KR102488424B1 - Vaginal inserted estradiol pharmaceutical compositons and methods - Google Patents

Abstract

According to various embodiments of the present invention, pharmaceutical compositions comprising solubilized estradiol are provided. In various embodiments, such compositions are encapsulated in soft capsules, which can be inserted vaginally for the treatment of vulvovaginal atrophy.

Description

Intravaginal estradiol pharmaceutical composition and method

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to the following U.S. patent applications: United States filed January 27, 2014 entitled "VAGINAL INSERTED ESTRADIOL PHARMACEUTICAL COMPOSITIONS AND METHODS" Provisional Application No. 61/932,140; and U.S. Provisional Application No. 61/894,411, filed on October 22, 2013, entitled "SOLUBLE ESTRADIOL CAPSULE FOR VAGINAL INSERTION." This application is also filed on June 18, 2013, claiming priority to U.S. Provisional Application Serial No. 61/745,313, entitled "Soluble Estradiol Capsules for Intravaginal Insertion," filed on December 21, 2012. is a continuation-in-part of PCT US2013/46443 entitled "Soluble Estradiol Capsules for Intravaginal Insertion". This application also includes U.S. Provisional Application No. 61/661,302, filed Jun. 18, 2012, entitled "ESTRADIOL PHARMACEUTICAL COMPOSITIONS"; U.S. Provisional Application No. 61/662,265 entitled "PROGESTERONE PHARMACEUTICAL COMPOSITIONS" filed on June 20, 2012; and on March 15, 2013, claiming priority to U.S. Provisional Application No. 61/563,408, entitled "NATURAL COMBINATION HORMONE REPLACEMENT THERAPIES," filed on November 23, 2011; Continuation-in-part of U.S. Patent Application Serial No. 13/843,428 entitled "NATURAL COMBINATION HORMONE REPLACEMENT FORMULATIONS AND THERAPIES", filed on November 21, 2012, US patent application Ser. No. 13/684,002 (currently US Patent No. 8,633,178) entitled "Natural Concomitant Hormone Replacement Formulations and Therapies," filed December 6, 2013, entitled "Natural Concomitant Hormone It is a continuation-in-part of U.S. Patent Application Serial No. 14/099,562, "Alternative Formulations and Therapies." All of the aforementioned applications are hereby incorporated by reference herein in their entirety.

background art

This application relates to pharmaceutical compositions, methods, and devices related to hormone replacement therapy.

Postmenopausal women frequently suffer from atrophic vaginitis or vulvar and vaginal atrophy (hereinafter "vulvovaginal atrophy" or "VVA"), which includes, for example, vaginal dryness, vaginal odor, vaginal or vulvar irritation or itching, and dysuria (urination). pain, burning, or stinging), dyspareunia (vaginal pain associated with sexual activity), or vaginal bleeding associated with sexual activity. Other symptoms include soreness; accompanied by urinary frequency and urinary urgency; Urinary discomfort and urinary incontinence also occur ("estrogen-deficient voiding condition(s)"). One symptom of vaginal atrophy is an increased vaginal pH, which creates an environment more susceptible to infections. The mucosal epithelium of VVA patients is also reported to show signs of severe atrophy and, upon cytological examination, to be accompanied by increased numbers of parabasal cells and decreased numbers of superficial cells.

Each of these VVA-related conditions exhibits symptoms associated with reduced estrogenization of the vulvovaginal tissue and can even occur in women treated with oral administration of estrogen-based pharmaceutical drug products. Although VVA is most common in postmenopausal women, it can occur at any time in a woman's life cycle.

Estrogen therapy has proven very successful in controlling menopausal symptoms, including vaginal atrophy (VVA). Several studies have shown that symptoms associated with vaginal atrophy are relieved by estrogen therapy, often given systemically or topically. Existing treatments have a number of problems, for example, patient compliance issues that prevent them from completing or continuing treatment due to problems related to the type of treatment.

Accordingly, disclosed herein are, among other things, novel soft gel vaginal pharmaceutical compositions and dosage forms containing solubilized estradiol for the treatment of VVA. The present soft gel vaginal pharmaceutical composition is designed to alleviate the limitations common to other vaginal formulations of estradiol. The present soft gel vaginal pharmaceutical composition is expected to facilitate vaginal administration, provide improved insertion safety, minimize vaginal discharge after administration, and provide a more effective dosage form with improved efficacy, safety and patient compliance. do.

According to various aspects and embodiments of the present invention, a soft gel vaginal pharmaceutical composition is provided as a potential treatment for postmenopausal women suffering from moderate to severe symptoms of VVA.

A) a therapeutically effective amount of estradiol; and b) a solubilizing agent comprising a medium chain oil.

In some embodiments, the pessary comprises about 1 μg to about 25 μg of estradiol. For example, the pessary may contain from about 1 μg to about 10 μg of estradiol; and about 10 μg to about 25 μg of estradiol.

In some embodiments, estradiol is solubilized.

In some embodiments, the medium chain oil comprises at least one C6-C12 fatty acid or glycol, monoglyceride, diglyceride, or triglyceride ester thereof.

In some embodiments, the solubilizing agent comprises at least one ester selected from the group consisting of esters of caproic fatty acids, esters of caprylic fatty acids, esters of capric fatty acids, and combinations thereof. For example, the solubilizing agent may include caprylic/capric triglycerides.

In some embodiments, the pessary further comprises a capsule. For example, the capsule may be a soft gelatin capsule.

A) a therapeutically effective amount of estradiol; b) caprylic/capric triglycerides; c) nonionic surfactants including PEG-6 palmitostearate and ethylene glycol palmitostearate; and d) a soft gelatin capsule.

In some embodiments, a pessary provided herein comprises about 25 μg of estradiol, wherein administration of the pessary to a patient results in: 1) correction of the peak plasma concentration of estradiol (C _max ) in a plasma sample from the patient; a geometric mean of about 19 pg*hr/ml to about 29 pg*hr/ml; and 2) an area under the curve (AUC) of estradiol of about 75 pg*hr/ml to about 112 pg*hr/ml, a calibrated geometric mean of _0-24 .

In some embodiments, a pessary provided herein comprises about 25 μg of estradiol, wherein administration of the pessary to a patient results in: 1) a corrected peak plasma concentration of estrone (C _max ) in a plasma sample from the patient; a geometric mean of about 9 pg*hr/ml to about 14 pg*hr/ml; and 2) an area under the curve for estrone (AUC) of about 43 pg*hr/ml to about 65 pg*hr/ml, a calibrated geometric mean of _0-24 .

In some embodiments, a pessary provided herein comprises about 25 μg of estradiol, wherein administration of the pessary to a patient results in: 1) correction of the peak plasma concentration of estrone sulfate (C _max ) in a plasma sample from the patient; a geometric mean of about 416 pg*hr/ml to about 613 pg*hr/ml; and 2) an area under the curve for estrone sulfate (AUC) of about 3598 pg*hr/ml to about 5291 pg*hr/ml, a calibrated geometric mean of _0-24 .

In some embodiments, a pessary provided herein comprises about 10 μg of estradiol, wherein administration of the pessary to a patient results in: 1) correction of the peak plasma concentration of estradiol (C _max ) in a plasma sample from the patient; a geometric mean of about 12 pg*hr/ml to about 18 pg*hr/ml; and 2) an area under the curve (AUC) of estradiol of about 42 pg*hr/ml to about 63 pg*hr/ml, a calibrated geometric mean of _0-24 . In some embodiments, the pessary further provides a corrected geometric mean of time to peak plasma concentration of estradiol (T _max ) of about 1 hr to about 3 hr.

In some embodiments, a pessary provided herein comprises about 10 μg of estradiol, wherein administration of the pessary to a patient results in: 1) a corrected peak plasma concentration of estrone (C _max ) in a plasma sample from the patient; a geometric mean of about 4 pg*hr/ml to about 7 pg*hr/ml; and 2) an area under the curve for estrone (AUC) of about 20 pg*hr/ml to about 31 pg*hr/ml, a calibrated geometric mean of _0-24 . In some embodiments, the pessary further provides a corrected geometric mean of time to peak plasma concentration of estrone (T _max ) of about 4 hr to about 8 hr.

In some embodiments, a pessary provided herein comprises about 10 μg of estradiol, wherein administration of the pessary to a patient results in: 1) correction of the peak plasma concentration of estrone sulfate (C _max ) in a plasma sample from the patient; a geometric mean of about 10 pg*hr/ml to about 16 pg*hr/ml; and 2) an area under the curve for estrone sulfate (AUC) of about 56 pg*hr/ml to about 84 pg*hr/ml, a calibrated geometric mean of _0-24 . In some embodiments, the pessary further provides a calibrated geometric mean of time to peak plasma concentration of estrone sulfate (T _max ) of about 4 hr to about 7 hr.

In some embodiments, a pessary provided herein comprises about 4 μg of estradiol, wherein administration of the pessary to a patient results in: 1) correction of the peak plasma concentration of estradiol (C _max ) in a plasma sample from the patient; a geometric mean of about 4 pg*hr/ml to about 8 pg*hr/ml; and 2) an area under the curve (AUC) of estradiol of about 16 pg*hr/ml to about 26 pg*hr/ml, a calibrated geometric mean of _0-24 . In some embodiments, the pessary further provides a corrected geometric mean of time to peak plasma concentration of estradiol (T _max ) of about 0.25 hr to about 2 hr.

In some embodiments, a pessary provided herein comprises about 4 μg of estradiol, wherein administration of the pessary to a patient results in: 1) a corrected peak plasma concentration of estrone (C _max ) in a plasma sample from the patient; a geometric mean of about 1 pg*hr/ml to about 3 pg*hr/ml; and 2) an area under the curve for estrone (AUC) of about 8 pg*hr/ml to about 13 pg*hr/ml, a calibrated geometric mean of _0-24 . In some embodiments, the pessary further provides a corrected geometric mean of time to peak plasma concentration of estrone (T _max ) of about 1 hr to about 4 hr.

In some embodiments, a pessary provided herein comprises about 4 μg of estradiol, wherein administration of the pessary to a patient results in: 1) correction of the peak plasma concentration of estrone sulfate (C _max ) in a plasma sample from the patient; a geometric mean of about 4 pg*hr/ml to about 7 pg*hr/ml; and 2) an area under the curve for estrone sulfate (AUC) of about 22 pg*hr/ml to about 34 pg*hr/ml, a calibrated geometric mean of _0-24 . In some embodiments, the pessary further provides a calibrated geometric mean of time to peak plasma concentration of estrone sulfate (T _max ) of about 1 hr to about 3 hr.

Also provided herein is a pessary comprising about 1 μg to about 25 μg of estradiol, wherein administration of the pessary to a patient achieves a corrected geometric mean of the peak plasma concentration (C _max ) of estradiol by about 30 pg*hr Provided in less than /ml. For example, administration of a pessary to a patient provides a corrected geometric mean of peak plasma concentrations of estradiol (C _max ) of less than about 18 pg*hr/ml.

In some embodiments, a pessary is provided comprising about 1 μg to about 25 μg of estradiol, wherein administration of the pessary to a patient reduces the calibrated geometric mean of the area under the curve (AUC) of estradiol _0-24 to about 112 Provides less than pg*hr/ml. For example, administration of a pessary to a patient provides a corrected geometric mean of the area under the curve (AUC) _0-24 for estradiol of less than about 63 pg*hr/ml.

In some embodiments, a pessary is provided comprising about 1 μg to about 25 μg of estradiol, wherein administration of the pessary to a patient produces a corrected geometric mean peak plasma concentration of estrone (C _max ) of about 14 pg*hr. Provided in less than /ml. For example, administration of a pessary to a patient provides a corrected geometric mean of peak plasma concentrations of estrone (C _max ) of less than about 7 pg*hr/ml.

In some embodiments, a pessary is provided that includes about 1 μg to about 25 μg of estradiol, wherein administration of the pessary to a patient produces a corrected geometric mean of an area under the curve (AUC) of estrone _0-24 of about 65 pg. * Provides less than hr/ml. For example, administration of the pessary to a patient provides a corrected geometric mean of the area under the curve (AUC) of estrone _0-24 of less than about 31 pg*hr/ml.

In some embodiments, a pessary is provided comprising about 1 μg to about 25 μg of estradiol, wherein administration of the pessary to a patient achieves a corrected geometric mean peak plasma concentration of estrone sulfate (C _max ) of about 613 pg* Provides less than hr/ml. For example, administration of the pessary to a patient provides a calibrated geometric mean of peak plasma concentrations of estrone sulfate (C _max ) of less than about 16 pg*hr/ml.

In some embodiments, a pessary is provided comprising about 1 μg to about 25 μg of estradiol, wherein administration of the pessary to a patient reduces the calibrated geometric mean of the area under the curve for estrone sulfate (AUC) _0-24 to about 5291 Provides less than pg*hr/ml. For example, administration of the pessary to a patient provides a corrected geometric mean of the area under the curve (AUC) _0-24 for estrone sulfate of less than about 84 pg*hr/ml.

Further provided herein is a pessary comprising about 1 μg to about 25 μg of estradiol, wherein administration of the pessary to the proximal vaginal area of a patient exceeds 24 hours in the proximal vaginal area to achieve a therapeutically effective concentration of estradiol provides

The present invention also provides a method for treating an estrogen-deficient condition, comprising administering a pessary provided herein to a patient in need of treatment for an estrogen-deficient condition. In some embodiments, a method of treating vulvovaginal atrophy is provided, comprising administering to a patient in need thereof a pessary provided herein.

In some embodiments of the methods provided herein, the treatment is one or more selected from the group consisting of vaginal dryness, dyspareunia, vaginal or vulvar irritation, vaginal or vulvar burning, vaginal or vulvar itching, dysuria, and vaginal bleeding associated with sexual activity. Including reducing the severity of symptoms.

In some embodiments of the methods provided herein, the treatment comprises reducing the patient's vaginal pH. For example, treatment includes reducing the patient's vaginal pH to a pH less than about 5.0.

In some embodiments of the methods provided herein, the treatment includes a change in the patient's cellular composition. For example, changes in cell composition include reducing the number of vaginal subbasal cells or increasing the number of vaginal surface cells. In some embodiments, the number of vaginal parabasal cells in the patient is reduced by at least about 35% (eg, by at least about 50%). In some embodiments, the number of vaginal surface cells is increased by at least about 5% (eg, by at least about 35%).

The present specification includes the step of administering a pessary provided herein to a patient in need of a reduction in vaginal release after administration of the pessary, wherein vaginal release after administration of the pessary is contrasted with vaginal release after administration of a reference drug. Methods of reducing vaginal discharge after administration are further provided.

The above-mentioned features and objects of the present invention will become more apparent with reference to the following description taken in conjunction with the accompanying drawings, in which like reference numerals denote like elements.
1 is a flow diagram illustrating a process according to various embodiments of the present invention.
2 illustrates a suppository according to various embodiments of the present invention.
Figure 3 is a linear plot of mean plasma estradiol - baseline adjusted concentrations versus time (N=36).
Figure 4 is a semi-log plot of mean plasma estradiol - baseline adjusted concentrations versus time (N=36).
Figure 5 is a linear plot of mean plasma estrone - baseline adjusted concentration versus time (N=36).
6 is a semi-log plot of mean plasma estrone over time - baseline adjusted concentration (N=36).
Figure 7 is a linear plot of mean plasma estrone sulfate - baseline adjusted concentration versus time (N=36).
Figure 8 is a semi-log plot of mean plasma estrone sulfate - baseline adjusted concentrations versus time (N=36).
Figure 9 is a linear plot of mean plasma estradiol - baseline adjusted concentrations versus time (N=34).
Figure 10 is a semi-log plot of mean plasma estradiol - baseline adjusted concentrations versus time (N=34).
Figure 11 is a linear plot of mean plasma estrone - baseline adjusted concentration versus time (N=33).
Figure 12 is a semi-log plot of mean plasma estrone over time - baseline adjusted concentration (N=33).
Figure 13 is a linear plot of mean plasma estrone sulfate - baseline adjusted concentration versus time (N=24).
Figure 14 is a semi-log plot of mean plasma estrone sulfate - baseline adjusted concentrations versus time (N=24).

In the following detailed description of the embodiments of the present invention, reference is made to the accompanying drawings, in which like reference numerals indicate like elements, in which specific embodiments in which the present invention can be practiced are shown by way of example. While these embodiments have been described in sufficient detail to enable one skilled in the art to practice the present invention, it is to be understood that other embodiments may be utilized and other changes may be made without departing from the scope of the present invention. Accordingly, the following detailed description should not be taken in a limiting sense, and the scope of the present invention is limited only by the appended claims. As used herein, the term "or" shall be understood to be defined as a logical sum (i.e., and/or), and the terms "either", "unless", "alternatively", and exclusive disjunctions using words with similar effect, unless expressly indicated as such.

Justice

As used herein, the term “active pharmaceutical ingredient” (“API”) refers to an active compound(s) used in formulating a drug product.

As used herein, the term “co-administered” means that two or more drug products are administered simultaneously or sequentially on the same or different days.

As used herein, the term "drug product" means at least one active pharmaceutical ingredient formulated with at least one excipient and presented in unit dosage form.

The term "area under the curve" ("AUC") refers to the amount of an active pharmaceutical ingredient (eg, estradiol or progesterone) over time following administration of a dose of the active pharmaceutical ingredient, or Refers to the area under the curve defined by the change in the blood concentration of a metabolite of a pharmaceutical ingredient. "AUC0-∞" is the area under the concentration-time curve extrapolated to infinity after administration of a dose. “AUC0-t” is the area under the concentration-time curve from time 0 to time t after administration of the dose, where t is the last time point for the measurable concentration.

The term "Cmax" refers to the maximum value of blood concentration seen on a curve representing the change in blood concentration of an active pharmaceutical ingredient (eg, progesterone or estradiol), or a metabolite of an active pharmaceutical ingredient, over time. refers to

The term "Tmax" refers to the time taken for the plasma concentration of an active pharmaceutical ingredient (eg, estradiol or progesterone), or a metabolite of the active pharmaceutical ingredient, to reach a maximum value.

The term "bioavailability" - it is 21 C.F.R. § 320.1(a) - refers to the rate and extent to which an API or active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. For example, bioavailability can be measured as the amount of API in blood (serum or plasma) as a function of time. Pharmacokinetic (PK) parameters such as AUC, Cmax, or Tmax can be used to measure and evaluate bioavailability. For drug products not intended to be absorbed into the bloodstream, bioavailability can be assessed by measurements intended to reflect the rate and extent to which the API or active ingredient or active moiety becomes available at the site of action.

The term "bioequivalent" - it is 21 C.F.R. § 320.1(e) - means that an API or active ingredient or active moiety in a pharmaceutical equivalent or pharmaceutical substitute, when administered in equal molar doses under similar conditions in a properly designed study Indicates no significant difference in the rate and extent of availability at the site. In case there is an intentional difference in rate (e.g., in certain extended release dosage forms), a given pharmaceutical equivalent or substitute will ensure that the active ingredient or moiety from each product is available at the drug's site of action. If there is no significant difference in the extent to which they occur, they can be considered as bioequivalent. It is merely that differences in the rate at which the active ingredient or moiety becomes available at the drug's site of action are intentional, are reflected in the proposed labeling, are not essential to achieving effective body drug concentrations in chronic use, and are not intended to provide a medical indication for the drug. applied only when it is considered insignificant. Indeed, two products are considered bioequivalent if the 90% confidence interval of AUC, Cmax, or, alternatively, Tmax is within 80.00% to 125.00%.

The terms “bio-identical,” “body-identical,” or “natural,” as used in reference to the hormones disclosed herein, refer to those that occur naturally or endogenously in the human body. Hormones that match the chemical structure and effects of hormones. An exemplary natural estrogen is estradiol.

The term "bio-identical hormone" or "bio-identical" hormone refers to active pharmaceutical ingredients that are structurally identical to hormones found naturally or endogenously in the human body (eg, estradiol and progesterone).

The term “estradiol” refers to (17β)-estra-1,3,5(10)-triene-3,17-diol. Estradiol is also referred to interchangeably as 17β-estradiol, oestradiol, or E2, and is found endogenously in the human body. As used herein, estradiol refers to the bio-identical or bio-identical form of estradiol found in the human body, having the structure:

Estradiol is supplied in anhydrous or hemihydrate form. For purposes of this invention, anhydrous or hemihydrate forms may be used in place of the other by taking into account water or lack of water according to well known and recognized techniques.

The term "solubilized estradiol" means that estradiol or a portion thereof is dissolved or solubilized in a formulation or solubilizing agent(s) disclosed herein. The solubilized estradiol is about 80% solubilized, about 85% solubilized, about 90% solubilized, about 95% solubilized, about 96% solubilized, about 97% solubilized, about 98% solubilized, about 99% solubilized, or about 100% solubilized. Estradiol may be included. In some embodiments, the estradiol is "fully solubilized" by solubilizing or dissolving all or substantially all of the estradiol in the solubilizing agent. Fully solubilized estradiol can include about 97% solubilized, about 98% solubilized, about 99% solubilized or about 100% solubilized estradiol. Solubility can be expressed as mass fraction (% w/w, also referred to as weight percent (wt%)).

The term “progesterone” refers to pregin-4-ene-3,20-dione. Progesterone is also referred to interchangeably as P4 and is found endogenously in the human body. As used herein, progesterone refers to the bio-identical or bio-identical form of progesterone found in the human body, having the structure:

The term “solubilized progesterone” means progesterone or a portion thereof is dissolved or solubilized in a formulation or solubilizing agent(s) disclosed herein. In some embodiments, progesterone is "partially solubilized" by solubilizing or dissolving a portion of progesterone in a solubilizing agent and by suspending a portion of progesterone in a solubilizing agent. Partially solubilized progesterone is about 1% solubilized, about 5% solubilized, about 10% solubilized, about 15% solubilized, about 20% solubilized, about 30% solubilized, about 40% solubilized, about 50% solubilized, about 60% solubilized, about 70% solubilized, about 80% solubilized, about 85% solubilized, about 90% solubilized or about 95% solubilized progesterone. In another embodiment, progesterone is "fully solubilized" by solubilizing or dissolving all or substantially all of the progesterone in a solubilizing agent. Fully solubilized progesterone can include about 97% solubilized, about 98% solubilized, about 99% solubilized or about 100% solubilized progesterone. Solubility can be expressed as mass fraction (% w/w, also referred to as weight percent (wt%)).

As used herein, the terms "micronized progesterone" and "micronized estradiol" refer to micronized progesterone and micronized estradiol having an X50 particle size value of less than about 15 microns or an X90 particle size value of less than about 25 microns. includes The term "X50" means that half of the particles in the sample are smaller in diameter than the given number. For example, micronized progesterone having an X50 of 5 microns means that for a given sample of micronized progesterone, half of the particles have a diameter of less than 5 microns. Similarly, the term "X90" means that ninety percent (90%) of the particles in the sample are smaller in diameter than the given number.

The term “glyceride” is an ester of glycerol (1,2,3-propanetriol) with acyl radicals of fatty acids, also known as acylglycerols. When only one position of the glycerol molecule is esterified with a fatty acid, a “monoglyceride” or “monoacylglycerol” is produced; When the two positions are esterified, a "diglyceride" or "diacylglycerol" is produced; When all three positions of glycerol are esterified with a fatty acid, a "triglyceride" or "triacylglycerol" is produced. It is a “simple” glyceride if all esterified positions contain the same fatty acid; On the other hand, when the esterified position contains different fatty acids, it is a “complex” glyceride. The carbons of the glycerol backbone are designated as sn-1, sn-2 and sn-3, where sn-2 is the middle carbon and sn-1 and sn-3 are the terminal carbons of the glycerol backbone.

The term “solubilizer” refers to an agent or combination of agents that solubilizes an active pharmaceutical ingredient (eg, estradiol or progesterone). For example and without limitation, suitable solubilizing agents include medium chain oils and other solvents and co-solvents that solubilize or dissolve the active pharmaceutical ingredient to a desired degree. Solubilizers suitable for use in the formulations disclosed herein are pharmaceutical grade solubilizers (eg, pharmaceutical grade medium chain oils). It will be appreciated by those skilled in the art that other excipients or ingredients may be added to or mixed with the solubilizer to enhance the properties or performance of the solubilizer or the resulting formulation. Examples of such excipients include, but are not limited to, surfactants, emulsifiers, thickeners, colorants, flavoring agents, and the like. In some embodiments, the solubilizing agent is a medium chain oil, and in some other embodiments, the medium chain oil is combined with co-solvent(s) or other excipient(s).

The term “medium chain” is used to describe the aliphatic chain length of a fatty acid containing molecule. “Medium chain” specifically refers to fatty acids containing 6 (C6) to 14 (C14) carbon atoms, 8 (C8) to 12 (C12) carbon atoms, or 8 (C8) to 10 (C10) carbon atoms. Refers to fatty acids, fatty acid esters, or fatty acid derivatives containing an aliphatic tail or carbon chain.

The terms "medium chain fatty acid" and "medium chain fatty acid derivative" are used to describe fatty acids or fatty acid derivatives having an aliphatic tail (ie, carbon chain) having from 6 to 14 carbon atoms. Fatty acids consist of an unbranched or branched aliphatic tail attached to a carboxylic acid functional group. Fatty acid derivatives include, for example, fatty acid esters and fatty acid containing molecules, including, without limitation, mono-, di- and triglycerides including components derived from fatty acids. Fatty acid derivatives also include fatty acid esters of ethylene or propylene glycol. Aliphatic tails can be saturated or unsaturated (ie, have one or more double bonds between carbon atoms). In some embodiments, the aliphatic tail is saturated (ie, no double bonds between carbon atoms). Medium chain fatty acids or medium chain fatty acid derivatives are those with an aliphatic tail of 6 to 14 carbons, including those of C6-C14, C6-C12, C8-C14, C8-C12, C6-C10, C8-C10, or others. include Examples of medium chain fatty acids include, without limitation, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, and derivatives thereof.

As used herein, the term "oil" refers to any oil capable of suspending or solubilizing the biologically equivalent progesterone or estradiol, including starting materials or precursors thereof, including micronized progesterone or micronized estradiol as described herein. Refers to any pharmaceutically acceptable oil, especially medium chain oil, specifically excluding peanut oil.

The term “medium chain oil” refers to an oil in which the composition of the fatty acid fraction of the oil is medium chain (ie, C6 to C14) fatty acids in nature, i.e. the compositional profile of the fatty acids in the oil is medium chain in nature. As used herein, "substantially" means that between 20% and 100% (inclusive) of the fatty acid fraction of the oil is medium-chain fatty acids, i.e., an aliphatic tail having 6 to 14 carbons (i.e., a carbon chain). It means that it is composed of fatty acids with In some embodiments, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70% of the fatty acid fraction of the oil, About 75%, about 85%, about 90% or about 95% is composed of medium chain fatty acids. When characterizing a given oil or solubilizing agent, the term "alkyl content" or "alkyl distribution" of an oil may be used in place of the term "fatty acid fraction" of an oil, and these terms are used interchangeably herein. will be easily understood. As such, medium chain oils suitable for use in the formulations disclosed herein include medium chain oils in which the fatty acid fraction of the oil is essentially medium chain fatty acids, or medium chain oils in which the alkyl content or alkyl distribution of the oil is essentially medium chain alkyl (C6-C12 alkyl). include It will be appreciated by those skilled in the art that suitable medium chain oils for use in the formulations disclosed herein are pharmaceutical grade (eg, pharmaceutical grade medium chain oils). Examples of medium chain oils include, for example and without limitation, medium chain fatty acids, medium chain fatty acid esters of glycerol (e.g., mono-, di-, and triglycerides), medium chain fatty acid esters of propylene glycol, medium chain polyethylene glycol fatty acid derivatives, and combinations thereof.

The term "ECN" or "equivalent carbon number" means the sum of the number of carbon atoms in the fatty acid chain of an oil and can be used, for example, to characterize an oil as a medium chain oil or a long chain oil. For example, the ECN of tripalmitin (glycerol tripalmitate), which is a simple triglyceride containing 3 fatty acid chains of 16 carbon atoms, is 3×16=48. In contrast, triglycerides with ECN=40 were 8, 16 and 16; 10, 14 and 16; It may have “complex” fatty acid chain lengths such as 8, 14 and 18. Naturally occurring oils are often "complexed" with respect to certain fatty acids, but do not tend to contain both long and medium chain fatty acids within the same glycerol backbone. Thus, triglycerides with an ECN of 21 to 42 typically contain predominantly medium-chain fatty acids; On the other hand, triglycerides with an ECN greater than 43 typically contain predominantly long-chain fatty acids. For example, the ECN of corn oil triglycerides in USP will range from 51 to 54. Medium chain diglycerides with an ECN of 12 to 28 will often contain predominantly medium chain fatty chains; On the other hand, diglycerides with an ECN of 32 or higher will typically contain predominantly long-chain fatty acid tails. The ECN of the monoglyceride will match the chain length of the single fatty acid chain. Thus, monoglycerides with an ECN ranging from 6 to 14 will contain predominantly medium chain fatty acids, and monoglycerides with an ECN greater than 16 will contain predominantly long chain fatty acids.

Medium chain triglyceride oils typically have an average ECN of 21 to 42. For example, as listed in the US Pharmacopeia (USP), medium chain triglycerides have the following compositions set forth in the table below as exemplary oils:

The average ECN would be 3*[(6*0.02) + (8*0.70) + (10*0.25) + (12*0.02) + (14*0.01)] = 25.8. The ECN of exemplary medium chain triglyceride oils can also be expressed in the range of 24.9 to 27.0 (according to the ranges described in the USP). For oils with mixed mono-, di-, and triglycerides, or single and double fatty acid glycols, the ECN of the whole oil is equal to each individual component (e.g., C8 monoglycerides, C8 diglycerides, It can be determined by calculating the ECN of the C10 monoglyceride, and the C10 monoglyceride) and taking the sum of the relative percentages of that component multiplied by the ECN normalized to the monoglyceride for each component. For example, the oil with C8 and C10 mono- and diglycerides shown in the table below has an ECN of 8.3 and is therefore a medium chain oil.

In other words, ECN can be calculated by multiplying each chain length of the composition by its relative percentage in oil: (8 * 0.85) + (10 * 0.15) = 8.3.

As used herein, the term "excipient" refers to non-API ingredients such as solubilizers, antioxidants, oils, lubricants, and other materials used to formulate pharmaceuticals.

The term “patient” or “subject” refers to an individual to whom a pharmaceutical composition is administered.

The term "pharmaceutical composition" refers to a pharmaceutical composition comprising at least a solubilizing agent and estradiol. As used herein, a pharmaceutical composition is delivered, for example via a pessary (ie, intravaginal suppository), or absorbed vaginally.

The term "progestin" means any substance, natural or artificial, that has pharmacological properties similar to progesterone.

The term “reference listed drug product” (“RLD”) means VAGIFEM® (estradiol vaginal tablet) or ESTRACE® vaginal cream.

The terms “treat,” “treating,” and “treatment” refer to any indication of success in treating or ameliorating an injury, disease, or condition, including: decline; remission; reducing symptoms or making the injury, disease, or condition more tolerable by the patient; slowing down the rate of denaturation or degradation; or any objective or subjective parameter such as an improvement in the patient's physical or mental well-being. Treatment or improvement of symptoms may be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examination, or psychoemotional evaluation.

The terms "atrophic vaginitis", "vulvovaginal atrophy", "vaginal atrophy", and "VVA" are used interchangeably herein. The molecular morphology of VVA is well known in the medical field.

Introduction

Provided herein are pharmaceutical compositions comprising solubilized estradiol designed for vaginal absorption. The pharmaceutical compositions disclosed herein are designed to be absorbed topically, eg in the vagina or into surrounding tissues, and have their therapeutic effect. Further disclosed herein are methods relating to the pharmaceutical compositions as well as data demonstrating the efficacy of the disclosed pharmaceutical compositions. In general, the pharmaceutical compositions disclosed herein are useful for VVA, dyspareunia, and other indications caused by a decrease or lack of estrogen.

Additional aspects and embodiments of the present invention are directed to potentially minimizing certain side effects from improper insertion while providing increased patient ease of use; minimizing the incidence of vulvovaginal mycotic infection compared to the incidence of vulvovaginal mycotic infection due to the use of other intravaginal estradiol products; and an improved side effect profile (eg, pruritus) compared to the reference drug VAGIFEM® (estradiol vaginal tablet, Novo Nordisk, Princeton, NJ).

pharmaceutical composition

Functional

According to embodiments, the pharmaceutical compositions disclosed herein are alcohol-free or substantially alcohol-free. The present pharmaceutical composition provides improved patient compliance due to improvements over prior art products. According to embodiments, the pharmaceutical compositions disclosed herein are encapsulated within soft gelatin capsules, which improve comfort during use. According to embodiments, the pharmaceutical composition is liquid in nature, which is more readily absorbed by the vaginal tissue and is also dispersed over a larger surface area of the vaginal tissue.

Estradiol

According to embodiments, the pharmaceutical compositions disclosed herein are for vaginal insertion in single or multi-unit dosage form. According to embodiments, the estradiol in the pharmaceutical composition is at least about 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86% , 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% solubilized. According to embodiments and when estradiol is not 100% solubilized, the remaining estradiol is present in a micronized (crystalline) form absorbable by the body, either in its micronized form or in another form to which the micronized form is converted after administration. It has biological functionality.

According to embodiments, all or some of the estradiol is solubilized in the solubilizing agent during the manufacturing process. According to embodiments, all or a portion of estradiol is solubilized after administration (eg, if estradiol is not 100% solubilized, an undifferentiated portion is solubilized in a body fluid after administration). According to embodiments, since estradiol is solubilized, solubilizing agents taught herein are liquid or semi-solid, with or without additional excipients in addition to the solubilizing agent. Unless estradiol is fully solubilized at the time of administration/insertion, estradiol is present at body temperature (average 37° C.) and, in general, at vaginal pH (range of 3.8 to 4.5 in healthy patients; and ranges from 4.6 to 6.5 in VVA patients). ) should be virtually solubilized.

According to embodiments, estradiol may be added to the pharmaceutical compositions disclosed herein in the form of estradiol, estradiol hemihydrate, or other grades of estradiol used in pharmaceutical compositions or formulations.

According to embodiments, the intensity of estradiol administration is varied. Estradiol (or estradiol hemihydrate, eg, to the extent the water content of estradiol hemihydrate is taken into account) dosage strength is from at least about 1 microgram (μg or μg) to at least about 50 μg. Specific dosage embodiments include at least about 1 μg, 2 μg, 3 μg, 4 μg, 5 μg, 6 μg, 7 μg, 8 μg, 9 μg, 10 μg, 11 μg, 12 μg, 13 μg, 14 μg, 15 μg, 16 μg, 17 μg, 18 μg, 19 μg, 20 μg, 21 μg, 22 μg, 23 μg, 24 μg, 25 μg, 26 μg, 27 μg, 28 μg, 29 μg, 30 μg, 31 μg , 32 μg, 33 μg, 34 μg, 35 μg, 36 μg, 37 μg, 38 μg, 39 μg, 40 μg, 41 μg, 42 μg, 43 μg, 44 μg, 45 μg, 46 μg, 47 μg, 48 μg, 49 μg, or 50 μg of estradiol. According to embodiments, the pharmaceutical composition contains at least about 2.5 μg, 4 μg, 6.25 μg, 7.5 μg, 12.5 μg, 18.75 μg of estradiol. According to embodiments, the pharmaceutical composition comprises about 1 μg to about 10 μg, 3 μg to 7 μg, about 7.5 μg to 12.5 μg, about 10 μg to about 25 μg, about 1 μg, about 2.5 μg, about 23.5 μg. to 27.5 μg, about 7.5 μg to 22.5 μg, 10 μg to 25 μg of estradiol. The lowest clinically effective dose of estradiol is used for the treatment of VVA and other indications described herein. In some embodiments, the estradiol dosage is about 4 μg. In one embodiment, the estradiol dose is about 10 μg. In another embodiment, the estradiol dose is about 25 μg.

solvent system

According to embodiments, the solvent system that solubilizes estradiol is, along with other excipients, a medium chain fatty acid based solvent. According to embodiments, the solvent system includes non-toxic pharmaceutically acceptable solvents, co-solvents, surfactants, and other excipients suitable for vaginal delivery or absorption.

According to an embodiment, an oil having medium chain fatty acids as a main component is used as a solubilizing agent to solubilize estradiol. According to embodiments, the solubilizing agent comprises medium chain fatty acid esters (eg, esters of glycerol, esters of ethylene glycol, or esters of propylene glycol) or mixtures thereof. According to an embodiment, the medium chain fatty acid comprises a chain length of C6 to C14. According to an embodiment, the medium chain fatty acid comprises a chain length of C6 to C12. According to an embodiment, the medium chain fatty acid substantially comprises a chain length of C8 to C10. The ECN for medium chain oils will range from 21 to 42 for triglycerides, from 12 to 28 for diglycerides and from 6 to 14 for monoglycerides.

According to embodiments, the medium chain fatty acids are saturated. According to embodiments, the medium chain fatty acids are predominantly saturated, i.e. greater than about 60% or greater than about 75% saturated.

According to embodiments, estradiol is soluble in the solubilizer at room temperature, but it may be desirable to warm certain solubilizers during manufacture to improve viscosity. According to embodiments, the solubilizing agent is liquid at room temperature to about 50°C, at or below 50°C, at or below 40°C, or at or below 30°C.

According to embodiments, the solubility of estradiol in medium chain oil, medium chain fatty acid, or solubilizing agent (or oil/surfactant) is at least about 0.01%, 0.02%, 0.05%, 0.06%, 0.08%, 0.1 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, or more.

According to embodiments, the medium chain solubilizing agent includes, for example and without limitation, the following saturated medium chain fatty acids: caproic acid (C6), enanthic acid (C7), caprylic acid (C8), pelargonic acid (C9). ), capric acid (C10), undecylic acid (C11), lauric acid (C12), tridecylic acid (C13), or myristic acid (C14). According to embodiments, the solubilizing agent is an oil of these free medium chain fatty acids; oils of medium chain fatty acid esters of glycerin, propylene glycol, or ethylene glycol; or combinations thereof. These examples include predominantly saturated medium chain fatty acids (ie, greater than 50% of the fatty acids are medium chain saturated fatty acids). According to an embodiment, primarily C6 to C12 saturated fatty acids are contemplated. According to embodiments, the solubilizing agent is selected from at least one of a solvent or a co-solvent.

According to embodiments, glycerin based solubilizers include mono-, di-, or triglycerides and combinations and derivatives thereof. Exemplary glycerin based solubilizers include caprylic/capric triglycerides, MIGLYOL® (SASOL Germany GMBH, Hamburg, Germany). MIGLYOL includes MIGLYOL 810 (caprylic/capric triglycerides), MIGLYOL 812 (caprylic/capric triglycerides), MIGLYOL 816 (caprylic/capric triglycerides), and MIGLYOL 829 (caprylic/capric/succinic triglycerides). Other caprylic/capric triglyceride solubilizers are likewise contemplated, for example caproic/caprylic/capric/lauric triglycerides; caprylic/capric/linoleic acid triglycerides; caprylic/capric/succinic triglycerides. According to an embodiment, CAPMUL MCM, a medium chain mono- and di-glyceride, is the solubilizing agent. Other and triglycerides of fractionated vegetable fatty acids, and combinations or derivatives thereof, may be solubilizers according to embodiments. For example, the solubilizing agent can be a 1,2,3-propanetriol (glycerol, glycerin, glycerin) ester of saturated coconut oil and saturated palm kernel oil and their derivatives.

Ethylene and propylene glycol (which includes polyethylene and polypropylene glycol) solubilizers include: glyceryl mono- and di-caprylate; propylene glycol monocaprylate (eg, CAPMUL® PG-8 (CAPMUL brand owned by ABITEC, Columbus, Ohio)); propylene glycol monocaprate (eg CAPMUL PG-10); propylene glycol mono- and dicaprylates; propylene glycol mono- and dicaprates; diethylene glycol mono esters (eg, TRANSCUTOL®, 2-(2-ethoxyethoxy)ethanol, ); and diethylene glycol monoethyl ether. Other combinations of propylene glycol or mono- and di-esters of ethylene glycol are expressly contemplated as solubilizing agents.

According to embodiments, solubilizing agents include combinations of mono- and di-propylene and ethylene glycol and combinations of mono-, di-, and triglycerides. According to embodiments, polyethylene glycol glycerides (GELUCIRE®, Saint-Priest, France) can be used in the present invention as a solubilizing agent or as a surfactant. For example, GELUCIRE 44/14 (PEG-32 Glyceryl Laurate EP), a medium-chain fatty acid ester of polyethylene glycol, is a polyethylene glycol glyceride composed of mono- and diesters and mono-, di- and triglycerides of polyethylene glycol. to be.

According to embodiments, commercially available fatty acid glycerol and glycol ester solubilizers are often prepared from natural oils and thus may include ingredients in addition to the fatty acid esters that primarily constitute and characterize the solubilizer. Such other ingredients include, for example, other fatty acid mono-, di-, and triglycerides; fatty acid mono- and diesters ethylene or propylene glycol; free glycerol or glycol; or free fatty acids. In some embodiments, when the oil/solubilizer is described herein as a saturated C8 fatty acid mono- or diester of glycerol, the major component of the oil, i.e. >50 wt% (e.g., >75 wt%, >85 wt%) % or >90% by weight) are caprylic monoglycerides and caprylic diglycerides. For example, the Technical Data Sheet by ABITEC for CAPMUL MCM C8 describes CAPMUL MCM C8 as consisting of mono- and diglycerides of medium-chain fatty acids (mainly caprylic acid), with an alkyl content of ≤1% C6, ≥95% C8, ≤5% C10, and ≤1.5% C12 and higher.

For example, MIGLYOL 812 is a solubilizing agent commonly described as a C8-C10 triglyceride because its fatty acid composition is at least about 80% triglyceride esters of caprylic (C8) and capric acid (C10). to be. However, it also contains small amounts of other fatty acids, such as less than about 5% of caproic acid (C6), lauric acid (C12), and myristic acid (C14). The product information sheets for the various MIGLYOLs illustrate the various fatty acid ingredients as follows:

According to embodiments, anionic or nonionic surfactants may be used in pharmaceutical compositions containing solubilized estradiol. The ratio of solubilizing agent(s) to surfactant(s) varies depending on the respective solubilizing agent(s) and the respective surfactant(s) and the desired physical properties of the resulting pharmaceutical composition. For example and without limitation, CAPMUL MCM and nonionic surfactants can be used in ratios including 65:35, 70:30, 75:25, 80:20, 85:15 and 90:10. Other non-limiting examples include: CAPMUL MCM and GELUCIRE 39/01 used in ratios including, for example and without limitation, 6:4, 7:3, and 8:2; CAPMUL MCM and GELUCIRE 43/01 used in ratios including, for example and without limitation, 7:3, and 8:2; CAPMUL MCM and GELUCIRE 50/13 used in ratios including, for example and without limitation, 7:3, and 8:2, and 9:1.

other excipients

According to embodiments, the pharmaceutical composition further comprises a surfactant. Surfactants can be nonionic surfactants, cationic surfactants, anionic surfactants, or mixtures thereof. Suitable surfactants include, for example, water-insoluble surfactants with a hydrophilic-lipophilic balance (HLB) value of less than 12 and water-soluble surfactants with an HLB value of greater than 12. Surfactants with high HLB and hydrophilicity aid in the formation of oil-water droplets. Surfactants are amphiphilic in nature and can dissolve or solubilize relatively high amounts of hydrophobic drug compounds.

Non-limiting examples include: TWEEN, dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), ethanol, glycerin, N-methyl-2-pyrrolidone (NMP), PEG 300, PEG 400 , Poloxamer 407, propylene glycol, phospholipids, hydrogenated soybean phosphatidylcholine (HSPC), distearoylphosphatidylglycerol (DSPG), L-α dimyristoylphosphatidylcholine (DMPC), L-α-dimyristoyl Phosphatidylglycerol (DMPG), Polyoxyl 35 Castor Oil (CREMOPHOR EL, CREMOPHOR ELP), Polyoxyl 40 Hydrogenated Castor Oil (CREMOPHOR RH 40), Polyoxyl 60 Hydrogenated Castor Oil (CREMOPHOR RH 60), Polysorbate ( Polysorbate) 20 (TWEEN 20), Polysorbate 80 (TWEEN 80), d-α-Tocopheryl Polyethylene Glycol 1000 Succinate (TPGS), Solutol HS-15, Sorbitan Monooleate (SPAN 20), PEG 300 Car Prilic/capric glycerides (SOFTIGEN 767), PEG 400 caprylic/capric glycerides (LABRASOL), PEG 300 oleic glycerides (LABRAFIL M-1944CS), polyoxyl 35 castor oil (ETOCAS 35), Glyceryl caprylate (mono- and diglycerides) (IMWITOR), PEG 300 linoleic acid glycerides (LABRAFIL M-2125CS), polyoxyl 8 stearate (PEG 400 monostearate), polyoxyl 40 stearate (PEG 1750 monostearate), and combinations thereof. Additionally, suitable surfactants include, for example, polyoxyethylene derivatives of sorbitan monolaurate, such as polysorbate, caprylcaproyl macrogol glycerides, polyglycolized glycerides, and the like.

According to embodiments, the nonionic surfactant is glycerol and polyethylene glycol esters of long chain fatty acids, such as GELUCIRE 39/01 (glycerol esters of saturated C12-C18 fatty acids), GELUCIRE 43/01 (hard fat NF/JPE) and GELUCIRE 50/13 (lauroyl macrogel-32 glycerides or lauroyl polyoxyl-32 glycerides, commercially available as GELUCIRE including stearoyl macrogol-32 glycerides EP; stearoyl polyoxyl-32 glycerides NF; stearoyl polyoxylglycerides (USA FDA IIG)). These surfactants can be used at concentrations greater than about 0.01%, and typically in various amounts from about 0.01% to 10.0%, 10.1% to 20%, and 20.1% to 30%. In some embodiments, the surfactant may be used at a concentration of about 1% to about 10% (e.g., about 1% to about 5%, about 2% to about 4%, about 3% to about 8%). .

According to embodiments, the nonionic surfactant includes, for example and without limitation, one or more of oleic acid, linoleic acid, palmitic acid, and stearic acid. According to embodiments, nonionic surfactants include polyethylene sorbitol esters, including polysorbate 80, available under the trademark TWEEN® 80 (Polysorbate 80) (Sigma Aldrich, St. Louis, Mo.) can be purchased Polysorbate 80 contains approximately 60% to 70% oleic acid, with the remainder mainly linoleic acid, palmitic acid, and stearic acid. Polysorbate 80 may be used in an amount ranging from about 5 to 50%, and in some embodiments, about 30% of the total mass of the pharmaceutical composition.

According to an embodiment, the nonionic surfactant includes PEG-6 palmitostearate and ethylene glycol palmitostearate, which are commercially available as TEFOSE® 63 (Saint-Priest, France), which are, for example, CAPMUL It can be used with MCM, for example at a MCM to TEFOSE 63 ratio of 8:2 or 9:1. According to embodiments, other solubilizer/nonionic surfactant combinations include, for example, MIGLYOL 812:GELUCIRE 50/13 or MIGLYOL 812:TEFOSE 63.

According to embodiments, the surfactant can be an anionic surfactant, such as ammonium lauryl sulfate, dioctyl sodium sulfosuccinate, perfluorooctane sulfonic acid, potassium lauryl sulfate, or sodium stearate. Cationic surfactants are also contemplated.

According to embodiments, the nonionic or anionic surfactant may be used alone with at least one solubilizing agent or may be used in combination with other surfactants. Accordingly, such surfactants, or any other excipients as described herein, may be used to solubilize estradiol. The combination of solubilizers, surfactants, and other excipients should be designed so that estradiol is absorbed into the vaginal tissue. According to embodiments, the pharmaceutical composition will result in minimal vaginal release.

According to an embodiment, the pharmaceutical composition further comprises at least one thickening agent. Generally, a thickening agent is added when the viscosity of the pharmaceutical composition is less than the desired absorption. According to embodiments, the surfactant(s) disclosed herein can also provide thickening of the pharmaceutical composition, which upon release helps estradiol to be absorbed by the vaginal mucosa while minimizing vaginal discharge. It will be. Examples of thickeners include: hard fats; propylene glycol; A mixture of hard fat EP/NF/JPE, glyceryl ricinoleate, ethoxylated fatty alcohols (Ceteth-20, Steareth-20) EP/NF (available as OVUCIRE® 3460, St. Priest, France) of material); A mixture of hard fat EP/NF/JPE, glycerol monooleate (type 40) EP/NF (OVUCIRE WL 3264); A mixture of hard fat EP/NF/JPE, glyceryl monooleate (type 40) EP/NF (OVUCIRE WL 2944); nonionic surfactants including PEG-6 stearate, ethylene glycol palmitostearate, and PEG-32 stearate; TEFOSE 63 or a similar product; and a mixture of various hard fats (WITEPSOL®, Sasol Germany GmbH, Hamburg, Germany). Other thickening agents are, for example, alginates, certain gums, such as xanthan gum, agar-agar, iota carrageenan, kappa carrageenan and the like. Several other compounds can act as thickeners, such as gelatin and polymers such as HPMC, PVC, and CMC. According to embodiments, the viscosity of the pharmaceutical composition according to various embodiments may comprise from about 50 cp to about 1000 cp at 25°C. One skilled in the art will readily understand and select from suitable thickening agents.

According to embodiments, the thickener is a nonionic surfactant. For example, polyethylene glycol saturated or unsaturated fatty acid esters or diesters are nonionic surfactant thickeners. In an embodiment, the nonionic surfactant comprises polyethylene glycol long chain (C16-C20) fatty acid esters, ethylene glycol long chain fatty acid esters such as saturated or unsaturated C16-C18 fatty acids such as oleic acid, lauric acid, palmitic acid , and PEG-fatty acid esters or diesters of stearic acid. In an embodiment, the nonionic surfactant comprises polyethylene glycol long chain saturated fatty acid esters, including ethylene glycol long chain saturated fatty acid esters such as saturated C16-C18 fatty acids such as PEG- and ethylene glycol-fatty acids of palmitic acid and stearic acid. Further contains esters. Such nonionic surfactants may include PEG-6 stearate, ethylene glycol palmitostearate, and PEG-32 stearate such as, but not limited to, TEFOSE 63.

According to embodiments, nonionic surfactants used as thickeners are non-hydrophilic and have good emulsifying properties. An illustrative example of such a surfactant is TEFOSE 63, which has a hydrophilic-lipophilic balance (HLB) value of about 9-10.

According to embodiments, the pharmaceutical composition further comprises one or more mucoadherent agents to improve vaginal absorption of estradiol. For example, a mucoadhesive agent may be present to help the pharmaceutical composition adhere to the mucous membrane upon activation by water. According to embodiments, polycarbophil is the mucoadhesive agent. According to embodiments, other mucoadhesives include, for example and without limitation, poly(ethylene oxide) polymers having a molecular weight of about 100,000 to about 900,000; chitosan carbopol, including polymers of acrylic acid crosslinked with allyl pentaerythritol or allyl sucrose; polymers of acrylic acid and C10-C30 alkyl acrylates, crosslinked with allyl pentaerythritol; carbomer homopolymers or copolymers containing block copolymers of polyethylene glycol and long-chain alkyl acid esters; and the like. According to embodiments, a variety of hydrophilic polymers and hydrogels can be used as mucoadhesive agents. According to certain embodiments, such polymers or hydrogels may swell upon contact with vaginal tissue or secretions to enhance moisturizing and mucoadhesive effects. The selection and amount of hydrophilic polymer may be based on the selection and amount of solubilizing agent. In some embodiments, the pharmaceutical composition includes a hydrophilic polymer, but optionally excludes a gelling agent. In embodiments with a hydrogel, from about 5% to about 10% of the total mass may be composed of hydrophilic polymers. In further embodiments, hydrogels may be used. The hydrogel may include chitosan, which swells upon contact with water. In various embodiments, the cream pharmaceutical composition can include PEG-90M. In some embodiments, the mucoadhesive agent is present in the pharmaceutical formulation, in a softgel capsule, or both.

According to embodiments, the pharmaceutical composition comprises one or more thermoreversible gels, typically of hydrophilic nature, which include, for example and without limitation, hydrophilic sucrose and other saccharoid-based monomers. (U.S. Patent No. 6,018,033, which is incorporated by reference).

According to embodiments, the pharmaceutical composition further comprises a lubricant. In some embodiments, a lubricant may be present to aid in formulation of the dosage form. For example, lubricants may be added to ensure that capsules or tablets do not stick together during processing or during storage. Any suitable lubricant may be used. For example, lecithin, a mixture of phospholipids, is a lubricant.

According to embodiments, the pharmaceutical composition further comprises an antioxidant. Any suitable antioxidant may be used. For example, butylated hydroxytoluene, butylated hydroxyanisole, and vitamin E TPGS.

According to an embodiment, the pharmaceutical composition comprises from about 20% to about 80% by weight of a solubilizing agent, from about 0.1% to about 5% by weight of a lubricant, and from about 0.01% to about 0.1% by weight of an antioxidant do.

The choice of excipient will depend on factors such as, for example, the effect of the excipient on solubility and stability. Additional excipients used in various embodiments may include colorants and preservatives. Examples of colorants include FD&C colors (eg, Blue No. 1 and Red No. 40), D&C colors (eg, Yellow No. 10), and opacifiers (eg, titanium dioxide). According to embodiments, the colorant constitutes about 0.1% to about 2% by weight of the pharmaceutical composition. According to an embodiment, the preservative in the pharmaceutical composition comprises methyl and propyl paraben, which are present in a ratio of about 10:1, and in proportions of about 0.005% and 0.05% by weight.

In general, solubilizers, excipients, and other additives used in the pharmaceutical compositions described herein are non-toxic, pharmaceutically acceptable, compatible with each other, and maintain stability of the pharmaceutical composition and the various components with respect to each other. . Additionally, the combination of the various components that make up the pharmaceutical composition will be maintained and will produce the desired therapeutic effect when administered to a subject.

Solubility of Estradiol

According to an embodiment, a medium chain fatty acid glyceride, such as a mixture of C6-C12, C8-C12, or C8-C10 fatty acid mono- and diglycerides or a mixture of mono-, di-, and triglycerides, is used. The solubilizing agent dissolves estradiol. As illustrated in the examples, good results were obtained with solubilizers that consisted primarily of mixtures of C8-C10 saturated fatty acid mono- and diglycerides, or mixtures of medium chain triglycerides (e.g., MIGLYOL 810 or 812). . Longer chain glycerides appear to be unsuitable for dissolution of estradiol.

Solubilizers including propylene glycol monocaprylate (eg CAPRYOL) and 2-(2-ethoxyethoxy)ethanol (eg TRANSCUTOL) solubilized estradiol well.

Manufacture of Pharmaceutical Compositions

According to an embodiment, the pharmaceutical composition is prepared by blending estradiol with a pharmaceutically acceptable solubilizer, which includes, for example and without limitation, at least one medium chain fatty acid , A medium chain fatty acid is, for example, a medium chain fatty acid consisting of at least one mono-, di-, or triglyceride, or a derivative thereof, or a combination thereof. According to an embodiment, the pharmaceutical composition also comprises at least one glycol or a derivative thereof or a combination thereof or a combination of at least one glyceride and a glycol. The glycol(s) can be used as a solubilizing agent or can be used to adjust viscosity and thus can be considered a thickening agent, as discussed further in the specification. Other excipients are optionally added including, for example and without limitation, antioxidants, lubricants, and the like. According to embodiments, the pharmaceutical composition includes sufficient solubilizing agent to completely solubilize estradiol. However, it is clearly understood that other volumes of solubilizing agent may be used depending on the desired level of solubilization of estradiol. One skilled in the art will know and understand how to determine the volume of solubilizing agent and other excipients according to the desired percentage of estradiol to be solubilized in a pharmaceutical composition.

In an exemplary embodiment, GELUCIRE 44/14 (Lauroyl Macrogol-32 Glyceride EP, Lauroyl Polyoxyl-32 Glyceride NF, Lauroyl Polyoxylglyceride (USA FDA IIG)) is prepared at about 65° C. , and heating the CAPMUL MCM to about 40° C. facilitates mixing of the oil and nonionic surfactant, but such heating is not necessary to dissolve the estradiol.

The specific examples disclosed herein provide additional principles and embodiments illustrating the manufacture of the pharmaceutical compositions disclosed herein.

delivery vehicle

Generally, the pharmaceutical compositions described herein are delivered intravaginally in a delivery vehicle, such as a capsule. According to an embodiment, the capsule is a soft capsule made of a material well known in the pharmaceutical art, for example gelatin. However, depending on the embodiment, the delivery vehicle is integral with the pharmaceutical composition (ie, the pharmaceutical composition is the delivery vehicle). In such embodiments, the pharmaceutical composition is a gel, cream, ointment, tablet, or other formulation applied directly and absorbed into the vagina.

According to embodiments, the pharmaceutical compositions disclosed herein are contained within capsules, such as soft gelatin capsules. According to embodiments, the capsule contains one or more of: a hydrophilic gel-forming bioadhesive agent (eg, mucoadhesive agent); lipophilic agents; Gelling agent for lipophilic agents, or water dispersing agent. According to embodiments, the hydrophilic gel-forming bioadhesive is carboxyvinylic acid; hydroxypropyl cellulose; carboxymethylcellulose; gelatin; xanthan gum; guar gum; aluminum silicate; or a mixture thereof. According to embodiments, the lipophilic agent is a liquid triglyceride; solid triglycerides (eg, those having a melting point of about 35° C.); carnauba wax; cocoa butter; or a mixture thereof. According to embodiments, the gelling agent is hydrophobic colloidal silica. According to an embodiment, the water dispersant is polyoxyethylene glycol; polyoxyethylene glycol 7-glyceryl cocoate; or a mixture thereof.

According to embodiments, the delivery vehicle is designed to facilitate insertion. According to embodiments, the delivery vehicle is sized so that it can be comfortably inserted into the vagina.

According to embodiments, delivery vehicles are made in a variety of geometries. For example, the delivery vehicle may be tear drop, conical with frustoconical ends, cylindrical, cylindrical with a larger "cap" portion, or suitable for and facilitating insertion into the vagina. shaped into different shapes. According to embodiments, the delivery vehicle is used with an applicator. According to another embodiment, the delivery vehicle is finger inserted.

Referring to FIG. 2 , a delivery vehicle 200 includes a pharmaceutical composition 202 and a capsule 204 . Width 208 represents the thickness of capsule 204, for example about 0.108 inches. The distance from one end of the delivery vehicle 200 to the other is indicated by distance 206 and is, for example, about 0.690 inches. The size of the delivery vehicle 200 can also be described as an arc drawn by a radius of a given length. For example, arc 210 defined by the exterior of gelatin 204 is an arc drawn by a radius of about 0.189 inches. Arc 212 defined by the interior of capsule 204 is an arc drawn by a radius of about 0.0938 inches. Arc 214, defined by the outside of gelatin 204 on the opposite side of arc 210, is an arc drawn by a radius of about 0.108 inches. Suitable capsules of other dimensions may be provided. According to an embodiment, the capsules 204 have dimensions equal to or similar to the ratios provided above relative to each other.

According to embodiments, the delivery vehicle is designed to remain in the vagina until the pharmaceutical composition is released. According to embodiments, the delivery vehicle dissolves vaginally and is absorbed into the vaginal tissue along with the pharmaceutical composition, wherein the pharmaceutical composition minimizes vaginal discharge. In such embodiments, the delivery mechanism is made from non-toxic ingredients, such as gelatin.

Design Factors for Intravaginal Pharmaceutical Compositions

According to embodiments, the pharmaceutical composition is designed to maximize beneficial properties that lead to patient compliance (of patients discontinuing treatment before completing the prescribed course of therapy) without sacrificing efficacy. Advantageous properties include, for example, absence or reduction of stimulation compared to other hormone replacement pessaries, absence or reduction of vaginal release of the pharmaceutical composition and delivery vehicle compared to other hormone replacement pessaries, retention of the pharmaceutical composition or delivery vehicle in the vagina. absence or reduction of water, ease of administration compared to other hormone replacement pessaries, or improved efficacy of the drug product compared to similar pharmaceutical compositions other than efficacy.

According to embodiments, the pharmaceutical composition is non-irritating or minimally irritating. Patient irritation includes pain, pruritus (itching), throbbing, excessive discharge, edema, or other similar conditions. Patient stimulation results in poor compliance. Non-irritation or reduced stimulation of the pharmaceutical composition is measured relative to competing hormonal pessaries, including tablets, creams, or other forms of intravaginal estrogen delivery.

According to embodiments, the pharmaceutical composition does not lead to systemic exposure (eg, blood circulation of estradiol), which improves safety. According to another embodiment, the pharmaceutical compositions disclosed herein lead to significantly reduced systemic exposure (eg, circulating blood of estradiol) as compared to RLD.

According to embodiments, the pharmaceutical composition does not leave a residue in the vagina. Rather, the pharmaceutical composition and delivery vehicle are substantially absorbed or dispersed without leaving an unabsorbed residue or incurring the discomfort of an unabsorbed or undispersed drug product. The absence of residue can be measured relative to other vaginal implantable products or objectively measured by examining the vaginal tissue. For example, certain other vaginal inserts contain starch, which may result in greater release from the vagina after administration. In some embodiments, the pharmaceutical compositions provided herein provide a lower release amount, release duration, or release frequency after administration as compared to other vaginal implantable products (eg, compressed tablets).

According to embodiments, the pharmaceutical composition improves vaginal release compared to other pessaries, including pessaries that deliver hormones. Ideally, vaginal discharge is eliminated, minimized, or improved compared to competitive products.

According to an embodiment, the pharmaceutical composition disclosed herein is inserted fingerwise. According to an embodiment, the pharmaceutical composition is finger inserted approximately 2 inches into the vagina without the need for an applicator. According to an embodiment, the pharmaceutical composition is designed to be also inserted using an applicator, if necessary. According to some embodiments, since the site of the VVA is in the proximal region of the vagina (towards the vaginal opening), the pharmaceutical compositions disclosed herein are designed to be inserted into the proximal region of the vagina.

Through extensive experimentation, various medium chain fatty acid esters of glycerol and propylene glycol have demonstrated one or more advantageous properties for development as human drug products. According to embodiments, the solubilizing agent is selected from at least one of a solvent or a co-solvent. Suitable solvents and co-solvents include any mono-, di- or triglycerides and glycols, and combinations thereof.

According to embodiments, the pharmaceutical composition is delivered via a gelatin capsule delivery vehicle. According to this embodiment, the pharmaceutical composition is a liquid pharmaceutical composition. According to embodiments, the delivery vehicle is a soft capsule, eg a soft gelatin capsule. Accordingly, the pharmaceutical composition of such embodiments is encapsulated within a soft gelatin capsule or other soft capsule.

According to embodiments, the pharmaceutical composition comprises estradiol solubilized to at least about 80% in a solubilizing agent comprising one or more C6 to C14 medium chain fatty acid mono-, di-, or triglycerides and, optionally, a thickening agent. . According to embodiments, the pharmaceutical composition comprises one or more C6 to C12 medium chain fatty acid mono-, di-, or triglycerides, such as one or more C6 to C14 triglycerides, such as one or more C6 to C12 triglycerides. estradiol solubilized at least about 80% in one or more C8 to C10 triglycerides. This embodiment specifically contemplates at least 80% solubilized estradiol. These embodiments specifically contemplate at least 90% solubilized estradiol. This embodiment specifically contemplates at least 95% solubilized estradiol. This embodiment specifically contemplates fully solubilized estradiol.

As described above, liquid pharmaceutical compositions are liquid at room temperature or body temperature. For example, in some embodiments, a pharmaceutical composition provided herein is a liquid formulation contained within a softgel capsule. Gels, hard fats, or other solid forms that are not liquid at room temperature or body temperature are less preferred in embodiments of the pharmaceutical composition that are liquid.

A thickener serves to increase the viscosity, for example up to about 10,000 cP (10,000 mPa-s), typically up to about 5000 cP, and more typically from about 50 to 1000 cP. In embodiments, the nonionic surfactant, such as GELUCIRE or TEFOSE, may be solid at room temperature and may require melting to mix effectively with the solubilizing agent. However, in this embodiment, the resulting pharmaceutical composition remains liquid rather than solid, even if it has a higher viscosity.

According to embodiments, the pharmaceutical composition includes estradiol, a heavy chain solubilizer, and a thickening agent as ingredients delivered via a soft capsule delivery vehicle. Other ingredients may be included as well, such as colorants, antioxidants, preservatives, or other ingredients. However, the addition of the other ingredients should be in amounts that do not substantially change the solubility of estradiol, the pharmacokinetic properties of the pharmaceutical composition, or the efficacy of the pharmaceutical composition. Other factors that must be considered when adjusting the ingredients of the pharmaceutical composition include irritation, vaginal discharge, vaginal residue, and other related factors, such as those that will result in reduced patient compliance. Other contemplated ingredients include oil or fatty acid esters, lecithin, mucoadhesive agents, gelling agents, dispersing agents, and the like.

Way

According to embodiments, the pharmaceutical compositions disclosed herein include, among other things, VVA, including treatment of at least one VVA symptom, including vaginal dryness, vaginal or vulvar irritation or itching, dysuria, dyspareunia, and vaginal bleeding associated with sexual activity. can be used for the treatment of According to embodiments, the treatment method is generally applicable to women.

According to embodiments, the pharmaceutical compositions disclosed herein can be used for the treatment of estrogen-deficient voiding conditions. According to embodiments, the pharmaceutical compositions disclosed herein can be used for the treatment of dyspareunia, or vaginal bleeding associated with sexual activity.

According to embodiments, treatment of VVA, estrogen-deficient voiding conditions, and dyspareunia and vaginal bleeding associated with sexual activity occurs by intravaginal administration of the present pharmaceutical composition. According to embodiments in which the delivery vehicle is a capsule, the patient obtains the capsule and inserts the capsule into the vagina, the capsule dissolves and the pharmaceutical composition is released into the vagina and absorbed into the vaginal tissue. In some embodiments, the pharmaceutical composition is completely absorbed into the vaginal tissue. In some embodiments, the pharmaceutical composition is substantially absorbed into the vaginal tissue (e.g., at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97% by weight of the composition). %, at least about 98% by weight, or at least about 99% by weight is absorbed). According to an embodiment, the capsule is inserted about 2 inches into the vagina by the fingers, but the insertion depth is generally any depth that allows adsorption of virtually any pharmaceutical composition. According to embodiments, the capsule may also be applied using an applicator that deposits the capsule at an appropriate vaginal depth as disclosed herein.

According to embodiments where the pharmaceutical composition is a cream, gel, ointment, or other similar formulation, the pharmaceutical composition is applied fingerwise, as is well known and recognized in the art.

Upon release of the pharmaceutical composition in the vagina, estradiol is absorbed topically. For example, after administration of the pessary to the proximal vaginal region of a patient, it provides a therapeutically effective concentration of estradiol in the proximal vaginal region for more than 24 hours.

According to embodiments, the timing of administration of the pharmaceutical composition of the present invention can be carried out by any safe means as prescribed by the attending physician. According to an embodiment, the patient will intravaginally administer the pharmaceutical composition (eg, capsule) daily for 14 days, then twice weekly thereafter.

According to embodiments, the pharmaceutical composition is an oral dosage form estrogen-based (or progestin-based or progestin- and estrogen-based) pharmaceutical drug product, or a patch, cream, gel, spray, transdermal delivery system, or other parenteral It is administered intravaginally with concomitant administration of orally-administered estrogen-based pharmaceutical drug products, each of which may contain a natural, bio-identical, or synthetic or otherwise derived estrogen or progestin. According to embodiments, the modulation of circulating estrogen levels, if any, provided through administration of the pharmaceutical compositions disclosed herein is believed to be additive to any co-administered estrogen product and its associated circulating blood levels. Not intended. According to another embodiment, the co-administered estrogen product is intended to have an additive effect, such an additive effect as to be determined by the patient's physician.

According to embodiments, the efficacy and safety of the pharmaceutical compositions described herein in the treatment of symptoms of VVA can be determined. According to embodiments, the size, effectiveness, cytology, biopsy of VVA to determine the efficacy and safety of the pharmaceutical compositions described herein or otherwise currently accepted in the art or as further developed in the future. (histology), and variability can be determined using various endpoints. For endpoints, the guidelines published by the US Food and Drug Administration (FDA) for the treatment of VVA with estradiol are used.

measure of efficacy

According to embodiments, administration of the pharmaceutical composition described herein results in treatment of VVA as well as improvement of one or more of the associated symptoms. Patients with VVA experience contraction of the vaginal canal in both length and diameter, and the vaginal canal has fewer glycogen-rich vaginal cells to maintain moisture and suppleness. Additionally, the vaginal walls can become thin, weak, dry, or sometimes inflamed (atrophic vaginitis). These changes can manifest as a variety of symptoms collectively referred to as VVA. Such symptoms include, without limitation, an increase in vaginal pH; decreased vaginal epithelial integrity, vaginal discharge, or epithelial surface thickness; pruritus; vaginal dryness; dyspareunia (pain or bleeding during sexual activity); urinary tract infection; or vaginal color change. According to embodiments, efficacy is measured as a reduction in the patient's vulvar and vaginal atrophy back to the premenopausal state. According to embodiments, this change is measured as a decrease in the severity of one or more atrophic effects measured at baseline (screening, day 1) and compared to measurements taken at day 15 (end of treatment). Severity of an atrophic effect can be measured using a scale of 0 to 3, where, for example, none = 0, mild = 1, moderate = 2, or severe = 3. Such scoring may be used to assess the patient's pre-treatment status; To determine an appropriate course of treatment plan, such as, among other things, dosage, frequency of administration, and duration; And implemented to determine the outcome after treatment.

One of the symptoms of VVA is increased vaginal pH. In a further aspect of the invention, treatment with the pharmaceutical composition described herein results in a decrease in vaginal pH. The decrease in vaginal pH is measured as a decrease from vaginal pH at baseline (screening) to vaginal pH at day 15, according to an embodiment. In some embodiments, a pH of 5 or greater may be associated with VVA. In some embodiments, pH is measured using a pH indicator strip placed on a wall. In some embodiments, the change in vaginal pH is a change in the patient's vaginal pH to a pH less than about pH 5.0. In some embodiments, the subject's vaginal pH is about pH 4.9, pH 4.8, pH 4.7, pH 4.6, pH 4.5, pH 4.4, pH 4.3, pH 4.2, pH 4.1, pH 4.0, pH 3.9, pH 3.8, pH 3.7, pH 3.6, or less than pH 3.5.

According to embodiments, treatment with the pharmaceutical composition described herein results in an improvement in the vaginal maturation index. Maturation indicators are measured as changes in cell composition. According to embodiments and in relation to VVA, the change in cell composition is a change in the percent composition or quantity of vaginal subbasal cells, intermediate cells, and vaginal surface cells, such as compared to or contrasted with a change in vaginal surface cells. It is measured as a change in the composition or amount of vaginal subbasal cells. Subjects with symptoms of VVA often have increased numbers of parabasal cells and reduced numbers of superficial cells (eg, less than about 5%) compared to women not suffering from VVA. In contrast, subjects whose VVA symptoms are decreasing or who are otherwise responding to treatment may show improvement in maturational markers, specifically a decrease in the amount of parabasal cells or an increase in the amount of superficial cells compared to baseline (screening). to be. In an embodiment, the decrease in parabasal cells is measured as a decrease in percent of parabasal cells; The percent reduction in the number of parabasal cells is at least about 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25 %, 20%, 15% or 10% reduction. In an embodiment, the percent reduction can be at least about a 54% reduction in the number of parabasal cells. In an embodiment, the increase in superficial cells is measured as an increase in percent of superficial cells; The percent increase in superficial cells can be at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% increase in the number of superficial cells. In a further embodiment, the percent increase can be at least about a 35% increase in the number of superficial cells.

In some embodiments, improvement in a maturity indicator is assessed as a change over time. For example, it is evaluated as a change in cell composition measured at baseline (screening) at day 1 compared to cell composition measured at day 15. Changes in cell composition may also optionally be assessed as changes in the amount of parabasal cells over time, in addition to measuring changes in parabasal cells and superficial cells as described above. Such cells can be obtained from vaginal mucosal epithelium during routine gynecological examination and examined by vaginal smear.

In various additional aspects of the present invention, treatment with the pharmaceutical composition described herein can result in an increase in superficial cells; reduction of subbasal cells; and an increase in intermediate cells.

In a further aspect of the invention, samples may be collected to determine hormone levels, particularly estradiol levels. In some embodiments, a blood sample may be taken from the subject and the level of estradiol measured (pg/ml). In some embodiments, the estradiol level is measured at hour 0 (eg, at the time of the first treatment), hour 1 (eg, after the first treatment), hour 3, and hour 6. can In some embodiments, samples may be taken on day 8 (eg, after the first treatment) and on day 15 (eg, 1 day after the last treatment on day 14). In some embodiments, a descriptive statistic of plasma estradiol concentrations and observed Cmax and Tmax values at each sampling time can be determined and an AUC calculated.

In some embodiments, the pessary may include about 25 μg of estradiol. In such cases, administration of the pessary to the patient may provide parameters, in a plasma sample from the patient, including one or more parameters selected from:

1) an adjusted geometric mean of peak plasma concentrations (Cmax) of estradiol between about 19 pg*hr/ml and about 29 pg*hr/ml (e.g., between 19.55 pg*hr/ml and about 28.75 pg*hr/ml ); or

2) an area under the curve for estradiol (AUC) between about 75 pg*hr/ml and about 112 pg*hr/ml (eg, between 75.82 pg*hr/ml and about 111.50). In some embodiments, administration of the pessary to a patient provides, in a plasma sample from the patient, one or more parameters selected from: 1) a corrected geometric mean of peak plasma concentration (Cmax) of estrone of about 9 pg* hr/ml to about 14 pg*hr/ml (eg, 9.17 pg*hr/ml to about 13.49 pg*hr/ml); and 2) an area under the curve for estrone (AUC) between about 43 pg*hr/ml and about 65 pg*hr/ml (eg, between 43.56 pg*hr/ml and about 64.06 pg* hr/ml). In some embodiments, administration of the pessary to the patient provides, in a plasma sample from the patient, one or more parameters selected from: 1) corrected peak plasma concentration of estrone sulfate (Cmax) a geometric mean of about 416 pg*hr/ml to about 613 pg*hr/ml (eg, 416.53 pg*hr/ml to about 612.55 pg*hr/ml); and 2) an area under the curve for estrone sulfate (AUC) between about 3598 pg*hr/ml and about 5291 pg*hr/ml (eg, between 3598.04 pg*hr/ml and about 5291.24 pg *hr/ml).

In some embodiments, the pessary can include about 10 μg of estradiol. In such cases, administration of the pessary to a patient may provide, in a plasma sample from the patient, one or more parameters selected from: 1) the corrected geometric mean of the peak plasma concentration (Cmax) of estradiol of about 12 pg*hr/ml to about 18 pg*hr/ml (eg, 12.22 pg*hr/ml to about 17.98 pg*hr/ml); 2) an area under the curve (AUC) of estradiol between about 42 pg*hr/ml and about 63 pg*hr/ml (e.g., between 42.18 pg*hr/ml and about 62.02 pg* hr/ml); and 3) an adjusted geometric mean of the time to peak plasma concentration of estradiol (Tmax) of about 1 hr to about 3 hr (eg, 1.49 hr to about 2.19 hr). In some embodiments, Administration of the pessary provides, in a plasma sample from the patient, one or more parameters selected from: 1) the corrected geometric mean of the peak plasma concentration (Cmax) of estrone from about 4 pg*hr/ml to about 7 pg* hr/ml (eg, 4.38 pg*hr/ml to about 6.44 pg*hr/ml); 2) an area under the curve for estrone (AUC) of about 20 pg*hr/ml to about 31 pg*hr/ml (e.g., 20.60 pg*hr/ml to about 30.30 pg*hr), a corrected geometric mean of 0-24 /ml); and 3) an adjusted geometric mean of the time to peak plasma concentration of estrone (Tmax) of about 4 hr to about 8 hr (eg, 4.99 hr to about 7.34 hr). In some embodiments, administration of the pessary to the patient provides, in a plasma sample from the patient, one or more parameters selected from: 1) a corrected geometric mean of peak plasma concentration (Cmax) of estrone sulfate of about 10 pg *hr/ml to about 16 pg*hr/ml (eg, 10.34 pg*hr/ml to about 15.20 pg*hr/ml); 2) an area under the curve (AUC) of estrone sulfate between about 56 pg*hr/ml and about 84 pg*hr/ml (eg, between 56.61 pg*hr/ml and about 83.25 pg* hr/ml); and 3) an adjusted geometric mean of the time to peak plasma concentration of estrone sulfate (Tmax) of about 4 hr to about 7 hr (eg, 4.67 hr to about 6.86 hr).

In some embodiments, the pessary may include about 4 μg of estradiol. In such cases, administration of the pessary to a patient may provide, in a plasma sample from the patient, one or more parameters selected from: 1) the corrected geometric mean of the peak plasma concentration (Cmax) of estradiol of about 4 pg*hr/ml to about 8 pg*hr/ml; 2) an estradiol area under the curve (AUC) of about 16 pg*hr/ml to about 26 pg*hr/ml; and 3) a corrected geometric mean of the time to peak plasma concentration of estradiol (Tmax) of about 0.25 hr to about 2 hr. In some embodiments, administration of the pessary to a patient provides, in a plasma sample from the patient, one or more parameters selected from: 1) a corrected geometric mean of peak plasma concentration (Cmax) of estrone of about 1 pg* hr/ml to about 3 pg*hr/ml; 2) an area under the curve for estrone (AUC) between about 8 pg*hr/ml and about 13 pg*hr/ml; and 3) a corrected geometric mean of the time to peak plasma concentration of estrone (Tmax) of about 1 hr to about 4 hr. In some embodiments, administration of the pessary to the patient provides, in a plasma sample from the patient, one or more parameters selected from: 1) a corrected geometric mean of peak plasma concentration (Cmax) of estrone sulfate of about 4 pg *hr/ml to about 7 pg*hr/ml; 2) an area under the curve for estrone sulfate (AUC) between about 22 pg*hr/ml and about 34 pg*hr/ml; and 3) a corrected geometric mean of the time to peak plasma concentration of estrone sulfate (Tmax) of about 1 hr to about 3 hr.

The pharmaceutical compositions provided herein may in fact result in topical delivery of estradiol. For example, the plasma concentrations of estradiol, estrone, and estrone sulfate measured in the plasma of a patient following administration of a pharmaceutical composition as provided herein are comparable to those after administration of a placebo formulation (ie, a similar formulation lacking estradiol). Statistically similar to measured plasma concentrations. Thus, in some embodiments, plasma concentrations of estradiol, estrone, or estrone sulfate measured after administration of a pharmaceutical composition provided herein may be lower compared to the RLD formulation.

In some embodiments, the pessary may include between about 1 μg and about 25 μg of estradiol. Upon administration of the pessary to a patient, a plasma sample from the patient can provide a corrected geometric mean of peak plasma concentration (Cmax) of estradiol of less than about 30 pg*hr/ml. For example, administration of a pessary to a patient provides a calibrated geometric mean peak plasma concentration (Cmax) of estradiol of less than about 18 pg*hr/ml. In some embodiments, administration of the pessary to the patient provides a corrected geometric mean of the area under the curve (AUC) 0-24 for estradiol of less than about 112 pg*hr/ml. For example, administration of a pessary to a patient provides a corrected geometric mean of the area under the curve (AUC) 0-24 for estradiol of less than about 63 pg*hr/ml.

In some embodiments, administration of the pessary to the patient provides a corrected geometric mean peak plasma concentration of estrone (Cmax) of less than about 14 pg*hr/ml. For example, administration of the pessary to a patient provides a corrected geometric mean of peak plasma concentrations (Cmax) of estrone of less than about 7 pg*hr/ml. In some embodiments, administration of the pessary to the patient provides a corrected geometric mean of the area under the curve for estrone (AUC) 0-24 of less than about 65 pg*hr/ml. For example, administration of the pessary to a patient provides a corrected geometric mean of the area under the curve (AUC) of estrone 0-24 of less than about 31 pg*hr/ml.

In some embodiments, administration of the pessary to the patient provides a corrected geometric mean peak plasma concentration (Cmax) of estrone sulfate of less than about 613 pg*hr/ml. For example, administration of the pessary to a patient provides a calibrated geometric mean peak plasma concentration (Cmax) of estrone sulfate of less than about 16 pg*hr/ml. In some embodiments, administration of the pessary to the patient provides a corrected geometric mean of the area under the curve (AUC) of estrone sulfate (AUC) 0-24 of less than about 5291 pg*hr/ml. For example, administration of the pessary to a patient provides a corrected geometric mean of the area under the curve (AUC) of estrone sulfate (AUC) 0-24 of less than about 84 pg*hr/ml.

In a further aspect of the invention, capsule disintegration can be determined. In some embodiments, delivery vehicle disintegration or absorption (presence or absence of delivery vehicle following administration) occurs on day 1 of treatment (eg, 6 hours after initial treatment) and on day 15 (eg, day 14). 1 day after the last treatment on day).

statistical measure

According to embodiments, the pharmacokinetic properties of the pharmaceutical compositions disclosed herein are measured using statistical analysis. According to an embodiment, a patient receiving treatment with a pharmaceutical composition comprising an active pharmaceutical composition (e.g., a pharmaceutical composition comprising estradiol) and a placebo (e.g., one containing no estradiol) Analysis of Variance ("ANOVA") or Analysis of Covariance ("ANCOVA") is used to evaluate differences between patients receiving treatment with the same pharmaceutical composition) or reference drug. do. One skilled in the art will understand how to perform statistical analysis of the collected data.

Example

The following examples relate to pharmaceutical compositions, delivery vehicles, and combinations thereof. A manufacturing method is also disclosed. Data generated using the pharmaceutical compositions disclosed herein are also disclosed.

Example 1: Pharmaceutical composition

In an embodiment, estradiol is obtained and combined with one or more pharmaceutically acceptable solubilizing agents. Estradiol is a pharmaceutical grade ingredient, often purchased as micronized estradiol, but other forms may also be used. In an embodiment, the pharmaceutical composition comprises estradiol at a dosage strength of about 1 μg to about 50 μg. In an embodiment, the pharmaceutical composition comprises 10 μg of estradiol. In an embodiment, the pharmaceutical composition comprises 25 μg of estradiol.

In an embodiment, estradiol is combined with a pharmaceutically acceptable solubilizing agent and optionally other excipients to form a pharmaceutical composition. In an embodiment, the solubilizing agent is one or more of CAPMUL MCM, MIGLYOL 812, GELUCIRE 39/01, GELUCIRE 43/01, GELUCIRE 50/13, and TEFOSE 63.

GELUCIRE 39/01 and GELUCIRE 43/01 each have an HLB value of 1. GELUCIRE 50/13 has an HLB value of 13. TEFOSE 63 has an HLB value of 9 to 10.

Various combinations of pharmaceutically acceptable solubilizers were formulated with estradiol and tested as shown in Table 1.

[Table 1]

The pharmaceutical compositions of Table 1, which are liquid or semi-solid at room temperature, were tested at room temperature using a Brookfield Viscometer (Brookefield Engineering Laboratories, Middleboro, Mass.). The pharmaceutical compositions shown in Table 1 that are solids at ambient temperature were tested using a Brookfield viscometer at 37°C.

The pharmaceutical compositions shown in Table 1 that are solids at room temperature were evaluated at 37° C. to determine their melting properties. The viscosity of a gel can be important during encapsulation of a formulation. For example, in some cases it is necessary to warm the formulation prior to filling the gelatin capsules. Moreover, the melting properties of the composition can have important implications after administration of the formulation into the body. For example, in some embodiments, the formulation will melt at a temperature less than about 37°C. For example, pharmaceutical composition 11 (CAPMUL MCM/TEFOSE 63) did not melt at 37°C or 41°C.

A dispersion evaluation of the pharmaceutical compositions shown in Table 1 was performed. Dispersion evaluation was performed by transferring 300 mg of each vehicle system into 100 ml of 37° C. water without agitation and observing the mixing characteristics. Results ranged from the formation of oil droplets in the upper phase, followed by separation of the phases, to a uniform but turbid dispersion. Generally speaking, it is believed that formulations that can be readily dispersed in aqueous solutions will have better dispersing properties upon administration. However, unexpectedly, as shown in Examples 7 to 9 below, formulations that are not easily dispersed in an aqueous solution (e.g. formulation 13) and instead form two phases when introduced into an aqueous solution can be administered to the human body. found to be most effective when

Example 2: Delivery vehicle

In an embodiment, the pharmaceutical composition is delivered within a gelatin capsule delivery vehicle. Gelatin capsule delivery vehicles include, for example, gelatin (e.g., gelatin, NF (150 Bloom, type B)), hydrolyzed collagen (e.g., GELITA®, GELITA AG, Eberbach, Germany), glycerin, Sorbitol Special, or other excipients, in proportions well known and appreciated by those skilled in the art. Sorbitol Special is commercially available and may tend to act as a plasticizer and humectant.

As shown in Table 2, Gel A-Gel F, a variety of delivery vehicles were developed. In Table 2, each delivery vehicle A through F differs in proportions of one or more components.

[Table 2]

Each delivery vehicle A through F was prepared in the temperature range of about 45°C to about 85°C. Each of the molten delivery vehicles A-F was cast into a film, dried, and cut into strips. The strip was cut into uniform pieces weighing about 0.5 g and having a thickness of about 0.5 mm. The strip was placed in a USP type 2 dissolution vessel in water or pH 4 buffer and the time it took for it to completely dissolve was recorded (see Table 2). Delivery vehicle A showed the fastest dissolution in both water and pH 4 buffer solution.

Example 3: Pharmaceutical Compositions and Delivery Vehicles

Various combinations of the pharmaceutical compositions from Table 1 and those from Table 2 were prepared. These combinations are shown in Table 3.

[Table 3]

Each aliquot of the pharmaceutical compositions of Table 3 was from about 300 mg to about 310 mg. Batch sizes are listed in Table 3. To encapsulate the vehicle system, each 300 mg to about 310 mg aliquot of the pharmaceutical composition is encapsulated in an about 200 mg gelatin capsule delivery vehicle. Thus, for example, in Trial 1, a pharmaceutical composition designated MCM:39/01 was encapsulated in a gelatin capsule delivery vehicle A for a total encapsulated weight of about 500 mg to about 510 mg. Aliquot size is arbitrary depending on the concentration of estradiol and the desired gelatin capsule delivery vehicle size. One skilled in the art will readily understand how to adjust the amount of estradiol in a pharmaceutical composition to be accommodated within a delivery vehicle of a given size when the delivery vehicle encapsulates the pharmaceutical composition.

Example 4: Solubility of Estradiol

In various experiments, solubilizing agents were tested to determine whether they could solubilize 2 mg of estradiol for a total pharmaceutical composition weight of 100 mg. Solubilizing agents were considered suitable if the solubility of estradiol in the solubilizing agent was greater than about 20 mg/g. Micronized estradiol was dissolved in various solubilizers until estradiol was saturated (estradiol/solubilizer equilibrated for 3 days), undissolved estradiol was filtered and generated for estradiol concentration by HPLC Initial solubility was measured by analyzing the pharmaceutical composition prepared.

[Table 4]

Example 5: Pharmaceutical composition

Consider the following pharmaceutical compositions.

gel mass

Pharmaceutical composition 1: 10 μg estradiol

Pharmaceutical composition 2: 10 μg estradiol

Pharmaceutical composition 3: 25 μg estradiol

Pharmaceutical composition 4: 4 μg estradiol

Example 6: Process

1 illustrates one embodiment 100 of a method for preparing a pharmaceutical composition comprising estradiol solubilized in CAPMUL MCM/GELUCIRE solubilizer encapsulated within a soft gelatin delivery vehicle. In operation 102, CAPMUL MCM is heated to 40°C ±5°C. Heating can be done through any suitable means. Heating may be performed in any suitable vessel, such as a stainless steel vessel. Other pharmaceutical compositions can be prepared using the same general method by substituting various excipients, including solubilizers.

In operation 104, GELUCIRE is mixed with CAPMUL MCM to form the finished solubilizer. As used herein, any form of GELUCIRE may be used in task 104. For example, one or more of GELUCIRE 39/01, GELUCIRE 43/01, GELUCIRE 50/13 may be used in task 104. As is known to those skilled in the art, mixing is effected by, for example, an impeller, agitator, stirrer, or other similar device used to mix pharmaceutical compositions. Operation 104 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas. Mixing can be carried out in any vessel known to those skilled in the art, such as a stainless steel vessel or a steel tank.

In operation 106, estradiol is mixed into the solubilizing agent. In an embodiment, estradiol is in a micronized state when mixed into the solubilizing agent. In another embodiment, the added estradiol is in non-micronized form. Mixing may be facilitated by an impeller, agitator, stirrer, or other similar device used to mix pharmaceutical compositions. Operation 106 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas.

However, in embodiments, the addition of estradiol may be performed prior to operation 104. In that regard, task 104 and task 106 may be interchangeable with respect to timing or executed concurrently with each other.

In operation 110, a gelatin delivery vehicle is prepared. Any of the gelatin delivery vehicles described herein may be used in operation 110. In an embodiment, gelatin, hydrolyzed collagen, glycerin, and other excipients are combined at a temperature ranging from about 45°C to about 85°C and formed as a film. Mixing may occur in a steel tank or other vessel used to prepare the gelatin delivery vehicle. Mixing may be facilitated by an impeller, agitator, agitator, or other device used to blend the contents of the gelatine delivery vehicle. Operation 110 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas. In an embodiment, the gelatin delivery vehicle mixture is degassed prior to being used to encapsulate the pharmaceutical composition.

In operation 112, the pharmaceutical composition is encapsulated with a gelatin delivery vehicle according to protocols well known to those skilled in the art. In operation 112, a soft gelatin capsule delivery vehicle is prepared by combining the pharmaceutical composition prepared in operation 106 with the gelatin delivery vehicle prepared in operation 110. The gelatin may be wrapped around the material to partially or completely encapsulate it or the gelatin may also be injected or otherwise filled with the pharmaceutical composition prepared in operation 106.

In an embodiment, operation 112 is completed in a suitable die to provide the desired shape. Vaginal softgel capsules can be made in a variety of geometries. For example, vaginal softgel capsules may be shaped as teardrops, conical with truncated conical ends, cylindrical, cylindrical with a larger "cap" portion as illustrated in Figure 2, or other shapes suitable for insertion into the vagina. It can be. The resulting pharmaceutical composition encapsulated within a soft gelatin delivery vehicle can be inserted by finger or using an applicator.

Example 7: Study of estradiol pharmaceutical composition for improvement of vulvovaginal atrophy (VVA)

The purpose of this study was to evaluate the efficacy and safety of a pharmaceutical composition containing 10 μg of estradiol (i.e., Pharmaceutical Composition 2) after 14 days of treatment in treating moderate to severe symptoms of VVA associated with menopause. and to estimate the effect size and variability of the vulvovaginal atrophy endpoint. In addition, systemic exposure to estradiol from single and multiple doses of the pharmaceutical composition was investigated.

This study is a phase 1, randomized, double-blind, placebo-controlled trial, which reduces moderate to severe symptoms of vaginal atrophy associated with menopause. To evaluate the safety and efficacy of the pharmaceutical composition in the study, and to investigate the systemic exposure to estradiol after intravaginal administration of the pharmaceutical composition once daily for 14 days.

Postmenopausal subjects who met the study entry criteria were randomly assigned to one of two treatment groups (pharmaceutical composition or placebo). During the screening period, subjects were asked to self-assess the symptoms of VVA, including vaginal dryness, vaginal or vulvar irritation or itching, dysuria, vaginal pain associated with sexual activity, and vaginal bleeding associated with sexual activity. Subjects with at least one self-rated moderate to severe VVA symptom identified by her as most bothersome to the subject were eligible for participation in the study.

Clinical evaluations were performed at the following time points:

● Screening period (up to 28 days);

● Visit 1 - Randomization/Baseline (Day 1);

● Visit 2 - Interim Assessment (Day 8); and

● Visit 3 - End of treatment (day 15).

Eligible subjects were randomized in a 1:1 ratio to administer a pharmaceutical composition containing 10 μg of estradiol or matched placebo vaginal softgel capsules and their first dose of study medication in a clinical facility under the supervision of a researcher was self-administered. Serial blood samples for monitoring estradiol levels were collected at 0.0, 1.0, 3.0, and 6.0 hours for the first dose administration on Day 1. Subjects remained at the clinical site until completion of the 6-hour blood draw and returned to the clinical facility for additional single blood draws for determination of estradiol concentrations on Days 8 (before the morning dose) and Day 15. Subjects were supplied with sufficient study medication until their next scheduled visit and instructed to self-administer their assigned study treatment intravaginally once daily at approximately the same time (±1 hour) each morning. Each subject was provided with a diary, in which she was asked to record daily the date and time of administration of the study drug. Subjects returned to the clinical facility on Day 8 for an interim evaluation visit and on Day 15 for end-of-treatment evaluations and post-study examinations. On Day 1 (6 hours after dosing) and Day 15, the capsule disintegration status was evaluated by the investigator.

The study included a screening period of up to 28 days before randomization and a treatment period of 14 days. The choice of dosing strength (estradiol 10 μg) and treatment regimen (once daily for 2 weeks) was based on FDA test results for safety and efficacy of RLD.

Number of subjects (planned and analyzed)

Up to 50 postmenopausal female subjects (25 per treatment group) between the ages of 40 and 75 years with moderate to severe VVA symptoms were randomly assigned. Fifty subjects were enrolled, 48 subjects completed the study, and 48 subjects were analyzed.

Diagnosis, and key selection criteria

Fifty female subjects were enrolled in this study. Postmenopausal female subjects between the ages of 40 and 75 years with a mean age of 62.3 years were enrolled. The average body weight (kg) of the subjects was 71.2 kg, ranging from 44.5 to 100 kg. The average height (cm) of the subjects was 162.6 cm, ranging from 149.9 to 175.2 cm, and the average BMI (kg/m2) was 26.8 kg/m2, ranging from 19 to 33 kg/m2. Inclusion criteria in this study included: at least one moderate to severe VVA symptom identified by the subject as most bothersome to the subject, e.g., vaginal dryness, dyspareunia, vaginal or vulvar irritation, burning, or itching. , dysuria, self-identification of vaginal bleeding associated with sexual activity; ≤5% superficial cells on vaginal smear cytology; vaginal pH>5.0; and estradiol level ≤50 pg/ml. Subjects who were otherwise judged to be in generally good health based on a pre-study physical examination, clinical laboratory tests, pelvic examination, and mammography were enrolled.

Estradiol 10 μg or placebo, dose, and mode of administration

Subjects were randomized (in a 1:1 allocation) to self-administer intravaginally once daily for 14 days with one of the following treatments:

• Therapeutic agent A: the pharmaceutical composition of Example 5 (Pharmaceutical composition 2: 10 μg of estradiol); or

• Treatment B: A placebo vaginal soft gel capsule containing the same formulation as Treatment A, except for 10 μg of estradiol.

The estradiol formulation was a teardrop-shaped pale pink soft gel capsule. Treatment B had the same composition, appearance, and route of administration as Treatment A, but did not contain estradiol.

duration of treatment

The study included a screening period of up to 28 days before randomization and a treatment period of 14 days.

Evaluation standard

Efficacy endpoint:

• Change from baseline (screening) to day 15 in maturation indicators (percentage of vaginal subbasal cells, vaginal superficial cells, and vaginal interstitial cells) of the vaginal smear. Data for this endpoint are presented in Tables 6-8.

• Change from baseline (screening) to day 15 in vaginal pH. Data for this endpoint are shown in Table 9.

• Change from baseline (randomized) to day 15 in the severity of the most bothersome symptoms: (1) vaginal dryness; (2) vaginal or vulvar irritation, burning, or itching; (3) dysuria; (4) dyspareunia; (5) Vaginal bleeding related to sexual activity. Data for this endpoint are shown in Tables 13 and 15.

● Change from baseline (randomization) to day 15 of investigator assessment of vaginal mucosa.

Data for this endpoint are presented in Tables 18-21.

Efficacy endpoints measured as change from visit 1-randomization/baseline (day 1) to visit 3-end of treatment (day 15), unless otherwise noted, except for vaginal bleeding expressed as treatment success or failure. did

Other endpoints include:

• Vital signs, weight, change in physical examination, pelvic and breast examination, and adverse events were evaluated as some of the safety endpoints.

• Concentration of estradiol at each sampling time.

• Peak concentration of estradiol on day 1 and the sampling time at which the peak occurred.

• Delivery vehicle disintegration to measure the amount of residual delivery vehicle remaining in the vagina after treatment.

Results from the evaluation of plasma concentrations of estradiol are presented in Table 5.

[Table 5]

Other Endpoints:

Maturity Indicator Results

Vaginal cytology data were collected as vaginal smears from the lateral vaginal wall according to standard procedures to evaluate vaginal cytology at screening and visit 3-end of treatment (day 15). Changes in maturational indices were assessed as changes in cell composition measured at Visit 1 - Baseline (Day 1) compared to cell composition measured at Visit 3 - End of Treatment (Day 15). Changes in the percentages of superficial cells, parabasal cells, and interstitial cells obtained from vaginal mucosal epithelium from vaginal smears were recorded. Results from these evaluations are presented in Tables 6, 7, and 8.

[Table 6]

[Table 7]

[Table 8]

Change in pH result

Vaginal pH was measured at Screening and Visit 3 - End of Treatment (Day 15). A pH measurement was obtained by pressing the pH indicator strip against the vaginal wall. Subjects entering this study were required to have a vaginal pH value greater than 5.0 at screening. pH values were recorded in the subject's case report. Subjects were advised to refrain from using vaginal douching and to refrain from sexual activity within 24 hours prior to measurement. Results from these evaluations are presented in Table 9.

[Table 9]

Data on the most annoying symptoms

Subjects were asked to specify a symptom she identified as "the most bothersome symptom". During the screening period, all subjects were given a questionnaire to self-assess the symptoms of VVA: (1) vaginal dryness; (2) vaginal or vulvar irritation, burning, or itching; (3) dysuria; (4) dyspareunia; (5) Vaginal bleeding related to sexual activity. Each symptom, with the exception of vaginal bleeding associated with sexual activity, was measured on a scale of 0 to 3, where 0 = none, 1 = mild, 2 = moderate, and 3 = moderate. Vaginal bleeding associated with sexual activity was measured on a two-item scale: N = no bleeding; Y = Bleeding. The subject's response was recorded. All randomized subjects were also provided with a questionnaire to self-assess the symptoms of VVA at Visit 1 - Randomization/Baseline (Day 1) and at Visit 3 - End of Treatment (Day 15). Subjects recorded their self-assessments daily in a diary, and responses were collected on days 8 and 15 (end of treatment). Pre-dose assessment results obtained at Visit 1 were considered baseline data for statistical analysis. Data from these evaluations are presented in Tables 10 and 11.

[Table 10]

[Table 11]

Changes from baseline to the most bothersome symptom were generally scored according to the assessment of VVA symptoms described above. Tables 13 and 14 show a comparison between Pharmaceutical Composition 1 and placebo for the most bothersome symptoms and vaginal atrophy symptoms in general. It is noteworthy to point out that these measurements showed a trend of improvement at day 15, although not statistically significant.

[Table 13]

[Table 14]

Regarding the most troublesome symptom data presented in Tables 13 and 14, it is generally believed that the time period over which the data were measured was insufficient to draw meaningful conclusions. However, trends observed as part of this study suggest that when data are collected over a longer period of time, the data will show improvement in the most bothersome symptoms.

The absence or presence of any vaginal bleeding associated with sexual activity was also measured as one of the most bothersome symptoms. Data on vaginal bleeding associated with sexual activity are recorded in Table 15.

[Table 15]

Estradiol levels/ pharmacokinetic data

In this study, systemic exposure to estradiol was investigated after intravaginal administration of 10 μg of estradiol once daily for 14 days. Descriptive statistics of plasma estradiol concentrations and observed Cmax and Tmax values taken at each sampling time are reported in Tables 16 and 17. No statistically significant difference was observed in systemic concentrations of the estradiol 10 μg group versus the placebo group, suggesting that estradiol is not transported into the bloodstream to have systemic effects. Rather, it remains within the localized tissue; Thus, the effects of estradiol are believed to be local to the site of administration (ie vagina). The lower limit of detection of the assay used to measure the pharmacokinetic data could have affected the measured accuracy of the pk value presented. Additional pk studies were performed using more precise assays in Examples 8 and 9.

For the purpose of monitoring estradiol levels during this study, at 0.0, 1.0, 3.0, and 6.0 hours for dosing on Day 1; prior to dosing on Day 8; And blood samples were collected prior to dosing on day 15. Efforts were made to collect blood samples at their scheduled times. Sample collection and handling procedures for the measurement of estradiol blood levels were performed according to procedures approved by the sponsor and lead investigator. All baseline and post-treatment plasma estradiol concentrations were determined using a validated bioanalytical (UPLC-MS/MS) method. These data are shown in Tables 16 and 17.

[Table 16]

[Table 17]

Evaluation of vaginal mucosal data

Investigators graded vaginal mucosal appearance on Day 1 (pre-dose) and Day 15. Vaginal color, vaginal epithelial integrity, vaginal epithelial surface thickness, and vaginal discharge were assessed according to the following severity scale: none, mild, moderate, or moderate, where 0 = none, 1 = mild, 2, using a scale of 0 to 3. = moderate severity, and 3 = moderate severity. The results from these investigators' graded evaluations are presented in Table 18, Table 19, Table 20, and Table 21.

[Table 18]

[Table 19]

[Table 20]

[Table 21]

Delivery vehicle disintegration data

Assessment of intravaginal capsule disintegration (presence or absence) on Day 1 (6 hours post-dose) and Day 15. The results of this evaluation are presented in Table 22.

[Table 22]

Serum hormone level data were collected to determine serum concentrations of estradiol. These data were used for screening selection and were determined using standard clinical chemistry methods.

validity of the measurement

The selection of efficacy measures used in this study was based on the study of estrogen and estrogen/progestin drug products for the treatment of moderate to moderate vasomotor symptoms associated with menopause and moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause. Based on FDA recommendations (Food and Drug Administration, Guidance for Industry, Estrogen and Estrogen/ Progestin Drug Products to Treat Vasomotor Symptoms and Vulvar and Vaginal Atrophy Symptoms - Recommendations for Clinical Evaluation. January 2003), which are hereby incorporated by reference. ).

Standard clinical, laboratory, and statistical procedures were used for this test. All clinical laboratory procedures were generally accepted and these procedures met quality standards.

Statistical method:

efficacy:

Analysis of variance (ANOVA) was used to assess the change from baseline difference between subjects receiving 10 μg estradiol and placebo capsules for all efficacy endpoints, except for vaginal bleeding, to determine effect variability and effect size. estimated. In some cases, for example, for some symptoms of vaginal atrophy, changes from baseline (response after dosing) were correlated with baseline values (p<0.05), and thus baseline was included as a covariate to adjust for these correlations. (analysis of covariance, ANCOVA). Effect size was assessed by determining a 90% confidence interval for the difference between the estradiol 10 μg endpoint mean and the placebo endpoint mean. Change from baseline in vaginal bleeding associated with sexual activity was assessed in terms of the proportion of subjects with treatment success or failure. Subjects who reported bleeding at baseline and did not report bleeding at Day 15 were considered successfully treated. Subjects who reported bleeding on day 15 were considered treatment failures regardless of whether they reported baseline bleeding or not. Subjects who reported no bleeding at both baseline and Day 15 were classified as no change and were excluded from statistical evaluation. Differences in the proportion of subjects who achieved success between the two treatment groups were statistically assessed using Fisher's exact test. The results of this difference in ratio are presented in Table 10.

Measurement of adherence to treatment

Subjects were asked to fill out a diary to record treatment compliance. At visits on days 8 and 15, the diary was reviewed for treatment compliance. A total of 45 subjects (21 subjects in the estradiol 10 μg group and 24 subjects in the placebo group) showed 100% compliance with the treatment plan.

Due to the investigative nature of this study, no adjustments were made for the multiplicity of endpoints.

safety:

The frequency and severity of all adverse events were descriptively summarized by treatment group.

Results: All 48 subjects who completed this study were included in the primary efficacy analysis. The results of the efficacy analysis are presented throughout Table 5, Table 6, and Table 7.

conclusion

efficacy

Two weeks of treatment with 10 μg of the pharmaceutical composition resulted in a statistically significant greater mean reduction than the placebo treatment group in the percentage of parabasal cells (54% vs. 5%, p<0.0001), which is shown in Table 6. As exemplified. At the same time, a significantly greater average increase in the percentage of superficial cells was observed with the pharmaceutical composition (35%) than with the placebo capsule (9%), with the difference being highly statistically significant (p=0.0002 ), which is as illustrated in Table 7. For the difference in pH reduction, that difference between the pharmaceutical compositions (0.97 units) compared to that for the placebo (0.34 units) was only slightly greater than 0.5 units, but the difference was statistically significant (p = 0.0002), which is shown in Table 9.

The reduction in the severity of the most bothersome symptom was essentially the same for both the pharmaceutical composition and the placebo (about 1 unit), but the reduction in the severity of individual symptoms of vaginal dryness, irritation and pain during sexual activity was all relative to the placebo treatment group. It was marginally better for the active treatment group. None of the differences between the two treatment groups, both <0.3 units, were detected as statistically significant. There was no difference between the 2 treatment groups with respect to reduction in pain/burning/stinging during urination (approximately 0.4 unit reduction). The duration of this study was not long enough to show a distinction between the most bothersome symptoms in the pharmaceutical composition and placebo. However, the trend of the most bothersome symptoms suggests that a fairly significant difference will be observed between the two treatment groups by the appropriate time period.

Two weeks of treatment with estradiol 10 μg capsules did not show statistically detectable differences in terms of vaginal color or decrease in severity from baseline according to investigator assessment of vaginal epithelial surface thickness. The pharmaceutical composition capsules showed a statistically significant greater decrease than placebo in the severity of vaginal epithelial integrity and atrophic effects on vaginal discharge as follows: vaginal epithelial integrity (-0.34 vs. 0.18, p=0.0001) and vaginal discharge (-0.64 vs -0.27, p=0.0401).

Descriptive statistical analysis (mean, median, geometric mean, standard deviation, CV, minimum and maximum values, Cmax, and Tmax) was performed on estradiol concentration at each sampling time, peak concentration at day 1 and time of peak concentration. ran about. Results from this evaluation are presented in Tables 16 and 17.

The pharmaceutical composition comprising 10 μg of estradiol outperformed the placebo treatment group with respect to improvement of maturation markers, reduction of vaginal pH, epithelial integrity and reduction of atrophic effects on vaginal discharge. The lack of statistical significance between the two treatment groups with respect to the reduction in severity for the most bothersome symptom and individual vaginal atrophy symptoms of dryness, irritation, pain associated with sexual activity, and pain/burning/stinging when urinating: This is not unexpected given the small number of subjects in this study and the short duration of therapy. Very few subjects in this study had vaginal bleeding associated with sexual activity, allowing any meaningful assessment of symptoms of vaginal atrophy.

Of the 48 subjects enrolled in this study, 45 subjects showed 100% compliance with the treatment plan. Of the remaining 3 subjects, 1 self-withdrew from the study due to personal reasons, and each of the other 2 subjects missed 1 dose due to an adverse event.

safety

Although the average plasma estradiol peak concentration on Day 1 for the pharmaceutical composition was somewhat higher than for the placebo (ratio of geometric means = 1.21: test product (estradiol 10 μg) 21% > placebo), statistically No significant differences were determined. However, these assay methods were questionable and resulted in questionable pk data. Additional pk studies were performed in Examples 8 and 9.

There were no serious adverse events in this study.

Overall, the pharmaceutical composition comprising 10 μg of estradiol was well tolerated when administered intravaginally on a once daily schedule for 14 days.

Example 8: pk study (25 μg formulation)

A pk study was conducted to compare the 25 μg formulation disclosed herein (Pharmaceutical Composition 3) with RLD. The results of the pk study for estradiol are summarized in Table 23. The p values for these data show statistical significance, as shown in Table 24.

[Table 23]

[Table 24]

As shown in Table 23, the baseline adjusted pk data illustrates that the formulations disclosed herein unexpectedly show a 54% reduction in Cmax and a 31% reduction in AUC compared to RLD. This result is desirable because estradiol is only intended for topical absorption. These data suggest a decrease in circulating levels of estradiol compared to RLD. Moreover, it is noteworthy to point out that there are no statistical differences in the Cmax and AUC levels of estradiol compared to placebo, suggesting that the formulations disclosed herein have negligible systemic effects. As shown in Table 24, there were no significant differences between the test and reference products due to sequence and timing effects. However, there were significant differences due to treatment effects for both Cmax and AUC.

The pharmacokinetic properties of total circulating estrone, a metabolite of estradiol, are shown in Table 25. These data show that total circulating estrone for the formulations disclosed herein resulted in a 55% reduction in Cmax for circulating estrone and a 70% reduction in AUC for circulating estrone.

[Table 25]

[Table 26]

For Cmax, there was a significant difference between the test and reference products due to the treatment effect, while there was no significant difference due to the sequence effect and the timing effect. For AUC, there were significant differences between the test and reference products due to treatment effect, sequence effect, and timing effect.

The pk for total circulating estrone sulfate is shown in Table 27. These data show that total circulating estrone sulfate for the pharmaceutical composition disclosed herein resulted in a 33% reduction in Cmax and a 42% reduction in AUC for circulating estrone sulfate.

[Table 27]

[Table 28]

For both Cmax and AUC, there was a significant difference between the test and reference products due to treatment effect, while there was no significant difference due to sequence effect and timing effect.

Example 9: pk study (10 μg formulation)

A pk study was conducted to compare the 10 μg formulation disclosed herein (Pharmaceutical Composition 2) with RLD. The results of the pk study for estradiol are summarized in Tables 29-40 and Figures 9-14.

A pk study was conducted to compare the pharmaceutical composition disclosed herein with 10 μg of estradiol to RLD. The results of the pk study for estradiol are summarized in Tables 29-34, demonstrating that the pharmaceutical compositions disclosed herein more effectively prevented systemic absorption of estradiol. Table 35 shows that the pharmaceutical composition disclosed herein had a 28% improvement over RLD for systemic blood concentration Cmax and a 72% AUC improvement over RLD.

[Table 29]

[Table 30]

[Table 31]

[Table 32]

Similarly, pk data for total estrone showed reduced systemic exposure when compared to RLD. Table 33 shows the reduced systemic exposure of the pharmaceutical compositions disclosed herein by 25% for Cmax and 49% for AUC.

[Table 33]

[Table 34]

[Table 35]

[Table 36]

Similarly, pk data for estrone sulfate showed reduced systemic exposure when compared to RLD. Table 37 shows the reduced systemic exposure of the pharmaceutical compositions disclosed herein by 25% for Cmax and 42% for AUC.

[Table 37]

[Table 38]

[Table 39]

[Table 40]

Although the present pharmaceutical compositions and methods have been described as presently believed to be practical and preferred embodiments, it should be understood that the invention need not be limited to the disclosed embodiments. It is intended to cover various modifications and similar arrangements included within the spirit and scope of the claims, and the scope of the claims is to be accorded the broadest interpretation so as to encompass all such modifications and similar embodiments. The invention includes any and all embodiments of the following claims.

Claims (51)

As a pessary, including pharmaceutical formulations and capsules,
The pharmaceutical formulation is encapsulated in a capsule, and
A pessary, wherein the pharmaceutical formulation is selected from the pharmaceutical formulations (i)-(vi) set forth below:
(i) a pharmaceutical formulation consisting of:
0.010 mg of estradiol hemihydrate;
270.0 mg of caprylic/capric triglyceride; and
30 mg of a mixture of PEG-6 stearate, ethylene glycol palmitostearate, and PEG-32 stearate;
(ii) a pharmaceutical formulation consisting of:
0.026 mg of estradiol hemihydrate;
270.0 mg of caprylic/capric triglyceride; and
30.02 mg of a mixture of PEG-6 stearate, ethylene glycol palmitostearate, and PEG-32 stearate;
(iii) a pharmaceutical formulation consisting of:
0.0041 mg of estradiol hemihydrate;
269.99 mg of caprylic/capric triglyceride; and
30 mg of a mixture of PEG-6 stearate, ethylene glycol palmitostearate, and PEG-32 stearate;
(iv) a pharmaceutical formulation consisting of:
0.010 mg of estradiol;
270.0 mg of caprylic/capric triglyceride; and
30 mg of a mixture of PEG-6 stearate, ethylene glycol palmitostearate, and PEG-32 stearate;
(v) a pharmaceutical formulation consisting of:
0.025 mg of estradiol;
270.0 mg of caprylic/capric triglyceride; and
30.02 mg of a mixture of PEG-6 stearate, ethylene glycol palmitostearate, and PEG-32 stearate; and
(vi) a pharmaceutical formulation consisting of:
0.004 mg of estradiol;
269.99 mg of caprylic/capric triglyceride; and
A mixture of 30 mg of PEG-6 stearate, ethylene glycol palmitostearate, and PEG-32 stearate. The pessary of claim 1 , wherein the capsule is a soft capsule. 3. The pessary of claim 2, wherein the soft capsule is a soft gelatin capsule. The pessary of claim 1 , wherein estradiol is solubilized. 5. The pharmaceutical formulation according to any one of claims 1 to 4,
A pessary, which is a pharmaceutical formulation (i) consisting of:
0.010 mg of estradiol hemihydrate;
270.0 mg of caprylic/capric triglyceride; and
A mixture of 30 mg of PEG-6 stearate, ethylene glycol palmitostearate, and PEG-32 stearate. 5. The pharmaceutical formulation according to any one of claims 1 to 4,
A pessary, which is a pharmaceutical formulation (ii) consisting of:
0.026 mg of estradiol hemihydrate;
270.0 mg of caprylic/capric triglyceride; and
A mixture of 30.02 mg of PEG-6 stearate, ethylene glycol palmitostearate, and PEG-32 stearate. 5. The pharmaceutical formulation according to any one of claims 1 to 4,
A pessary, which is a pharmaceutical formulation (iii) consisting of:
0.0041 mg of estradiol hemihydrate;
269.99 mg of caprylic/capric triglyceride; and
A mixture of 30 mg of PEG-6 stearate, ethylene glycol palmitostearate, and PEG-32 stearate. 5. The pharmaceutical formulation according to any one of claims 1 to 4,
A pessary, which is a pharmaceutical formulation (iv) consisting of:
0.010 mg of estradiol;
270.0 mg of caprylic/capric triglyceride; and
A mixture of 30 mg of PEG-6 stearate, ethylene glycol palmitostearate, and PEG-32 stearate. 5. The pharmaceutical formulation according to any one of claims 1 to 4,
A pessary, which is a pharmaceutical formulation (v) consisting of:
0.025 mg of estradiol;
270.0 mg of caprylic/capric triglyceride; and
A mixture of 30.02 mg of PEG-6 stearate, ethylene glycol palmitostearate, and PEG-32 stearate. 5. The pharmaceutical formulation according to any one of claims 1 to 4,
A pessary, which is a pharmaceutical formulation (vi) consisting of:
0.004 mg of estradiol;
269.99 mg of caprylic/capric triglyceride; and
A mixture of 30 mg of PEG-6 stearate, ethylene glycol palmitostearate, and PEG-32 stearate. 5. The pessary according to any one of claims 1 to 4 for use in the treatment of estrogen-deficient conditions via intravaginal delivery. The pessary according to claim 11, wherein the estrogen-deficient condition is selected from the group consisting of vaginal dryness, dysuria, dyspareunia, estrogen-deficient urination condition, and vaginal bleeding associated with sexual activity. 13. The pessary of claim 12, wherein the estrogen-deficient condition is vaginal dryness. 14. The pessary of claim 13, wherein the estrogen-deficient condition is dyspareunia. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete

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