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Title:  Methods for treating postmenopausal women using ultra-low doses of estrogen

United States Patent:  6,692,763

Issued:  February 17, 2004

Inventors:  Cummings; Steven R. (Mill Valley, CA); Ettinger; Bruce (San Francisco, CA); Ellman; Herman (Mountain Lakes, NJ)

Assignee:  The Regents of the University of California (Oakland, CA); Kaiser Foundation Health Plan, Inc. (Oakland, CA); The Permanente Medical Group, Inc. (Oakland, CA); Berlex Laboratories, Inc. (Richmond, CA)

Appl. No.:  554789

Filed:  July 11, 2000

PCT Filed:  November 21, 1998

PCT NO:  PCT/US98/24677

PCT PUB.NO.:  WO99/26631

PCT PUB. Date:  June 3, 1999

Abstract

The present invention provides methods for treating physical conditions resulting from postmenopausel estrogen decline in a postmenopausel subject, and in particular methods for reducing the risk of osteoporotic bone fractures in a postmenopausal subject. The present invention also provides a kit for carrying out the methods of the present invention.

SUMMARY OF THE INVENTION

As a first aspect, the present invention provides a method for treating physical conditions resulting from estrogen decline in a postmenopausal subject. The method comprises administering to the subject, an amount of estrogen which is effective to produce a serum estradiol level of between about 5 pg/ml and about 15 pg/ml.

As a second aspect, the present invention provides a method for reducing the risk of osteoporotic bone fractures in a subject afflicted with or susceptible to postmenopausal osteoporosis. The method comprises administering to the subject, an amount of estrogen which is effective to produce a serum estradiol level of between about 5 pg/ml and about 15 pg/ml.

As a third aspect, the present invention provides a kit for use by a consumer afflicted with or susceptible to physical conditions resulting from postmenopausal estrogen decline. The kit comprises a) a transdermal patch capable of transdermally administering less than about 20 .mu.g of estrogen per day; and b) instructions describing a method of using the transdermal patch to reduce the risk of bone fracture in the consumer.

As a fourth aspect, the present invention provides another method for treating physical conditions resulting from postmenopausal estrogen decline in a postmenopausal subject. The method includes administering less than about 20 .mu.g of estrogen per day in the absence of exogenous progestin.

As a fifth aspect, the present invention provides another method for reducing the risk of osteoporotic bone fractures in a subject afflicted with or susceptible to osteoporosis. The method includes administering less than about 20 .mu.g of estrogen per day in the absence of exogenous progestin.

These and other aspects of the present invention are described further in the drawings, description of the preferred embodiment and examples of the invention which follow.

DESCRIPTION OF THE PREFERRED EMBODIMENT

Unless otherwise defined, all technical and scientific terms employed herein have their conventional meaning in the art. As used herein, the following terms have the means ascribed to them.

"Physical conditions resulting from postmenopausal estrogen decline" refers to physical conditions which are common among postmenopausal women and which are caused, at least in part, by a decline in estrogen in the body. These conditions include but are not limited to osteoporosis, headaches, nausea, depression, hot flashes, decrease in bone mineral density, and increased risk or incidence of bone fracture, including vertebral and/or hip fracture.

"Postmenopausal subject" refers to women in the period of life after menopause. Subjects afflicted with postmenopausal symptoms include women after menopause who exhibit any of the foregoing physical conditions after menopause, and particularly women after menopause who exhibit decreased bone mineral density, in the vertebrae, hip or other site, or who have experienced either vertebral or hip fracture. Subjects susceptible to physical conditions resulting from postmenopausal estrogen decline include women approaching the onset of menopause who are exhibiting a decrease in serum estradiol levels as compared to premenopausal women, and women after menopause who are exhibiting a decrease in serum estradiol levels but who have not yet exhibited physical conditions caused by postmenopausal estrogen decline. Subjects exhibiting decreased serum estradiol levels include subjects exhibiting a serum estradiol level at or below 20 pg/ml, including subjects exhibiting undetectable levels of serum estradiol. For purposes of this invention, sex hormone levels, including serum estradiol levels were measured using by radioimmunoassay after extraction and column separation. The lower limit of detectability is 5 pg/ml of estradiol.

"Osteoporotic bone fractures" refers to bone fractures, typically in the vertebrae or hip for which osteoporosis is a contributing factor.

The methods of the present invention are useful for the treatment of postmenopausal subjects, particularly subjects afflicted with or susceptible to postmenopausal physical conditions of the type discussed hereinabove. The methods of the present invention involve the administration of estrogen in an amount effective to produce the desired serum estradiol level in the subject. As used herein, the phrase "treating physical conditions" contemplates eliminating or reducing the severity or incidence of such physical conditions in the subject afflicted with such conditions, and also preventing the occurrence of postmenopausal physical conditions in a subject susceptible to such conditions as a result of postmenopausal estrogen decline. Although treatment of these postmenopausal physical conditions may include the complete elimination of such conditions in a subject afflicted therewith, complete elimination of the condition is not required to meet the definition of the term which is contemplated by the instant invention. Thus, the present invention involves the use of ultra-low doses of estrogen for the treatment of physical conditions resulting from estrogen decline and for reducing the risk of osteoporotic bone fractures in a subject afflicted with or susceptible to postmenopausal osteoporosis.

The methods of the present invention may also include the additional step of testing the serum estradiol level of the postmenopausal subject to be treated and determining that the serum estradiol level of the subject to be treated is normal for postmenopausal women in the same age group as the subject. In other words, the methods of the present invention are not reserved for treatment of women having lower than normal serum estradiol levels than the average of postmenopausal women in the same age group. The methods of the present invention may be used to treat postmenopausal subjects whose serum estradiol is normal for postmenopausal women of the same age group. As used herein, a "normal" serum estradiol level is a serum estradiol level which is relatively close to the average serum estradiol level for women of the same age group.

The present inventors have unexpectedly discovered that loss of bone mineral density is not the only contributing factor leading to an increased risk of osteoporotic bone fractures in subjects afflicted with postmenopausal osteoporosis. Low levels of serum estradiol, i.e., below 5 pg/ml, especially when accompanied by sex hormone binding globulin (SHBG) levels of 1 .mu.g/dl or more substantially increase the risk of hip and vertebral fractures. In addition, low serum levels of 1,25(OH)2 Vitamin D also leads to increased risk of hip fractures. The method of assessing the risk of osteoporotic bone fractures involves the use of logistic models developed by SAS Institute, Cary, N.C., to analyze the relationship between predictors and vertebral fractures, and proportional hazards models that take into account the case-cohort sampling design to analyze the relationship between predictors and hip fractures. The analyses are adjusted for baseline age and weight, and reported as relative risks with 95% confidence intervals. The proportion of fractures attributed to various hormone levels are estimated using the technique described in W. S. Browner, American Journal of Epidemiology 123:143 (1986), the disclosure of which is incorporated herein by reference in its entirety. By "reducing the risk of osteoporotic bone fracture" is meant that the risk, as measured using the foregoing techniques, is lower for a given subject who is treated with the methods of the present invention, as compared to the risk for the same subject prior to treatment using the methods of the present invention. Thus, the risk of osteoporotic bone fractures is reduced for a subject treated with the methods of the present invention as compared to an untreated postmenopausal subject afflicted with or susceptible to osteoporotic bone fractures.

The present inventors have also unexpectedly discovered that the treatment of physical conditions resulting from estrogen decline can be affected by ultra low doses of estrogen without the need for administration of progestin. The administration of estrogen, excluding the administration of progestin has now been found by the present inventors to be effective for treatment of postmenopausal women who have a uterus and ovaries. Previous hormone replacement therapies have relied upon the co-administration of progestin for effective treatment, particularly of women who have not undergone hysterectomy or ovariectomy.

The source of exogenous estrogen for use in the methods of the present invention may include any suitable form of estrogen for administration to a subject. Suitable forms of exogenous estrogen include both natural and synthetic compounds exhibiting estrogenic activity. Several forms of exogenous estrogen are commercially available. For example, suitable forms of exogenous estrogen include but are not limited to estradiols, including .alpha.-estradiol, 17.beta.-estradiol, ethinyl estradiol, estradiol benzoate, and estradiol 17.beta.-cypionate; estrone; estriol; conjugated equine estrogens; and salts of the forgoing. The foregoing are all examples of steroids which exhibit estrogenic activity. Examples of nonsteroidal compounds exhibiting estrogenic activity include but are not limited to diethylstilbestrol diphosphate, diethylstilbestrol dipropionate, and hexestrol. Currently, the preferred form of exogenous estrogen for use in the methods of the present invention is estradiol.

The amount of exogenous estrogen to be administered to the subject is sufficient to achieve a serum estradiol level of at least about 5 pg/ml but not more than about 20 pg/ml and preferably not more than 15 pg/ml. In other words, according to the methods of the present invention, sufficient exogenous estrogen is administered to achieve a total serum estradiol level of at least about 5 pg/ml/ml and about 20 pg/ml. Since the serum estradiol level of an untreated subject will differ for each individual, different individuals may require administration of different doses of estrogen to achieve the required serum estradiol level. It is not required that the serum estradiol level of each subject being treated be increased by between about 5 and about 20 pg/ml; rather the total serum estradiol level of each treated subject must be at least about 5 and not more than about 20 pg/ml. Often, the amount of exogenous estrogen to be administered is sufficient to achieve a serum estradiol level of between about 5 pg/ml and about 10 pg/ml. Contrary to previous understanding, the present inventor(s) have now discovered that serum estradiol levels of between 5 pg/ml and 15 pg/ml advantageously produce a decrease in the risk of vertebral and hip fracture. The administration of this lower than conventional amount of exogenous estrogen has the further advantage of decreasing the risk of undesirable side effects associated with hormone replacement therapy.

The administration of exogenous estrogen can be accomplished by any suitable route. For example, formulations for oral and parenteral administration of exogenous estrogen are known in the art, and may be employed in the methods of the present invention. Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder, or granules; or as a solution, dispersion, or suspension in an aqueous or non-aqueous liquid. Such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound and a suitable carrier (which may contain one or more accessory ingredients). In general, the formulations of the invention are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture. For example, a tablet may be prepared by compressing or molding a powder or granules containing the active compound, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, and/or surface active/dispersing agent(s). Molded tablets may be made by molding in a suitable tableting machine, the powdered compound moistened with an inert liquid binder.

The amount of exogenous estrogen in the oral formulation is an ultra-low dose of estrogen which will depend upon the precise form of estrogen to be administered, but is typically less than 0.5 mg per day. Preferably, the amount of estrogen administered orally is between about 0.1 mg and about 0.25 mg of estrogen per day. For example, the amount of estradiol administered orally is from about 0.1 mg to about 0.25 mg per day. It is well within the skill of those in the art to determine equivalent dosages of other forms of estrogen as well.

In the preferred embodiments of the present invention, estrogen is administered parenterally or transdermally rather than orally. The former routes of administration are preferred over oral administration because oral administration of estrogen may lead to increased levels of sex hormone binding globulin. Sex hormone binding globulin may diminish the beneficial effects of administering estrogen to postmenopausal subjects, particularly subjects exhibiting signs of osteoporosis or loss of bone mineral density. Although oral administration is not the preferred route, the methods of the present invention may be carried out using oral formulations.

Formulations of the present invention suitable for parenteral administration conveniently comprise sterile aqueous preparations of the active compound, which preparations are preferably isotonic with the blood of the intended recipient. These preparations may be administered by means of subcutaneous, intravenous, intramuscular, intradermal injection, or vaginal ring. Such preparations may conveniently be prepared by admixing the active ingredient, an estrogen, with water or a glycine buffer and rendering the resulting solution sterile and isotonic with the blood.

The amount of exogenous estrogen in the parenteral formulation is an ultra-low dose of estrogen which will depend upon the precise form of estrogen to be administered, but is typically not more than 20 .mu.g per day. Preferably, the amount of estrogen administered parenterally is between about 5 .mu.g and about 15 .mu.g of estrogen per day, and more preferably about 10 .mu.g of estrogen per day. For example, the amount of estradiol administered parenterally is from about 5 .mu.g to about 15 .mu.g per day. It is well within the skill of those in the art to determine equivalent dosages of other forms of estrogen as well.

More preferably, the methods of the present invention include the transdermal administration of exogenous estrogen. Suitable formulations for the transdermal administration of estrogen are known in the art, and may be employed in the methods of the present invention. For example, suitable transdermal patch formulations for the administration of exogenous estrogen is described in U.S. Pat. No. 4,460,372 to Campbell et al., U.S. Pat. No. 4,573,996 to Kwiatek et al., U.S. Pat. No. 4,624,665 to Nuwayser, U.S. Pat. No. 4,722,941 to Eckert et al., and U.S. Pat. No. 5,223,261 to Nelson et al., the disclosures of which are hereby incorporated by reference for their discussion of transdermal patch technology.

One suitable type of transdermal patch for use in the methods of the present invention is shown in FIG. 1. In general, a suitable transdermal patch 10 includes a backing layer 12 which is non-permeable, a permeable surface layer 13, an adhesive layer (not shown) substantially continuously coating the permeable surface layer 13, and a reservoir 16 located or sandwiched between the backing layer 12 and the permeable surface layer 13 such that the backing layer 12 extends around the sides of the reservoir 16 and is joined to the permeable surface layer 13 at the edges of the permeable surface layer 13. The reservoir 16 contains estrogen and is in fluid contact with the permeable surface layer 13. The transdermal patch 10 is adhered to the skin by the adhesive layer on the permeable surface layer 13, such that the permeable surface layer 13 is in substantially continuous contact with the skin when the transdermal patch 10 is adhered to the skin. While the transdermal patch 10 is adhered to the skin of the subject, the estrogen contained in the reservoir 16 of the transdermal patch 10 is transferred via the permeable surface layer 13, from the reservoir 16, through the adhesive layer, and to and through the skin of the subject. The transdermal patch 10 may optionally also include one or more penetration-enhancing agents in the reservoir 16 that enhance the penetration of the estrogen through the skin.

Examples of suitable materials which may comprise the backing layer are well known in the art of transdermal patch delivery, and any conventional backing layer material may be employed in the transdermal patch of the instant invention. Specific examples of suitable backing layer materials include but are not limited to polyester film, such as high density polyethylene, low density polyethylene or composites of polyethylene; polypropylene; polyvinyl chloride, polyvinylidene chloride; ethylene-vinyl acetate copolymers; and the like.

Examples of suitable permeable surface layer materials are also well known in the art of transdermal patch delivery, and any conventional material which is permeable to the active ingredient to be administered, i.e., estrogen, may be employed in the transdermal patch of the instant invention. Specific examples of suitable materials for the permeable surface layer include but are not limited to dense or microporous polymer films such as those comprised of polycarbonates, polyvinyl chlorides, polyamides, modacrylic copolymers, polysulfones, halogenated polymers, polychloroethers, acetal polymers, acrylic resins, and the like. Specific examples of these types of conventional permeable membrane materials are described in U.S. Pat. No. 3,797,494 to Zaffaroni.

Examples of suitable adhesives which may be coated on the backing layer to provide the adhesive layer are also well known in the art and include, for example pressure sensitive adhesives such as those comprising acrylic and/or methacrylic polymers. Specific examples of suitable adhesives include polymers of esters of acrylic or methacrylic acid (e.g., n-butanol, n-pentanol, isopentanol, 2-methyl butanol, 1-methyl butanol, 1-methyl pentanol, 3-methyl pentanol, 3-methyl pentanol, 3-ethyl butanol, isooctanol, n-decanol, or n-dodecanol esters thereof) alone or copolymerized with ethylenically unsaturated monomers such as acrylic acid, methacrylic acid, acrylamide, methacrylamide, N-alkoxymethyl acrylamides, N-alkoxymethyl methacrylamides, N-t-butylacrylamide, itaconic acid, vinyl acetate, N-branched C10-24 alkyl maleamic acids, glycol diacrylate, or mixtures of the foregoing; natural or synthetic rubbers such as silicon rubber, styrene-butadiene rubber, butyl-ether rubber, neoprene rubber, nitrile rubber, polyisobutylene, polybutadiene, and polyisoprene; polyurethane elastomers; vinyl polymers such as polyvinyl alcohol, polyvinyl ethers, polyvinyl pyrrolidone, and polyvinyl acetate; ureaformaldehyde resins; phenol formaldehyde resins; resorcinol formaldehyde resins; cellulose derivatives such as ethyl cellulose, methyl cellulose, nitrocellulose, cellulose acetatebutyrate, and carboxymethyl cellulose, and natural gums such as guar, acacia, pectin, starch, destria, gelatin, casein, etc. As will be apparent to those skilled in the art, the adhesive layer should be inert to the active ingredient, estrogen, and should not interfere with the transdermal delivery of the estrogen through the permeable surface layer. Pressure sensitive adhesives are preferred for the adhesive layer of the transdermal patch to facilitate the application of the patch to the skin of the subject.

Suitable penetration-enhancing agents are well known in the art as well. Examples of conventional penetration-enhancing agents include alkanols such as ethanol, hexanol, cyclohexanol, and the like; hydrocarbons such as hexane, cyclohexane, isopropylbenzene; aldehydes and ketones such as cyclohexanone, acetamide; N,N-di(lower alkyl)acetamides such as N,N-diethylacetamide, N,N-dimethyl acetamide,; N-(2-hydroxyethyl) acetamide; esters such as N,N-di-lower alkyl sulfoxides; essential oils such as propylene glycol, glycerine, glycerol monolaurate, isopropyl myristate, and ethyl oleate; salicylates; and mixtures of any of the above.

FIG. 2 is an example of second type of transdermal patch which is suitable for the transdermal delivery of estrogen according to the present invention. In this example, the active ingredient is incorporated in to the adhesive layer rather than being contained in a reservoir. Examples of these types of patches are conventionally known and include, for example, the CLIMERA.RTM. patch available from Berlex. The transdermal patch 20 comprises a backing layer 22 and an adhesive/drug layer 24. The adhesive/drug layer 24 has the combined function of adhering the patch 20 to the skin of the subject and containing the active ingredient, estrogen, which is to be administered. The active ingredient is leached from the adhesive/drug layer 24 to and through the skin of the subject when the patch is adhered to the skin.

Any of the backing layers described herein above may be employed in this embodiment as well. In addition, any of the suitable adhesives described above may be employed. The adhesive/drug layer comprises a relatively homogeneous mixture of the selected adhesive and the active ingredient. Typically, the adhesive/drug layer comprises a coating substantially covering one surface of the backing layer. The adhesive/drug layer may also include a penetration enhancing agent such as those described above by incorporating the penetration enhancing agent into the substantially homogeneous mixture of the adhesive and the active ingredient.

As will be readily apparent to those skilled in the art, the transdermal patches according to the present invention may include a variety of additional excipients which are conventionally employed to facilitate the transdermal administration of an active agent, particularly a steroidal active agent. Examples of such excipients include but are not limited to carriers, gelling agents, suspending agents, dispersing agents, preservatives, stabilizers, wetting agents, emulsifying agents, and the like. Specific examples of each of these types of excipients are well known in the art and any conventional excipients may be employed in the transdermal patches of the instant invention. It is important to note, however, that the transdermal patches of the present invention exclude progestins. Accordingly, progestin is not a suitable excipient for use in the transdermal patch formulations of the present invention.

The amount of exogenous estrogen in the transdermal patch formulations is an ultra-low dose of estrogen which will depend upon the precise form of estrogen to be administered, but is sufficient to deliver less than 20 .mu.g, and typically not more than 15 .mu.g per day. Preferably, the amount of estrogen administered via the transdermal patch is between about 5 .mu.g and about 15 .mu.g of estrogen per day. More preferably, the amount of estrogen administered is about 10 .mu.g per day. Although the typical dose of estrogen according to the method of the present invention is less than 20 .mu.g, doses as high as 25 .mu.g may be employed. For example, the amount of estradiol administered parenterally is from about 5 .mu.g to about 15 .mu.g per day. It is well within the skill of those in the art to determine equivalent dosages of other forms of estrogen as well. The ultra-low level of estrogen employed in the methods of the present invention has unexpectedly been found to substantially reduce the risk of osteoporotic bone fractures in postmenopausal women.

Typically, the transdermal patches are designed to be worn for several days before replacement is required. Thus the amount of estrogen in the reservoir must be sufficient to permit the administration of less than 20 .mu.g per day for a period of several days. As an example, a transdermal patch according to the present invention which is designed to administer 10 .mu.g of estrogen per day for seven (7) days would contain approximately 1 mg of estrogen. A patch suitable for the administration of 15 .mu.g per day for seven (7) days would contain approximately 1.4 mg of estrogen. Based upon these specific examples, one skilled in the art would be able to discern the necessary amount of estrogen to be included in the transdermnal patch to achieve the delivery of the correct daily dose of estrogen.

Advantageously, the present invention also provides a kit for use by a consumer afflicted with or susceptible to postmenopausal symptoms which includes the transdermal patch and instructions describing the method of using the transdermal patch to treat postmenopausal symptoms and/or reduce the risk of osteoporotic bone fracture in the consumer. The instructions would direct the consumer to adhere the transdermal patch, using the adhesive thereon, directly to the skin surface, for example at the upper arm, to achieve the transdermal administration of the ultra-low dose of estrogen from the patch and thereby increase the serum estradiol level in the consumer to between about 5 pg/ml and about 20 pg/ml. The instructions would also direct the consumer to replace the patch as required to continue the administration of estrogen as necessary to maintain this serum estradiol level by using the transdermal patch. In particular, the instructions might direct the consumer to replace the transdermal patch every seven (7) day to ensure the administration of less than 20 .mu.g, and preferably 10 .mu.g of estrogen per day when a seven-day patch is utilized in the kit. Such kits could advantageously be packaged and sold in single or multiple patch units.

Claim 1 of 23 Claims

That which is claimed is:

1. A method for treating a physical condition resulting from estrogen decline in a postmenopausal subject, said method comprising administering to said subject an amount of estrogen which is effective to produce a resulting serum level of said estrogen in said subject that is equivalent to a serum estadiol level not exceeding of between about 5 pg/ml and about 15 pg/ml, wherein:

the estrogen is administered orally, parenterally, or transdermally; said physical condition is selected from the group consisting of osteoporosis, headaches, nausea, depression, hot flashes, decrease in bone mineral density, and increased risk or incidence of bone fracture; and

the resulting serum level of the estrogen is responsive to the administering of the estrogen.




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