JP2016534025A - Estradiol pharmaceutical composition and method for vaginal insertion - Google Patents

Abstract

Various embodiments of the present disclosure provide pharmaceutical compositions comprising solubilized estradiol. In various embodiments, such compositions are encapsulated in soft capsules that can be inserted into the vagina for the treatment of vulva vaginal atrophy.

Description

(Cross-reference of related applications)
This application is based on the following US patent application: US Provisional Application No. 61 / 932,140, filed on Oct. 22, 2013, entitled “VAGINAL INSERTED ETRADIOL PHARMACEUTICAL COMPOSITIONS AND METHODS” filed on Jan. 27, 2014. Claims priority to US Provisional Application No. 61 / 894,411 entitled “SOLUBELE STRADIOL CAPSULE FOR VAGINAL INSERTION”. This application also claims priority to US Provisional Application No. 61 / 745,313, filed December 21, 2012, entitled “SOLUBE ESTRADIOL CAPSULE FOR VAGINAL INSERTION”, filed on June 18, 2013. This is a partial continuation of PCT No. US2013 / 46443 entitled “ENTRADIOL CAPSULE FOR VAGINAL INSERTION”. This application is also entitled “NATURAL COMBINATION HORMONE REPLACEEMENT” filed on March 15, 2013, claiming priority to US Provisional Application No. 61 / 661,302 entitled “ESTRADIOL PHARMAUTUAL COMPOSTIONS” filed on June 18, 2012. United States Patent Application No. 13 / 843,428, entitled “FORMULATIONS AND THERAPIES”, filed November 21, 2012, which is a continuation of US Patent Application No. 13 / 843,428 Claiming priority over (currently US Pat. No. 8,633,178), 201 US patent application No. 14 / 099,562 entitled “NATUREL COMBINATION HORMONE REPLACEMENT FORMULATIONS AND THERAPIES” filed on December 6, 2012 662,265, and a continuation of US Provisional Application No. 61 / 563,408 entitled “NATURER COMBINATION HORMONE REPLACEMENT THERAPIES” filed on November 23, 2011. All the above-mentioned applications are hereby incorporated by reference in their entirety.

  The present application is directed to pharmaceutical compositions, methods, and devices relating to hormone replacement therapy.

  Postmenopausal women often suffer from atrophic vaginitis or vulva and vaginal atrophy (hereinafter “vulva vaginal atrophy” or “VVA”), among which symptoms include, for example, vaginal dryness, vaginal malodor, vagina or vulva Includes irritation or pruritus, dysuria (pain when urinating, burning, or stinging), sexual pain (vaginal pain associated with sexual activity), and vaginal bleeding vagina associated with sexual activity. Other symptoms include a tingling sensation, with frequent urination and urgency, and urination discomfort and incontinence ("estrogen-deficient urinary state (s)"). One symptom of vaginal atrophy is an increase in vaginal pH, which creates an environment that is more susceptible to infection. The mucosal epithelium of VVA patients also showed signs of severe atrophy and was reported to be accompanied by an increase in the number of parabasal cells and a decrease in the number of superficial cells according to cytodiagnosis.

  Each of these VVA-related conditions presents symptoms associated with decreased estrogenization of the vulva and vaginal tissue, and can occur even in women receiving oral estrogen medication. Although VVA is most common in menopausal women, it can occur at any time during a woman's lifetime.

  Estrogen treatment has proven very successful in controlling climacteric symptoms including vaginal atrophy (VVA). Several studies have shown that symptoms associated with vaginal atrophy are often alleviated by estrogen treatment given either systemically or locally. Existing treatments have a number of problems, for example compliance issues where patients do not complete or continue treatment due to problems associated with the form of treatment.

  Accordingly, disclosed herein are, among other things, new soft gel vaginal pharmaceutical compositions and dosage forms containing solubilized estradiol for the treatment of VVA. Soft gel vaginal pharmaceutical compositions were designed to alleviate the general limitations found with other vaginal forms of estradiol. Soft gel vaginal pharmaceutical composition facilitates vaginal administration, provides improved insertion safety, minimizes vaginal discharge after administration, as well as efficacy, safety and patient It is expected to provide more effective dosage forms with improved compliance.

  Various aspects and embodiments of the present disclosure provide soft gel vaginal pharmaceutical compositions as a potential treatment for postmenopausal women suffering from moderate to severe symptoms of VVA.

  Provided herein is a pessary comprising a) a therapeutically effective amount of estradiol and b) a solubilizer comprising a medium chain oil.

  In some embodiments, the pessary comprises about 1 μg to about 25 μg estradiol. For example, the pessary can comprise about 1 μg to about 10 μg estradiol, and about 10 μg to about 25 μg 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 capron fatty acid esters, capryl fatty acid esters, caprin fatty acid esters, and combinations thereof. For example, the solubilizer can comprise caprylic / capric triglycerides.

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

  As used herein, a non-ionic surfactant comprising a) a therapeutically effective amount of estradiol, b) caprylic / capric triglyceride, and c) PEG-6 palmitostearate and ethylene glycol palmitostearate D) soft gelatin capsules are also provided.

In some embodiments, the pessary provided herein comprises about 25 μg estradiol, and administration of the pessary to the patient is in a plasma sample from the patient 1) about 19 pg ^* hr / ml to about 29 pg ^* correction geometric mean peak plasma concentration of hr / ml of estradiol _{(C max),} 2) about 75 pg ^* hr / ml to about 112pg ^* hr / ml of estradiol correction geometric mean area under the curve _{(AUC) 0-24} And provide.

In some embodiments, a pessary provided herein comprises about 25 μg estradiol, and administration of the pessary to a patient is in a plasma sample from the patient 1) about 9 pg ^* hr / ml to about 14 pg ^* and hr / ml for correcting geometric mean peak plasma concentrations of estrone _{(C max),} 2) about 43pg ^* hr / ml~ about 65 pg ^* hr / ml for correcting geometric mean area under the curve of estrone _{(AUC) 0-24} And provide a pessary.

In some embodiments, a pessary provided herein comprises about 25 μg estradiol and administration of the pessary to a patient is in a plasma sample from the patient 1) about 416 pg ^* hr / ml to about 613Pg ^* and hr / ml for correcting geometric mean peak plasma concentrations of estrone sulfate _{(C max),} 2) about 3598pg ^* hr / ml~ about 5291pg ^* hr / ml for correcting geometric mean area under the curve of estrone sulfate _{(AUC) 0 To 24} .

In some embodiments, the pessary provided herein comprises about 10 μg estradiol, and administration of the pessary to the patient is in a plasma sample from the patient 1) about 12 pg ^* hr / ml to about 18 pg ^* correction geometric mean peak plasma concentration of hr / ml of estradiol _{(C max),} 2) about 42 pg ^* hr / ml to about 63 pg ^* hr / ml of estradiol correction geometric mean area under the curve _{(AUC) 0-24} And provide. In some embodiments, the pessary further provides a corrected geometric mean time from about 1 hour to about 3 hours to the peak plasma concentration of estradiol (T _max ).

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

In some embodiments, the pessaries provided herein comprise about 10 μg estradiol and administration of the pessary to the patient is in a plasma sample from the patient 1) about 10 pg ^* hr / ml to about 16 pg ^* and hr / ml for correcting geometric mean peak plasma concentrations of estrone sulfate _{(C max),} 2) about 56pg ^* hr / ml~ about 84pg ^* hr / ml for correcting geometric mean area under the curve of estrone sulfate _{(AUC) 0 To 24} . In some embodiments, the pessary further provides a corrected geometric mean time to estrone sulfate peak plasma concentration (T _max ) of about 4 hours to about 7 hours.

In some embodiments, a pessary provided herein comprises about 4 μg estradiol, and administration of the pessary to a patient is in a plasma sample from the patient 1) about 4 pg ^* hr / ml to about 8 pg ^* correction geometric mean peak plasma concentration of hr / ml of estradiol _{(C max),} 2) about 16 pg ^* hr / ml to about 26 pg ^* hr / ml of estradiol correction geometric mean area under the curve _{(AUC) 0-24} And provide. In some embodiments, the pessary further provides a corrected geometric mean time to a peak plasma concentration (T _max ) of estradiol from about 0.25 hours to about 2 hours.

In some embodiments, the pessaries provided herein comprise about 4 μg estradiol, and administration of the pessary to the patient is in a plasma sample from the patient 1) about 1 pg ^* hr / ml to about 3 pg ^* and hr / ml for correcting geometric mean peak plasma concentrations of estrone _{(C max),} 2) about ^{8 pg} * hr / ml to about 13 pg ^* hr / ml for correcting geometric mean area under the curve of estrone _{(AUC) 0-24} And provide. In some embodiments, the pessary further provides a corrected geometric mean time to an estrone peak plasma concentration (T _max ) of about 1 hour to about 4 hours.

In some embodiments, the pessary provided herein comprises about 4 μg estradiol and administration of the pessary to the patient is in a plasma sample from the patient,
1) about ^{4 pg} * hr / ml to correct geometric mean peak plasma concentration of about ^{7 pg} * hr / ml for estrone sulfate _{(C max),} 2) from about 22 pg ^* hr / ml to about 34pg ^* hr / ml for estrone sulfate The area under the corrected geometric mean curve (AUC) _0-24 . In some embodiments, the pessary further provides a corrected geometric mean time from about 1 hour to about 3 hours to the peak plasma concentration (T _max ) of estrone sulfate.

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

In some embodiments, a pessary comprising about 1 μg to about 25 μg estradiol is provided, wherein administration of the pessary to the patient is less than about 112 pg ^* hr / ml, the area under the corrected geometric mean curve (AUC) of estradiol _{Provide 0-24} . For example, administration of a pessary to a patient provides an area under the corrected geometric mean curve (AUC) _0-24 of estradiol that is less than about 63 pg ^* hr / ml.

In some embodiments, a pessary comprising about 1 μg to about 25 μg estradiol is provided, and administration of the pessary to the patient is less than about 14 pg ^* hr / ml, the corrected geometric mean peak plasma concentration (C _{max) of} estrone )I will provide a. For example, administration of pessary to a patient provides a corrected geometric mean peak plasma concentration (C _max ) for estrone, which is about 7 pg ^* hr / ml.

In some embodiments, a pessary comprising about 1 μg to about 25 μg estradiol is provided, and administration of the pessary to a patient is less than about 65 pg ^* hr / ml, the area under the corrected geometric mean curve (AUC) of estrone _{Provide 0-24} . For example, administration of pessary to a patient provides an area under the corrected geometric mean curve (AUC) _0-24 of estrone, which is less than about 31 pg ^* hr / ml.

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

In some embodiments, a pessary comprising about 1 μg to about 25 μg of estradiol is provided, and administration of the pessary to a patient is less than about 5291 pg ^* hr / ml, the area under the corrected geometric mean curve (AUC) of estrone sulfate ) _{Provide 0-24} . For example, administration of pessary to a patient provides an area under the corrected geometric mean curve (AUC) _0-24 for estrone sulfate that is less than about 84 pg ^* hr / ml.

  Also provided herein is a pessary comprising about 1 μg to about 25 μg estradiol, wherein administration of the pessary to the proximal region of the patient's vagina provides a therapeutically effective concentration of estradiol within the proximal region of the vagina for 24 hours. provide.

  The present disclosure also provides a method of treating an estrogen deficiency condition, comprising administering to a patient in need thereof the pessary provided herein. In some embodiments, a method of treating vulva vaginal atrophy is provided, the method comprising administering a pessary provided herein to a patient in need thereof.

  In some embodiments of the methods provided herein, the treatment is associated with vaginal dryness, sexual pain, vaginal or vulvar stimulation, vaginal or vulvar burning, vaginal or vulvar pruritus, dysuria, and sexual activity. Reducing the severity of one or more symptoms selected from the group consisting of vaginal bleeding.

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

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

  There is further provided herein a method for reducing vaginal secretions after administration of a pessary, the method comprising administering to a patient in need thereof a pessary provided herein. The vaginal secretion after administration of the pessary is compared with the vaginal secretion after administration of the reference drug.

The foregoing features and objects of the present disclosure will become more apparent with reference to the following description taken in conjunction with the accompanying drawings, wherein like reference numerals designate like elements, and in which:
FIG. 4 is a flow diagram illustrating a process according to various embodiments of the invention. 2 illustrates a suppository according to various embodiments of the invention. A linear plot of mean plasma estradiol (baseline adjusted concentration) versus time (N = 36). A semi-log plot of mean plasma estradiol (baseline adjusted concentration) versus time (N = 36). Linear plot of mean plasma estrone (baseline adjusted concentration) versus time (N = 36). A semi-log plot of mean plasma estrone (baseline adjusted concentration) versus time (N = 36). A linear plot of mean plasma estrone sulfate (baseline adjusted concentration) versus time (N = 36). A semi-log plot of mean plasma estrone sulfate (baseline adjusted concentration) versus time (N = 36). A linear plot of mean plasma estradiol (baseline adjusted concentration) versus time (N = 34). A semi-log plot of mean plasma estradiol (baseline adjusted concentration) versus time (N = 34). Linear plot of mean plasma estrone (baseline adjusted concentration) versus time (N = 33). A semi-log plot of mean plasma estrone (baseline adjusted concentration) versus time (N = 33). Linear plot of mean plasma estrone sulfate (baseline adjusted concentration) versus time (N = 24). A semi-log plot of mean plasma estrone sulfate (baseline adjusted concentration) versus time (N = 24).

  In the following detailed description of the embodiments of the present disclosure, reference is made to the accompanying drawings, in which like reference numerals designate like elements and in which are shown by illustrations of specific embodiments in which the present disclosure may be implemented. These embodiments have been described in sufficient detail to enable those skilled in the art to practice the present disclosure, other embodiments may be used, and depart from the scope of the present disclosure. It should be understood that other changes may be made. The following detailed description is, therefore, not to be taken in a limiting sense, and the scope of the present disclosure is defined only by the appended claims. As used in this disclosure, the term “or” is understood to be defined as a logical OR (ie, and / or), and the terms “either”, “unless ( unless stated explicitly with the words “unless”, “alternatively”, and similar effects, does not indicate an exclusive OR.

Definitions The term “active pharmaceutical ingredient” (“API”) as used herein means the active compound (s) used in the formulation of a formulation.

  The term “in combination”, as used herein, means that two or more formulations are administered simultaneously or sequentially on the same day or on different days.

  The term “formulation” as used herein means at least one active pharmaceutical ingredient provided in unit dosage form in combination with at least one excipient.

The term “area under the curve” (“AUC”) is defined by the change in blood concentration of the active pharmaceutical ingredient (eg, estradiol or progesterone) or metabolite of the active pharmaceutical ingredient after administration of a dose of the active pharmaceutical ingredient. Refers to the area under the curve. “AUC _o˜∞ ” is the area under the concentration-time curve extrapolated to infinity after administration of one dose. “AUC _o-t ” is the area under the concentration-time curve from time 0 to time t after administration of a dose, where t is the last time point with a measurable concentration.

The term “C _max ” refers to the maximum value of the blood concentration shown on a curve representing the change over time in the blood concentration of an active pharmaceutical ingredient (eg, progesterone or estradiol) or a metabolite of the active pharmaceutical ingredient.

The term “T _max ” refers to the time it takes for the blood 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”, having the meaning defined in Article 21. 320.1 (a) of the Federal Regulations, refers to the rate at which an API or active ingredient or active part is absorbed from the formulation and becomes available at the site of action. Refers to the degree. 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, C _max , or T _max can be used to measure and assess bioavailability. For formulations that are not intended to be absorbed into the bloodstream, bioavailability is 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. May be.

The term “bioequivalence”, having the meaning defined in Article 21. 320.1 (e) of the Federal Regulations, refers to the API or active ingredient or active part in a pharmaceutical equivalent or pharmaceutical substitute. This means that there is no significant difference in the rate and extent available at the site of drug action when administered at the same molar dose under similar conditions in a properly designed study. Where there is a deliberate difference in rate (eg, in certain sustained release dosage forms), certain pharmaceutical equivalents or alternatives may allow the active ingredient or portion from each formulation to be used at the site of drug action Can be considered bioequivalent if not significantly different. This is the intentional difference in the rate at which an active ingredient or part can be used at the site of drug action and is reflected in the label presented and is not essential to achieving an effective in-vivo drug concentration for continuous use. And only if it is considered medically unimportant for the drug. In practice, two formulations are considered bioequivalent if the 90% confidence interval for AUC, C _max , or optionally T _max is within 80.00% to 125.00%.

  The terms “bio-identical”, “body-identical”, or “natural” as used in connection with the hormones disclosed herein are the chemical structures of those that exist naturally or endogenously in the human body and It means a hormone that matches the action. An exemplary natural estrogen is estradiol.

  The term “bio-identical hormone” or “body-identical hormone” refers to an active pharmaceutical ingredient that is structurally identical to hormones found naturally or endogenously in the human body (eg, estradiol and progesterone).

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

  Estradiol is supplied in anhydrous or hemihydrate form. For the purposes of this disclosure, the anhydrous or hemihydrate form can be substituted for others by accounting for moisture or water deficiencies according to well-known and understood techniques.

  The term “solubilized estradiol” means that estradiol or a portion thereof is solubilized or dissolved in the solubilizer (s) or formulations disclosed herein. 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, estradiol is “fully solubilized” with all or substantially all of the estradiol solubilized or dissolved in the solubilizer. Fully solubilized estradiol may comprise about 97% solubilized, about 98% solubilized, about 99% solubilized or about 100% solubilized estradiol. Solubility can be expressed as a mass fraction (wt / wt%, also referred to as wt%).

  The term “progesterone” refers to pregn-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 a bioidentical or body-identical form of progesterone found in the human body having the structure:

  The term “solubilized progesterone” means that progesterone or a portion thereof is solubilized or dissolved in the solubilizer (s) or formulations disclosed herein. In some embodiments, progesterone is “partially solubilized” with a portion of progesterone solubilized or dissolved in the solubilizer and a portion of progesterone suspended in the solubilizer. Partially solubilized progesterone is about 1% solubilized, about 5% solubilized, about 10% solubilized, about 15% solubilized, about 20% solubilized, about 30% solubilized, about 40% acceptable Contains progesterone solubilized, about 50% solubilized, about 60% solubilized, about 70% solubilized, about 80% solubilized, about 85% solubilized, about 90% solubilized, or about 95% solubilized Good. In other embodiments, the progesterone is “fully solubilized” with all or substantially all of the progesterone solubilized or dissolved in the solubilizer. Fully solubilized progesterone may comprise about 97% solubilized, about 98% solubilized, about 99% solubilized, or about 100% solubilized progesterone. Solubility can be expressed as a mass fraction (wt / wt%, also referred to as wt%).

The terms “micronized progesterone” and “micronized estradiol” as used herein have a micronization having an X ₅₀ particle size value of less than about 15 microns or an X ₉₀ particle size value of less than about 25 microns. Contains progesterone and micronized estradiol. The term “X ₅₀ ” means that half the diameter of the particles in the sample is smaller than a given number. For example, for a given sample of micronized progesterone, micronized progesterone having an X ₅₀ of 5 μm means that the half-particle diameter is less than 5 μm. Similarly, the term “X ₉₀ ” means that the diameter of 90% of the particles in the sample is smaller than a given number.

  The term “glyceride” is an ester of glycerol (1,2,3-propanetriol) with an acyl radical of a fatty acid, also known as acylglycerol. When only one position of the glycerol molecule is esterified with a fatty acid, a “monoglyceride” or “monoacylglycerol” is produced, and when two positions are esterified, a “diglyceride” or “diacylglycerol” is produced. If all three positions of glycerol are esterified with fatty acids, “triglycerides” or “triacylglycerols” are produced. If all esterification positions contain the same fatty acid, the glyceride is “simple”, whereas if the esterification position contains different fatty acids, the glyceride is “mixed”. The carbons of the glycerol backbone are designated as sn-1, sn-2, and sn-3, sn-2 is in the intermediate carbon, and sn-1 and sn-3 are the terminal carbons of the glycerol backbone.

  The term “solubilizing agent” refers to an agent or combination of agents that solubilizes an active pharmaceutical ingredient (eg, estradiol or progesterone). For example, without limitation, suitable solubilizers include medium chain oils and other solvents and cosolvents that solubilize or dissolve the active pharmaceutical ingredient to the desired extent. Suitable solubilizers for use in the formulations disclosed herein are pharmaceutical grade solubilizers (eg, pharmaceutical grade medium chain oils). One skilled in the art will appreciate that other excipients or ingredients can be added to or mixed with the solubilizer to enhance the properties or performance of the solubilizer or 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 solubilizer is a medium chain oil, and in some other embodiments, the medium chain oil is combined with the co-solvent (s) or other excipient (s). .

  The term “medium chain” is used to describe the fatty chain length of a fatty acid-containing molecule. “Medium chain” is specifically a fatty acid aliphatic tail or 6 (C6) -14 (C14) carbon atoms, 8 (C8) -12 (C12) carbon atoms, or 8 (C8) -10 (C10). A fatty acid, a fatty acid ester, or a fatty acid derivative containing a carbon chain containing a carbon atom.

  The terms “medium chain fatty acid” and “medium chain fatty acid derivative” are used to describe a fatty acid or fatty acid derivative having an aliphatic tail (ie, carbon chain) having 6 to 14 carbon atoms. Fatty acids are composed of unbranched or branched aliphatic tails attached to carboxylic acid functional groups. Examples of fatty acid derivatives include, but are not limited to, fatty acid esters and fatty acid-containing molecules, including mono-, di-, and triglycerides containing components derived from fatty acids. Fatty acid derivatives also include fatty acid esters of ethylene or propylene glycol. An aliphatic tail can be saturated or unsaturated (ie, having one or more double bonds between carbon atoms). In some embodiments, the aliphatic tail is saturated (ie, there are no double bonds between carbons). Examples of medium chain fatty acids or medium chain fatty acid derivatives include those having an aliphatic tail having 6-14 carbons, C6-14, C6-C12, C8-C14, C8-C12, C6-C10, C8-C10, Or anything else. Examples of medium chain fatty acids include, but are not limited to caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, and derivatives thereof.

  The term “oil” as used herein refers to any pharmaceutically acceptable oil, particularly medium chain oil (specifically excluding peanut oil), including its starting materials or precursors. Bioidentical progesterone or estradiol (including micronized progesterone or micronized estradiol as described herein) can be suspended or solubilized.

  The term “medium chain oil” means that the composition of the fatty acid fraction of the oil is substantially medium chain (ie, C6-C14) fatty acids, ie, the composition profile of the fatty acids in the oil is substantially medium chain. It refers to oil. As used herein, “substantially” means a fat in which 20% to 100% (including upper and lower limits) of the fatty acid fraction of the oil has medium chain fatty acids, ie 6 to 14 carbons. It means that it consists of fatty acids with a family tail (ie carbon chain). In some embodiments, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 65% of the fatty acid fraction of the oil 70%, about 75%, about 85%, about 90%, or about 95% consists of medium chain fatty acids. One skilled in the art can use the terms “alkyl content” or “alkyl distribution” of an oil in place of the term “fatty acid fraction” of the oil in characterizing a given oil or solubilizer. It will be readily appreciated that these terms can be used interchangeably herein. As such, medium chain oils suitable for use in the formulations disclosed herein are those in which the fatty acid fraction of the oil is substantially medium chain fatty acid or medium chain oil, and the alkyl content of the oil. Includes medium chain oils whose amount or alkyl distribution is substantially medium chain alkyl (C6-C12 alkyl). 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, but are not limited to, medium chain fatty acids, glycerol medium chain fatty acid esters (e.g., mono, di, and triglycerides), propylene glycol medium chain fatty acid esters, polyethylene glycol medium chain 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 the oil and can be used to characterize the oil, for example, as a medium chain oil or a long chain oil. For example, tripalmitin (tripalmitin glycerol), a simple triglyceride containing 3 fatty acid chains of 16 carbon atoms, has an ECN of 3 × 16 = 48. Conversely, triglycerides with ECN = 40 may have “mixed” fatty acid chain lengths such as 8, 16, and 16; 10, 14, and 16; 8, 14, and 18. Naturally occurring oils are often “mixed” with respect to specific fatty acids, but tend not to contain both long and medium chain fatty acids in the same glycerol backbone. Thus, triglycerides with an ECN of 21 to 42 typically contain mainly medium chain fatty acids, whereas triglycerides with an ECN of more than 43 typically contain mainly long chain fatty acids. For example, the ECN of corn oil triglycerides in USP is in the range of 51-54. Medium chain diglycerides with ECNs of 12-28 often contain mainly medium chain fatty acids, while diglycerides with 32 or more ECNs typically contain mainly long chain fatty acid tails. Monoglycerides have an ECN that matches the chain length of a single fatty acid chain. Therefore, monoglycerides with ECNs in the range of 6-14 contain mainly medium chain fatty acids, and monoglycerides with ECNs of 16 or more contain mainly long chain fatty acids.

  The average ECN of medium chain triglyceride oil is typically 21-42. For example, as listed in the United States Pharmacopeia (USP), medium chain triglycerides have the following composition as exemplary oils listed in the table below:

  Average ECN of 3 × [(6 × 0.02) + (8 × 0.70) + (10 × 0.25) + (12 × 0.02) + (14 × 0.01)] = 25.8 Have The ECN of an exemplary medium chain triglyceride oil can also be expressed as a range from 24.9 to 27.0 (per range described in USP). In the case of mixed mono, di, and triglycerides or single and double fatty acid glycols, the total oil ECN calculates the ECN of each individual component (e.g., C8 monoglyceride, C8 diglyceride, C10 monoglyceride, and C10 monoglyceride); It can be determined by taking the sum of the relative percentages of the components multiplied by the ECN normalized to the monoglyceride for each component. For example, the oils with C8 and C10 mono and diglycerides shown in the table below have an ECN of 8.3 and are therefore medium chain oils.

  In other words, ECN can be calculated as each chain length in the composition x its relative percentage in oil, ie (8 x 0.85) + (10 x 0.15) = 8.3. it can.

  The term “excipient” as used herein refers to non-API ingredients such as solubilizers, antioxidants, oils, lubricants, and others used in formulating pharmaceuticals. Point to.

  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 solubilizer and estradiol. As used herein, a pharmaceutical composition is delivered or absorbed vaginally, for example, by a pessary (ie, vaginal suppository).

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

  The term “reference list formulation” (“RLD”) means VAGIFEM® (estradiol vaginal tablet) or ESTRACE® vaginal cream.

  The terms “treat”, “treating”, and “treatment” refer to any sign of success in the treatment or amelioration of an injury, disease, or condition, which can be alleviated, ameliorated, Any such as making symptoms attenuated or injured, disease or condition more acceptable to the patient, slowing down the rate of degeneration or decline, or improving the physical or mental health of the patient Includes objective or subjective parameters. The treatment or alleviation of symptoms may be based on objective or subjective parameters, including the results of physical examination, neuropsychological examination, or psychiatric evaluation.

  The terms “atrophic vaginitis”, “vulva vaginal atrophy”, “vaginal atrophy”, and “VVA” are used interchangeably herein. In the medical field, the molecular form of VVA is well known.

Introduction Provided herein is a pharmaceutical composition comprising solubilized estradiol designed to be absorbed vaginally. The pharmaceutical compositions disclosed herein are designed to be absorbed and have their therapeutic effects locally, for example, in the vagina or surrounding tissue. Further disclosed herein are data demonstrating the effectiveness of the disclosed pharmaceutical compositions as well as methods relating to the pharmaceutical compositions. In general, the pharmaceutical compositions disclosed herein are useful in VVA, sexual pain, and other indications caused by reduced or absent estrogen.

  Additional aspects and embodiments of the present disclosure include increasing the ease of patient use while potentially minimizing certain side effects from improper insertion, and other vaginally applied estradiol products. Minimize the incidence of vulva vaginal fungal infection compared to the incidence of vulva vaginal fungal infection and reference drug VAGIFEM® (estradiol vaginal tablets, Novo Nordisk, Princeton, NJ) And an improved side effect profile (eg pruritus).

Pharmaceutical Composition Functionality According to embodiments, the pharmaceutical composition disclosed herein is free or substantially free of alcohol. Providing a pharmaceutical composition results in improved patient compliance due to improvements over previous offerings. According to embodiments, the pharmaceutical compositions disclosed herein are encapsulated in soft gelatin capsules to improve comfort during use. According to embodiments, the pharmaceutical composition is substantially liquid and is readily absorbed by the vaginal tissue and dispersed over a greater surface area of the vaginal tissue.

Estradiol According to embodiments, the pharmaceutical compositions disclosed herein are for vaginal insertion in single or multiple unit dosage forms. 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 an embodiment, if estradiol is not 100% solubilized, the remaining estradiol can be absorbed by the body either in its micronized form or in another form in which the micronized form is converted after administration. It exists in a finely divided (crystalline) form that retains functionality.

  According to embodiments, all or part of estradiol is solubilized in the solubilizer during the manufacturing process. According to embodiments, all or a portion of estradiol is solubilized after administration (eg, micronized portions that are not 100% solubilized with estradiol are solubilized in body fluids after administration). According to embodiments, since estradiol is solubilized, the solubilizer taught herein is liquid or semi-solid with or without additional excipients other than the solubilizer. To the extent that estradiol is not completely solubilized at the time of administration / insertion, estradiol is at body temperature (average 37 ° C.) and generally at the vaginal pH (3.8-4.5 in healthy patients, and VVA Should be substantially solubilized (range 4.6-6.5 for patients).

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

  According to an embodiment, the content of estradiol varies. The content of estradiol (or estradiol hemihydrate, eg, to the extent that the water content of estradiol hemihydrate is occupied) is at least about 1 microgram (μg or μg) to at least about 50 μg. Certain dosage embodiments are 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 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 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 VVA and other indications described herein. In some embodiments, the estradiol dosage is about 4 μg. In one embodiment, the estradiol dosage is about 10 μg. In another embodiment, the estradiol dosage is about 25 μg.

Solvent System According to an embodiment, the solvent system that solubilizes estradiol is a medium chain fatty acid solvent combined with other excipients. 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 a medium chain fatty acid as a main component is used as a solubilizer to solubilize estradiol. According to embodiments, the solubilizer comprises a medium chain fatty acid ester (eg, an ester of glycerol, ethylene glycol, or propylene glycol) or mixtures thereof. According to embodiments, the medium chain fatty acid comprises a C6 to C14 chain length. According to an embodiment, the medium chain fatty acid comprises a C6 to C12 chain length. According to embodiments, the medium chain fatty acids substantially comprise a C8-C10 chain length. The ECN of the medium chain oil is in the range of 21-42 for triglycerides, 12-28 for diglycerides, and 6-14 for monoglycerides.

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

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

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

  According to embodiments, as the medium chain solubilizer, for example, but not limited to, saturated medium chain fatty acids, ie caproic acid (C6), enanthic acid (C7), caprylic acid (C8), pelargonic acid (C9), capric acid (C10), undecyl acid (C11), lauric acid (C12), tridecyl acid (C13), or myristic acid (C14). According to embodiments, the solubilizer comprises oils made from these free medium chain fatty acids, oils of glycerin, propylene glycol, or ethylene glycol medium chain fatty acid esters, or combinations thereof. These examples mainly contain saturated medium chain fatty acids (ie, more than 50% of the fatty acids are medium chain saturated fatty acids). According to embodiments, primarily C6-C12 saturated fatty acids are contemplated. According to embodiments, the solubilizer 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 solubilizers include MIGLYOL® (SASOL Germany GMBH, Hamburg), which is caprylic / capric triglyceride. MIGLYOL includes MIGLYOL 810 (caprylic acid / capric acid triglyceride), MIGLYOL 812 (caprylic acid / capric acid triglyceride), MIGLYOL 816 (caprylic acid / capric acid triglyceride), and MIGLYOL 829 (caprylic acid / capric acid / capric acid / cotriglyceride) ). Other caprylic / capric triglyceride solubilizers are similarly contemplated, such as caproic / caprylic / capric / lauric triglycerides, caprylic / capric / linoleic triglycerides, caprylic / capric / succinic acid Contains triglycerides. According to embodiments, CAPMUL MCM, medium chain mono and diglycerides are solubilizers. According to embodiments, other and fractionated vegetable fatty acid triglycerides, and combinations or derivatives thereof, may be solubilizers. For example, the solubilizer can be saturated coconut and palm kernel oil 1,2,3-propanetriol (glycerol, glycerin, glycerin) esters, and derivatives thereof.

  Ethylene and propylene glycol (including polyethylene and polypropylene glycol) solubilizers include glyceryl mono and dicaprylate, propylene glycol monocaprylate (for example, CAPMUL® PG-8 (the CAPMUL brand is ABITEC (Columbus, Ohio)). ))), Propylene glycol monocaprate (eg, CAPMUL PG-10), propylene glycol mono and dicaprylate, propylene glycol mono and dicaprate, diethylene glycol monoester (eg, TRANSCUTOL®, 2- (2-Ethoxyethoxy) ethanol, GATTEFOSSE SAS), and diethylene glycol monoethyl ether. Other combinations of propylene glycol or ethylene glycol mono- and diesters explicitly contemplated are solubilizers.

  According to embodiments, the solubilizer comprises mono and dipropylene and ethylene glycol and a combination of mono, di, and triglycerides. According to embodiments, polyethylene glycol glycerides (GELUCIRE (R), GATTEFOSSE SAS (Saint-Priest, France)) can be used herein as solubilizers or as surfactants. For example, GELUCIRE 44/14 (PEG-32 glyceryl laurate EP), polyethylene glycol medium chain fatty acid ester, consists of mono, di, and triglycerides and mono and diesters of polyethylene glycol.

According to embodiments, commercially available fatty acid glycerol and glycol ester solubilizers are often prepared from natural oils and thus may constitute components in addition to the fatty acid esters that primarily constitute and characterize the solubilizer. Such other components may be, for example, other fatty acid mono, di, and triglycerides, such as fatty acid mono and diester ethylene or propylene glycol, free glycerol or glycol, or free fatty acids. In some embodiments, when the oil-solubilizing agent, which is described as a saturated C ₈ fatty acid mono- or diesters of glycerol herein, the main component of the oil, i.e., 50 wt.% (E.g., 75 wt.% , More than 85% by weight, or more than 90% by weight) is caprylic acid monoglyceride and caprylic acid diglyceride. For example, the technical data sheet for CAPMUL MCM C8 by ABITEC describes that CAPMUL MCM C8 is composed of mono- and diglycerides of medium chain fatty acids (mainly caprylic acid), and the alkyl content is C6 1% or less, C8 is 95% or more, C10 is 5% or less, and C12 or more is described as 1.5% or less.

  For example, MIGLYOL 812 is a solubilizer generally described as a C8-C10 triglyceride because at least about 80% of the fatty acid composition is a triglyceride ester of caprylic acid (C8) and capric acid (C10). However, it also contains small amounts of other fatty acids, such as less than about 5% caproic acid (C6), lauric acid (C12), and myristic acid (C14). The various MIGLYOL product information sheets describe the various fatty acid components as follows.

  According to embodiments, anionic or non-ionic surfactants may be used in pharmaceutical compositions containing solubilized estradiol. The ratio of solubilizer (s) to surfactant (s) is determined by the desired amount of each solubilizer (s) and each surfactant (s), and the resulting pharmaceutical composition. Depending on the physical characteristics of For example, without limitation, CAPMUL MCM and nonionic surfactant may be used in ratios of 65:35, 70:30, 75:25, 80:20, 85:15, and 90:10. Other non-limiting examples include, but are not limited to, CAPMUL MCM and GELUCIRE 39/01 used in ratios including 6: 4, 7: 3, and 8: 2, such as, but not limited to, 7: 3 And CAPMUL MCM and GELUCIRE 43/01 used in ratios including 8: 2, such as, but not limited to, CAPMUL MCM and GELUCIRE used in ratios including 7: 3, and 8: 2, and 9: 1 50/13.

Other excipients According to embodiments, the pharmaceutical composition further comprises a surfactant. The surfactant can be a nonionic surfactant, a cationic surfactant, an anionic surfactant, or a mixture thereof. Suitable surfactants include, for example, water-insoluble surfactants having a hydrophilic-lipophilic balance (HLB) value of less than 12 and water-soluble surfactants having an HLB value of greater than 12. Surfactants with high HLB and hydrophilicity assist in the formation of oil-water droplets. Surfactants are amphiphilic in nature and can dissolve or solubilize relatively large 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, phospholipid, Hydrogenated soybean phosphatidylcholine (HSPC), distearoylphosphatidylglycerol (DSPG), L-α-dimyristoylphosphatidylcholine (DMPC), L-α-dimyristoylphosphatidylglycerol (DMPG), polyoxyl 35 castor oil (CREMOPHOR EL, CREMOPHOR ELP) , Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40), polyoxyl 60 hydrogenated castor oil (CREMOPHOR RH 6) ), Polysorbate 20 (TWEEN 20), polysorbate 80 (TWEEN 80), d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), saltol HS-15, sorbitan monooleate (SPAN 20), PEG 300 caprylic acid / Capric acid glyceride (SOFTIGEN 767), PEG 400 caprylic acid / capric acid glyceride (LABRASOL), PEG 300 oleic acid glyceride (LABRAFIL M-1944CS), polyoxyl 35 castor oil (ETOCAS 35), glyceryl caprylate (mono and diglycerides) (IMWITOR), PEG 300 linoleic acid glyceride (LABRAFIL M-2125CS), polyoxyl 8 stearate (PEG 400 mono Teareto), 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 selected from one or more of glycerol and polyethylene glycol esters of long chain fatty acids, such as lauroyl macrogol-32 glyceride or lauroyl polyoxyl-32 glyceride, eg, GELUCIRE 39 / 01 (glycerol esters of saturated C12-C18 fatty acids), GELUCIRE 43/01 (hard fat NF / JPE) and GELUCIRE 50/13 (stearoyl macrogol-32 glyceride EP, stearoyl polyoxyl-32 glyceride NF, stearoyl polyoxyl glyceride) (USA FDA IIG)) and is commercially available as GELUCIRE. These surfactants are used in various concentrations above about 0.01%, typically from about 0.01% to 10.0%, 10.1% to 20%, and 20.1% to 30%. Can be done. In some embodiments, the surfactant is used at a concentration of about 1% to about 10% (eg, about 1% to about 5%, about 2% to about 4%, about 3% to about 8%). May be.

  According to embodiments, the nonionic surfactant includes, for example, without limitation, one or more of oleic acid, linoleic acid, palmitic acid, and stearic acid. According to an embodiment, the nonionic surfactant comprises a polyethylene sorbitol ester comprising polysorbate 80 marketed under the trademark TWEEN® 80 (polysorbate 80) (Sigma Aldrich (St. Louis, Mo.)). May include. Polysorbate 80 contains about 60% to 70% oleic acid, the remainder of which mainly contains linoleic acid, palmitic acid, and stearic acid. Polysorbate 80 can be used in an amount ranging from about 5-50% of the total weight of the pharmaceutical composition, and according to embodiments, can be used in an amount of about 30%.

  According to embodiments, the nonionic surfactants include PEG-6 palmitostearate and ethylene glycol palmitostearate, which are TEFOSE® 63 (GATTE FOSSE SAS (Saint-Priest, France)). For example, can be used with a CAPMUL MCM, for example a ratio of MCM to TEFOSE 63, for example a 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, perfluoro-octane sulfonic acid, potassium lauryl sulfate, or sodium stearate. Cationic surfactants are also contemplated.

  According to embodiments, the nonionic or anionic surfactant can be used alone or in combination with at least one solubilizer or can be used in combination with other surfactants. Thus, such a surfactant or any other excipient described herein may be used to solubilize estradiol. The combination of solubilizer, surfactant, and other excipients must be designed so that estradiol is absorbed into the vaginal tissue. According to embodiments, the pharmaceutical composition provides minimal vaginal secretions.

  According to an embodiment, the pharmaceutical composition further comprises at least one thickener. In general, thickeners are added when the viscosity of the pharmaceutical composition results in lower absorption than is desired. According to embodiments, the surfactant (s) disclosed herein can also provide thickening of the pharmaceutical composition, and when released, estradiol can be applied to the vagina while minimizing vaginal secretions. Helps to be absorbed by mucous membranes. Examples of thickeners include: hard fat; propylene glycol; hard fat EP / NF / JPE, glyceryl ricinoleate, ethoxylated fatty alcohol ((ceteth-20, steareth-20) EP / NF (GATIEFOSSE, Saint-Priest, France) A mixture of hard fat EP / NF / JPE, glycerol monooleate (type 40) EP / NF (OVUCIRE WL 3264); hard fat EP / NF / JPE, Mixture of glyceryl monooleate (type 40) EP / NF (OVUCIRE WL 2944); PEG-6 stearate, ethylene glycol palmitostearate, and PEG-32 stearate Non-ionic surfactants including bets; Tefose 63 or similar products; and various hard fat mixture (Witepsol (registered trademark), Sasol Germany GmbH (Hamburg, Germany)) and the like. Other thickeners are specific gums such as arginate, xanthan gum, agar, iota carrageen, kappa carrageenan and the like. Some 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 can comprise from about 50 cps to about 1000 cps at 25 ° C. One skilled in the art will readily understand and select a suitable thickener.

  According to an embodiment, the thickening agent is a nonionic surfactant. For example, polyethylene glycol saturated or unsaturated fatty acid esters or diesters are nonionic surfactant thickeners. In embodiments, the nonionic surfactant comprises a polyethylene glycol long chain (C16-C20) fatty acid ester, and an ethylene glycol long chain fatty acid ester, such as a saturated or unsaturated C16-C18 fatty acid, such as oleic acid, laurin. Further included are PEG-fatty acid esters or diesters of acids, palmitic acid, and stearic acid. In embodiments, the nonionic surfactant comprises a polyethylene glycol long chain saturated fatty acid ester, an ethylene glycol long chain saturated fatty acid ester, such as a saturated C16-C18 fatty acid, such as PEG- and ethylene of palmitic acid and stearic acid. Further comprising a glycol-fatty acid ester. 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 an embodiment, the nonionic surfactant used as a thickener is not hydrophilic and has good emulsion properties. An 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 mucoadhesive agents to enhance vaginal absorption of estradiol. For example, a mucoadhesive agent may be present to assist adhesion of the pharmaceutical composition to the mucosa upon activation with water. According to an embodiment, polycarbophil is a mucoadhesive agent. According to embodiments, other mucoadhesive agents include, but are not limited to, acrylic acid crosslinked with a poly (ethylene oxide) polymer having a molecular weight of about 100,000 to about 900,000, allyl sucrose, or allyl pentaerythritol. Polymer containing chitosan carbopol, polymers of acrylic acid and C10-C30 alkyl acrylate cross-linked with allylpentaerythritol, carbomer homopolymers or copolymers containing block copolymers of polyethylene glycol and long chain alkyl acid esters, and the like Can be mentioned. According to embodiments, various hydrophilic polymers and hydrogels may be used as mucoadhesive agents. According to certain embodiments, the polymer or hydrogel can swell in response to contact with vaginal tissue or secretions, enhancing the moisturizing and mucoadhesive effects. The choice and amount of hydrophilic polymer may be based on the choice and amount of solubilizer. In some embodiments, the pharmaceutical composition includes a hydrophilic polymer but optionally does not include a gelling agent. Embodiments having a hydrogel may include from about 5% to about 10% hydrophilic polymer of the total mass. In further embodiments, hydrogels may be used. The hydrogel may include chitosan, which swells when contacted with water. In various embodiments, the cream pharmaceutical composition may comprise PEG-90M. In some embodiments, the mucoadhesive agent is present in the pharmaceutical formulation, in the soft gel capsule, or both.

  According to embodiments, the pharmaceutical composition typically comprises one or more thermoreversible gels that are hydrophilic, such as, but not limited to, hydrophilic sucrose and other polysaccharide monomers (US incorporated by reference). Patent No. 6,018,033).

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

  According to an embodiment, 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 embodiments, the pharmaceutical composition comprises about 20% to about 80% solubilizer, about 0.1% to about 5% lubricant, and about 0.01% to about 0%. Contains 1 wt% antioxidant.

  The choice of excipient will depend on factors such as, for example, the influence of the excipient on solubility and stability. Additional excipients used in various embodiments may include colorants and preservatives. Examples of the colorant include FD & C color (for example, blue No. 1 and red No. 40), D & C color (for example, yellow No. 10), and opacifier (for example, titanium dioxide). According to embodiments, the colorant comprises from about 0.1% to about 2% by weight of the pharmaceutical composition. According to embodiments, the preservative in the pharmaceutical composition comprises methyl and propylparaben in a ratio of about 10: 1 and a ratio of about 0.005 wt% and 0.05 wt%.

  In general, the solubilizers, excipients, and other additives used in the pharmaceutical compositions described herein are non-toxic, pharmaceutically acceptable, compatible with each other, and the pharmaceutical composition And maintaining the stability of the various components relative to each other. Additionally, the combination of various ingredients, including the pharmaceutical composition, will maintain and provide the desired therapeutic effect when administered to the subject.

Soluble Estradiol According to embodiments, the solubilizer comprises a mixture of medium chain fatty acid glycerides, such as C6-C12, C8-C12, or C8-C10 fatty acid mono- and diglycerides, or mono-, di-, and triglycerides are Dissolve estradiol. As demonstrated in the examples, good results have been obtained with solubilizers that are mainly mixtures of C8-C10 saturated fatty acid mono and diglycerides or medium chain triglycerides (eg Miglyol 810 or 812). Long chain glycerides appear to be less well suited for dissolution of estradiol.

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

Manufacture of a pharmaceutical composition According to an embodiment, the pharmaceutical composition comprises estradiol, for example but not limited to at least one medium chain fatty acid such as a medium chain fatty acid consisting of at least one mono, di, or triglyceride. Or a derivative thereof, or a combination thereof, and is prepared by blending with a pharmaceutically acceptable solubilizer. According to embodiments, the pharmaceutical composition also comprises at least one glycol or derivative thereof or a combination thereof, or a combination of at least one glyceride and glycol. The glycol (s) may be used as a solubilizer or to adjust viscosity and can therefore be considered a thickener as discussed further herein. Optionally, other excipients are added, including but not limited to antioxidants, lubricants, and the like. According to embodiments, the pharmaceutical composition comprises sufficient solubilizer to completely solubilize estradiol. However, it is clearly understood that other amounts of solubilizer can be used depending on the level of estradiol solubilization desired. One skilled in the art knows and understands how to determine the amount of solubilizer and other excipients depending on the desired proportion of estradiol solubilized in the pharmaceutical composition. Let's go.

  In an exemplary embodiment, GELUCIRE 44/14 (lauroyl macrogol-32 glyceride EP, lauroyl polyoxyl-32 glyceride NF, lauroyl polyoxyl glyceride (USA FDA IIG)) is heated to about 65 ° C. and the CAPMUL MCM is about 40 Heating to 0 ° C. promotes mixing of the oil and nonionic surfactant, but such heating is not necessary for dissolution of estradiol.

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

Delivery Carrier In general, the pharmaceutical compositions described herein are delivered intravaginally within a delivery carrier, such as a capsule. According to an embodiment, the capsule is a soft capsule made of materials well known in the pharmaceutical art, such as gelatin. However, according to embodiments, the delivery carrier is integral with the pharmaceutical composition (ie, the pharmaceutical composition is the delivery carrier). In such embodiments, the pharmaceutical composition is a gel, cream, ointment, tablet, or other preparation that is applied directly and absorbed vaginally.

  According to embodiments, the pharmaceutical compositions disclosed herein are contained in capsules such as soft gelatin capsules. According to embodiments, the capsule contains one or more of the following: a hydrophilic gel-forming bioadhesive (eg, mucoadhesive) agent, a lipophilic agent, a gelling agent or lipophilic agent for the lipophilic agent. According to embodiments, the hydrophilic gel-forming bioadhesive is carboxyvinyl acid, hydroxypropyl cellulose, carboxymethyl cellulose, gelatin, xanthan gum, guar gum, aluminum silicate, or mixtures thereof. According to embodiments, the lipophilic agent is a liquid triglyceride, a solid triglyceride (eg, having a melting point of about 35 ° C.), carnauba wax, cocoa butter, or mixtures thereof. According to an embodiment, 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 carrier is designed for easy insertion. According to embodiments, the delivery carrier is sized so that it can be comfortably inserted into the vagina. According to embodiments, the delivery carrier is prepared in various shapes. For example, the delivery carrier facilitates insertion into the vagina with a teardrop shape, a truncated cone shape, a cylindrical shape, a cylindrical shape with a large “cap” portion, or other shapes suitable for insertion into the vagina Molded as a thing. According to embodiments, the delivery carrier is used in connection with an applicator. According to another embodiment, the delivery carrier is inserted with a finger.

  With reference to FIG. 2, the delivery carrier 200 includes a pharmaceutical composition 202 and a capsule 204. The width 208 represents the thickness of the capsule 204, for example, about 0.274 centimeters (0.108 inches). The distance from one end of delivery carrier 200 to the other is represented by distance 206, for example, about 1.75 centimeters (0.690 inches). The size of the delivery carrier 200 can also be described by an arc drawn by a radius of a given length. For example, the arc 210 defined by the outer surface of the gelatin 204 is an arc drawn by a radius of 0.480 centimeters (0.189 inches). The arc 212 defined by the inner surface of the capsule 204 is an arc described by a radius of about 0.2382 centimeters (0.0938 inches). The arc 214 opposite the arc 210, defined by the outer surface of the gelatin 204, is an arc drawn by a radius of 0.274 centimeters (0.108 inches). Other sizes of suitable capsules may be provided. According to embodiments, the capsules 204 have the same or similar dimensions as the ratio provided above with respect to each other.

  According to embodiments, the delivery carrier is designed to remain in the vagina until the pharmaceutical composition is released. According to embodiments, the delivery carrier is absorbed into the vaginal tissue along with a pharmaceutical composition that dissolves in the vagina and minimizes vaginal secretions. In such embodiments, the delivery mechanism is made from a construct that is non-toxic, eg, gelatin.

Vaginally Inserted Pharmaceutical Composition Design Factors According to embodiments, the pharmaceutical composition can be used in patients (patients who cease treatment before completion of the prescribed course of treatment) without sacrificing efficacy. Designed to maximize favorable features that lead to compliance. Preferred features include, for example, lack or reduction of irritation to other hormone replacement pessaries, lack or reduction of vaginal secretions of pharmaceutical compositions and delivery carriers for other hormone replacement pessaries, pharmaceutical compositions or delivery carriers inside the vagina The absence or reduction of residues, ease of administration compared to other hormone replacement pessaries, or improved efficacy of formulations against otherwise similar pharmaceutical compositions.

  According to embodiments, the pharmaceutical composition is non-irritating or minimizes irritation. Patient irritation includes pain, pruritus (itching), tingling, excessive secretions, swelling, or other similar conditions. Patient stimulation results in poor compliance. Nonirritating or hypoallergenic pharmaceutical compositions are measured against competing hormone pessaries, including tablets, creams, or other vaginal estrogen delivery forms.

  According to embodiments, the pharmaceutical composition does not result in systemic exposure (eg, blood circulation of estradiol), which improves safety. According to other embodiments, the pharmaceutical compositions disclosed herein provide significantly reduced systemic exposure (eg, blood circulation of estradiol) when compared to RLD.

  According to embodiments, the pharmaceutical composition leaves no residue inside the vagina. Rather, the pharmaceutical composition and delivery carrier are substantially absorbed or dispersed without causing unabsorbable residue or discomfort of the unabsorbed or undispersed formulation. The measurement of the lack of residue is relative to other vaginally inserted products or can be objectively measured by examination of the vaginal tissue. For example, certain other vaginally inserted products contain starch, which can result in more secretion from the vagina after administration. In some embodiments, a pharmaceutical composition provided herein has a lower amount, duration, or frequency after administration compared to other vaginally inserted products (eg, compressed tablets). Causes secretions.

  According to embodiments, the pharmaceutical composition improves vaginal secretions compared to other pessaries, including those that deliver hormones. Ideally, vaginal secretions are eliminated, minimized or improved compared to competing products.

  According to embodiments, the pharmaceutical compositions disclosed herein are inserted with a finger. According to embodiments, the pharmaceutical composition is inserted about 5 centimeters (2 inches) with a finger into the vagina without the need for an applicator. According to embodiments, the pharmaceutical composition is designed to be inserted with an applicator as needed. According to some embodiments, the VVA site is in the proximal region of the vagina (towards the vaginal opening) so that the pharmaceutical compositions disclosed herein are inserted into the proximal region of the vagina Designed to be.

  Through extensive experimentation, various medium chain fatty acid esters of glycerol and propylene glycol have demonstrated one or more preferred characteristics for development as a human formulation. According to embodiments, the solubilizer was selected from at least one of a solvent or a co-solvent. Suitable solvents and co-solvents include any mono, di, or triglyceride, and glycol, and combinations thereof.

  According to embodiments, the pharmaceutical composition is delivered by a gelatin capsule delivery carrier. According to these embodiments, the pharmaceutical composition is a liquid pharmaceutical composition. According to an embodiment, the delivery carrier is a soft capsule, such as a soft gelatin capsule. Thus, the pharmaceutical composition of such embodiments is encapsulated in soft gelatin capsules or other soft capsules.

  According to embodiments, the pharmaceutical composition is solubilized by at least about 80% in a solubilizer comprising one or more C6-C14 medium chain fatty acid mono, di, or triglycerides, and optionally a thickener. Contains estradiol. According to embodiments, the pharmaceutical composition comprises one or more C6-C12 medium chain fatty acid mono, di, or triglycerides, such as one or more C6-C14 triglycerides, such as one or more C6-C12 triglycerides, For example, estradiol that is solubilized in at least about 80% in one or more C8-C10 triglycerides. These embodiments specifically contemplate estradiol solubilized by at least 80%. These embodiments specifically contemplate estradiol solubilized by at least 90%. These embodiments specifically contemplate estradiol solubilized by at least 95%. These embodiments specifically contemplate estradiol to be fully solubilized.

  As noted above, liquid pharmaceutical compositions are liquid at room temperature or body temperature. For example, in some embodiments, the pharmaceutical compositions provided herein are liquid formulations contained within soft gel capsules. Gels, hard fats, or other solids that are not liquid at room temperature or body temperature are less desirable in pharmaceutical composition embodiments that are liquid.

  Thickeners, for example, serve to increase the viscosity up to about 10,000 cP (10,000 mPa-s), typically up to about 5000 cP, more typically up to about 50-1000 cP. In embodiments, non-ionic surfactants such as GELUCIRE or TEFOSE may be solid at room temperature and require melting to effectively mix with the solubilizer. However, in these embodiments, the resulting pharmaceutical composition remains liquid and has a higher viscosity but is not solid.

  According to embodiments, the pharmaceutical composition comprises estradiol, a medium chain solubilizer, and a thickener as ingredients delivered by a soft capsule delivery carrier. Other ingredients, such as colorants, antioxidants, preservatives, or other ingredients may be included as well. However, the addition of other ingredients should be in an amount that does not materially alter the solubility of estradiol, the pharmacokinetics of the pharmaceutical composition, or the efficacy of the pharmaceutical composition. Other factors to be considered when adjusting the ingredients of the pharmaceutical composition include irritation, vaginal secretions, vaginal residues, and other related factors such as those that lead to reduced patient compliance. Other contemplated ingredients include oils or fatty acid esters, lecithin, mucoadhesives, gelling agents, dispersing agents, or the like.

Method According to an embodiment, the pharmaceutical composition disclosed herein comprises at least one VVA comprising, inter alia, vaginal dryness, vaginal or vulvar stimulation or pruritus, dysuria, sexual pain, and sexual activity-related vaginal bleeding. It can be used to treat VVA, including treating symptoms. According to embodiments, the method of treatment is generally applicable to women.

  According to embodiments, the pharmaceutical compositions disclosed herein can be used to treat estrogen deficiency urine conditions. According to embodiments, the pharmaceutical compositions disclosed herein can be used for the treatment of vaginal bleeding associated with sexual pain or sexual activity.

  According to embodiments, treatment of VVA, estrogen deficiency urine status, and vaginal bleeding associated with sexual pain and sexual activity occurs by administering the pharmaceutical composition intravaginally. According to an embodiment in which the delivery carrier is a capsule, the patient obtains the capsule, and when the capsule is inserted into the vagina, the capsule dissolves and releases the pharmaceutical composition into the vagina, which is absorbed into the vaginal tissue. Is done. 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 (eg, at least about 80%, at least about 85%, at least about 90%, at least about 95% of the composition). Weight percent, at least about 97 weight percent, at least about 98 weight percent, or at least about 99 weight percent is absorbed). According to an embodiment, the capsule is inserted about 5 centimeters (2 inches) with a finger into the vagina, although the depth of insertion is generally optional to allow substantially all absorption of the pharmaceutical composition. Is the depth of. According to embodiments, the capsule can also be applied using an applicator that places the capsule at the appropriate vaginal depth disclosed herein.

  According to embodiments where the pharmaceutical composition is a cream, gel, ointment, or other similar preparation, the pharmaceutical composition is well known in the art and applied with the fingers as understood.

  Upon release of the pharmaceutical composition in the vagina, estradiol is absorbed locally. For example, after administration of a pessary to the proximal region of the patient's vagina, a therapeutically effective concentration of estradiol is provided in the proximal region of the vagina for 24 hours.

  According to embodiments, the timing of administration of the pharmaceutical composition of the present disclosure may be by any safe means prescribed by the attending physician. According to embodiments, the patient administers the pharmaceutical composition (eg, capsule) intravaginally daily for 14 days and then twice a week thereafter.

  According to embodiments, the pharmaceutical composition comprises an orally administered estrogen (or progestin or progestin and estrogen) pharmaceutical formulation, or patch, cream, gel, spray, transdermal delivery system, or each natural It is administered vaginally in combination with other parenterally administered estrogenic pharmaceutical formulations, which may include biosimilars, or synthetic or other derived estrogens or progestins. According to embodiments, the modulation of circulating estrogen levels resulting from administration of the pharmaceutical compositions disclosed herein, if any, is in addition to any concomitant estrogen product and the accompanying circulating blood levels. Not intended to do. According to another embodiment, the combined estrogen product is intended to have an additional effect 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 may be determined. According to embodiments, VVA size, effects, cytology, histology, and variability are described herein or otherwise currently accepted or further developed in the art. It may be determined using various endpoints for determining the efficacy and safety of a pharmaceutical composition. Endpoint sources are guidelines for the treatment of VVA with estradiol published by the US Food and Drug Administration (FDA).

Measuring Efficacy According to embodiments, administration of the pharmaceutical compositions described herein resulted in treatment of VVA as well as improvement of one or more of the associated symptoms. VVA patients experience vaginal canal contraction in both length and diameter, and the vaginal canal is low in glycogen-rich vaginal cells to maintain fluidity and flexibility. In addition, the vaginal wall can be thinned, lightened, dried, or in some cases inflamed (atrophic vaginitis). These changes can appear as various symptoms collectively referred to as VVA. Such symptoms include, but are not limited to, increased vaginal pH, vaginal epithelial integrity, vaginal secretion, or reduced epithelial surface thickness, pruritus, vaginal dryness, sexual pain (pain or bleeding during sexual activity), urinary tract Infection or vaginal discoloration may be mentioned. According to embodiments, efficacy is measured as the reduction of vulva and vaginal atrophy in patients returning to the premenopausal state. According to embodiments, this change is measured at baseline (screening, day 1) and reduced in severity of one or more atrophy effects compared to measurements taken at day 15 (end of treatment). As measured. The severity of the atrophy effect may be measured using a scale of 0-3 (eg, none = 0, mild = 1, moderate = 2, or severe = 3). Such scoring is performed to assess the patient's pretreatment status, to determine the appropriate course of the treatment plan, such as, inter alia, dosage, dosing frequency and duration, and post-treatment outcome.

  One of the symptoms of VVA is an increase in vaginal pH. In a further aspect of the present disclosure, treatment with the pharmaceutical compositions described herein resulted 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 on day 15 according to an embodiment. In some embodiments, a pH of 5 or greater may be associated with VVA. In some embodiments, the pH is measured using a pH indicator strip placed against the vaginal wall. In some embodiments, the change in vaginal pH is a change in the patient's vaginal pH relative 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, It is less than pH 4.0, pH 3.9, pH 3.8, pH 3.7, pH 3, 6, or pH 3.5.

  According to embodiments, treatment with the pharmaceutical compositions described herein resulted in an improvement of the vaginal maturity index. This maturity index is measured as a change in cell composition. Depending on the embodiment, in relation to VVA, the change in cell composition was compared to the rate of change in the composition or amount of parabasal vaginal cells, intermediate cells, and superficial vaginal cells, eg, changes in superficial vaginal cells Alternatively, it is measured as a change in the composition or amount of parabasal vaginal cells associated therewith. Subjects with VVA symptoms often have an increased number of parabasal cells and a reduced number of superficial cells (eg, less than about 5%) compared to women not suffering from VVA. Conversely, subjects with reduced VVA symptoms or otherwise responding to treatment will have an improved maturity index, specifically a reduced amount of parabasal cells compared to baseline (screening) Or an increase in the amount of superficial cells may be manifested. In embodiments, the reduction in parabasal cells is measured as a reduction in the percentage of parabasal cells, the reduction rate being at least about 85%, 80%, 75%, 70%, 65% of the number of parabasal cells, There may be a 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10% reduction. In embodiments, the reduction rate can be at least about 54% reduction in the number of parabasal cells. In embodiments, the increase in superficial cells is measured as an increase in the percentage of superficial cells, and the rate of increase in superficial cells is at least about 5%, 10%, 15% of the number of superficial cells. , 20%, 25%, 30%, 35%, 40%, 45%, or 50% increase. In a further embodiment, the rate of increase can be at least about 35% increase in superficial cell count.

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

  In various further aspects of the present disclosure, treatment with a pharmaceutical composition described herein results in any of superficial cell increase, parabasal cell decrease, and intermediate cell increase. It was.

In a further aspect of the present disclosure, a sample may be collected to determine hormone concentrations, particularly estradiol concentration. In some embodiments, a blood sample can be taken from a subject to measure estradiol concentration (pg / mL). In some embodiments, estradiol concentration may be measured at 0 hours (eg, at the first treatment), 1 hour (eg, after the first treatment), 3 hours, and 6 hours. In some embodiments, samples may be taken on day 8 (eg, after the first treatment) and day 15 (eg, 1 day after the last treatment on day 14). In some embodiments, descriptive statistics of plasma estradiol concentration at each sampling and the observed C _max and T _max values can be measured and the AUC calculated.

In some embodiments, the pessary can comprise about 25 μg estradiol. In such a case, administration of pessaries for the patient, in plasma samples from patients, 1) about 19 pg ^* hr / ml to about 29pg ^* hr / ml (e.g., 19.55pg ^* hr / ^ml~ about 28 .75pg ^* hr / ml corrected geometric mean peak plasma concentrations of estradiol) _{(C max),} or 2) from about 75 pg ^* hr / ml to about 112pg ^* hr / ml (e.g., 75.82pg ^* hr / ^ml~ about 111 .50) estradiol corrected geometric mean curve area under the curve (AUC). Parameters comprising one or more parameters selected from _0-24 can be provided. In some embodiments, the administration of pessaries for the patient, in plasma samples from patients, 1) about ^{9 pg} * hr / ml to about 14pg ^* hr / ml ^{(e.g., 9.17pg} * hr / ml~ about 13.49pg ^* hr / ml for estrone) correcting geometric mean peak plasma concentration _{(C max),} and 2) from about 43pg ^* hr / ml~ about 65pg ^* hr / ml (e.g., 43.56pg ^* hr / ^ml~ about The area under the corrected geometric mean curve (AUC) of Estrone of 64.06 pg ^* hr / ml) provides one or more parameters selected from _0-24 . In some embodiments, the administration of pessaries for the patient, in plasma samples from patients, 1) about 416pg ^* hr / ml~ about 613pg ^* hr / ml (e.g., 416.53pg ^* hr / ^ml~ about 612.55pg ^* hr / ml) correcting geometric mean peak plasma concentrations of estrone sulfate of _{(C max),} and 2) about 3598pg ^* hr / ml~ about 5291pg ^* hr / ml (e.g., 3598.04pg ^* hr / ^ml~ The area under the corrected geometric mean curve (AUC) of estrone sulfate of about 5291.24 pg ^* hr / ml) provides one or more parameters selected from _0-24 .

In some embodiments, the pessary can comprise about 10 μg estradiol. In such a case, administration of pessaries for the patient, in plasma samples from patients, 1) about 12 pg ^* hr / ml to about 18pg ^* hr / ml (e.g., 12.22pg ^* hr / ^ml~ about 17 .98pg ^* hr / ml corrected geometric mean peak plasma concentrations of estradiol) _(C max), 2) about 42 pg ^* hr / ml to about 63pg ^* hr / ml (e.g., 42.18pg ^* hr / ^ml~ about 62. 02 pg ^* hr / ml) Estradiol corrected geometric mean area under the curve (AUC) _0-24 , and 3) Estradiol peak from about 1 hour to about 3 hours (eg, 1.49 hours to about 2.19 hours) One or more parameters selected from a corrected geometric mean time (T _max ) to plasma concentration can be provided. In some embodiments, the administration of pessaries for the patient, in plasma samples from patients, 1) about ^{4 pg} * hr / ml to about ^7pg * hr / ml ^{(e.g., 4.38pg} * hr / ml~ about 6.44pg ^* hr / ml corrected geometric mean peak plasma concentrations of estrone) _(C max), 2) about 20 pg ^* hr / ml to about 31pg ^* hr / ml (e.g., 20.60pg ^* hr / ^ml~ 30 .30 pg ^* hr / ml) Estrone's corrected geometric mean area under the curve (AUC) _0-24 , and 3) about 4 hours to about 8 hours (eg, 4.99 hours to about 7.34 hours) of estrone. One or more parameters selected from a corrected geometric mean time (T _max ) to peak plasma concentration are provided. In some embodiments, the administration of pessaries for the patient, in plasma samples from patients, 1) about 10 pg ^* hr / ml to about 16pg ^* hr / ml (e.g., 10.34pg ^* hr / ^ml~ about 15.20pg ^* hr / ml) correcting geometric mean peak plasma concentrations of estrone sulfate of _(C max), 2) about 56pg ^* hr / ml~ about 84pg ^* hr / ml (e.g., 56.61pg ^* hr / ^ml~ about 83.25 pg ^* hr / ml) Estrone sulfate corrected geometric mean area under the curve (AUC) _0-24 , and 3) about 4 hours to about 7 hours (eg, 4.67 hours to about 6.86 hours) One or more parameters selected from the corrected geometric mean time (T _max ) to the peak plasma concentration of estrone sulfate are provided.

In some embodiments, the pessary can comprise about 4 μg estradiol. In such a case, administration of pessaries for the patient, in plasma samples from patients, 1) the correction geometric mean peak plasma concentration of about ^{4 pg} * hr / mL to about ^{8 pg} * hr / mL of estradiol _{(C max)} , 2) about 16 pg ^* hr / ml to about 26 pg ^* hr / ml of estrone correction geometric mean area under the curve _{(AUC) 0-24,} and 3) a peak plasma concentration of estradiol in about 0.25 hours to about 2 hours One or more parameters selected from up to a corrected geometric mean time (T _max ) can be provided. In some embodiments, administration of a pessary to a patient is performed in a plasma sample from the patient: 1) a corrected geometric mean peak plasma concentration (C _max) of estrone from about 1 pg ^* hr / ml to about 3 pg ^* hr / ml. ), 2) Area under the corrected geometric mean curve (AUC) _0-24 of estrone from about 8 pg ^* hr / ml to about 13 pg ^* hr / ml, and 3) to peak plasma concentration of estrone from about 1 hour to about 4 hours. One or more parameters selected from a corrected geometric mean time (T _max ) can be provided. In some embodiments, the administration of pessaries for the patient, in plasma samples from patients, 1) about ^{4 pg} * hr / ml to correct geometric mean peak plasma concentration of about ^{7 pg} * hr / ml for estrone sulfate (C _max), 2) about 22 pg ^* hr / ml to about 34pg ^* hr / ml for the correction of estrone sulfate geometric mean area under the curve _{(AUC) 0-24,} and 3) a peak of about 1 hour to about 3 hours of estrone sulfate One or more parameters selected from a corrected geometric mean time (T _max ) to plasma concentration are provided.

  The pharmaceutical compositions provided herein can provide substantial local delivery of estradiol. For example, the plasma concentrations of estradiol, estrone, and estrone sulfate measured in the patient's plasma following administration of the pharmaceutical compositions provided herein can be determined by administration of a placebo formulation (ie, a similar formulation lacking estradiol). Statistically similar to those measured later. Thus, in some embodiments, the plasma concentration of estradiol, estrone, or estrone sulfate measured after administration of the pharmaceutical compositions provided herein may be low compared to RLD formulations.

In some embodiments, the pessary may comprise about 1 μg to about 25 μg estradiol. Upon administration of the pessary to the patient, the plasma sample from the patient can provide a corrected geometric mean peak plasma concentration (C _max ) of estradiol that is less than about 30 pg ^* hr / mL. For example, administration of pessary to a patient provides a corrected geometric mean peak plasma concentration (C _max ) for estradiol that is less than about 18 pg ^* hr / ml. In some embodiments, administration of a pessary to a patient provides an area under the corrected geometric mean curve (AUC) _0-24 of estradiol that is less than about 112 pg ^* hr / ml. For example, administration of a pessary to a patient provides an area under the corrected geometric mean curve (AUC) _0-24 of estradiol that is less than about 63 pg ^* hr / ml.

In some embodiments, administration of a pessary to a patient provides a corrected geometric mean peak plasma concentration (C _max ) of estrone that is less than about 14 pg ^* hr / ml. For example, administration of pessary to a patient provides a corrected geometric mean peak plasma concentration (C _max ) for estrone, which is about 7 pg ^* hr / ml. In some embodiments, administration of a pessary to a patient provides an area under the corrected geometric mean curve (AUC) _0-24 of estrone that is less than about 65 pg ^* hr / ml. For example, administration of pessary to a patient provides an area under the corrected geometric mean curve (AUC) _0-24 of estrone, which is less than about 31 pg ^* hr / ml.

In some embodiments, administration of a pessary to a patient provides a corrected geometric mean peak plasma concentration (C _max ) of estrone sulfate that is less than about 613 pg ^* hr / ml. For example, administration of pessary to a patient provides a corrected geometric mean peak plasma concentration (C _max ) of estrone sulfate that is less than about 16 pg ^* hr / ml. In some embodiments, administration of a pessary to a patient provides an area under the corrected geometric mean curve (AUC) _0-24 of estrone sulfate that is less than about 5291 pg ^* hr / ml. For example, administration of pessary to a patient provides an area under the corrected geometric mean curve (AUC) _0-24 for estrone sulfate that is less than about 84 pg ^* hr / ml.

  In a further aspect of the present disclosure, capsule disintegration may be determined. In some embodiments, delivery carrier disintegration or absorption (after administration) on day 1 of therapy (eg, 6 hours after first treatment) and day 15 (eg, 1 day after last treatment on day 14). The presence or absence of a delivery carrier).

Statistical Measurements According to embodiments, the pharmacokinetics of the pharmaceutical compositions disclosed herein are measured using statistical analysis. According to an embodiment, treatment with a pharmaceutical composition comprising an effective pharmaceutical composition (eg, a pharmaceutical composition comprising estradiol) using analysis of variance (“ANOVA”) or covariance analysis (“ANCOVA”) The difference between a patient receiving and a patient receiving a placebo (eg, the same pharmaceutical composition but no estradiol) or a reference drug is assessed. Those skilled in the art will understand how to perform a statistical analysis of the collected data.

  The following examples relate to pharmaceutical compositions, delivery carriers, and combinations thereof. A method of making is also disclosed. Data generated using the pharmaceutical compositions disclosed herein is also disclosed.

Example 1: Pharmaceutical Composition In an embodiment, estradiol is procured and combined with one or more pharmaceutically acceptable solubilizers. Estradiol is purchased as a pharmaceutical grade ingredient, often as micronized estradiol, although other forms can be used. In embodiments, the pharmaceutical composition comprises estradiol at a content of about 1 μg to about 50 μg. In an embodiment, the pharmaceutical composition comprises 10 μg estradiol. In embodiments, the pharmaceutical composition comprises 25 μg estradiol.

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

  Each of GELUCIRE 39/01 and GELUCIRE 43/01 has an HLB value of 1. The HLB value of GELUCIRE 50/13 is 13. The HLB value of TEFOSE 63 is 9-10.

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

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

  The pharmaceutical compositions appearing in Table 1 that were solid at room temperature were evaluated at 37 ° C. to determine their melting properties. The viscosity of the gel can be important during encapsulation of the formulation. For example, in some cases it may be necessary to warm the formulation prior to filling the gelatin capsule. In addition, the melting properties of the composition can have significant implications after administration of the formulation into the body. For example, in some embodiments, the formulation melts at a temperature below about 37 ° C. For example, pharmaceutical composition 11 (Capmul MCM / Tefose 63) did not melt at 37 ° C or 41 ° C.

  Dispersion evaluation of the pharmaceutical compositions appearing in Table 1 was performed. The dispersion evaluation was performed by transferring 300 mg of each carrier system to 100 mL of water at 37 ° C. without stirring and observing the mixing characteristics. The results differed from the formation of top oil droplets to phase separation, a uniform but cloudy dispersion. Generally speaking, a formulation that can be easily dispersed in an aqueous solution would have better dispersion properties at the time of administration. Surprisingly, however, as shown below in Examples 7-9, a formulation that did not disperse easily in an aqueous solution (eg, formulation 13) but instead formed two phases upon introduction into the aqueous solution. It was found to be most effective when administered to the human body.

Example 2: Delivery Carrier In an embodiment, the pharmaceutical composition is delivered in a gelatin capsule delivery carrier. Gelatin capsule delivery carriers include, for example, gelatin (eg, gelatin NF (150 Bloom, type B)), hydrolyzed collagen (eg, GELITA®, GELITA AG (Eberbach, Germany)), glycerin, sorbitol special, or Other excipients are included in proportions well known and understood by those skilled in the art. Sorbitol specials are commercially available and may tend to act as plasticizers and wetting agents.

  A variety of delivery carriers were developed as shown in Table 2 Gels AF. In Table 2, each delivery carrier AF has a different ratio of one or more components.

  Each delivery carrier A-F was prepared at a temperature ranging from about 45 ° C to about 85 ° C. Each melt delivery carrier 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 strips were placed in a USP type 2 dissolution vessel in either water or pH 4 buffer and the time until they were completely dissolved was recorded (see Table 2). Delivery carrier A dissolved most rapidly in both water and pH 4 buffer.

Example 3: Pharmaceutical Compositions and Delivery Carriers Various combinations of pharmaceutical compositions from Tables 1 and 2 were prepared. The combinations are shown in Table 3.

  Each aliquot of the pharmaceutical composition of Table 3 was from about 300 mg to about 310 mg. Batch sizes were as listed in Table 3. To encapsulate the carrier system, an aliquot of each 300 mg to about 310 mg of the pharmaceutical composition was encapsulated in an about 200 mg gelatin capsule delivery carrier. Thus, for example, in Test 1, the pharmaceutical composition represented by MCM: 39/01 was encapsulated in gelatin capsule delivery carrier A to a total encapsulation weight of about 500 mg to about 510 mg. The aliquot size is arbitrary depending on the concentration of estradiol and the desired gelatin capsule delivery carrier size. One skilled in the art will readily understand how to adjust the amount of estradiol in a pharmaceutical composition to accommodate a given size of the delivery carrier when the delivery carrier encapsulates the pharmaceutical composition. Will.

Example 4: Estradiol Solubility In various embodiments, solubilizers were tested to determine if they could solubilize 2 mg estradiol for a total weight of 100 mg pharmaceutical composition. A solubilizer is considered suitable if the estradiol solubility in the solubilizer is about 20 mg / g or greater. Initial solubility is obtained by dissolving micronized estradiol in various solubilizers and filtering undissolved estradiol until estradiol is saturated (estradiol / solubilizer equilibrated for 3 days). The target composition was determined by analyzing by HPLC for estradiol concentration.

Example 5 Pharmaceutical Compositions The following pharmaceutical compositions are contemplated.

^* 1.0 mg estradiol is equivalent to 1.03 mg estradiol hemihydrate.

^* 1.0 mg estradiol is equivalent to 1.03 mg estradiol hemihydrate.

Example 6: Process FIG. 1 shows an embodiment of a method for making a pharmaceutical composition comprising estradiol solubilized in a CapmulMCM / Gelucire solubilizer encapsulated in a soft gelatin delivery carrier 100. In operation 102, CapmulMCM is heated to 40 ° C. ± 5 ° C. Heating may be accomplished by any suitable means. Heating can be performed in any suitable container, such as a stainless steel container. Other pharmaceutical compositions can be made using the same general method by substituting various excipients including solubilizers.

  In operation 104, GELUCIRE is mixed with CapmulMCM to form the final solubilizer. Any form of GELUCIRE may be used in operation 104 as used herein. For example, one or more GELUCIRE 39/01, GELUCIRE 43/01, GELUCIRE 50/13 may be used in operation 104. Mixing is performed as known to those skilled in the art, for example, by an impeller, stirrer, stir bar, or other similar device used to mix the pharmaceutical composition. Operation 106 may be performed under an inert or relatively inert gas atmosphere such as nitrogen gas. Mixing may take place in any container known to those skilled in the art, such as a stainless steel container or a steel tank.

  In operation 106, estradiol is mixed with the solubilizer. In embodiments, estradiol is micronized when mixed with a solubilizer. In other embodiments, the added estradiol is in a non-micronized form. Mixing may be facilitated by an impeller, stirrer, stir bar, or other similar device used to mix the pharmaceutical composition. Operation 106 may be performed under an inert or relatively inert gas atmosphere such as nitrogen gas.

  However, in embodiments, estradiol may be added prior to operation 104. In that regard, operations 104 and 106 are interchangeable with respect to timing or can be performed simultaneously with each other.

  In operation 110, a gelatin delivery carrier is prepared. Any of the gelatin delivery carriers described herein may be used in operation 110. In embodiments, gelatin, hydrolyzed collagen, glycerin, and other excipients are combined at a temperature in the range of about 45 ° C. to about 85 ° C. and prepared as a film. Mixing may occur in a steel tank or other container used to prepare the gelatin delivery carrier. Mixing may be facilitated by an impeller, stirrer, stir bar, or other device used to combine the contents of the gelatin delivery carrier. Operation 106 may be performed under an inert or relatively inert gas atmosphere such as nitrogen gas. In embodiments, the gelatin delivery carrier mixture is degassed before being used to encapsulate the pharmaceutical composition.

  In operation 112, the gelatin delivery carrier encapsulates the pharmaceutical composition according to protocols well known to those skilled in the art. In operation 112, a soft gelatin capsule delivery carrier is prepared by combining the pharmaceutical composition made in operation 106 with the gelatin delivery carrier made in operation 110. Gelatin may be wrapped around the material, encapsulating it partially or completely, or injecting gelatin or otherwise filling with a pharmaceutical composition made in operation 106 You can also.

  In an embodiment, operation 112 is completed in a suitable die to provide the desired shape. Vaginal soft gel capsules may be prepared in various shapes. For example, vaginal softgel capsules are molded into a teardrop shape, a cone shape with a frustoconical end, a cylindrical shape, a cylindrical shape with a large “cap” portion shown in FIG. 2, or other shapes suitable for insertion into the vagina. May be. The resulting pharmaceutical composition encapsulated in a soft gelatin delivery carrier may be inserted with a finger or applicator.

Example 7: Study of estradiol pharmaceutical composition for improvement of vulvovaginal atrophy (VVA) The purpose of this study was to treat 10 μg in treating moderate to severe symptoms of VVA associated with menopause after 14 days of treatment. Designed to evaluate the efficacy and safety of a pharmaceutical composition comprising a large amount of estradiol (ie, pharmaceutical composition 2) and to estimate the effect size of the vulva vaginal atrophy endpoint. In addition, systemic exposure to estradiol from single and multiple dose pharmaceutical compositions was investigated.

  This study was conducted to assess the safety and efficacy of pharmaceutical compositions in reducing moderate to severe symptoms of vaginal atrophy associated with menopause, and once a day for 14 days of pharmaceutical compositions. This was a one-phase, randomized, double-blind, placebo-controlled study to investigate systemic exposure to estradiol after intravaginal administration.

  Postmenopausal subjects meeting the entry criteria for this study were randomized into one of two treatment groups (pharmaceutical composition or placebo). During the screening period, subjects were asked to self-assess symptoms of VVA, including vaginal dryness, vaginal or vulvar irritation, 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 as the most troublesome by the subject met the conditions to participate in the study.

Clinical evaluation was performed at the following time points.
・ Screening period (up to 28 days)
・ Visit 1-Randomization / Baseline (Day 1)
-Visit 2-Intermediate (Day 8) and-Visit 3-End of Treatment (Day 15)

  Eligible subjects were randomized to receive either a pharmaceutical composition containing 10 μg estradiol or a matching placebo vaginal soft gel capsule in a 1: 1 ratio and in the clinical facility under the supervision of the investigator The first dose was self-administered. Serial blood samples for monitoring estradiol concentrations were collected at 0.0, 1.0, 3.0, and 6.0 hours for the first dose administration on day 1. Subjects remained in the clinic until the completion of the 6 hour blood draw and revisited the clinical facility for additional single blood draws on day 8 (before morning dosing) and day 15 for estradiol concentration measurements. Subjects were provided with sufficient study medication until their next scheduled visit and were instructed to self-administer the assigned study treatment once a day each morning at approximately the same time (± 1 hour). Each subject was provided with a diary and asked to record the study drug dosing date and time daily. Subjects revisited the clinical facility on day 8 for an interim visit and on day 15 for the end of treatment evaluation and post-study testing. On day 1 (6 hours after administration) and day 15, the investigator evaluated the capsule disintegration state.

  The study included a screening period of up to 28 days and a treatment period of 14 days prior to randomization. The choice of content (estradiol 10 μg) and treatment plan (once a day for 2 weeks) was based on FDA findings regarding the safety and efficacy of RLD.

Number of targets (planning and analysis)
Randomized postmenopausal female subjects aged 40 to 75 years with moderate to severe VVA symptoms with a maximum of 50 (25 per treatment group). Fifty subjects were enrolled, 48 subjects completed the study, and 48 subjects were analyzed.

Diagnosis and Main Inclusion Criteria 50 female subjects were enrolled in the study. Postmenopausal female subjects aged 40 to 75 years (average age 62.3 years) were enrolled. The average body weight (kg) of subjects ranged from 71.2 kg, 44.5-100 kg. The average height (cm) of the subject is 162.6 cm, the range is 149.9 to 175.2 cm, and the average BMI (kg / m ² ) is 26.8 kg / m ² , and the range is 19 to 33 kg. / M ² . The criteria for inclusion in the study were at least one moderate to severe VVA symptom identified as the most troublesome, such as vaginal dryness, sexual pain, vaginal or vulvar stimuli, burning or pruritus, dysuria, and sexual activity Self-specific vaginal smear cytology related to vaginal bleeding included 5% or less superficial cells, a vaginal pH greater than 5.0, and an estradiol concentration of 50 pg / ml or less. Subjects enrolled that were otherwise determined to be generally in good health based on pre-study physical examination, clinical examination, pelvic examination, and mammography.

Estradiol 10 μg or placebo, dose, and dosage form Subjects were randomly assigned (on a 1: 1 assignment) to self-administer one of the following treatments once a day for 14 days.
Treatment A: Pharmaceutical composition of Example 5 (Pharmaceutical Composition 2: 10 μg estradiol) or Treatment B: Placebo vaginal soft gel capsule containing the same formulation as Treatment A except 10 μg estradiol.

  The estradiol formulation was a light pink soft gel capsule with teardrop shape. 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 and a treatment period of 14 days prior to randomization.

Evaluation criteria Effectiveness endpoint:
• Changes in maturity index of vaginal smear from baseline (screening) to day 15 (ratio of parabasal vaginal cells, superficial vaginal cells, and intermediate vaginal cells) The data for this endpoint is shown in Tables 6-8. Shown in
Changes in vaginal pH from baseline (screening) to day 15 The data for this endpoint is shown in Table 9.
Change in severity of most troublesome symptoms from baseline (randomized) to day 15: (1) Vaginal dryness (2) Vaginal or vulvar stimulation, burning sensation, or pruritus (3) Urination disorder (4) Sexual intercourse Pain (5) Vaginal bleeding associated with sexual activity Data for this endpoint are shown in Tables 13 and 15.
Changes in investigator assessment of vaginal mucosa from baseline (randomized) to day 15 The data for this endpoint is shown in Tables 18-21.

  Unless otherwise noted, efficacy endpoints are from Visit 1—Randomized / Baseline (Day 1) to Visit 3—End of Treatment, except for vaginal bleeding expressed as either treatment success or failure Measured as change up to (day 15).

Other endpoints include:
Vital signs, weight, physical examination changes, pelvic and breast examinations, and adverse events were evaluated as part of the safety endpoint.
• Estradiol concentration at each sample collection • Peak concentration of estradiol at day 1 and at the time of peak sampling • Delivery carrier disintegration to measure the amount of residual delivery carrier remaining in the vagina after treatment

  The results from the assessment of estradiol plasma concentration are presented in Table 5.

Other endpoints:
Maturity Index Results Vaginal cytology data was collected as vaginal smears from the lateral vaginal wall according to standard procedures, and vaginal cytology was evaluated at screening and at the end of Visit 3-treatment (day 15). The change in maturity index was assessed as the change in cell composition measured at Visit 1-Baseline (Day 1) compared to the cell composition measured at Visit 3-End of Treatment (Day 15) . Changes in the proportion of superficial cells, parabasal cells, and intermediate cells obtained from vaginal mucosal epithelium from vaginal smears were recorded. Results from these assessments are presented in Tables 6, 7, and 8.

Changes in pH Results Vaginal pH was measured at screening and at Visit 3-at the end of treatment (Day 15). pH measurements were obtained by pressing a pH indicator strip against the vaginal wall. Subjects participating in the study needed to have a vaginal pH value greater than 5.0 at screening. The pH value was recorded on the subject case report form. Subjects were advised not to have sexual activity within 24 hours prior to measurement and not to use vaginal lavage. The results from these evaluations are presented in Table 9.

The most troublesome symptom data The subject was asked to designate the symptom identified as “the most troublesome symptom”. During the screening period, all subjects are associated with symptoms of VVA: (1) vaginal dryness, (2) vaginal or vulvar stimulation, burning sensation, or pruritus (3) dysuria (4) sexual pain (5) sexual activity Vaginal bleeding Each symptom was measured on a scale 0-3 (0 = none, 1 = mild, 2 = moderate, and 3 = severe), excluding vaginal bleeding related to sexual activity. Vaginal bleeding associated with sexual activity was measured on a binary scale (N = no bleeding, Y = bleeding). Subject's response was recorded. All randomized subjects were also provided with a questionnaire to self-assess symptoms of VVA at Visit 1—Randomization / Baseline (Day 1) and Visit 3—at the end of treatment (Day 15). Subjects recorded self-assessments daily in their diaries and collected responses on the 8th and 15th days (end of treatment). The results of the pre-dose assessment obtained at Visit 1 were considered as baseline data for statistical analysis. Data from these assessments are presented in Tables 10 and 11.

  The most annoying symptom change from baseline was generally scored according to the VVA symptom assessment described above. Tables 13 and 14 show a comparison between the pharmaceutical composition and placebo for generally the most troublesome symptoms and vaginal atrophy symptoms. It is worth noting that these measurements showed a trend of improvement but were not statistically significant at day 15.

^{1 The} ANOVA model included a fixed effect of treatment. ANCOVA added a baseline as a covariate to the model.
² Confidence interval for difference between TX-12-004-HR and placebo treatment least mean square

Symptoms For the most troublesome symptom data presented in Tables 13 and 14, the period over which the data was measured is generally considered insufficient to make a meaningful conclusion. However, the trends observed as part of this study suggest that it shows the most troublesome symptom improvement when longer periods of data are collected.

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

Estradiol Concentration / Pharmacokinetic Data In this study, systemic exposure to estradiol after intravaginal administration of 10 μg estradiol once daily for 14 days was investigated. Descriptive statistics of plasma estradiol concentration taken at each sampling and observed C _max and T _max values were recorded in Tables 16 and 17. No statistically significant difference was observed in the systemic concentration of 10 μg estradiol versus placebo, suggesting that estradiol is not carried into the bloodstream with systemic effects. Rather, it remains in the localized tissue, and thus the effects of estradiol are considered to be localized at the place of administration (ie, vagina). The lower limit of detection of the assay used to measure pharmacokinetic data can affect the accuracy of measurement of the displayed pk value. Additional pk studies were performed using the more accurate assay in Examples 8 and 9.

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

Evaluation of vaginal mucosa data The investigator scored the appearance of the vaginal mucosa on day 1 (prior to administration) and day 15. Vaginal color, vaginal epithelial integrity, vaginal epithelial surface thickness, and vaginal secretions were measured using the following severity levels: none, mild, moderate, or severe (0 = None, 1 = Mild, 2 = Moderate, and 3 = Severe). Results from the evaluations scored by these investigators are presented in Tables 18, 19, 20, and 21.

Delivery Carrier Disintegration Data Evaluation of capsule disintegration in the vagina on day 1 (6 hours after administration) and day 15 The results of this evaluation are presented in Table 22.

  Serum hormone concentration data was collected to determine the serum concentration of estradiol concentration. These data were used for screening incorporation and were determined using standard clinical chemistry methods.

Appropriateness of measurement The selection of efficacy measures used in this study is for the treatment of moderate to severe vasomotor symptoms associated with menopause, and moderate to severe symptoms of vulva and vaginal atrophy associated with menopause. It was based on the FDA's recommendations for the study of estrogen and estrogen / progestin formulation (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, by reference It is incorporated in the specification).

  Standard clinical, laboratory, and statistical procedures were used for testing. All clinical laboratory procedures were generally acceptable and met quality standards.

Statistical method:
Effectiveness:
Analysis of variance (ANOVA) was used to evaluate the difference in change from baseline between subjects receiving 10 μg estradiol and placebo capsules against all efficacy endpoints except vaginal bleeding, effect size and effect The variability of was estimated. In some cases, for example, for some vaginal atrophy symptoms, changes from baseline (post-dose response) were correlated with baseline values (p <0.05), so baseline was adjusted for this correlation To be included as a covariate (Covariance Analysis, ANCOVA). The effect size was assessed by determining a 90% confidence interval for the difference between 10 μg estradiol and placebo endpoints. Changes from baseline in vaginal bleeding related to sexual activity were assessed with respect to the percentage of subjects with successful or unsuccessful treatment. Any subject who reported bleeding at baseline and did not report bleeding on day 15 was considered well treated. Any subject who reported bleeding on day 15 was considered a treatment failure, regardless of whether they reported baseline bleeding. Subjects who did not report bleeding at baseline or on day 15 were classified as unchanged and excluded from statistical evaluation. Differences in the proportion of successful subjects between the two treatment groups were statistically assessed using Fisher's exact test. The results of this percentage difference are presented in Table 10.

Measurement of treatment compliance Subjects needed to complete a diary to record treatment compliance. The diary was reviewed during visits on days 8 and 15 for treatment compliance. A total of 45 subjects (21 subjects in the 10 μg estradiol group and 24 subjects in the placebo group) were 100% compliant with the treatment plan.

  Due to the research nature of the study, no adjustments were made for many endpoints.

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

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

Conclusion Efficacy Two weeks of treatment with 10 μg of the pharmaceutical composition led to a significant average reduction in the percent of parabasal cells that was statistically significant over placebo treatment (54% vs. 5), as shown in Table 6. %, P <0.0001). At the same time, a significantly larger mean increase in the percentage of superficial cells was observed with the pharmaceutical composition (35%) than with the placebo capsule (9%), as shown in Table 7, the difference being higher in statistical Significantly significant (p = 0.0002). The difference in pH reduction with the pharmaceutical composition (0.97 units) compared to that of the placebo (0.34 units) was only slightly greater than 0.5 units, but as shown in Table 9 This difference was detected as statistically significant (p = 0.0002).

  The reduction in severity of the most troublesome symptoms was essentially the same (about 1 unit) for both the pharmaceutical composition and placebo, but individual symptoms of vaginal dryness, irritation, and pain during sexual activity All reductions in severity were slightly better with active treatment than with placebo treatment. The differences between the two treatments were all below 0.3 units, and none were detected as statistically significant. There was no difference between the two treatments in terms of pain / burning / reducing stinging during urination (approximately 0.4 unit reduction). The length of the study was not sufficient to show the distinction between the most troublesome symptoms in pharmaceutical compositions and placebo. However, the most annoying symptom trend suggests that with a suitable period, a significantly significant difference between the two treatments is observed.

  Two weeks of treatment with 10 μg estradiol capsules showed no statistically detectable difference in reducing severity from baseline, according to investigator assessment of vaginal color or vaginal epithelial surface thickness. Pharmaceutical composition capsules for vaginal epithelial integrity (−0.34 vs. 0.18, p = 0.0001) and vaginal secretions (−0.64 vs −0.27, p = 0.0401) A significant statistically significant reduction in the severity of the atrophy effect was demonstrated over that shown by placebo.

Descriptive statistical analysis (mean, median, geometric mean, standard deviation, CV, minimum and maximum, C _max , and T _max ), estradiol concentration, day 1 peak concentration, and peak concentration at each sampling time Went against time. The results from this evaluation are presented in Tables 16 and 17.

  The pharmaceutical composition containing 10 μg estradiol was superior to placebo treatment in terms of improved maturity index, reduced vaginal pH, epithelial integrity and reduced atrophy effect on vaginal secretions. Lack of statistical significance between the two treatments regarding the most troublesome symptoms and reduced severity of individual vaginal atrophy symptoms such as dryness, irritation, pain associated with sexual activity, and pain / burning / stinging pain during urination Is not unexpected considering the small number of subjects and short-term treatment in this study. In this study, too few subjects had vaginal bleeding related to sexual activity, so any meaningful assessment of this vaginal atrophy symptom could not be made.

  Of the 48 subjects enrolled in this study, 45 subjects were 100% compliant with the treatment plan. Of the remaining three subjects, one withdrew from the study for personal reasons and the other two did not take each dose due to adverse events.

Safety The average plasma estradiol peak concentration on the first day of the pharmaceutical composition is somewhat higher than that of placebo (ratio of geometric mean = 1.21: test product (estradiol 10 μg) 21%> placebo), statistically No significant difference was determined. However, the assay method was suspicious and resulted in suspicious 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 containing 10 μg estradiol was well tolerated when administered intravaginally for 14 days on a once daily schedule.

Example 8: pk study (25 μg formulation)
A pk study was conducted and the 25 μg formulation (Pharmaceutical Composition 3) disclosed herein was compared to RLD. The results of the pk study for estradiol are summarized in Table 23. The p-values for these data demonstrate statistical significance as shown in Table 24.

As shown in Table 23, baseline adjusted pk data unexpectedly shows that the formulations disclosed herein show a 54% reduction in C _max and a 31% reduction in AUC relative to RLD. This result is desirable because estradiol is intended for local absorption only. These data suggest a decrease in circulating concentration of estradiol relative to RLD. Furthermore, it is noteworthy to point out that the C _max and AUC levels of estradiol relative to placebo are not statistically distinguishable, indicating that the formulations disclosed herein have negligible systemic effects. Suggest. As shown in Table 24, there was no significant difference between the test product and the reference product due to sequence and duration effects. However, there was a significant difference due to therapeutic effect for both _Cmax and AUC.

The pharmacokinetics of circulating total estrone, estradiol metabolites are shown in Table 25. These data indicate that the total circulating estrone of the formulations disclosed herein resulted in a 55% decrease in circulating estrone C _max and a 70% decrease in circulating estrone AUC.

There was a significant difference due to treatment effect between the test product and the reference product, but there was no significant difference due to C _max sequence and duration effect. In the case of AUC, there was a significant difference between the test product and the reference product due to treatment, sequence, and duration effects.

The pk of circulating total estrone sulfate is shown in Table 27. These data indicate that the total circulating estrone sulfate of the pharmaceutical compositions disclosed herein resulted in a 33% decrease in the C _max of the circulating estrone sulfate and a 42% decrease in AUC.

There was a significant difference due to treatment effect between the test product and the reference product, but there was no significant difference due to sequence and duration effects for both _Cmax and AUC.

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

A pk study was performed and the pharmaceutical composition disclosed herein with 10 μg estradiol was compared to RLD. The results of the pk study for estradiol are summarized in Tables 29-34 and demonstrate that the pharmaceutical compositions disclosed herein more effectively avoided systemic absorption of estradiol. Table 35 shows that the pharmaceutical compositions disclosed herein had a 28% improvement in systemic blood circulation C _{max over} RLD and an AUC improvement of 72% over RLD.

Total estrone pk data also demonstrated a reduction in systemic exposure when compared to RLD. Table 33 shows a reduction in systemic exposure of 25% for C _max and 49% for AUC.

^* Comparison was detected as statistically significant by ANOVA (α = 0.05).

The pk data for estrone sulfate also demonstrated reduced systemic exposure when compared to RLD. Table 37 shows a reduction in systemic exposure of 25% for C _max and 42% for AUC.

^* Comparison was detected as statistically significant by ANOVA (α = 0.05).

  Although the pharmaceutical compositions and methods have been described with respect to what are presently considered to be practical and preferred embodiments, it is to be understood that the disclosure is not limited to the disclosed embodiments. It is intended to cover various modifications and similar arrangements that fall within the scope and spirit of the claims, and the scope is consistent with the broadest interpretation so as to encompass all such modifications and similar embodiments. Should. This disclosure includes any and all embodiments of the following claims.

Claims (51)

A pessary comprising a) a therapeutically effective amount of estradiol and b) a solubilizer comprising a medium chain oil.   The pessary of claim 1, wherein the pessary comprises about 1 μg to about 25 μg of estradiol.   The pessary of claim 1, wherein the pessary comprises about 1 μg to about 10 μg of estradiol.   The pessary of claim 1, wherein the pessary comprises from about 10 μg to about 25 μg estradiol.   The pessary according to any one of claims 1 to 4, wherein the estradiol is solubilized.   The pessary according to any one of claims 1 to 5, wherein the medium chain oil comprises at least one C6 to C12 fatty acid, or a glycol, monoglyceride, diglyceride, or triglyceride ester thereof.   The solubilizer comprises at least one ester selected from the group consisting of capron fatty acid esters, capryl fatty acid esters, caprin fatty acid esters, and combinations thereof. The pessary described.   The pessary according to any one of claims 1 to 7, wherein the solubilizer comprises caprylic / capric triglycerides.   The pessary according to any one of claims 1 to 8, wherein the pessary further comprises a capsule.   The pessary according to any one of claims 1 to 10, wherein the capsule is a soft gelatin capsule. a) a therapeutically effective amount of estradiol;
b) caprylic / capric triglycerides;
c) a pessary comprising: a nonionic surfactant comprising PEG-6 palmitostearate and ethylene glycol palmitostearate; and d) a soft gelatin capsule. A pessary comprising about 25 μg estradiol, wherein administration of said pessary to a patient in a plasma sample from said patient,
1) about 19 pg ^* hr / ml to the corrected geometric mean peak plasma concentration of about 29 pg ^* hr / ml for estradiol _{(C max),} and 2) from about 75 pg ^* hr / ml to about 112pg ^* hr / ml for the correction of estradiol A pessary providing an area under the geometric mean curve (AUC) _0-24 . A pessary comprising about 25 μg estradiol, wherein administration of said pessary to a patient in a plasma sample from said patient,
1) about ^{9 pg} * hr / ml to about 14 pg ^* hr / ml for correcting geometric mean peak plasma concentrations of estrone _{(C max)} and Oyobi 2) about 43pg ^* hr / ml~ about 65 pg ^* corrected geometry hr / ml for estrone A pessary providing an area under the mean curve (AUC) _0-24 . A pessary comprising about 25 μg estradiol, wherein administration of said pessary to a patient in a plasma sample from said patient,
1) about 416pg ^* hr / ml~ about 613pg ^* hr / ml of estrone sulfate corrected geometric mean peak plasma concentration _{(C max)} and Oyobi 2) of approximately 3598pg ^* hr / ml~ about 5291pg ^* hr / ml for estrone sulfate A pessary providing an area under the corrected geometric mean curve (AUC) _0-24 . A pessary comprising about 10 μg estradiol, wherein administration of said pessary to a patient in a plasma sample from said patient,
1) about 12 pg ^* hr / ml to about 18 pg ^* hr / correction geometric mean peak plasma concentration of ml of estradiol _{(C max)} and Oyobi 2) about 42 pg ^* hr / ml to about 63 pg ^* corrected geometry hr / ml for estradiol A pessary providing an area under the mean curve (AUC) _0-24 . 16. The pessary of claim 15, wherein the pessary further provides a corrected geometric mean time to a peak plasma concentration of estradiol ( _Tmax ) of about 1 hour to about 3 hours. A pessary comprising about 10 μg estradiol, wherein administration of said pessary to a patient in a plasma sample from said patient,
1) about ^{4 pg} * hr / ml to about ^{7 pg} * hr / ml for correcting geometric mean peak plasma concentrations of estrone _{(C max)} and Oyobi 2) about 20 pg ^* hr / ml to about 31 pg ^* corrected geometry hr / ml for estrone A pessary providing an area under the mean curve (AUC) _0-24 . 18. The pessary of claim 17, wherein the pessary further provides a corrected geometric mean time to an estrone peak plasma concentration ( _Tmax ) of about 4 hours to about 8 hours. A pessary comprising about 10 μg estradiol, wherein administration of said pessary to a patient in a plasma sample from said patient,
1) about 10 pg ^* hr / ml to about 16 pg ^* hr / ml of estrone sulfate corrected geometric mean peak plasma concentration _{(C max)} and Oyobi 2) of about 56pg ^* hr / ml~ about 84pg ^* hr / ml for estrone sulfate A pessary providing an area under the corrected geometric mean curve (AUC) _0-24 . 20. The pessary of claim 19, wherein the pessary further provides a corrected geometric mean time to a peak plasma concentration ( _Tmax ) of estrone sulfate from about 4 hours to about 7 hours. A pessary comprising about 4 μg estradiol, wherein administration of said pessary to a patient is in a plasma sample from said patient,
1) about ^{4 pg} * hr / ml to about ^{8 pg} * hr / correction geometric mean peak plasma concentration of ml of estradiol _{(C max)} and Oyobi 2) about 16 pg ^* hr / ml to about 26 pg ^* corrected geometry hr / ml for estradiol A pessary providing an area under the mean curve (AUC) _0-24 . 24. The pessary of claim 21, wherein the pessary further provides a corrected geometric mean time to a peak plasma concentration ( _Tmax ) of estradiol of about 0.25 hours to about 2 hours. A pessary comprising about 4 μg estradiol, wherein administration of said pessary to a patient is in a plasma sample from said patient,
1) about ^{1 pg} * hr / ml to about ^{3 pg} * hr / ml for correcting geometric mean peak plasma concentrations of estrone _{(C max)} and Oyobi 2) about ^{8 pg} * hr / ml to about 13 pg ^* corrected geometry hr / ml for estrone A pessary providing an area under the mean curve (AUC) _0-24 . 24. The pessary of claim 23, wherein the pessary further provides a corrected geometric mean time to an estrone peak plasma concentration ( _Tmax ) of about 1 hour to about 4 hours. A pessary comprising about 4 μg estradiol, wherein administration of said pessary to a patient is in a plasma sample from said patient,
1) about ^{4 pg} * hr / ml to about ^{7 pg} * hr / ml of estrone sulfate corrected geometric mean peak plasma concentration _{(C max)} and Oyobi 2) from about 22 pg ^* hr / ml to about 34pg ^* hr / ml for estrone sulfate A pessary providing an area under the corrected geometric mean curve (AUC) _0-24 . 26. The pessary of claim 25, wherein the pessary further provides a corrected geometric mean time to a peak plasma concentration ( _Tmax ) of estrone sulfate from about 1 hour to about 3 hours. A pessary comprising about 1 μg to about 25 μg estradiol, wherein administration of said pessary to a patient provides a corrected geometric mean peak plasma concentration (C _max ) of estradiol that is less than about 30 pg ^* hr / ml . 28. The pessary of claim 27, wherein administration of the pessary to a patient provides a corrected geometric mean peak plasma concentration ( _Cmax ) of estradiol that is less than about 18 pg ^* hr / ml. A pessary comprising about 1 μg to about 25 μg estradiol, wherein administration of said pessary to a patient provides an area under the corrected geometric mean curve (AUC) _0-24 of estradiol that is less than about 112 pg ^* hr / ml ,pessary. 30. The pessary of claim 29, wherein administration of said pessary to a patient provides an area under the corrected geometric mean curve (AUC) _0-24 of estradiol that is less than about 63 pg ^* hr / ml. A pessary comprising about 1 μg to about 25 μg of estradiol, wherein administration of said pessary to a patient provides a corrected geometric mean peak plasma concentration (C _max ) of estrone that is less than about 14 pg ^* hr / ml . 32. The pessary of claim 31, wherein administration of said pessary to a patient provides a corrected geometric mean peak plasma concentration ( _Cmax ) of estrone that is less than about 7 pg ^* hr / ml. A pessary comprising about 1 μg to about 25 μg estradiol, wherein administration of said pessary to a patient provides an area under the corrected geometric mean curve (AUC) _0-24 of estrone, which is less than about 65 pg ^* hr / ml ,pessary. 34. The pessary of claim 33, wherein administration of the pessary to a patient provides an area under the corrected geometric mean curve (AUC) _0-24 of estrone, which is less than about 31 pg ^* hr / ml. A pessary comprising about 1 μg to about 25 μg estradiol, wherein administration of said pessary to a patient provides a corrected geometric mean peak plasma concentration (C _max ) of estrone sulfate that is less than about 613 pg ^* hr / ml; pessary. 36. The pessary of claim 35, wherein administration of the pessary to a patient provides a corrected geometric mean peak plasma concentration ( _Cmax ) of estrone sulfate that is less than about 16 pg ^* hr / ml. A pessary comprising about 1 μg to about 25 μg estradiol, wherein administration of said pessary to a patient provides an area under the corrected geometric mean curve (AUC) of estrone sulfate less than about 5291 pg ^* hr / ml _0-24 Yes, pessary. 38. The pessary of claim 37, wherein administration of the pessary to a patient provides an area under the corrected geometric mean curve (AUC) _0-24 of estrone sulfate that is less than about 84 pg ^* hr / ml.   A pessary comprising about 1 μg to about 25 μg estradiol, wherein administration of said pessary to the proximal region of the patient's vagina provides a therapeutically effective concentration of estradiol within said proximal region of said vagina for 24 hours .   40. A method of treating an estrogen deficiency condition, comprising administering to a patient in need thereof a pessary according to any one of claims 1-39.   40. A method of treating vulva vaginal atrophy comprising administering to a patient in need thereof a pessary according to any one of claims 1 to 39.   One or more symptoms selected from the group consisting of vaginal dryness, sexual pain, vaginal or vulvar stimulation, vaginal or vulvar burning, vaginal or vulvar pruritus, dysuria, and vaginal bleeding related to sexual activity. 42. The method of claim 40 or 41, comprising reducing the severity.   43. The method of any one of claims 40 to 42, wherein the treatment comprises reducing the patient's vaginal pH.   44. The method of claim 43, wherein the treatment comprises reducing the patient's vaginal pH to a pH of less than about 5.0.   45. The method of any one of claims 40-44, wherein the treatment comprises a change in the patient's cellular composition.   46. The method of claim 45, wherein the change in the cell composition comprises reducing the number of parabasal vaginal cells or increasing the number of superficial vaginal cells.   48. The method of claim 46, wherein the number of parabasal vaginal cells in the patient is reduced by at least about 35%.   48. The method of claim 47, wherein the number of parabasal vaginal cells in the patient is reduced by at least about 50%.   48. The method of claim 46, wherein the number of superficial vaginal cells is increased by at least about 5%.   50. The method of claim 49, wherein the number of superficial vaginal cells is increased by at least about 35%.   40. A method for reducing vaginal secretions after administration of a pessary, comprising administering to a patient in need thereof a pessary according to any one of claims 1 to 39, comprising: The method wherein the vaginal secretion after administration is compared to the vaginal secretion after administration of a reference drug.