmasamples assayed forfulvestrant content using Ic-ms/ms detection following solvent extraction). As can be seen the castor oil formulation showed a particularly even release profile with no evidence of precipitation of fulvestrant at the injection site. [0049] Therefore we present as a further feature of the invention an extended release pharmaceutical formulation adapted for intramuscular injection comprising fulvestrant; 35% (preferably 30% or ideally 25%) or less weight of a pharmaceutically-acceptable alcohol per volume of formulation, at least 1% (preferably at least 5% or ideally 10%) weight of a pharmaceutically-acceptable non-aqueous ester solvent miscible In a ricinoleate vehicle per volume of formulation and sufficient amount of a ricinoleate vehicle, taking into account the addition of any further optional pharmaceuticallyacceptable excipients, so as to prepare a formulation of at least 45mgml-1 of fulvestrant. [0050] A feature of the invention is a pharmaceutical formulation for intramuscular injection, as defined above, for use in the treatment of a benign or malignant diseases of the breast or reproductive tract, preferably treating breast cancer, by administration to a human in need of such treatment by intramuscular injection an extended release ricinoleate vehicle based pharmaceutical formulation comprising at least 45mgml-1 of fulvestrant; 35% (preferably 30% or ideally 25%) or less weight of a pharmaceutically-acceptable alcohol per volume of formulation, at least 1 % (preferably at least 5% orideally 10%) weight of a pharmaceutically-acceptable non-aqueous ester solvent miscible in a ricinoleate vehicle per volume of formulation. [0051] Preferably 5ml of the intramuscular injection is administered. [0052] A further feature of the invention is use of fulvestrant in the preparation of a pharmaceutical formulation as describe hereinabove, for the treatment of a benign or malignant disease of the breast or reproductive tract, preferably treating breast cancer. [0053] 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. [0054] As described above fulvestrant is useful in the treatment of oestrogen-dependent indications such as breast cancer and gynaecological conditions, such as endometriosis. [0055] In addition tofulvestrant another similar type of molecule is currently underclinical investigation. SH-646 (11βfluoro-7α-(14,14,15,15,15-pentafluoro-6-methyl-10-thia-6-azapentadecyl)estra-1,3,5(10)-triene-3,17β-diol) is also putatively a compound with the same mode of action as fulvestrant and has a very similarchemical structure. It is believed that the compound will also share with fulvestrant similar physical properties and therefore the current invention will also have application with this compound. Formulation Example 50 55 [0056] Fulvestrant is mixed with alcohol 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 0.2mm 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 facilitate removal of the dose volume. The primary packs are overlaid with sterile nitrogen, before aseptically sealing. 11 EP 1 250 138 B2 See also process flow diagram below 5 10 [0057] Quantities of each component of the formulation is chosen according to the required formulation specification, examples are described above. For example quantities are added of each component to prepare a formulation which contains 10% weight per volume of benzyl alcohol 10% weight per volume of ethanol 15% weight per volume of benzyl benzoate 250mg of fulvestrant for each 5ml of finished formulation and the remaining amount as castor oil 15 20 25 30 35 40 45 50 References [0058] 1. Bowler J, Lilley TJ, Pittam JD, Wakeling AE. Novel steroidal pure antioestrogens. Steroids 989; 5471-99. 55 2. Wakeling AE. Novel pure antioestrogens: mode of action and therapeutic prospects. American New York Academy Science 1990a; 595: 348-56. 12 EP 1 250 138 B2 3. Wakeling AE. Steroidal pure antioestrogens. In Lippman M, Dickson R, editors. Regulatory mechanisms in breast cancer. Boston: Kluwer Academic, 1990b: 239-57. 4. Wakeling AE. Therapeutic potential of pure antioestrogens in the treatment of breast cancer. Journal Steroid Biochemistry 1990c; 37: 771-5. 5 5. Wakeling AE, Bowler J. Steroidal pure antioestrogens. Journal Endocrinology 1987; 112: R7-10. 6. Wakeling AE, Bowler J. Biology and mode of action of pure antioestrogens. Journal Steroid Biochemistry 1988; 3: 141-7. 10 Claims 15 1. Use of fulvestrant in the preparation of a pharmaceutical formulation for the treatment of a benign or malignant disease of the breast or reproductive tract by intra-muscular administration, wherein the formulation comprises fulvestrant in a ricinoleate vehicle, a pharmaceutically acceptable non-aqueous ester solvent, and a pharmaceutically acceptable alcohol, and wherein the formulation is adapted for attaining a therapeutically significant blood plasma fulvestrant concentration for at least 2 weeks. 2. Use of fulvestrant in the preparation of a pharmaceutical formulation for the treatment of a benign or malignant disease of the breast or reproductive tract by intra-muscular administration, wherein the formulation comprises fulvestrant, 30 % or less weight of a pharmaceutically-acceptable alcohol per volume of formulation, at least 1 % weight of a pharmaceutically-acceptable non-aqueous ester solvent miscible in a ricinoleate vehicle per volume of formulation and a sufficient amount of a ricinoleate vehicle so as to prepare a formulation which is capable after injection of attaining a therapeutically significant blood plasma fulvestrant concentration for at least 2 weeks. 3. The use as claimed in claim 1 or 2, wherein the blood plasma fulvestrant concentration attained is at least 2.5 ngml-1 for at least 2 weeks. 4. Use of fulvestrant in the preparation of a pharmaceutical formulation for the treatment of a benign or malignant disease of the breast or reproductive tract by intra-muscular administration, wherein the pharmaceutical formulation comprises fulvestrant, 30 % or less weight of a pharmaceutically-acceptable alcohol per volume of formulation, at least 1 % weight of a pharmaceutically-acceptable non-aqueous ester solvent miscible in a ricinoleate vehicle per volume of formulation and a sufficient amount of a ricinoleate vehicle so as to prepare a formulation of at least 45 mgml-1 of fulvestrant. 5. The use as claimed in claim 1 to 4 wherein the pharmaceutical formulation contains 25 % w/v or less of a pharmaceutically-acceptable alcohol. 6. The use as claimed in claim 5 wherein the pharmaceutical formulation contains 20 % w/v or less of a pharmaceuticallyacceptable alcohol. 7. The use as claimed in claim 5 wherein the pharmaceutical formulation contains 15-25 % w/v of a pharmaceuticallyacceptable alcohol. 8. The use as claimed in claim 5 wherein the pharmaceutical formulation contains 17-23 % w/v of a pharmaceuticallyacceptable alcohol. 9. The use as claimed in any claim from 1 to 8 wherein the pharmaceutical formulation contains 60 % w/v or less of a pharmaceutically-acceptable non-aqueous ester solvent. 20 25 30 35 40 45 50 10. The use as claimed in claim 9 wherein the pharmaceutical formulation contains 50 % w/v or less of a pharmaceuticallyacceptable non-aqueous ester solvent. 55 11. The use as claimed in claim 9 wherein the pharmaceutical formulation contains 45 % w/v or less of a pharmaceuticallyacceptable non-aqueous ester solvent. 13 EP 1 250 138 B2 12. The use as claimed in claim 9 wherein the pharmaceutical formulation contains 40 % w/v or less of a pharmaceuticallyacceptable non-aqueous ester solvent. 5 13. The use as claimed in claim 9 wherein the pharmaceutical formulation contains 35 % w/v or less of a pharmaceuticallyacceptable non-aqueous ester solvent. 14. The use as claimed in claim 9 wherein the pharmaceutical formulation contains 30 % w/v or less of a pharmaceuticallyacceptable non-aqueous ester solvent. 10 15. The use as claimed in claim 9 wherein the pharmaceutical formulation contains 25 % w/v or less of a pharmaceuticallyacceptable non-aqueous ester solvent. 16. The use as claimed in claim 9 wherein the pharmaceutical formulation contains 10-25 % w/v of a pharmaceuticallyacceptable non-aqueous ester solvent. 15 17. The use as claimed in claim 9 wherein the pharmaceutical formulation contains 12-18 % w/v of a pharmaceuticallyacceptable non-aqueous ester solvent. 20 18. Use of fulvestrant in the preparation of a pharmaceutical formulation for the treatment of a benign or malignant disease of the breast or reproductive tract by intra-muscular administration, wherein the pharmaceutical formulation comprises fulvestrant, 15-25 % weight of a pharmaceutically-acceptable alcohol per volume of formulation, 10-25 % weight of a pharmaceutically-acceptable non-aqueous ester solvent miscible in a ricinoleate vehicle per volume of formulation and a sufficient amount of a ricinoleate vehicle so as to prepare a formulation of at least 45 mgml-1 of fulvestrant. 25 30 19. Use of fulvestrant in the preparation of a pharmaceutical formulation for the treatment of a benign or malignant disease of the breast or reproductive tract by intra-muscular administration, wherein the pharmaceutical formulation comprises fulvestrant, 17-23 % weight of a pharmaceutically-acceptable alcohol per volume of formulation, 12-18 % weight of pharmaceutically-acceptable non-aqueous ester solvent miscible in a ricinoleate vehicle per volume of formulation and a sufficient amount of a ricinoleate vehicle so as to prepare a formulation of at least 45 mgml-1 of fulvestrant. 20. The use as claimed in any claim from 1 to 19 wherein the pharmaceutically-acceptable alcohol is a mixture of ethanol and benzyl alcohol. 35 21. The use as claimed in any claim from 1 to 20 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. 40 45 50 55 22. The use as claimed in any claim from 1 to 21 wherein the pharmaceutically-acceptable non-aqueous ester solvent is benzyl benzoate. 23. Use of fulvestrant in the preparation of a pharmaceutical formulation for the treatment of a benign or malignant disease of the breast or reproductive tract by intra-muscular administration, wherein the pharmaceutical formulation comprises fulvestrant, 15-25 % weight of a pharmaceutically-acceptable alcohol per volume of formulation, 10-25 % weight of benzyl benzoate in a ricinoleate vehicle per volume of formulation and a sufficient amount of a ricinoleate vehicle so as to prepare a formulation of at least 45 mgml-1 of fulvestrant. 24. Use of fulvestrant in the preparation of a pharmaceutical formulation for the treatment of a benign or malignant disease of the breast or reproductive tract by intra-muscular administration, wherein the pharmaceutical formulation comprises fulvestrant, 17-23 % weight of a pharmaceutically-acceptable alcohol per volume of formulation, 12-18 % weight of benzyl benzoate in a ricinoleate vehicle per volume of formulation and a sufficient amount of a ricinoleate vehicle so as to prepare a formulation of at least 45 mgml-1 of fulvestrant. 25. The use as claimed in claim 23 or 24 wherein the pharmaceutically-acceptable alcohol is a mixture of ethanol and benzyl alcohol. 26. The use as claimed in claim 25 wherein the ethanol and benzyl alcohol are present at about equal % weight per volume of formulation. 14 EP 1 250 138 B2 27. The use as claimed in any claim from 1 to 26 wherein the total volume of the formulation is 6 ml, or less, and the concentration of fulvestrant is at least 45 mgml-1. 5 28. The use as claimed in any claim from 1 to 27 wherein the total amount of fulvestrant in the formulation is 250 mg, or more, and the total volume of the formulation is 6 ml, or less. 29. The use as claimed in claim 28 wherein the total amount of fulvestrant in the formulation is 250 mg and the total volume of the formulation is 5 to 5.25 ml. 10 30. The use as claimed in any of claims 1 to 29 wherein the pharmaceutically-acceptable alcohol is a mixture of 10 % weight of ethanol per volume of formulation, 10 % weight of benzyl alcohol per volume of formulation, and the formulation contains 15 % weight of benzyl benzoate per volume of formulation and the ricinoleate vehicle is castor oil. 31. The use as claimed in claim 30 wherein the formulation is present in a syringe or vial. 15 Patentansprüche 1. Verwendung von Fulvestrant bei der Herstellung einer pharmazeutischen Formulierung zur Behandlung einer gutartigen oder bösartigen Erkrankung der Brust oder des Reproduktionstrakts mittels intramuskulärer Verabreichung, wobei die Formulierung Fulvestrant in einer Ricinoleat-Trägersubstanz, ein pharmazeutisch annehmbares nichtwässriges Esterlösungsmittel und einen pharmazeutisch annehmbaren Alkohol umfasst, und wobei die Formulierung zur Erzielung einer mindestens 2 Wochen anhaltenden, therapeutisch signifikanten Fulvestrantkonzentration im Blutplasma hergerichtet ist. 2. Verwendung von Fulvestrant bei der Herstellung einer pharmazeutischen Formulierung zur Behandlung einer gutartigen oder bösartigen Erkrankung der Brust oder des Reproduktionstrakts mittels intramuskulärer Verabreichung, wobei die Formulierung Fulvestrant, 30 Gew.-% oder weniger eines pharmazeutisch annehmbaren Alkohols, bezogen auf das Volumen der Formulierung, mindestens 1 Gew.-%, bezogen auf das Volumen der Formulierung, eines pharmazeutisch annehmbaren nichtwässrigen Esterlösungsmittels, das in einer Ricinoleat-Trägersubstanz mischbar ist, und eine ausreichende Menge einer Ricinoleat-Trägersubstanz, um eine Formulierung herzustellen, die nach Injektion zur Erzielung einer mindestens 2 Wochen anhaltenden, therapeutisch signifikanten Fulvestrantkonzentration im Blutplasma fähig ist. 3. Die Verwendung wie in Anspruch 1 oder 2 beansprucht, wobei die im Blutplasma erzielte Fulvestrantkonzentration mindestens 2 Wochen lang mindestens 2,5 ngml-1 beträgt. 4. Verwendung von Fulvestrant bei der Herstellung einer pharmazeutischen Formulierung zur Behandlung einer gutartigen oder bösartigen Erkrankung der Brust oder des Reproduktionstrakts mittels intramuskulärer Verabreichung, wobei die pharmazeutische Formulierung Fulvestrant, 30 Gew.-% oder weniger eines pharmazeutisch annehmbaren Alkohols, bezogen auf das Volumen der Formulierung, mindestens 1 Gew.-%, bezogen auf das Volumen der Formulierung, eines pharmazeutisch annehmbaren nichtwässrigen Esterlösungsmittels, das in einer Ricinoleat-Trägersubstanz mischbar ist, und eine ausreichende Menge einer Ricinoleat-Trägersubstanz enthält, um eine Formulierung mit mindestens 45 mgml-1 Fulvestrant herzustellen. 5. Die Verwendung wie in Anspruch 1 bis 4 beansprucht, wobei die pharmazeutische Formulierung 25% w/v oder weniger eines pharmazeutisch annehmbaren Alkohols enthält. 6. Die Verwendung wie in Anspruch 5 beansprucht, wobei die pharmazeutische Formulierung 20 % w/v oder weniger eines pharmazeutisch annehmbaren Alkohols enthält. 7. Die Verwendung wie in Anspruch 5 beansprucht, wobei die pharmazeutische Formulierung 15-25 % w/v eines pharmazeutisch annehmbaren Alkohols enthält. 8. Die Verwendung wie in Anspruch 5 beansprucht, wobei die pharmazeutische Formulierung 17-23 % w/v eines pharmazeutisch annehmbaren Alkohols enthält. 9. Die Verwendung wie in einem der Ansprüche 1-8 beansprucht, wobei die pharmazeutische Formulierung 60 % w/v 20 25 30 35 40 45 50 55 15 EP 1 250 138 B2 oder weniger eines pharmazeutisch annehmbaren nichtwässrigen Esterlösungsmittels enthält. 10. Die Verwendung wie in Anspruch 9 beansprucht, wobei die pharmazeutische Formulierung 50 % w/v oder weniger eines pharmazeutisch annehmbaren nichtwässrigen Esterlösungsmittels enthält. 5 11. Die Verwendung wie in Anspruch 9 beansprucht, wobei die pharmazeutische Formulierung 45 % w/v oder weniger eines pharmazeutisch annehmbaren nichtwässrigen Esterlösungsmittels enthält. 10 12. Die Verwendung wie in Anspruch 9 beansprucht, wobei die pharmazeutische Formulierung 40 % w/v oder weniger eines pharmazeutisch annehmbaren nichtwässrigen Esterlösungsmittels enthält. 13. Die Verwendung wie in Anspruch 9 beansprucht, wobei die pharmazeutische Formulierung 35 % w/v oder weniger eines pharmazeutisch annehmbaren nichtwässrigen Esterlösungsmittels enthält. 15 14. Die Verwendung wie in Anspruch 9 beansprucht, wobei die pharmazeutische Formulierung 30 % w/v oder weniger eines pharmazeutisch annehmbaren nichtwässrigen Esterlösungsmittels enthält. 15. Die Verwendung wie in Anspruch 9 beansprucht, wobei die pharmazeutische Formulierung 25 % w/v oder weniger eines pharmazeutisch annehmbaren nichtwässrigen Esterlösungsmittels enthält. 20 16. Die Verwendung wie in Anspruch 9 beansprucht, wobei die pharmazeutische Formulierung 10-25 % w/v eines pharmazeutisch annehmbaren nichtwässrigen Esterlösungsmittels enthält. 25 30 35 40 17. Die Verwendung wie in Anspruch 9 beansprucht, wobei die pharmazeutische Formulierung 12-18 % w/v eines pharmazeutisch annehmbaren nichtwässrigen Esterlösungsmittels enthält. 18. Verwendung von Fulvestrant bei der Herstellung einer pharmazeutischen Formulierung zur Behandlung einer gutartigen oder bösartigen Erkrankung der Brust oder des Reproduktionstrakts mittels intramuskulärer Verabreichung, wobei die pharmazeutische Formulierung Fulvestrant, 15-25 Gew.-% eines pharmazeutisch annehmbaren Alkohols, bezogen auf das Volumen der Formulierung, 10-25 Gew.-%, bezogen auf das Volumen der Formulierung, eines pharmazeutisch annehmbaren nichtwässrigen Esterlösungsmittels, das in einer Ricinoleat-Trägersubstanz mischbar ist, und eine ausreichende Menge einer Ricinoleat-Trägersubstanz enthält, um eine Formulierung mit mindestens 45 mgml-1 Fulvestrant herzustellen. 19. Verwendung von Fulvestrant bei der Herstellung einer pharmazeutischen Formulierung zur Behandlung einer gutartigen oder bösartigen Erkrankung der Brust oder des Reproduktionstrakts mittels intramuskulärer Verabreichung, wobei die pharmazeutische Formulierung Fulvestrant, 17-23 Gew.-% eines pharmazeutisch annehmbaren Alkohols, bezogen auf das Volumen der Formulierung, 12-18 Gew.-%, bezogen auf das Volumen der Formulierung, eines pharmazeutisch annehmbaren nichtwässrigen Esterlösungsmittels, das in einer Ricinoleat-Trägersubstanz mischbar ist, und eine ausreichende Menge einer Ricinoleat-Trägersubstanz enthält, um eine Formulierung mit mindestens 45 mgml-1 Fulvestrant herzustellen. 20. Die Verwendung wie in einem der Ansprüche 1-19 beansprucht, wobei der pharmazeutisch annehmbare Alkohol ein Gemisch aus Ethanol und Benzylalkohol ist. 45 21. Die Verwendung wie in einem der Ansprüche 1-20 beansprucht, wobei das pharmazeutisch annehmbare nichtwässrige Esterlösungsmittel aus Benzylbenzoat, Ethyloleat, Isopropylmyristat, Isopropylpalmitat oder einem beliebigen Gemisch davon ausgewählt ist. 50 55 22. Die Verwendung wie in einem der Ansprüche 1-21 beansprucht, wobei das pharmazeutisch annehmbare nichtwässrige Esterlösungsmittel Benzylbenzoat ist. 23. Verwendung von Fulvestrant bei der Herstellung einer pharmazeutischen Formulierung zur Behandlung einer gutartigen oder bösartigen Erkrankung der Brust oder des Reproduktionstrakts mittels intramuskulärer Verabreichung, wobei die pharmazeutische Formulierung Fulvestrant, 15-25 Gew.-% eines pharmazeutisch annehmbaren Alkohols, bezogen auf das Volumen der Formulierung, 10-25 Gew.-% Benzylbenzoat in einer Ricinoleat-Trägersubstanz, bezogen auf das Volumen der Formulierung, und eine ausreichende Menge einer Ricinoleat-Trägersubstanz enthält, um eine Formulierung mit mindestens 45 mgml-1 Fulvestrant herzustellen. 16 EP 1 250 138 B2 5 24. Verwendung von Fulvestrant bei der Herstellung einer pharmazeutischen Formulierung zur Behandlung einer gutartigen oder bösartigen Erkrankung der Brust oder des Reproduktionstrakts mittels intramuskulärer Verabreichung, wobei die pharmazeutische Formulierung Fulvestrant, 17-23 Gew.-% eines pharmazeutisch annehmbaren Alkohols, bezogen auf das Volumen der Formulierung, 12-18 Gew.-% Benzylbenzoat in einer Ricinoleat-Trägersubstanz, bezogen auf das Volumen der Formulierung, und eine ausreichende Menge einer Ricinoleat-Trägersubstanz enthält, um eine Formulierung mit mindestens 45 mgml-1 Fulvestrant herzustellen. 25. Die Verwendung wie in Anspruch 23 oder 24 beansprucht, wobei der pharmazeutisch annehmbare Alkohol ein Gemisch aus Ethanol und Benzylalkohol ist. 10 26. Die Verwendung wie in Anspruch 25 beansprucht, wobei der gewichtsprozentige Anteil an Ethanol und Benzylalkohol bezogen auf das Volumen der Formulierung etwa gleich ist. 15 27. Die Verwendung wie in einem der Ansprüche 1-26 beansprucht, wobei das Gesamtvolumen der Formulierung 6 ml oder weniger ist und die Fulvestrantkonzentration mindestens 45 mgml-1 beträgt. 28. Die Verwendung wie in einem der Ansprüche 1-27 beansprucht, wobei die Gesamtmenge an Fulvestrant in der Formulierung 250 mg oder mehr beträgt und das Gesamtvolumen der Formulierung 6 ml oder weniger ist. 20 25 29. Die Verwendung wie in Anspruch 28 beansprucht, wobei die Gesamtmenge an Fulvestrant in der Formulierung 250 mg beträgt und das Gesamtvolumen der Formulierung 5 bis 5,25 ml ist. 30. Die Verwendung wie in einem der Ansprüche 1-29 beansprucht, wobei der pharmazeutisch annehmbare Alkohol ein Gemisch aus 10 Gew.-% Ethanol, bezogen auf das Volumen der Formulierung, 10 Gew.-% Benzylalkohol, bezogen auf das Volumen der Formulierung, und die Formulierung enthält 15 Gew.-% Benzylbenzoat, bezogen auf das Volumen der Formulierung, und die Ricinoleat-Trägersubstanz Rizinusöl ist. 31. Die Verwendung wie in Anspruch 30 beansprucht, wobei die Formulierung in einer Spritze oder einem Fläschchen enthalten ist. 30 Revendications 1. Utilisation de fulvestrant dans l’élaboration d’une préparation pharmaceutique destinée au traitement d’une maladie bénigne ou maligne du sein ou de l’appareil reproducteur par injection intramusculaire, dans laquelle la préparation comprend du fulvestrant dans un véhicule de ricinoléate, un solvant d’ester non aqueux acceptable d’un point de vue pharmaceutique et un alcool acceptable d’un point de vue pharmaceutique, et dans laquelle la préparation est adaptée pour atteindre une concentration en fulvestrant dans le plasma sanguin significative d’un point de vue thérapeutique pendant au moins 2 semaines. 2. Utilisation de fulvestrant dans l’élaboration d’une préparation pharmaceutique destinée au traitement d’une maladie bénigne ou maligne du sein ou de l’appareil reproducteur par injection intramusculaire, dans laquelle la préparation comprend du fulvestrant, 30% ou moins en poids d’un alcool, acceptable d’un point de vue pharmaceutique, par volume de préparation, au moins 1% en poids d’un solvant d’ester non aqueux, acceptable d’un point de vue pharmaceutique et miscible dans un véhicule de ricinoléate, par volume de préparation et une quantité suffisante d’un véhicule de ricinoléate, de sorte à élaborer une préparation qui soit capable, après injection, d’atteindre une concentration en fulvestrant dans le plasma sanguin significative d’un point de vue thérapeutique pendant au moins 2 semaines. 3. Utilisation selon la revendication 1 ou 2, dans laquelle la concentration en fulvestrant dans le plasma sanguin atteinte est de 2,5 ng.ml-1 au moins pendant 2 semaines au moins. 4. Utilisation de fulvestrant dans l’élaboration d’une préparation pharmaceutique destinée au traitement d’une maladie bénigne ou maligne du sein ou de l’appareil reproducteur par injection intramusculaire, dans laquelle la préparation pharmaceutique comprend du fulvestrant, 30% ou moins en poids d’un alcool, acceptable d’un point de vue pharmaceutique, par volume de préparation, au moins 1% en poids d’un solvant d’ester non aqueux, acceptable d’un point de vue pharmaceutique et miscible dans un véhicule de ricinoléate, par volume de préparation et une quantité suffisante d’un véhicule de ricinoléate, de sorte à élaborer une préparation à 45 mg.ml-1 au moins de fulvestrant. 35 40 45 50 55 17 EP 1 250 138 B2 5. Utilisation selon les revendications 1 à 4, dans laquelle la préparation pharmaceutique contient 25% p/v ou moins d’un alcool acceptable d’un point de vue pharmaceutique. 6. Utilisation selon la revendication 5, dans laquelle la préparation pharmaceutique contient 20% p/v ou moins d’un alcool acceptable d’un point de vue pharmaceutique. 7. Utilisation selon la revendication 5, dans laquelle la préparation pharmaceutique contient de 15 à 25% p/v d’un alcool acceptable d’un point de vue pharmaceutique. 8. Utilisation selon la revendication 5, dans laquelle la préparation pharmaceutique contient de 17 à 23% p/v d’un alcool acceptable d’un point de vue pharmaceutique. 9. Utilisation selon l’une quelconque des revendications 1 à 8, dans laquelle la préparation pharmaceutique contient 60% p/v ou moins d’un solvant d’ester non aqueux acceptable d’un point de vue pharmaceutique. 5 10 15 10. Utilisation selon la revendication 9, dans laquelle la préparation pharmaceutique contient 50% p/v ou moins d’un solvant d’ester non aqueux acceptable d’un point de vue pharmaceutique. 20 11. Utilisation selon la revendication 9, dans laquelle la préparation pharmaceutique contient 45% p/v ou moins d’un solvant d’ester non aqueux acceptable d’un point de vue pharmaceutique. 12. Utilisation selon la revendication 9, dans laquelle la préparation pharmaceutique contient 40% p/v ou moins d’un solvant d’ester non aqueux acceptable d’un point de vue pharmaceutique. 25 13. Utilisation selon la revendication 9, dans laquelle la préparation pharmaceutique contient 35% p/v ou moins d’un solvant d’ester non aqueux acceptable d’un point de vue pharmaceutique. 14. Utilisation selon la revendication 9, dans laquelle la préparation pharmaceutique contient 30% p/v ou moins d’un solvant d’ester non aqueux acceptable d’un point de vue pharmaceutique. 30 15. Utilisation selon la revendication 9, dans laquelle la préparation pharmaceutique contient 25% p/v ou moins d’un solvant d’ester non aqueux acceptable d’un point de vue pharmaceutique. 35 16. Utilisation selon la revendication 9, dans laquelle la préparation pharmaceutique contient de 10 à 25% p/v d’un solvant d’ester non aqueux acceptable d’un point de vue pharmaceutique. 17. Utilisation selon la revendication 9, dans laquelle la préparation pharmaceutique contient de 12 à 18% p/v d’un solvant d’ester non aqueux acceptable d’un point de vue pharmaceutique. 40 45 50 55 18. Utilisation de fulvestrant dans l’élaboration d’une préparation pharmaceutique destinée au traitement d’une maladie bénigne ou maligne du sein ou de l’appareil reproducteur par injection intramusculaire, dans laquelle la préparation pharmaceutique comprend du fulvestrant, 15 à 25% en poids d’un alcool, acceptable d’un point de vue pharmaceutique, par volume de préparation, 10 à 25% en poids d’un solvant d’ester non aqueux, acceptable d’un point de vue pharmaceutique et miscible dans un véhicule de ricinoléate, par volume de préparation et une quantité suffisante d’un véhicule de ricinoléate, de sorte à élaborer une préparation à 45 mg.ml-1 au moins de fulvestrant. 19. Utilisation de fulvestrant dans l’élaboration d’une préparation pharmaceutique destinée au traitement d’une maladie bénigne ou maligne du sein ou de l’appareil reproducteur par injection intramusculaire, dans laquelle la préparation pharmaceutique comprend du fulvestrant, 17 à 23% en poids d’un alcool, acceptable d’un point de vue pharmaceutique, par volume de préparation, 12 à 18% en poids d’un solvant d’ester non aqueux, acceptable d’un point de vue pharmaceutique et miscible dans un véhicule de ricinoléate, par volume de préparation et une quantité suffisante d’un véhicule de ricinoléate, de sorte à élaborer une préparation à 45 mg.ml-1 au moins de fulvestrant. 20. Utilisation selon l’une quelconque des revendications 1 à 19, dans laquelle l’alcool acceptable d’un point de vue pharmaceutique est un mélange d’éthanol et d’alcool benzylique. 21. Utilisation selon l’une quelconque des revendications 1 à 20, dans laquelle le solvant d’ester non aqueux, acceptable d’un point de vue pharmaceutique, est choisi parmi : le benzoate de benzyle ; l’oléate d’éthyle ; le myristate 18 EP 1 250 138 B2 d’isopropyle ; le palmitate d’isopropyle ; ou un mélange de n’importe lesquels d’entre eux. 22. Utilisation selon l’une quelconque des revendications 1 à 21, dans laquelle le solvant d’ester non aqueux, acceptable d’un point de vue pharmaceutique, est le benzoate de benzyle. 5 10 15 20 23. Utilisation de fulvestrant dans l’élaboration d’une préparation pharmaceutique destinée au traitement d’une maladie bénigne ou maligne du sein ou de l’appareil reproducteur par injection intramusculaire, dans laquelle la préparation pharmaceutique comprend du fulvestrant, 15 à 25% en poids d’un alcool, acceptable d’un point de vue pharmaceutique, par volume de préparation, 10 à 25% en poids de benzoate de benzyle, dans un véhicule de ricinoléate, par volume de préparation et une quantité suffisante d’un véhicule de ricinoléate, de sorte à élaborer une préparation à 45 mg.ml-1 au moins de fulvestrant. 24. Utilisation de fulvestrant dans l’élaboration d’une préparation pharmaceutique destinée au traitement d’une maladie bénigne ou maligne du sein ou de l’appareil reproducteur par injection intramusculaire, dans laquelle la préparation pharmaceutique comprend du fulvestrant, 17 à 23% en poids d’un alcool, acceptable d’un point de vue pharmaceutique, par volume de préparation, 12 à 18% en poids de benzoate de benzyle, dans un véhicule de ricinoléate, par volume de préparation et une quantité suffisante d’un véhicule de ricinoléate, de sorte à élaborer une préparation à 45 mg.ml-1 au moins de fulvestrant. 25. Utilisation selon la revendication 23 ou 24, dans laquelle l’alcool, acceptable d’un point de vue pharmaceutique, est un mélange d’éthanol et d’alcool benzylique. 26. Utilisation selon la revendication 25, dans laquelle l’éthanol et l’alcool benzylique sont présents avec des % en poids environ égaux par volume de préparation. 25 27. Utilisation selon l’une quelconque des revendications 1 à 26, dans laquelle le volume total de la préparation est de 6 ml ou moins et la concentration en fulvestrant est de 45 mg.ml-1 au moins. 30 28. Utilisation selon l’une quelconque des revendications 1 à 27, dans laquelle la quantité totale de fulvestrant dans la préparation est de 250 mg ou plus et le volume total de la préparation est de 6 ml ou moins. 29. Utilisation selon la revendication 28, dans laquelle la quantité totale de fulvestrant dans la préparation est de 250 mg et le volume total de la préparation est de 5 à 5,25 ml. 35 30. Utilisation selon l’une quelconque des revendications 1 à 29, dans laquelle l’alcool, acceptable d’un point de vue pharmaceutique, est un mélange de 10% en poids d’éthanol par volume de préparation, de 10% en poids d’alcool benzylique par volume de préparation, la préparation contient 15% en poids de benzoate de benzyle par volume de préparation et le véhicule de ricinoléate est de l’huile de castor. 40 31. Utilisation selon la revendication 30, dans laquelle la préparation est présente dans une seringue ou un flacon. 45 50 55 19 20 ewseld [m 1311 Bu) mensanlng 40 I L- F1 Formulation F(Castor oil) If F2 812CastorlSesame 0" 1:1 I I I Time EP1250138 BZ EP 1 250 138 B2 REFERENCES CITED IN THE DESCRIPTION This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard. Patent documents cited in the description • EP 0138504 A [0010] • US 5183814 A [0014] • WAKELING AE. Therapeutic potential of pure antioestrogens in the treatment of breast cancer. Journal Steroid Biochemistry, 1990, vol. 37, 771-5 [0058] WAKELING AE ; BOWLER J. Steroidal pure antioestrogens. Journal Endocrinology, 1987, vol. 112, R7-10 [0058] WAKELING AE ; BOWLER J. Biology and mode of action of pure antioestrogens. Journal Steroid Biochemistry, 1988, vol. 3, 141-7 [0058] Non-patent literature cited in the description • • • • RIFFKIN. J. Pharm. Sci., 1964, vol. 53, 891 [0016] BOWLER J ; LILLEY TJ ; PITTAM JD ; WAKELING AE. Novel steroidal pure antioestrogens. Steroids, 1989, 5471-99 [0058] WAKELING AE. Novel pure antioestrogens: mode of action and therapeutic prospects. American New York Academy Science, 1990, vol. 595, 348-56 [0058] Steroidal pure antioestrogens. WAKELING AE. Regulatory mechanisms in breast cancer. Boston: Kluwer Academic, 1990, 239-57 [0058] • • 21