Link:  Pharm/Biotech Resources

Title:  Methods and compositions for treating benign gynecological disorders

United States Patent:  6,960,337

Issued:  November 1, 2005

Inventors:  Daniels; Anne-Marie (Pacific Palisades, CA); Daniels; John R. (Pacific Palisades, CA); Pike; Malcolm C. (Marina Del Rey, CA); Spicer; Darcy V. (La Canada, CA)

Assignee:  Balance Pharmaceuticals, Inc. (Santa Monica, CA)

Appl. No.:  298851

Filed:  November 15, 2002

An improvement in a method of treating benign gynecological disorders is described. In the method, treatment of a benign gynecological disorder with a composition comprised of a gonadotropin releasing hormone (GnRH) compound and an estrogenic compound, and optionally, an androgenic compound, is extended to premenopausal women who are not receiving an exogenously supplied progestin on a regular or periodic basis. Treatment in accord with the invention does not increase significantly the risk of endometrial hyperplasia. The method is also suitable for contraception.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the invention to provide a method of treating benign gynecological disorders by administering a composition comprised of a GnRH compound and an estrogenic compound and, optionally, an androgenic compound, in the absence of a co-administered or sequentially administered progestin.

It is another object of the invention to provide a method of preventing pregnancy, i.e., a method of contraception, by administering a composition comprised of a GnRH compound and an estrogenic compound and, optionally, an androgenic compound, in the absence of a co-administered or sequentially administered progestin.

The present invention is based on the finding that women who are not receiving an exogenously supplied progestin can be treated with a GnRH compound combined with an estrogenic compound and, optionally, an androgenic compound for an extended period of time (i.e., 6 to 12 months or more) with no increase in the risk of endometrial hyperplasia. That is, treatment of a benign gynecological disorder with a composition comprised of a GnRH compound and an estrogenic compound and, optionally, an androgenic compound need not be accompanied by simultaneous administration of an exogenously supplied progestin in order to prevent endometrial hyperplasia. Similarly, administration of a GnRH compound and an estrogenic compound and, optionally, an androgenic compound for contraception need not be in conjunction with administration of an exogenously supplied progestin in order to prevent endometrial hyperplasia.

Accordingly, in one aspect, the invention includes an improvement in a method of treating benign gynecological disorders in a female. In the method, co-administration of a GnRH compound in an amount effective to suppress ovarian estrogen and progesterone production, and an estrogenic compound along with, optionally an androgen, in an amount effective to prevent signs and symptoms of estrogen deficiency and androgen deficiency, is extended to a female patient population of premenopausal women who are not receiving an exogenously supplied progestin on a regular or periodic basis and who do not have a history of endometrial hyperplasia, without a significant increase in the risk of endometrial hyperplasia relative to the patient population of women who are receiving an exogenously supplied progestin.

In one embodiment, the GnRH compound is a GnRH peptide agonist, and exemplary GnRH agonist compounds include deslorelin, leuprolide, nafarelin, goserelin, decapeptyl, buserelin, histrelin, gonadorelin, and analogs thereof. Exemplary GnRH antagonist compounds include azaline B, abarelix, cetrorelix, degarelix, and analogs thereof.

In another embodiment, the GnRH agonist is administered by an intranasal route. The co-administered estrogenic compound, in one embodiment, is also administered intranasally, and in another embodiment, it is administered transdermally. A preferred estrogenic compound is 17β-estradiol. When administered transdermally, 17-β-estradiol is administered at a daily dose between about 0.025 mg and about 0.1 mg.

As noted above, the composition can optionally include an androgen. Thus, in one embodiment, the method includes co-administering an androgenic compound such as testosterone. The androgen can be administered intranasally or by a transdermal route with the estrogenic compound. When the androgen is testosterone it can be administered at a daily dose sufficient to increase the average serum testosterone level over 24 hours to the premenopausal range of about 15 ng/dL to 80 ng/dL.

In another embodiment, the GnRH agonist and the estrogenic compound are co-administered intranasally, in an aerosol spray containing a daily spray volume between about 30 and 200 μL, and between about 0.15 mg and 0.6 mg of 17β-estradiol. In yet another embodiment, the intranasal administration further includes co-administering testosterone by an intranasal route, in an aerosol spray containing a daily spray volume between 30 and 200 μL, and between 0.15 mg and 0.6 mg of 17β-estradiol and between 0.15 mg and about 1 mg of testosterone.

In another aspect, the invention includes a method of treating benign gynecological disorders in a patient population composed of premenopausal women who do not have a history of endometrial hyperplasia, and who are not receiving an exogenously supplied progestin on a regular or periodic basis. The method includes administering by daily intranasal administration, over an extended period of time between 6 and 12 months, a formulation containing a GnRH compound, in an amount effective to suppress ovarian estrogen and progesterone production, and an estrogenic compound and optionally an androgen, in an amount effective to prevent signs and symptoms of estrogen deficiency and androgen deficiency over a time period of between about 6 and 12 months.

In one embodiment, the nasal formulation is an aqueous formulation, and said administering is effective to deliver a daily spray volume between 30 and 200 μL.

In another embodiment, the spray volume administered includes between 0.15 and 0.6 mg of 17β-estradiol. In yet another embodiment, the spray volume further includes testosterone in an amount between 0.15 mg and 1 mg.

The spray volume can further include, in another embodiment, a cyclodextrin, such as 2-hydroxypropyl-β-cyclodextrin. Preferably, the 2-hydroxypropyl-β-cyclodextrin, when present, is present in a mole ratio of cyclodextrin to total steroid of between 1:1 and 3:1.

The nasal formulation can also take the form of an aerosolizable dry powder, as will be further described below. In one embodiment, the dry powder also includes testosterone, in a mole ratio of estrogenic compound: testosterone of between 1:1 and 1:2.

In another aspect, the invention includes an improvement in a method for contraception. The improvement comprises extending the contraceptive method of administering a GnRH compound and an estrogenic compound to women who are not receiving an exogenously supplied progestin on a regular or periodic basis. The method includes administering by daily intranasal administration, over an extended period of time between about 6 and 12 months, a formulation containing a GnRH compound, in an amount effective to suppress ovarian estrogen and progesterone production, and an estrogenic compound, and optionally an androgen, in an amount effective to prevent signs and symptoms of estrogen deficiency and androgen deficiency over a time period of between about 6 and 12 months.

These and other objects and features of the invention will be more fully appreciated when the following detailed description of the invention is read in conjunction with the accompanying drawings and examples.

DETAILED DESCRIPTION OF THE INVENTION

Method of Treatment

As noted above, in one aspect the invention includes a method of treating a benign gynecological disorder in a woman by administration of a GnRH compound in combination with an estrogenic compound and optionally an androgenic compound. In this section, each component in the composition and exemplary routes of administration will be described.

A1. Composition Components: GnRH Compound

The composition for use in the method of the invention comprises a GnRH compound. Native GnRH is a decapeptide comprised of naturally-occurring amino acids having the L-configuration, except for the achiral amino acid glycine. The sequence of GnRH is (pyro)Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH₂ (SEQ ID NO:1). A large number of analogs of this natural peptide have been prepared and are effective to inhibit the release and/or the action of GnRH. Analogs having agonist and antagonist activity have been described, and as used herein, the term "a GnRH compound" or "GnRH compounds" intends agonists and antagonists, synthetically prepared or naturally-occurring, peptides and non-peptide compounds alike. The following description focuses in particular on GnRH agonists, however, it will be appreciated that native GnRH, GnRH antagonists, such as azaline B, abarelix, cetrorelix, and degarelix, and other GnRH analogs are also suitable for use in the composition and method of treatment. Further, the following discussion focuses on peptide analogs, however, it will be appreciated that non-peptide compounds, such as those disclosed in U.S. Pat. No. 6,346,534, are also contemplated.

GnRH agonists are compounds that work in two phases. The first phase stimulates the ovaries to produce more estradiol. During the second phase, the messenger hormones that control the ovaries are no longer produced, resulting in a drop in estrogen. An exemplary agonist is obtained by changing the 6-position residue in the naturally-occurring GnRH from Gly to a D-amino acid, to give a GnRH analog having a sequence (pyro)Glu-His-Trp-Ser-Tyr-X-Leu-Arg-Pro-Gly-NH₂ (SEQ ID NO:2), where X represents an amino acid in the D-configuration. When X is D-Leu the analog is known as Lupron™ and is commercially available from TAP Pharmaceuticals (Lake Forest, Ill.). Agonists often have the N-terminus prolyl modified with an n-ethylamide addition. For example, the agonist deslorelin is (pyro)Pro-His-Trp-Ser-Tyr-DTrp-Leu-Arg-Pro-ethylamide (SEQ ID NO:3). Another exemplary analog is where the 6-position residue is D-Ala to give a peptide having the following sequence: (pyro)Glu-His-Trp-Ser-Tyr-D-Ala-Leu-Arg-Pro-Gly-NH₂ (SEQ ID NO:4; U.S. Pat. No. 4,072,668). Another exemplary agonist is obtained by eliminating the Gly-NH₂ in position 10 to give a nonapeptide as an alkyl, cycloalkyl, or fluoroalkylamide, or by replacing Gly-NH₂ by an a-azaglycine amide. Modifications to the naturally-occurring GnRH sequence at positions 1 and 2 are also possible. A number of GnRH agonists are described in the art, many of which are commercially available, and include deslorelin, leuprolide, nafarelin, goserelin, decapeptyl, buserelin, histrelin, and gonadorelin, and analogs thereof.

The amount of GnRH compound effective to achieve the desired suppression of ovarian estrogen production may readily be determined with respect to any given GnRH compound and for any given mammal. The dose range depends upon the particular GnRH compound used and may also depend upon patient characteristics, such as age and weight. Further, the effective amount of GnRH compound also depends upon route of administration. Determination of an effective dose range after consideration of these factors is routine for those of skill in the art.

By way of example of a specific formulation, the amount of GnRH compound when the GnRH compound is deslorelin in a daily nasal spray formulation with a volume between about 30 to 200 μL can deliver a daily dose of GnRH compound of between about 0.025 mg to about 1.5 mg, more preferably from about 0.025 mg to about 0.1 mg. It will be appreciated that the daily spray volume can be administered in one, two, or more separate deliveries to achieve the desired total daily spray volume. It will further be appreciated that the spray volume and the amount of GnRH compound in the nasal formulation are both individually adjustable to achieve the desired daily dosage.

A2. Composition Components: Estrogenic Compound

A second component in the composition for use in the method of the invention is an effective amount of an estrogenic compound. The estrogenic compound is effective to prevent symptoms and signs of estrogen deficiency including bone loss, vaginal atrophy, and hot flashes.

The estrogenic compound can be a single-component natural or synthetic estrogen composition, or a combination of such compounds. As used herein, the term "estrogenic compound" refers to both natural and synthetic materials having activity to mitigate the signs and symptoms of estrogen deficiency. Natural and synthetic estrogenic compositions which can be used according to the invention described herein include natural estrogenic hormones and congeners, including but not limited to estradiol, estradiol benzoate, estradiol cypionate, estradiol valerate, estrone, diethylstilbestrol, piperazine estrone sulfate, ethinyl estradiol, mestranol, polyestradiol phosphate, estriol, estriol hemisuccinate, quinestrol, estropipate, pinestrol, and estrone potassium sulfate. Equine estrogens, such as equilelinin, equilelinin sulfate, and estetrol, and synthetic steroids combining estrogenic, androgenic, and progestogenic properties such as tibolone may also be employed.

Typical dose ranges for estrogenic compounds depend on the compound and on the characteristics of the patient. For an adult human female patient treated with a transdermal 17β-estradiol preparation, a typical dose range is one that maintains a serum level of estradiol of about 25 to about 140 pg/mL, more preferably between about 30 to about 50 pg/mL. A specific example of a composition containing an estrogenic compound is one comprised of a GnRH agonist and 17-β-estradiol. The two compounds, along with other optional excipients or an androgenic compound, are formulated for transdermal or intranasal delivery. In a transdermal formulation, a preferred daily dosage range for 17-β-estradiol is between about 0.025 mg and 0.1 mg. For an intranasal preparation, a preferred daily dosage range for 17-β-estradiol is between about 0.15 mg and 0.6 mg.

As discussed below, the estrogenic compound is preferably co-administered from the same delivery vehicle or via the same route as the GnRH compound. However, delivery of the estrogenic compound can be from a different vehicle and/or by a different route than the GnRH compound, and some examples of such "mixed modes" of administration are provided below. As can be appreciated, the composition comprised of a GnRH compound and an estrogenic compound suppresses gonadotropin activity while providing a replacement of estrogen to minimize or eliminate the side effects associated with suppression of gonadotropin activity.

A3. Composition Components: Androgenic Compound

The composition comprised of a GnRH compound and an estrogenic compound can optionally include an androgenic compound. When present in the composition, the androgenic compound is in an amount effective to increase a patient's androgen level to a level not exceeding a "normal" premenopausal level, and in particular in concert with the estrogenic composition to maintain bone mineral density. Such "normal" androgen levels are on the order of about 15 ng/dL to about 80 ng/dL for testosterone.

Suitable androgenic compounds for use in the composition include but are not limited to testosterone, androstenedione, dihydrotestosterone, testosterone propionate, testosterone enanthate, testosterone cypionate, methyltestosterone, danazol, dromostanolone propionate, ethylestrenol, methandriol, nandrolone decanoate, nandrolone phenpropionate, oxandrolone, oxymethalone, and stanozolol.

Typical dose ranges for androgenic hormones depend upon the choice of compound and the individual patient. For an adult human female administered testosterone, typical doses are administered to provide average serum levels of testosterone of from about 15 ng/dL to about 80 ng/dL, and preferably about 40 ng/dL to about 60 ng/dL. A specific example of a composition containing an androgenic compound is one comprised of a GnRH agonist and 17-β-estradiol and testosterone. The compounds, along with other optional excipients, are formulated for delivery transdermally or intranasally. For an intranasal preparation, a typical daily dose of testosterone can range from about 0.15 mg to about 1 mg.

B. Exemplary Modes of Administration

As noted above, the compositions described herein are beneficial for use in female contraception and/or in the treatment of benign gynecological disorders. In general, the compositions can be administered by any vehicle or route that achieves efficacious therapy. Parenteral (e.g., non-gastrointestinal, such as subcutaneous, intramuscular, intravenous), transdermal, pulmonary, mucosal (nasal, vaginal, rectal, buccal) routes of delivery are contemplated and preparation of suitable dosage forms can be prepared by methods well-known in the pharmaceutical art, for example, as described in Remington's Pharmaceutical Sciences, 17^th ed., Mack Publishing Co., Easton, Pa. (1985). Some exemplary formulations for various routes of administration are discussed below.

For example, in one embodiment it is contemplated that the composition is administered mucosally by contacting the composition in a suitable dosage form with mucosal tissue of the vagina, nose, rectum, or mouth. In a preferred embodiment, the composition is administered via the nasal mucosa, e.g., intranasally. The nasal mucosa provides a useful anatomical site for systemic delivery. The nasal tissue is highly vascularized, providing an attractive site for rapid and efficient absorption. The adult nasal cavity has a capacity of around 20 mL, with a large surface area of approximately 180 cm² for drug absorption, due in part to the microvilli present along the psuedostratified columnar epithelial cells of the nasal mucosa.

A nasal preparation comprised of the composition described above can take a variety of forms for administration in nasal drops, nasal spray, gel, ointment, cream, powder or suspension, using a dispenser or other device as needed. A variety of dispensers and delivery vehicles are known in the art, including single-dose ampoules, atomizers, nebulizers, pumps, nasal pads, nasal sponges, nasal capsules, and the like.

More generally, the preparation can take a solid, semi-solid, or liquid form. In the case of a solid form, the components may be mixed together by blending, tumble mixing, freeze-drying, solvent evaporation, co-grinding, spray-drying, and other techniques known in the art. Such solid state preparations preferably provide a dry, powdery composition with particles in the range of between about 20 to about 500 microns, more preferably from 50 to 250 microns, for administration intranasally.

A semi-solid preparation suitable for intranasal administration can take the form of an aqueous or oil-based gel or ointment. For example, the components described above can be mixed with microspheres of starch, gelatin, collagen, dextran, polylactide, polyglycolide, or other similar materials that are capable of forming hydrophilic gels. The microspheres can be loaded with drug, and upon administration form a gel that adheres to the nasal mucosa.

In a preferred embodiment, the nasal preparation is in liquid form, which can include an aqueous solution, an aqueous suspension, an oil solution, an oil suspension, or an emulsion, depending on the physicochemical properties of the composition components. The liquid preparation is administered as a nasal spray or as nasa drops, using devices known in the art, including nebulizers capable of delivering selected volumes of formulations as liquid-droplet aerosols. For example, a commercially available spray pump with a delivery volume of 50 μL or 100 μL is available from, for example, Valois (Congers, N.Y.) with spray tips in adult size and pediatric size. In one embodiment, the composition comprised of a GnRH agonist and an estrogenic compound are co-administered intranasally via an aerosol spray in a daily volume of between about 10 to 500 μL, more preferably between about 30 to about 200 μL.

The liquid preparation can be produced by known procedures. For example, an aqueous preparation for nasal administration can be produced by dissolving, suspending, or emulsifying the polypeptide and the steroid compounds in water, buffer, or other aqueous medium, or in a oleaginous base, such as a pharmaceutically-acceptable oil like olive oil, lanoline, silicone oil, glycerine fatty acids, and the like.

It will be appreciated that excipients necessary for formulation, stability, and/or bioavailability can be included in the preparation. Exemplary excipients include sugars (glucose, sorbitol, mannitol, sucrose), uptake enhancers (chitosan), thickening agents and stability enhancers (celluloses, polyvinyl pyrrolidone, starch, etc.), buffers, preservatives, and/or acids and bases to adjust the pH.

In a preferred embodiment, an absorption promoting component is included. Exemplary absorption promoting components include surfactant acids, such as cholic acid, glycocholic acid, taurocholic acid, and other cholic acid derivatives, chitosan, and cyclodextrins. In a preferred embodiment, a cyclodextrin is included in the preparation. Cyclodextrins are cyclic oligosaccharides of α-D-gluco-pyranose and can be formed by the catalytic cycilization of starch. Due to a lack of free rotation about the bonds connecting the glycopyranose units, cyclodextrins are toroidal or cone shaped, rather than cylindrical. The cyclodextrins have a relatively hydrophobic central cavity and a hydrophilic outer surface. The hydrophobic cage-like structure of cyclodextrins has the ability to entrap a variety of guest compounds to form host-guest complexes in the solid state and in solution. These complexes are often termed inclusion complexes and the guest compounds are released from the inclusion site.

The most common cyclodextrins are α-, β-, and γ-cyclodextrin, which consist of six, seven, or eight glucopyranose units, respectively. Cyclodextrins containing nine, ten, eleven, twelve, and thirteen glucopyranose units are designated δ-, ε-, ξ-, η-, and θ-cyclodextrin, respectively. Characteristics of α-, β-, γ-, and δ-cyclodextrin are shown in Table 1.

Derivatives formed by reaction with the hydroxyl groups lining the upper and lower ridges of the toroid are readily prepared and offer a means of modifying the physicochemical properties of the parent cyclodextrins. The parent cyclodextrins, and in particular β-cyclodextrin, have limited aqueous solubility. Substitution of the hydroxyl groups, even with hydrophobic moieties such as methoxy and ethoxy moieties, typically increases solubility. Since each cyclodextrin hydroxyl group differs in chemical reactivity, reaction with a modifying moiety usually produces an amorphous mixture of positional and optical isomers. The aggregate substitution that occurs is described by a term called the degree of substitution. For example, a 2-hydroxypropyl-β-cyclodextrin with a degree of substitution of five would be composed of a distribution of isomers of 2-hydroxypropyl-β-cyclodextrin in which the average number of hydroxypropyl groups per 2-hydroxypropyl-β-cyclodextrin molecule is five. Degree of substitution can be determined by mass spectrometry or nuclear magnetic resonance spectroscopy. These methods do not give information as to the exact location of the substituents (C1, C2, C3, etc.) or the distribution of the substituents on the cyclodextrin molecule (mono, di, tri, poly). Theoretically, the maximum degree of substitution is 18 for α-cyclodextrin, 21 for β-cyclodextrin, and 24 for γ-cyclodextrin, however, substituents with hydroxyl groups present the possibility for additional hydroxylalkylations.

The cyclodextrin used in the present invention is preferably an α-, β-, or γ-cyclodextrin. The cyclodextrin is selected for use depending on which cyclodextrin binds the guest compounds and yields the desired bioavailability. In a preferred embodiment, a derivative of a cyclodextrin is selected, and derivatives such as hydroxypropyl, dimethyl, and trimethyl substituted cyclodextrins are contemplated, as are cyclodextrins linked with sugar molecules, sulfonated cyclodextrins, carboxylated cyclodextrins, and amino derivatives such as diethylamino cyclodextrins. In a preferred embodiment, the cyclodextrin is a β-cyclodextrin, and in a more preferred embodiment, the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin. In yet another embodiment, the 2-hydroxypropyl-β-cyclodextrin has a degree of substitution between 2 and 8, more preferably between 4 and 8, most preferably between 5 and 8.

In a study performed in support of the invention, an intranasal formulation comprised of the GnRH compound deslorelin and of estradiol, testosterone, and cyclodextrin was prepared, as described in Example 1 and further discussed below.

Another exemplary mode of administration suitable for the method of the invention is an intravaginal device, such as an intravaginal ring or a vaginal thin-film laminate. Vaginal rings are well-known in the art (see for example Duncan et al., Silicone Based Release Systems, in POLYMERS INMEDICINE ANDSURGERY, Kronenthal et al. Eds., Plenum, N.Y., 1975, p. 205; U.S. Pat. Nos. 4,012,496; 5,869,081) and are made by polymerizing in a simple mold a mixture of the drug dispersion and a suitable polymer, such as silicone rubber. The ring or device is inserted into the vaginal cavity and retained there for a desired period of time for administration of the compounds incorporated into the device. Vaginal devices are described in LONG-ACTINGCONTRACEPTIVEDELIVERYSYSTEMS, Zatuchni, G., L., et al. Eds., 1984, and the particular chapters by Jackanicz, T. M., "Vaginal Ring Steroid-Releasing Systems, p. 201-212; by Diczfalusy & Landgren, "Some Pharmacokinetic and Pharmacodynamic Properties of Vaginal Delivery Systems that Release Small Amounts of Progestogens at a Near Zero-Order Rate", p. 213-227; and by Roy & Mishell, "Vaginal Ring Clinical Studies: Update", p. 581-594, are incorporated by reference herein.

Another exemplary mode of administration is transdermal. Transdermal administration is one approach to achieving a constant blood level of drug in a patient for a period of time. Transdermal administration offers, in addition to the benefit of a more constant blood level, other benefits such as a more efficient utilization of the drug, the potential for localized, site specific delivery, and less frequent administration (Baker, R. W., CONTROLLEDRELEASE OFBIOLOGICALLYACTIVEAGENTS, John Wiley and Sons, New York, (1987) p. 5-10). More efficient utilization of the drug is an important benefit, since often less drug, when administered in a controlled release manner, is required to produce a given duration of effect than when administered by another route. This is particularly true if the half-life of the drug is short compared with the desired treatment period. Since the drug is utilized more efficiently, a considerably lower dose may be required, depending on the drug half-life and the desired time of treatment.

Transdermal delivery devices, also referred to as transdermal patches, have been widely described (see, for example, Baker, R. W., Id.). The transdermal device can be a simple adhesive matrix type device with the active agents incorporated into the adhesive layer, or a more complicated device with one or more drug reservoirs defined by an impermeable backing layer and a retaining membrane. Design of the device and selection of suitable materials is readily accomplished by those of skill in the art. An exemplary device for use in the present invention is one designed to administer to a patient a dose of GnRH and an estrogenic compound and, optionally, an androgenic compound in an amount sufficient to treat a benign gynecological disorder and/or achieve contraception.

The present invention contemplates administration of the GnRH compound and the estrogenic compound, optionally containing an androgen, as a single composition by a single route of administration. For example, a dry powder comprised of the GnRH compound, the estrogenic compound, and, optionally, an androgen, and any desired excipients or enhancers, such as cyclodextrin, are mixed into a dosage form suitable for co-administration intranasally in the form of a dry aerosol. Or, for example, the same compounds are formulated into a liquid preparation for intranasal administration as a spray. Or, for example, the same compounds are incorporated into a transdermal device for co-administration of the GnRH, estrogenic compound, and the androgenic compound, if present, via the skin.

The invention further contemplates administration of the GnRH compound and the estrogenic compound, optionally containing an androgenic compound, in the form of two or more compositions for administration by two or more routes of administration. For example, the GnRH compound can be formulated into an intranasal preparation, and the estrogenic compound and, optionally, the androgenic compound can be formulated into a transdermal device. The two formulations are administered to a patient for treatment of a benign gynecological disorder or for contraception. That is, the GnRH is administered intranasally as needed to achieve the desired daily dose, and the estrogenic compound and, optionally, the androgenic compound is administered transdermally. It will be appreciated that the androgenic compound can be included in either formulation, preferably in the transdermal device, or administered as a separate, third composition by any suitable route. Other 'mixed modes' of administration will be readily apparent to those of skill in the art.
 

Claim 1 of 7 Claims

1. A method of treating a benign gynecological disorder in a patient population composed of premenopausal women, comprising, administering a gonadotropin releasing hormone (GnRH) compound, in an amount effective to suppress ovarian estrogen and progesterone production, and an estrogenic compound, in an amount effective to prevent signs and symptoms of estrogen deficiency, along with, optionally, an androgen, in an amount effective to prevent signs and symotoms of androgen deficiency, for a time oeriod of more than about 4 months, with the proviso that women in the patient population do not receive an exogenously supplied progestin during said time period to prevent endometrial hyperplasia.

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