The present invention relates to an improvement in a method of contraception, in treatment of benign gynecological disorders, and in hormone replacement. The improved method includes administering intranasally an estrogenic compound and an androgenic compound, and in some embodiments an optional progestin compound, in a once-daily bolus formulation comprised of the two or three steroids complexed with a cyclodextrin. An intranasal delivery system for administration of the formulation is also described.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the invention to provide a nasal preparation having an estrogenic compound and an androgenic compound and, an optional progestin compound, in the form of a complex with a cyclodextrin.

It is another object of the invention to provide a bolus-form of delivery of a composition comprised of an estrogenic compound and an androgenic compound and, optionally a progestin compound, that offers a therapeutic activity similar to that of a slow-release composition of the same active agents, with similar hormonal areas under the curves (AUCs) in a concentration-time plot of the two formulations or in achieving a similar biological effect such as amelioration of symptoms related to sex-steroid deprivation, specifically, loss of bone mineral density, atrophic vaginitis, and vasomotor instability.

In one aspect, the invention includes improvements in methods for contraception, for treatment of benign gynecological disorders, both in conjunction with a GnRH compound, and for hormone replacement for post-menopausal or surgically-postmenopausal women, where an estrogenic compound and an androgenic compound, such as testosterone, and an optional progestin compound, are administered, often on a long-term basis of longer than about 6 to about 12 months. The improvement comprises administering the estrogenic compound and the androgenic compound (an the optional progestin compound when present) intranasally in a once-daily bolus of an aqueous formulation containing the two or three compounds in the form of soluble complexes with a cyclodextrin. The amount of the two or three compounds administered is such as to produce estrogen and androgen and, optionally, progestin serum concentrations levels having substantially the same area-under-the-curve concentrations as are produced when therapeutically effective doses of the two or three compounds are administered transdermally. That is, administration of the estrogenic compound and the androgenic compound and, optionally, a progestin compound intranasally in bolus form achieves the same desired biological effect as that produced when the two or three compounds are administered transdermally.

The method of the invention, when used for treatment of a benign gynecological disorder or for contraception in conjunction with a GnRH compound, in one embodiment, includes administering the GnRH compound by any suitable route of administration, which may be different than an intranasal route employed for administration of the estrogenic compound and the androgenic compound and, optionally a progestin compound. The GnRH compound can be administered simultaneously or sequentially.

In one embodiment, the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin and is present at a concentration between about 50 mg/mL and 300 mg/mL. In another embodiment, 2-hydroxypropyl-β-cyclodextrin has a degree of substitution of between 2 and 8, more preferably between 5 and 8.

In another embodiment, the estrogenic compound is 17β-estradiol and the androgenic compound is testosterone and together they have a combined molar occupancy with respect to the cyclodextrin that is greater than the molar occupancy achievable with either steroid alone. For example, the combined molar occupancy of the two steroids is greater than 50%, in one embodiment. In another embodiment, the combined molar occupancy of the two steroids is greater than 60%.

In another embodiment, the estrogenic compound is 17β-estradiol at a daily dose between 0.15 mg and 0.6 mg and the androgenic compound is testosterone at a daily dose between 0.15 mg and 1 mg.

The mole ratio of 17β-estradiol to testosterone is between 1:1 and 1:2, in some embodiments.

In yet other embodiments, the molar occupancies of 17β-estradiol and testosterone are greater than 20% and 40%, respectively.

In another aspect, the invention includes an intranasal drug-delivery system for use in contraception or in treatment of benign gynecological disorders in conjunction with a GnRH compound, or in hormone replacement for postmenopausal or surgically postmenopausal women. The system is comprised of (a) a nasal-spray nebulizer effective to deliver a spray volume of between about 30 to about 200 μL, and (b) contained in the nebulizer, a drug formulation containing an estrogenic compound and an androgenic compound such as testosterone and, optionally, a progestin compound in an aqueous medium, in solubilized form complexed with a cyclodextrin. The amount of the two or three compounds administered in the spray volume is such as to produce estrogen and androgen, and progestin when present, serum concentrations having substantially the same area-under-the-curve concentrations as those produced when therapeutically effective doses of the two or three compounds are administered transdermally. That is, the biological effect achieved by intranasal administration of the two or three compounds is comparable to that produced when the two or three compounds are administered transdermally.

In one embodiment, the nasal preparation and the system are used on a long-term basis, i.e., for longer than about 6 months, more preferably for longer than about 12 months.

In yet another aspect, the invention includes a method of formulating two or more different steroids in a water-soluble form suitable for uptake by a human subject through mucosal tissue. The method is comprised of forming an aqueous solution of a cyclodextrin and adding the first, second and, optionally, third steroid to the solution in amounts effective to achieve a combined molar occupancy of the two or three steroids which is greater than the molar occupancy achievable with any single steroid alone.

In one embodiment, the aqueous solution of cyclodextrin is heated to above about 70° C. prior to said adding, and the solution is cooled slowly after solubilization of the added steroids.

In another embodiment, the first steroid is added to the solution until a maximum or near-maximum molar occupancy is reached, then the second and, optionally a third steroid, is/are added until a combined maximum or near-maximum molar occupancy is reached.

The cyclodextrin can be 2-hydroxypropyl-β-cyclodextrin, the estrogenic compound can be 17β-estradiol, the second steroid can be testosterone, and the third steroid can be progesterone.

DETAILED DESCRIPTION OF THE INVENTION

I. Nasal Formulation for Use in the Method

As noted above, the invention includes a nasal preparation for use in a variety of treatment modalities. For example, the nasal preparation finds use as add-back hormone replacement in women who have hormone production suppressed with a gonadotropin releasing hormone (GnRH) compound. "GnRH compound" refers to peptide and non-peptide GnRH analogs, including agonists and antagonists. These compounds are administered, for example, for female contraception and in the treatment of benign gynecological disorders. Thus, women currently taking a GnRH compound for treatment of a benign gynecological disorder or for contraception are candidates for treatment with the nasal preparation described herein. The nasal preparation also is suitable for use in hormone replacement therapy for both postmenopausal and surgically postmenopausal women. The nasal preparation is also suitable in peri-menopausal women, i.e., women entering menopause who have a low hormone level, and in women with a low hormone level as a result of another condition, disorder, or treatment regimen. The nasal preparation suitable for these various situations and conditions will now be described.

A1. Composition Components: Estrogenic Compound

The composition for use in the method of the invention includes an estrogenic compound. The estrogenic compound is effective to prevent one or more of the clinically recognized symptoms or signs of estrogen deficiency, including but not limited to 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 pg/mL to about 140 pg/mL, more preferably between about 30 pg/mL to about 50 pg/mL. A specific example of a composition containing an estrogenic compound is one comprised of 17β-estradiol and testosterone. The two compounds, along with other optional excipients, are formulated for delivery intranasally. For an intranasal preparation, a preferred dosage range for 17β-estradiol is between about 0.15 mg and 0.6 mg.

A2. Composition Components: Androgenic Compound

The composition further includes an androgenic compound. 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 serum levels of testosterone of from about 15 ng/dL to about 80 ng/d, and preferably about 40 ng/dL to about 60 ng/dL. For an intranasal preparation, a typical daily dose can range from between about 0.15 mg to about 1 mg. The steroid compounds, along with other optional excipients, are formulated for delivery intranasally, and exemplary formulations are described below.

A3. Composition Components: Cyclodextrin Excipient

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 6, 7, or 8 glucopyranose units, respectively. Cyclodextrins containing 9, 10, 11, 12, and 13 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 5. 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. Exemplary formulations that include the cyclodextrin 2-hydroxypropyl-β-cyclodextrin are described below.

A4. Composition Components: Progestin Compound

The composition comprised of an estrogenic compound and an androgenic compound can optionally include a progestin. Formulations that include a progestin can be administered for a limited period of time, for example on the order of 5 to 20 days, and preferably 10 to 15 days after each extended treatment regimen with a composition comprised of an estrogenic compound and an androgenic compound. The extended treatment regimen, during which the estrogenic and androgenic compounds are administered, is typically for at least about 4 months, more preferably for greater than about 6 months, and more specifically, of from about 4 months to about 12 months. The progestin is provided for a limited time period after such an extended time period. The progestin is given in an amount effective to minimize or eliminate the occurrence of endometrial hyperplasia or to preserve the efficacy achieved with hormone suppression by GnRH compounds in certain benign gynecologic disorders such as endometriosis and uterine fibroids by substantially reducing the possibility of endometrial hyperstimulation which may occur during prolonged treatment with estrogenic steroids without a progestin.

Suitable progestational agents (progestins) include but are not limited to dydrogesterone, ethynodiol diacetate, hydroxyprogesterone caproate, medroxyprogesterone acetate, norethindrone, norethindrone acetate, norethynodrel, norgestrel, progesterone, and megestrol acetate. Typical dose ranges for progestins depend upon the choice of steroid and the individual patient. Doses are selected as adequate to produce a secretory uterine endothelium after the time interval of progestin treatment (about 5 to about 20 contiguous days, and preferably about 10 to about 15 contiguous days). The serum level of progesterone is generally less than about 50 ng/dL after the time interval of progestin treatment.
 

Claim 1 of 10 Claims

1. A method for contraception, for treatment of benign gynecological disorders, or for hormone replacement, comprising,

administering intranasally a bolus of a formulation comprised of an estrogenic compound and an androgenic compound complexed with a cyclodextrin;

whereby said intranasal administering of said bolus is effective to achieve a physiologic effect comparable to that produced when the estrogenic compound and the androgenic compound are administered transdermally.

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