WO2005063276A1 - Procedes et compositions faisant appel a la gonadoliberine - Google Patents

Procedes et compositions faisant appel a la gonadoliberine Download PDF

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WO2005063276A1
WO2005063276A1 PCT/IB2004/004276 IB2004004276W WO2005063276A1 WO 2005063276 A1 WO2005063276 A1 WO 2005063276A1 IB 2004004276 W IB2004004276 W IB 2004004276W WO 2005063276 A1 WO2005063276 A1 WO 2005063276A1
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composition
sustained release
gnrh
release formulation
hormone
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PCT/IB2004/004276
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English (en)
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Hervé PORCHET
Eija Lundstrom
Catherine Curdy
Marie-Anne Bardet
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Debiopharm S.A.
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    • 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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Gonadotropin hormone releasing hormone (GnRH) agonist and antagonist analogs have been used to treat benign gynaecological disorders including premenstrual syndrome and androgen-dependent cancer of the prostate.
  • GnRH is also known as luteinizing hormone releasing hormone.
  • GnRH is secreted by the hypothalamus in the pituitary portal system in a pulsating fashion. Because the hormone has a half-life of the order of minutes, the pituitary gland is exposed to pulses of hormone. This exposure results in the secretion of the gonadotropins, i.e., luteinizing hormone (LH) and follicle-stimulating hormone (FSH).
  • LH luteinizing hormone
  • FSH follicle-stimulating hormone
  • LH acts on the Leydig cells of the testes, stimulating the secretion of testosterone.
  • FSH is responsible for spermatogenesis. Testosterone appears to feedback-inhibit secretion of GnRH and reduce the sensitivity of the pituitary to the hormone.
  • FSH acts on the ovaries, stimulating secretion of estrogen.
  • the main functions of LH in women are to support follicular maturation and to trigger ovulation at mid-follicular cycle.
  • estrogen appears to be capable of feedback inhibition of GnRH secretion and action.
  • GnRH agonists are clinically equally as effective in inducing prostate cancer remission as orchiectomy, the gold standard of treatment efficacy, their use is accompanied by important other toxicities, including fatigue, weight gain, depression, bone loss, anaemia, muscle atrophy, gynecomastia, hot flushes, loss of cognitive function, and decrease in high-density lipoprotein. Hellerstedt and Pienta. CA Cancer J Clin 2002; 52: 154-179. Perhaps, the complications that most severely affect quality of life are loss of bone mineral density and hot flushes.
  • the invention relates to compositions comprising a first sustained release formulation of a gonadotropin hormone releasing hormone (abbreviated GnRH herein) composition capable of releasing the GnRH composition during a period of at least about one month at a rate sufficient to induce and maintain chemical castration of a male patient, and a second sustained release formulation of an estrogenic composition capable of maintaining for said period a serum level sufficient to reduce the enhanced loss of bone mineral density and/or the hot flushes that are normally caused by the administration of a GnRH composition that chemically castrates a male patient.
  • GnRH gonadotropin hormone releasing hormone
  • the first sustained release formulation of a composition of the invention releases a GnRH composition at a rate of between about 10 and about 1 ,000 ⁇ g per day.
  • the second sustained release formulation of the invention releases an estrogenic composition at a rate between about 5 and 100 ⁇ g of estradiol equivalent per day, preferably at a rate not exceeding about 50 ⁇ g of estradiol equivalent per day.
  • the composition is not limited by reference to chemical castration of a male patient. It is defined as comprising a first sustained release formulation of a GnRH composition capable of releasing the GnRH composition for a period of at least about one month at an average rate between about 10 and 1 ,000 ⁇ g per day and a second sustained release formulation of an estrogenic composition capable of releasing during said period the estrogenic composition at a rate between about 5 and 100 ⁇ g of estradiol equivalent per day, preferably at a rate not exceeding about 50 ⁇ g of estradiol equivalent per day.
  • the GnRH composition of the first sustained release formulation is selected from the group consisting of GnRH, agonists of GnRH, antagonists of GnRH and mixtures thereof.
  • the GnRH composition is a GnRH agonist selected from the group consisting of leuprorelin, goserelin, triptorelin, buserelin, nafarelin, deslorelin, histerelin, gonadorelin, and salts and/or mixtures thereof.
  • the estrogenic composition present in the second sustained release formulation is a polyester of a phosphorous acid and an estrogenic compound containing at least two hydroxyl groups. Said polyester contains at least two recurrent moieties.
  • said polyester contains between 3 to 80 recurrent moieties, preferably between 3 and 15 recurrent moieties.
  • said phosphorous acid is selected from a phosphoric acid, i.e. orthophosphoric acid and metaphosphoric acid, thiophosphoric acid, phosphonic acid, and said hydroxyl group-containing estrogenic compound is selected from the group consisting of dienestrol, diethylstilbestrol, estetrol, estradiol, estradiol, (3 ⁇ ,17 ⁇ )-estr-4-ene-3, 17-diol, estriol, ethinylestradiol, hexestrol, and raloxifene.
  • the GnRH composition of the first sustained release formulation is triptorelin or a salt thereof
  • the estrogenic composition of the second sustained release formulation is a polyester of a phosphoric acid and estradiol.
  • the GnRH composition of the first sustained release formulation is triptorelin, or a salt thereof, that is released at a rate of about 100 ⁇ g per day
  • the estrogenic composition of the second sustained release formulation is a polyester of a phosphoric acid and estradiol, said second sustained release formulation releasing estradiol at a rate between about 5 and 100 ⁇ g per day, preferably at a rate not exceeding about 50 ⁇ g per day.
  • the invention further relates to a method for the treatment of prostate cancer, involving administration to a prostate cancer patient of a composition comprising a first sustained release formulation of a GnRH composition capable of releasing the GnRH composition during a period of at least about one month at a rate sufficient to induce and maintain chemical castration of a male patient, and a second sustained release formulation of an estrogenic composition capable of maintaining for said period a serum level sufficient to reduce the enhanced loss of bone mineral density and/or the hot flushes that are normally caused by the administration of a GnRH composition that chemically castrates a male patient.
  • the invention relates also to the use of a composition comprising a first sustained release formulation of a GnRH composition, and a second sustained release formulation of an estrogenic composition for the preparation of a medicament capable of maintaining for said period a serum level sufficient to reduce the enhanced loss of bone mineral density and/or the hot flushes that are normally caused by the administration of a GnRH composition that chemically castrates a male patient capable to induce and maintain chemical castration of a male patient and to reduce the enhanced loss of bone mineral density and/or the hot flushes that are normally caused by the administration of a GnRH composition that chemically castrates a male patient, said first sustained release formulation of a GnRH composition being capable of releasing the GnRH composition during a period of at least about one month at a rate sufficient to induce and maintain chemical castration of a male patient, and a second sustained release formulation of an estrogenic composition being capable of maintaining for said period a serum level sufficient to reduce the enhanced loss of bone mineral density and/or the hot flushes that are normally
  • the first sustained release formulation of a composition administered to a prostate cancer patient releases a GnRH composition at a rate of between about 10 and about 1 ,000 ⁇ g per day
  • the second sustained release formulation releases an estrogenic composition at a rate between about 5 and 100 ⁇ g of estradiol equivalent per day, preferably at a rate not exceeding about 50 ⁇ g of estradiol equivalent per day.
  • the GnRH composition of the first sustained release formulation is selected from the group consisting of GnRH, agonists of GnRH, antagonists of GnRH and mixtures thereof.
  • the GnRH composition is a GnRH agonist selected from the group consisting of leuprorelin, goserelin, triptorelin, buserelin, nafarelin, deslorelin, histerelin, gonadorelin, and salts and/or mixtures thereof.
  • the estrogenic composition present in the second sustained release formulation is selected from a group consisting of a polyester of a phosphorous acid and an estrogenic compound containing at least two hydroxyl groups.
  • Said polyester contains at least two recurrent moieties.
  • said polyester contains between 3 to 80 recurrent moieties, preferably between 3 and 15 recurrent moieties.
  • said phosphorous acid is selected from a phosphoric acid, i.e. orthophosphoric acid and metaphosphoric acid, thiophosphoric acid, phosphonic acid, and said hydroxyl group-containing estrogenic compound is selected from the group consisting of dienestrol, diethylstilbestrol, estetrol, estradiol, estradiol, (3 ⁇ ,17 ⁇ )-estr-4-ene-3,17-diol, estriol, ethinylestradiol, hexestrol, and raloxifene.
  • the GnRH composition of the first sustained release formulation is triptorelin, or a salt thereof, that is released at a rate of about 100 ⁇ g per day
  • the estrogenic composition of the second sustained release formulation is a polyester of a phosphoric acid and estradiol, said second sustained release formulation releasing estradiol at a rate between about 5 and 100 ⁇ g per day, preferably at a rate not exceeding about 50 ⁇ g per day.
  • the present invention relates to novel compositions and the use of these compositions to treat hormone-responsive prostate cancer without eliciting the severe side effects characteristic of prior art hormone ablation therapies.
  • the compositions of the invention comprise two sustained release formulations, the first comprising a gonadotropin hormone releasing hormone (GnRH) composition and the second an estrogenic composition, that are administered to a patient simultaneously.
  • the first formulation and the second formulation may be combined at the time of administration or may be joined at the time of manufacture.
  • the sustained release formulations of the invention are effective for a period of at least about one month. The period of effectiveness may be as long as one year. Formulations that are even longer-lasting are considered as being within the scope of the present invention.
  • compositions of the invention are designed for treatment periods of one to three months, after which periods the compositions are re-administered. It is understood that the scope of the present invention includes any modification the clinician may conceive regarding the schedule of administration of first formulation and the second formulation in order to reach the respective steady-state of serum concentrations.
  • the first sustained release formulation comprises a GnRH composition.
  • GnRH compositions include both agonist and antagonist analogs of GnRH as well as GnRH itself.
  • GnRH compositions of the invention may also consist of mixtures of the latter compounds.
  • GnRH antagonists act by competing with GnRH for GnRH receptor in the pituitary gland. Normally, GnRH is secreted in a pulsating fashion.
  • GnRH receptors are exposed to waves of GnRH signalling release of LH and FSH.
  • the signalling pathway is shut down through down-regulation of GnRH receptor, resulting in reduction of LH and FSH release.
  • LH and FSH release are completely suppressed, and estrogen and testosterone concentrations reach oophorectomized levels in women and orchiectomized or castrate levels in men, respectively.
  • feedback inhibition of GnRH no longer occurs. Consequently, GnRH release is maximal.
  • GnRH receptor down-modulation This release pattern assists the maintenance of GnRH receptor down-modulation.
  • GnRH agonists include leuprorelin, goserelin, triptorelin, buserelin, nafarelin, deslorelin, histrelin, gonadorelin and salts thereof.
  • a well-known GnRH antagonist is abarelix.
  • GnRH agonists A variety of sustained release formulations of GnRH agonists were developed and are commercially available. Examples of commercial sustained release formulations of GnRH agonists include Lupron Depot 3.75 mg, Lupron Depot - 3 7.5 mg, and Lupron Depot - 4 30 mg of TAP Pharmaceuticals Inc. of Lake Forrest, IL. Lupron Depot 3.75 mg comprises 3.75 mg leuprorelin acetate, 0.65 mg gelatin, 33.1 mg DL-lactic and glycolic acids co-polymer, and 6.6 mg D-mannitol. The accompanying diluent contains 7.5 mg carboxymethylcellulose sodium, 75 mg mannitol, 1.5 mg polysorbate 80, water, USP, and glacial acetic acid.
  • Lupron Depot - 3 Month 22.5 mg and Lupron Depot - 4 Month 30 mg are formulations for intramuscular injection at respectively three months intervals comprising 22.5 mg leuprorelin acetate in polylactide microspheres and four months intervals.
  • sustained release formulations of leuprorelin acetate include Eligard formulations (respectively 7.5 mg, 22.5 mg, and 30 mg) by Atrix Laboratories and Viadur, a 12-months formulation by ALZA Corporation.
  • Zoladex 3.6 mg and 10.8 mg are one-month and three-months depot formulations, respectively, of goserelin acetate marketed by AstraZeneca.
  • the Zoladex 3.6 mg formulation comprises goserelin acetate in an amount corresponding to 3.6 mg of goserelin in 13.3-14.3 mg D,L-lactic and glycolic acids co-polymer. Decapeptyl distributed by Ferring Corp.
  • Ipsen-Beaufour is a depot formulation of triptorelin acetate or pamoate.
  • the one-month formulation of Decapetyl includes 3.75 mg triptorelin encapsulated in polylactide co-glycolide microcapsules.
  • Similar sustained release formulations of triptorelin pamoate have been approved in the U.S. by the Food and Drug Administration and will be distributed by Watson Laboratories under the trade names Trelstar and those formulations are distributed in Europe under the name Pamorelin.
  • Trelstar is available as one-month or three- months sustained release formulation (Trelstar Depot 3.75 mg, Trelstar 11.25 mg).
  • Trelstar Depot 3.75 mg is a sterile, lyophilised biodegradable microgranule formulation supplied as a single dose vial containing triptorelin pamoate (3.75 mg of triptorelin peptide), 170 mg poly-d,l-lactide-co-glycolide, 85 mg mannitol, 30 mg carboxymethylcellulose sodium and 2 mg polysorbate 80.
  • triptorelin pamoate 3.75 mg of triptorelin peptide
  • 170 mg poly-d,l-lactide-co-glycolide 85 mg mannitol
  • 30 mg carboxymethylcellulose sodium and 2 mg polysorbate 80 for injection, the formulation is suspended in 2 ml water and injected intramuscularly.
  • Trelstar 11.25 mg is a similar formulation containing triptorelin pamoate (11.25 mg of triptorelin peptide), 145 mg poly-d,l-lactide-co-glycolide, 85 mg mannitol, 30 mg carboxymethylcellulose sodium and 2 mg polysorbate 80.
  • the formulation is suspended in 2 ml water and injected intramuscularly.
  • Similar formulations are described in U.S. Pat. Nos. 5,134,122, 5,192,741 and 5,225,205. These patents are incorporated herein in their entirety by this reference.
  • Analogous sustained release formulation of GnRH, a GnRH agonist, a GnRH antagonist or mixtures thereof can be used in the compositions of the invention.
  • sustained release formulations may be based on biodegradable and/or biocompatible polymers other than the polylactide-glycolide co-polymers present in the above-described commercial formulations, including ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid. These and other polymers as well as methods for preparing appropriate formulations using such polymers are well known to those skilled in the art.
  • the first sustained release formulation of the present invention is preferably a depot formulation of triptorelin pamoate such as the Trelstar formulations
  • other sustained release formulations of an agonist or antagonist of GnRH, or of GnRH itself could also be employed.
  • Any depot formulation that continuously releases an agonist or antagonist of GnRH or GnRH at a rate sufficient to cause down- regulation of GnRH receptor and reduction of sex hormone concentrations to oophorectomized levels in women and orchiectomized or castrate levels in men, respectively, would be suitable for use with the present invention.
  • a suitable first sustained release formulation will release a GnRH agonist or antagonist at a rate of between about 10 and 1 ,000 ⁇ g per day.
  • compositions of this invention comprise a second sustained release formulation that releases an estrogenic composition. Observational studies indicate that loss of bone mineral density in men may not occur if the serum level of bioavailable estradiol is at or above about 11 pg/ml. Khosla et al. J Clin Endocrinol Metab 2002; 87: 1443-1450.
  • Estrogenic compositions delivered by the second sustained release formulations include a polyphosphoric ester of both natural and non-natural estrogenic compounds containing at least two hydroxyl groups.
  • the preferred estrogenic compounds is estradiol (chemical name: ⁇ -estra-1 ,3,5(10)-triene-3, 17-diol; CAS RN: 50-28-2).
  • Such a polymeric ester is known under the names of Polyestradiol phosphate, Estradiol phosphate polymer, and PEP.
  • the Registry Number and present name attributed by the Chemical Abstracts Service to this polymeric ester are respectively 28014-46-2 and "(17 ⁇ )-Estra-1 ,3,5(10)-triene-3,17-diol, polymer with phosphoric acid".
  • the above-mentioned pharmaceutical preparation is described in the
  • “Compendiumiere des Medicaments” as being a preparation of a hydrosoluble polymerised estradiol with a long acting effect, the polymerised chain comprising around 13 molecules of estradiol, each of these molecules being linked together by a phosphoric group.
  • phosphatases induce hydrolytic degradation of polyestradiol phosphate and estradiol is slowly released in the body. Once steady-state is obtained, estradiol is released on a long term period at constant rates. For instance, with one administration per month, steady-state is generally obtained after 6 to 12 months and estradiol concentrations are proportional to the amount of administrated polyestradiol phosphate.
  • estrogenic compounds examples include dienestrol, diethyl-stilbestrol, estetrol, estradiol, estradiol, (3 ⁇ ,17 ⁇ )-estr-4-ene-3,17-diol, estriol, ethinylestradiol, hexestrol.
  • estrogenic compositions are defined by their equivalence to amounts and concentrations of estradiol. Equivalence means similarity of desirable biological effects achieved, e.g., reduction in loss of bone mineral density and/or reduction in frequency and severity of hot flushes in prostate cancer patients undergoing hormone ablation therapy.
  • estrogenic compounds include estrogen receptor modulators (SERM) such as raloxifene. Because of the selectivity of these compositions, their use in a second sustained release formulation of this invention may only produce some but not all of the beneficial effects resulting from estradiol administration. For example, raloxifene, toremifene and tamoxifen can be expected to slow bone resorption but not to reduce (but, possibly, to enhance) the incidence and severity of hot flushes.
  • Estrogenic compositions also include so-called ANGELS (Activators of Non-Genotropic Estrogen-like Signalling) compounds that were described in patent application PCT/US02/18544.
  • ANGELS compounds are small molecules that mimic the non-genotropic effects of estrogen and androgen but substantially lack their genotropic effects.
  • a preferred ANGELS compound is (3 ⁇ ,17 ⁇ )-estr- 4-ene-3,17-diol (CAS RN: 35950-87-9) that was shown to reverse bone loss in mouse models. Kousteni et al. 2002. Science 298, 843-846.
  • Estrogens are well known to increase the probability of cardiovascular events, in particular oedema and deep venous thrombosis. This realization was an important reason why diethylstilbesterone therapy was abandoned for GnRH agonist therapies. Analogous observations were made for estrogen replacement therapies for postmenopausal women. Although the toxicity of estrogens to prostate cancer patients may be mitigated to some extent if the route of administration of the hormone is changed from oral to parenteral, there still may be a significant remainder risk associated with the administration of elevated doses of estrogens.
  • the second sustained release formulation releases an estrogenic composition at a low rate that is calculated to be only sufficient to provide a serum estrogen level equivalent to about 15 pg/ml to about 50 pg/ml of estradiol. Because of biological differences between subjects, the actual serum estradiol or estradiol equivalent level achieved by administration of the second sustained release formulation may vary between about 10 pg/ml and about 100 pg/ml.
  • Sustained release formulations generally show a bimodal kinetics of drug release, comprising an initial slight burst of release that is followed by a prolonged phase of sustained release at a considerably lower rate.
  • a preferred second sustained release composition of this invention displays a release profile that approaches unimodality. Because of the absence of an important initial burst of drug release from this second sustained release formulation, estrogen concentrations will never greatly exceed target levels.
  • the calculated ideal rate of release of estrogenic composition is equivalent to about 25 ⁇ g/day of estradiol (clearance x desired serum level or increase in serum level).
  • the maximal rate of release of estrogenic composition during the first days following administration of the second slow release formulation will be equivalent to about 50 ⁇ g estradiol per day. As a consequence of these narrowly defined release characteristics of the second sustained release formulation, the risk associated with a high estrogen level will be kept to a minimum.
  • the commercially available pharmaceutical preparation comprising polyestradiol phosphate is available under its lyophilisate form and it contains additives such as nicotinamide as a co-adjuvant, and mepivacaine as a local anaesthetic.
  • solution is reconstituted by addition of an appropriate amount of solvent, for instance water as ppi grade.
  • Polyestradiol phosphate may be prepared by chemical synthesis following the instructions given in U.S. Pat. No. 2,928,849. Chemical reaction and work-up conditions may be monitored by the person skilled in the art in order to obtained batches satisfying to criteria of the present invention. Quality of the production may be assessed by relying upon the rules based on a biological duration test and a 31 P NMR analysis and given by Thelin et al. in Chemometrics and Intelligent Laboratory Systems, (1995), 27, 135-145.
  • the first formulation and the second formulation may be combined at the time of administration or may be joined at the time of manufacture. In the latter case, it may be recommended, due in particular to differences between each individual patient in the rate of estradiol metabolism caused by e.g.
  • first formulation comprising triptorelin pamoate and the second formulation comprising polyestradiol phosphate
  • commercially available preparations may be used.
  • both available preparations need to be reconstituted prior use as an injectable preparation, the same solvent may be used thus allowing a single injection.
  • the first formulation comprising triptorelin pamoate and the second formulation comprising polyestradiol phosphate may also be joined at the time of manufacture following the appropriate amount as mentioned above.
  • polyestradiol phosphate used as raw material may be dispersed in an appropriate aqueous medium at a pH comprised between 5.5 and 8.0, preferably between 6.0 and 7.8 and the homogeneous mixture obtained may be subsequently added to the triptorelin sustained release formulation and the obtained mixture is then lyophilised.
  • a pH comprised between 5.5 and 8.0 preferably between 6.0 and 7.8
  • the homogeneous mixture obtained may be subsequently added to the triptorelin sustained release formulation and the obtained mixture is then lyophilised.
  • Fig. 1 represents estradiol kinetic profiles as obtained with formulation of Example 1 ;
  • Fig. 2 represents estradiol kinetic profile as obtained with composition of Example 3.
  • composition of the present invention and its use are presented in the following Examples.
  • Example 1 Preparation of a formulation comprising polyestradiol phosphate (Combination 1)
  • Example 2 Preparation of a combination in which the first and second formulations are combined at the time of administration (Combination2)
  • Both formulations are reconstituted ex-temporis.
  • a first vial containing 80 mg of polyestradiol phosphate (Estradurin ® , marketed product) 2 ml of water for injection are added.
  • the vial is shacked vigorously until complete dissolution.
  • 1 ml of that solution and 1 ml of water for injection are injected in a second vial containing the triptorelin formulation "3-months" (12 mg triptorelin per vial) and the vial is shaken in order to obtain a homogeneous suspension ready for injection.
  • Example 3 Preparation of a combination in which the first and second formulations are combined at the time of manufacture (Combination 3)
  • a first formulation of microgranules of triptorelin pamoate was prepared according to the following method.
  • triptorelin pamoate Approximately 12 wt% of triptorelin pamoate was mixed with approximately 88 wt% PLGA 75:25 in a ball mill, at room temperature. The given mixture was duly homogenized, subjected to a progressive compression and simultaneously to a progressive heating, before extruded at a temperature of approximately 110°C. The extrudate was cut into pellets and ground at a temperature of about -100°C. The microgranules obtained after grinding were sieved below 180 microns.
  • the second formulation was obtained by dissolving polyestradiol phosphate in a phosphate buffer pH 7.8 medium at a concentration of 20 mg/ml.
  • the final combination was obtained by adding polyestradiol phosphate solution to triptorelin pamoate microgranules in order to have a dose of 12 mg of triptorelin and 40 mg of polyestradiol phosphate per vial. After homogenisation, the obtained suspension was frozen and lyophilised. The product is finally sterilized by gamma radiation.
  • Example 4 Preparation of a combination in which the first and second formulations are combined at the time of manufacture (Combination 4)
  • a formulation of microgranules of triptorelin pamoate was prepared according to the method described in Example 3.
  • Polyestradiol phosphate was dispersed in an aqueous medium pH around 6.4 at a concentration of 20 mg/ml.
  • the final combination was prepared by adding polyestradiol phosphate dispersion to triptorelin pamoate microgranules in order to have a dose of 12 mg of triptorelin and 40 mg of polyestradiol phosphate per vial. After homogenisation, the suspension obtained is frozen and lyophilised. The product is finally sterilized by gamma radiation.
  • the aim of this experimental study was to follow the estradiol and/or triptorelin serum release following a single intramuscular injection of formulation and combinations in the rat.
  • Example 1 Under mild ether anaesthesia, male Sprague Dawley orchidectomized rats were given an intramuscular injection (i.m.) of the formulation of Example 1 and the combination of Example 3, in the posterior thigh muscle. Six animals were studied per group. The day before the injection of the formulation (Day 0), a reference blood sample was collected. Each injection was carried out on Day 1 at time TO. This was considered as the reference time for the following blood samples.
  • Serum estradiol and/or triptorelin were measured in the serum of treated animals by Radio-lmmuno-Assay (RIA). 4. Results
  • Fig. 1 reports the kinetic profile of the estradiol release of formulation of Example 1 in rat serum. This profile shows a very slight burst effect occurring at a maximum of 4600 pmol/l during the first day. Then, the estradiol level in serum reach a plateau at least for the next following 42 days.
  • Fig. 2 reports the kinetic profile of estradiol releases of combined formulation of Example 3 in rat serum during 92 days following a single intramuscular injection. This profile is very similar to the one as obtained with formulation of Example 1 and a control curve, not shown on Fig 2, demonstrates that the presence of triptorelin seems to have no effect on the release of estradiol.
  • Fig. 3 reports the triptorelin profile of serum triptorelin release in rat serum following the IM injection of combined formulation of Example 3 in rat serum during 92 days following a single intramuscular injection.
  • a control curve, not shown on Fig 3, demonstrates that the presence of polyestradiol phosphate seems to have no effect on the release of triptorelin.
  • Example 6 Effects of the combined formulation on treatment on bone mineral densities, hot flushes, testosterone serum levels and prostate specific antigen level in a patient suffering from advanced prostate cancer.
  • the mean number of hot flushes daily was in average 5 and the mean severity of hot flushes based on a visual analog scale (from 1 to 10) was 4.0.
  • the patient had achieved chemical castration (serum testoterone ⁇ 1.735 nmol/L) at Day 29 and remained castrated between Days 29 and day 336 (48 weeks).
  • Serum PSA levels The PSA concentration decreased from 46.0 mg/L at baseline to 1.2 mg/L at 48 weeks.
  • Example 7 A study comparing the effects of a sustained release triptorelin (alone) and the combined formulation triptorelin+polvestradiol phosphate treatments on bone mineral density, hot flushes, testosterone serum levels and prostate specific antigen in men receiving GnRH agonist therapy for prostate cancer
  • the bone mineral density (BMD) is measured at the baseline and at 48 weeks.
  • the incidence and severity of hot flushes are measured at the baseline and monthly using a patient diary.
  • the serum testosterone and prostate specific antigen (PSA) levels are measured at the baseline and at regular intervals.
  • the mean number of hot flushes daily is 7 in the triptorelin alone group and 5 in the triptorelin+polyestradiol phosphate arm.
  • the mean severity of hot flushes based on a visual analog scale is 6.3 in the triptorelin alone arm and 4.3 in the triptorelin+polyestradiol phosphate arm.
  • ⁇ 1.735 nmol/L at Day 29 is 94.3% in the triptorelin alone arm, and 95.1% in the triptorelin+polyestradiol phosphate group.
  • the mean percentage of patients maintaining castration between Day 29 and Day 336 is 98.0% in the triptorelin alone group and 98.1% in the triptorelin+polyestradiol phosphate group. The mean differences between the treatment groups are not significant.
  • Serum PSA levels Reduction in PSA levels by Day 336 vs. baseline was 97.1% in the triptorelin alone group and 97.3% in the triptorelin+estradiol group, respectively.

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  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Urology & Nephrology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Compositions comportant deux formulations à libération prolongée, dont la première est apte à libérer une composition de gonadolibérine et la deuxième une composition oestrogène. Les compositions selon l'invention peuvent être utilisées dans le cadre d'une thérapie de blocage androgénique améliorée, pour le cancer de la prostate, qui permet de minimiser la perte thérapeutique de la teneur minérale de l'os et l'apparition et la gravité de bouffées de chaleur grâce au maintien d'un niveau d'oestrogène minimum suffisant.
PCT/IB2004/004276 2003-12-23 2004-12-23 Procedes et compositions faisant appel a la gonadoliberine WO2005063276A1 (fr)

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IBPCT/IB2003/06159 2003-12-23
IB0306159 2003-12-23

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WO2005063276A1 true WO2005063276A1 (fr) 2005-07-14

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008045461A2 (fr) * 2006-10-11 2008-04-17 Oregon Health & Science University Diéthylstilbestrol transdermique pour le traitement du cancer de la prostate
WO2019025031A1 (fr) * 2017-08-01 2019-02-07 Pantarhei Oncology B.V. Traitement adjuvant destiné à être utilisé dans le traitement du cancer de la prostate

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US5134122A (en) * 1989-07-28 1992-07-28 Debiopharm S.A. Method for preparing a pharmaceutical composition in the form of microparticles
US5340584A (en) * 1991-04-12 1994-08-23 University Of Southern California Methods and formulations for use in inhibiting conception and in treating benign gynecological disorders
WO1994026207A1 (fr) * 1993-05-17 1994-11-24 University Of Southern California Therapies et formulations utiles pour le traitement de desordres gynecologiques benins
WO1999051243A1 (fr) * 1998-04-03 1999-10-14 Jenapharm Gmbh & Co. Kg UTILISATION DE DERIVES D'ESTRADIOL POUR LE TRAITEMENT D'EFFETS SECONDAIRES PENDANT OU APRES UNE THERAPIE GnRHa
US20020065260A1 (en) * 1998-04-15 2002-05-30 Mcihael Oettel Pharmaceutical preparations for treating side effects during and/or after GnRHa therapy

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Publication number Priority date Publication date Assignee Title
US2928849A (en) * 1953-11-20 1960-03-15 Leo Ab High-molecular weight derivatives of steroids containing hydroxyl groups and method of producing the same
US5134122A (en) * 1989-07-28 1992-07-28 Debiopharm S.A. Method for preparing a pharmaceutical composition in the form of microparticles
US5340584A (en) * 1991-04-12 1994-08-23 University Of Southern California Methods and formulations for use in inhibiting conception and in treating benign gynecological disorders
WO1994026207A1 (fr) * 1993-05-17 1994-11-24 University Of Southern California Therapies et formulations utiles pour le traitement de desordres gynecologiques benins
WO1999051243A1 (fr) * 1998-04-03 1999-10-14 Jenapharm Gmbh & Co. Kg UTILISATION DE DERIVES D'ESTRADIOL POUR LE TRAITEMENT D'EFFETS SECONDAIRES PENDANT OU APRES UNE THERAPIE GnRHa
US20020065260A1 (en) * 1998-04-15 2002-05-30 Mcihael Oettel Pharmaceutical preparations for treating side effects during and/or after GnRHa therapy

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008045461A2 (fr) * 2006-10-11 2008-04-17 Oregon Health & Science University Diéthylstilbestrol transdermique pour le traitement du cancer de la prostate
WO2008045461A3 (fr) * 2006-10-11 2008-12-11 Univ Oregon Health & Science Diéthylstilbestrol transdermique pour le traitement du cancer de la prostate
WO2019025031A1 (fr) * 2017-08-01 2019-02-07 Pantarhei Oncology B.V. Traitement adjuvant destiné à être utilisé dans le traitement du cancer de la prostate
US11771705B2 (en) 2017-08-01 2023-10-03 Fund Sa Adjuvant therapy for use in prostate cancer treatment

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