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WO1995008329A1 - Methods for the reduction of postmenopausal ldl cholesterol - Google Patents

Methods for the reduction of postmenopausal ldl cholesterol 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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WIPO (PCT)
Prior art keywords
estrogen
progestin
days
dosage
administration
Prior art date
Application number
PCT/US1994/010846
Other languages
French (fr)
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/en

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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
    • A61K31/565—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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Abstract

The present invention is directed to methods for reducing LDL cholesterol in postmenopausal women 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 regimen 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.

Description

METHODS FOR THE REDUCTION OF POSTMENOPAUSAL LDL CHOLESTEROL
Field of the Invention
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.
Background of the Invention
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.
It is widely believed that estrogen as a postmenopausal therapy, will reduce the level of LDL cholesterol. There is also clear documentation in the literature that the addition of norethindrone and other progestins- to hormone replacement therapy regimens can cause a clinically significant deterioration in the levels of LDL cholesterol. The worsening of lipid levels has been associated with high daily doses of norethindrone. Recently, estrogen replacement regimens with lower doses of norethindrone or other progestins have been shown to preserve the expected lowering of LDL cholesterol seen with estrogen therapy alone.
It is the object of the present invention to go beyond the prior art and provide an augmented reduction of LDL cholesterol in postmenopausal women by treatment with estrone sulfate and norethindrone in specific treatment regimens.
Summary of the Invention
As embodied and broadly described herein, 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. In preferred embodiments of the method of the invention 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. In certain embodiments 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.
In preferred embodiments of the invention, the estrogen composition comprises substantially natural human estrogen which metabolizes to estradiol and estrone sulfate, particularly preferred is the estrogen estropipate. In preferred embodiments of the invention the progestin is selected from the group consisting of 19-nortestosterones, particularly norethindrone. In preferred embodiments of the invention, 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.
In other embodiments of the invention, 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. In preferred embodiments of the HRT regimen of the invention the progestin and estrogen compositions and dosages are as described above in the preferred method of the invention for reducing LDL cholesterol.
Brief Description of the Drawing
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.
Detailed Description of Preferred Embodiments of the Invention
Reference will now be made in detail to preferred embodiments of the invention. Examples of the preferred embodiments are illustrated in the following Examples section.
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. Such a finding for the combination of estropipate with norethindrone has never before been described and is unexpected given the previously documented norethindrone effect of negating estrogen-alone LDL cholesterol changes. 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.
As embodied and fully described herein, 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. In certain embodiments 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. For example, it is preferred in accordance with the invention to provide 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.
In preferred embodiments of the invention, 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.
As embodied and fully described herein, 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. 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. For example, 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).
Pharmaceutical 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.
Sterile water solutions of the active component or sterile solutions of the active components in solvents comprising water, ethanol, or propylene glycol are examples of liquid preparations suitable for parenteral 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. Other 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. 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 Their Manufacture , pp. 1409-1677 (1985) .
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.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease- of administration and uniformity of dosage.
The term "unit dosage form" as used herein 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. The term "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, however, 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.
The invention will now be illustrated by an exemplary study involving the method of the invention. The examples are not intended to be limiting of the scope of the present invention but read in conjunction with the detailed and general description above, provide further understanding of the invention and outline a protocol for carrying out the methods of the invention to reduce LDL cholesterol in postmenopausal women.
Examples
The following ingredients, procedures and medical testing are generally known and available to those skilled in the pharmaceutical and medical arts.
Example 1-6
1. The Protocol
Study Description
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.
Materials and Supplies Test medication were supplied as follows:
Regimen #1
Estropipate 1.5 mg - 11 days
Estropipate 1.5 mg+NET 1.0 mg - 10 days
Placebo - 7 days (1.5, 11/10 vs 21) Regimen #2
Estropipate 1.5 mg - 18 days
Estropipate 1.5 mg+NET 1.0 mg - 10 days
(1.5, 18/10 vs 21)
Regimen #3 Estropipate 1.5 mg - 21 days
Placebo - 7 days
Regimen #4
Estropipate 0.75 mg - 11 days
Estropipate 0.75 mg+NET 1.0 mg - 10 days Placebo - 7 days (.75, 11/10 vs 21)
Regimen #5
Estropipate 0.75 mg - 18 days
Estropipate 0.75 mg+NET 1.0 mg - 10 days
(.75, 18/10 vs 21) Regimen #6
Estropipate 0.75 mg - 21 days
Placebo - 7 days
All tablets were identical smooth, hard, white, diamond-shaped tablets. c. Study Population
Seven hundred and eighty (780) normal, healthy, peri- and post-menopausal female volunteers 40 years or older were enrolled.
d. Methods-Lipid Measurements
All clinical laboratory evaluations were standard industry tests performed by a central laboratory. The lipid evaluations were to be performed at baseline, cycle 3, cycle 6 and cycle 12. Three of the lipid values were measured by standard clinical laboratory methods. They were total cholesterol HDL, and triglycerides. LDL was calculated by the Friedewald formula. See Friedewald, W. T. , et al., Estimated Concentration of Low-Density Lipoprotein Cholesterol in Plasma, without use of the Preparative Ultracentrifuge, Clinical Chemistry, Vol . 18 , 499 (1972) . The Friedewald formula continues to be the most commonly used method of determine the LDL value by clinical laboratories. Even though there are methods available to more directly determine the LDL value, these methods are difficult, time consuming, and not generally available in clinical laboratories. Even in experimental laboratories where more direct measurements are made, methodologies differ. It should be noted that this Friedewald formula has shown greater than 0.99 correlation to the more direct methods of measurement. 2. The Results
The result of the study are provided in Figure 1 which 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. In all four norethindrone regimens (i.e.. 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. Also disclosed is the average difference of these four regimens (comb) versus estropipate (EP). alone.
When the four norethindrone-containing regimens are grouped and compared to a grouping of the two estropipate- alone regimens for the decrease from baseline in LDL cholesterol at cycle 3, cycle 6 and cycle 12, the difference in a two-way analysis of variance is statistically significant at each of the three cycles where lipid determinations were done (p<0.03). When each norethindrone regimen is compared to its respective estropipate-alone control regimen for the decrease in LDL cholesterol from baseline, there are 4 comparisons at each of the three cycles for a total of 12 comparisons. Four of the 12 individual regimen comparisons show differences in the change from baseline that are statistically significant (p<0.03). At cycle 12, 2 of the 4 individual regimen comparison have statistically significant differences (p<0.05).
Discussion of Results
Prior to this discovery, there has been the perception that combination hormone replacement therapy (i.e., estrogen with a progestin) provides the added benefit (over estrogen alone) of endometrial protection while at the same time having either no additional benefit or a negative effect on the cardiovascular system though undesirable LDL cholesterol changes. 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.
The scope of the present invention is not limited by the description, examples and suggested methods described herein and modifications can be made without departing from the spirit of the invention. For example, other estrogens and progestins may be substituted for those provided in the examples herein to achieve similar advantageous results.
Applications of the 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.

Claims

What is claimed is:
1. 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 of estrogen and progestin composition for 8 to 16 days of the remaining days of said 28 day cycle.
2. The method of claim 1 wherein the estrogen composition comprises substantially natural human estrogens which metabolize to estradiol and estrone sulfate.
3. The method of claim 1 wherein the progestin is selected from the group consisting of 19-nortestosterones.
4. The method of claim 1 wherein the estrogen is estropipate and the progestin is norethindrone.
5. The method of claim 1 wherein the dosage of progestin provided in the 8 to 16 days of administration is from about 0.5 to 1.5 mg per day.
6. The method of claim 1 wherein the dosage of progestin is from 1.0 to 1.5 mg per day for 8 to 12 days of administration.
7. The method of claim 1 wherein the dosage of progestin is from 0.5 to 1.0 mg per day for 10 to 16 days of administration.
8. The method of claim 1 wherein the dosage of progestin is about 1 mg per day for 10 days of administration.
9. The method of claim 4 wherein the dosage of progestin is 1 mg per day for 10 days of administration.
10. The method of claim 1 wherein the dosage of estrogen is about 0.5 to 3.0 mg throughout the 28 day cycle.
11. The method of claim 1 wherein the dosage of estrogen is about 0.75 to 1.5 mg throughout the 28 day cycle.
12. The method of claim 1 wherein the estrogen and estrogen and progestin compositions are given in a continuous regimen throughout the cycle.
13. The method of claim 4 wherein the estrogen and estrogen and progestin compositions are given in a continuous regimen throughout the cycle.
14. The method of claim 5 wherein the estrogen .and estrogen and progestin compositions are given in a continuous regimen throughout the cycle.
15. A hormone replacement therapy regimen having LDL reducing benefit comprising 28 daily doses comprising daily doses of an estrogen composition alone for 10 to 20 days of a 28 day cycle and daily doses of a combination of estrogen and progestin composition for 8 to 16 days of the remaining days of said 28 day cycle.
16. The kit of claim 5 wherein the dosage of progestin provided in the 8 to 16 days of administration is from about 0.5 to 1.5 mg per day.
17. The kit of claim 5 wherein the dosage of progestin is from 1.0 to 1.5 mg per day for 8 to 12 days of administration.
18. The kit of claim 5 wherein the dosage of progestin is from 0.5 to 1.0 mg per day for 10 to 16 days of administration.
19. The kit of claim 5 wherein the dosage of progestin is 1 mg per day for 10 days of administration.
20. The kit of claim 15 wherein the daily doses of estrogen and estrogen and progestin compositions . are arranged to be given in a continuous regimen.
21. The kit of claim 15 wherein the daily doses of estrogen and estrogen and progestin compositions are arranged to be given in a continuous regimen and the dosage range of estrogen is about 0.75 mg to 1.5 mg per day for each day of the 28 day cycle and the dosage of progestin is from about 0.5 to 1.5 mg per day for 8 to 10 days of administration during the 28 day cycle.
PCT/US1994/010846 1993-09-23 1994-09-21 Methods for the reduction of postmenopausal ldl cholesterol WO1995008329A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996032114A1 (en) * 1995-04-08 1996-10-17 Schering Aktiengesellschaft Combined hormonal contraception pharmaceutical preparation
WO2000041699A1 (en) * 1999-01-18 2000-07-20 Novo Nordisk A/S Use of estrogens and delta-gonadien-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 (en) * 1995-04-08 1996-10-17 Schering Aktiengesellschaft Combined hormonal contraception pharmaceutical preparation
CN1077430C (en) * 1995-04-08 2002-01-09 舍林股份公司 Combined hormonal contraception pharmaceutical perparation
WO2000041699A1 (en) * 1999-01-18 2000-07-20 Novo Nordisk A/S Use of estrogens and delta-gonadien-21-ol-3,20-diones

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