US 2015O133421A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0133421 A1 Bernick et al. (43) Pub. Date: May 14, 2015 (54) VAGINAL INSERTED ESTRADIOL (60) Provisional application No. 61/894,411, filed on Oct. PHARMACEUTICAL COMPOSITIONS AND 22, 2013, provisional application No. 61/932,140, METHODS filed on Jan. 27, 2014, provisional application No. 61/745,313, filed on Dec. 21, 2012. (71) Applicant: TherapeuticsMD, Inc., Boca Raton, FL (US) Publication Classification (72) Inventors: Brian A. Bernick, Boca Raton, FL (US); (51) Int. Cl. Julia M. Amadio, Boca Raton, FL (US) A613 L/565 (2006.01) A619/00 (2006.01) (21) Appl. No.: 14/521,002 (52) U.S. Cl. CPC ............. A6 IK3I/565 (2013.01); A61 K9/0036 (22) Filed: Oct. 22, 2014 (2013.01) Related U.S. Application Data (57) ABSTRACT (63) Continuation-in-part of application No. PCT/US 13/ 46433, filed on Jun. 18, 2013, Continuation-in-part of According to various embodiments of this disclosure, phar application No. 14/099,562, filed on Dec. 6, 2013, now maceutical compositions comprising Solubilized estradiol are Pat. No. 8,987.237, which is a continuation of appli provided. In various embodiments, such compositions are cation No. 13/684,002, filed on Nov. 21, 2012, now encapsulated in Soft capsules which may be vaginally inserted Pat. No. 8,633,178. for the treatment of vulvovaginal atrophy. Patent Application Publication May 14, 2015 Sheet 1 of 7 US 201S/O133421 A1 100 102 AGENT 104 106 110 112 ASSEMBLE SUPPOSITORY FIG. 1 210 Patent Application Publication May 14, 2015 Sheet 2 of 7 US 201S/O133421 A1 25 f ---O---Treatment-R --Treatment-T 15 1 O 5 100.0 N=36 2 "o. ---O---Treatment-R 3. o-o O--- --Treatment-T 10.0 - N ---. O-.......... S. --O su s CD i > 1.0 s E 3 ?h 0.1 O 5 10 15 20 25 Time (hr) FIG. 4 Patent Application Publication May 14, 2015 Sheet 3 of 7 US 201S/O133421 A1 14. N=36 e 12 -O , o-. p ', - “...... f , r O 10 t 8 ---O---Treatment-R --Treatment-T Time (hr) FIG. 5 100 N=36 10 ---O---Treatment-R -O-Treatment-T Time (hr) FIG. 6 Patent Application Publication May 14, 2015 Sheet 4 of 7 US 2015/O133421 A1 ---O---Treatment-R - Treatment-T ---O---Treatment-R --Treatment-T Time (hr) FIG. 8 Patent Application Publication May 14, 2015 Sheet 5 of 7 US 201S/O133421 A1 ---O--- R. Reference -- T. Test 100.0 5, 100 e s O s ---O---R: Reference e O- O. -O-T. Test O 's t - e ro- ---- - - - - - - - O S3 & 1.0 0.1 O 5 10 15 20 25 Time (hr) FIG 10 Patent Application Publication May 14, 2015 Sheet 6 of 7 US 2015/O133421 A1 ---O- - - R. Reference Time (hr) FIG. 1 ? 10.0 10 ---O--- R. Reference -- T. Test Time (hr) FIG. 12 Patent Application Publication May 14, 2015 Sheet 7 of 7 US 201S/O133421 A1 12 O 10 ? ---O--- R. Reference p , -H T. Test g 8 ; o 9 O. 6- If Y - - - E --- CD W -- d s s O 4 2 O 5 1O 15 20 25 Time (hr) FIG. 13 100 ---O--- R. Reference : 1 O O 5 1O 15 20 25 Time (hr) FIG. 14 US 2015/O 133421 A1 May 14, 2015 VAGINAL INSERTED ESTRADIOL 0005 Estrogen treatment has proven to be very successful PHARMACEUTICAL COMPOSITIONS AND in controlling menopausal symptoms, including vaginal atro METHODS phy (VVA). Several studies have shown that the symptoms connected with vaginal atrophy are often relieved by estrogen CROSS REFERENCE TO RELATED treatment given either systemically or topically. The existing APPLICATIONS treatments have numerous problems, for example compliance issues with patients not completing or continuing treatment 0001. This application claims priority to the following due to the problems associated with the form of treatment. U.S. patent applications: U.S. Provisional Application Ser. 0006. Accordingly, disclosed herein is, among other No. 61/932,140, entitled “VAGINAL INSERTED ESTRA things, a new soft gel vaginal pharmaceutical composition DIOL, PHARMACEUTICAL COMPOSITIONS AND and dosage form containing solubilized estradiol for the treat METHODS, which was filed on Jan. 27, 2014; U.S. Provi ment of VVA. The soft gel vaginal pharmaceutical composi sional Application Ser. No. 61/894,411, entitled “SOLUBLE tion has been designed to mitigate common limitations found ESTRADIOL CAPSULE FOR VAGINAL INSERTION, with other vaginal forms of estradiol. The soft gel vaginal which was filed on Oct. 22, 2013: U.S. Provisional Applica pharmaceutical composition is expected to ease vaginal tion Ser. No. 61/745,313, entitled “SOLUBLE ESTRADIOL administration, provide improved safety of insertion, mini CAPSULE FORVAGINAL INSERTION, which was filed mize vaginal discharge following administration, and provide on Dec. 21, 2012; U.S. Provisional Application Ser. No. a more effective dosage form with improved efficacy, safety 61/889,483, entitled “Natural Combination Hormone and patient compliance. Replacement Pharmaceutical compositions and Therapies.” which was filed on Oct. 10, 2013: U.S. Provisional Applica SUMMARY tion Ser. No. 61/661,302, entitled “ESTRADIOL PHARMA CEUTICAL COMPOSITIONS, which was filed on Jun. 18, 0007 According to various aspects and embodiments of 2012; U.S. Provisional Application Ser. No. 61/662,265, this disclosure, a softgel vaginal pharmaceutical composition entitled “PROGESTERONE PHARMACEUTICAL COM as a potential treatment for post-menopausal women Suffer POSITIONS,” which was filed on Jun. 20, 2012; U.S. patent ing with moderate to severe symptoms of VVA is provided. application Ser. No. 13/684,002, entitled “Natural Combina 0008 Provided herein is a pessary comprising: a) a thera tion Hormone Replacement Pharmaceutical compositions peutically effective amount of estradiol; and b) a solubilizing and Therapies,” which was filed Nov. 21, 2012; U.S. Patent agent comprising a medium chain oil. Application Serial No. PCT/US2013/023309, entitled 0009. In some embodiments, the pessary comprises about “Transdermal Hormone Replacement Therapies, which was 1 ug to about 25ug of estradiol. For example, the pessary can filed Jan. 25, 2013; and U.S. patent application Ser. No. include about 1 Jug to about 10g of estradiol; and about 10 ug 13/843,362, entitled “Transdermal Hormone Replacement to about 25 ug of estradiol. Therapies, which was filed Mar. 15, 2013. All aforemen 0010. In some embodiments, the estradiol is solubilized. tioned applications are hereby incorporated by reference 0011. In some embodiments, the medium chain oil com herein in their entirety. prises at least one C6-C12 fatty acid or a glycol, monoglyc eride, diglyceride, or triglyceride ester thereof. BACKGROUND 0012. In some embodiments, the solubilizing agent com prises at least one ester selected from the group consisting of 0002 This application is directed to pharmaceutical com an ester of caproic fatty acid, an ester of caprylic fatty acid, an positions, methods, and devices related to hormone replace ester of capric fatty acid, and combinations thereof. For ment therapy. example, the Solubilizing agent can include a caprylic/capric 0003 Postmenopausal women frequently suffer from triglyceride. atrophic vaginitis or Vulvar and vaginal atrophy (hereinafter 0013. In some embodiments, the pessary further com “vulvovaginal atrophy” or “VVA) with symptoms including, prises a capsule. For example, the capsule can be a softgelatin for example, vaginal dryness, vaginal odor, vaginal or Vulvar capsule. irritation or itching, dysuria (pain, burning, or stinging when 0014. Also provided herein is a pessary comprising: a) a urinating), dysparuenia (vaginal pain associated with sexual therapeutically effective amount of estradiol; b) a caprylic/ activity), or vaginal bleeding associated with sexual activity. capric triglyceride; c) a non-ionic Surfactant comprising Other symptoms include Soreness; with urinary frequency PEG-6 palmitostearate and ethylene glycol palmitostearate; and urgency; urinary discomfort and incontinence also occur and d) a soft gelatin capsule. ring (“estrogen-deficient urinary State(s)'). One symptom of 0015. In some embodiments, a pessary provided herein vaginal atrophy is an increased vaginal pH, which creates an comprises about 25ug of estradiol, wherein administration of environment more Susceptible to infections. The mucosal the pessary to a patient provides, in a plasma sample from the epithelium of the VVA patients also reported to show signs of patient: 1) a corrected geometric mean peak plasma concen severe atrophy and upon cytological examination accompa tration (C) of estradiol of about 19 pg.hr/ml to about 29 nied by an increased number of the parabasal cells and a pg.hr/ml; and 2) a corrected geometric mean area under the reduced number of superficial cells. curve (AUC) of estradiol of about 75 pg.hr/ml to about 0004 Each of these VVA-related states manifest symp 112 pg.hr/ml. toms associated with decreased estrogenization of the Vul 0016. In some embodiments, a pessary provided herein Vovaginal tissue, and can even occur in women treated with comprises about 25ug of estradiol, wherein administration of oral administration of an estrogen-based pharmaceutical drug the pessary to a patient provides, in a plasma sample from the product. Although VVA is most common with menopausal patient: 1) a corrected geometric mean peak plasma concen women, it can occur at any time in a woman's life cycle. tration (C) of estrone of about 9 pg.hr/ml to about 14 US 2015/O 133421 A1 May 14, 2015 pg.hr/ml; and 2) a corrected geometric mean area under the the pessary to a patient provides, in a plasma sample from the curve (AUC) of estrone of about 43 pg.hr/ml to about 65 patient: 1) a corrected geometric mean peak plasma concen pg.hr/ml. tration (C) of estrone sulfate of about 4 pg.hr/ml to about 0017.