US3758687A - Contraceptive method and composition - Google Patents

Contraceptive method and composition Download PDF

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Publication number
US3758687A
US3758687A US00135814A US3758687DA US3758687A US 3758687 A US3758687 A US 3758687A US 00135814 A US00135814 A US 00135814A US 3758687D A US3758687D A US 3758687DA US 3758687 A US3758687 A US 3758687A
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United States
Prior art keywords
progestogene
effect
ovulation
administration
progestogenes
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US00135814A
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English (en)
Inventor
J Ufer
K Kimbel
U Lachnit
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Bayer Pharma AG
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Schering AG
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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
    • A61K31/57—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

Definitions

  • ABSTRACT Conception is prevented in a female of reproductive age without suppressing ovulation by administering to such female within the period starting with the fifth and ending with the eighth day of the menstrual cycle an effective amount of a progestogene which when administered in such amount effective for preventing conception has at most an insignificant suspension effect on gonadotropin secretion.
  • the present invention relates to a contraceptive method and composition and, more particularly, the pres ent invention is concerned with the administration of a contraceptive agent which, upon a single administration, will prevent conception for a prolonged period of time, such as one menstrual cycle or longer without inhibiting ovulation.
  • - SUMMARY OF THE INVENTION ably should be administered between the fifth and eighth day, both inclusive, of the menstrual cycle and in such amount that one administration will suffice at least for one cycle.
  • the progestogene is administered in the form of an oily solution which also may include diluents and solubilizing agents.
  • the progestogenes which are administered according to the present invention preferably will be such which do not have a significant ovulation-suppressing and pi tuitary hypothalamic-inhibiting effect, or the ovulationsuppressing and pituitary hypothalamic-inhibiting effect of the administered progestogenes should be sufficiently small so that the threshold value of these effects is not reached when administering an amount thereof which is effective with respect to achieving the desired contraceptive result, i.e., which is sufficient to inhibit the periovulatory changes of the cervical mucus and endometrium which, it is thought, are substantially responsible for the desired contraceptive effect.
  • the present invention is also concerned with a composition in, dosage form for parenteral administration for the purpose of achieving a contraceptive effect in a female of reproductive age, which composition comprises an effective amount of a progestogene of the type described above and a pharmaceutical diluent.
  • the method for preventing conception without suppression of ovulation provides parenteral, preferably intramuscular or subcutaneous, administration or implantation of a suitable progestogene.
  • the administration of the progestogene preferably should be carried out about one day prior to the start of the above-described periovulatory changes. It is known that the periovulatory changes start about the eighth or ninth day after the beginning of the menstrual bleeding or the menstrual cycle. How ever, there are certain individual differences with respect to the exact time lapse between the start of the menstrual cycle and the start of the periovulatory changesand it is difficult to determine in the individual case the exact time of the periovulatory changes.
  • the administration of the progestogene in accordance with the presentinvention should be carried out between the fifth and eighth day after the start of the menstrual cycle (both days inclusive) in order to achieve with certainty the desired contraceptive effect.
  • a single administration of an effective amount of the progestogene will suffice for one menstrual cycle.
  • the required dosage may be administered between the fifth and eighth day of each menstrual cycle.
  • progestogene By correspondingly increasing the amount of progestogene and particularly utilizing progestogenes having a long-lasting effect, it is also possible with a single administration of the progestogene to effectively prevent conception for two or even more menstrual cycles.
  • Progestogenes which may be used in accordance with the present invention include all progestogenes which, upon parenteral administration or implantation, will not have an ovulation-suppressing effect. Furthermore, the dosage of the progestogene should be so chosen that no suspension effect on gonadotropin secretion, or only an insignificant suspension effect, is caused thereby.
  • progestogenes which in addition to their progestogenic effect do not also cause pituitary hypothalamic inhibition, particularly do not have an ovulation-suppressing effect.
  • progestogenes which give excellent results in accordance with the present invention, the esters of hydroxyprogesterone and of l9-nor-hydroxyprogesterone, particularly the corresponding l7-caproates and l7-oenenthates, may be mentioned.
  • a second group of suitable progestogenes includes thosein which the desired progestogenic effect and the anti-estrogenic effect) is substantially dissociated from the undesirable ovulation-suppressing effect.
  • the dosage must be sufficiently small so that, on the one hand, the change in the composition and condition of the cervical mucus which is achieved thereby is sufficient for achieving a reliable contraceptive effect and, on the other hand, the threshold dosage of the pituitary hypothalamic inhibition will not be exceedecl.
  • progestogenes includes progesterone and its pharmaceutically valuable 3-enol esters and pharmaceutically acceptable l7a-hydroxyprogesterone derivatives.
  • Specific compounds included in this group are the 'l7-esters with pharmaceutically acceptable acids of 6- a-methyll 7a-hydroxyprogesterone, 6-methyl-6- dehydrol 7a-hydroxy-progesterone, 6-chloro-6- dehydro-l 70z-hydroxyprogesterone, 6-fluoro-6- dehydro-l 7a-hydroxyprogesterone, 6-chloro-6- progesterone, and also l7a-ethinyl l8-homo-l9*nor-' testosterone and esters thereof with pharmaceutically acceptable acids.
  • progestogenes which have only relatively small dissociation between the desired progestogenic effect and the undesired ovulationsuppressing effect, such as nor-ethisterone caproate,
  • the last-mentioned, third group of effective progestogenes is less desirable since due to the lesser dissociation between the proges- 1 togenic effect and the ovulation-suppressing effect, the
  • the progestogenes which may be utilized according to the present invention are in the form of esters, it is possible to utilize all physiologically active and pharmaceutically acceptable straight-chain or branched esters, for instance the acetates, valerates, butyrates, caproates, oenanthates, undecylates, etc. "is possible thereby that the ester-forming acid residue may also be substituted in conventional manner, for instance with one or more halogen atoms, hydroxyl, carbonyl, keto or amino groups.
  • a contraceptive effect can be obtained which will last for at least one menstrual cycle, and by suitably increasing the dose and/or utilizing a longlasting progestogene, it is also possibleto achieve a contraceptive effect for longer periods of time, such as for instance for three to four months, or even longer.
  • progestogenes of the secondgroup i.e. progestogenes with substantial dissociation between the progestogenic and ovulation-suppressing. effect, the.
  • effective dosage is generally between aboutl and 250 mg of the progestogene.
  • the progestogene which is administered according to the present invention should be of a type and administered in an amount sufficient to inhibit the periovulatory changes of the cervical mucus and endometrium and possibly also of the tubal motility, which changes facilitate conception and/or nidation; however, by its type or dosage the administered progestogene should be incapable of suppressing hypothalamic/pituitary stimuli which induce ovulation.
  • the observed periovulatory changes of the cervical mucus include increased viscosity, certain crystallization phenomena (fern phenomena) and an increase in the quantity of cervical mucus.
  • biochemical parameters for instance glucose and protein content of the mucus, which indicate the cervical changes.
  • the cervix is enlarged and certain changes of the endometrium occur which favor nidation.
  • the preferred method of administering the progestogene in accordance with the present invention is intramucularly. Implantation, while also possible, is less desirable due to the uncontrollable resorption of the progestogene, and subcutaneous administration is connected with the disadvantage that the effective agent, i.e. the progestogene may be resorbed too quickly.
  • the progestogenes are applied according to the present invention, preferably dissolved in a solvent suitable for parenteral administration.
  • a solvent suitable for parenteral administration Such solvents and the manner in which the injectable solutions of active agents such as progestogenes are made, are well known to those skilled in the art.
  • the progestogene is dissolved in the solvent, filtered under sterile conditions, and filled under aseptic conditions into ampoules of the desired size.
  • Preferred solvents are oily solvents, for instance sesame oil or castor oil.
  • other vegetable oils such as linseed oil, cottonseed oil, sunflower oil and peanut oil, olive oil, wheat germ oil and others are also suitable solvents.
  • diluents or solubilizing agents for instance benzylbenzoate.
  • the vegetable oils which serve as solvents may also be replaced with synthetic solvents, for instance glycol, lactic acid ester, benzyl alcohol and the like.
  • synthetic solvents for instance glycol, lactic acid ester, benzyl alcohol and the like.
  • EXAMPLE I Five g l9'nor-l7a-hydroxyprogesterone caproate are dissolved in sesame oil. The solution is made up with sesame oil to a volume of about 1000 ml, filtered under sterile conditions and filled in conventional manner under aseptic conditions into 1 ml ampoules. Thereafter, sterilization is completed for 2 hours at l20C.
  • EXAMPLE lII One-hundred fifty g l7a-hydroxyprogesterone caproate is dissolved in a mixture of 6 parts by weight castor oil and 4 parts by weight benzylbenzoate so as to obtain a total volume of 1000 ml. After filtration under sterile conditions, the solution is filled under aseptic conditions, in conventional manner, into 1 ml or 2 ml ampoules which, after closing, are then further sterilized for 2 hours at 120C.
  • a single injection for at least one menstrual cycle method of preventing conception by inhibiting the periovulatory changes of the cervical mucus and endometrium required for conception and nidation without suppressing ovulation the improvement which consists of parenterally administering a single injection for at least one menstrual cycle to a female of reproductive age on the fifth to eighth day of the menstrual cycle, of either (a) from about 1 to 20 mg of l9-nor-l7ahydroxyprogesterone caproate, or (b) from about 5 to mg. of l7a-hydroxyprogesterone caproate, said progesterone when administered in such amount in said method being effective to prevent conception without effecting ovulation.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
US00135814A 1967-04-19 1971-04-20 Contraceptive method and composition Expired - Lifetime US3758687A (en)

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DESC040583 1967-04-19

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US3758687A true US3758687A (en) 1973-09-11

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US (1) US3758687A (enrdf_load_stackoverflow)
BE (1) BE713958A (enrdf_load_stackoverflow)
DE (1) DE1617839A1 (enrdf_load_stackoverflow)
FR (1) FR8061M (enrdf_load_stackoverflow)
GB (2) GB1231412A (enrdf_load_stackoverflow)
NL (1) NL6805612A (enrdf_load_stackoverflow)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4018919A (en) * 1975-07-16 1977-04-19 Eli Lilly And Company Sequential contraceptive method using two types of progestational agents
US4171358A (en) * 1974-04-19 1979-10-16 Eli Lilly And Company Novel contraceptive method
US5108995A (en) * 1987-09-24 1992-04-28 Jencap Research Ltd. Hormone preparation and method
US5433219A (en) * 1992-09-23 1995-07-18 Spery; Nanette S. Receptive condom assembly
US20040254240A1 (en) * 1999-09-17 2004-12-16 Antonio Ferrante Anti-cancer nitro- and thia-fatty acids
US9844558B1 (en) 2015-04-30 2017-12-19 Amag Pharmaceuticals, Inc. Methods of reducing risk of preterm birth
US10556922B2 (en) 2015-09-29 2020-02-11 Amag Pharmaceuticals, Inc. Crystalline and amorphous forms of 17-alpha-hydroxyprogesterone caproate

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4171358A (en) * 1974-04-19 1979-10-16 Eli Lilly And Company Novel contraceptive method
US4018919A (en) * 1975-07-16 1977-04-19 Eli Lilly And Company Sequential contraceptive method using two types of progestational agents
US5108995A (en) * 1987-09-24 1992-04-28 Jencap Research Ltd. Hormone preparation and method
US5433219A (en) * 1992-09-23 1995-07-18 Spery; Nanette S. Receptive condom assembly
US20040254240A1 (en) * 1999-09-17 2004-12-16 Antonio Ferrante Anti-cancer nitro- and thia-fatty acids
US9844558B1 (en) 2015-04-30 2017-12-19 Amag Pharmaceuticals, Inc. Methods of reducing risk of preterm birth
US10471075B1 (en) 2015-04-30 2019-11-12 Amag Pharmaceuticals, Inc. Methods of reducing risk of preterm birth
US11154562B2 (en) 2015-04-30 2021-10-26 Covis Pharma Gmbh Methods of reducing risk of preterm birth
US11304962B2 (en) 2015-04-30 2022-04-19 Covis Pharma Gmbh Methods of reducing risk of preterm birth
US11730744B2 (en) 2015-04-30 2023-08-22 Covis Pharma Gmbh Methods of reducing risk of preterm birth
US10556922B2 (en) 2015-09-29 2020-02-11 Amag Pharmaceuticals, Inc. Crystalline and amorphous forms of 17-alpha-hydroxyprogesterone caproate

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Publication number Publication date
FR8061M (enrdf_load_stackoverflow) 1970-07-06
BE713958A (enrdf_load_stackoverflow) 1968-10-21
NL6805612A (enrdf_load_stackoverflow) 1968-10-21
GB1231412A (enrdf_load_stackoverflow) 1971-05-12
GB1253500A (en) 1971-11-17
DE1617839A1 (de) 1971-04-08

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