WO2012055840A1 - Composition et préparation pour le traitement de la dysménorrhée et de la douleur menstruelle et utilisation d'un agent hormonal et d'un sel de zinc pour le traitement de troubles menstruels - Google Patents

Composition et préparation pour le traitement de la dysménorrhée et de la douleur menstruelle et utilisation d'un agent hormonal et d'un sel de zinc pour le traitement de troubles menstruels Download PDF

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Publication number
WO2012055840A1
WO2012055840A1 PCT/EP2011/068596 EP2011068596W WO2012055840A1 WO 2012055840 A1 WO2012055840 A1 WO 2012055840A1 EP 2011068596 W EP2011068596 W EP 2011068596W WO 2012055840 A1 WO2012055840 A1 WO 2012055840A1
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Prior art keywords
zinc
pharmaceutical composition
zinc salt
preparation according
progestin
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PCT/EP2011/068596
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English (en)
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Samer Lezzaiq
Axel Schneeweis
Vladimir Patched
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Bayer Pharma Aktiengesellschaft
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Publication of WO2012055840A1 publication Critical patent/WO2012055840A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/34—Gestagens

Definitions

  • compositions and preparation for treatment of dysmenorrhea Composition and preparation for treatment of dysmenorrhea and
  • the present invention is related to a composition and a preparation (regime) for the treatment of dysmenorrhea (or dysmenorrhoea) and menstrual pain, otherwise known as menstrual cramping.
  • a preparation comprising a progestin or an agent having a progestogenic activity and a sufficient amount of zinc to alleviate menstrual disorders, especially dysmenorrhea and menstrual pain.
  • the invention refers furthermore to the use of a progestin and a biocompatible zinc salt for the preparation of a medicament for treatment of menstrual disorders.
  • Dysmenorrhea Greek for painful menstruation is one of the most common gynecological complaints in young women who visit clinicians (Dawood, 2006 (4) ; Jamieson and Steege, 1996 (5i ).
  • Dysmenorrhea is a medical condition characterized by severe uterine pain during menstruation. While many individuals experience minor pain during
  • dysmenorrhea is diagnosed when the pain is so severe as to limit normal activities, or require medication. Most women begin having dysmenorrhea during adolescence, usually within four to five years of the first menstrual period. Painful periods become less common as women age. Dysmenorrhea may coexist with excessively heavy blood loss, known as menorrhagia or heavy menstrual bleeding (HMB). For clinical purposes, dysmenorrhea is divided into two broad categories, primary and secondary (congestive) dysmenorrhea (Dawood, 1985 (1i ).
  • Dysmenorrhea caused 14% of patients to miss school frequently. Although black adolescents reported no increased incidence of dysmenorrhea, they were absent from school more frequently (23.6%) than whites (12.3%), even after adjusting for socioeconomical status.
  • Prostaglandins are modified forms of unsaturated fatty acids and function as mediators of a variety of physiological responses such as inflammation, vascular dilation, platelet aggregation and muscle contraction by regulating the tone of smooth muscles.
  • the levels of prostaglandins formed in the lining of the uterus increase as menstruation approaches, with the highest levels at the onset of the menstrual period.
  • An excessive amount of prostaglandins increases uterine contractions causing cramps and pain, also resulting from vasoconstriction, decreased blood perfusion and hypoxia.
  • Generalized effects of prostaglandin excess may account for the headaches, dizziness, hot and cold flashes, diarrhea and nausea that can accompany painful periods.
  • Prostaglandins are considered essential factors in the pathogenesis of dysmenorrhea, excess menstrual bleeding and associated pelvic pain (Rosenwaks , Seegar-Jones (2003) in Wright et al. (21 >. Accordingly, suppression of prostaglandin production or diminution of the uterus liability to their action represent efficient therapeutic
  • Prostaglandin synthesis and metabolism in the uterus is controlled by progesterone (Rebsamen et a/.,2004) ⁇ 24 >; Young M and Funder J (2003) ⁇ 25 >; Zhang Z et al. (2002) (26i . Deficient progesterone secretion (e.g. as a result of anovulation or corpus luteum insufficiency in adolescents), and the resulting increase in prostaglandin production, causally contribute to painful menstruation and increased menstrual blood loss.
  • progestin treatment e.g. in the form of oral contraceptives
  • abrupt treatment cessation e.g. hormone-free pause of oral contraceptive administration
  • the clinical symptoms of primary dysmenorrhea are similar to those induced by the administration of prostaglandins (PGF-2ct and PGE2) for the induction of labour.
  • the increased production of prostaglandins by the endometrium during the luteal and menstrual phases of ovulatory cycles is consistent with the occurrence of primary dysmenorrhea mainly in ovulatory cycles.
  • the concentrations of prostaglandins in the endometrium and menstrual fluid of dysmenorrheic women are significantly higher than in controls [Dawood (2006) after Pickles (1957) and Pickles et al. (1963)] ⁇ 19 > and certain prostaglandin inhibitors are useful in the treatment of dysmenorrhea.
  • prostaglandin production can explain the major symptoms of primary dysmenorrhea, including the increased uterine contractility, uterine ischemia and the lowering of the pain threshold to chemical and physical stimuli in the pelvic nerve terminals. Since ovulation is a prerequisite for primary dysmenorrhea, ovarian steroid hormones are likely to be involved in regulating the intrauterine production of prostaglandins at menstruation. It has been suggested that high circulating estrogen levels in the luteal phase may cause the excessive prostaglandin production. Prostaglandin action on the uterus has been determined to be dependent on progesterone levels, with high levels of progesterone rendering the uterus resistant to prostaglandin stimulation. When progesterone falls prior to menses, excess prostaglandins cause dysmenorrhea.
  • Secondary dysmenorrhea is defined as menstrual pain resulting from anatomic and/or macroscopic pelvic pathology (Dawood, 1990 (3) ; Klotz in Lemeke et a!., 1992 (7) ). This condition is most often observed in women aged 30-45 years. Approximately 40% of adult females have menstrual pain, and 10% are incapacitated for 1-3 days each month.
  • Non-steroidal anti-inflammatory drugs are effective in reducing pain associated with primary dysmenorrhea (Dawood 1988 (2) ). They have a direct analgesic effect through inhibition of prostaglandin synthesis and also have other properties that act against inflammatory factors that may be responsible for heavy menstrual bleeding. NSAIDs may be most effective when therapy is started before the onset of menstrual pain and flow or as soon as the symptoms begin, and then are taken on a regular schedule for two to three days. Unfortunately, the pain of primary dysmenorrhea is generally of such intensity that more potent analgesics are often required.
  • Common side effects of NSAIDs used intermittently include nausea, vomiting, and diarrhea, and may include effects on the nervous system such as headache, drowsiness, and dryness of the mouth. Caution should be exercised in using these medications in patients with existing cardiovascular or renal issues or with difficulty handling intravascular volume, as they may worsen or lead to the onset of hypertension. Long-term use of any NSAID can cause increasing adverse effects, for example increase the risk for gastrointestinal bleeding and ulcers, and the overuse of NSAIDs for menstrual disorders may contribute to iron deficiency anaemia due to Gl blood loss.
  • birth control pills are know to be effective in treating women with dysmenorrhea.
  • Combined oral contraceptive pills comprising estrogen and progestin attenuate myometrial activity by lowering endometrial prostaglandin production and by thinning the lining of the uterus, where prostaglandins are formed, thereby decreasing the uterine contractions and menstrual bleeding that contribute to pain and cramping.
  • Continuous OCs have the potential for helping women with either heavy bleeding, painful periods, or both.
  • Combined oral contraceptives and NSAIDs are often considered first-line therapy for women with primary or secondary dysmenorrhea. Estrogen and progestin may each cause different side effects, especially during the first two to three months of treatment, but this usually declines with time.
  • caution must be given to prevent estrogen deficiencies and loss of bone mineral density; also unscheduled bleeding episodes are a frequent untoward effect of progestin-only contraceptives.
  • Progestin and especially levonorgestrel (LNG) releasing intrauterine systems (IUS) are shown to be very beneficial for menstrual disorders.
  • the hormones in these types of devices help control the growth of the lining of the uterus so less prostaglandin is made resulting in fewer contractions, less blood flow, and less pain. Hormones may stop the growth of fibroids and endometriosis.
  • Some studies suggest that the LNG-IUS is more effective than oral contraceptives for controlling heavy menstrual bleeding. Since progestin released by an intrauterine system mainly affects the uterus and cervix and serum levels of levonorgestrel are usually very low, the device causes far fewer side effects than the progestin pills do.
  • Zinc at sufficient doses has been shown to prevent essentially menstrual cramping (Kelly 1983 ⁇ 11 >; Prasad 2000 ⁇ 171 ).
  • RDA daily allowance
  • Zinc may interfere with different pathways of prostaglandin synthesis and/or metabolism.
  • Another hypothesis is that zinc might improve micro-vessel circulation in the uterus, as is seen with angina pectoris (Eby, 2006) (15 ⁇ . Since strong uterine contractions temporarily reduce or stop the blood supply to the uterus, thus depriving the uterus of oxygen resulting in contractions and pain, improvement in micro- vessel circulation by zinc treatment may be sufficient to prevent cramping and pain. Ischemia followed by reperfusion, results in the release of active oxygen species which can cause tissue damage and pain.
  • Copper-zinc dismutase enzyme in the uterus controls prostaglandin production by inactivating and preventing accumulation of these oxygen radicals (see for example Sugino (2000) ( 6! ). These radicals, stimulate human endometrial stromal cells (ESC) to produce Prostaglandins (F2a), which are involved in endometrial breakdown Zinc treatment enhances the levels of this enzyme, which in turn could result in relieving cramping and pain.
  • Zinc is an effective anti-inflammatory and antioxidant agent, and it can readily down-regulate inflammatory cytokines.
  • Zinc also protects plasma cell membranes preventing damage to cells by a wide variety of cytotoxic agents in a dose dependent manner extending far above physiologic concentrations. Zinc may regulate cyclooxygenase-2 (COX-2), an enzyme involved in pain and inflammation, and implicated in certain cancers, and COX-2 can be lowered by zinc treatment.
  • COX-2 cyclooxygenase-2
  • the problem to be solved by the present invention is to provide a
  • a second problem to be solved is to provide a pharmaceutical preparation which ensures a timely intake of the zinc salt, preferably 1-4 days prior the menses.
  • the first object is solved by making available a pharmaceutical composition
  • a pharmaceutical composition comprising a hormonal agent, in particular an estrogen and/or one or more progestin and a biocompatible zinc salt and pharmaceutically acceptable excipients and carriers.
  • the second aspect of the invention (timely intake of zink salt) is met by providing a pharmaceutical preparation/regime, which is, e.g. predetermined by a blister package with a fixed sequence of dosage units containing a an oral contraceptive active hormone and/or a biocompatible zinc salt and optionally placebo pills.
  • a pharmaceutical preparation/regime which is, e.g. predetermined by a blister package with a fixed sequence of dosage units containing a an oral contraceptive active hormone and/or a biocompatible zinc salt and optionally placebo pills.
  • placebo pill means hormone free tablet.
  • hormone free tablets can contain other ingredients such as vitamins, nutritional supplements and/or etafolin respectively folic acid.
  • the invention is based on the realization, which is surprising in relation to the state of the art, that treatment and prevention of menstrual disorders with a combination of a biocompatible zinc salt and pharmaceutical composition comprising progestin and/or estrogen allows for a dose reduction regarding the effective amount of zinc.
  • the present invention makes available a pharmaceutical composition for treatment (prevention or alleviation) of dysmenorrhea and menstrual pain, which is effective with reduced zinc doses.
  • composition comprising an hormonal agent and a biocompatible zinc salt in a pharmaceutical acceptable carrier.
  • biocompatible zinc salts are suitable with regard to the present invention, preferred is zinc- acetate, zinc-bis(hydrogen-DL-aspartate), -orotate, -gluconate, -sulphate or -cetrate.
  • Reduced zinc doses in the context of the present invention means daily doses which are below 31 mg/day.
  • the lower limit with regard to the zinc dose is 5 mg/day.
  • higher doses of zinc e.g. up to 50 mg/day, are feasible.
  • RAD Recommended Daily Allowance
  • high zinc doses should be considered only for short-term use, e.g. if the zinc is administered exclusively in the hormone-free interval.
  • the zinc dose should be in the range of 5-40 mg, preferably in the range of 10-40 mg. In a particular preferred embodiment of the invention the zinc dose is in the range of 15-30 mg.
  • the zinc salt is administered either during the hormone free phase or in combination with progestin alone, or with estrogen plus progestin.
  • the quantity of zinc given in this specification refers to the zinc ions, as zinc salts are ionic compounds consisting, for example, of two moles of a monovalent radical for each mole of zinc. Therefore, the total amount of salt present in the composition has to be calculated against the respective negative ion selected. In those cases where crystal water is present in the zinc salt (e.g. ZnSO 4 x 7 H 2 O), the crystal water has also to be considered.
  • the zinc salt e.g. ZnSO 4 x 7 H 2 O
  • hormones which are bioavailable after oral administration are used.
  • Preferred estrogens are estradiol valerate, ethinylestradiol, mestranol, quinestranol, estradiol, estrone, estrane, estriol, estetrol and conjugated equine estrogens.
  • a preferred composition according to the present invention contains an estrogen/progestin hormonal combination containing Drospirenone and Ethinyl Estradiol.
  • Drospirenone DRSP
  • EE Ethinyl Estradiol
  • the present invention furthermore provides a pharmaceutical preparation / regime, e.g. predetermined by a blister package with a fixed sequence of dosage units containing the hormone and/or a biocompatible zinc salt and optionally placebo pills.
  • regimens with a different hormone dose fall under the scope of the present invention.
  • Such regimens with a varying hormone dose are, for example, known from the product Qlaira ® / ATAZIA TM , where initially on days 1 and 2 only 3 mg estradiol valerate (E 2 V) are administered followed by, 2 mg E 2 V and 2 mg Dienogest (DNG) on days 3-7, followed by 3 mg DNG 2 mg E 2 V on days 8-24 respectively 1 mg E 2 V on days 25 and 26.
  • a 2 day hormone free interval completes the 28 cycle pack.
  • Zinc can be added in various regimens, for example:
  • a x-phase system with m separately packed single dosage units containing only a hormonal agent, followed by n dosage units containing a hormonal agent plus a zinc salt, followed by o dosage units containing the zinc salt only followed by p placebo units is possible.
  • m can be 0 to 21 and p can be 0-7 under the proviso that m+n+o+p is 28, n is 21 minus m and o is 7 minus p.
  • x can be 2, 3 or 4. (If m and p are zero x is 2, if m or p are zero x is 3 if m and p are unequal 0, x is 4).
  • n 21 and p is 7 or n is 21 and o is
  • Particular preferred is a 2-phase regime, where m is 21 and o is 7 or a 3-phase system where m plus n are 21 and o is 7.
  • m can be 0 to 24 and p can be 0-4 under the proviso that m+n+o+p is 28, n is 24 minus m and o is 4 minus p.
  • x can be 2,3 or 4. (If m and p are zero x is 2, if m or p are zero x is 3 if m and p are unequal 0, x is 4).
  • n 24 and p is 4 or n is 24 and o is 4.
  • the amount of the hormonal agent and zinc is variable, e.g. in the market product Q I a i ra s /N AT AZ I ATM the progestin hormone dose (dienogest) is in the initial phase 2 mg (day 4 to 7) followed by 3 mg (16 days).
  • the zinc dose If, e.g. the zinc salt is concomitantly administered with the hormone, a lower zinc dose is possible compared to the scenario where zinc is given in a separate dosage unit instead of a placebo pill in the hormone free interval.
  • the zinc is administered 3 to 5 days prior the menses only.
  • the preferred administered dose is 20-30 mg. If it is concomitantly administered with the hormone(s), then the dose could be lower and is preferably between 10-20 mg per single dosage unit.
  • the pharmaceutical preparation contains 5-30 mg zinc and as a zinc salt zinc acetate, -gluconate, -sulphate zinc-bis(hydrogen-DL-aspartate), zinc-orotate or -cetrate.
  • the preparation contains progestin or a progestin derivative, cyproterone acetate, desogestrel, etonogestrel, levonorgestrel, lynestrenol, medroxyprogesterone, norethisterone, norethisterone acetate, norgestimate, drospirenone, dienogest, gestodene, 19-nor- 17- hydroxy progesterone esters, 17a- ethinyltestosterone and derivatives thereof, 17a-ethinyl-19-nor-testosterone and derivatives thereof, ethynodiol diacetate, megestrol, dydrogesterone, norethynodrel, chlormadinone acetate, allylestrenol, tibolone, medrogestone, norgestrienone, ethisterone, dl-norgest
  • the preparation contains a combination of Drospirenone and an Estrogen and as zinc salt zinc acetate or zinc gluconate.
  • the preparation contains Levonorgestrel and an Estrogen and zinc acetate or zinc gluconate.
  • estradiol ester estradiol ester
  • estradiol valerate estradiol hemihydrate or ethinyl estradiol is preferred.
  • ethinylestradiol mestranol, quinestranol, estradiol, estradiol valerate, estrone, estrane, estriol, estetrol and conjugated equine estrogens and/or a progestin.
  • the tablets used in the preparation can be prepared by the known methods.
  • a zinc and hormone-containing tablet can be prepared analogue to the hormone- containing pills, such as by fluidized bed granulation or by direct tableting.
  • the usual pharmaceutical excipients are used.
  • the tablet can then be coated or painted with a film former.
  • Another aspect of the invention refers to the use of the a.m. compositions or pharmaceutical preparations for the treatment of dysmenorrhea and/or menstrual pain.
  • prostaglandin F2a is the principal factor accounting for the contractile activity of the myometrium and, thus, is causally contributing to cramps and pelvic pain during menstruation (i.e. a situation which is invariably associated with precipitous decrease of endogenous progesterone concentrations).
  • the examples 1 and 2 underline the capacity of zinc to exert therapeutic effects in such conditions by decreasing the concentrations of PGF2a in the affected organ, as well as the responsiveness of the myometrium to this endogenous mediator of smooth muscle contractions.
  • Zinc gluconate (Merck, Darmstadt) was administered daily to the animals of the group "progestin withdrawal plus Zn" upon Levonorgestrel pellet removal for 4 consecutive days.
  • the daily dose of 30 mg/rat was formulated as aqueous solution and administered by oral gavage in a volume of 0.5 ml.
  • the remaining groups received daily an equal volume of the solvent (distilled water).
  • Zinc treatment suppresses prostaglandin-induced uterine contractions
  • the isolated horn preparation was placed horizontally between two ring platinum electrodes (4 mm diameter) located at a distance of 10 mm and 26 mm from the outlet of a 1 ml plastic double-jacketed tissue chamber (37° C) and superfused at a constant flow rate of 1 ml/min by means of a peristaltic pump (Miniplus 2, Gilson 312) with a medium of the following composition (mM): NaCI 136.9, KCI 2.7, CaCI 2 1.8, gSO 4 0.6, NaHCO 3 1 1.9, KH 2 PO 4 0.5, Glucose 1 1.5, supplemented with albumin 25 mg/l and EDTA 10 mg/l gassed with 5% CO 2 in O 2 (pH 7.3-7.5).
  • One end of the preparation was tied to a Grass FT 03C force-displacement transducer connected by tensometric bridge (Microtechna) to a Lineacorder (TZ 4620) for registration of isometric changes in tension.
  • the preparation was stretched (0.5-0.8 rrsN) until reached approximately the in situ length and allowed to equilibrate for 60 min.
  • Myotropic electrical stimulation with 5 s trains of rectangular pulses of 50 V, 10 Hz, 6 ms, was delivered at 180 s by MFS-1 stimulator to evoke myogenic contractions.
  • Prostaglandin F2a Prostin, Pfizer, PGF2a was applied with the medium for 20 min at a concentration of 50 nM.
  • progestin withdrawal (mean frequency 4.5 ⁇ 0.866) and only 2 preparations of the group “progestin withdrawal + Zn” (mean frequency 4.5 ⁇ 0.5).
  • PGF2a produced a very strong increase in the spontaneous contractile activity of the group “progestin withdrawal” (response ratio 131 ⁇ 109), while its effect was modest in preparations originating from animals of the treatment groups “continuous progestin” (response ratio 4.0 ⁇ 0.8) or "progestin withdrawal + Zn” (response ratio 3.3 ⁇ 1.0).
  • Zinc treatment reduces uterine content of PGF2a
  • Prostaglandin F2a was determined by enzyme immunoassay kit (Assay Designs, In., Cat. No. 900-069, Lot No. 042409 13); photometric measurements were made with GENios Plus Multi-Detection Reader, Tecan Inc. The calibration curve covered the range between 3 and 50000 pg/ml; the assay sensitivity was 6.7 pg/ml. The data are expressed in ng/100 mg tissue.
  • FC fertility control
  • Tablet on day 25 has the highest zinc dose, tablet on day 26 has less zinc than day 25, tablet on day 27 has less zinc than day 26, and tablet 28 has less zinc than day 27.
  • zinc dose is A > B > C > D tablets 1-24: 3mg DRSP + 20-30 EE
  • fluidized bed granulation granules consisting of ethinyl estradiol [as ⁇ - Cyclodextrin (CD complex)] and drospirenone are prepared.
  • the hormones and other fillers, binders and disintegrants are granulated in a fluidized bed granulator with a binder solution consisting of water and a binder. After completion of the granulation, the granules are mixed with zinc-D- gluconate and other fillers, disintegrants and lubricants. The mixture is then compressed into tablets and subsequently coated.
  • a film coating consisting of a film former, a plasticizer with the addition of color pigments is used.
  • the respective amounts and the used excipients can be taken from Table 4.
  • the hormones, the zinc salt, other fillers, binders, and disintegrants are granulated in a fluidized bed granulator with a binder solution consisting of water and a binder. After completion of the granulation disintegrant and lubricant are added as external phase to the granules. The mixture is then compressed into tablets and subsequently coated.
  • a film coating consisting of a film former, a plasticizer with the addition of color pigments is used.
  • the particular amounts, the selected zinc salt and the used excipients can be taken from Table 5.
  • the hormones and the zinc salt with other fillers and dry binders are mixed. Then, disintegrant and lubricant are added as external phase to the mixture. The mixture is then compressed into tablets and subsequently coated.
  • a film coating comprising a film former, a plasticizer and color pigments is used.

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Abstract

L'invention porte sur une composition pharmaceutique et sur une préparation (régime) contenant une hormone et un sel de zinc biocompatible, ainsi que sur l'utilisation d'un sel de zinc et d'une hormone active contraceptive pour le traitement de troubles menstruels, en particulier pour soulager la dysménorrhée.
PCT/EP2011/068596 2010-10-28 2011-10-25 Composition et préparation pour le traitement de la dysménorrhée et de la douleur menstruelle et utilisation d'un agent hormonal et d'un sel de zinc pour le traitement de troubles menstruels WO2012055840A1 (fr)

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US8933059B2 (en) 2012-06-18 2015-01-13 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US8987237B2 (en) 2011-11-23 2015-03-24 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US9180091B2 (en) 2012-12-21 2015-11-10 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
US9289382B2 (en) 2012-06-18 2016-03-22 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
WO2018024912A1 (fr) * 2016-08-05 2018-02-08 Estetra Sprl Méthode de gestion de la dysménorrhée et de la douleur menstruelle.
US9931349B2 (en) 2016-04-01 2018-04-03 Therapeuticsmd, Inc. Steroid hormone pharmaceutical composition
WO2018065076A1 (fr) * 2016-10-28 2018-04-12 Estetra Sprl Méthode de prise en charge de la dysménorrhée et des douleurs menstruelles
US10052386B2 (en) 2012-06-18 2018-08-21 Therapeuticsmd, Inc. Progesterone formulations
US10206932B2 (en) 2014-05-22 2019-02-19 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10258630B2 (en) 2014-10-22 2019-04-16 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
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