EP0378533A1 - PROCEDE ET KIT CONTRACEPTION AVEC UN ANTAGONISTE DE GnRH ET DE LA PROGESTINE - Google Patents

PROCEDE ET KIT CONTRACEPTION AVEC UN ANTAGONISTE DE GnRH ET DE LA PROGESTINE

Info

Publication number
EP0378533A1
EP0378533A1 EP88904009A EP88904009A EP0378533A1 EP 0378533 A1 EP0378533 A1 EP 0378533A1 EP 88904009 A EP88904009 A EP 88904009A EP 88904009 A EP88904009 A EP 88904009A EP 0378533 A1 EP0378533 A1 EP 0378533A1
Authority
EP
European Patent Office
Prior art keywords
gnrh
antagonist
progestin
administered
day
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP88904009A
Other languages
German (de)
English (en)
Other versions
EP0378533A4 (en
Inventor
Gary D. Hodgen
Daniel Kenigsberg
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eastern Virginia Medical Authority
Original Assignee
Eastern Virginia Medical Authority
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eastern Virginia Medical Authority filed Critical Eastern Virginia Medical Authority
Publication of EP0378533A1 publication Critical patent/EP0378533A1/fr
Publication of EP0378533A4 publication Critical patent/EP0378533A4/en
Ceased legal-status Critical Current

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Classifications

    • 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

Definitions

  • This invention relates to a method and kit for achieving contraception in gonadal ' female mammals with GnR antagonists without inducing an agonadal state.
  • GnRH antagonists lack stimulatory activity, causing prompt reduction of gonadotropin secreti and an agonadal state.
  • Kenigsberg, D. et al. Dose-respon using a gonadotropin-releasing hormone antagonist. Fertil
  • reproductive endocrinologists have sought an adequate strategy to employ GnRH analogs (agnonists and antagonists) for contraception in women.
  • GnRH antagonists for reliable ovulation inhibition, while avoiding frank estrogen deficiency and relying on natural ovarian steroids to maintain normal metabolic homeostasis.
  • Another object is to provide such a method which does not interfere with menses, and which regulates the onset thereof.
  • Another object is to provide such a method in which the medication is self-administered.
  • a further object is to provide such a method which do not have the side effects associated with estrogen-progest oral contraception.
  • Another object is to provide kits for practicing the 5 method of this invention. other objects will be apparent to those skilled in th art to which this invention pertains.
  • this invention relates to a metho of contraception in and regulation of the menstrual cycle a gonadal female mammal, which comprises a) administering thereto periodically at predetermined intervals longer than daily throughout her
  • this invention comprises a kit in th form of a dispenser-type package containing (a) sufficient
  • the intermittent administration of the GnRH-antagonist achieves fertility control in gonadal female mammals, e.g., husbandry animals and humans, by acutely suppressing the release of endogenous luteinizing hormone and follicle stimulating hormone from the pituitary gland, thereby preventing maturation of the dominant follicle and release of oocytes.
  • the intermittent adminstration of the GnRH-antagonist does not impair adequate ovarian estadiol secretion.
  • the term "folliculogenesis” is used herein to ref r to the gametogenic activity and "hormonogenesis” refers to the secretory activity. It is known that hypoestrogenic states can cause hot flashes, increase the risk of osteoporosis, and precipitate urogenital atrophy in women.
  • the intermittent use of the GnRH antagonist for fertility control according to this invention obviates these symptoms by maintaining a near normal fpllicular phase level of serum estradiol by distinguishing blockage of hormonogenesis (which is sustained) from gametogenesis (which is inhibited) .
  • progesterone is produced from the corpus luteum created after ovulation. Since ovulation is prevented, progesterone secretion remains low.
  • An oral progestin supplement converts proliferative endometrium to the secretory phase, thereby reducing the risks of endometrial carcinomas associated with unopposed estrogen action.
  • progestins which can be employed in this invention are micronized progesterone (50-150 mg/day) , norethindrone (0.5-2.5 mg/day), norethynodrel (1 mg/day); ethynodiol diacetate (1-2 mg/day), norgestrel (0.2-0.5 mg) and levo-norgestrel (0.1-0.3 mg/day).
  • the progestin can be administered in the conventional manner by any route that the selected progestin is active. Most synthetic progestins are orally active and therefore are preferably administered by that route, e.g., in the for of a tablet, dragee, capsule or pill. If the progestational agent of this invention is to be administered in tablet or dragee form, it may contain a pharmaceutically-acceptable diluent which includes a binder, such as tragacanth, corn starch or gelatin; a disintegrating agent, such as alginic acid; and a lubricant, such as magnesium stearate.
  • a binder such as tragacanth, corn starch or gelatin
  • a disintegrating agent such as alginic acid
  • a lubricant such as magnesium stearate.
  • sweetening and/or flavoring may be used as part of the pharmaceutically- acceptable diluent, and intravenous administration in isotonic saline, phosphate buffer solutions or the like may be effected.
  • the progestin can also be administered intranasally, as a suspension or dispersion in an appropriate vehicle, by inhalation as an aerosol discharged from a conventional inhalator, sublingually, in the form of a lozenge, rectally or intravaginally, e.g., in the form of a suppository, alone or in admixture with the GnRH antagonist, when appropriate according to the day of the menstrual cycle.
  • an implant which discharges the progestin, for about 7-15 days, about 14-16 days after implant, (e.g., at the onset of menses); intradermally, as a skin patch containing a mixture of the progestin and a skin penetrant, e.g. , DMSO; and imbedded in a vaginal ring which discharges the progestin for about 14- 16 days after insertion.
  • a skin patch containing a mixture of the progestin and a skin penetrant, e.g. , DMSO
  • DMSO skin penetrant
  • GnRH antagonist which can be employed in this invention is (Ac-p-Cl-Ph ⁇ p-Cl-Phe 2 ,D-Trp 3 ,D-Arg 6 ,D- Ala 10 )NET-GnRH.
  • Others are known in the prior art. See, e.g., 4,409,208; 4,547,370; 4,565,804; 4,569,927; and the 619,914, whose disclosures are incorporated herein by reference.
  • Such other antagonists include: D2Nal-DPhe-D3Pal-Ser-Arg-d2nAL-Leu-Arg-Pro-DAla-NH 2 Ac 4C1
  • a gametogenesis blocked state is usually achieved withinabout 1 day thereafter, provided the first dose of the GnRH- antagonist is administered on day 1, 2 or 3 of menses.
  • a longer delay may not abate selection of the oncoming dominant-follicle during that menstrual cycle and therefore another form of contraception should be practiced during that cycle, or at least for the first ⁇ days thereof.
  • the GnRH-antagonists employed in this invention can be administered in the form of pharmaceutically acceptable, nontoxic salts, such as acid addition salts, or of metal complexes, e.g., with zinc, barium, calcium, magnesium, aluminum or the like, or of combinations thereof.
  • acid addition salts are hyd ochloride, hydrobromide, sulphate, phosphate, nitrate, oxalate, fumarate, gluconate, tannate, aleate, acetate, citrate, benzoate, succinate, alginate, alate, ascorbate, tartrate and the like.
  • compositions employed in the process of this invention will usually contain the GnRH-antagonist in conjunction with a conventional, pharmaceutically acceptable carrier.
  • the effective dosage of the GnRH-antagonist is from about 1 to about 100 micrograms of the GnRH-antagonist per kilogram of the body weight of the host when given intravenously; therefore, oral dosages and dosages by other routes will be higher..
  • SUBSTITUTE SHEET of subjects with these GnRH-antagonists is generally carri out in the same manner as other clinical treatments using GnRH antagonists, except for the total amount thereof whic is administered.
  • the GnRH-antagonists can be administered to the mamma intravenously, subcutaneously, intramuscularly, sublingually, orally by inhalation, percutaneously, rectally, intranasally or intravaginally, to achieve contraception. Effective dosages will vary with the selected mode of administration and the particular species of mammal being treated.
  • An example of one typical dosage form is a bacteriostatic water solution containing the GnR antagonist which solution is administered as a nasal mist provide a dose in the range of about 0.1 to 2.5 mg/kg of body weight.
  • Oral administration of the GnRH-antagonist m be in the form of a lozenge, to be dissolved under the tongue, or as an aerosol, to be inhaled.
  • one or two of the doses of GnRH-antagonist can be administered in admixture with doses of the progesti on appropriate days of the cycle, e.g., day 16 and day 23.
  • this invention relates to materials, reagents and kits for practicing the method of this invention.
  • this invention is directed to a two-stage multiple dosage unit article of manufacture comprising a) four dosage units, adapted for self-administration, . each dosage unit containing an amount of a GnRH-antagonist effective when one unit thereof is administered every seven days, the first on day 1, 2 or 3 o mensus, to block follicultogenesis for one cycle but which is less than the an thereof effective to block hormonogenesis; and b) 5-7 units, adapted for self- administration, collectively containing an amount of a progestin effective, when a dosage unit is administered daily on successive days, beginning on day 14, 15 or 16 of the cycle until all of the units have been administered, to produce a secretory endometrium and thereafter induce menses.
  • the kit also comprises a plurality of placebo dosage units corresponding to those of a) which collectively therewith total about 23 to about 28 units, th GnRH-antagonist-containing, the progestin-containing and th placebo units being arranged in appropriate sequential order.
  • the third and fourth GnRH- antagonist-containing dosage units are contained in same dosage units which contain the progestin.
  • the GnRH-antagonist units are adapted for sub-lingual, rectal, vaginal or topical (on the skin) application.
  • the progestin units are adapted for oral ingestion e.g., tablets, capsules or dragees, or for administration b the same route : as the GnRH antagonist units.
  • the GnRH-antagonist units, the progestin dosage - units and any placebo dosage units all are adapted for administration by the same route.
  • this invention is directed to a combination of (a) a nasal spray plastic squeeze bottle containing a GnRH-antagonist in a vehicle adapted for administration thereof as a mist, at a concentration effective upon squeezing the bottle either once, twice or three times while the dispensing tip is inserted into a nostril of the female mammal, once every seven days, an amount of the antagonist effective to block folliculogenesis but less than the amount required to block hormonogenesis; and either 5-11 individual dosage units, preferably adapted for oral ingestion, e.g.
  • tablets or capsules collectively containing an amount of a progestin effective upon administration thereof during the third week of the menstrual cycle to produce a secretory endometrium and to thereafter induce menses, or 23 or 28 such individua dosage units arranged in appropriate sequential order, 5 to 11 of which units contain the ⁇ progestin and the remainder are placebos, to be taken daily for the first 23 days of a menstrual cycle or every day of a 28 day menstrual cycle.
  • a plurality of skin patches or an aerosol inhaler is employed to dispense the required amount of GnR antagonist.
  • both the GnRH and progesti are in a unit dosage form adapted.for vaginal or rectal administration, e.g., suppositories.
  • a kit comprises 4 suppositories containing the GnRH-antagoni and either 5-8 separately identified suppositories containing the progestin for administration on successive days of the third week of one menstrual cycle, or the kit comprises 23 to 28 such suppositories, arranged for sequential administration, every 7th one of which contains the GnRH-antagonist; the 16th through the 22nd of which contain the progestin; and the remainder are placebos.
  • the test kit contains the GnRH-antagonist incorporated in another delivery system, e.g., adhesive skin patches containing the medication in a intradermal and delivery system for application to the ski suppositories for administration of the medication rectall or vaginally; an inhaler for delivery of the medication as an aerosol, or lozenges for administration sublingually; i each case once or twice daily on the same or on two successive days of each weak.
  • the materials, reagents and kits optionally and preferably also contains instructions for administering th GnRH-antagonist and the progestin.
  • a specific example of materials, reagents and kits of this invention intended for use by a gonadal female who is to be rendered infertile but not agonadal is a box with li containing (a) a conventional nasal mist squeeze bottle containing a GnRH-antagonist, in an inert, physiologically acceptable carrier in which the antagonist is stable, at a concentration effective to deliver into the nostril, when.
  • the bottle is squeezed twice while the dispensing tip thereof is inserted into the nostril, an amount of the GnR antagonist effective to place the female in a folliculogenesis blocked state for 7 days, and containing a amount thereof sufficient for four such administrations on weekly basis throughout one menstrual cycle, and (b) seven to 11 tablets of an orally active progestin effective when taken orally on successive days, e.g., beginning on day 15 of the menstrual cycle, to produce a secretory endometrium and thereafter to induce menses. If eleven tablets are employed, about a 30 day cycle will usually be achieved whereas a lesser number will produce a correspondingly shorter cycle.
  • Intermittent GnRH-antagonist therapy alone blocks folliculogenesis while sustaining hormonogenesis.
  • the maintenance of hormonogenesis provides circulating estrogen levels sufficient to preclude hypoestrogenic effects.
  • the blockage of folliculogenesis prevents the selection and maturation of a functional dominant follicle. Consequently, anovulation ensues concurrently with subnormal levels of luteal phase serum progesterone.
  • metabolic homeostasis is not maintained by intermittent GnRH-antagonist therapy alone, i is maintained by the combination of intermittent GnRH- antagonist and a progestin, which combination inhibits ovulation while assuring that proliferative endometrium wil be shed during menses.
  • the combination therapy 1) synergistically enhances the contraceptive action of each, 2) reliably inhibits ovulation, and 3) provides for cyclic menstruation.
  • progestin as well as
  • GnRH-antagonist administration it will be apparent that because contraception may be achieved primarily although no exclusively by the GnRH-antagonist, if a normal menstrual cycle is not mandated, for example, where the GnRH- antagonist is to be administered only on a short term basis e.g., when only temporary contraception is desired for medical reasons, the progestin can be omitted, in which ca a normal menstrual cycle will not occur until GnRH- antagonist administration is terminated.
  • the GnRH-antagonist and the progestin not only collectivel mimic a normal menstrual cycle, they act synergistically i achieving contraception, they are preferably employed together in accordance with this invention to ensure an unplanned pregnancy does not occur and to avoid the potential adverse effects of a retained endometrium.
  • the following preferred specific embodiments are, therefore, t be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. In the following examples, all temperatures are set forth uncorrected in degrees celsius; unless otherwise indicated, all parts and percentages are by weight.
  • GnRH as a 50-ug bolus dose given on cycle day 6
  • GnRH-antagonist regimen elicited unambiguous LH responses (four of four monkeys) of seemingly normal strength and duration. All responses exceeded 4-fold elevations and did not differ significantly from the responses of control monkeys given the same iv bolus dose of GnRH.
  • a kit is prepared which contains four unit doses adapted for self-administration of the GnRH-antagonist (Ac p-ClPhe 1 ,pClDphe 2 ,DTrp 3 ,DArg 6 , DAla 10 ) -NET.GnRH; 11 conventional tablets adapted for oral ingestion, each containing 0.1-0.5 mg.
  • the progestin norgestrel a 4- week chart on which the first day of menses can be oriented with the day of the week on which it occurs as day 1 of the 4 week chart and administration instructions.
  • Days 2, 9, 16, and 23 on the chart (which are aligned with the same day of the week) bear indica informing the female to self- administer, in the manner and by the route indicated in the instructions, a unit dosage of the GnRH-antagonist on those days.
  • Days 15 through 25, inclusive bear indica informing the female to ingest one of the progestin ' tablets on each of those days.
  • the instructions inform the female to obtain a second kit for the next menstrual cycle.
  • the GnRH-antagonist is in admixture with a dry diluent, e.g., dextrose, in the form of a dry micronized powder which is dispensed from a conventional pressurized (under C0 2 ) container which is springload mounted in a conventional inhalator which dispenses about 10 mg of the GnRH-antagonist when the container is depressed into the inhalator.
  • a dry diluent e.g., dextrose
  • the instructions instruct the female to activate the inhalator twice while inhaling, on the same day of each week as indicated by the chart.
  • the inhalator dispenses about 75 mg of the GnRH-antagonist each time the container is squeezed.
  • the GnRH-antagonist is present in four conventional foil wrapped anhydrous suppositories, each containing 150 mg. thereof, and the instructions instruct the female to insert one of the suppositories into the rectum on each day of the week indicated on the chart.
  • the GnRH-antagonist is present in four conventional dry, foil wrapped saliva dissolvable lozenges, each containing 150 mg thereof, and the instructions instruct the female to dissolve a lozenge under the tongue on the same day of each week as indicated by the chart.
  • the norgestrel in the tablets is replaced by 1 mg of norethindrone, 5 mg of norethynodrel, 1 mg of ethynodiol diacetate or 0.2 mg of levonorgestrel.
  • the GnRH-antagonist therein is replaced by a GnRH-antagonist of U.S. 4,409,208; 4,444,759; 4,547,370; 4,565,804; 4,569,927; or 4,619,914.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Reproductive Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Procédé de contraception et de régulation du cycle menstruel d'un mammifaire femelle gonadal qui consiste a) à lui administrer environ une fois par semaine au cours de son cycle menstruel un antagoniste effectif de GnRH (hormone libérant de la gonadotrophine) pour bloquer la folliculogenèse, mais dans une moins grande quantité que celle nécessaire pour bloquer l'hormonogenèse; à lui administrer également avant la fin de ce cycle une quantité de progestine adéquate pour produire un endromètre sécrétoire; et b) ensuite à terminer l'administration de progestine, provoquant ainsi des règles.
EP19880904009 1987-03-10 1988-03-09 Method and kit for contraception with gnrh-antagonist and progestin Ceased EP0378533A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US2420587A 1987-03-10 1987-03-10
US24205 1987-03-10

Publications (2)

Publication Number Publication Date
EP0378533A1 true EP0378533A1 (fr) 1990-07-25
EP0378533A4 EP0378533A4 (en) 1990-12-05

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP19880904009 Ceased EP0378533A4 (en) 1987-03-10 1988-03-09 Method and kit for contraception with gnrh-antagonist and progestin

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EP (1) EP0378533A4 (fr)
WO (1) WO1988007056A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9282995B2 (en) * 2011-12-22 2016-03-15 Previvo Genetics, Llc Recovery and processing of human embryos formed in vivo
US20150272622A1 (en) 2011-12-22 2015-10-01 Previvo Genetics, Llc Recovery and processing of human embryos formed in vivo
US9216037B2 (en) 2013-06-21 2015-12-22 Previvo Genetics, Llc Uterine lavage for embryo retrieval

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3836651A (en) * 1972-02-22 1974-09-17 Biolog Concepts Inc Novel oral contraceptive combination
US4143136A (en) * 1976-11-20 1979-03-06 Akzona Incorporated Method of contraception
US4292315A (en) * 1977-12-30 1981-09-29 Nichols Vorys Follicular phase estrogen or progestin with physiologic estrogen/progestin luteal phase replacement drug delivery system
US4409208A (en) * 1980-04-15 1983-10-11 The Salk Institute For Biological Studies GnRH antagonists
US4481190A (en) * 1982-12-21 1984-11-06 Syntex (U.S.A.) Inc. Nonapeptide and decapeptide analogs of LHRH useful as LHRH antagonists
US4547370A (en) * 1983-11-29 1985-10-15 The Salk Institute For Biological Studies GnRH Antagonists
US4569927A (en) * 1984-02-23 1986-02-11 The Salk Institute For Biological Studies GnRH Antagonists IV

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 103, 1985, page 62, abstract no. 48340h, Columbus, Ohio, US; A. LEMAY et al.: "Inhibition of ovulation during discontinuous intranasal luteinizing hormone-releasing hormone agonist dosing in combination with gestagen-induced bleeding", & FERTIL. STERIL. 1985, 43(6), 868-77 *
CHEMICAL ABSTRACTS, vol. 106, 1987, page 96, abstract no. 13100q, Columbus, ohio, US; A. LEMAY et al.: "Fourteen-day versus twenty-one-day regimens of intermittent intranasal luteinizing hormone-releasing hormone agonist combined with an oral progestogen as antiovulatory contraceptive approach", & J. CLIN. ENDOCRINOL. METAB. 1986, 63(6), 1379-85 *
See also references of WO8807056A1 *

Also Published As

Publication number Publication date
EP0378533A4 (en) 1990-12-05
WO1988007056A1 (fr) 1988-09-22

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