US20030092691A1 - Pharmaceutical composition based on micronized progesterone, method for the preparation thereof and uses thereof - Google Patents

Pharmaceutical composition based on micronized progesterone, method for the preparation thereof and uses thereof Download PDF

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Publication number
US20030092691A1
US20030092691A1 US10/097,526 US9752602A US2003092691A1 US 20030092691 A1 US20030092691 A1 US 20030092691A1 US 9752602 A US9752602 A US 9752602A US 2003092691 A1 US2003092691 A1 US 2003092691A1
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Prior art keywords
pharmaceutical composition
progesterone
oil
oestradiol
preferentially
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US10/097,526
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English (en)
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Jerome Besse
Antoine Besins
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Besins International Belgique
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Assigned to BESINS INTERNATIONAL BELGIQUE reassignment BESINS INTERNATIONAL BELGIQUE ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BESINS, ANTOINE, BESSE, JEROME
Publication of US20030092691A1 publication Critical patent/US20030092691A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/63—Oleaceae (Olive family), e.g. jasmine, lilac or ash tree
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61P15/06—Antiabortive agents; Labour repressants
    • 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
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • 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
    • 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
    • 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
    • A61P5/32—Antioestrogens
    • 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

  • the present invention relates to a pharmaceutical composition containing micronized progesterone, sunflower oil and/or olive oil, and soya bean lecithin. It also relates to pharmaceutical products comprising said pharmaceutical composition.
  • the invention also relates to the method for manufacturing this pharmaceutical composition, as well as to the uses thereof.
  • Progesterone is a hormone which is synthesized, in women, essentially by the ovary during the post-ovulation or luteal phase (more precisely by the cells of the corpus luteum) and, to a lesser degree, by the adrenal glands and the placenta during the second part of pregnancy. Non-endocrine synthesis of progesterone, in particular in neurons, is also possible.
  • progesterone insufficiency A consequence of insufficiency of progesterone secretion in a woman is a loss of its biological effects: progestative effect, anti-androgen effect (action on the skin) and anti-oestrogen effect (the consequence being high oestrogen production: hot flushes, psychogenic difficulties of the anxious or depressive type, weight gain, etc.).
  • This progesterone insufficiency may lead to functional difficulties and diverse clinical manifestations, in particular:
  • progesterone suffers from a serious handicap due to the poor intestinal absorption and to the intense hepatic metabolism (short plasmatic half-life) of this hormone. Only the vaginal, rectal and intramuscular pathways would, to date, make it possible to maintain blood progesterone level at the physiological level of the luteal phase, for several hours.
  • the LABORATOIRES BESINS-ISCOVESCO have already proposed a solution in order to improve the quality and intensity of the digestive absorption of natural progesterone, in Patent Application FR 76 36007. Specifically, they have developed a formulation of soft capsules containing micronized progesterone in oily suspension. The synergistic effect of the micronization and the use of molecules containing long-chain fatty acids has made it possible to indisputably increase the bioavailability of progesterone taken orally. This formulation has known a great deal of success worldwide. It is sold in France under the trade mark UTROGESTAN®.
  • the oil which serves as a basis for the oily suspension in UTROGESTAN® is peanut oil.
  • Peanut Arachis hypogae is a leguminous plant, a bushy annual plant with yellow flowers, of the Papilionacea family.
  • UTROGESTAN® may be prescribed in many cases of therapeutic indications, including as a supplement to the luteal phase during cycles of in vitro fertilization (IVF), and in the case of a danger of abortion or of prevention of repeat abortion due to luteal insufficiency, up to the 12th week of pregnancy. It is therefore possible, in theory, for a foetus to be exposed to UTROGESTAN® in utero.
  • IVF in vitro fertilization
  • the micronized progesterone is preferably in suspension in sunflower oil and/or in olive oil.
  • U.S. Pat. No. 5,140,021 only describes a laboratory scale preparation of the progesterone capsules and provides no teaching regarding the preparation of capsules on an industrial scale.
  • the progesterone capsules according to said American patent do not contain soya bean lecithin, which is an essential element of the pharmaceutical composition according to the present invention.
  • the soya bean lecithin plays the role of an agent for suspending the progesterone particles in the sunflower oil and of a lubricant during encapsulation of the content on an industrial scale.
  • the invention therefore relates to a pharmaceutical composition
  • a pharmaceutical composition comprising micronized progesterone, sunflower oil and/or olive oil, and soya bean lecithin.
  • the micronized progesterone is in suspension in sunflower oil and/or olive oil.
  • micronized progesterone is intended to mean a progesterone in which at least 80% of the particles have a particle size of between 1 and 15 ⁇ m, preferably 50% of the particles have a particle size of between 1 and 10 ⁇ m, and even more preferentially 25% of the particles have a particle size of between 1 and 5 ⁇ m, these particle sizes being measured using a laser particle sizer of the Malvern type, by the procedure described in the examples of the present patent application.
  • the particle size was not the same in the presence or absence of the soya bean lecithin.
  • the main advantage of the sunflower oil and/or the olive oil in physicochemical terms compared to the peanut oil is to simultaneously ensure both:
  • the progesterone/oil(s) ratio is between 0.15/1 and 3/1, preferably between 0.25/1 and 2/1, preferentially between 0.40/1 and 1/1, and even more preferentially is 0.67/1.
  • the soya bean lecithin/oil(s) ratio is between 0.005/1 and 0.3/1, preferably between 0.01/1 and 0.2/1, preferentially between 0.040/1 and 0.1/1, and even more preferentially is 0.067/1.
  • the pharmaceutical composition according to the invention may also comprise an oestrogen, preferably selected from the group consisting of 17- ⁇ -oestradiol, oestrone, 17- ⁇ -ethinyl oestradiol and oestradiol valerianate, and even more preferentially is 17- ⁇ -oestradiol.
  • an oestrogen preferably selected from the group consisting of 17- ⁇ -oestradiol, oestrone, 17- ⁇ -ethinyl oestradiol and oestradiol valerianate, and even more preferentially is 17- ⁇ -oestradiol.
  • the pharmaceutical composition according to the invention may be in the form, inter alia, of a soft capsule, of a hard capsule or of a tablet.
  • each dosage unit advantageously comprises between 2 mg and 600 mg of micronized progesterone, preferably between 30 mg and 300 mg, and even more preferentially between 100 mg and 200 mg.
  • composition according to the invention may be administered orally or vaginally, depending on the therapeutic indications.
  • Vaginal administration also represents an alternative to oral administration in the case of side effects due to the progesterone (drowsiness after oral absorption) or of contraindication to oral administration (hepatopathy).
  • the capsule comprises gelatin or an equivalent.
  • the invention also relates to a method for preparing a pharmaceutical composition comprising micronized progesterone, sunflower oil and/or olive oil, and soya bean lecithin.
  • This method comprises the following successive steps:
  • micronized progesterone is added, with stirring, to the mixture thus obtained in order to obtain a homogeneous suspension.
  • This suspension may be conditioned directly in the form of soft capsules, but may also be used to impregnate an absorbent support presented in the form of powder.
  • This absorbent support may be of the maltodextrin and/or derivatives, silica and/or derivatives, cyclodextrin and/or derivatives or cellulose powder and/or derivatives type, or a combination thereof, or any other pharmaceutical raw material which possesses equivalent properties.
  • the powder thus obtained may then be presented in the form of hard capsules or tablets.
  • the hard capsules or tablets containing the powder may also comprise binding agents, disintegrating agents, diluents and/or lubricants.
  • the invention also relates to the use of the micronized progesterone, of the sunflower oil and/or the olive oil, and of the soya bean lecithin, for preparing a medicinal product for treating a physiological condition linked to insufficiency of progesterone secretion.
  • luteal insufficiency Menstrual irregularity, premenstrual syndromes, mastodynia, benign mastopathies, premenopause, sterility due to luteal insufficiency, disorders due to menopause, local contraception, for prevention of repeated abortions in the case of luteal insufficiency, danger of premature birth, acne, alopecia, for prevention of osteoporosis, endometrial cancers and epilepsy.
  • the invention also relates to the use of the micronized progesterone, of the sunflower oil and/or olive oil, and of the soya bean lecithin, and also an oestrogen, for preparing a medicinal product for treating a physiological condition linked to insufficiency of progesterone secretion.
  • the oestrogen is preferably selected from the group consisting of 17- ⁇ -oestradiol, oestrone, 17- ⁇ -ethinyl oestradiol and oestradiol valerianate, and even more preferentially is 17- ⁇ -oestradiol.
  • the applicant company has also prepared 500 mg capsules which are homothetic with the 250 mg capsules described above.
  • the 500 mg capsules contain 200 mg of micronized progesterone, 298 mg of sunflower oil and 2 mg of soya bean lecithin.
  • sunflower oil with a high oleic acid content sunflower oil with a high oleic acid content
  • Standard solutions were prepared as follows: - concentrated solution: progesterone batch A0098 10 mg oil qs for 20 ml - diluted solution: concentrated solution 1 ml tetrahydrofuran (THF) 10 ml acetonitrile qs for 20 ml magnetic stirring: 5 minutes.
  • the capsules are prepared according to one of the methods known per se to those skilled in the art.
  • the atmosphere is controlled at 22° C. ⁇ 3° C. and at a relative humidity of 35% ⁇ 10%.
  • a mixer with a volume of 600 litres is placed under vacuum.
  • the mixer is again placed under vacuum (between 0.7 bar and 0.9 bar), followed by stirring at low speed between 10 rpm and 15 rpm.
  • progesterone is added under vacuum, followed by the remaining quarter of sunflower oil, and the temperature is brought to 23° C. ⁇ 3° C.
  • the mixer with vigorous stirring is placed under a pressure up to a maximum of 1 bar.
  • the storage containers are placed under vacuum and then stirred at between 2400 and 2000 rpm for 15 minutes. They are again placed under vacuum and restirred for 30 minutes at a speed of between 2000 and 2500 rpm.
  • Amount of sample per measurement 1 or 2 drops deposited using a pipette
  • Medium filtered saturated sunflower oil. This oil is prepared with magnetic stirring, maintaining the temperature at 37° C., for 1 hour, and then filtered on filter paper.
  • control solution is filtered on a fibreglass syringe filter with a porosity of 1 ⁇ m.

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US10/097,526 2001-11-13 2002-03-14 Pharmaceutical composition based on micronized progesterone, method for the preparation thereof and uses thereof Abandoned US20030092691A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0114653A FR2832065B1 (fr) 2001-11-13 2001-11-13 Composition pharmaceutique a base de progesterone micronisee son procede de preparation et ses utilisations
FR0114653 2001-11-13

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US10/097,526 Abandoned US20030092691A1 (en) 2001-11-13 2002-03-14 Pharmaceutical composition based on micronized progesterone, method for the preparation thereof and uses thereof
US10/495,242 Expired - Lifetime US7431941B2 (en) 2001-11-13 2002-11-13 Pharmaceutical composition based on micronized progesterone, preparation method and uses thereof
US12/071,822 Expired - Lifetime US7829115B2 (en) 2001-11-13 2008-02-27 Pharmaceutical composition based on micronized progesterone, preparation method and uses thereof
US12/916,795 Abandoned US20110135719A1 (en) 2001-11-13 2010-11-01 Pharmaceutical composition based on micronized progesterone, preparation method and uses thereof
US13/542,164 Expired - Lifetime US8435561B2 (en) 2001-11-13 2012-07-05 Pharmaceutical composition based on micronized progesterone, preparation method and uses thereof

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US10/495,242 Expired - Lifetime US7431941B2 (en) 2001-11-13 2002-11-13 Pharmaceutical composition based on micronized progesterone, preparation method and uses thereof
US12/071,822 Expired - Lifetime US7829115B2 (en) 2001-11-13 2008-02-27 Pharmaceutical composition based on micronized progesterone, preparation method and uses thereof
US12/916,795 Abandoned US20110135719A1 (en) 2001-11-13 2010-11-01 Pharmaceutical composition based on micronized progesterone, preparation method and uses thereof
US13/542,164 Expired - Lifetime US8435561B2 (en) 2001-11-13 2012-07-05 Pharmaceutical composition based on micronized progesterone, preparation method and uses thereof

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US (5) US20030092691A1 (es)
EP (1) EP1443940B1 (es)
KR (1) KR100911790B1 (es)
CN (1) CN1263453C (es)
AT (1) ATE339958T1 (es)
AU (1) AU2002352334B2 (es)
BR (1) BRPI0214043B8 (es)
CY (1) CY1106293T1 (es)
DE (1) DE60214876T2 (es)
DK (1) DK1443940T3 (es)
EA (1) EA006550B1 (es)
ES (1) ES2272793T3 (es)
FR (1) FR2832065B1 (es)
HK (1) HK1064606A1 (es)
HU (1) HU229341B1 (es)
IL (2) IL161668A0 (es)
MA (1) MA27081A1 (es)
NO (1) NO335044B1 (es)
NZ (1) NZ532659A (es)
OA (1) OA12726A (es)
PL (1) PL206096B1 (es)
PT (1) PT1443940E (es)
UA (1) UA77451C2 (es)
WO (1) WO2003041720A1 (es)
ZA (1) ZA200403288B (es)

Cited By (22)

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US20060275360A1 (en) * 2005-05-26 2006-12-07 Ahmed Salah U Oral dosage forms comprising progesterone and methods of making and using the same
JP2007523872A (ja) * 2003-07-17 2007-08-23 バナー ファーマキャップス，インコーポレイティド 制御放出製剤
US20080188829A1 (en) * 2007-02-06 2008-08-07 George Creasy Progesterone for the treatment or prevention of spontaneous preterm birth
US8633178B2 (en) 2011-11-23 2014-01-21 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US8933059B2 (en) 2012-06-18 2015-01-13 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
US9931349B2 (en) 2016-04-01 2018-04-03 Therapeuticsmd, Inc. Steroid hormone pharmaceutical composition
US10052386B2 (en) 2012-06-18 2018-08-21 Therapeuticsmd, Inc. Progesterone formulations
US10098894B2 (en) 2014-07-29 2018-10-16 Therapeuticsmd, Inc. Transdermal cream
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
US10285998B1 (en) 2018-04-04 2019-05-14 The Menopause Method, Inc. Composition and method to aid in hormone replacement therapy
US10286077B2 (en) 2016-04-01 2019-05-14 Therapeuticsmd, Inc. Steroid hormone compositions in medium chain oils
US10328087B2 (en) 2015-07-23 2019-06-25 Therapeuticsmd, Inc. Formulations for solubilizing hormones
US10471148B2 (en) 2012-06-18 2019-11-12 Therapeuticsmd, Inc. Progesterone formulations having a desirable PK profile
US10471072B2 (en) 2012-12-21 2019-11-12 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10537581B2 (en) 2012-12-21 2020-01-21 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10806740B2 (en) 2012-06-18 2020-10-20 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US11246875B2 (en) 2012-12-21 2022-02-15 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11266661B2 (en) 2012-12-21 2022-03-08 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11633405B2 (en) 2020-02-07 2023-04-25 Therapeuticsmd, Inc. Steroid hormone pharmaceutical formulations

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FR2832065B1 (fr) 2001-11-13 2004-11-05 Besins Int Belgique Composition pharmaceutique a base de progesterone micronisee son procede de preparation et ses utilisations
AT12800U1 (de) * 2007-11-05 2012-11-15 Bayer Schering Pharma Ag Pharmazeutisches Präparat zur Verwendung bei der oralen Kontrazeption von Frauen mit Laktoseintoleranz
FR2947178B1 (fr) 2009-06-29 2012-07-06 Effik Composition pharmaceutique a base de progesterone micronisee et ses utilisations
CN102091054B (zh) * 2009-12-14 2014-04-16 浙江爱生药业有限公司 黄体酮制剂组合物及其制备方法
US9375437B2 (en) 2010-06-18 2016-06-28 Lipocine Inc. Progesterone containing oral dosage forms and kits
US8951996B2 (en) 2011-07-28 2015-02-10 Lipocine Inc. 17-hydroxyprogesterone ester-containing oral compositions and related methods
DK2755498T3 (en) * 2011-09-15 2018-05-22 Friulchem Spa COMPOSITION FOR ORAL ADMINISTRATION FOR ANIMALS AND PROCEDURE FOR OBTAINING
CN103957888B (zh) 2011-09-29 2017-11-21 PLx 制药公司 用于将药物沿胃肠道靶向释放的pH依赖性载体、其组合物及其制备和应用
CN107847506A (zh) 2015-06-22 2018-03-27 来普卡公司 含17‑羟基孕酮酯的口服组合物和相关方法
EP3395332A1 (en) 2017-04-28 2018-10-31 Chemo Research, S.L. Hormone softgel capsules and a process for the preparation thereof
US11576920B2 (en) 2019-03-18 2023-02-14 The Menopause Method, Inc. Composition and method to aid in hormone replacement therapy
KR20220158031A (ko) 2020-03-26 2022-11-29 피엘엑스 옵코 인코포레이티드 pH 의존성 재구성이 가능한 제약 담체 및 그의 제조 및 사용 방법

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KR20050058231A (ko) 2005-06-16
US20110135719A1 (en) 2011-06-09
OA12726A (en) 2006-06-27
HK1064606A1 (es) 2005-02-04
BRPI0214043B1 (pt) 2019-12-31
FR2832065B1 (fr) 2004-11-05
KR100911790B1 (ko) 2009-08-12
US20050004076A1 (en) 2005-01-06
EA200400668A1 (ru) 2004-10-28
DK1443940T3 (da) 2007-01-29
HUP0401935A3 (en) 2011-02-28
PL206096B1 (pl) 2010-06-30
US7431941B2 (en) 2008-10-07
CN1263453C (zh) 2006-07-12
HUP0401935A2 (hu) 2005-01-28
DE60214876D1 (de) 2006-11-02
EP1443940B1 (fr) 2006-09-20
NO335044B1 (no) 2014-09-01
ES2272793T3 (es) 2007-05-01
CN1585644A (zh) 2005-02-23
US20090123534A1 (en) 2009-05-14
NZ532659A (en) 2006-04-28
DE60214876T2 (de) 2007-04-05
NO20042002L (no) 2004-05-14
EP1443940A1 (fr) 2004-08-11
WO2003041720A1 (fr) 2003-05-22
US7829115B2 (en) 2010-11-09
PL369131A1 (en) 2005-04-18
IL161668A (en) 2009-09-01
FR2832065A1 (fr) 2003-05-16
ATE339958T1 (de) 2006-10-15
BR0214043A (pt) 2004-10-13
EA006550B1 (ru) 2006-02-24
CY1106293T1 (el) 2011-10-12
MA27081A1 (fr) 2004-12-20
HU229341B1 (en) 2013-11-28
UA77451C2 (en) 2006-12-15
PT1443940E (pt) 2007-01-31
IL161668A0 (en) 2004-09-27
BRPI0214043B8 (pt) 2021-05-25
US8435561B2 (en) 2013-05-07
AU2002352334B2 (en) 2008-10-23
US20120276194A1 (en) 2012-11-01
ZA200403288B (en) 2005-07-27

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