Link:  Pharm/Biotech Resources

Title:  Nasal spray formulation and method

United States Patent:  6,958,142

Issued:  October 25, 2005

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

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

Appl. No.:  298378

Filed:  November 15, 2002

A nasal spray formulation for use in female contraception or in the treatment of benign gynecological disorders is described. The nasal preparation is comprised of a GnRH compound and an estrogenic compound in the form of a water-soluble complex with a water-soluble cyclodextrin. The preparation effectively suppresses ovarian estrogen and progesterone production, and prevents signs and symptoms of estrogen deficiency, without a significant increase in the risk of endometrial hyperplasia.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the invention to provide a nasal preparation having a GnRH compound and an estrogenic compound, and optionally an androgenic compound, where uptake of the GnRH compound in the presence of the estrogenic and optional androgenic compounds is sufficient for therapeutic activity; i.e., uptake of the GnRH compound is substantially unhindered by the steroids.

It is another object of the invention to provide a bolus-form of delivery of a composition comprised of a GnRH compound and an estrogenic compound, and optionally an androgenic 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 curve.

In one aspect, the invention includes a nasal spray formulation for use in female contraception or in the treatment of benign gynecological disorders, the composition comprising an aqueous medium having dissolved therein (i) a GnRH compound and (ii) an estrogenic compound present in the form of a water-soluble complex with a water-soluble cyclodextrin. The concentration of GnRH compound and estrogenic compound in the formulation are effective, when administered daily in the form of a liquid aerosol having a total liquid volume between 30 and 200 μL, and over an extended period of administration, to suppress ovarian estrogen and progesterone production and to prevent signs and symptoms of estrogen deficiency, without a significant increase in the risk of endometrial hyperplasia.

The GnRH compound can be an agonist or an antagonist, and exemplary compounds include deslorelin, leuprolide, nafarelin, goserelin, decapeptyl, buserelin, histrelin, gonadorelin, abarelix, cetrorelix, azaline B, and degarelix, and analogs thereof.

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

In a preferred embodiment, the GnRH compound is deslorelin, at a daily dose between 0.025 and 1.5 mg.

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

In another embodiment, the formulation further includes testosterone as a second or third steroid in the form of a water-soluble complex with the cyclodextrin, and at a daily dose of between 0.15 and 1 mg.

In still another embodiment, the formulation further includes a progestin as a second or third steroid in the form of a water-soluble complex with the cyclodextrin.

The estrogenic compound and the second and or third steroid can have a combined molar occupancy with respect to the cyclodextrin that is greater than the molar occupancy achievable with any of the steroids alone.

In another aspect, the nasal preparation described above when intranasally administered as a daily bolus (i) is effective to achieve an average serum concentration over 24 hours of the estrogenic compound that is within 10% of the average serum concentration over 24 hours of the estrogenic compound when delivered transdermally and (ii) is as effective in preventing bone mineral density loss as transdermal administration of the estrogenic compound.

In another aspect, the invention includes an intranasal drug-delivery system for use in female contraception or in the treatment of benign gynecological disorders. The system is comprised of a nebulizer operable to deliver a selected volume between 30 and 200 μL of an aqueous formulation in the form of a liquid-droplet aerosol. Contained in the nebulizer is a liquid formulation composed of (i) a liquid carrier, (ii) a GnRH compound capable of suppressing ovarian estrogen and progesterone production, and (iii) an estrogenic compound capable of preventing signs and symptoms of estrogen deficiency when co-administered with the GnRH compound. The concentration of GnRH compound and estrogenic compound in the formulation are effective, when administered once daily in the form of a liquid aerosol having a total liquid volume between 30 and 200 μL, and over an extended period of administration, to suppress ovarian estrogen and progesterone production and to prevent signs and symptoms of estrogen deficiency, without a significant increase in the risk of endometrial hyperplasia.

DETAILED DESCRIPTION OF THE INVENTION

Nasal Formulation

As noted above, the invention includes a nasal preparation for use in female contraception or in the treatment of benign gynecological disorders. In this section, each component in the composition 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, peptide 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 suppressed, 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 α-azalglycine 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 dose of the GnRH compound is preferably sufficient to suppress ovarian estrogen and progesterone production, so that estrogen effects are predictably related to the co-administered estrogenic compound, described below. 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 in a daily nasal spray formulation with a volume between about 30 to about 200 μL can deliver a daily dose of GnRH compound of between about 0.025 mg to about 1.5 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 each 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, estrone potassium sulfate, and tibolone. 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 17-β-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 a GnRH agonist and 17-β-estradiol. The two compounds, along with other optional excipients and/or a progestin and/or an androgenic compound, are formulated for delivery intranasally. 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.

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 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 typical daily dose can range from between about 0.15 mg to about 1 mg. 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 intranasally, and exemplary formulations are described below.

A4. Composition Components: Progestin Compound

The composition comprised of a GnRH compound and an estrogenic compound, in some embodiments, can further 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 of, for example, about 4 months, more preferably greater than about 6 months, and more specifically, of from about 4 months to about 12 months. The progestin is provided in an amount effective to minimize or eliminate the occurrence of endometrial hyperplasia 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 progestogen 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 18 Claims

1. A nasal spray formulation, consisting essentially of an aqueous medium having dissolved therein

(i) a GnRH compound, and

(ii) an estrogenic compound, and optionally an androgenic compound, present in the form of a water-soluble complex with a water-soluble cyclodextrin

where the concentration of GnRH compound and estrogenic compound in the formulation are effective, when administered intranasally, to suppress ovarian estrogen and progesterone production and to prevent signs and symptoms of estrogen deficiency, without a significant increase in the risk of endometrial hyperplasia.

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