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WO1995008329A1 - Procedes de reduction du ldl cholesterol post-menopausique - Google Patents

Procedes de reduction du ldl cholesterol post-menopausique Download PDF

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Publication number
WO1995008329A1
WO1995008329A1 PCT/US1994/010846 US9410846W WO9508329A1 WO 1995008329 A1 WO1995008329 A1 WO 1995008329A1 US 9410846 W US9410846 W US 9410846W WO 9508329 A1 WO9508329 A1 WO 9508329A1
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WO
WIPO (PCT)
Prior art keywords
estrogen
progestin
days
dosage
administration
Prior art date
Application number
PCT/US1994/010846
Other languages
English (en)
Inventor
George W. Creasy
William Olson
Frank Sacks
Original Assignee
Ortho Pharmaceutical Corporation
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 Ortho Pharmaceutical Corporation filed Critical Ortho Pharmaceutical Corporation
Priority to AU78430/94A priority Critical patent/AU7843094A/en
Publication of WO1995008329A1 publication Critical patent/WO1995008329A1/fr

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Classifications

    • 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

Definitions

  • the present invention is directed to methods for the reduction of LDL cholesterol in postmenopausal women. Particularly, methods for reducing LDL cholesterol in postmenopausal women are accomplished by administering a specific regimen of an estrogen composition and a combination of an estrogen and progestin composition during a twenty-eight day cycle.
  • the invention also concerns a hormone replacement therapy kit having LDL reducing benefits comprising conjunctive doses of an estrogen composition alone and a combination of estrogen and progestin composition for a specific regimen in a twenty-eight day cycle.
  • Coronary heart disease (CHD) mortality in women is the most common cause of death in the postmenopausal age group. Women differ from men in their risk of CHD in the premenopausal age group but have a risk similar to men in postmenopause.
  • An important observation to help explain this change in risk is the increase in LDL cholesterol that women experience during postmenopause. This observation is important because LDL cholesterol has been positively correlated with CHD risk. If LDL cholesterol is a factor in the occurrence of CHD, then one clear approach to reduce such risk would be to lower the serum levels of LDL cholesterol. Studies done worldwide have strongly suggested a positive correlation between the reduction of LDL cholesterol and CHD. Such medical intervention has led to the introduction of products such as lovastatin which is specifically indicated for the reduction of LDL cholesterol.
  • the present invention provides a method for reducing LDL cholesterol in postmenopausal women comprising the steps of administering a specific regimen of an estrogen composition alone for 10 to 20 days of a 28 day cycle and administering a combination estrogen and progestin composition for 8 to 16 days of remaining days of said 28 day cycle.
  • the estrogen composition and the combination estrogen and progestin composition are provided in 10 to 20 and 8 to 16 continuous days, respectively of a 28 day cycle.
  • no estrogen or estrogen and progestin compositions are administered for about 1 to 7 days or a placebo is administered for about 1 to 7 days to fulfill the 28 day cycle.
  • the estrogen composition comprises substantially natural human estrogen which metabolizes to estradiol and estrone sulfate, particularly preferred is the estrogen estropipate.
  • the progestin is selected from the group consisting of 19-nortestosterones, particularly norethindrone.
  • the dosage of progestin is from about 0.5 to 1.5 mg per day in an 8 to 16 day administration regimen. More preferably, the dosage of progestin is about 1 mg per day for 10 days of administration.
  • the present invention provides a hormone replacement therapy (HRT) regimen having LDL cholesterol reducing benefit comprising 28 daily doses (e.g. dosage units) of an estrogen composition alone for 10 to 20 days of a 28 day cycle and a combination of an estrogen and progestin composition for 8 to 16 days of the remaining days of said 28 day cycle.
  • HRT hormone replacement therapy
  • the progestin and estrogen compositions and dosages are as described above in the preferred method of the invention for reducing LDL cholesterol.
  • Figure 1 is a plot of the differences between changes in LDL cholesterol effects by selected estrogen/progestin (i.e. estropipate/norethindrone) regimens of the invention as compared to a control estrogen alone (i.e. estropipate) regimen.
  • the differences in the changes in the LDL cholesterol in postmenopausal women between the comparative regimens is plotted against a base line of zero from the results obtained from the estrogen control.
  • the data points are provided for measurements taken at the completion of each of 28 day cycles 3, 6 and 12.
  • a 12-month study of more than 532 patients involving estropipate and norethindrone administration revealed an unexpected synergistic effect between norethindrone and estropipate such that the combination results in a statistically significant further reduction in LDL cholesterol over estropipate (estrone sulfate) administration alone.
  • estropipate with norethindrone
  • the present invention thus steps beyond the prior art and provides an augmented reduction of LDL cholesterol in postmenopausal women by treatment with an estrogen, e.g. estropipate, and a progestin, e.g. norethindrone, in specific treatment regimens.
  • the present invention provides a method for reducing LDL cholesterol in postmenopausal women comprising the steps of administering a specific regimen of an estrogen composition alone for 10-20 days of a 28 day cycle and a combination estrogen and progestin composition for 8-16 days of remaining days of such 28 day cycle.
  • the present invention is thus directed to a specific regimen whereby an estrogen is given for a portion of a woman's 28 day cycle and a combination of an estrogen and a progestin are given for the remaining days of the cycle such as, for example, an estrogen composition may be given alone for 16 days in a cycle and an estrogen and progestin composition would then be given for 12 days or the remainder of the days of the 28 day cycle.
  • no estrogen or estrogen and progestin compositions are administered for 1 to 7 days or a placebo is administered for 1 to 7 days to fulfill the 28 day cycle.
  • Particularly preferred estrogen compositions in accordance with the invention are those which comprise substantially natural human estrogens which metabolize to estradiol and estrone sulfate, particularly preferred is estropipate.
  • Estropipate is a piperazine salt which provides a stable source of estrone sulfate.
  • the progestin compounds in accordance with the invention are preferably selected from the group consisting of 19-nortestosterones; particularly preferred is norethindrone.
  • the dosing of these compositions may vary with the days of administration identified above and may be guided by a sliding scale whereby the frequency of the progestin administered is inversely proportional to the amount of progestin administered per dose.
  • progestin for a period of 8-16 days of the 28 day cycle when the dosage is in an amount of from 0.5-1.5 mg per day. It is also, however, preferred to provide progestin for a reduced number of days such as 8-12 days if the amount of progestin administered per dose is raised to 1.0-1.5 mg per day. More preferably the dosage of progestin is provided from 0.5-1.0 mg per day for 10-16 days of administration out of the 28 day cycle. Most preferably, the dosage of progestin is about 1 mg per day for 10 days of administration of the 28 day cycle.
  • the dosage of estrogen may remain constant through the cycle at a dosage of about 0.5 to 3.0 mg and preferably 0.75 to 1.5 mg daily throughout the 28 day cycle or may be varied in accordance with the particular needs of the patient being treated.
  • the estrogen and estrogen and progestin combination compositions are given in continuous regimens throughout the cycle on a daily basis. Such a daily continuous regimen has been found to be efficacious and is believed to aid in patient compliance whereby a patient gets into a daily routine of taking the prescribed medication without any distracting starting and stopping periods.
  • the above described dosages are generally preferred in accordance with the invention but may be varied depending upon the results of specific clinical testing, requirements of the patient, the weight and age of the patient, severity of the condition being treated in light of the patients response to the drug and the particular compound or hormone combination composition being employed. The determination of optimum dosages for a particular situation is within the skill of the medical arts.
  • the invention also comprises a hormone replacement therapy regimen having LDL reducing benefit comprising 28 daily doses comprising an estrogen composition alone for 10-28 days of a 28 day cycle and a combination of estrogen and progestin composition for 8-16 days of the remaining days of said 28 day cycle.
  • a hormone replacement therapy regimen having LDL reducing benefit comprising 28 daily doses comprising an estrogen composition alone for 10-28 days of a 28 day cycle and a combination of estrogen and progestin composition for 8-16 days of the remaining days of said 28 day cycle.
  • the dosage ranges of the compositions used as well as the particular compositions used are as described above for the methods of the invention.
  • the estrogen and progestin compositions can be administered by way of any art recognized means as practiced in the pharmaceutical arts.
  • the estrogen and progestin alone or in combination may be so formulated so that it can be administered orally, via a skin patch for transdermal absorption, contained within an inert matrix which is implanted within the body and in the depot state or intravaginally in a matrix that slowly releases the active compositions (such implants are taught for example in U.S. Patent Nos. 4,957,119 and 5,088,505).
  • compositions containing compounds of the invention may further comprise pharmaceutically acceptable carriers and be in either solid or liquid form.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, etc.
  • the carrier may also be one or more substances which act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents as well as encapsulating materials.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, peptin, dextrin, starch, methyl cellulose, sodium carboxyl methyl cellulose, and the like.
  • Liquid form preparations include solutions which are suitable for oral or parenteral administration, or suspensions and emulsions suitable for oral administration.
  • Aqueous solutions for oral administration can be prepared by dissolving the active compound in water and adding suitable flavorants, coloring agents, stabilizers and thickening agents as required.
  • Aqueous suspensions for oral use can be made by dispersing the active component in water together with a viscous material such as a natural or synthetic gum, methyl cellulose, sodium carboxy methyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • solid dosage forms include topical dosage forms which include solutions, powders, fluid emulsions, fluid suspensions, semi-solids, ointments, pastes, creams, gels or jellies and foams; and parenteral dosage forms which include solutions, suspensions,_ emulsions or dry powder comprising an effective amount of estrogen and progestin as taught in this invention.
  • topical dosage forms which include solutions, powders, fluid emulsions, fluid suspensions, semi-solids, ointments, pastes, creams, gels or jellies and foams
  • parenteral dosage forms which include solutions, suspensions,_ emulsions or dry powder comprising an effective amount of estrogen and progestin as taught in this invention.
  • Various conventional techniques for preparing pharmaceutical compositions including solutions, suspensions, tablets or caplets can be employed, as would be known to those skilled in the art and as is disclosed for example by Remington's Pharmaceutical Sciences, Mack Publishing Co., Part 8, Chapters 76-93 , Pharmaceutical Preparations and
  • the pharmaceutical formulations may be provided in kit form containing preferably about 28 tablets, intended for ingestion on successive days of an administration cycle. Where administration of the progestin is intended to be periodic, a plurality of pills may be provided whereby a portion contains estrogen only and the remaining tablets additionally contain progestin. Where administration is intended to be daily, generally at least about 8 of the 28 tablets contain a combination of estrogen and progestin.
  • unit dosage form refers to physically discrete units suitable as unit dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • doses as used herein broadly encompasses the term unit dosage form or dosage units as well as continuous dosing of compositions by depot or other methods.
  • the dosages may be varied depending upon the results of specific clinical testing, the requirements of the patient, the weight and age of the patient, the severity of the condition being treated, and the compound being employed. Determination of optimum dosages for a particular situation is within the skill of the art.
  • This study was a controlled, double-blind, randomized, multi-center Phase II study.
  • Six test estrogen replacement regimens were studied for efficacy and safety. Each investigator tested all six regimens.
  • the objective of this study was to evaluate the efficacy and safety of continuous versus interrupted regimens of estropipate combined with norethindrone (NET) , compared to estropipate alone, when administered for the treatment of estrogen deficiency.
  • NET norethindrone
  • Test medication were supplied as follows:
  • Figure 1 shows the differences between each norethindrone regimen and its respective estropipate-alone control regimen in the change from baseline for LDL cholesterol.
  • the differences have been plotted for each regimen comparison at cycle 3, cycle 6 and cycle 12.
  • Regimen #1, 2, 4 and 5 the decrease in LDL cholesterol from baseline to cycle 3, 6, or 12 was greater than in the estropipate-alone control regimen.
  • combination hormone replacement therapy i.e., estrogen with a progestin
  • the use of the specific combination norethindrone regimens described herein should not only provide the expected endometrial benefit, but would also provide the unexpected additional benefit of a greater reduction in LDL cholesterol over that obtained with administration of estrogen alone.
  • compositions, protocols and methods of the present invention can be accomplished by any pharmaceutical and medical methods and techniques as are presently or prospectively known to those skilled in the art. It is intended that the invention cover any modifications and variations of this invention provided that they come within the scope of the appended claims and their equivalents.

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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)

Abstract

L'invention concerne des procédés de réduction du LDL cholestérol chez des femmes post-ménopausiques consistant à administrer un schéma spécifique d'une composition d'÷strogènes et une composition d'un ÷strogène et de progestines combinés pendant un cycle de 21 jours. L'invention concerne également un schéma thérapeutique de remplacement d'hormones présentant des caractéristiques du LDL comprenant des doses conjointes d'une composition d'÷estrogènes seule et d'une composition d'÷strogènes et de progestine combinés pour un schéma spécifique en un cycle de 21 jours.
PCT/US1994/010846 1993-09-23 1994-09-21 Procedes de reduction du ldl cholesterol post-menopausique WO1995008329A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU78430/94A AU7843094A (en) 1993-09-23 1994-09-21 Methods for the reduction of postmenopausal ldl cholesterol

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US12587493A 1993-09-23 1993-09-23
US125,874 1993-09-23

Publications (1)

Publication Number Publication Date
WO1995008329A1 true WO1995008329A1 (fr) 1995-03-30

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Application Number Title Priority Date Filing Date
PCT/US1994/010846 WO1995008329A1 (fr) 1993-09-23 1994-09-21 Procedes de reduction du ldl cholesterol post-menopausique

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AU (1) AU7843094A (fr)
WO (1) WO1995008329A1 (fr)
ZA (1) ZA947406B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996032114A1 (fr) * 1995-04-08 1996-10-17 Schering Aktiengesellschaft Preparation pharmaceutique combinee de contraception hormonale
WO2000041699A1 (fr) * 1999-01-18 2000-07-20 Novo Nordisk A/S Utilisation d'oestrogenes et de delta-gonadiene-21-ol-3,20-diones

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHRISTIANSEN C ET AL: "Low-risk lipoprotein pattern in post-menopausal women on sequential oestrogen/progestogen treatment.", MATURITAS (NETHERLANDS), MAR 1984, VOL. 5, NO. 3, PAGE(S) 193-9, *
SHERWIN BB ET AL: "A prospective one-year study of estrogen and progestin in postmenopausal women: effects on clinical symptoms and lipoprotein lipids.", OBSTET GYNECOL (UNITED STATES), MAY 1989, VOL. 73, NO. 5 PT 1, PAGE(S) 759-66, *
SOMA ET AL.: "Plasma Lp(a) concentration after oestrogen and progestagen in postmenopauslal women", LANCET, vol. 337, 9 March 1991 (1991-03-09), pages 612 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996032114A1 (fr) * 1995-04-08 1996-10-17 Schering Aktiengesellschaft Preparation pharmaceutique combinee de contraception hormonale
CN1077430C (zh) * 1995-04-08 2002-01-09 舍林股份公司 激素避孕法的药物复合制剂
WO2000041699A1 (fr) * 1999-01-18 2000-07-20 Novo Nordisk A/S Utilisation d'oestrogenes et de delta-gonadiene-21-ol-3,20-diones

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Publication number Publication date
ZA947406B (en) 1996-03-22
AU7843094A (en) 1995-04-10

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