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WO2018156960A1 - Composés de traitement d'inflammation cutanée, de troubles sexuels féminins et d'amélioration de la fonction sexuelle - Google Patents

Composés de traitement d'inflammation cutanée, de troubles sexuels féminins et d'amélioration de la fonction sexuelle Download PDF

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Publication number
WO2018156960A1
WO2018156960A1 PCT/US2018/019530 US2018019530W WO2018156960A1 WO 2018156960 A1 WO2018156960 A1 WO 2018156960A1 US 2018019530 W US2018019530 W US 2018019530W WO 2018156960 A1 WO2018156960 A1 WO 2018156960A1
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catechin
sexual
pharmaceutical composition
gto
egcg
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PCT/US2018/019530
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Wendy Anne EPSTEIN
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Epstein Wendy Anne
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Priority to US16/488,936 priority Critical patent/US20200016116A1/en
Publication of WO2018156960A1 publication Critical patent/WO2018156960A1/fr
Priority to US17/095,876 priority patent/US20210059981A1/en
Priority to US17/838,865 priority patent/US20230000819A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/82—Theaceae (Tea family), e.g. camellia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • A61K38/34—Melanocyte stimulating hormone [MSH], e.g. alpha- or beta-melanotropin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants

Definitions

  • DSM Diagnostic and Statistical Manual of Mental Disorders
  • GPPD Genitopelvic Pain/Penetration Disorder
  • FOD Female Orgasmic Disorder
  • the DSM-V defines Genitopelvic Pain/Penetration Disorder, (GPPD) as difficulty in vaginal penetration, marked vulvovaginal or pelvic pain during penetration, or attempt at penetration (dyspareunia), fear or anxiety about pain in anticipation of, during, or after penetration, and tightening or tensing of pelvic floor muscles during attempted penetration (vaginismus).
  • GPPD Genitopelvic Pain/Penetration Disorder
  • VVA vulvovaginal atrophy
  • Vulvar pain is also a frequently occurring problem that affects both pre and postmenopausal women.
  • vulvodynia may present as more diffuse, constant vulvar pain, exhibiting a general sensation of burning or rawness in affected areas.
  • Localized vulvodynia also known as vestibulodynia is pain around the opening of the vagina, the vulvar vestibule, most commonly found around the posterior hymenal ring between 4 and 8 o'clock, a region sometimes referred to by medical practitioners as the "posterior fourchette.” This is the most common cause of vulvar pain and the leading cause of dyspareunia in women under the age of 50.
  • This condition may manifest itself as primary vestibulodynia (i.e. pain with first attempted tampon and /or intercourse) or secondary vestibulodynia (i.e. development of vulvar pain following previously painless tampon use and/or intercourse).
  • Primary vestibulodynia i.e. pain with first attempted tampon and /or intercourse
  • secondary vestibulodynia i.e. development of vulvar pain following previously painless tampon use and/or intercourse.
  • Conservative estimates indicate that at least 16% of women in the United States (-14 million women) have experienced some form of chronic vulvar pain. This pain and discomfort seriously impacts and degrades the quality of life. Women suffering from this condition are in need of a clinically-proven, effective treatment, as they regularly self-treat symptoms, wasting both time and money on ineffective treatments.
  • Genitopelvic pain in general tends to be underdiagnosed because many women are either not asked about it in connection with regular medical exams or are uncomfortable discussing it with their healthcare professional.
  • Genitopelvic Pain/Penetration Disorder frequently becomes the cause (or a significant contributing factor) in the manifestation of Sexual Interest/ Arousal Disorder (SIAD) because the anticipation of pain during sexual encounters may, over time, form a negative cognitive response that inhibits sexual interest, desire and/or arousal.
  • VVA vulvovaginal atrophy
  • Symptoms may include difficulty or inability to allow penetration, painful intercourse (dyspareunia), irritation, soreness, pain of the external genitalia, specifically of the vulva (vulvodynia), and dryness or decrease in lubrication from loss of mucous secretion. These symptoms exert a negative impact on the quality of life of up to 50% of all postmenopausal women.
  • Clinical diagnostic indicators of VVA include elevation of vaginal pH and a decrease in the vaginal maturation index.
  • the low glycogen content of the thinned epithelium leads to a reduction in lactic acid production by lactobacilli bacteria, thereby increasing vaginal pH.
  • a vaginal pH of greater than 5, in the absence of other causes, such as infection or semen from recent intercourse, is typically considered an indicator of vaginal atrophy due to lack of estrogen.
  • Maturation index is a term used to indicate the percentage of vaginal cell types as determined from a cytological exam of epithelial cells from the upper one third of the vagina. It is typically expressed as percentages of each of three cell types (i.e. , parabasal, intermediate and superficial cells) found on a wet prep exam. Premenopausal women with adequate estrogen levels have a maturation index of 40% to 70% intermediate cells, 30% to 60% superficial cells, and substantially no parabasal cells ( ⁇ 1%). In vaginal atrophy, there is an increase in the parabasal cell population and a corresponding decrease in superficial cells, evidence of the thinning of the vaginal epithelium.
  • VVA vulvovaginal atrophy
  • estrogen is believed to be responsible for some VVA symptoms in women. This estrogen deficiency may be due to age-related menopause, or iatrogenically induced menopause which is more likely the cause of estrogen deficiency in younger, premenopausal, women who are estrogen deficient.
  • age-related menopause or iatrogenically induced menopause which is more likely the cause of estrogen deficiency in younger, premenopausal, women who are estrogen deficient.
  • genital pain involving both dyspareunia and vulvodynia, do occur in pre-menopausal women and/or in other women having essentially normal estrogen levels.
  • Genitopelvic Pain/Penetration Disorders can be adequately addressed with exogenous estrogens.
  • estrogens are currently available to treat women with, vulvovaginal atrophy, VVA, associated Genitopelvic Pain/Penetration Disorder, GPPD. They include oral estrogens with or without progestins, topical estrogens as creams, suppositories or solid hormone releasing rings (Estring). Bioidentical estrogens are 17 beta-estradiol, estrone, and estriol. Sources of estrogen maybe synthetic, animal source, (Premarin), or plant based extracted from soy or yams. DHEA is metabolized, in vivo, in peripheral tissues to both androgens and estrogens. DHEA causes proliferation of estrogen receptor-positive breast cancer cells. Regardless of the source, however, such compounds are all still estrogenic in their inherent effects, both beneficial and adverse, on estrogen sensitive target tissues.
  • the Women's Health Initiative determined the following risks to be associated with estrogen use: 1) An increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens; 2) An increased risk of stroke and deep venous thrombosis ("DVT") in post-menopausal women using unopposed estrogens; 3) An increased risk of probable dementia in post-menopausal women using unopposed estrogens.
  • a WHI study reported that women taking estrogen plus progestin had an increased risks of deep venous thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women. Additionally, an estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women. The WHI estrogen plus progestin sub-study further demonstrated an increased risk of invasive breast cancer. Presently, there are no known safety studies to support the use of oral or topical vaginal estrogen in breast cancer survivors, and any estrogen use by breast cancer survivors is, considered to be, contraindicated by many health-care professionals.
  • SERMs selective estrogen receptor modulators
  • OSPHENA ® Ospemifene
  • GPPD moderate to severe dyspareunia
  • SERMs act as a hormone by binding to the estrogen receptors ERa and ER , but bind more selectively to certain target organs such as the vagina, and thus produce less systemic estrogenic side effects compared to more non selective oral estrogens.
  • Ospemifene exerts a strong, nearly full estrogen agonist effect in the vaginal epithelium as evidenced by improvement of the vaginal maturation index and decreased vaginal pH. It is an oral medication with both systemic and local estrogenic effects that has to be taken indefinitely to maintain its therapeutic effects. Oral Ospemifene carries the risk of increased cardiovascular events such as deep venous thrombosis, stroke, myocardial infarction, thickening of the endometrium, endometrial polyps, breast tenderness, and breast lumps.
  • VVA vaginal moisturizers and lubricants
  • vaginal moisturizers and lubricants to provide temporary relief from vaginal dryness and dyspareunia by reducing friction.
  • Such compounds do nothing to restore the normal anatomy or function of the female genitalia; thus, they have no long-term therapeutic effects.
  • These exogenous topically applied intravaginal therapeutics can be messy as they will leak out of the vagina when a woman is in the upright position, and are not produced by a woman's body in response to normal physiological responses to sexual stimulation.
  • Vaginal estrogen therapy has proven more effective for VVA than all forms of non-hormonal therapy.
  • GPPD Genitopelvic Pain/Penetration Disorder
  • Female vestibulodynia may be generally described as a disorder of unknown etiology where there is localized provoked vulvar pain upon penetration of the vagina. There is also tenderness to touch around the vaginal opening (vestibule) during normal self or partner's manual sexual contact or during a health professional's physical examination. The entire area of the vestibule around the vaginal introitus can be affected but the experienced discomfort or pain is most commonly pronounced in the localized area of the posterior fourchette. The affected tissue in the vestibule has increased nerve endings and signs of inflammation and is typically painful. It occurs in women of all ages. It is estimated that approximately 15% of women (about 1 in 7) will experience this type of vulvar pain sometime in their lifetime.
  • Vestibulodynia may lead to dyspareunia or painful intercourse and thus interfere with sexual function by causing pain in genitalia.
  • Vestibulodynia is a challenging disorder and to date there is no definitive treatment for this condition despite a range of treatments, which include: oral tricyclics, neuromodulators (i.e., gabapentin), topical anesthetics, botulinum injections, intralesional corticosteroid injections, biofeedback, sexual therapy, psychotherapy, physical therapy, and surgery as a last resort in an attempt to remove the painful tissue.
  • Her who have vestibulodynia often simultaneously suffer from sexual Interest/ Arousal Disorder (SIAD) and Female Orgasmic Disorder (FOD) directly because of experiencing
  • SIAD sexual Interest/ Arousal Disorder
  • FOD Female Orgasmic Disorder
  • SIAD Sexual Interest/ Arousal Disorder
  • FOD Female Orgasmic Disorder
  • SIAD Sexual Interest/ Arousal Disorder
  • a woman has SIAD if she experiences personal distress caused by a decrease or lack of at least three of the following four criteria: 1) initiation of sexual activity or responsiveness to a partner's attempts to initiate it, 2) excitement and pleasure, 3) response to sexual cues, and 4) sensations during sexual activity, whether genital or non- genital. Again, three of the foregoing criteria are required for diagnosis. It may be expressed generally as lack of subj ective excitement or lack of genital (lubrication/swelling) or other somatic responses.
  • the disorder had no FDA-approved treatments (until August 2015 when Flibanserin, Addyi, was approved), and the FDA has recognized the condition as an area of unmet medical need.
  • Female orgasmic disorder, (FOD) as defined in the DSM is the absence of orgasm (anorgasmia), infrequency or delay of orgasm, and/or reduced intensity of said orgasm. Such orgasmic dysfunction may also occur when a woman has difficulty reaching orgasm, even when sexually aroused with sufficient sexual stimulation. Many women have difficulty reaching orgasm with a partner, or during masturbation, even after ample sexual stimulation.
  • Female Orgasmic Disorder (FOD) affects approximately one in three women.
  • FOD Female Orgasmic Disorder
  • Women may have difficulty reaching orgasm due to one or more physical, emotional, and/or psychological factors. Contributing factors include: older age, medical conditions, such as diabetes, a history of gynecological surgeries, such as a hysterectomy, the use of certain medications, particularly selective serotonin reuptake inhibitors (SSRIs), mental health conditions, such as depression or anxiety, stress, societal negative stereotypes of women's sexuality, lack of adequate or effective sexual stimulation, etc. Sometimes, a combination of these factors can make achieving an orgasm difficult or not possible.
  • SSRIs selective serotonin reuptake inhibitors
  • orgasmic disorder The inability to orgasm can lead to distress, which may make it even more difficult to achieve orgasm in the future.
  • the main symptom of orgasmic disorder is the inability to achieve sexual climax. Women with Female Orgasmic Disorder (FOD) may have difficulty achieving orgasm during either sexual intercourse or during masturbation.
  • FOD Female Orgasmic Disorder
  • the initial goal of therapy for Female Orgasmic Disorder is to enable the patient to reach an orgasm as desired under any circumstance.
  • Underlying medical etiologies must first be considered including antidepressant-induced anorgasmia, anorgasmia secondary to substance abuse, and underlying neurological disorders.
  • over-the-counter (OTC) products Zestra ®
  • nutritional supplements are marketed, but are ineffective in treating women with FOD. Tims, there is currently no safe or effective treatment for Female Orgasmic Disorder (FOD) that enables an orgasm or enhances the intensity of said orgasm. Therefore, for the treatment of Female Orgasmic Disorder (FOD), it is desirable to provide a therapeutic compound and associated treatment that is easy for the patient to use (e.g., a medication that can be applied to the affected area by the patient themselves) that shows significant improvement in orgasmic ease and intensity in a relatively short period of use and having no significant side-effects.
  • a therapeutic compound and associated treatment that is easy for the patient to use (e.g., a medication that can be applied to the affected area by the patient themselves) that shows significant improvement in orgasmic ease and intensity in a relatively short period of use and having no significant side-effects.
  • Flibanserin (BIMT 17 BS; 2H-benzimidazol-2-one, l,3 - dihydro-l-[2-[4- [3(tri-fluoromethyl) phenyl] -1-piperazinyl] ethyl]) is a non-hormonal, centrally acting molecule that acts as an agonist at postsynaptic 5 -HT1A receptors and as an antagonist at 5 -HT2 A receptors
  • Flibanserin is the first and only drug indicated for pre-menopausal women for SIAD related disorders (formerly termed hypoactive sexual desire disorder).
  • SIAD related disorders originally termed hypoactive sexual desire disorder.
  • Flibanserin was twice rejected because according to FDA reviewers: "Flibanserin has a challenging benefit/risk assessment.” This is due to its relative lack of efficacy for the intended indication as well as the prevalence of certain undesirable side effects. For example, from a median baseline of about 2-3 satisfying sexual events ("SSEs") per month, Flibanserin resulted in a median placebo-corrected increase of only about 0.5-1.0 SSEs per month over a six month period. Moreover, this marginal benefit was seen in only 18% of women taking l OOmg daily of the systemic drug for a minimum of 28 days.
  • Flibanserin acts on the central nervous system and must be taken continuously and indefinitely. Side effects of Flibanserin are significant and include hypotension, syncope and somnolence. The risk of such side effects is amplified by drug interactions with CYP3A4 inhibitors such as oral contraceptives or Fluconazole and with concomitant alcohol intake.
  • CYP3A4 inhibitors such as oral contraceptives or Fluconazole and with concomitant alcohol intake.
  • the FDA concluded that the clinically significant pharmacodynamic interaction between Flibanserin and alcohol is challenging to mitigate, particularly because Flibanserin requires daily use and alcohol consumption, including excessive drinking, is not uncommon in many cultures and further common for those engaging in sexual activity.
  • Flibanserin trials were limited to generally healthy women who were not taking additional medication such as benzodiazepines, sleep aids, narcotics, or other medicines. As with many drug trials, Flibanserin trials were of short duration relative to the potential length of time that Flibanserin could be indicated. Further, it is noteworthy that Flibanserin demonstrated no therapeutic effect at all on Genitopelvic Pain/Penetration Disorder (GPPD) including vestibulodynia and dyspareunia or on Female Orgasmic Disorder (FOD).
  • GPPD Genitopelvic Pain/Penetration Disorder
  • FOD Female Orgasmic Disorder
  • GPPD Genitopelvic Pain/Penetration Disorder
  • SIAD Sexual Interest/ Arousal Disorder
  • FOD Female Orgasmic Disorder
  • the invention provides safe and efficacious treatments for Female sexual Disorders, Genitopelvic Pain/Penetration Disorders; vulvovaginal atrophy, vestibulodynia, dyspareunia, sexual Interest/ Arousal Disorder, Female Orgasmic Disorder, and low female libido.
  • the invention provides safe and efficacious compositions and treatments that improve or have a positive effect on male libido, sexual performance, improve sexual sensation, as well as treat certain cutaneous inflammation disorders.
  • the invention provides safe and efficacious catechin compositions and treatments that improve and/or treat cutaneous inflammations associated with urinary tract disorders in both males and females.
  • the catechin compounds and treatment methods described herein show significant efficacy for treatment of Genitopelvic Pain /Penetration Disorder (GPPD), Sexual Interest Arousal Disorder (SIAD) and Female Orgasmic Disorder (FOD). They are efficacious in treating Genitopelvic Pain/Penetration Disorder (GPPD) due to VVA without estrogenic side effects as demonstrated by lack of change in pH or vaginal maturation index.
  • the catechin compounds of the present invention are further efficacious in reducing vestibulodynia or provoked genital pain and dyspareunia (GPPD), increasing vaginal lubrication as well as improving Sexual Interest/ Arousal Disorder (SIAD) by increasing sexual interest and arousal.
  • Additional benefits of the present invention include increasing the intensity and frequency of a woman's orgasm, and therefore is efficacious in treating Female Orgasmic Disorder (FOD).
  • FOD Female Orgasmic Disorder
  • prior art 15% catechin formulations used, as indicated, three times daily, to treat human papilloma virus (HPV) infections are associated with significant vulvovaginal irritation, discomfort or pain.
  • HPV human papilloma virus
  • the methods and compositions of the inventions described herein have substantially the opposite effect. They soothe the vulvovaginal area and relieve the symptoms of GPPD, SIAD, FOD, and VVA.
  • the invention provides a method for improving male or female sexual function, comprising applying a pharmaceutical composition to an individual's genital or erogenous area, wherein the pharmaceutical composition comprises a catechin or catechin analog.
  • said catechin is a tea catechin.
  • said catechin is a green tea catechin.
  • said catechin includes Epigallocatechin gallate.
  • said catechin is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Epigallocatechin gallate at a concentration of between about 1 % and 50% weight per weight of total composition (w/w), also referred to herein as "by weight.”
  • the EGCg is at a concentration of between about 1 % and 10% weight per weight of total composition (w/w).
  • said catechin is Epigallocatechin gallate with a concentration between about 2.5% and 25% by weight.
  • said catechin is Epigallocatechin gallate with a concentration between about 1 % and 15% by weight. In another embodiment, said catechin is Epigallocatechin gallate with a concentration between about 2.5% and 10% by weight. In another embodiment, said catechin is Epigallocatechin gallate with a concentration between about 1% and 7.5%. In a most preferred embodiment, said catechin is Epigallocatechin gallate with a concentration about 5%. In some embodiments of the methods described herein, said catechin is applied to a vulva, a clitoris, a vaginal introitus, a vagina, a nipple, or a penis. In other embodiments, said pharmaceutical composition is an ointment, a lotion, an emulsion, an aqueous solution, or a non-aqueous solution.
  • said pharmaceutical composition further comprises a selective estrogen receptor modulator (SERM).
  • SERM selective estrogen receptor modulator
  • said SERM is ospemifene.
  • said SERM is ospemifene.
  • the pharmaceutical composition further comprises estrogen.
  • said pharmaceutical compositions further comprise a combination of both a SERM and an estrogen hormone.
  • the pharmaceutical composition comprises a selective androgen receptor modulator (SARM).
  • the pharmaceutical composition comprises an androgen.
  • the pharmaceutical composition comprises a capsaicin.
  • the pharmaceutical composition includes a cannabinoid. The invention provides methods and compositions for improving sexual function of both males and females, comprising applying a pharmaceutical composition to an individual's genital or erogenous area, wherein the pharmaceutical composition comprises a catechin or catechin analog.
  • the catechin comprises Epigallocatechin gallate (EGCg) at a concentration of between about 1% and 50% weight per weight of total composition (w/w). In other embodiments, the catechin comprises Epigallocatechin gallate (EGCg) at a concentration of between about 1% and 25% weight per weight of total composition (w/w). In other embodiments, the catechin comprises Epigallocatechin gallate (EGCg) at a concentration of between about 2.5% and 25% by weight. In other
  • the catechin comprises Epigallocatechin gallate (EGCg) at a concentration of between about 1% and 15% by weight.
  • oral formulations are used having higher concentrations.
  • the EGCg concentration in oral formulations may be as high as about 90-100% EGCg.
  • Topical formulations wherein Epigallocatechin gallate (EGCg) is at a concentration above about 50% by weight may be difficult to emulsify and may be in a liquid, a transdermal patch or other suitable form for application to a desired area.
  • the pharmaceutical composition further includes a
  • the pharmaceutical composition further includes a vasodilator.
  • the pharmaceutical composition further includes a selective estrogen receptor modulator (SERM) or a selective androgen receptor modulator (SARM).
  • the pharmaceutical composition further comprises an estrogen and/or an androgen.
  • the pharmaceutical composition further comprises one or more catechin analogs which may include an Epigallocatechin gallate analog.
  • the pharmaceutical composition further comprises melatonin or Bremelanotide (PT-141) in addition to the combinations described above.
  • the invention also provides methods and compositions for treating a male sexual disorder (MSD) or female sexual disorder (FSD), comprising applying a pharmaceutical composition to an individual's genital area or erogenous zone, wherein the pharmaceutical composition comprises an catechin.
  • the catechin comprises
  • Epigallocatechin gallate at a concentration of between about 1% and 50% weight per weight of total composition (w/w).
  • the catechin comprises
  • the catechin comprises Epigallocatechin gallate (EGCg) at a concentration of between about 1% and 15% by weight.
  • the pharmaceutical composition further includes a cannabinoid.
  • the pharmaceutical composition further includes a vasodilator. In other embodiments, the pharmaceutical composition further includes a selective estrogen receptor modulator (SERM) or a selective androgen receptor modulator (SARM). In other embodiments, the pharmaceutical composition further includes an estrogen, an androgen, or Capsaicin.
  • SERM selective estrogen receptor modulator
  • SARM selective androgen receptor modulator
  • the catechin and/or Epigallocatechin is applied to a vulva, a vestibule, a vaginal introitus, a clitoris, a vagina, a nipple, or a penis or other erogenous zone.
  • the invention also provides a condom for use in sexual activity, wherein said condom comprises a pharmaceutical composition applied thereon, wherein said pharmaceutical composition comprises a catechin.
  • said pharmaceutical composition comprises a catechin.
  • the catechin comprises a pharmaceutical composition applied thereon, wherein said pharmaceutical composition comprises a catechin.
  • the pharmaceutical composition comprises Epigallocatechin gallate (EGCg) at a concentration of between about 1% and 50% weight per weight of total composition (w/w) (e.g., about 25%).
  • the pharmaceutical composition further includes a cannabinoid.
  • the pharmaceutical composition further includes a vasodilator.
  • the pharmaceutical composition further includes a melatonin or Bremelanotide (PT-141).
  • a pharmaceutical composition for improving sexual function including libido comprising a catechin and a cannabinoid.
  • the catechin and a cannabinoid.
  • composition further includes a vasodilator.
  • pharmaceutical composition further includes a selective estrogen receptor modulator (SERM) and/or a selective androgen receptor modulator (SARM).
  • SERM selective estrogen receptor modulator
  • SARM selective androgen receptor modulator
  • the pharmaceutical composition further includes an estrogen or an androgen.
  • the pharmaceutical composition further comprises a melatonin or
  • the invention further provides methods and compositions for treating a cutaneous inflammation, comprising topically applying a pharmaceutical composition to an individual's affected area, wherein the pharmaceutical composition comprises a catechin such as Epigallocatechin.
  • the catechin includes Epigallocatechin gallate (EGCg) at a concentration of between about 1% and 50% weight per weight of total composition (w/w).
  • the catechin includes Epigallocatechin gallate (EGCg) at a concentration of between about 2.5% and 25% by weight.
  • the catechin includes Epigallocatechin gallate (EGCg) at a concentration of between about 3% and 15% by weight.
  • EGCg Epigallocatechin gallate
  • oral formulations are used having higher concentrations.
  • the EGCg concentration in oral formulations may be as high as about 90-100% EGCg.
  • Epigallocatechin gallate is at a concentration above about 50% by weight may be difficult to emulsify and may be in a liquid, a transdermal patch or other suitable form for application to a desired area.
  • the cutaneous inflammation is psoriasis, rosacea, an inflammatory alopecia, involves photo-aging, involves arthritis, is a dermatitis, is eczema, is an alopecia, is a bullous dermatosis, is a sclerotic dermatosis, is vitiligo, is Hashimoto's Thyroiditis, is seborrheic dermatitis, or causes dandruff.
  • the catechin may be delivered in a shampoo or body wash.
  • the shampoo or body wash may further comprise salicylic acid, selenium sulfide, or a suitable surfactant, wetting, adhesion and/or penetration agent.
  • the Epigallocatechin gallate may be combined with a corticosteroid for steroid sparing effect or synergistic efficacy.
  • the Epigallocatechin gallate may be combined with a calcineurin inhibitor (i.e. tacrolimus, pimecrolimus), a Vitamin D, (i.e. calcipotriene), a retinoid, (i.e. , tazarotene),
  • the topical EGCg is combined or supplemented with, a systemic Epigallocatechin gallate (or analog) dosage.
  • the topical catechin application includes Epigallocatechin gallate (EGCg) at a concentration of between about 1% and 50% weight per weight of total composition (w/w).
  • the systematic catechin includes Epigallocatechin gallate (EGCg) at a dose of about 200-400 mg.
  • the method for treating cutaneous inflammation further comprises applying ultraviolet (UV) or laser light to the affected area.
  • UV ultraviolet
  • the invention provides a method for treating a cutaneous inflammation in an individual's scalp, comprising topically applying a pharmaceutical composition to the scalp, wherein said pharmaceutical composition comprises a catechin.
  • the invention further comprises applying ultraviolet (UV) light to the affected area.
  • the Epigallocatechin gallate may be combined with a corticosteroid for steroid sparing effect or synergistic efficacy.
  • the Epigallocatechin gallate may be combined with a calcineurin inhibitor (i.e. tacrolimus, pimecrolimus), a Vitamin D, (i.e. calcipotriene), or a retinoid, (i.e. tazarotene).
  • the invention provides a medicament comprising a catechin for treating a male sexual function, a female sexual function, a female sexual disorder (FSD), cutaneous inflammation, a urinary tract indication, or improving libido.
  • the catechin is Epigallocatechin gallate (EGCg) at a concentration of between 1% and 50%, 2.5% and 25%, or 1% and 15% by weight.
  • the invention provides the use of a catechin for the treatment of a male sexual function, a female sexual function, a female sexual disorder (FSD), cutaneous inflammation, a urinary tract indication, or improving libido.
  • the invention provides the use of a catechin for the manufacture of a medicament for treating a male sexual function, a female sexual function, a female sexual disorder (FSD), cutaneous inflammation, a urinary tract indication, or improving libido.
  • the catechin in the uses described herein is Epigallocatechin gallate (EGCg) at a concentration of between 1% and 50%, 2.5% and 25%, or 1% and 15% by weight.
  • ECCg Epigallocatechin gallate
  • the pharmaceutical compositions of the invention further comprise an extract or essential oil from a source selected from the group consisting of ascorbic acid, vitamin E, omega 3, salt water, menthol, agar essential oil, agar extract, ajwain, aloe vera, amyris, angelica root, anise, balsam, basil, bay rum, bergamot, black pepper, buchu, butterbur, cajeput, cannabis flower, caraway, cardamom seed, carrot seed, cedarwood, Cedarleaf, chamomile, cinnamon, cistus, citrus vulgaris, citronella, clary sage, clove leaf, coriander, costmary, cranberry seed, cumin/black seed, cypress, davana, dill, eucalyptus, fennel seed, fenugreek, frankincense, galbanum, geranium, ginger, grapefruit, grape seed (e.g.Vitis vinifera)
  • FIG. 1 A is a generalized chemical structure (1) of a catechin in accordance with one embodiment of the present invention. Functional groups can be added at Rl and R2. “S” and “R” refer to the stereochemistry at the indicated position.
  • FIG. IB is a chemical domain structure (2) of one embodiment of Rl shown in Fig. lA.
  • FIG. 2 shows the chemical structures (3, 4, 5) of exemplary catechin molecules known in the art that may be used in accordance with embodiments of the present invention. It also shows the names of multiple catechin molecules for use with the invention.
  • the functional groups that may be inserted at positions Rl, R2, R3, R4, and R5 are indicated.
  • Chemical structure 6 shows a function group labeled "G" that may be attached at position Rl or R3 as indicated.
  • FIG. 3 is a flow chart illustrating an exemplary treatment regimen using the catechin preparations of the invention.
  • FIG. 4A is a statistical analysis of the increased arousal resulting from use of the catechin compositions of the invention.
  • FIG. 4B is a statistical analysis of the increased desire resulting from use of the catechin compositions of the invention.
  • FIG. 4C is a statistical analysis of the increased lubrication resulting from use of the catechin compositions of the invention.
  • FIG. 4D is a statistical analysis of the increased orgasm resulting from use of the catechin compositions of the invention.
  • FIG. 4E is a statistical analysis of the increased satisfaction resulting from use of the catechin compositions of the invention.
  • FIG. 4F is a statistical analysis of the decreased pain resulting from use of the catechin compositions of the invention.
  • FIG. 4G is a statistical analysis of the increased satisfactory sexual events resulting from use of the catechin compositions of the invention.
  • FIG. 4H is a statistical analysis of the decreased sexual distress resulting from use of the catechin compositions of the invention.
  • the invention provides, for the first time, a method of treating female sexual disorders with green tea catechins.
  • topically-applied green tea catechins were used to treat human papilloma-based (HPV) neoplasms.
  • HPV human papilloma-based
  • These topical formulations caused significant vulvovaginal discomfort or pain at the catechin concentrations and/or frequency used.
  • lower concentrations of catechins had the opposite effect, namely, soothing vaginal discomfort, pain, increasing vaginal lubrication, increasing sexual interest and desire, and increasing the frequency and intensity of orgasms.
  • the result was an amelioration of a variety of Female Sexual Disorders, FSDs.
  • Catechins found in green tea including Epigallocatechin gallate, epigallocatechiu and epicatechin are effective in treating FSD and improving overall sexual function of both men and women.
  • the FSDs includes sexual Interest /Arousal Disorder, Female Orgasmic Disorder, Genitopelvic Pain Penetration Disorder including its cutaneous inflammatory components, decreased lubrication, aberrant innervation of vulvodynia, and vulvovaginal atrophy.
  • Catechins were also found to increase female libido. (See U.S. Pat. No. 9,750,716, incorporated by reference herein in its entirety.)
  • effective primary catechin treatment preparations may start at about 1% and go up to about 15% catechin measured by weight of active ingredient per weight of total formulation (w/w).
  • the formulations are, for example, ointments, lotions, emulsions, water soluble solutions, and water-insoluble solutions. Further exemplary compositions include liposomes, microparticles, and nanoparticles.
  • Secondary treatment preparations for maintenance of therapeutic effect may be about 1-3% catechin by weight water soluble extract in various deployment preparations.
  • the catechin preparations may be directly applied to the external genitalia, vulvar skin, vestibule, clitoris and the vaginal introitus at regular intervals in a manner to cover intended treatment and/ or affected areas with a thin layer of the preparation such as an ointment, liquid, dermal patch, or other suitable topical deployment vector.
  • Other preparations may include spray on or other suitable topical deployment vectors.
  • the frequency of application may start at once a day and either be increased up to about twice a day or decreased to about twice per week for women with either very sensitive skin, or for women who have achieved the desired therapeutic effect and are using it for maintenance.
  • preparations of 5-10% by weight catechin in petrolatum base spread across the intended treatment and /or affected area are sufficient for treatment.
  • Preparations that have a concentration of more than about 10% by weight catechin may cause irritation in some subjects and "cancel out" or otherwise mask or diminish the therapeutic effects of the present invention if used during initial treatment.
  • a preparation of about 2.5%-7.5% by weight catechin is initially prescribed.
  • Preparations with lower concentration may be used for women with sensitive skin types (e.g., 2.5%).
  • the catechin percentage may be increased to about 7.5-10%.
  • daily use of about 0.25cc-1.5 cc (cubic centimeter) of 5% by weight catechin in petrolatum base spread across the intended treatment and/or affected area is sufficient for treatment.
  • the catechin preparations of the present invention are topical, well tolerated, have no significant side-effects, may be safely applied for a long period of time by the patients themselves and is notably effective in treating and alleviating the signs and symptoms of Female Sexual Disorders (SIAD, GPPD, and FOD). Furthermore, the present invention will likely be classified by the FDA as a phase 3 botanical drug according to the 2004 USA FDA CDER guidelines.
  • catechins The mechanism of action of catechins according to the present inventions is not fully understood.
  • green tea catechins demonstrate antioxidative properties. Antioxidants have anti-inflammatory effects. Catechins also possess immune-stimulating effects and antiviral and anticarcinogenic properties that cause inhibition of enzymes involved in the pathogenesis of human papilloma virus.
  • catechins have anticarcinogenic properties, estrogens, the current standard of care for VVA, can promote carcinogenesis and are contraindicated in breast and uterine cancer patients.
  • the exact mechanism of action of the present invention in not fully understood, it is known that sensations of pain interfere with sexual response.
  • one mechanism of action for female sexual arousal and orgasmic response in accordance with an aspect of the present invention is believed to be attributable, at least in part, to a
  • catechins neuromodulatory effect of catechins on portions of the nervous system innervating the vulva, vestibule, clitoris, vaginal introitus, labium, perineum and vagina whereby aberrant nociceptive sensory innervation is reduced so as not to interfere with the perception of pleasurable sexual sensations.
  • Another neuromodulatory mechanism of action of catechins is believed to be attributed to a positive stimulatory effect of catechins on sensory afferents located in these same areas of female anatomy.
  • vestibulodynia may involve reducing the pathological proliferation of nerves (both autonomic and peripheral) of affected vaginal mucous membranes found in all three conditions. This may be shown by histopathological analysis of relevant tissues.
  • catechin preparations of the present invention may act to selectively bind to certain estrogen receptors in the female genitalia providing localized relief, but with little or no systemic side effects. This is evidenced by the lack of proliferation of vaginal epithelium in response to GTO treatment. Rather, GTO acts locally and specifically as a topical phytoestrogen on the normalization of innervation to the genital skin. This is further evidenced by the lack of alteration in the vaginal maturation index. The effect of topical GTO is localized to the external genitalia, and, particularly the vaginal introitus and vestibule where it was necessary and was sufficient for treatment being applied only to those areas.
  • VVA and GPPD vulvodynia and dyspareunia
  • vulvodynia and dyspareunia can be caused by proliferation of autonomic and sensory nerve vulvar vaginal innervation density.
  • topical estrogens are more effective than systemic estrogens in the treatment of VVA pain by causing a reduction of abnormal vulvar vaginal innervation the same or similar mechanism may explain why topical GTO's (a phytoestrogen) application to vulvar mucosa is so effective in alleviating vulvar pain and dyspareunia.
  • GTO's a phytoestrogen
  • Catechins are used to treat genital warts and other HPV-related conditions because of their antiviral and immunostimulatory activity. Prior to the present invention, they were not used to treat female sexual disorders. This is likely because the highly-concentrated catechin preparations described in Chen et al. are preferably in the 12%-18% range by weight. At such concentrations, the irritation they cause, together with HPV pain, obfuscated the benefits of the inventions described herein. The known anti-viral effects of catechins were not known to have any effect on Female sexual Disorders as described in the present invention. The regenerative and restorative effects of the present invention are an apparent opposing effect when compared to the prior art highly -concentrated catechin preparations. Accordingly, the results and findings herein were unexpected.
  • the invention provides a topical formulation for the treatment of Female sexual Disorders including Genitopelvic Pain/Penetration Disorder (GPPD); Sexual Interest/ Arousal Disorder (SIAD); Female Orgasmic Disorder (FOD), vulvovaginal atrophy (VVA) and other vulvovaginal disorders, including but not limited to vestibulodynia.
  • GPPD Genitopelvic Pain/Penetration Disorder
  • SIAD Sexual Interest/ Arousal Disorder
  • FOD Female Orgasmic Disorder
  • VVA vulvovaginal atrophy
  • the content of catechin may be between about 2.5-7.5% by weight for initial treatment.
  • the prevalence of Sexual Interest/ Arousal Disorder SIAD may range from about 26.7% of premenopausal women to 52.4% of naturally postmenopausal women. Between 4 and 10% of women do not have orgasms, and up to 26% of women report some difficulty with having an orgasm with a condition known as Female Orgasmic Disorder (FOD).
  • FOD Female Orgasmic Disorder
  • Topical GTO can increase a woman's desire, arousal, lubrication, satisfaction and orgasm (intensity and/or frequency) and her frequency of satisfying sexual events, as well as decrease her genital pain and dissatisfaction about her level of sexual desire (Item #13 in Sexual Distress Revised).
  • Topical GTO demonstrates far greater efficacy without any serious side effects as compared to Flibanserin, marketed under the tradename, Addyi, or the "The Pink Pill”.
  • Flibanserin has marginal efficacy in only 18% of patients taking it for a minimum of 28 days.
  • Flibanserin is a systemic drug that must be taken indefinitely with potential serious side effects of syncope, hypotension and somnolence especially if combined with alcohol.
  • GTO has a rapid onset of action with all demonstrated clinical changes occurring within days to weeks after regular topical application of GTO. Clinical improvement continues over the month of use and concentration of the drug may be increased as tolerated to maximize efficacy.
  • Topical GTO has no known systemic side effects. Potential local side effects and the safety profile are well documented for GTO because of the FDA approved botanical drug Veregen, (15% GTO), indicated to be applied to each genital wart, three times a day, which has been safely used for more than 15 years. Local irritation is the most common local side effect, and it is more likely to occur the higher the concentration of GTO. Clinical evidence of direct anti-inflammatory effects of the lower concentration (5%) GTO on the genital mucosa are documented in the application presented herein.
  • the invention provides increasing female sexual interest find arousal and orgasmic response is through amelioration of genital pain
  • the benefits of the invention may be, at least in part, due to neuromodulatory effect of catechins on portions of the nervous system innervating the vulva, clitoris, vaginal introitus, labium, perineum and vagina.
  • One mechanism of action for female sexual arousal and orgasmic response in accordance with an aspect of the present invention is believed to be attributable, at least in part, to substantially direct neuromodulatory effects of green tea catechins on nerves innervating the female genitalia.
  • the innervation of the female genital tract is mediated through the somatic and the autonomic nervous systems.
  • Green tea polyphenols and catechins demonstrate both a positive stimulatory and negative inhibitory effects on portions of the autonomic and somatic nervous systems innervating the vulva, clitoris, vaginal introitus, labium, perineum and vagina.
  • Polyphenols and catechins, of green tea can interact with a range of
  • the normal female sexual response depends on the function of the peripheral autonomic nervous system and intact signaling pathways controlling the tone of genital vascular and nonvascular smooth muscle.
  • Autonomic adrenergic systems are active in women when they become sexually aroused and their activation facilitates female sexual arousal.
  • Adrenaline and noradrenaline metabolite vanillylmandelic acid, increases prior to intercourse and continues to be elevated over baseline up to 23 hours following sexual activity.
  • ephedrine an a- and ⁇ - adrenergic agonist, can significantly facilitate the initial stages of physiological sexual arousal in women.
  • EGCg action on stimulation can be attributed to its substantially direct effect on autonomic adrenergic receptors.
  • GTO 5%-7.5%
  • exogenous progesterone such as found in certain contraceptives, has been shown to be a factor in causing vulvodynia and vestibulodynia.
  • estrogen withdrawal is a known etiology of genital pain seen in VVA.
  • estrogen cream reduces the pain in both VVA and in some cases of vulvodynia/vestibulodynia but has no effect whatsoever on HPV. In fact, high estrogenic states such as pregnancy can increase the proliferation of HPV. Thus, GTO's beneficial therapeutic effect on female sexual disorders is not due to GTO's effect on HPV.
  • the primary focus for sensual response in the human female is the clitoris.
  • the first branch of the pudendal nerve, the dorsal nerve of the clitoris is a purely sensory nerve without any known motor functions.
  • the second branch of the pudendal nerve, the perineal nerve provides sensory branches to the perineum, labia majora, labia minora and distal third (the perceptually most erogenous portion) of the vagina and also has motor effectors.
  • the dorsal nerve (the first branch of the pudendal nerve) only carries somatosensory impulses from the clitoris. Its' only known function is that of serving as an erotic focus.
  • the clitoris in its entirety, has been shown to be the most erotically sensitive part of female genital anatomy. Maximum nerve density is known to be in and around the clitoris. The most intense sexual sensations in the human female come from clitoral stimulation. The anatomical site with the strongest orgasmic response requiring the least amount of stimulation necessary to obtain an orgasm involves the clitoral stimulation.
  • the distribution of enhanced sexual sensations correlate most closely with dorsal nerve or clitoral branch of the pudendal nerve, innervating the entire clitoris, the central external visible glans and body of the clitoris and the so called "internal" or hidden clitoral cms which bifurcate and extend alongside the right and left ischial pubic rami innervating the lateral walls of the vagina extending anteriorly to the vaginal introitus.
  • vestibulodynia is characteristically localized to the lateral edges of the vaginal introitus.
  • One effect of GTO is thought to be due to its therapeutic effect on reducing the pathogenic hyper innervation of this area of the vaginal vestibule also termed posterior fourchette in females afflicted with VVA and or vestibulodynia/vulvodynia (i.e., excessive innervation in the "wrong" area of the genitalia). This decreases nociceptive innervation and thus sensations of pain.
  • GTO's effect here may be due in part because of GTO's inherent property as a phytoestrogen in its selective effect on target tissues without systemic side effects of exogenous estrogen.
  • the first branch of the pudendal nerve is responsible for sensations in the clitoris and increased estrogen levels expand the size and sensitivity of the pudendal perineal innervation.
  • Topical application of Green Tea Ointment, GTO may be acting to increase the sexual sensitivity, arousal and orgasm by expanding the size and sensitivity of the pudendal nerve's innervation.
  • topical GTO may act to selectively bind to certain estrogen receptors in the female genitalia, specifically the vaginal introitus and vestibule. This reduces abnormal hyperproliferation of nociceptive nerves and provides localized pain relief with no systemic side effects or risks inherent in either topical or systemic estrogens.
  • GTO is a known phytoestrogen without the inherent side effects of exogenous estrogens. This is evidenced by the lack of proliferation of vaginal epithelium in response to topical GTO treatment and by the lack of alteration in the vaginal maturation index of woman using GTO. The safety of GTO use is further demonstrated by the lack of alteration in systemic estrogen levels, even with systemic, rather than topical use of Green Tea catechins. Even when given in large systemic doses to postmenopausal women, green tea and associated catechins have substantially no effects on any systemic estrogen levels. Thus, the use of GTO of the present invention is preferred in the treatment of female sexual disorders as compared to the current conventional use of exogenous estrogens in women, which had numerous well-known risks.
  • Autonomic innervation of the female genitalia is comprised of nerve fibers from both the sympathetic and parasympathetic nervous systems.
  • Sympathetic fibers are derived from the lower thoracic and upper lumbar spinal segments (T10-L2), and the parasympathetic nerve fibers are derived from S2-4.
  • T10-L2 lower thoracic and upper lumbar spinal segments
  • S2-4 parasympathetic nerve fibers
  • These autonomic fibers, both sympathetic and parasympathetic then coalesce in the pelvis and redistribute to the genital target organs (uterus, cervix, proximal 2/3 's of the vagina).
  • Autonomic sensory afferent fibers are believed to follow the same course starting at the genital target organs coalescing in the pelvis and returning to the spinal cord segments.
  • Female sexual responsivity is a result of sensory input through the peripheral nerves of the somatic and autonomic nervous systems, as well as through cranial nerves and psychogenic stimulation. How and where the afferent information is processed within the spinal cord and brain is not fully known.
  • Reflex lubrication where a tactile stimuli from the genitalia travels up the spinal cord to and reflexively connect to spinal efferent pathways travels back down the spinal cord to the nerves innervating the vaginal vasculature can occur if an injury is above T9 and not involving T10 to T12 where presumably the reflexive autonomic lubrication center in the spinal cord is located.
  • GTO and Orgasmic response The afferent sensory sensations are conducted upwards through the spinal cord where there is a pathway for a spinal reflexive orgasmic response as evidenced by the ability of some women with spinal cord injuries to experience orgasms. However, even with complete spinal cord injuries, some women can experience an orgasm, indicating other nerve pathways that bypass the spinal cord. Impulses ultimately reaching the cerebral cortex, in particular the temporal lobe and the posterior pituitary via the
  • hypothalamus effect perception of pleasure and among other efferent response, posterior pituitary release of oxytocin and prolactin during enhanced female orgasmic experience.
  • posterior pituitary release of oxytocin and prolactin during enhanced female orgasmic experience.
  • blood flow in the posterior pituitary during a human female's orgasm with its release of oxytocin and prolactin.
  • GTO normalizes the nervous innervation by increasing sensory nerve innervation of the dorsal branch of the pudendal nerve in and around the clitoris while GTO acts to decrease the abnormally high nociceptive nerve density around the vaginal vestibule.
  • GTO increases positive sexual sensory sensations and resultant orgasmic responses but decreases genital pain in and around the vaginal introitus and vestibule as seen in VVA and vulvodynia and vestibulodynia.
  • GTO increases neural innervation of the dorsal nerve of the clitoris and thereby stimulating or augmenting sexual sensations and arousal. It also decreases the aberrant hyperinneration of both autonomic and somatic sensory fibers in and around the vaginal introitus, specifically posterior fourchette. This decreases genital pain.
  • Sexual response includes desire, arousal, lubrication and orgasm. It is known that, if perceived as unpleasant or toxic, sensations of pain can interfere with a woman's sexual response.
  • Genital pelvic pain disorder in VVA and vulvodynia, vestibulodynia is characterized by genital hypersensitivity and sensory hyperinnervation with unmyelinated sensory nociceptor neurons.
  • direct effects of estrogen withdrawal on vaginal cells is implicated in VVA, (e.g., thinning of the vaginal epithelium) estrogen withdrawal also causes both autonomic and somatic sensory nerves to proliferate, suggesting that indirect effects mediated by changes in vulvar vaginal innervation may be a major contributor to pain associated with VVA.
  • estradiol is a well-documented and effective therapeutic for pain associated with VVA.
  • Exogenous progesterone use in contraceptives, in premenopausal women, may be one etiology of vulvar hyperinnervation in vestibulodynia and or vulvodynia.
  • Progesterone can induce both autonomic and somatic sensory nerves to proliferate.
  • Oral progesterones can increase the risk of developing vestibulodynia by four to ninefold.
  • Topical estradiol has been shown to reduce the sensory hyperinnervation and vulvar pain associated with vestibulodynia and vulvodynia.
  • the mechanism of action of the catechin preparations of the present invention on VVA and vulvodynia, vestibulodynia may involve reducing the pathological proliferation of sensory nerves, hyperinnervation of affected vulvovaginal mucous membranes found in the conditions associated with female Genital Pelvic Pain Disorder (VVA, dyspareunia, vulvodynia, vestibulodynia).
  • VVA Genital Pelvic Pain Disorder
  • Immuno- histochemistry analysis of vulvar skin of women with VVA and vulvodynia, vestibulodynia have shown increased density of nociceptor nerve endings and an increased number of intraepithelial free nerve endings, lowered tactile and pain thresholds, nociceptor sensitization and overall peripheral nerve hyperplasia.
  • GTO This sensory nociceptor axon proliferation may contribute to symptoms of pain, burning and itching associated with VVA and some forms of vulvodynia and vestibulodynia.
  • GTO in accordance with aspects of the present invention is thought to be acting as a topical phytoestrogen on the normalization of innervation to the genital skin.
  • the effect of topical GTO is localized to the external genitalia, and, particularly the vaginal introitus and vestibule where it is both necessary and sufficient for alleviation of pain associated with VVA, vulvodynia and vestibulodynia.
  • VVA and GPPD vulvodynia, vestibulodynia and dyspareunia
  • vulvodynia, vestibulodynia and dyspareunia can be caused by proliferation of autonomic and sensory nerve vulvar vaginal innervation density.
  • topical estrogens are more effective than systemic estrogens in alleviating the pain in VVA and vulvodynia/vestibulodynia by reducing and therefore normalizing of abnormal vulvar vaginal hyper innervation.
  • vulvodynia and vestibulodynia Reduction or normalization of nociceptive (or pain afferent) pathways that are localized in the area of the vulva, vestibule, vaginal introitus, and posterior fourchette, in VVA, vulvodynia and vestibulodynia is the most likely mechanism for the therapeutic efficacy of the application of topical estrogens. It is hypothesized that the same or a similar mechanism is the reason why applying a topical GTO (a phytoestrogen) to vulvar mucosa and vaginal introitus is so effective in alleviating vulvar pain and dyspareunia in both VVA and vulvodynia/vestibulodynia. In view of these observations, the GTO, catechin preparations of the present invention are believed to be acting locally without any known systemic effects whatsoever (as a phytoestrogen).
  • Antiandrogens exert estrogenic effects on target tissue by blocking the effect of androgens at the cellular level.
  • Green tea catechins estrogenic-like effects may be attributed to epigallocatechin gallate by inhibiting 5 -alpha reductase. This reduces the conversion of testosterone to the more potent androgen dihydrotestosterone.
  • Another mode of action of the present invention is on mucous membranes, in connection with its antioxidant effect which might help reduce inflammation and irritation that can be a factor in VVA, vulvodynia, and vestibulodynia.
  • Lubrication is controlled by both somatic and autonomic neural impulses that travel through the spinal cord. Autonomic fibers send efferent impulses back to genitalia smooth muscle with effects on both vasodilation and therefore lubrication. There is absence of lubrication in women either reflex or psychogenic when the spinal cord is severed between T10 and T12. Psychogenic lubrication, or lubrication in response to non-tactile stimuli is possible if the spinal cord is severed below T12, presumably from neural pathways traveling from cerebral cortex down to spinal centers responsible for autonomic efferent neural pathways innervating smooth muscle and nerves of the vagina.
  • Reflex lubrication is where tactile stimuli from the genitalia travels up the spinal cord to and reflexively connect to spinal efferent pathways travels back down the spinal cord to the nerves innervating the vaginal vasculature can occur if an injury is above T9 and not involving T10 to T12 where presumably the reflexive autonomic lubrication center in the spinal cord is located.
  • vaginal dysfunction during menopause may be attributable to changes in innervation. Increased sympathetic innervation may augment vasoconstriction and promote vaginal dryness. GTO acting as a phytoestrogen, decreasing aberrant hyperinnervation may be one mechanism whereby GTO increases vaginal lubrication.
  • GTO catechins on vaginal lubrication Another mechanism of the action of GTO catechins on vaginal lubrication would be its direct effect on neurotransmitters on vascular smooth muscle.
  • the normal female sexual response depends on the function of the peripheral autonomic nervous system and intact signaling pathways controlling the tone of genital vascular and nonvascular smooth muscle.
  • the first measurable sign of sexual arousal is an increase in vaginal blood flow. This creates the engorged condition, that saturates the fluid resabsorptive capacity of the vaginal epithelium. This results in increase in vaginal fluid, i.e. lubrication which enables less friction during coitus.
  • Genital motor responses to sexual stimulation including vaginal lubrication is mediated by autonomic vasoactive neurotransmitters including, vasoactive intestinal peptide (VIP) and Nitric oxide synthetases.
  • VIP vasoactive intestinal peptide
  • Nitric oxide synthetases include, vasoactive intestinal peptide (VIP) and Nitric oxide synthetases.
  • vaginal lubrication appears to be mediated by several vasoactive neurotransmitters especially Vasoactive Intestinal Peptide (VIP).
  • VIP Vasoactive Intestinal Peptide
  • VIP injection into or topical application to the vaginal wall increases vaginal blood flow and induces vaginal fluid production.
  • Nitric Oxide cyclic guanosine monophosphate pathway is involved in the physiological mechanism of female genital arousal.
  • Endothelial Nitric Oxide Synthases (NOS) and VIP vasoactive intestinal peptides are co- localized in the human vagina.
  • Nitric Oxide synthases are located on the vaginal vessels in close proximity to vasoactive intestinal peptides (VIP) on the vaginal nerve fibers. They are both directly involved in effecting vaginal blood flow and thus lubrication. Disturbances in these pathways are thought to contribute to the pathophysiology of sexual dysfunction.
  • Nitric oxide relaxes genital vascular and nonvascular smooth muscle which plays a pivotal role in mediating the normal sexual response to visual and/or tactile erotic stimulation.
  • Insufficient bioavailability of Nitric Oxide (NO) and/or Vasoactive Intestinal Peptide (VIP) decreases vasodilation which decreases vaginal lubrication.
  • Catechin isolated from green tea has been shown to substantially directly affect the level of NO in endothelial cells. It is by this effect of green tea catechin on the level of Nitric Oxide in endothelial cells that the application of GTO in accordance with aspects of the present invention increase lubrication is efficacious.
  • ECCg Epigallocatechin gallate
  • Activation of epithelial beta-adrenergic receptor pathways facilitates vaginal lubrication during sexual arousal.
  • Green tea's action on facilitating vaginal lubrication may be attributed to its direct effect on beta adrenergic receptor pathways.
  • Activation of epithelial beta adrenergic receptors facilitates vaginal lubrication during sexual arousal by stimulating vaginal epithelial Cl(-) secretion in a cAMP-dependent pathway.
  • Adrenergic alpha-receptors are an important regulator of genital physiological responses involved in mediating vascular and nonvascular smooth muscle contractility.
  • concentration of EGCg effects which of the adrenergic receptors (alpha or beta) will be activated.
  • EGCG can activate the 2Areceptor.
  • Topical application of GTO directly to genital mucosa would enable higher concentrations of EGCg and facilitate enhancement of vaginal lubrication.
  • tea catechin is used in accordance with the present inventions
  • FIG. 1A wherein Ri may represent H or OH and R2 may represent H or the chemical structure shown in FIG. IB.
  • green tea (Cameilia sinensis) catechins are used.
  • epicatechin, epicatechin gallate, and gallocatechin (including derivatives thereof) are used.
  • combinations of the catechins disclosed herein are used.
  • epigallocatechin gallate (EGCg) is used.
  • An exemplary starting source of tea catechins is Polyphenon 100® (Mitsui Norin Co., Tokyo, Japan). It comprises gallocatechin 1.44%, epicatechin 5.81%, epigallocatechin 17.57%, epicatechin gallate 12.51 %, and epigallocatechin gallate 53.90%.
  • Another exemplary starting source is Polyphenon E® (Mitsui Norin Co., Tokyo, Japan). It comprises epicatechin 10.8%, epigallocatechin 9.2%, epicatechin gallate 6.5%, epigallocatechin gallate 54.8%, allocatechin gallate 4.0%). These values are the relative percentages of catechins but are not the final concentration in the ointment.
  • tea catechins Another exemplary starting source of tea catechins is Theaphenon 85-95% green tea catechins (Tea Solutions, Hara Offices, Inc.) It comprises epicatechin 1.63%, epigallocatechin 19.58%, epicatechin gallate 4.67%, and epigallocatechin gallate 64.04%.
  • Another exemplary source of catechin used in accordance with the principles of the present invention includes Veregen® (sinecatechins) Ointment, 15% ( Medigene AG, Martinsried, Germany). It is a botanical drug product for topical use to treat viral warts (general chemical formula shown in FIG. 2).
  • the water-soluble fraction from the green tea leaves comes from plants that may be cultivated to have a great degree of consistency from the extract of the leaves.
  • the FDA may require approval of the source of the plants prior to equivalent drug approval.
  • the invention provides a method for treating female sexual dysfunctions using catechin percentage by weight that is about 1%-10%.
  • the catechin concentration is between about 2.5%-7.5% by weight.
  • the catechin concentration is 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% by weight.
  • the catechin concentration is between 0.1 and 0.9% by weight.
  • tea catechins including green tea catechins, or any other suitable catechin-based or catechin-derived compound is used in accordance with the principles of the present invention at the above-referenced concentrations.
  • a third catechin preparation formulated by the inventor, may be used if desired.
  • This third preparation was used in connection with many of the patient examples herein which was a 5% green tea ointment preparation, in which 5 grams of a 100-gram tube was comprised of 90% green tea catechin polyphenols. It was compounded and formulated by Custom Scripts Pharmacy of Wesley Hills, Florida.
  • the specific active ingredient(s) in this drug substance is not identified and the entire drug substance is determined to be active.
  • Oil of Peppermint NF from 0.1 to 1%, other similar flavor, olfactory or warming compounds may be added to the formulation of the present invention for added stimulatory effect and improved esthetics including improved taste and smell of the catechin product.
  • Veregen® The main active ingredient in Veregen® is sinecatechin polyphenols, which is a partially purified fraction of the water extract of green tea leaves from Camellia sinensis and is a mixture of catechins and other green tea components.
  • Inactive components of Veregen® ointment include: isopropyl myristate, white petrolatum, cera alba (white wax), propylene glycolpalmitostearate, and oleyl alcohol.
  • Catechins constitute 85 to 95% (by weight) of the total drug substance which includes more than 55% of Epigallocatechin gallate (EGCg), and other catechin derivatives such as Epicatechin (EC), Epigallocatechin (EGC), Epicatechin gallate (ECg), and some additional minor catechin derivatives i.e., Gallocatechin gallate (GCg), Gallocatechin (GC), Catechin gallate (Cg), and Catechin (C) in varying amounts.
  • ECGg Epigallocatechin gallate
  • ECg Epicatechin gallate
  • GCg Gallocatechin gallate
  • GC Gallocatechin
  • Cg Catechin gallate
  • Catechin (C) Catechin in varying amounts.
  • it also contains gallic acid, caffeine, and theobromine which together constitute about 2.5% of the drug substance.
  • the remaining amount of the drug substance contains undefined botanical constituents derived from green tea leaves.
  • Epigallocatechin gallate may constitute from about 45-%-95% of the active catechin ingredient.
  • the ointment may also include one or more of the following compounds: isopropyl myristate, white petrolatum, cera alba (white wax), propylene glycol palmitostearate, and oleyl alcohol analogous to Veregen®.
  • the active catechins may be formulated with different suitable compounds: isopropyl myristate, white petrolatum, cera alba (white wax), propylene glycol palmitostearate, and oleyl alcohol analogous to Veregen®.
  • the active catechins may be formulated with different suitable
  • 5% catechin ointment as described herein is applied as a thin layer substantially covering the affected area of the external genital organs.
  • the ointment is applied once.
  • the ointment is applied several times daily, daily, weekly, monthly, or on an as-needed basis.
  • the ointment is applied for a period of about 1 week, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.
  • the compounds of the present invention may generally be applied to the area around and into the vaginal introitus, clitoris and/or labia as desired by the user for maximum effect.
  • suppositories or douches as is known in the art may be used as further described below.
  • Patient studies indicate once daily use in many instances is sufficient for clinical efficacy. However, some cases may require multiple daily applications.
  • the catechin ointment may be applied every other day, twice weekly or at another interval to achieve the desired clinical results without adverse reaction (e.g. , skin irritation).
  • 1.0 to 1.5 cm of ointment may be applied to the affected area about one to three times daily. It may be used up to about 4 months or indefinitely without interruption. Mild local skin reactions are not uncommon and initial adverse reactions tend to decrease over the course of treatment.
  • a patient may be clinically diagnosed with a Female Sexual Disorder. Where medically indicated, appropriate confirmatory testing may be performed (e.g. , vaginal pH test, epithelium maturation index, cultures for bacteria and or yeast, and if medically indicated, biopsy).
  • a health care provider may prescribe a catechin-based treatment of the type described herein.
  • Treatment instructions may include the application of the catechin-based ointment once a day for a period of about one month.
  • the catechin ointment may be applied at bedtime or after bathing in the morning.
  • bathing soon after application of the catechin ointment of the present invention is not optimal as it may be washed off before ample absorption.
  • Certain embodiments, however, may be formulated for fast acting absorption and washing may occur at a reasonable time thereafter. It will be understood the treatment duration described above is merely exemplary, and others may be used as appropriate.
  • the treatment duration may vary based on patient specifics such as degree of severity of condition, which condition(s) are present, age, physiological specifics, etc.
  • the concentration of the medication may also vary based on the same or similar considerations including skin sensitivity and severity of the underlying condition (e.g. , about 2%, 5%, 7.5%, or 10%).
  • the patient may return to the healthcare provider to observe the results of the treatment (step 306).
  • further treatment may be prescribed or additional diagnosis performed (step 308). This may include altering diagnosis and changing treatment, continuing treatment, or if the result is an acceptable outcome, tapering or possibly terminating treatment. If the patient is without any substantial adverse effects and is benefiting from the treatment, it may be continued substantially indefinitely.
  • the health care provider may continue for another period of time and observe results again, in an iterative fashion.
  • maintenance products may include feminine hygiene soaps, washes, lubricants or other products that contain a lower amount of catechins suitable for long term use and continued clinical efficacy. This may include catechins in the amount of about 1-5% by weight catechin. These products may be used daily or periodically to maintain the desired results.
  • one treatment protocol in accordance with the present invention may include, after diagnosis, primary treatment with a 5% by weight catechin-based ointment for 2-8 weeks, followed by continued secondary treatment, if appropriate, with a feminine wash, soap or lubricant of about 1-3% by weight catechin for several times per week for an extended period or as needed for maintenance (which, in some cases may be long term).
  • a diagnosis and treatment plan may, in some instances, be prescribed at the initial patient visit and diagnosis, with secondary treatment following the resolution of primary symptoms.
  • steps 306 and 308 above may be omitted or may occur after secondary treatment step 310 has begun.
  • an increase in the concentration or frequency of treatment may be instituted.
  • maintenance treatment may require an increase in the percentage of catechin depending upon a subject's individual response and/or tolerance. For example, an increase from about 5% to about 10% catechin by weight may be indicated.
  • Embodiments of the invention are also contemplated for over the counter (“OTC") applications.
  • OTC over the counter
  • catechin preparations of the present invention may be formulated with active ingredients that allow it to be sold OTC.
  • the manufacturer may describe the symptoms and/or desired results for certain afflictions and instruct a user to apply an effective amount of the preparation for a certain period of time. If the symptoms resolve, the manufacturer may instruct the user to continue, discontinue or taper treatment (e.g., maintenance or secondary treatment described herein), and if not, seek further assistance from a medical professional.
  • discontinue or taper treatment e.g., maintenance or secondary treatment described herein
  • the formulations of the invention might comprise additional active ingredients or flavor enhancers.
  • additional active ingredients or flavor enhancers include compounds, extracts or essential oils from one or more of the following sources: ascorbic acid, vitamin E, omega 3, salt water, menthol, agar essential oil, agar extract, ajwain, aloe vera, amyris, angelica root, anise, balsam, basil, bay rum, bergamot, black pepper, buchu, butterbur, cajeput, cannabis flower, caraway, cardamom seed, carrot seed, cedarwood, Cedarleaf, chamomile, cinnamon, cistus, citrus vulgaris, citronella, clary sage, clove leaf, coriander, costmary, cranberry seed, cumin/black seed, cypress, davana, dill, eucalyptus, fennel seed, fenugreek, frankincense, galbanum, geranium, ginger, grape
  • the concentration of lemon oil may be about 0.10% to 10% v/v lemon oil.
  • the concentration may be about 0.10%, 0.20%, 0.30% 0.40%, 0.5%, 0.60%, 0.70%, 0.80%, 0.90%, or 1.0% v/v.
  • the lemon oil concentration is 0.24% or 0.48% v/v.
  • the concentration may be between about 1.0% to 2.0%, 2.0% to 3.0%, 3.0% to 4.0%, 4.0% to 5.0%, 5.0% to 6.0%, 6.0% to 7.0%, 7.0% to 8.0%, 8.0% to 9.0%, or 9.0% to 10.0% v/v, or increments there between.
  • the formulations of the invention comprise an emulsifier, surfactant, wetting or adhesion agent.
  • the concentration of the emulsifier is about 1.0% to 10% v/v.
  • the concentration may be about 1.0% to 2.0%, 2.0% to 3.0%, 3.0% to 4.0%, 4.0% to 5.0%, 5.0% to 6.0%, 6.0% to 7.0%, 7.0% to 8.0%, 8.0% to 9.0%, or 9.0% to 10.0% v/v, or increments therebetween.
  • the concentration is about 3.0%.
  • Emulsifiers for pharmaceutical, nutraceutical, and other human consumption are well- known in the art.
  • Exemplary emulsifiers for use in the formulations of the invention include food emulsifiers such as egg yolk (lecitihin), mustard (mucilage), soy lecithin, pickering stabilization, sodium stearoyl lactylate, and DATEM (Diacetyl Tartaric Acid Ester of Monoglyceride) and anise.
  • Other emulsifiers include emulsifying wax, cetearyl alcohol, polysorbate 20, and ceteareth 20.
  • the formulations of the invention comprise alcohol as surfactant or penetration enhancer.
  • the concentration of alcohol is about 1.0% to 10% v/v.
  • the concentration of alcohol may be about 1.0% to 2.0%, 2.0% to 3.0%, 3.0% to 4.0%, 4.0% to 5.0%, 5.0% to 6.0%, 6.0% to 7.0%, 7.0% to 8.0%, 8.0% to 9.0%, or 9.0% to 10.0% v/v, or increments therebetween.
  • the concentration is about 3.0%.
  • Exemplary alcohols include ethanol, isopropyl alcohol, and benzyl alcohol.
  • the present invention may include certain other active ingredients to treat the afflictions described herein.
  • low doses of hormones, SERMs, and/or vitamins may be included, if desired for an improved treatment response.
  • the 5% catechin preparation described herein may include about 400-800 IU of Vitamin E, about 1% DHEA, about 0.001.0 - 1 % estrogen and/or if FDA approved about 0.001 - 0.01 % testosterone.
  • a specific example may include about 5% catechin by weight, about 0.01 % or less estradiol, estriol, estrone and 400-800 IU of vitamin E.
  • Another embodiment may include about 5% catechin, combined with lower doses of oral medications such as estrogens or SERMS, Ospemifene. Combinations of any of the above may combined together in one topical formulation.
  • the catechin ointment can be used as an "estrogen sparing" agent lessening the chance of adverse effects from estrogen therapeutics.
  • the present invention may also be suitable for internal use, for example, through ointment or other application vectors such as suppository or douche. Such uses may require additional FDA approval.
  • the content of tea catechin may be around 100-500 mg/capsule, in some embodiments about 200-300 mg/capsule, and in one specific embodiment a 250 mg/capsule.
  • tea catechin suppositories have the added benefit of reducing uterine fibroids and cervical dysplasia.
  • Another embodiment of the present invention may include a douche having a solution including a catechin preparation at the concentrations of the invention as disclosed herein.
  • the douche solution may include a suitable film-forming or absorption agent so that the active ingredients remain attached to the affected internal areas for a period of time after use.
  • the douche solution comprises time-release formulations such that the solution need only be introduced periodically (i.e. , every several days or weekly).
  • a typical usage example for the suppository in the case where for example the affected area is the cervix or the vagina is to insert a capsule containing 100-500 mg tea catechin, from once to several times every day for a period of 1-2 months.
  • a douche may be used every other day, or twice a week, or periodically as indicated for 1-2 months depending on whether a film-forming or absorption agent used.
  • a lubricant such as K-Y jelly ® (Reckitt Benckiser, Parsippany, NJ), or other personal lubricant as known in the art, may include about 1-10% by weight catechins as well as certain soap or wash formulations. These may be used, during, after (or before) the treatment regimens described herein to increase or maintain their benefits. In some embodiments, they also may be sold as OTC products that may be used without consulting a health care provider. It will be further understood that time release formula may be achieved using any suitable method including the use of esters to achieve the desired application of active ingredient.
  • time release formulations comprise formate, acetate, propionate, phenylpropionate, butyrate, valerate, hexanoate, caproate, isocaproate, heptanoate, enanthate, octanoate, cypionate, nonanoate, decanoate, or undecanoate.
  • shorter esters such as formate, acetate, and propionate are used for ointments, feminine wash and lubricants which are applied frequently.
  • longer esters such as enanthate and cypionate are used for products applied less frequently such as suppositories, tampons, maxipads, sanitary napkins, panty liners and douches.
  • dermal patches may be used if desired.
  • the invention provides a method for treating a female sexual disorder comprising administering an effective amount of a pharmaceutical comprising between 1% and 10% catechin to an individual that suffers from the disorder.
  • an “effective amount” refers to an amount of therapeutic compound that is effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.
  • a “therapeutically effective amount” of a therapeutic compound may vary according to factors such as the disease state, age, sex, and weight of the individual. A therapeutically effective amount may be measured, for example, by improved survival rate, more rapid recovery, or amelioration, improvement or elimination of symptoms, or other acceptable biomarkers or surrogate markers. A therapeutically effective amount is also one in which any toxic or detrimental effects of the therapeutic compound are outweighed by the therapeutically beneficial effects.
  • a “prophylactically effective amount” refers to an amount of therapeutic compound that is effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, but not necessarily, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.
  • an “individual,” “subject” or “patient” is a vertebrate.
  • the vertebrate is a mammal.
  • Mammals include, but are not limited to, primates (including human and non-human primates) and rodents (e.g., mice, hamsters, guinea pigs, and rats).
  • rodents e.g., mice, hamsters, guinea pigs, and rats.
  • a mammal is a human.
  • a “control subject” refers to a healthy subject who has not been diagnosed as having a disease, dysfunction, or condition that has been identified in an individual, subject, or patient. A control subject does not suffer from any sign or symptom associated with the disease, dysfunction, or condition.
  • a “medicament” is an active drug that has been manufactured for the treatment of a disease, disorder, or condition.
  • Patient response or “response” can be assessed using any endpoint indicating a benefit to the patient, including, without limitation, (1) inhibition, to some extent, of disease progression, including stabilization, slowing down and complete arrest; (2) reduction in the number of disease episodes and/or symptoms; (3) inhibition (i.e., reduction, slowing down or complete stopping) of a disease cell infiltration into adjacent peripheral organs and/or tissues; (4) inhibition (i.e.
  • a "pharmaceutically acceptable carrier” or “therapeutic effective carrier” is aqueous or nonaqueous (solid), for example alcoholic or oleaginous, or a mixture thereof, and can contain a film-forming agent, adhesion agent, surfactant, emollient, lubricant, stabilizer, dye, perfume, preservative, acid or base for adjustment of pH, a solvent, emulsifier, gelling agent, moisturizer, stabilizer, wetting agent, time release agent, humectant, or other component commonly included in a particular form of pharmaceutical composition.
  • Pharmaceutically acceptable carriers include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, and oils such as olive oil or injectable organic esters.
  • a pharmaceutically acceptable carrier can contain physiologically acceptable compounds that act, for example, to stabilize or to increase the absorption of specific inhibitor, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
  • treatment refers to clinical intervention in an attempt to alter the natural course of the individual or cell being treated and can be performed before or during the course of clinical pathology. Desirable effects of treatment include preventing the occurrence or recurrence of a disease or a condition or symptom thereof, alleviating a condition or symptom of the disease, diminishing any direct or indirect pathological consequences of the disease, decreasing the rate of disease progression, ameliorating or palliating the disease state, and achieving remission or improved prognosis.
  • methods and compositions of the invention are useful in attempts to delay development of a disease or disorder.
  • the invention provides effective routes for catechin administration.
  • effective routes of drug administration include transdermal, topical, and vaginal, modes.
  • Exemplary drug formulations of the invention include aqueous solutions, organic solutions, powder formulations, solid formulations and mixed phase formulations.
  • the pharmaceutical compositions may contain any conventional, non-toxic, pharmaceutically- acceptable carriers, adjuvants or vehicles.
  • compositions of this invention comprise any of the compounds of the present invention, and pharmaceutically acceptable salts thereof, with any pharmaceutically acceptable carrier, adjuvant or vehicle.
  • Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium
  • carboxymethylcellulose polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • salts retain the desired biological activity of the therapeutic composition without toxic side effects.
  • examples of such salts are (a) acid addition salts formed with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like/ and salts formed with organic acids such as, for example, acetic acid, trifluoroacetic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tanic acid, pamoic acid, alginic acid, poly glutamic acid, naphthalenesulfonic acid, naphthalene disulfonic acid, polygalacturonic acid and the like; (b) base addition salts or complexes formed with polyvalent metal cations such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, and the like; or with an organic acids
  • compositions may conveniently be administered in unit dosage form and may be prepared by any of the methods well-known in the pharmaceutical art, for example, as described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Co., Easton, PA (1985), incorporated herein by reference in its entirety.
  • delivery across the barrier of the skin would be enhanced using electrodes (e.g. iontophoresis), electroporation, or the application of short, high-voltage electrical pulses to the skin, radiofrequencies, ultrasound (e.g. sonophoresis), microprojections (e.g. microneedles), jet injectors, thermal ablation, magnetophoresis, lasers, velocity, or photomechanical waves.
  • the drug can be included in single-layer drug-in-adhesive, multi-layer drug-in-adhesive, reservoir, matrix, or vapor style patches, or could utilize patchless technology. Delivery across the barrier of the skin could also be enhanced using encapsulation, a skin lipid fluidizer, or a hollow or solid
  • microstructured transdermal system such as that manufactured by 3M
  • jet injectors additives to the formulation to aid in the passage of therapeutic compounds through the skin include prodrugs, chemicals, surfactants, cell penetrating peptides, permeation enhancers, encapsulation technologies, enzymes, enzyme inhibitors, gels, nanoparticles and peptide or protein chaperones.
  • controlled-release formulation contains the therapeutic compound or its salt dispersed or encapsulated in a slowly degrading, non-toxic, non-antigenic polymer such as copoly(lactic/gly colic) acid, as described in the pioneering work of Kent et al., US Patent No. 4,675,189, incorporated by reference herein.
  • the compounds, or their salts may also be formulated in cholesterol or other lipid matrix pellets, or silastomer matrix implants.
  • One embodiment of the present invention may be used as a topical ointment for the treatment of Female sexual Disorders including Genitopelvic Pain Penetration Disorder (GPPD); Sexual Interest/ Arousal Disorder (SIAD); Female Orgasmic Disorder (FOD), Vulvovaginal Atrophy VVA and other vulvovaginal disorders including but not limited to vestibulodynia.
  • GPPD Genitopelvic Pain Penetration Disorder
  • SIAD Sexual Interest/ Arousal Disorder
  • FOD Female Orgasmic Disorder
  • VVA Vulvovaginal Atrophy VVA and other vulvovaginal disorders including but not limited to vestibulodynia.
  • the content of catechin may be between about 2.5%-7.5% weight.
  • Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application.
  • the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, poly oxy ethylene poly oxy propylene compound, emulsifying wax and water.
  • the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation.
  • Topical transdermal patches are also included in this invention. Dosage levels of between about 0.01 and about 100 mg/kg body weight per day, preferably 0.5 and about 50 mg/kg body weight per day of the active ingredient compound are useful in the prevention and treatment of disease. Such administration can be used as a chronic or acute therapy.
  • the amount of drug that may be combined with the carrier to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a typical preparation will contain from about 5% to about 95% active compound (w/w). Preferably, such preparations contain from about 20% to about 80% active compound.
  • a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary.
  • the dosage or frequency of administration, or both may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease.
  • Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • lower or higher doses than those recited above may be required.
  • Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, gender, diet, time of administration, rate of excretion, drug combination, the severity and course of an infection, the patient's disposition to the infection and the judgment of the treating physician.
  • Tests were performed on these patients using a Catechin Green Tea Ointment, 15% by weight catechin (Custom Scripts Pharmacy Wesley Hills, Florida) applied to the affected external genital organs continuously once a day for 2-10 weeks and intermittently for up to one year. During that period of monthly treatment examinations of the affected areas were conducted.
  • Green Tea Ointment 5% (Custom Scripts Pharmacy) intermittently, applying approximately 0.5cm daily for a week at a time when she notes reoccurrence of symptomology. She has been followed for over a year.
  • Patient 2 was unable to have intercourse and suffered from chronic genital pain.
  • SG is a 68 y/o female who was followed by her gynecologist for the past 11 years prior to using 15% GTO. She had a normal menarche, 3 children delivered vaginally, and essentially no significant issues during her reproductive years. She developed menopausal symptoms in her early 40s and was started on low dose PREMPRO ® and continued on that regimen through 2004. At that point she became increasingly nervous about taking hormones and the decision was made to attempt changing to a bio-identical regimen of hormones.
  • VAGIFEM was used for vaginal issues. She maintained this regimen and felt fairly good, despite no libido, until 2011 at which time she developed a benign breast lump and decided to stop all hormonal therapy. Her vagina became increasingly dry, sensitive and ultimately painful. Intercourse was essentially nonexistent due to her pain (dyspareunia), and she presented late in 2014 wanting to address this issue. Examination at that time revealed an atrophic vulva and vagina, mucosa was very dry and flat with some scarring at the perineum and skin changes consistent with Lichens Sclerosis. Green Tea Ointment, 15% catechin (Custom Scripts Pharmacy) was prescribed and lubrication issues reviewed in detail. PMH: Sulfa allergy
  • the PGI-I is an instrument designed to measure a patient's interpretation of symptom changes following intervention.
  • the PBE essentially asks the question: "Overall, do you believe that you have experienced a meaningful benefit from the study medication?" Additionally, the participants were asked to keep a Sexual Activity Log (SAL). The following questions were answered once a week: 1. Indicate your most intense level of sexual desire in the past 7 days (one week)
  • test subjects were not recruited for, nor did they complain of, low libido symptoms. Test subjects were not told the present invention may have an effect on sexual arousal, desire or orgasm. It was understood, however, by the subjects, that the catechin preparations of the present invention may (or may not) help relieve symptoms of
  • Genitopelvic Pain/Penetration Disorder Patients were a mix of premenopausal and postmenopausal women. The age range was from 38 to 68 years old.
  • GTO Green Tea Ointment
  • Subjects read, discussed and then signed a consent form for enrollment into the study, a consent form for use of their clinical photographs, a non-disclosure agreement, and an instruction sheet for use of GTO. They were asked to complete several standard
  • Vaginal maturation index is an indication of estrogenic effect on the vaginal epithelium. The test was done, in postmenopausal subjects, to demonstrate that the mechanism of action of GTO is independent or void of any estrogenic effects in the vagina and therefore safe for women who for a variety of medical or personal choice issues cannot or will not use estrogenic compounds or other hormones to treat their sexual disorder. A brushing of the lateral vaginal wall was, spread on a glass slide, fixative applied immediately and the sample allowed to dry then sent for evaluation of the vaginal maturation index to either Quest Diagnostics or LabCorp.
  • the Female Sexual Function Index is a known standard questionnaire, designed and validated for assessment of female sexual function and quality of life in clinical trials or epidemiological studies. It is a multidimensional self-reporting measure of female sexual function designed to be a clinical trials assessment instrument.
  • the 19-item assessment of overall sexual function is divided into 6 domains: desire, subjective arousal, lubrication, orgasm, satisfaction, and pain. Every domain contributes a maximum of six points to the total score. Thus, the maximal score is 36. Higher scores indicate better sexual function.
  • Significant and positive statistical differences have been observed in each domain between controls and women with female sexual arousal disorder. It has proven a valid indicator in the assessment of key dimensions of female sexual function.
  • the FSFI is appropriately used only for subjects who have had some level of sexual activity during the measurement period.
  • the Sexual Distress Scale-Revised is a known standard questionnaire to assess the frequency of personal distress that a woman may have been experiencing because of a sexual dysfunction during the past 30 days. It helps quantify the extent to which the sexual dysfunction is causing her emotional distress. It was developed to provide a standardized, quantitative measure of sexually related personal distress in women.
  • the questionnaire was originally designed to validate a diagnosis of hypoactive sexual desire disorder which required a woman to be distressed about the lack of desire. Question 13 specifically assesses distress due to low sexual desire. The questionnaire was used more generally to validate that a woman has distress caused by any of the three disorders of female sexuality despite the lack of specific questions about pain or discomfort.
  • Thel3 items are rated on a 5-point scale from 0 (never) to 4 (always); thus, the total score ranges from 0 to 52, with lower scores indicating less distress.
  • a score of > 11 indicates Female Sexual Dysfunction.
  • Vulvovaginal Symptom Questionnaire is a known standard
  • the questionnaire more specifically addresses female Genitopelvic Pain/ Penetration Disorders (GPPD's). (See Erekson, Elisabeth A. et al. "The VSQ: A Questionnaire to Measure Vulvovaginal Symptoms in Postmenopausal Women.” Menopause (New York, N.Y.) 20.9 (2013): 973-979. PMC. Web. 17 Mar. 2016.)
  • the questionnaire's focus is to determine the nature and effect of a woman's vulvar symptoms.
  • the VSQ is a 21-item written questionnaire with four scales: symptoms, emotions, life impact, and sexual impact.
  • SAL Sexual Activity Log
  • PKI-I Patient's Global Impression of Improvement
  • the Narrative Questionnaire was developed with questions focused primarily on characterizing the nature of a woman's genitopelvic pain disorder, its impact on her emotional and sexual life and later on the benefit, if any, from the study medication.
  • Test Set 2 Patient
  • PD was a 61 -year-old post-menopausal woman with (GPPD) Genitopelvic Pain/Penetration Disorder (dyspareunia) secondary to Vulvovaginal atrophy (VVA), with decreased lubrication and decreased sexual desire (interest) and arousal (SIAD) Sexual Interest/ Arousal Disorder.
  • GPPD Genitopelvic Pain/Penetration Disorder
  • VVA Vulvovaginal atrophy
  • SIAD arousal
  • PD After using 5% GTO for one month, PD noted decreased vestibulodynia, vulvodynia and dyspareunia (GPPD). Unexpectedly, she noted an increase in her level of sexual desire and arousal and an increase in her orgasms.
  • FSFI questionnaire Female Sexual Function Index (FSFI questionnaire) results after 4 months (patient had noticeable effects within one month (see SAL) but was delayed in filling out forms) of using 5% Catechin-based GTO were as follows: BEFORE AFTER
  • a score of >11 is indicative of Female Sexual Distress. Prior to use of GTO subject had a score of 46 qualifying her as Female Sexual Distress. After use of the medication, she had a score of 5. She no longer was distressed by her sexual function. Of notable significance, item 13 specifically assesses distress due to low sexual desire. Before using 5% catechin-based GTO, the patient was "Always" bothered by low sexual desire. After using the topical green tea ointment, she was "rarely” bothered by low sexual desire.
  • Vulvovaginal Symptom Questionnaire The Vulvovaginal Symptom Questionnaire:
  • the questionnaire is to determine the nature and effect of a woman's vulvovaginal symptoms. PD's distress significantly decreased from a pre-GTO score of 13/21 to 1/21 indicating lack of physical symptoms, emotional concerns, life impact, and sexual impact. This indicated a very positive overall result.
  • DG was a 47-year-old postmenopausal despite taking an oral estrogen (Loestrin Fe), DG had symptoms of vulvovaginal atrophy (VVA) manifested as both decreased in lubrication and dyspareunia, Genitopelvic Pain/Penetration Disorder (GPPD)
  • DG showed a significant increase in her ability to become lubricated; a decrease in her dyspareunia and an unexpected increase in her sexual arousal and desire and orgasm. She continued to use 5% GTO from Custom Scripts
  • Patient DG had female sexual dysfunction prior to using the study medication and her female sexual dysfunction resolved after using the 5% GTO without any adverse effects.
  • DG Prior to using GTO, DG had strong sexual desire which was maintained throughout the test period. She was a little bit distressed about her level of sexual desire yet had three sexual activities in the prior week and did have an orgasm. At the end of four weeks of using the 5% green tea ointment she had strong sexual desire, was not at all distressed about her level of desire and had five satisfying sexual events with orgasms in the prior week. The subject had a very active sexual life prior to using GTO but this was further enhanced, much to the patient's intimidment, after using GTO. She continues to use GTO for over 9 months with continued satisfaction.
  • a score of >11 is indicative of Female Sexual Distress.
  • subject Prior to use of GTO, subject had a score of 10, one point short of qualifying her as Female Sexual Distress. After use of GTO, she had a score of 4.
  • DG was significantly less distressed by her sexual function after using the 5% green tea ointment primarily because of a resolution of her dyspareunia.
  • Vulvovaginal Symptom Questionnaire The Vulvovaginal Symptom Questionnaire
  • the questionnaire is to determine the nature and effect of a woman's vulvovaginal symptoms.
  • the subject's distressed significantly decreased from a pre-GTO score of 7/21 to post- GTO score of 0/21 indicating lack of physical symptoms, emotional concerns, life impact, and sexual impact. Physical symptoms of reduced pain and improved lubrication were the main reasons for this improvement.
  • PF was a 57-year-old postmenopausal woman with symptoms of vulvovaginal atrophy manifested as vestibulodynia, vulvodynia and dyspareunia i.e.
  • Patient is a 57-year-old fair complexion, red haired Irish Caucasian one year postmenopausal woman, in a long term relationship, who for 1-5 years had moderate burning/soreness some of the time around the entire circumference of her vaginal introitus, vestibulodynia, causing her mild discomfort during vaginal penetration, dyspareunia. She had pain or discomfort most of the time after intercourse with vaginal penetration.
  • the patient had female sexual dysfunction before using the study medication that resolved after using the medication for one month. In fact, she began to notice a decrease in pain after 5 days of daily use. She had no adverse effects. Of note was the particular and significant increase in satisfaction accompanied by a decrease in pain.
  • Sexual Activity Log Prior to using the 5% GTO, the subject had a moderate desire that was maintained throughout the study period. PF had one sexual activity in the prior week to using GTO because "would be too sore" (to have more). After using the medication every day for a month, she had two sexual activities during the week prior to filling out the questionnaire that were satisfying. This log was not taken each week because patient's partner travels for weeks at a time and travels internationally.
  • Sexual Distress Scale Revised A score of > 11 is indicative of Female Sexual Distress. Prior to use of the study medication subject had a score of 16 qualifying her as having Sexual Distress. After one month of use of the medication she had a score of 4. She was no longer distressed by her sexual function. Item #13 pre: 0 (never) post: 0 (never)
  • Vulvovaginal Symptom Questionnaire The Vulvovaginal Symptom Questionnaire:
  • AM was a 48-year-old pre-menopausal woman with complains of Genitopelvic Pain/Penetration Disorder (GPPD) manifesting as vestibulodynia and pain inside her vagina during intercourse, dyspareunia.
  • GPPD Genitopelvic Pain/Penetration Disorder
  • Patient is a 48-year-old Italian Caucasian, medium complexion premenopausal woman with regular menses in a long term relationship who, for more than 10 years, had
  • a score of > 11 is indicative of Female Sexual Distress.
  • Pre-GTO score was 20 Post GTO score was 10.
  • Her score before qualified as sexual distress After using 5% GTO she no longer qualified as having sexual distress. The decrease in her discomfort/pain was notable as well as increase in orgasmic intensity.
  • Vulvovaginal Symptom Questionnaire The Vulvovaginal Symptom Questionnaire
  • This patient illustrates that a woman with sensitive skin may need to use 5% GTO less often (2-3 times per week) until a tolerance is built up frequency of usage can increase to optimize therapeutic effects.
  • Genitopelvic Pain/ Disorder GPPD
  • dyspareunia secondary to post-menopausal VVA
  • vulvodynia GPPD
  • Vaginal Maturation Index Pre-5% GTO: 10% parabasal cells, 90% intermediate cells; 0% superficial cells
  • Vaginal Maturation Index Post5% GTO 100% parabasal cells Benefit of 5%GTO (3 x/ week) Genitopelvic Pain/Penetration Disorder, vulvodynia and dyspareunia improved as did lubrication
  • DI was an early entrant into the study and was only given one of the questionnaire forms as the other forms were not prepared and issued until later.
  • Vaginal maturation index was moderate with 10% parabasal cells; 90% intermediate and 0% superficial cells. Vaginal pH was 6.0. Upon repeat in October she had 100% parabasal cells indicating no estrogenic effects of the 5%GTO use at 2 times per week.
  • Patient Global Patient Global Impression of Improvement Her vulvodynia resolved and she maintained a higher level of lubrication scoring the highest with "very much improved” She reported significantly less discomfort than before using study medication.
  • the Vulvovaginal Symptom Questionnaire Patient still has symptoms using the 5% GTO only 2 times per week with a score of 9/21. There is no pretest for this subject however because as an early entrant into the study not all questionnaires had been instituted. After continued use of 5% GTO over several months (which she now tolerated every other day) her score improved significantly and was 2/21 with resolution of pain and dryness. In sum, the patient's symptoms improved after she was able to use the correct lower percentage of GTO at a frequency she could tolerate without irritation. She continues to use GTO for over 9 months, renewing her medication.
  • Patient is a 43-year-old Hispanic premenopausal female without any complaints serving as a control.
  • Vaginal pH was 5.5 before and after daily use of study medication for one month.
  • Patient did not meet the criteria for female sexual dysfunction but still had an improvement in her symptoms particularly in increase of lubrication and decrease in pain.
  • Vulvovaginal Symptom Questionnaire Pre-GTO score 3. Post GTO score 2. Pain was noted on the pre-questionnaire but resolved after 4 weeks of daily use of 5% GTO. She still noted dryness despite use of medication.
  • Sexual Activities Log Patient had a "moderate" desire throughout the study period, was not at all distressed by her level of desire and had 3 episodes of sexual activity with orgasms each week. There was no change for this patient.
  • Patient LT Presenting Complaint: Genitopelvic Pain/Penetration Disorder (vulvodynia and dyspareunia.):
  • Benefit of 5%GTO decrease in Genitopelvic Pain/Penetration (vulvodynia and dyspareunia); increase arousal/desire; orgasm
  • the Vulvovaginal Symptom Questionnaire The subjects distressed significantly decreased from a pre-GTO score of 5/21 to post-GTO score of 1/21 indicating lack of physical symptoms, emotional concems, life impact, and sexual impact. Physical symptoms of hurting, irritation pain and bleeding resolved and were the reasons for this improvement. 8 Patient SW- control
  • Vitamin D prescription 50,000 units twice a week
  • the Vulvovaginal Symptom Questionnaire The questionnaire is to determine the nature and effect of a woman's vulvovaginal symptoms.
  • Vulvovaginal Symptom Questionnaire The Vulvovaginal Symptom Questionnaire:
  • the questionnaire is to determine the nature and effect of a woman's vulvovaginal symptoms.
  • the subject's pre-score of 0/21 to 0/21. There was no change.
  • SAL Sexual Activity Log SAL: Prior to using the study medication subject had "moderate” sexual desire for the week prior to using the medication. She was not distressed about her level of sexual desire yet had one sexual activity in the prior week and an orgasm. This was the same after one week. However, by the end of two weeks of using the 5% green tea ointment she had "strong sexual desire", was not at all distressed about her level of desire and had one satisfying sexual events with orgasm in the prior week. This level of desire was maintained for the duration of the study. 10.
  • Patient CD Patient CD (Patient 1)
  • Patient is a 56-year-old post-menopausal female and an initial trial study patient who only filled out forms on the first visit and was seen in the office for a follow up exam and discussion of her condition. She had thinning of her vulvar and vaginal epithelium, the vaginal introitus was somewhat firm and fibrous upon examination with her gynecologist, with a vaginal pH of 7 consistent with atrophic vaginitis. CD was given 15% GTO to use "a dab" once a day at night to vulvar area and one inch into vagina. She had not had any intercourse for six months because of lack of desire.
  • Medications Low Dose Aspirin oral; 5%GTO atorvastatin oral; Effexor XR oral; losartan oral acyclovir
  • a score of >11 is indicative of Female Sexual Distress. Her score was 27 prior to use of 5%GTO and 23 after the use of the medication. Item #13 pre (3 frequently) post: (2 occasionally)
  • Vulvovaginal Symptom Questionnaire The Vulvovaginal Symptom Questionnaire:
  • the questionnaire is to determine the nature and effect of a woman's vulvovaginal symptoms.
  • the subject's pre-score of 1/21 to 0/21 dryness was the one symptom that she reported before, which then resolved after use of the 5%GTO.
  • Subject is a 52-year-old women who in years prior had a hysterectomy but retained her ovaries. She was experiencing menopausal symptoms of vulvovaginal atrophy, dyspareunia and vestibulodynia for the past one to five years. She always had discomfort of pain of moderate severity located in the entire area of the vulva inside her labia minora and particularly in the posterior fourchette characterized by burning, throbbing, and soreness. After four weeks of use 5%GTO she had no longer had any pain or discomfort. She was able to become lubricated most of the time and only rarely needed external lubricant before use of the 5%GTO and after use never used lubricant.
  • Prior to use of the study medication subject had a score of 24.2.
  • a requirement of the study is that patients have an ongoing personal sexual relationship throughout the study period. Therefore, her values were not included in the statistical analysis of the FSFI. This patient did not despite significant improvement in her pain and desire.
  • a score of >11 is indicative of Female Sexual Distress. Her score was 25 prior to use of 5% GTO and 13 after the use of the medication. There was a significant improvement in her sexual distress score after using 5% GTO. Item #13 (pre: 0 never post: 2 occasionally)
  • the Vulvovaginal Symptom Questionnaire The questionnaire is to determine the nature and effect of a woman's vulvovaginal symptoms. The subjects pre-GTO score of 11/21 to post GTO score of 0/21 pain was the one symptom that she reported before and which then resolved after use of the 5% GTO
  • SAL Sexual Activity Log SAL: Prior to using the study medication subject had low sexual desire for the week prior to using the medication. She was "a little bit distressed" about her level of sexual desire yet had one sexual activity in the prior week. Because of difficulty in her personal relationship with her spouse she did not have sex after the first week of the study. This patient did not masturbate or engage in non-coital sexual activity.
  • Benefit of 5% GTO resolution of Genitopelvic Pain/Penetration Disorder, dyspareunia and increase in lubrication.
  • Medications Crestor oral; felodipine oral; Hyzaar oral.
  • Maturation Index pre-GTO 50% parabasal cells; 40% Intermediate cells; 10% superficial cells
  • a score of >11 is indicative of Female Sexual Distress. Her score was prior to use of 5%GTO was 9 (nine) and 1 (one) after the use of the medication. There was a significant improvement in her sexual distress score after using 5% GTO. Item #13 pre: (3 frequently) post: (0 never)
  • Vulvovaginal Symptom Questionnaire The Vulvovaginal Symptom Questionnaire:
  • the questionnaire is to determine the nature and effect of a woman's vulvovaginal symptoms.
  • the subject's pre-score of 5/21 to 0/21 pain was the one symptom that she reported before and which then resolved after use of the 5% GTO.
  • Vaginal Maturation index Pre: 100% superficial cells
  • Patient is a 52-year-old woman, two to three years post-menopausal that was referred by her gynecologic nurse practitioner. She always experienced "very significant,” burning, throbbing, knife like cutting, soreness pain/dis comfort, in the area of the posterior forchette, for the past 1-5 years during vaginal penetration which affected her sexual life "very much”. She “frequently” felt distressed about her sexual life. She” rarely” became lubricated and “always” required external lubricant, only “sometimes” became aroused during sexual activity only "rarely” experiencing an orgasm. She “seldom” felt sexual desire and
  • subject Prior to use of the study medication, subject had qualified for female sexual dysfunction with a score of 3.5. After use of the medication, despite still meeting the standard for having sexual dysfunction, she remarkably improved with a score of 21.4. Most notably she had increase in all categories, especially in satisfaction, orgasm, and lubrication.
  • a score of >11 is indicative of Female Sexual Distress. Her score was prior to use of 5%GTO was 35and after the use of the 5%GTO medication it was 29. There was a significant improvement in her sexual distress score afterwards.
  • FIG. 4G illustrates mean difference in Sexual Activities Log of Satisfying Sexual Events (SSE) scores compared to the test subjects prior to treatment.
  • SSE Sexual Activities Log of Satisfying Sexual Events
  • FIG. 4H illustrates the mean difference in the sexual distress scores (Item #13 in the Sexual Distress Score -Revised), of the test subjects post and prior to treatment.
  • users of the present invention although not reaching level of significance, trended to be less likely to experience sexual distress.
  • GTO Green Tea Ointment
  • GPPD Genitopelvic Pain/Penetration Disorder
  • SIAD Sexual Interest Arousal Disorder
  • FOD Female Orgasmic Disorder
  • Topical GTO was shown to be efficacious in reducing or completely eliminating vestibulodynia, a common cause of dyspareunia in both premenopausal and postmenopausal women. This condition may be seen in 15% of all premenopausal women sometime in their lifetime. It is a cause of genital pain and dyspareunia in postmenopausal often unrelated to vulvovaginal atrophy. Vestibulodynia is a challenging disorder and there has been no definitive treatment for this condition despite use of a range of treatments.
  • the catechin preparations of the present invention are the first and only chemical compound known to effectively treat vestibulodynia in both premenopausal and postmenopausal women.
  • Vulvovaginal atrophy also a cause of genital pain and dyspareunia, exerts a negative impact on the quality of life of fifty percent (50%) of all postmenopausal women.
  • topical GTO was effective in reducing or eliminating genital pain and dyspareunia caused by vulvovaginal atrophy without causing therapeutically significant changes in the vaginal maturation index or the vaginal pH. This is evidence that GTO has no apparent estrogenic effects and is therefore safe in women with risk of breast or other reproductive malignancies, and carries no risk of stroke, deep venous thrombosis or dementia.
  • EGCg Epigallocatechin gallate
  • synthetic analogs of EGCg or other catechins present in green tea formulated to increase their stability or bioavailability are also contemplated by the invention.
  • synthetic oligomers of EGCg may be used if desired as well as any other suitable analog that improves stability or bioavailability. They may include methylation or similar known compounding techniques to improve or stability, efficacy, bioavailability or strength of the underlying effective ingredient.
  • EGCg prodrugs.
  • One such formulation of the present invention may include about 5-15% by weight per unit volume of a combination of the Epigallocatechin(s) and Epicatechin(s) mentioned above or substantially by themselves.
  • One such formulation may include about 50% Epigallocatechin gallate, 25% Epigallocatechin, and 25% Epicatechin. However, other ratios are possible (e.g., 33% for each, etc.).
  • a preferred embodiment may include at least some Epigallocatechin gallate, other embodiments may include just
  • Epigallocatechin, and/or Epicatechin in a suitable mixture e.g., 50% each, 75/25, etc., without substantially any EGCg.
  • a suitable mixture e.g. 50% each, 75/25, etc., without substantially any EGCg.
  • Epigallocatechin gallate, and/or an analog thereof, as a majority component e.g., 50-95% of the 5-15% w/w with other components in any suitable mixture.
  • the active ingredient may be substantially about 100% Epigallocatechin gallate (e.g., emulsified in a suitable base such as petroleum or other waxes, gels, ointments, lotions, and the like).
  • the compounds of the invention disclosed herein may include embodiments having about 1% - 50% by weight per unit volume of the active ingredients described above.
  • topically applied ointments of the present invention as compounded (e.g. , about 1-50% EGCg), is that the formulation is substantially colorless (milky white) and therefore does not stain the clothing or underwear of the user. This is in contrast to topically applied GTO that tends to have a rust or red brown color, stains underwear, and may require a prophylactic layer.
  • the compounds of the present invention are more aesthetically pleasing, easier to use, and therefore preferable to the user.
  • Epigallocatechin ointment may be used to obtain the desired therapeutic effect. Thus, it may be viewed as more effective on a unit volume by weight perspective as compared to GTO compounds.
  • compositions of the invention can be applied on 1, 2, 3, 4, 5, 6, or 7-day intervals for a duration of 2, 3, 4, 5, 6, 7, 8, or more weeks as required to achieve the desired therapeutic results.
  • EGCg may be useful either alone or in combination with other compounds for the indications noted herein including both male and female sexual indications.
  • Various analogs of Epigallocatechin, EGCg or other green tea catechins may be used to improve stability, bioavailability or efficacy.
  • catechin compounds which may include GTO components such as epicatechin gallate, epigallocatechins, epigallocatechin gallate, epicatechin, or analogs thereof, may be combined with certain other compounds including vasodilators such as L- arginine, erectile dysfunction medications (some of which have vasodilator effects) such as alprostadil, tadalafil, vardenafil, sildenafil, and/or cannabinoids to treat both male and female sexual disorders.
  • vasodilators such as L- arginine
  • erectile dysfunction medications such as alprostadil, tadalafil, vardenafil, sildenafil, and/or cannabinoids to treat both male and female sexual disorders.
  • cannabinoids such as alprostadil, tadalafil, vardenafil, sildenafil, and/or cannabinoids
  • epigallocatechins, epicatechin and/or EGCg is combined with a cannabinoid.
  • Cannabinoids are pharmacologically-active compounds found in cannabis.
  • the cannabinoid is tetrahydrocannabinol (THC).
  • THC is a strong anti-inflammatory and pain killer.
  • THC is also psychoactive and may facilitate sexual interest and arousal.
  • the cannabinoid is Cannabidiol (CBD).
  • CBD is considered to have a wide scope of potential medical applications due to clinical reports showing the lack of side effects, particularly a lack of psychoactivity. (See, e.g. , Nagarkatti et al, Future Med. Chem.
  • SERMs selective estrogen receptor modulators
  • OSPHENA ® Ospemifene
  • a compound contemplated by the present invention may include 1-25% EGCg (and/or epigallocatechins, epicatechin including analogs), a vasodilator such as L-arginine and/or alprostadil along with a Cannabinoid which may include THC and/or CBD.
  • Suitable dosages may be between about 2-20 mg of a suitable THC/CBD product.
  • One such example of a suitable cannabinoid preparation is the FORI A product currently available at foriapleasure.com, which is hereby incorporated by reference.
  • Other compounds that may be added may include melatonin II and Bremelanotide (PT-141).
  • one specific embodiment may include about 5-25% EGCg or suitable analog, about 10 mg THC/CBD per dose, and a vasodilator such as L-arginine or alprostadil in an effective topical dose.
  • a vasodilator such as L-arginine or alprostadil in an effective topical dose.
  • Other compounds such as estrogen, a SERM (e.g., Osphimene), an androgen (e.g., DHEA, testosterone) melatonin II and/or Bremelanotide (PT-141) may also be added alone, or in any suitable combination, if desired.
  • Another specific embodiment may include, for example, about 5-25% EGCg or suitable analog, a vasodilator such L-arginine or alprostadil in an effective topical dose.
  • Other compounds such as melatonin II and Bremelanotide (PT-141) may also be added, if desired.
  • certain embodiments of the present invention have a positive effect on male libido, performance and sexual sensation.
  • This may include a GTO, EGCg or suitable analog preparations of about 5-50% and may further include a vasodilator such L-arginine, alprostadil, tadalafil, vardenafil, sildenafil in an effective topical dose and may also include a suitable absorption catalyst and/or acceleration agent in order to obtain a predictable and desirable time to onset of therapeutic effect.
  • DHEA Dehydroepiandrosterone
  • SARM selective androgen receptor modulator
  • PT-141 Bremelanotide
  • Such formulation may be prepared for both topical and oral formulations.
  • one suitable oral formulation in accordance with aspects of the present invention may include about 200-400 mg EGCg or suitable analog with known doses of a vasodilator, a hormone(s), or a SARM as described above may be used orally, or both orally and topically if desired to increase, improve or otherwise optimize therapeutic effect.
  • This may include use of an ointment, liquid, spray application, dermal patch, specially designed underwear, etc. Any suitable application vector may be used if desired.
  • any of the above preparations may be deposited or disposed on a male or female condom or other known devices for sexual enhancement (e.g., vibrator).
  • Other embodiments may include a suitable application vector such as feminine hygiene products including tampons, sanitary napkins panty liners, underwear, dermal patches and the like. These embodiments include, but are not limited to, a physical or mechanical device designed to induce sexual pleasure or enhancement. This may include any of the GTO or catechin derived preparations described herein.
  • a condom may be combined with about a 5-35% EGCg preparation on the outside, the inside, or within the packaging.
  • the preparation combined with the condom includes a cannabinoid.
  • the preparation incudes a vasodilator. In other embodiments, the preparation incudes an androgen (DHEA, testosterone). In other embodiments, the preparation includes a SARM (Selective Androgen Receptor Modulator). For females only, other embodiments may contain a SERM or estrogen. In other embodiments, the preparation includes melatonin.
  • the invention contemplates a male or female condom that is combined with
  • GTO GTO, EGCg, or another catechin preparation as described herein.
  • embodiments comprise about a 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,
  • EGCg preparation or more on the outside, inside, or in the packaging of the condom.
  • the EGCg preparation is at about 15-40% concentration.
  • Other embodiments further include a vasodilator component.
  • DHEA DHEA
  • testosterone DHEA
  • SARM SARM
  • melatonin a SERM or estrogen
  • Cannabis and cannabinoid preparations have been linked to improvements of subjective indices of sexual function in women. These include self-reported increases in sexual desire, orgasmic function, sexual satisfaction, enjoyment, and pleasure. (Osborne & Fogfel, Substance Use & Misuse 43 :539-572 (2008); Palamar et al. , Arch Sex Behav.
  • EGCg catechin derived ointment(s)
  • cannabinoids treat Male and/or Female Sexual Disorders.
  • EGCg catechin derived ointment(s)
  • cannabinoids treat Male and/or Female Sexual Disorders.
  • Other inflammatory indications such as rosacea may be treated using aspects of the present invention.
  • topical preparations having EGCg concentrations of about 0.1%-10% may be used if desired. In some embodiments, this may be combined with retinoids (e.g.
  • vasoconstricting agents e.g. brimonidine Mirvaso
  • topical or systemic antimicrobials antibiotics, antiparasitics, ivemectin (Soolantra), azelaic acid (Finacea), tacrolimus (Protopic), or Elidel (pimecrolimus).
  • the topical regimen may be supplemented or replaced by systemic (oral) EGCg at about 200-500mg daily.
  • arthritis e.g. , psoriatic or rheumatoid arthritis
  • this may include a regimen of topically applying about 3%-50% EGCg (e.g. , 25%) to affected areas such as joints and may optionally be supplemented (or replaced) by systemic (oral) EGCg at about 200-500mg daily.
  • EGCg e.g. , 25%
  • systemic EGCg e.g., systemic (oral) EGCg at about 200-500mg daily.
  • Such a treatment regimen is less toxic than other immunosuppressive drugs such as methotrexate, cyclosporine, Azothiprine, certain biologies (e.g.
  • Topical EGCg alone or in combination with corticosteroids would decrease the toxicity associated with corticosteroid treatments, i.e. EGCg would have a steroid sparing effect.
  • the topical EGCg is combined with a topical
  • corticosteroid to enable steroid sparing in the treatment of a cutaneous inflammation.
  • systemic EGCg would enable toxicity reduction or sparing from antimetabolites, biologies, corticosteroids, and other known drugs in the treatment of systemic inflammatory conditions including arthritis.
  • inflammatory indication(s) that may be treated with the above regimen include dermatitis conditions (e.g. , Psoriasis, Urinary Tract indications, Atopic Dermatitis, Seborrheic dermatitis, Nummular eczema, Stasis dermatitis, eczema, alopecia areata, lichen planopilaris and dandruff).
  • dermatitis conditions e.g. , Psoriasis, Urinary Tract indications, Atopic Dermatitis, Seborrheic dermatitis, Nummular eczema, Stasis dermatitis, eczema, alopecia areata, lichen planopilaris and dandruff.
  • this may include a regimen of topically applying about 5%-50% EGCg (e.g. , 10-25%) to affected areas, and in the case of cutaneous inflammatory dermatoses of the scalp, may include the use
  • a suitable body wash or other general application vector may include soap or soap-like compounds and any suitable absorption, adhesion and/or wetting agent and may further include dermal patches and specially designed clothes or underwear.
  • Scalp treatments may also be supplemented with the periodic use of a UV or laser comb (with -250-350 nm wavelength) as described in more detail below.
  • the topical EGCg may be combined with a topical Crisaborole (Eucrisa, a topical phosphodiesterase 4 inhibitor, calcineurin inhibitors or JAK inhibitors).
  • Alopecia including androgenetic alopecia
  • alopecia areata ankylosing spondylitis
  • celiac disease chronic obstructive spondylitis
  • an underlying inflammatory dermatosis such as hyperkeratosis of palms and soles may be treated with EGCg preparation of about 2-50% EGCg (e.g., 25%) and may include a salicylic acid and/or urea cream which may be mixed and/or used in a two-step process (e.g., to resolve thickened skin impediment (first) to allow for penetration of EGCg into affected area (second)) so that once stratum corneum is sufficiently thinned, it enables action of EGCg to treat the underlying inflammation.
  • EGCg preparation of about 2-50% EGCg (e.g., 25%) and may include a salicylic acid and/or urea cream which may be mixed and/or used in a two-step process (e.g., to resolve thickened skin impediment (first) to allow for penetration of EGCg into affected area (second)) so that once stratum corneum is sufficiently thinned, it enables action of EGCg to treat the
  • EGCg 5% EGCg ointment
  • She noticed an increase in her libido and localized genital sexual sensations. She also noted an increase in vaginal lubrication during sexual activity. The effect continued even if she skipped a day of use. "EGCg was more effective as rapid onset of effect and sustained effect vs GTO.” She preferred the 5%EGCg because it was essentially white and colorless and did not stain her underwear. She continues to use the 5% EGCg on a daily basis.
  • an underlying inflammatory dermatosis such as hyperkeratosis of palms and soles may be treated with EGCg preparation of about 3-50% EGCg (or suitable analog) and may include a salicylic acid and/or urea cream (or other suitable penetration and/or absorption agent) which may be mixed and/or used in a two-step process (e.g. , to resolve thickened skin impediment (first) to allow for penetration of EGCg compound into affected area (second)) so that once stratum corneum is sufficiently thinned, it enables action of EGCg to treat the underlying inflammation.
  • EGCg preparation of about 3-50% EGCg (or suitable analog) and may include a salicylic acid and/or urea cream (or other suitable penetration and/or absorption agent) which may be mixed and/or used in a two-step process (e.g. , to resolve thickened skin impediment (first) to allow for penetration of EGCg compound into affected area (second)) so that once strat
  • psoriasis underlying inflammation causes both dilated tortuous blood vessels and secondary hyperkeratosis or thickening of epidermis with both living and dead skin cells (stratum corneum).
  • Treatment with a preparation of about 3-50% EGCg in addition to certain penetration, adhesion and/or adsorbtion agents as mentioned above may used as desired.
  • the topical regimen may be supplemented and/or replaced with systemic (oral) EGCg at about 200-400mg daily to treat the
  • Periodic follow up with additional topical applications can be used as indicated.
  • the topical regimen may be supplemented or replaced with a systemic (oral) EGCg at about 200-500mg daily.
  • treatment with topical EGCg and or GTO as described herein may be supplemented by periodic application of UV light to affected areas.
  • UV light between about 250-350 nm may be periodically applied to affected areas in addition to application of the various embodiments of the GTO/EGCg compounds described herein.
  • UV light may be applied prior to application of GTO/EGCg compounds.
  • UV light between about 290-320 nm may be applied anywhere between about 30 seconds to 5 minutes to affected areas. After exposure to such UV light, GTO/EGCg compounds may then be applied shortly thereafter. This may be thought of essentially as "concurrent" use or treatment.
  • application of UV light may be given some time to have a desired effect, and GTO/EGCg compounds may be applied in an alternating fashion such that UV light is applied one day and GTO/EGCg compounds applied on the next day etc.
  • Such treatments may also be alternated at other intervals as desired to meet therapeutic goals (at alternating 12, 24, 36, or 72-hour intervals, etc.).
  • Other parameters of this two-tiered treatment approach may also be modified in order to achieve a desired effect may include altering the wavelength of the applied UV light and/or alerting duration of application of UV light as well as altering the strength and composition of the GTO/EGCg compounds (or a combination of the above).
  • UV light For example, longer wavelengths of UV light are known to have a superior penetration effect and thus may be preferred at the onset of treatment to penetrate initial plaque deposits.
  • a wavelength of about 250-290 nm may be applied initially and then raised to about 300-320 nm (e.g., 311 nm). It is generally desirable that such light penetrate to the basal layer to remodel plaques.
  • high concentrations of UV light are known to have a superior penetration effect and thus may be preferred at the onset of treatment to penetrate initial plaque deposits.
  • a wavelength of about 250-290 nm may be applied initially and then raised to about 300-320 nm (e.g., 311 nm). It is generally desirable that such light penetrate to the basal layer to remodel plaques.
  • GTO/EGCg compounds with a penetration and/or absorption agent may be used initially and then reduced somewhat to maintain the desired therapeutic effect.
  • 40% by weight GTO/EGCg preparation may be used in conjunction with the application of about 290 nm UV light, which may, after a period of time be reduced to 5-15% concentration with UV applications at about 310 nm for a reduced period of time.
  • such treatments initially may be applied daily, every other day, 2-3 times a week or as needed (e.g., once per week) to obtain and maintain the desired results.
  • Each patient will differ somewhat and may require optimization of the treatment protocol for best results. This may include changing the wavelength or duration of applied UV light and/or the strength and/or composition of the GTO/EGCg preparation
  • Other light-based treatments include the use of lasers such as an excimer laser at about 300-320 nm (e.g., 308 nm) in conjunction with the various GTO/EGCg preparations described herein. Some patients may respond better to such laser irritation than to UV light as described herein. Moreover, in some embodiments, exposure to laser light may reduce the amount of treatment time.
  • Other treatments that may be combined with various GTO/EGCg preparations described herein may also include the oral psoralen and UVA light to resolve psoriasis.
  • a similar approach may be used when treating a scalp. This may include a UV or laser comb at the wavelengths described above along with a shampoo or body wash having concentrations of about 1-15% GTO/EGCg. Moreover, such treatments initially may be applied daily, every other day, 2-3 times a week or as needed (e.g., one per week) to obtain and maintain the desired results. Each patient will differ somewhat and may require optimization of the treatment protocol for best results. This may include changing the wavelength or duration of applied UV light and/or the strength and/or composition of the GTO/EGCg preparation.
  • Example 5 Enhancement of Male Sexual Function.
  • the male patient of Example 5 topically applied 15% and 25% and 50 % EGCg ointment to his glans penis at varying intervals. He noticed an increased libido, intensity and duration (length) of orgasm during sexual encounters, increased speed and ease with which climax was achieved.
  • EGCg ointment 15% and 25% and 50 % EGCg ointment to his glans penis at varying intervals. He noticed an increased libido, intensity and duration (length) of orgasm during sexual encounters, increased speed and ease with which climax was achieved.
  • EGCg ECGg
  • concentrations of EGCg tended to have a greater efficacy and a more rapid onset of effect when treating sexual function indications. Accordingly, treatment with higher concentrations (and/or and absorption agent to accelerate uptake) may be used for periodic or situational use whereas lower concentrations are suitable for daily use.
  • certain absorption agents may be used in conjunction with the EGCg in order to decease the time to onset of the therapeutic effect of GTO/EGCg preparations described herein.
  • EGCg preparations may be applied regularly (e.g., daily or twice daily application) for a substantially continuous effect whereas about 25-50% EGCg preparations are used for a shorter time before or during a time period more immediately prior to sexual activity.
  • the more immediate time period includes one, two, three or four applications with about 24 hours prior to sex.
  • the time period is within about one to three hours before sexual activity.
  • certain patients may benefit from a "loading" period during which GTO/EGCg preparations described herein are applied 1-3 times a day for 2-5 days prior to sexual activity. This may enhance absorption and assimilation in neural pathways to provide the enhanced effect.
  • Such a loading period may include concentrations between about 10-50% by weight GTO/EGCg and may further include absorption assimilation agents.
  • concentrations between about 10-50% by weight GTO/EGCg and may further include absorption assimilation agents.
  • After the initial loading period once daily applications (or less, e.g., 2-3 times per week) may be used in order maintain the enhanced effect.
  • test subject showed marked improvement of her urinary tract indications using 5% GTO preparation.
  • the invention contemplated hereunder provides for the antiinflammatory effects of catechins as efficacious in treating, alleviating symptoms of, or curing inflammatory conditions of the urinary tract in both males and females.
  • the embodiments of the invention described herein may also be used to treat such urinary tract indications (which may include systemic and/or topical treatments).
  • EGCg ointment per weight per unit volume of EGCg
  • GTO Green Tea Ointment
  • EGCg appears to be more effective than a heterogeneous mixture of catechins and the ointment was found to be simpler to apply, more hygienic, without red brown color and staining of underwear, and more pleasant.
  • the 5% EGCg had a smoother consistency compared to Green Tea ointment that has a more particulate consistency.
  • EGCg ointments of 5%, 15% and 25% were formulated in a petrolatum base (US Pharmacy Lab, Northvale, New; Custom Scripts Pharmacy, Wesley Chapel Florida). It was effective in alleviating pain from certain cutaneous indications including
  • the ointment may have substantially "cured" the vulvodynia, vestibulodynia and other associated forms of discomfort. After one week of continuous use, the relief lasted for at least over two years.
  • EGCg ointment has been observed to have a more rapid onset of action (as compared to GTO compounds in US20160271102). Improvements in sexual arousal, pleasurable sexual sensations, intensity of perceived sexual sensations, and orgasm were perceived. In some instances, the effect was enjoyed within hours of a single application.
  • the addition of 0.05%-0.1% Capsaicin to the EGCg partially increased light touch sexual sensations and decreased aberrant painful sensations on pressure stimulation of both nipples in the same patient.
  • EGCg modified molecular derivatives, and analogs determined using known techniques, may be used in place of, or in addition to, the GTO and EGCg and related catechin or sinecatechin derived compounds described herein.

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Abstract

L'invention concerne des traitements sûrs et efficaces d'amélioration de la fonction sexuelle masculine et féminine, d'une inflammation cutanée telle que le psoriasis, l'eczéma, la dermatite et des troubles sexuels féminins, tels que les troubles de la douleur/pénétration génito-pelvienne ; l'atrophie vulvovaginale, la vestibulodynie, la dyspareunie, le trouble d'intérêt sexuel/d'excitation, la faible libido féminine et le trouble orgasmique féminin.
PCT/US2018/019530 2015-03-19 2018-02-23 Composés de traitement d'inflammation cutanée, de troubles sexuels féminins et d'amélioration de la fonction sexuelle WO2018156960A1 (fr)

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US16/488,936 US20200016116A1 (en) 2015-03-19 2018-02-23 Compounds for treating cutaneous inflammation, female sexual disorders, and improving sexual function
US17/095,876 US20210059981A1 (en) 2015-03-19 2020-11-12 Compounds and forms of treatment for female sexual disorders
US17/838,865 US20230000819A1 (en) 2015-03-19 2022-06-13 Compounds for treating cutaneous inflammation, female sexual disorders, and improving sexual function

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US201762464354P 2017-02-27 2017-02-27
US62/464,354 2017-02-27

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US17/095,876 Continuation US20210059981A1 (en) 2015-03-19 2020-11-12 Compounds and forms of treatment for female sexual disorders
US17/838,865 Continuation US20230000819A1 (en) 2015-03-19 2022-06-13 Compounds for treating cutaneous inflammation, female sexual disorders, and improving sexual function

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Cited By (8)

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US10624873B2 (en) 2015-03-19 2020-04-21 Wendy Anne Epstein Compounds and forms of treatment for Female Sexual Disorders
WO2020160452A1 (fr) * 2019-02-01 2020-08-06 Tess Ventures, Inc. Combinaison de serm, de sarm et de cannabinoïdes destinée à améliorer la sécurité et l'efficacité d'endocrinothérapies
WO2021091908A1 (fr) * 2019-11-08 2021-05-14 Vella Bioscience, Inc. Compositions contenant du cannabidiol (cbd) à action périphérique et leurs utilisations pour améliorer la fonction sexuelle féminine ou traiter des troubles sexuels féminins
US20210275621A1 (en) * 2020-03-09 2021-09-09 Amorepacific Corporation Composition for preventing, alleviating, improving, or treating the female hormone controlling disorder syndrome or symptoms comprising green tea extract which has modified amounts of ingredients
EP3890725A4 (fr) * 2018-07-03 2022-05-18 Truetiva Inc. Compositions pour traiter des maladies dermatologiques
WO2022264127A1 (fr) * 2021-06-13 2022-12-22 Innocan Pharma Ltd. Compositions pour le traitement de l'atrophie vaginale
EP4181916A4 (fr) * 2020-07-17 2024-12-18 Canna-Chemistries LLC Compositions solides de delta9-tétrahydrocannabinol (delta9-thc)
WO2025106649A1 (fr) * 2023-11-17 2025-05-22 Curive Healthcare, Inc. Mélange de facteurs de croissance de vip et de vegf pour la santé vaginale

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US20030105132A1 (en) * 2001-03-28 2003-06-05 Stephen Challenger N-phenpropylcuclopentyl-substituted glutaramide derivatives as inhibitors of neutral endopeptidase
US20110129546A1 (en) * 2008-06-20 2011-06-02 Ignacio Umbert Mill Dermatological pharmaceutical composition for the treatment of skin inflammation diseases, such as dermatitis, atopic dermatitis, vitiligo, alopecia areata, acne, psoriasis, pruritus or combinations of same
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10624873B2 (en) 2015-03-19 2020-04-21 Wendy Anne Epstein Compounds and forms of treatment for Female Sexual Disorders
US11395814B2 (en) 2015-03-19 2022-07-26 Wendy Anne Epstein Compounds and forms of treatment for female sexual disorders
US12029723B2 (en) 2015-03-19 2024-07-09 Gto Pharma, Llc. Compounds and forms of treatment for female sexual disorders
EP3890725A4 (fr) * 2018-07-03 2022-05-18 Truetiva Inc. Compositions pour traiter des maladies dermatologiques
WO2020160452A1 (fr) * 2019-02-01 2020-08-06 Tess Ventures, Inc. Combinaison de serm, de sarm et de cannabinoïdes destinée à améliorer la sécurité et l'efficacité d'endocrinothérapies
WO2021091908A1 (fr) * 2019-11-08 2021-05-14 Vella Bioscience, Inc. Compositions contenant du cannabidiol (cbd) à action périphérique et leurs utilisations pour améliorer la fonction sexuelle féminine ou traiter des troubles sexuels féminins
CN114901071A (zh) * 2019-11-08 2022-08-12 维拉生物科技有限公司 外周作用的含有大麻二酚(cbd)的组合物及其用于增强女性性功能或治疗女性性障碍的用途
US20210275621A1 (en) * 2020-03-09 2021-09-09 Amorepacific Corporation Composition for preventing, alleviating, improving, or treating the female hormone controlling disorder syndrome or symptoms comprising green tea extract which has modified amounts of ingredients
US11633449B2 (en) * 2020-03-09 2023-04-25 Amorepacific Corporation Method for preventing, alleviating, improving, or treating the female hormone controlling disorder syndrome or symptoms comprising a step of administering green tea extract which has modified amounts of ingredients
EP4181916A4 (fr) * 2020-07-17 2024-12-18 Canna-Chemistries LLC Compositions solides de delta9-tétrahydrocannabinol (delta9-thc)
WO2022264127A1 (fr) * 2021-06-13 2022-12-22 Innocan Pharma Ltd. Compositions pour le traitement de l'atrophie vaginale
WO2025106649A1 (fr) * 2023-11-17 2025-05-22 Curive Healthcare, Inc. Mélange de facteurs de croissance de vip et de vegf pour la santé vaginale

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