Compositions and methods for improving sexual sensation disorders

Abstract

The present invention relates generally to methods and topical compositions for treating sensory disorders associated with sexual function in a subject, and more specifically, disorders of anogenital sensory function in a subject. In one embodiment, the present invention relates to topical, transdermal or transmucosal formulations comprising pirenzepine for improving anogenital sensory disorders.

Description

[Technical field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 300,008, filed January 16, 2022. The disclosures of the above-referenced applications are incorporated by reference in their entireties.

[0002] Books Disclosure The present invention relates generally to methods and topical compositions for treating sensory disorders associated with sexual function in a subject, and more specifically, disorders of anogenital sensory function in a subject. More specifically, the present invention relates to methods and topical compositions for treating sensory disorders associated with sexual function in a subject, and more specifically, disorders of anogenital sensory function in a subject. Disclosure relates to topical, transdermal or transmucosal formulations containing pirenzepine for improving anogenital sensory disorders. [Background technology]

[0003] The penis and vulva are highly sensitive organs in men and women, respectively, and contain thousands of nerve endings. These nerve endings must be properly stimulated in order for sexual arousal to occur. Disturbances in sensation can make it difficult for both men and women to become aroused, achieve orgasm or ejaculation, and enjoy sexual activity. These sensory disturbances can be sudden / acute changes, for example due to illness or injury, or gradual / chronic changes, such as those observed with aging. These disturbances can lead to loss / hyposensitivity, hypersensitivity or pain, or other sensory problems or disorders, each of which can result in relationship difficulties, tension in relationships, reduced sexual satisfaction for the partner, and psychological damage for the sufferer.

[0004] Regarding reduced sensitivity, many factors can lead to decreased sensitivity of the penis or vulva. Poor circulation due to poor cardiovascular health, or Nerve disorders such as peripheral neuropathy caused by systemic diseases such as diabetes (also known as diabetic neuropathy) or glycation due to high blood sugar, the effects of certain medications, or traumatic injury. Health problems such as diabetes, lupus, multiple sclerosis, cancer and prostate cancer treatments, vascular diseases and treatments such as statins, Peyronie's disease, and other biological / chemical causes. Other factors that lead to decreased sensitivity include age, lack of exercise, and obesity. Drug and alcohol use, smoking, use of prescription medications such as antidepressants, low testosterone, and age are also thought to lead to decreased sensation. In addition, damage to organs can lead to sensory impairment, for example, the sensation of a man's penis can be impaired by repeated masturbation or circumcision, which removes the highly sensitive foreskin tissue.

[0005] Furthermore, among the major categories of male sexual dysfunction, delayed ejaculation (DE) has received the least attention, despite the fact that it can lead to significant distress and interpersonal difficulties. DE is associated with problems with genital sensation and includes ejaculatory disorders ranging from delayed ejaculation to complete inability to ejaculate, including DE, retrograde ejaculation (RE), anejaculation, anorgasmia, and painful ejaculation.

[0006] Most efforts have focused on improving genital sensitivity by optimizing health, such as losing weight and quitting smoking. For circumcised men, methods to restore the foreskin may be available, but such procedures have mixed results and undesirable side effects. Surgical foreskin restoration procedures are risky and cost-prohibitive for most men. Topical creams that increase penile sensitivity are also available due to their ease of application and low cost compared to other treatments. Examples of sensitizing creams are disclosed in U.S. Patent Nos. 9,821,021 and 9,833,488.

[0007] Improving blood flow to the penis can also enhance penile function, improve symptoms of erectile dysfunction, and increase sexual arousal. There are several drugs that improve blood flow, including PDE5 inhibitors such as sildenafil and tadalafil. U.S. Patent No. 5,439,938 discloses a treatment method consisting of a compound that produces sufficient amounts of nitric oxide to initiate an erection of the man's penis. Also, injection of L-arginine, a precursor of nitric oxide in the body, promotes vasodilation and blood flow (see Morikawa et al, Stroke 1994; 25:429-435). Topical administration of arginine to promote penile blood flow is disclosed in U.S. Patent No. 7,914,814. However, increasing blood flow is not the same as improving sensory impairment.

[0008] Diabetic neuropathy is a group of nerve disorders caused by diabetes. Diabetic patients can develop neuropathy throughout the body over time, and neuropathy can occur in any organ system, including the digestive tract, heart, and genitals. Approximately 60-70% of diabetic patients have some form of neuropathy, which can cause peripheral neuropathy in the feet and hands, resulting in changes in sexual response, such as inability to achieve erection or reach sexual climax. Increasing the sensitivity of the remaining nerves in neuropathy patients can increase sensation, alleviate symptoms of neuropathy, and significantly improve quality of life.

[0009] Hypersensitivity and hyperalgesia lead to pain. Many of the same things that cause hyposensitivity can also cause hypersensitivity.

[0010] In women, vulvodynia is a complex gynaecological disorder characterized by chronic pain localized to the vulva. It is a potentially debilitating condition that can last for years and cause physical disability, sexual dysfunction, and psychological difficulties. Daily activities and quality of life can be significantly impaired, with many patients having difficulty walking or sitting for long periods of time, hypersensitivity to clothing in the vaginal area, and mild to severe pain described as burning, stinging, or itching. Although often difficult to diagnose, it is generally estimated that more than 15% of adult women in Western countries will experience vulvodynia at some point in their lives. Vulvodynia most commonly affects women of childbearing age.

[0011] The most common form of vulvar pain is vulvar vestibulitis. Women with vulvar vestibulitis typically experience pain localized to the vestibule and only upon or after touch or pressure. Vulvar vestibulitis is characterized by pain, tenderness, vestibular erythema, pruritus, swelling, and urethritis. The pain is described as a sharp, burning, or sore sensation. Generalized vulvodynia is characterized by diffuse pain and / or burning in the vaginal opening, labia majora, labia minora, and / or vestibule. The pain may be constant or intermittent, and symptoms are not necessarily triggered by touching or pressure on the vulva, although physical contact to the area may aggravate the condition.

[0012] The etiology of vulvodynia is unknown; however, hypotheses include viral, fungal, and bacterial attack, allergic reactions, neuropathic processes, and autoimmune reactions. Irritation of the muscles that support the uterus, bladder, and rectum (pelvic floor muscles or levator ani) and irritation of the nerves in the vulvar tissues, known as pudendal neuralgia, can cause additional pain symptoms related to the vulva.

[0013] Pudendal neuralgia (also known as chronic perineal pain) is a term used to describe chronic pain that radiates to the pudendal nerve, which in women consists of the vaginal opening, labia majora, perianal skin, and parts of the labia majora. The clitoral nerve also innervates the urethra and anal mucosa. Thus, dysfunction of the clitoral nerve affects not only the sensory function of the perineal skin (including the vulva), but also elimination and defecation. Symptoms such as a constant urge to urinate and a foreign body sensation in the rectum may occur. Although these symptoms are not classified as pain in themselves, they nevertheless contribute to the individual's disability.

[0014] Pelvic pain is very common in men, with an estimated 1 in 9 men suffering from pain in the area behind the penis between the pubic bone and the tailbone. This is called the "perineum". The main nerve that controls sensation and muscles in the perineum is the clitoral nerve. Additionally, in men, penile pain can affect the base, shaft, or head of the penis. It can also affect the foreskin. Pain can also be accompanied by an itchy, burning, or throbbing sensation. Penile pain can also be the result of an accident or illness. It can occur in men of any age. The pain varies depending on what underlying condition or disease is causing it. Causes of penile pain include Peyronie's disease, priapism (caused by side effects of erectile dysfunction medications or depression medications, blood clotting disorders, psychiatric disorders, blood disorders such as leukemia or sickle cell anemia, alcohol or drug use, or injuries to the penis or spinal cord), balanitis, phimosis and paraphimosis, sexually transmitted diseases, injuries to the penis, certain cancers, and certain skin conditions such as psoriasis.

[0015] Chronic pain is difficult to treat because it has multiple possible causes. First-line treatment is to treat the suspected cause, usually by pharmacological treatment of infection and discontinuation of any irritants or medications believed to be causing the problem. Oral medications such as antihistamines and tricyclic antidepressants, oral supplements such as calcium citrate, physical therapy, and dietary modifications may provide relief. More invasive treatments include local injections of interferon, laser therapy, and surgery, but these methods are expensive and may be associated with complications such as hematomas, wound avulsions, and uneven healing. There is no established cure for chronic pain syndromes. Summary of the Invention

[0016] stomach Some embodiments provide a topical composition for improving genital sensitivity in a subject, comprising pirenzepine or a pharma- ceutically acceptable salt in a topical carrier.

[0017] In some embodiments, the composition further comprises one or more pharma- ceutically acceptable excipients. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] One embodiment is a method for ameliorating sexual sensory disorders in a subject by applying to the subject's anogenital tract an effective amount of a composition comprising a therapeutically effective amount of pirenzepine or a pharma- ceutically acceptable salt thereof.

[0019] Books Disclosure While specific embodiments of the present invention have been illustrated and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Many variations, modifications, and substitutions may be made to the present invention. Disclosure The invention described herein may be practiced by those skilled in the art without departing from the spirit and scope of the invention. Fruit Various alternatives to the embodiment are possible. , taken Attachment Special It is intended to cover methods and structures within the scope of the claims and their equivalents.

[0020] Unless otherwise defined, all technical and scientific terms used herein are defined by the Disclosure" has the same meaning as commonly understood by one of ordinary skill in the art to which it pertains. All patents and publications mentioned herein are incorporated by reference.

[0021] As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0022] When ranges are used herein for physical properties such as molecular weight, or chemical properties such as chemical formulas, all combinations and subcombinations of the ranges and specific embodiments are intended to be included. The term "about" when referring to a numerical value or numerical range means that the numerical value or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the numerical value or numerical range may vary, for example, between 1% and 15% of the stated numerical value or numerical range. The term "comprising" (and related terms such as "comprise" or "comprise" or "consist" or "comprising") includes, for example, any composition of matter, composition, method, or process, etc., that "consists" or "consists essentially of" the described features.

[0023] The abbreviations used herein have their conventional meaning within the chemical and biological arts.

[0024] As used herein, the term "subject" or "patient" refers to any subject to which the drug is administered. The subject may be a vertebrate, e.g., a mammal. Thus, the subject may be a human. The term does not denote a particular age or sex. Thus, adult, juvenile, and neonatal subjects, whether male or female, are intended to be subjects. A patient refers to a subject suffering from a disease or disorder. The term "patient" includes human and animal subjects.

[0025] As used herein, the term "anogenital region" or "anogenital" refers to the anus and genital area. In certain embodiments, the female anogenital region comprises the external genitalia, cervix, vagina, vulva and vulvar skin, labia, inner vulva, clitoris, urethral meatus, urethral folds, vulvar vestibule, perineum, and / or anus. In certain embodiments, the male anogenital region comprises the penis, base of the penis, foreskin, urethral meatus, scrotum, perineum, and anus. As used herein, the term "urogenital region" refers to the distal urinary tract and genital area. In some subjects, the anogenital and / or urogenital region may be ambiguous, intersex, or transitional from male to female or female to male due to ectopic (e.g., surgery or hormone therapy) or natural / genetic causes.

[0026] As used herein, the terms "treatment" and "treatment," or "improvement," "enhancement," and "improvement" are used interchangeably. These terms refer to an approach to obtain a beneficial or desired result, including, but not limited to, therapeutic benefit and / or prophylactic benefit. Therapeutic benefit is achieved by eradication or amelioration of the underlying disease being treated. Therapeutic benefit is also achieved by eradication or amelioration of one or more physiological symptoms of the underlying disease, such that the patient is observed to improve, even though the patient may still be suffering from the underlying disease. It also refers to the restoration of lost function or sensation. For prophylactic benefit, the composition can be administered to patients at risk of developing a particular disease, or to patients who report one or more physiological symptoms of the disease, even if they have not been diagnosed with the disease. The composition can be administered to a subject to prevent the progression of a physiological symptom or to prevent the progression of the underlying disease. For example, the composition can be administered to a subject to prevent the progression of a physiological symptom or to prevent the progression of the underlying disease. DisclosureWith respect to, these terms refer to the prevention and / or restoration of sensory disorders / problems related to the sexual function of a subject, more specifically, the prevention of and / or restoration of disorders of the anogenital sensory function of a subject. This includes biological improvements such as reversing, preventing, or delaying neurodegeneration. Or, it includes improvements in functional symptoms such as the restoration, prevention, or delay of sexual function symptoms such as hyposensitivity, hypersensitivity, reduction in ejaculation disorders ranging from various delays in ejaculation delay to complete inability to ejaculate, DE, retrograde ejaculation (RE), anaejaculation, anorgasmia, painful ejaculation, reduced ability to become excited or maintain arousal or intensity of arousal, reduced potency / intensity or ability to reach orgasm or ejaculation, prolonged refractory ejaculation, or the improvement of normal sexual activity, including unperceived or subclinical changes in sexual function that occur with aging. In one embodiment, the present invention Disclosure is to stimulate other erogenous zones such as the nipples. Disclosed The use of the formulation is contemplated.

[0027] As used herein, a "therapeutic effect" includes a therapeutic effect and / or a prophylactic effect as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of a disease or symptom, slowing, halting or reversing the progression of a disease or condition, or a combination thereof, including, for example, preventing and / or reversing peripheral neuropathy, or improving one or more sexual functions or dysfunctions.

[0028] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein sufficient to affect the intended administration, including but not limited to disease treatment, as defined below. A therapeutically effective amount may vary depending on the intended administration (in vitro or in vivo), a reasonable benefit / risk ratio applicable to any medical treatment, the severity of the disease state, the method of administration, or the subject and disease state to be treated, such as the subject's weight and age, and these can be readily determined by one of ordinary skill in the art. The specific dosage will vary depending on the particular compound selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system in which it is delivered.

[0029] As used herein, the term "pharmaceutically acceptable salts" refers to salts suitable for pharmaceutical use, preferably suitable for use in the tissues of humans and lower animals without undue irritation, allergic reactions, etc. Pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. For example, SM Berge et al. provide a detailed description of pharmaceutically acceptable salts in J Pharmaceutical Sciences, 66: 1-19 (1977), which is incorporated herein by reference. Salts are used in the present invention as a method of treating or preventing osteoarthritis. Disclosure They can be prepared in situ during the final isolation and purification of the compounds of the present invention, or can be prepared separately by reacting a free base or free acid function with a suitable reagent, as generally described below. For example, a free base function can be reacted with a suitable acid. DisclosureWhen the compound of formula (I) contains an acidic moiety, suitable pharma- ceutically acceptable salts include metal salts such as alkali metal salts, e.g., sodium or potassium salts; and alkaline earth metal salts, e.g., calcium or magnesium salts. Examples of pharma-ceutically acceptable non-toxic acid addition salts include salts of amino groups formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid, and the like; organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, and the like; or by other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfonate, heptanoate, hexanoate, hydroiodide, and 2-hydroxy-ethanesulfonate. Representative salts include, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharma- ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, amine cation salts, and the like, formed, where appropriate, by direct reaction with the drug carboxylic acid or with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, sulfonates, arylsulfonates, and the like:

[0030] The pharmacological agent can be formulated into a pharmaceutical composition in combination with a suitable pharma- ceutically acceptable carrier. By "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" is meant a carrier, diluent, excipient, solvent, enhancer, or other component of the subject pharmacological agent composition, which is compatible with one or more pharmacological agents and any other components of the subject pharmacological agent composition in that the pharma-ceutically acceptable carrier can be combined with the pharmacological agent without eliminating the biological or therapeutically effective activity of the one or more pharmacological agents (e.g., pirenzepine), and is suitable for use in subjects as provided herein without excessive side effects (such as toxicity, irritation, allergic reactions, and death). A side effect is "excessive" when the risk outweighs the benefit provided by the pharmaceutical agent. Supplementary or other active ingredients can also be incorporated into the composition.

[0031] As used herein, the terms "co-administration," "concomitant administration," and their grammatical equivalents encompass the administration of two or more agents to an animal such that both agents and / or their metabolites are present in the animal at the same time. Concomitant administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0032] As used herein, "topical treatment" refers to the treatment of anogenital sensitivity disorder of a subject, in which the drug is delivered locally and not via systemic delivery.This can include, for example, in the treatment of the skin, where the drug is applied to many or several different locations on the skin, and the drug is delivered into the skin and to the tissue adjacent to the skin by absorption through the skin, in many or several different localized areas.

[0033] As used herein, "local delivery" refers to delivery of a drug compound to the site of therapeutic use, including, for example, applying the formulation directly to the area of ​​skin to be treated, spraying the formulation onto the area of ​​skin to be treated, spraying, using suppositories or tampons to deliver the formulation intravaginally to administer the drug to the vaginal or anal passages, or using wipes or pads / patches to apply the formulation to the skin of the anogenital area (e.g., penis, vulva, or anus).

[0034] As used herein, "local tissue concentration" means , cure This refers to the concentration of pirenzepine in the tissue area where the therapy is delivered and absorbed.

[0035] Books Disclosure provides compositions and methods for treating disorders of anogenital sensation. In one embodiment, the present invention Disclosure Provided are compositions and methods for improving anogenital sensitivity. In another embodiment, the present invention provides Disclosure presents compositions and methods for treating anogenital hypersensitivity in subjects, including treating chronic vulvodynia and perineal pain, and chronic pelvic and penile pain; and symptoms and conditions related to such pain.More specifically, presented herein is a composition comprising pirenzepine, which is formulated for topical, transdermal or transmucosal administration.

[0036] Books Disclosure The methods and compositions are applicable to the treatment of various conditions and symptoms associated with disturbance of normal anogenital sensation, including, but not limited to, anogenital hypersensitivity or hypersensitivity, penile numbness, delayed ejaculation or orgasm, vulvar numbness or reduced sensitivity, or alternatively, vulvodynia, clitoral neuralgia, pelvic floor tension muscle pain, and pain associated with any of these conditions or symptoms. The vulvodynia may be localized vulvodynia or generalized vulvodynia. The condition may be selected, for example, from vulvar vestibulitis, localized evoked vestibulopathy (LPV), anesthetic vulvodynia, vulvodermatopathy, or cyclic vulvitis. In one embodiment, the present invention is directed to a method for treating vulvar vestibulitis. Methods and compositions described hereinis used to treat ejaculation disorders, which range from delayed ejaculation due to sensory problems to complete inability to ejaculate. useful and includes delayed ejaculation (DE), anejaculation, anorgasmia, and painful ejaculation.

[0037] Pirenzepine, an M1 selective antagonist, is used to treat peptic ulcers because it reduces gastric acid secretion and muscle spasms. Acetylcholine is a parasympathetic nervous system neurotransmitter that initiates a state of rest and digestion (as opposed to fight or flight), leading to increased gastric motility and digestion; pirenzepine inhibits these actions, causing decreased gastric motility, delayed gastric emptying, and constipation. Pirenzepine cannot cross the blood-brain barrier and therefore has no effect on the brain or spinal cord. Pirenzepine is being studied as a treatment for myopia. Pirenzepine is currently being investigated as a treatment for peripheral neuropathy (see WIPO Patent Applications WO / 2012 / 055018A1, "Therapeutic Compositions for Diabetic Symmetric Polyneuropathy," WIPO Patent Applications WO / 2015 / 089664A1, "Methods and Compositions for the Treatment of Peripheral Neuropathy," and WO / 2020 / 198252A1, "Topical Formulations for the Treatment of Peripheral Neuropathy").

[0038] "Pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with human or animal tissues without undue toxicity, irritation, allergic response, etc., and that offers a reasonable benefit / risk ratio. "Pharmaceutically acceptable salt" refers to an at least substantially non-toxic salt or ester salt of a compound disclosed herein that, upon administration to a recipient, is capable of directly or indirectly providing a compound disclosed herein, or a metabolite or residue thereof, having inhibitory activity.

[0039] Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail by SM Berge et al. in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. The pharmaceutically acceptable salts of the compounds disclosed herein include those derived from suitable inorganic and organic acids, including pirenzepine free base or pirenzepine monohydrate. Examples of pharmaceutically acceptable non-toxic acid addition salts are the amino salts formed by mineral acids such as hydrochloric acid (e.g., pirenzepine dihydrochloride or monohydrochloride), hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by other methods in the art such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, esylate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfonate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, The salts lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0040] Books Formulations as described in the specificationis suitable for the localized treatment of sensory disorders in the anogenital region of a subject. The formulation contains pirenzepine in a composition suitable for topical administration to a subject. The compositions include gels, creams, lotions, solutions, suspensions, emulsions, ointments, powders, crystalline forms, sprays, foams, ointments, pastes, plasters, paints, bioadhesives, suppositories, tampons, body wipes, wound dressings, skin patches, genital pads, transdermal patches, and the like. The formulation may further include additional components, such as components that enhance the delivery of the active compound, enhance the therapeutic effect, have secondary effects, or minimize side effects. Such formulations allow for efficient delivery of pirenzepine to the site of administration, such as, but not limited to, the penis, vagina, and surrounding tissues and organs.

[0041] Topical compositions can be formulated, for example, as gels, lotions, creams, mousses, aerosols, ointments, or lubricants, so long as the formulation remains substantially in place when the composition is applied, particularly when applied to the genitals. For example, after application, the composition does not substantially run off for a sufficient time to spread over the relevant parts of the penis, including over the glans of the penis, and over the relevant parts of the vagina, including over the vulva of the vagina. They can also be formulated to dry relatively quickly and penetrate the subject's skin. Other factors to consider include transfer (or non-transfer) to a sexual partner, the ability to wash off residual formulation, and the chronic effect of the formulation with repeated use.

[0042] In some embodiments, the topical compositions provided herein may include a pharmaceutical carrier, a diluent, a cosolvent, an emulsifier, a penetration enhancer, a preservative, an emollient, or a combination thereof. Therapeutically acceptable carriers or diluents are well known in the pharmaceutical art and are described, for example, in Florence AT and Siepmann J, editors. Modern Pharmaceutics Volume 1: Basic Principles and Systems. 5th ed. CRC Press, 2009; Augsburger LL and Hoag SW, editors. Pharmaceutical Dosage Forms: Tablets. 3rd ed. CRC Press, 2016; Ansel HC. Introduction to Pharmaceutical Dosage Forms, 2nd ed. Lea & Febiger, 1976; Adejare A, editor. Remington: The Science and Practice of Pharmacy, 23rd ed. Academic Press, 2020; Brunton L, et al., editors.goodman &gilman's The Pharmacological Basis of Therapeutics, 13th ed. McGraw-Hill, 2017; Shah VP et al., editors. Topical Drug Bioavailability, Bioequivalence, and Penetration, 2nd ed. Springer, 2015; Hillery AM, & Park K. Drug Delivery and Targeting: For Pharmacists and Pharmaceutical Scientists, CRC Press, 2016; Allen L. Pharmaceutical Dosage Forms and Drug Delivery Systems, 11th ed. LWW, 2017 (respectively).

[0043] Excipients The pharmaceutical compositions may include one or more inert excipients including water, aqueous buffer solutions, surfactants, volatile liquids, starches, polyols, granulating agents, microcrystalline cellulose, diluents, lubricants, acids, bases, salts, emulsions such as oil / water emulsions, oils such as mineral oils and vegetable oils, humectants, chelating agents, antioxidants, sterile solutions, complexing agents, disintegrants, etc. The CTFA Cosmetic Ingredient Handbook, Eighth Edition, 2000 and Tenth Edition, 2004, which are incorporated by reference, describe a wide variety of cosmetic and pharmaceutical ingredients commonly used in skin care compositions, which are included herein. Disclosure Examples of these functional classes disclosed in this document include: absorbents, abrasives, anti-caking agents, antifoaming agents, antimicrobial agents, antioxidants, binders, biological additives, buffers, bulking agents, chelating agents, chemical additives, colorants, cosmetic astringents, cosmetic biocides, denaturants, pharmaceutical astringents, topical analgesics, film formers, fragrance ingredients, moisturizers, opacifiers, pH adjusters, plasticizers, preservatives, reducing agents, skin whitening agents, skin conditioning agents (emollients, moisturizers, miscellaneous agents, occlusive agents), skin protectants, solvents, foam boosters, hydrotropes, solubilizers, steroidal anti-inflammatory agents, surfactants / emulsifiers, suspending agents (non-surfactant), sunscreens, topical analgesics, UV absorbers, SPF boosters, thickeners, waterproofing agents, viscosity increasing agents (aqueous and non-aqueous).

[0044] medicine Surfactants that can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof, i.e., a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.

[0045] One of the surfactants can be the sodium salt form of the compound, and can include monosodium salt form.Suitable sodium salt surfactant can be selected based on desirable properties, including fast polymerization rate, small particle size suitable for delivery, good polymerization yield, stability including freeze-thaw stability and storage stability, improved surface tension properties, and lubricating properties.

[0046] The surfactant may be any suitable non-toxic compound that is non-reactive with the pharmaceutical agent and that substantially reduces the surface tension between the pharmaceutical agent, the excipient, and the site of administration. Surfactants include oleic acid available under the tradenames Medique 6322 and Emersol 6321 (Cognis Corp, Cincinnati, Ohio); cetylpyridinium chloride (Arrow Chemical, Inc. Westwood, NJ); soy lecithin available under the tradename Epikuron 200 (Lucas Meyer, Decatur, Ill.); Tween 20 (available from ICI Specialty Chemicals, Wilmington, Del.); polyoxyethylene (20) sorbitan monostearate available under the tradename Tween 60 (ICI); polyoxyethylene (20) sorbitan monooleate available under the tradename Tween 80 (ICI); polyoxyethylene (10) stearyl ether available under the tradename Brij 76 (ICI); polyoxyethylene (2) oleyl ether available under the tradename Brij 92 (ICI); Tetronic 150 Polyoxyethylene-polyoxypropylene-ethylenediamine block copolymers available under the tradenames Pluronic L-92, Pluronic L-121 and Pluronic F 68 (BASF); castor oil ethoxylates available under the tradename Alkasurf CO-40 (Rhone-Poulenc Mississauga, Ontario, Canada); and mixtures thereof.

[0047] Suitable hydrophilic surfactants can generally have an HLB value of at least 10, while suitable lipophilic surfactants can generally have an HLB value of about 10 or less. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with low HLB values ​​are more lipophilic or hydrophobic and more soluble in oils, while surfactants with high HLB values ​​are more hydrophilic and more soluble in aqueous solutions. Hydrophilic surfactants are generally considered to be compounds with HLB values ​​greater than about 10, as well as anionic, cationic, or zwitterionic compounds to which the HLB scale does not generally apply. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds with HLB values ​​equal to or less than about 10. However, the HLB value of a surfactant is only a rough guide that is commonly used to enable the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0048] The hydrophilic surfactant may be ionic or non-ionic.Suitable ionic surfactants include, but are not limited to, alkyl ammonium salts.Fusidates;Fatty acid derivatives of amino acids, oligopeptides, and polypeptides;Glyceride derivatives of amino acids, oligopeptides, and polypeptides;Lecithin and hydrogenated lecithin;Lysolecithin and hydrogenated lysolecithin;Phospholipids and derivatives thereof;Lysophospholipids and derivatives thereof;Carnitine fatty acid ester salts;Alkyl sulfates;Fatty acid salts;Docosate sodium;Acyl lactylates;Mono- and diacetylated tartaric acid esters of mono- and diglycerides;Succinated mono- and diglycerides;Citrate esters of mono- and diglycerides;And mixtures thereof.

[0049] Among the aforementioned groups, ionic surfactants include, by way of example only: lecithin, lysolecithin, phospholipids, lysophospholipids and their derivatives; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium doxorate; acyl lactylates; mono- and diglycerides of monoacetylated and diacetylated tartaric acid esters; succinated mono- and diglycerides; citrate esters of mono- and diglycerides; and mixtures thereof.

[0050] Ionic surfactants include lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactate esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono / diglycerides, glyceryl esters of ... Ionized forms of glycerides include mono / diacetylated tartaric acid esters, mono / diacetylated tartrate esters, mono / diglycerides citrate esters, cholyl sarcosine, caproate, caprylate, caprate, laurate, myristic acid ester, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teraceyl sulfate, docusate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and salts and mixtures thereof.

[0051] Hydrophilic nonionic surfactants include, but are not limited to, alkyl glucosides; alkyl maltosides; alkyl thioglucosides; lauryl macrogol glycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenol fatty acid esters such as polyoxyalkylene alkylphenol polyethylene glycol fatty acid monoesters, polyethylene glycol fatty acid diesters, such as polyethylene glycol alkylphenols; polyethylene glycol glycerin fatty acid esters; polyglycerin fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of at least one of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols with polyols; polyoxyethylene sterols, derivatives and analogs thereof; polyoxyethylenated vitamins and their derivatives polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; hydrophilic transesterification products of at least one of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils with polyethylene glycol sorbitan fatty acid esters, and polyols. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a sugar.

[0052] Other hydrophilic nonionic surfactants include PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 dilaurate, PEG-1 ...32 dilaurate, PEG-32 dilaurate, PEG-32 dilaurate, PEG-32 dilaurate, PEG-32 dilaurate, PEG-32 dilaurate, PEG-32 dilaurate, PEG-32 dilaurate, PEG-32 dilaurate, PEG-32 dilaurate, PEG-32 dilaurate, PEG-32 dilaurate, PEG-32 dilaurate, PEG-32 dilaurate, PEG-32 dilaurate, PEG-32 dilaurate, PEG-32 dilaurate, PEG-32 dilaurate, PEG-32 dilaurate, PEG-32 dilaurate, Stearate, PEG-40 Stearate, PEG-100 Stearate, PEG-20 Dilaurate, PEG-25 Glyceryl Trioleate, PEG-32 Glyceryl Dioleate, PEG-20 Glyceryl Laurate, PEG-30 Glyceryl Laurate, PEG-20 Glyceryl Stearate, PEG-20 Glyceryl Oleate, PEG-30 Glyceryl Oleate, PEG-30 Glyceryl Laurate, PEG-40 Glyceryl Laurate Lyceryl, PEG-40 Palm Kernel Oil, PEG-50 Hydrogenated Castor Oil, PEG-40 Castor Oil, PEG-35 Castor Oil, PEG-60 Castor Oil, PEG-40 Hydrogenated Castor Oil, PEG-60 Hydrogenated Castor Oil, PEG-60 Corn Oil, PEG-6 Capric / Caprylic Glycerides, PEG-8 Capric / Caprylic Glycerides, Polyglyceryl-10 Laurate, PEG-30 Cholesterol, PEG-25 Phytosterols, PEG-30 Soy Sterols , PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, PEG-100 tocopherol succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG 15-100 octylphenol series, poloxamer.

[0053] Suitable lipophilic surfactants include, by way of example only, fatty alcohols, glycerol fatty acid esters, acetylated glycerol fatty acid esters, lower alcohol fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters, polyethylene glycol sorbitan fatty acid esters, sterols and sterol derivatives, polyoxyethylated sterols and sterol derivatives, polyethylene glycol alkyl ethers, sugar esters, sugar ethers, lactic acid derivatives of mono- and diglycerides, hydrophobic transesterification products of at least one of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols with polyols, oil-soluble vitamins / vitamin derivatives, and mixtures thereof. Within this group, lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of at least one of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides with polyols.

[0054] Surfactants are used in accordance with this specification unless their use is otherwise consistent. As stated in the specification Can be used in any formulation .stomach In some embodiments, it may be desirable to use no surfactants or to use a limited class of surfactants. As stated in the specificationTopical formulations may be free or substantially free of surfactants, i.e., less than about 0.0001% by weight of surfactants. This is particularly true when using chromones as described above. However, if necessary, the formulation may contain surfactants that are conventionally used in topical formulations, such as oleic acid, lecithin, sorbitan trioleate, cetylpyridinium chloride, benzalkonium chloride, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate, polyoxypropylene / polyoxyethylene block copolymers, polyoxypropylene / polyoxyethylene / ethylenediamine block copolymers, ethoxylated castor oil, etc., and the proportion of surfactants, if present, may be about 0.0001-1%, particularly about 0.001-0.1%, by weight of the total formulation. Other suitable surfactants / emulsifiers will be known to those skilled in the art and are listed in the CTFA International Cosmetic Ingredient Dictionary and Handbook, Vol. 2, 7th Edition (1997).

[0055] Other suitable aqueous vehicles include, but are not limited to, Ringer's solution and isotonic saline. Aqueous suspensions include suspending agents such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and wetting agents such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.

[0056] medicineChelating agents that can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, ethylenediaminetetraacetic acid (EDTA), disodium EDTA, calcium disodium edetate, trisodium EDTA, albumin, transferrin, desferoxamine, desferal, desferoxamine mesylate, tetrasodium and dipotassium EDTA, sodium metasilicate, or any combination thereof. In some embodiments, up to about 0.1% W / V of a chelating agent, such as EDTA or a salt thereof, is added to the subject formulations. As stated in the specification is added to the formulation.

[0057] medicine Preservatives that can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, sulfites, peroxides, perborates, imidazolidinyl urea, diazolidinyl urea, phenoxyethanol, alkali chlorides including benzalkonium chloride, methylparaben, ethylparaben, and propylparaben. ,set Suitable preservatives for the composition include benzalkonium chloride, sulfites, peroxides, perborates, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, edetate disodium, sorbic acid, Onamer M, or other agents known to those skilled in the art. .stomach In some embodiments, such preservatives may be employed at a level of 0.004% to 0.02% W / V. wish In some compositions, preservatives, such as benzalkonium chloride, methylparaben, and / or propylparaben, may be employed at levels of about 0.001% to less than about 0.01%, such as about 0.001% to about 0.008%, or about 0.005% W / V. A concentration of about 0.005% benzalkonium chloride is preferred. DisclosureIt has been found that the amount of methylparaben in the composition of claim 1 can be sufficient to preserve the composition from microbial attack. Those skilled in the art can determine the appropriate concentration of ingredients and the combination of various ingredients to generate a suitable topical formulation. For example, a formulation for application to the eye or skin may use a mixture of methylparaben and propylparaben at about 0.02% W / V and about 0.04% W / V, respectively. In some embodiments, these formulations use methylparaben and / or propylparaben in amounts up to about 0.02% W / V and about 0.04% W / V, respectively, including embodiments that do not use methylparaben or propylparaben.

[0058] medicine Lubricants that can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, soybean oil), zinc stearate, ethyl oleate, ethyl laurate, or mixtures thereof.

[0059] medicine Viscosifiers that can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, isopropyl myristate, isopropyl palmitate, isodecyl neopentanoate, squalene, mineral oil, C12-C15 benzoic acid esters, and hydrogenated polyisobutene.It is desirable to use a thickener that does not destroy other compounds in the final product, such as a non-ionic thickener.The selection of additional thickeners is within the skill of the art.

[0060] Skin conditioning agents include emollients, moisturizers, and humectants. Humectants are humectants that promote water retention due to their hygroscopic properties. Suitable skin conditioning agents include urea; guanidine; aloe vera; glycolic acid and glycolates such as ammonium and quaternary alkyl ammonium; lactic acid and lactates such as sodium lactate, ammonium lactate, and quaternary alkyl ammonium lactate; polyhydroxy alcohols such as sorbitol, glycerol, mannitol, xylitol, hexanetriol, polymeric glycols such as propylene glycol, butylene glycol, hexylene glycol, polyethylene glycol, and polypropylene glycol; carbohydrates such as alkoxylated glucose; starch; starch derivatives; glycerin; pyrrolidone carboxylic acid (PCA); lactamide monoethanolamine; acetamide monoethanolamine; volatile silicone oils; non-volatile silicone oils; and mixtures thereof. Suitable silicone oils can be polydialkylsiloxanes, polydiarylsiloxanes, polyalkarylsiloxanes, and cyclomethicones having 3 to 9 silicon atoms.

[0061] Emollients are greasy or oily substances that help smooth and soften the skin and may also reduce roughness, cracking or irritation.Typical and preferred emollients include mineral oils having viscosities ranging from 50 to 500 centipoise (cps), lanolin oil, coconut oil, cocoa butter, olive oil, almond oil, macadamia nut oil, aloe extracts such as aloe vera lipoquinone, synthetic jojoba oil, natural Sonora jojoba oil, safflower oil, corn oil, liquid lanolin, cottonseed oil and peanut oil. In some embodiments, the emollient is a cocoglyceride, a mixture of mono-, di- and triglycerides of cocoa oil, sold under the trade name Myritol 331 by Henkel KGaA, dicaprylyl ether available under the trade name Cetiol OE by Henkel KGaA, or a C12-C15 alkyl benzoate sold under the trade name Finsolv TN by Finetex. Another suitable emollient is DC 200 Fluid 350, a silicone oil available from Dow Corning Corp, and caprylic acid, a fatty acid found in coconut oil, which is a medium chain fatty acid believed to have strong antibacterial, antifungal and anti-inflammatory properties.

[0062] Other suitable emollients include squalane, castor oil, polybutene, sweet almond oil, avocado oil, calophyllum oil, ricin oil, vitamin E acetate, olive oil, silicone oils such as dimethylpolysiloxane and cyclomethicone, linoleic alcohol, oleyl alcohol, cereal germ oils such as wheat germ oil, isopropyl palmitate, octyl palmitate, isopropyl myristate, hexadecyl stearate, butyl stearate, decyl oleate, acetyl glycerides, octanoates of (C12-C15) alcohols, and the like. Benzoates, octanoates and decanoates of alcohols and polyalkylates, butyl stearate, decyl oleate, acetyl glycerides, octanoates and benzoates of (C12-C15) alcohols, octanoates and decanoates of alcohols and polyhydric alcohols such as glycol and glyceryl, ricinoleates such as isopropyl adipate, hexyl laurate, octyl dodecanoate, dicaprylyl maleate, hydrogenated vegetable oils, phenyl trimethicone, jojoba oil, and aloe vera extract.

[0063] Other suitable emollients that are solid or semi-solid at room temperature can also be used. Such solid or semi-solid cosmetic emollients include glyceryl dilaurate, hydrogenated lanolin, hydroxylated lanolin, acetylated lanolin, petrolatum, isopropyl lanolate, butyl myristate, cetyl myristate, myristyl myristate, myristyl lactate, cetyl alcohol, isostearyl alcohol and isocetyl lanolate. Optionally, one or more emollients can be incorporated into the formulation.

[0064] medicineAntioxidants that can be used to form pharmaceutical compositions and dosage forms include propyl, octyl, and dodecyl esters, butylated hydroxyanisole (BHA, usually purchased as a mixture of ortho and meta isomers), green tea extract, uric acid, cysteine, pyruvic acid, nordihydroguaiaretic acid, ascorbic acid, salts of ascorbic acid such as ascorbyl palmitate and sodium ascorbate, ascorbyl glucosamine, vitamin E (i.e., tocopherols such as α-tocopherol), derivatives of vitamin E (e.g., tocopherol acetate), retinoic acid, retinol, trans-retinol, cis-retinol, trans-retinol and cis-retinol, and combinations of these with methyltransferase and methyltransferase. Retinoids such as retinol mixtures, 3-dehydroretinol, and derivatives of vitamin A (such as retinyl acetate, retinal, retinyl palmitate (also known as thethinyl palmitate)), sodium citrate, sodium sulfite, lycopene, anthocyanoids, bioflavinoids (such as hesperitin, naringenin, rutin, quercetin), superoxide dismutase, glutathione peroxidase, butylated hydroxytoluene (BHT), indole-3-carbinol, pycnogenol, melatonin, sulforaphane, pregnenolone, lipoic acid, 4-hydroxy-5-methyl-3[2H]-furanone, and the like.

[0065] Skin protectants are agents that protect the skin from chemical and / or physical irritants, such as ultraviolet light, and include sunscreens, anti-acne additives, anti-wrinkle agents, and anti-skin atrophy agents. Examples of sunscreens suitable as skin protectants include 2-ethylhexyl p-methoxycinnamate, 2-ethylhexyl N,N-dimethyl-p-aminobenzoate, p-aminobenzoic acid, 2-phenylbenzimidazole-5-sulfonic acid, octocrylene, oxybenzone, homodiphenylbenzimidazole-5-sulfonic acid, homodiphenylbenzimidazole-5-sulfonic acid, octocrylene, oxybenzone, homomethyl salicylate, octyl salicylate, 4,4'-methoxy-t-butyldibenzoylmethane, 4-isopropyldibenzoylmethane, 3-benzylidene camphor, 3-(4-methylbenzyl)-2-methyl-1,2-dimethyl ... 4-N,N-(2-ethylhexyl)methylaminobenzoate with 4-hydroxydibenzoylmethane, 4-N,N-(2-ethylhexyl)methylaminobenzoate with 2-hydroxy-4-(2-hydroxyethoxy)benzophenone, and 4-N,N-(2-ethylhexyl)methylaminobenzoate with 4-(2-hydroxyethoxy)dibenzoylmethane. Suitable anti-acne agents include salicylic acid; 5-octanoyl salicylic acid; resorcinol; retinoids, such as retinoic acid and its derivatives; sulfur-containing D and L amino acids other than cysteine; lipoic acid; antibiotics and antibacterial agents, such as benzoyl peroxide, octopirox, tetracycline, 2,4,4'-trichloro-2'-hydroxydiphenyl ether, 3,4,4'-trichlorovanillide, azelaic acid, phenoxyethanol, phenoxypropanol, phenoxyisopropanol, ethyl acetate, clindamycin, merclocycline, and the like; flavonoids; and bile salts, such as simnol sulfate, deoxycholate, cholate, and the like.Examples of anti-wrinkle and anti-skin atrophy agents include retinoic acid and its derivatives, retinol, retinyl esters, salicylic acid and its derivatives, sulfur-containing D- and L-amino acids except cysteine, alpha-hydroxy acids (such as glycolic acid and lactic acid), phytic acid, lipoic acid, lysophosphatidic acid, and the like.

[0066] The formulation may also contain an irritation-relieving additive to minimize or eliminate the possibility of skin irritation or skin damage resulting from the penetration enhancer base, drying agent or other components of the composition.Suitable irritation-relieving additives include, for example, α-tocopherol; monoamine oxidase inhibitors, especially phenyl alcohols such as 2-phenyl-1-ethanol; glycerin; salicylic acid and salicylates; ascorbic acid and ascorbates; ionophores such as monensin; amphiphilic amines; ammonium chloride; N-acetylcysteine; cis-urocanic acid; capsaicin; and chloroquine.Irritation-relieving additives, if present, may be incorporated into the formulation at a concentration effective for relieving irritation or skin damage, and typically represent about 20 wt% or less of the composition, more typically about 5 wt% or less.

[0067] Dry-feel modifiers are agents added to emulsions to impart a "dry feel" to the skin when the emulsion dries. Dry-feel modifiers can include talc, kaolin, chalk, zinc oxide, silicone oil, inorganic salts such as barium sulfate, surface treated silica, precipitated silica, and fumed silica such as Aerosil available from Degussa Inc., New York, NY, USA. Another dry-feel modifier is epichlorohydrin cross-linked glyceryl starch of the type disclosed in 6,488,916.

[0068] In certain embodiments, the compositions of the instant disclosure are formulated to have an optimal viscosity for target tissue (e.g., anogenital region) and mimic the characteristics of normal genital fluid. For example, compositions formulated as gels to be applied to mucous membranes can be designed to have viscosity values ​​that match or are similar to normal mucus and to exhibit non-Newtonian, shear-thinning (pseudoplastic) flow properties. Standardized methodologies for quantitative comparison of commercially available vaginal products based on characteristics such as tackiness, viscosity, peaking, rubberiness, thickness, smoothness, and slipperiness are known in the art (Mahan et al, Contraception, 84:184, 2011). In some embodiments, compositions formulated as gels to be applied to mucous membranes can enhance mucus and / or mucinous coating of body surfaces. In certain embodiments, the compositions can improve mucoadhesion and stimulate or provide production of an acidic barrier in the urogenital and / or anogenital area, thereby increasing the bioavailability of one or more active ingredients of the composition, which can result in beneficial effects on the genital microbiome, particularly as related to the development of mucoadhesive carriers, as disclosed in N Peppas et al, J Biomater Sci Polym Ed. 20 (2209):1-20, which is incorporated by reference in its entirety.

[0069] For compositions applied to the skin (vulva, perineum, penis, etc.) or vaginally, a viscosity increasing agent can be added in an amount that allows the composition to spread easily to form a thin layer when minimal physical pressure is applied and has suitable viscosity and shear thinning properties so that the composition does not "run off" the genital tissue when applied topically. Mucoadhesive formulations that are retained on genital surfaces (e.g., vulva, vagina, penis, foreskin surfaces) for extended periods of biological activity are known in the art (Khutoryanskiy, Macromol.Biosci.11:748, 2011; Brooks, Front.Chem.3:65, 2015). Mucoadhesive formulations should have a polymeric composition that actively miscible and interacts with the physiological mucins and mucus of secretions. Some common gelling agents do not entangle with natural mucins and therefore are not mucoadhesive and are rapidly lost from the epithelium.

[0070] The compositions of the present disclosure may include a viscosity increasing agent, for example, in an amount ranging from about 0.05% to about 10% by weight of the composition. In certain embodiments, the viscosity increasing agent includes a viscoelastic cellulose or gum. Tensioactive celluloses and gums can act to emulsify particles and essential oils and draw them into solution. In certain embodiments, additional surfactants that may have harsh effects on cells are not required or included in the topical composition. In certain embodiments, the viscosity increasing agent includes guar gum, methylcellulose, ethylcellulose, ethylmethylcellulose, ethylhydroxyethylcellulose, carboxymethylcellulose hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose (hypromellose), hydroxyethylcellulose, cetylhydroxyethylcellulose, hydroxypropylguar gum glycosaminoglycans (e.g., hyaluronic acid), nonionic triblock copolymers such as poloxamers, gelatin, alginates, carrageenans, and agar, or any combination thereof. In some embodiments, the composition may include a viscosity increasing agent consisting of glycosaminoglycans (eg, hyaluronic acid), non-ionic triblock copolymers such as poloxamers, gelatin, carrageenan, agar, and combinations thereof.

[0071] In certain embodiments, the topical composition may further comprise a pH adjusting agent to adjust the final pH of the composition to a target or desired pH. The pH adjusting agent may comprise an acidifying agent, an alkalizing agent, and / or both an acidifying agent and an alkalizing agent. In certain embodiments, the pH adjusting agent is in an amount ranging from about 0.01% to about 1%.

[0072] In certain embodiments, the topical composition of the present disclosure further comprises a buffering agent. The buffering agent may be in an amount ranging from about 0.01% to about 0.9% by weight of the composition. A buffering agent refers to a compound or mixture of compounds that, when present in solution, resists a change in the pH of the solution when a small amount of acid or base is added, or when diluted with a solvent or body fluid. Buffering capacity refers to the resistance of a solution to a change in pH when an acid or base is added to the solution. The total amount of buffering agent (e.g., conjugate acid-base pair) is selected to maintain the pH of the composition at a desired pH or pH range. Thus, the greater the amount of buffering capacity, the less likely the pH of the composition will change. In certain embodiments, the buffering agent is a hydroxide (OH - ) ions and hydrogen (H + ) ions. However, the acidic and basic species of the buffer must not consume each other in a neutralization reaction.

[0073] In certain embodiments, the buffer is a simple buffer solution that includes a weak acid and a salt of a weak acid, or a weak base and a salt of a weak base. Thus, the buffer can include a weak acid-base conjugate pair or a weak base-acid conjugate pair. Examples of weak acid / salt of a weak acid and weak base / salt of a weak base include citric acid / sodium citrate, lactic acid / sodium lactate, acetic acid / sodium acetate, monosodium phosphate / disodium phosphate, propionic acid / sodium propionate, butyric acid / sodium butyrate, carbonic acid / sodium bicarbonate, malic acid / sodium malate, ascorbic acid / sodium ascorbate, benzoic acid / sodium benzoate, succinic acid / sodium succinate, boric acid / sodium borate, etc. In certain embodiments, the buffer is composed of unrelated weak acid-base pairs. Examples of such combinations include disodium phosphate / citric acid, disodium phosphate / lactic acid, monosodium phosphate / sodium lactate, monosodium phosphate / sodium citrate, sodium citrate / lactic acid, sodium lactate / citric acid, monopotassium phosphate / citric acid, monopotassium phosphate / lactic acid, monopotassium phosphate / sodium lactate, monopotassium phosphate / sodium citrate, monopotassium citrate / lactic acid, potassium lactate / citric acid. Furthermore, for polyvalent anions, calcium salts may be used instead of sodium salts (e.g., calcium citrate). An example of a buffer solution may also include gluconolactone / gluconic acid.

[0074] In certain embodiments, the buffering agent is selected from surfaces and fluids that physiologically occur in the anogenital region (e.g., vaginal mucin acid barrier, cervix-vaginal secretions, semen, menses, or combinations thereof) or fluids that maintain the pH of the target epithelial surface, such that the acid form of the buffering agent has a pKa that is the same as or close to the desired pH of the composition, or within the range of desired pH values ​​(Rastogi et al., Contraception. 93:337, 2016). In certain embodiments, the buffering agent comprises a monocarboxylate, a dicarboxylate, a carboxylic acid, or a combination thereof. In some embodiments, the buffering agent may comprise an acetate, a borate, a citrate, a fumarate, a lactate, a malate, a malonate, a nitrate, a phosphate, a propionate, a succinate, a tartrate, a tromethamine, or any combination thereof. In some embodiments, the buffer may include lactic acid, sodium lactate, sodium phosphate (monobasic, dibasic, or both), potassium phosphate (monobasic, dibasic, or both), sodium citrate, potassium citrate, calcium citrate, acetic acid, sodium acetate citric acid, disodium citrate, trisodium citrate, boric acid / sodium, succinic acid, sodium succinate, gluconolactone, disodium succinate, tartaric acid, sodium tartrate, sodium ascorbate, ascorbic acid, tromethamine (Tris), or any combination thereof. In certain embodiments, the buffer consists of citric acid and disodium phosphate, lactic acid and sodium lactate, gluconolactone, or monosodium phosphate or disodium phosphate and lactic acid.

[0075] In one embodiment, the topical compositions of the present disclosure are specifically isotonic with respect to the target genital fluids or tissues they contact. Tonicity is a measure of the effective osmotic gradient (defined by the water potential of the two solutions) of two solutions separated by a semipermeable membrane. Tonicity is often used to describe the response of cells bathed in an external solution. In other words, osmotic pressure is the relative concentration of the solutions that determines the direction and extent of diffusion from a liquid across a cell membrane in a tissue. Typically, the osmotic pressure of blood is approximately equal to the osmotic pressure of a 0.9% sodium chloride solution ( about 280 mOsm / kg). However, the osmolality of physiological fluids occurring in the anogenital region is much higher than that of the low levels of cervico-vaginal fluids (e.g. about 128 mOsm / kg) to menstrual blood about 280 mOsm / kg, high levels of semen (e.g. about The tonicity of a composition (e.g., a solution or gel) can vary widely, up to 320+ mOsm / kg. A composition (e.g., a solution or gel) is considered isotonic when its tonicity matches that of the physiological fluid it comes into contact with. A composition is isotonic with a physiological fluid when the salt (ion) sizes between the composition and the physiological fluid are equal. In physiological fluids, tension equilibrium is reached by water moving across cell membranes while the salts and ions remain in the original fluid. A solution is isotonic with living cells when individual water molecules can move freely across cell membranes with no net gain or loss of water by the cells and no change in the cell ultrastructure.

[0076] Hypertonic solutions cause a net movement of water out of cells (as water moves to balance the high salt concentration outside the cells). This dehydration of cells is concentration-dependent and leads to osmotic stress, increasing reactive oxygen species, causing cytoskeletal rearrangements, and damaging DNA and mitochondrial function within minutes. Most current reproductive products are hypertonic, killing epithelial cells and sperm on contact. Hypotonic solutions cause a net influx of water into cells, causing cell rupture and death. The deviation of salt concentrations in physiological fluids from those in blood and tissues may serve a purpose. For example, the low osmolality of cervicovaginal fluids promotes the lysis and death of vaginal epithelial cells as part of normal vaginal function. In another example, the high osmolality of semen can protect sperm cells from the low osmolality of cervicovaginal secretions that accompany ejaculation and the mixing of fluids during vaginal intercourse.

[0077] Osmotic pressure is the movement of solute across a semipermeable membrane from an area of ​​high solute concentration to an area of ​​low solute concentration to reach equilibrium. The osmotic pressure of a solution is the pressure that must be applied to stop the flow of solvent across a semipermeable membrane.

[0078] In certain embodiments, the composition of the present disclosure further comprises an osmotic agent for adjusting the tonicity of the composition.Exemplary osmotic agents include electrolytes, monosaccharides or disaccharides, inorganic salts (e.g., sodium chloride, calcium chloride, potassium chloride, sodium sulfate, magnesium chloride), or combinations thereof.In some embodiments, the osmotic agent is glucose, sucrose, sodium chloride, potassium chloride, calcium chloride, sodium sulfate, magnesium chloride, dextrose, mannitol, or combinations thereof.

[0079] In certain embodiments, the osmolality range of the compositions disclosed herein is from about 120 mOsm / kg to about 450 mOsm / kg, or from about 240 mOsm / kg to about 450 mOsm / kg. In certain embodiments, the osmolality of the compositions of the present disclosure is about 120 mOsm / kg, about 125 mOsm / kg, about 130 mOsm / kg, about 135 mOsm / kg, about 140 mOsm / kg, about 145 mOsm / kg, about 150 mOsm / kg, about 155 mOsm / kg, about 160 mOsm / kg, about 165 mOsm / kg, about 170 mOsm / kg. about 175 mOsm / kg, about 180 mOsm / kg, about 185 mOsm / kg, about 190 mOsm / kg, about 195 mOsm / kg, about 200 mOsm / kg, about 205 mOsm / kg, about 210 mOsm / kg, about 215 mOsm / kg, about 220 mOsm / kg, about 230 mOsm / kg, about 240 mOsm / kg, about 250 mOsm / kg, about 260 mOsm / kg, about 270 mOsm / kg, about 280 mOsm / kg, about 290 mOsm / kg, about 300 mOsm / kg, about 310 mOsm / kg, about 320 mOsm / kg, about 330 mOsm / kg, about 340 mOsm / kg, about 350 mOsm / kg, about 360 mOsm / kg, about 370 mOsm / kg, about 380 mOsm / kg, about 390 mOsm / kg, about 400 mOsm / kg, about 410 mOsm / kg, about 420 mOsm / kg, about mOsm / kg, about 225 mOsm / kg, about 230 mOsm / kg, about 235 mOsm / kg, about 240 mOsm / kg, about 245 mOsm / kg, about 250 mOsm / kg, about 255 mOsm / kg, about 260 mOsm / kg, about 265 mOsm / kg, about 270 mOsm / kg, about 280 mOsm / kg, about 285 mOsm / kg, about 290 mOsm / kg, about 295 mOsm / kg, about 300 mOsm / kg, about 305 mOsm / kg, about 310 mOsm / kg, about 315 mOsm / kg, about 320 mOsm / kg, about 325 mOsm / kg, about 330 mOsm / kg is about 335 mOsm / kg, about 340 mOsm / kg, about 345 mOsm / kg, about 350 mOsm / kg, about 355 mOsm / kg, about 360 mOsm / kg, about 365 mOsm / kg, about 370 mOsm / kg, about 375 mOsm / kg, about 380 mOsm / kg, about 385 mOsm / kg, about 390 mOsm / kg, about 395 mOsm / kg, about 400 mOsm / kg, or about 450 mOsm / kg.

[0080] In certain embodiments, the tonicity (e.g., salt / ion levels) of the topical composition is matched to the normal physiological genital fluid pH of the subject (e.g., CVF, urethral fluid, semen, smegma); the anogenital tissue of the subject (e.g., vaginal mucosa, anogenital skin); or a tonicity appropriate for the particular method of use. In certain embodiments, the tonicity ranges from about 125 mOsm / kg to about 240 mOsm / kg. Such embodiments are compatible with hypotonic CVF, which supports lysis of vaginal epithelial cells and the "self-cleaning" of the vagina. This cell lysis releases glycogen, which is available for the growth and development of healthy genital microflora. Such embodiments are ideal for intravaginal administration. In other embodiments, the tonicity ranges from about 240 mOsm / kg to about 280 mOsm / kg. Such embodiments are compatible with the tonicity of anogenital tissue and are ideal for contact with skin anogenital tissue surfaces. In certain embodiments, tonicity ranges from about 280 mOsmo / kg to about 450 mOsmo / kg, corresponding to the tonicity of semen deposited in the vagina. In certain embodiments, tonicity is expressed as mOsm / kg or mOsm / L. Osmolarity is a measure of the osmolality (Osm) of solute per kg of solvent. Depending on the density of the solvent, osmolarity and osmolality (Osm of solute per L of solution) may differ. In certain embodiments, the values ​​of osmolarity and osmolality are substantially interchangeable.

[0081] In certain embodiments, the topical isotonic composition further comprises a solvent (e.g., an aqueous solvent, water) in an amount greater than about 88% (e.g., in the range of about 88% to about 98%). In further embodiments, the solvent comprises water.

[0082] Topical penetration enhancers Administering drugs locally to the skin has many advantages. It is comfortable, convenient, and non-invasive for the patient. It avoids the variable rates of absorption and metabolism that can occur with oral treatments, as well as other inherent inconveniences (e.g., gastrointestinal irritation and the need to administer with or without food in some cases). Such localized treatments avoid high systemic drug levels and the subsequent side effects that can occur.

[0083] However, topical administration of drugs to the skin is generally difficult. Skin is a structurally complex and relatively thick membrane. Molecules moving from the outside to and through intact skin must first penetrate the stratum corneum and the materials on its surface. The stratum corneum is a layer about 10-15 micrometers thick in most parts of the body and is composed of dense, highly keratinized cells. The high degree of keratinization within these cells and their tight packing are thought to be the most significant factor in forming a virtually impermeable barrier to drug penetration in most cases. For many drugs, the rate of penetration through the skin is extremely low unless some means of increasing the permeability of the skin is used. The stratum corneum of many inflammatory skin diseases is generally thicker than normal skin, making it particularly difficult for topical drugs to penetrate into affected areas of the skin.

[0084] Various approaches have been taken to increase the extent and rate at which drugs penetrate the skin, using either chemical or physical penetration enhancers. Physical penetration enhancers include, for example, electrophoretic methods such as iontophoresis. The use of ultrasound (or "phonophoresis") as a physical penetration enhancer has also been investigated. Chemical penetration enhancers are more commonly used. These are compounds that are administered topically with the drug (or sometimes before drug administration) to increase the permeability of the stratum corneum and facilitate the penetration of the drug through the skin. Ideally, such chemical penetration enhancers (or compounds as we refer to them herein as "penetration enhancers") are harmless compounds that simply serve to facilitate the diffusion of the drug through the stratum corneum.

[0085] Various compounds for increasing skin permeability are known in the art and described in the relevant texts and literature. Compounds that have been used to increase skin permeability include: sulfoxides such as dimethyl sulfoxide (DMSO) and decyl methyl sulfoxide (C10MSO); ethers such as diethylene glycol monoethyl ether (commercially available as Transcutol®) and diethylene glycol monomethyl ether; sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer (231, 182, 184), Tween (20, 40, 60, 80), and lecithin (U.S. Pat. No. 4,783,450); 1-substituted azacycloheptan-2-ones, particularly 1-n-dodecylcyclazacycloheptan-2-one (Nelson Research & Development Co. Irvine, Calif. under the trademark Azone®. See U.S. Patents 3,989,816, 4,316,893, 4,405,616 and 4,557,934; alcohols such as ethanol, propanol, octanol, benzyl alcohol, etc.; fatty acids such as lauric acid, oleic acid and valeric acid; fatty acid esters such as isopropyl myristate, isopropyl palmitate, methyl propionate, ethyl oleate, etc.; propylene glycol, ethylene glycol, glycerol, polyols and their esters, such as butanediol, polyethylene glycol, polyethylene glycol monolaurate (PEGML; see, e.g., U.S. Pat. No. 4,568,343); amides and other nitrogen compounds, such as urea, dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine, diethanolamine and triethanolamine; terpenes; alkanones; and organic acids, particularly salicylic acid and salicylates, citric acid and succinic acid.The book Percutaneous Penetration Enhancers (Smith et al., editors, CRC Press, 1995) provides an excellent overview of the field and further background information on some of the chemical and physical enhancers.

[0086] For a long time, it was thought that strong bases such as NaOH would damage the skin and therefore would not be suitable as penetration enhancers. It has now been discovered that in skin-contact preparations and patches, exposing the skin to a base or a basic solution can enhance the skin permeability of various drugs without damaging the skin. The desired pH of the solution on the skin can be obtained using various bases or base concentrations. Thus, the pH is selected to be low enough not to damage the skin, but high enough to promote the skin permeability of various active agents. Thus, In some embodiments, It is important that the amount of base in the patch or formulation be optimized to increase the flux of the drug across the body surface while minimizing the potential for skin damage. Generally, this is , Made This means that the pH of the body surface in contact with the agent or drug delivery system is in the range of about pH 8.0 to about pH 13.0, about pH 8.0 to about pH 11.5, about pH 8.5 to about pH 11.5, or about pH 8.5 to about pH 10.5. In some embodiments, the pH is in the range of about pH 9.5 to about pH 11.5, or about pH 10.0 to about pH 11.5.

[0087] In one embodiment, the pH at the skin surface is the primary design consideration, i.e., the composition or system is designed to provide the desired pH at the skin surface. Anhydrous formulations and transdermal systems may not have a measurable pH, and the formulation or system may be designed to provide a target pH at the skin surface. Moisture from the body surface can migrate into the formulation or system and dissolve the base, thereby releasing the base into solution and providing the desired target pH at the body surface. In such cases, a hydrophilic composition is desirable. In addition, when using an aqueous formulation, the pH of the formulation may change over time after application to the skin. For example, gels, solutions, ointments, etc. may experience a net loss of moisture after application to the body surface, i.e., the amount of moisture lost is greater than the amount of moisture received from the body surface. In that case, the pH of the formulation may differ from the pH at the time of manufacture. This problem can be easily remedied by designing the aqueous formulation to provide the target pH at the body surface.

[0088] others In some embodiments, the pH of the formulation or drug composition contained within the delivery system is in the range of about pH 8.0 to about pH 13.0, about pH 8.0 to about pH 11.5, about pH 8.5 to about pH 11.5, or about pH 8.5 to about pH 10.5. In some embodiments, the pH is in the range of about pH 9.5 to about pH 11.5, or about pH 10.0 to about pH 11.5. . one In embodiments, the pH of the formulation is higher than the pH of the body surface.For example, when an aqueous formulation is used, the moisture from the body surface can dilute the formulation, resulting in a different pH at the body surface, which is typically lower than the pH of the formulation itself.

[0089] In one embodiment, the body surface is exposed to a basic or alkaline solution for a sufficient time to increase the pH of the skin surface and form a channel through which the drug passes into the skin or mucosa. Drug flux is expected to be proportional to the strength of the solution and the exposure time. However, it is desirable to balance maximizing drug flux with minimizing skin damage. There are many ways to achieve this. For example, skin damage can be minimized by selecting a low pH in the range of 8.0 to 13.0, by exposing the skin to the formulation or system for a short period of time, or by including at least one irritation-relieving additive. Alternatively, the patient can be advised to change the application site for each subsequent administration.

[0090] Specific amounts are provided below, but it is understood that for all inorganic and organic bases described herein, the optimal amount of such base depends on the strength or weakness of the base and its molecular weight, as well as other factors such as the number of ionizable sites in the administered active agent and whether acidic species are present in the formulation or patch. Those skilled in the art can easily determine the optimal amount of a particular base that optimizes the degree of enhancement while eliminating or at least substantially minimizing the possibility of damage to the body surface.

[0091] Exemplary inorganic bases are inorganic hydroxides, inorganic oxides, inorganic salts of weak acids, and combinations thereof. Some inorganic bases have high pH in their aqueous solutions and are acceptable as food or pharmaceutical additives. Examples of such inorganic bases include ammonium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, magnesium oxide, calcium oxide, Ca(OH)2, sodium acetate, sodium borate, sodium metaborate, sodium carbonate, sodium bicarbonate, sodium phosphate, potassium carbonate, potassium bicarbonate, potassium citrate, potassium acetate, potassium phosphate, ammonium phosphate, and combinations thereof.

[0092] Inorganic hydroxides include, for example, ammonium hydroxide, alkali metal hydroxides, alkaline earth metal hydroxides, and mixtures thereof. Some inorganic hydroxides include ammonium hydroxide; monovalent alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; divalent alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide; and combinations thereof.

[0093] Books As stated in the specification The amount of inorganic hydroxide included in the compositions and systems typically represents about 0.3-7.0 W / V %, about 0.5-4.0 W / V %, about 0.5-3.0 W / V %, or about 0.75-2.0 W / V % of the topical formulation or drug reservoir of the drug delivery system or patch.

[0094] Examples of inorganic oxides include magnesium oxide and calcium oxide.

[0095] Books As stated in the specification The amount of inorganic oxide included in the compositions and systems may be substantially greater than those given above for inorganic hydroxide, and may be as high as 20 wt.%, and in some cases as high as 25 wt.% or more, but will generally be in the range of about 2-20 wt.%. These amounts may be adjusted to account for the presence of base-neutralizable species.

[0096] Inorganic salts of weak acids include ammonium phosphate (dibasic); alkali metal salts of weak acids such as sodium acetate, sodium borate, sodium metaborate, sodium carbonate, sodium bicarbonate, sodium phosphate (tribasic), sodium phosphate (dibasic), potassium carbonate, potassium bicarbonate, potassium citrate, potassium acetate, potassium phosphate (dibasic), potassium phosphate (tribasic); alkaline earth metal salts of weak acids such as magnesium phosphate, calcium phosphate, and combinations thereof.

[0097] messengerSuitable organic bases for use are compounds having amino groups, amide groups, oxime groups, cyano groups, aromatic or non-aromatic nitrogen-containing heterocycles, urea groups, and combinations thereof.More specifically, examples of suitable organic bases are nitrogen bases, including but not limited to primary amines, secondary amines, tertiary amines, amidines, guanidines, hydroxylamines, cyanoguanidines, cyanoamidines, oximes, cyano (-CN)-containing groups, aromatic and non-aromatic nitrogen-containing heterocycles, ureas, and mixtures thereof.In some embodiments, the organic base is a primary amine, a secondary amine, a tertiary amine, aromatic and non-aromatic nitrogen-containing heterocycles, and mixtures thereof.

[0098] For all penetration enhancing bases herein, the optimal amount of a particular drug will depend on the strength or weakness of the base, the molecular weight of the base, and other factors such as the number of ionizable sites in the drug being administered and other acidic species in the formulation or patch. One skilled in the art can easily determine the optimal amount of a particular drug, ensuring that the formulation is effective to provide a pH at the skin surface in the range of about pH 7.5 to about pH 13.0, about pH 8.0 to about pH 11.5, or about pH 8.5 to about pH 10.5 upon application of the formulation. In some embodiments, the pH will be in the range of about pH 9.5 to about pH 11.5, or about pH 10.0 to about pH 11.5. This ensures that the extent of treatment is maximized while eliminating or at least substantially minimizing the potential for damage to the body surface.

[0099] Additional penetration enhancers are known to those of ordinary skill in the art of topical drug delivery and are described in the appropriate texts and literature, see, for example, Percutaneous Penetration Enhancers Drug Penetration Into / Through the Skin, Dragicevic & Maibach. (Springer Link, 2017).

[0100] Other activators In certain embodiments ,directionThe method includes administering one or more additional agents to improve anogenital sensory function. In some embodiments, the second therapeutic agent is an antioxidant, an anti-inflammatory agent, an antibacterial agent, including bactericides, an antihistamine, a mast cell stabilizer, an antiviral and antifungal agent, an antiangiogenic agent, an antiapoptotic agent, a lubricant, a vasodilator, and / or a secretagogue.

[0101] Inflammation is induced by the adhesion of leukocytes and the process of angiogenesis. Therefore, other anti-inflammatory agents may be used in combination with this As stated in the specificationThe anti-inflammatory agent may be administered before, after, or in combination with the compound. Anti-inflammatory agents include dexamethasone, fluoromethalone, medrysone, betamethasone, triamcinolone, triamcinolone acetonide, prednisone, prednisolone, hydrocortisone, rimexolone, and pharma- ceutically acceptable salts thereof, prednicarbate, deflazacort, halometasone, tixocortol, prednylidene, prednival, paramethasone, methylprednisolone, meprednisone, mazipredone, isoflupredone, halopredone acetate, halcinonide, formocortal, flurandrenolide, fluprednisolone, fluprednidine acetate, fluoperonolone acetate, fluocortolone, fluocortin butyl, fluocinonide, fluocinolone acetonide, flunisolide, fluocortin butyl, fluocinonide, fluocinolone acetonide, flunisolide, fluocortin butyl, fluocinolone acetonide ...ortin butyl, fluocinolone acetonide, fluocortin butyl, fluocortin butyl, fluocinolone aceton Corticosteroid-related drugs may be selected from corticosteroid-related drugs including, but not limited to, methasone, fludrocortisone, fluchlorinide, enoxolone, difluprednate, diflucortolone, diflorasone diacetate, desoximethasone (desoxymethasone), desonide, decinolone, cortivazol, corticosterone, cortisone cloprednol, clocortolone, clobetasone, clobetasol, chloroprednisone, cafestol, budesonide, beclomethasone, amcinonide, allopregnane acetonide, alclometasone, 21-acetoxypregnenolone, tralonide, diflorasone acetate, deacylcortivazol, RU-26988, budesonide, deacylcortivazol, and the like. Further anti-inflammatory agents include 5-aminosalicylate (5-ASA) compounds such as sulfasazine (azulfidine), osalazine (dipentam), mesalamine (e.g., Pentasa, Asacol, Dipentam, Corazar, Lowasa enema, Canasa suppository, etc.) Similarly, anti-inflammatory agents may be selected from the cyclosporine class, other related calcineurin antagonists, and cyclosporine-related drugs (e.g., calcineurin antagonists), including, but not limited to, sirolimus, tacorimus, and pimecrolimus.Alternatively, the anti-inflammatory agent may be acetaminophen, acemetacin, aceclofenac, aluminoprofen, amfenac, bendazac benoxaprofen, bromfenac, bucloxic acid, butibufen, carprofen, celecoxib, cinmetacin, clopirac, diclofenac, etodolac, etoricoxib, felbinac, fenclozic acid, fenbufen, fenoprofen, fentiazac flunoxaprofen, flurbiprofen, ibufenac, ibuprofen, indomethacin, isofezolac, isoxicam, isoxepac, indoprofen, ketoprofen, lonazolac, loxoprofen, mefenamic acid, meclofenamic acid meloxicam, The NSAIDs may be selected from methazinic acid, mofezolac, miloprofen, naproxen, niflumic acid, oxaprozin, pirozolac, pirprofen, pranoprofen, protizinic acid, rofecoxib, salicylic acid and its derivatives (e.g., aspirin), sulindac, suprofen, suxibuzone, triaprofenic acid, tolmetin, valdecoxib, zenbucin, xymoprofen, zaltoprofen, zomepirac, aspirin, acemetine, bumadizone, carprofenac, clidanac, diflunisal, enfenamic acid, fendosal, flufenamic acid, flunixin, gentisic acid, ketorolac, mesalamine and their prodrugs. Additionally, immunomodulatory drugs such as 6-mercaptopurine (6-MP), azathioprine (Imuran), methotrexate (Rheumatrex, Trexol), infliximab (Remicade), and adalimumab (Humira) can also be used.

[0102] Books As stated in the specificationA class of therapeutic agents useful for administration before, after, or in combination with the compounds are antihistamines, including the alkylamine, ethanolamine, and phenothiazine classes. For example, chlorpheniramine maleate, chlorphenamylamine tannate, diphenhydramine hydrochloride, promethazine hydrochloride, acrivastine, azatadine maleate, azelastine hydrochloride, brompheniramine maleate, carbinoxamine maleate cetirizine hydrochloride, clemastine fumarate, cyproheptadine hydrochloride, desloratadine, dexbrompheniramine maleate, dexchlorpheniramine maleate, dimenhydriunate, diphenhydramine hydrochloride, emedastine difumarate, fexofenadine hydrochloride, hydroxyzine hydrochloride, ketotifen fumarate, loratadine, meclizine hydrochloride, olopatadine hydrochloride, phenindamine tartrate, quetiapine, tripelennamine citrate, tripelennamine hydrochloride, and triprolidine hydrochloride. .stomach In some embodiments, formulations administered intranasally or ophthalmically include one or more antihistamines.

[0103] Books As stated in the specification Therapeutic agents useful prior to, after, or in combination with the compounds include mast cell stabilizers such as cromolyn sodium and nedocromil.

[0104] Oxidative stress may be induced in cells with impaired autoregulatory and ischemic processes. Therefore, antioxidants are As stated in the specification It is useful to administer the compound before, after, or in combination with the compound. As stated in the specificationExamples of suitable antioxidants useful in the methods include, but are not limited to, ascorbic acid, tocopherols, tocotrienols, carotenoids, glutathione, alpha-lipoic acid, ubiquinol, bioflavonoids, carnitine, and superoxide dismutase mimetics, such as 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), DOXYL, PROXYL nitroxide compounds; 4-hydroxy-2,2,6,6-tetramethyl-1-piperidinyloxy (Tempol), M-40401, M-40403, M-40407, M-40419, M-40484, M-40587, M-40588, and the like.

[0105] stomach In some embodiments, an anti-apoptotic therapeutic agent is As stated in the specification Methods are provided in which the compounds can be administered before, after, or in combination with other compounds. Examples of suitable anti-apoptotic agents are, for example, inhibitors of caspases, cathepsins, and TNF-α.

[0106] Books As stated in the specificationAnother class of therapeutic agents useful for administration before, after, or in combination with the compounds are antibacterial agents. Suitable antibacterial compounds include, for example, penicillins, such as amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, penicillin, piperacillin, ticarcillin, etc.; beta-lactamase inhibitors; carbapenem antibiotics, such as ertapenem, imipenem, meropenem, etc.; cephalosporins, such as cefaclor, cefamandole, cefoxitin, cefprozil, cephalosporins, such as cephalosporins, ... cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, cefadroxil, ceftazidime, ceftibuten, ceftizoxime, cefiriaxone, cefazolin, cefixime, cephalexin, cefepime, etc.; quinolone antibacterial drugs, such as ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, morifloxacin, norfloxacin, ofloxacin, trovafloxacin and the like; macrolides such as azithromycin, clarithromycin, dirithromycin, erythromycin, milbemycin, troleandomycin, and the like; monbactams, and the like; tetracyclines such as demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, and the like; aminoglycosides such as amikacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, streptomycin, tobramycin, and the like; carbacephems such as loracarbef, and the like; streptogramins; sulfonamides such as mephanide, prontocil, sulfacetamide, sulfamethizole, sulfanilamide, sulfasalazine, sulfisoxazole, trimethoprim, trimethoprim-sultamethoxazole, and the like; other antibacterial agents such as metronidazole; and combination drugs such as sulfamethoxazole and trimethoprim.

[0107] Other antibacterial agents include antiviral agents. Antiviral agents include, but are not limited to, therapeutic agents such as entry inhibitors, reverse transcriptase inhibitors, nucleoside or nucleotide analogs, protease inhibitors, and inhibitors of viral release from host cells. Some exemplary therapeutic agents in this group include abacavir, acyclovir, adefovir, amantadine, amprenavir, arbidol, atazanavir, atripla, brivudine, cidofovir, combivir, darunavir, delavirdine, didanosin docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen, foscarnet, fosfonet, ganciclovir, gardasil, ibatitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II ... These include, but are not limited to, alpha-feron type I, interferon, lamivudine, lopinavir, loviride, maraviroc, moroxydine, nelfinavir, neviapine, nexavir, oseltamivir, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine ritonavir, saquinavir, stavudine, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, zidovudine, and the like.

[0108] fruit In some embodiments, the formulation administered to the skin includes one or more antimicrobial agents or antibiotics.

[0109] Secretagogues can also be administered before or after pirenzepine. Increasing the production of mucin and other fluids in the eye can be beneficial. Examples include, but are not limited to, Diquafasol, Rebamipide, and Eicosanoid 15-(S)-HETE.

[0110] One group of therapeutic agents that are useful before, after, or in combination with pirenzepine are vasodilators, which relax blood vessels and improve blood flow, such as phosphodiesterase inhibitors (papaverine, pentoxifylline, amrinone), local anesthetics (lidocaine), calcium channel blockers (nicardipine, verapamil, nifedipine, magnesium sulfate), direct vasodilators (sodium nitroprusside, prostaglandin E1, nitroglycerin, and hydralazine), and alpha antagonists (phentolamine and chlorpromazine).

[0111] Alprostadil is a vasodilator that effectively treats erectile dysfunction in many men. It is a synthetic analog of prostaglandin E1 (PGE1) and exhibits multiple pharmacological actions. It binds to prostaglandin receptors such as EP2 as an agonist, activating adenylate cyclase and causing the accumulation of 3'5'-cAMP (cyclic adenosine monophosphate).

[0112] Non-limiting examples of phosphodiesterase type 5 inhibitors include, but are not limited to, avanafil, lodenafil, mirodenafil (pKa 6.0), sildenafil (or an analog thereof, such as actetildenafil, hydroxyacetyldenafil, or dimethylsildenafil), tadalafil (pKa 18), vardenafil (pKa 3.4, 6.7, 8.8, 14), udenafil (pKa 10.53), acetyldenafil, or thiomethylsildenafil.

[0113] Many phosphodiesterase type 5 inhibitors are readily available commercially. In some cases, the phosphodiesterase type 5 inhibitor can be obtained as a racemic mixture of, for example, tadalafil (e.g., (R,R)-tadalafil, (R,S)-tadalafil, (S,R)-tadalafil, and (S,S)-tadalafil). However, in other cases, one of the enantiomers may be present in a greater amount than the other. For example, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% of the phosphodiesterase type 5 inhibitor in the composition may be present as one of the enantiomers. Techniques for preparing or separating racemic phosphodiesterase type 5 inhibitors are known; see, e.g., Gao et al., "Chiral Separation of Two Pairs of Enantiomers of Tadalafil by High-Performance Liquid Chromatography," J. Chromatogr.Sci., 45:540-543, 2007.

[0114] The composition may also include a nitric oxide donor, such as L-arginine and / or L-arginine hydrochloride, in some embodiments. In some cases, such nitric oxide donors may be used to increase local blood flow at the site where the composition is applied, thereby enhancing delivery of the pharmaceutical agent. The nitric oxide donor may be present in any suitable concentration in the composition. For example, in some cases, the nitric oxide donor is present in a concentration of at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 7.5%, at least about 8%, at least about 9%, or at least about 10% by weight of the composition. In some cases, one or more nitric oxide donors (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, etc. nitric oxide donors) may be used. In some cases, there may be no more than 3, 5, 7, or 10 nitric oxide donors present in the composition.

[0115] As used herein, a "nitric oxide donor" is a compound that can release nitric oxide and / or chemically transfer a nitric oxide moiety to another molecule, for example, directly or indirectly through a biological process. The nitric oxide donor can release nitric oxide to tissues such as the skin and / or muscle and / or elements of the circulatory system adjacent to the skin surface. Non-limiting examples of nitric oxide donors include arginine (e.g., L-arginine and / or D-arginine), arginine derivatives (e.g., L-arginine hydrochloride and / or D-arginine hydrochloride), nitroglycerin, polysaccharide-bound nitric oxide-nucleophile adducts, N-nitroso-N-substituted hydroxylamines, 1,3-(nitrooxymethyl)phenyl-2-hydroxybenzoates, and the like, and / or any combination of these compounds.

[0116] In addition to L-arginine and L-arginine hydrochloride, other non-limiting examples of nitric oxide donors include D,L-arginine, D-arginine, or alkyls (e.g., ethyl, methyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.) of L-arginine and / or D-arginine, esters (e.g., methyl esters, ethyl esters, propyl esters, butyl esters, etc.) and / or salts thereof, as well as other derivatives of arginine and other nitric oxide donors. For example, non-limiting examples of pharma- ceutically acceptable salts include hydrochlorides, glutamates, butyrates, or glycolates (e.g., resulting in L-arginine glutamate, L-arginine butyrate, L-arginine glycolate, D-arginine hydrochloride, D-arginine glutamate, etc.). Further examples of nitric oxide donors include, but are not limited to, L-arginine-based compounds, such as L-homoarginine, N-hydroxy-L-arginine, nitrosylated L-arginine, nitrosylated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, citrulline, ornithine, linsidomine, nipride, glutamine, and the like, and salts thereof (e.g., hydrochloride, glutamate, butyrate, glycolate, and the like), and / or any combination of these compounds. Further non-limiting examples of nitric oxide donors include S-nitrosothiols, nitrites, 2-hydroxy-2-nitrosohydrazine, or various forms of substrates of nitric oxide synthase. In some cases, the nitric oxide donor may be a compound that stimulates the endogenous production of nitric oxide in vivo. Examples of such compounds include, but are not limited to, L-arginine, substrates for various forms of nitric oxide synthase, certain cytokines, adenosine, bradykinin, calreticulin, bisacodyl, phenolphthalein, OH-arginine, or endothelin, and / or any combination of these compounds.

[0117] Other agents, such as antimicrobial agents, may also be added to prevent spoilage during storage, i.e., to inhibit the growth of microorganisms such as yeasts and molds. Suitable antimicrobial agents are typically selected from the group consisting of methyl and propyl esters of p-hydroxybenzoic acid (i.e., methyl and propyl parabens), sodium benzoate, sorbic acid, imidurea, phosphates, peroxides, perborates, and combinations thereof.

[0118] The formulation may also include cosmetic agents. Examples of cosmetic agents include fragrances, pigments, colorants, essential oils, skin sensates, astringents, etc. Suitable cosmetic agents include clove oil, menthol, camphor, eucalyptus oil, eugenol, methyl lactate, bisabolol, witch hazel distillate, green tea extract, etc.

[0119] A fragrance is an aromatic substance that imparts an aesthetically pleasing smell. Representative fragrances include aromatic substances extracted from plant sources (such as rose petals, gardenia flowers, jasmine flowers, etc.), which can be used alone or in any combination to make essential oils. Alternatively, alcoholic extracts can be prepared to formulate the fragrance. However, since obtaining fragrances from natural materials is relatively costly, the recent trend is to use synthetically prepared fragrances, especially in mass-produced products. Optionally, one or more fragrances can be included in the sunscreen composition in an amount ranging from about 0.001 to about 5%, p or about 0.01 to about 0.5% by weight. Additional preservatives can also be used if necessary, including well-known preservative compositions such as benzyl alcohol, phenylethyl alcohol, and benzoic acid, diazolidinyl, urea, chlorphenesin, iodopropynyl, and butyl carbamate.

[0120] In one embodiment, formulation teeth, such as topical formulations in combination with DMSO and polyether surfactants, e.g. polyalkylene glycol alkyl ethers; In a formulation as described in WIPO patent application WO / 2020 / 198252 "Topical formulation for the treatment of peripheral neuropathy" be.

[0121] composition object The active agent may be administered to the patient in any pharma- ceutically acceptable and effective form, for example, topically via a cream, gel, ointment, emulsion, solution, lotion, suspension, tincture, paste, foam, aerosol, irrigation, spray, suppository, or other formulation or pharmaceutical composition suitable for topical administration. . medicine Formulations for topical use of pharmaceutical compositions may be provided as topical compositions in which the pharmacologically active ingredient is mixed with an excipient to form a semi-solid consistency. Examples of such topical pharmaceutical compositions include, but are not limited to, gels, creams, lotions, suspensions, emulsions, ointments, foams, pastes, etc. , outside The topical pharmaceutical composition can also be formulated in a semi-liquid form. Examples of such topical pharmaceutical compositions include, but are not limited to, topical liquids, sprays, mists, drops, and the like. , outside The pharmaceutical composition for use may also be formulated in the form of a dry powder. The pharmaceutical composition of the present invention may also be administered by a transdermal patch.

[0122] Ointments are semi-solid preparations, typically based on mineral oil or other petroleum derivatives, as is well known in the art of pharmaceutical formulations. As an ointment, the composition has a viscosity that allows for uniform skin application. In addition, ointments may be substantially viscous to remain in contact with the skin regardless of sweating, excess moisture, or environmental conditions. The particular ointment base used is one that provides optimal drug delivery, as well as other desired properties, such as emollience, as will be understood by those skilled in the art. As with other carriers or vehicles, ointment bases should be inert, stable, non-irritating, and non-sensitizing. As explained in Remington: The Science and Practice of Pharmacy, 19th Ed. (Easton, Pa.: Mack Publishing Co., 1995), pages 1399-1404, ointment bases can be divided into four classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases. Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semi-solid hydrocarbons obtained from petroleum. Emulsifiable ointment bases, also called absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin, and hydrophilic petrolatum. Emulsion ointment bases are either water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions and include, for example, cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. Some water-soluble ointment bases are prepared from polyethylene glycols of different molecular weights: see Remington: The Science and Practice of Pharmacy for more information.

[0123] Creams, as also well known in the art, are viscous liquids or semisolid emulsions, either oil-in-water or water-in-oil. Cream bases are water-washable and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, also called the "internal phase," is generally composed of petrolatum and fatty alcohols such as cetyl alcohol or stearyl alcohol. The aqueous phase usually, although not necessarily, exceeds the oil phase in volume and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic, or amphoteric surfactant.

[0124] Gels are semi-solid suspension-type systems and are well known in the art. A gel former, as used herein, is any gelling agent commonly used in the pharmaceutical arts as a topical semi-solid dosage form. Single-phase gels contain organic macromolecules substantially uniformly dispersed in a carrier liquid, which is typically aqueous, but may also contain alcohol and optionally oil. To prepare a homogeneous gel, dispersants such as alcohol, glycerin, etc., can be added, or the gelling agent can be dispersed by grinding, mechanical mixing or stirring, or combinations thereof. The amount of gelling agent added can vary widely, typically ranging from about 0.1% to about 2.0% by weight, based on the total weight of the composition. Gel formers also work on the principle of copolymerization. At alkaline pH, carbomers undergo cross-linking in the presence of water to form a gel-like structure. The degree of polymerization is pH dependent. At a certain threshold pH, the viscosity achieved by the polymer grade is maximum.

[0125] Lotion is a preparation that is applied to the skin surface without friction, and is usually a semi-liquid preparation in which solid particles containing active agent are present in a water or alcohol base.Lotion is usually a suspension of solids, and for the present purpose, it is composed of a liquid oily emulsion of the oil-in-water type.Lotion is considered to be a desirable preparation herein for treating large body areas, since it is easier to apply a more fluid composition.In general, it is necessary that the insoluble material in lotion is finely divided.Lotion generally contains a suspending agent to produce a better dispersion, and a compound that is useful for localizing and retaining the active agent in contact with the skin, such as methylcellulose, sodium carboxymethylcellulose, etc.

[0126] Pastes are semi-solid dosage forms in which the active agent is suspended in a suitable base. Depending on the nature of the base, they are divided into fatty pastes and pastes made from single-phase aqueous gels. The base of fatty pastes is generally petrolatum or hydrophilic petrolatum, etc. Pastes made from single-phase aqueous gels are generally formulated with carboxymethylcellulose, etc. as a base.

[0127] Bandages consist of a paste-like mixture that is applied to the body either directly or after being saturated with a substrate such as fabric. .medicine A drug containing a physiologically active agent can be dissolved or dispersed within the plaster to provide a medicated plaster.

[0128] Bioadhesives are preparations that adhere to the surface of living tissue. Polymeric bioadhesive preparations are well known in the art; for example, Heller et al., "Biodegradable polymers as drug delivery systems", Chasin, M. and Langer, R. Dekker, NY, pp. 121-161 (1990); and U.S. Patent No. 6,201,065. Suitable non-polymeric bioadhesives are also known in the art, including certain fatty acid esters (U.S. Patent No. 6,228,383).

[0129] The pharmaceutical composition for transdermal administration may be provided, for example, as a hydrogel containing pirenzepine incorporated into an adhesive patch composition. It is intended to be in intimate contact with the epidermis of the subject for an extended period of time. An exemplary adhesive patch composition may include a monolithic layer made by mixing a muscarinic acetylcholine receptor antagonist with a silicone-type adhesive or alternatively an acrylate-vinyl acetate adhesive in a solvent exemplified by methylene chloride, ethyl acetate, isopropyl myristate, and propylene glycol. The mixture is extruded with a precision wet film applicator onto a polyester backing film to a uniform thickness of about 100 microns or greater. The solvent is evaporated in a drying oven, and the resulting "patch" is trimmed to the appropriate size.

[0130] Another type of carrier useful for delivering copper ion treatments to the vagina or rectum is the suppository. Suppositories are commonly used as a means of administering various active ingredients and medications to the vagina or rectum (anus). Suppositories are made in a variety of shapes and sizes, including oval, spherical, conical, and bullet shapes. Suppositories usually range in weight from 1 to 5 grams. Suppositories can be solid bodies consisting of a mixture of a suitable suppository base and the active ingredient or medication. Alternatively, suppositories can be solid bodies that encase a non-solid active ingredient or medication within the solid outer wall of a suppository base. The suppository base used in suppositories dissolves or melts when exposed to moisture (body fluids) or heat (body temperature) found in the vagina or rectum (rectal or anal canal), thereby releasing the active ingredient or medication into the vagina or rectum. Suitable suppository bases include oleaginous (fatty) bases including cocoa butter, theobroma oil, and synthetic triglycerides, or water-soluble or miscible bases including glycerinated gelatin and polyethylene glycol (PEG) polymers. The bases are preferably non-toxic, non-irritating, inert, and biocompatible. DisclosureSuppositories suitable for use in this respect can be prepared in a variety of ways according to conventional methods for preparing suppositories, including compression molding and fusion molding. Suppositories can be inserted into the vagina and rectum using a finger, or an applicator can be used to facilitate insertion into the vagina and rectum.

[0131] Another type of carrier that can be used to administer a therapeutic agent to the vagina is a tampon. The tampon used can be a commercially available tampon or similar. The tampon can have an applicator and includes a barrel containing an absorbent tampon body and a plunger that can slide within the barrel to discard or expel the absorbent tampon body from the open front end of the barrel after the front end is inserted into the vagina a suitable distance in a commonly known manner. Other suitable tampons include those without an applicator, i.e., digital tampons, where the absorbent tampon body is inserted into the vagina by pushing with a finger.

[0132] Another type of carrier that can be used to deliver the treatment to the anatomical tissue is a body wipe. A body wipe consists of a thin sheet of material with the treatment folded over itself for removal from the package. Once removed from the package, the body wipe can be unfolded to a size significantly larger than the folded size and used to wipe the anatomical tissue, transferring the copper ion treatment to the anatomical tissue.

[0133] Another type of carrier for treatment is a similar device such as a band-aid, gauze pad, or wound dressing. Such a carrier can be selected from products commercially available as removable temporary coverings for protection of affected areas of the skin.

[0134] Another type of carrier for treatment is a skin patch, such as a dermal patch or a transdermal patch. A skin patch has a drug delivery surface that contains a therapeutic agent surrounded by an adhesive border. The patch is applied to the skin and left with the drug delivery surface in contact with the skin for a period of time, allowing the active ingredient to diffuse through the skin, where it acts locally or penetrates into capillaries to exert a wider systemic effect. Examples of suitable transdermal patches include the Transdermal and Microneedle 3M Drug Delivery Systems manufactured by 3M.

[0135] Treatment with topical pirenzepine In some embodiments, The compound is therapeutically and / or prophylactically useful for treating anogenital sensory disease or condition in a subject.Accordingly, in one aspect, a method is provided for treating a sexual sensory disease or condition in a subject by topically administering to the anogenital area of ​​the subject a formulation comprising pirenzepine or a pharma-ceutically acceptable salt or ester thereof and a pharma-ceutically acceptable excipient.

[0136] Advantages of local administration include localized delivery of the therapeutic agent and minimization of systemic side effects due to low systemic bioavailability. , bureau The formulations can be administered directly to the skin and the anogenital area of ​​a subject, including the vaginal or anal mucosa. . station The administration method is particularly suitable for topical administration of the formulation. Suitable formulations and additional carriers are discussed herein and further described in Remington "The Science and Practice of Pharmacy" (20th Ed., Lippincott Williams & Wilkins, Baltimore Md.), the teachings of which are incorporated herein by reference.

[0137] The composition can be delivered with a pharmacokinetic profile that results in the delivery of an effective amount of pirenzepine. The actual effective amount of the drug can vary depending on the specific drug or combination utilized, the specific composition formulated, the mode of administration, and the age, weight, condition, and severity of the symptom or condition being treated of the patient. The dosage for a particular patient can be determined by those skilled in the art using conventional considerations (e.g., by appropriate, conventional pharmacological protocols).

[0138] In another embodiment, provided herein is a method of improving skin sensitivity in the anogenital area by applying to the skin an effective amount of a topical composition comprising pirenzepine.

[0139] In some embodiments, provided herein is a method of ameliorating the symptoms of neuropathy by applying to the skin of the anogenital area an effective amount of a topical composition comprising pirenzepine. In a preferred embodiment, the neuropathy is diabetic neuropathy.

[0140] In certain embodiments, the topical compositions provided herein are for localized, non-invasive application to the anogenital area, particularly the penis, the entirety thereof, or preferably only the glans penis. Additionally, the compositions may be applied to the shaft of the penis.

[0141] Administration The method of delivery of the pharma- ceutically active composition can vary, but In some embodiments , to the anogenital area affected by sensory impairment Made of This includes application of the agent. Some embodiments In the method, the formulation is applied topically to the anogenital area, including the skin, vaginal mucosa, or anal mucosa. Gels, creams, ointments, pastes, bandages, or lotions can be spread on the affected area of ​​skin and gently rubbed in. Similarly, polymeric or other bioadhesive formulations can be applied or dabbed on the affected area of ​​skin. Solutions can be applied in a similar manner, but are more typically applied carefully to the affected area of ​​skin using a dropper, cotton swab, or the like. Petrolatum may also be applied to the skin surrounding the affected area to protect the skin from irritation during treatment.

[0142] The dosing regimen depends on many factors that can be easily determined, such as the size of the affected area, the severity of the affected area, and the responsiveness of the affected area to treatment, but is usually one or more doses per day, and the course of treatment lasts for several days to several months, or until healing is effective or a significant reduction in the size and / or severity of the sensory impairment is achieved. Those skilled in the art can easily determine the optimal dosage, method of administration, and repetition frequency. In general, it is contemplated that the formulation will be applied 1 to 4 times per day. Skin patches, suppositories, or other carriers are generally maintained in place on the body surface for the duration of drug delivery, which typically ranges from 8 to 72 hours, and are replaced as needed.

[0143] In some embodiments, pirenzepine is present in an amount sufficient to provide a therapeutic effect with an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 90% or more, or substantially all, of the symptoms relieved.

[0144] In some embodiments, the effective amount of pirenzepine is about 1×10 -11 , 1×10 -10 , 1×10 -9 , 1×10 -8 , 1×10 -7 , 1×10 -6 , 1×10 -5 , 1×10 -4 , 1×10 -3 , 1×10 -2 , 1×10 -1 , 1, 1×10 1 or 1×10 2 grams.

[0145] How to treat sensory disorders , Made The method comprises administering the agent locally.

[0146] useThe total daily dosage of the pharmaceutical agent contemplated for administration, and thus the weight concentration of the pharmaceutical agent in each composition, may vary widely, but are within the typical skill of the routine practitioner. The specific therapeutically effective dose level for a particular patient and pharmaceutical agent will depend on a variety of factors, including the disorder being treated and the severity of the disorder, the activity of the specific compound employed, the specific composition employed, the age, weight, general health, sex and diet of the patient, the administration time, route of administration and excretion rate of the specific pharmaceutical agent employed, the duration of treatment, drugs used in combination or simultaneously with the specific compound employed, and factors well known in the medical industry. For example, it is within the skill of the art to start administration at a level lower than that required to obtain the desired therapeutic effect, and gradually increase the dosage until the desired effect is obtained.

[0147] In some embodiments, composition is administered in a single dose. Single doses of pirenzepine may also be used when co-administered with other substances (e.g., painkillers) for the treatment of acute conditions.

[0148] In some embodiments, pirenzepine (by itself or in combination with other drugs) is administered multiple times. Administration may be about once, about twice, about three times, about four times, about five times, about six times, about seven times, about eight times, about nine times, about ten times, or more than about ten times per day. Administration may be once a year, twice a year, every six months, every four months, every three months, every 60 days, once a month, once every two weeks, once a week, or about once every other day. In one embodiment, the drug is an analgesic. In another embodiment, pirenzepine and another therapeutic agent are administered together about once to about ten times per day. In another embodiment, the additional therapeutic agent is administered simultaneously with, before, or after administration of pirenzepine. In another embodiment, administration of pirenzepine and another therapeutic agent continues for less than about seven days. In yet another embodiment, the co-administration continues for about 6, 10, 14 times, 1 month, 2 months, 6 months, or 1 year or more. In some cases, the co-administration is maintained for as long as necessary, such as administration for a chronic or degenerative complication.

[0149] set Administration of the composition can be continued for as long as necessary. ,set The composition is administered for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, or 28 days or more. ,set The composition is administered for less than 28 days, 14 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day. ,set The composition is administered chronically on an ongoing basis, for example for the treatment of chronic pain.

[0150] Books As stated in the specification In the method Made by The dosage of the agent can be found by routine experimentation. The daily dosage is about 1×10 -7The daily dosage may range from about 1 to 5000 mg, or about 1 to 3000 mg, or about 1 to 2000 mg, or about 1 to 1000 mg, or about 1 to 500 mg, or about 1 to 100 mg, or about 10 to 5000 mg, or about 10 to 3000 mg, or about 10 to 2000 mg, or about 10 to 1000 mg, or about 10 to 500 mg, or about 10 to 200 mg, or about 10 to 100 mg, or about 20 to 2000 mg, or about 20 to 1500 mg, or about 20 to 1000 mg, or about 20 to 500 mg, or about 20 to 100 mg, or or about 50-5000 mg, or about 50-4000 mg, or about 50-3000 mg, or about 50-2000 mg, or about 50-1000 mg, or about 50-500 mg, or about 50-100 mg, or about 100-5000 mg, or about 100-4000 mg, or about 100-3000 mg, or about 100-2000 mg, or about 100-1000 mg, or about 100-500 mg, or within a range defined by any two of the foregoing amounts per application. In some embodiments, the daily dose of pirenzepine is about 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg. In some embodiments, the daily dose of pirenzepine is 0.1 mg. In some embodiments, the daily dose of pirenzepine is 1.0 mg. In some embodiments, the daily dose of pirenzepine is 10 mg. In some embodiments, the daily dose of pirenzepine is 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 mg. In some embodiments, the daily dose of pirenzepine is 500 mg. In some embodiments, the daily dose of pirenzepine is 1000 mg.

[0151] Typical daily dosage ranges include, for example, about 1×10 -7g to 5.0 g, or approximately 1 × 10 -7 g to 2.5 g, or approximately 1 × 10 -7 g to 1.00 g, or approximately 1 x 10 -7 g to 0.5 g, or approximately 1 × 10 -7 g to 0.25 g, or approximately 1 × 10 -7 g to 0.1 g, or approximately 1 x 10 -7 g to 0.05 g, or approximately 1 × 10 -7 g to 0.025 g, or approximately 1 × 10 -7 g~1×10 -2 g, or approximately 1 × 10 -7 g~5×10 -3 g, or approximately 1 × 10 -7 g~2.5×10 -3 g, or approximately 1 × 10 -7 g~1×10 -3 g, or approximately 1 × 10 -7 g~5×10 -4 g, or approximately 1 x 10 6 g to 5.0 g, or approximately 1 × 10 -6 g to 2.5 g, or approximately 1 × 10 -6 g to 1 g, or about 1 × 10 -6 g to 0.5 g, or approximately 1 × 10 -6 g to 0.25 g, or approximately 1 × 10 -6 g to 0.1 g, or approximately 1 x 10 -6 g~5×10 -2 g, or approximately 1 × 10 -6 g~5×10 -2 g, or approximately 1 × 10 -6 g~2.5×10 -2 g, or approximately 1 × 10 -6 g~1×10 -2 g, or approximately 1 × 10 -6 g~5×10 -3 g, or approximately 1 × 10 -6 g~2.5×10 -3 g, or approximately 1 × 10 -6 g~1×10 -3 g, or approximately 1 × 10 -6 g~5×10 -4 g, or approximately 1 × 10 -5 g to 5 g, or about 1 × 10 -5 g to 2.5 g, or approximately 1 × 10 -5g to 1 g, or about 1 × 10 -5 g to 0.5 g, or approximately 1 × 10 -5 g to 0.25 g, or approximately 1 × 10 -5 g to 0.1 g, or approximately 1 x 10 -5 g to 0.05 g, or approximately 1 × 10 -5 g~2.5×10 -2 g, or approximately 1 × 10 -5 g~1×10 -2 g, or approximately 1 × 10 -5 g~5×10 -3 g, or approximately 1 × 10 -5 g~2.5×10 -3 g, or approximately 1 × 10 -5 g~1×10 -3 g, or approximately 1 × 10 -5 g~5×10 -4 g. In some embodiments, the daily dose of pirenzepine is about 1×10 -7 , 1×10 -6 , 1×10 -5 , 1×10 -4 , 1×10 -3 g, 1×10 -2 g, 1×10 1 g, or 1 g. In some embodiments, the daily dose of pirenzepine is 1×10 -7 g. In some embodiments, the daily dose of pirenzepine is 1×10 -5 g. In some embodiments, the daily dose of pirenzepine is 1×10 -3 g. In some embodiments, the daily dose of pirenzepine is 1×10 -2 In some embodiments, each dose is about 1×10 -7 g to 5.0 g, or approximately 1 × 10 -7 g to 2.5 g, or approximately 1 × 10 -7 g to 1.00 g, or approximately 1 x 10 -7 g to 0.5 g, or approximately 1 × 10 -7 g to 0.25 g, or approximately 1 × 10 -7 g to 0.1 g, or approximately 1 x 10 -7 g to 0.05 g, or approximately 1 × 10 -7 g to 0.025 g, or approximately 1 × 10-7 g~1×10 -2 g, or approximately 1 × 10 -7 g~5×10 -3 g, or approximately 1 × 10 -7 g~2.5×10 -3 g, or approximately 1 × 10 -7 g~1×10 -3 g, or approximately 1 × 10 -7 g~5×10 -4 g, or approximately 1 × 10 -6 g to 5.0 g, or approximately 1 × 10 -6 g to 2.5 g, or approximately 1 × 10 -6 g to 1 g, or about 1 × 10 -6 g to 0.5 g, or approximately 1 × 10 -6 g to 0.25 g, or approximately 1 × 10 -6 g to 0.1 g, or approximately 1 x 10 -6 g~5×10 -2 g, or approximately 1 × 10 -6 g to 5×10-2g, or about 1×10 -6 g~2.5×10 -2 g, or approximately 1 × 10 -6 g~1×10 -2 g, or approximately 1 × 10 -6 g~5×10 -3 g, or approximately 1 × 10 -6 g~2.5×10 -3 g, or approximately 1 × 10 -6 g~1×10 -3 g, or approximately 1 × 10 -6 g to 5×10-4 g, or about 1×10-5 g to 5 g, or about 1×10-5 g to 2.5 g, or about 1×10 -5 g to 1 g, or about 1 × 10 -5 g to 0.5 g, or approximately 1 × 10 -5 g to 0.25 g, or approximately 1 × 10 -5 g to 0.1 g, or approximately 1 x 10 -5 g to 0.05 g, or approximately 1 × 10 -5 g~2.5×10 -2 g, or approximately 1 × 10 -5 g~1×10 -2 g, or approximately 1 × 10 -5 g~5×10 -3 g, or approximately 1 × 10-5 g~2.5×10 -3 g, or approximately 1 × 10 -5 g~1×10 -3 g, or approximately 1 × 10 -5 g~5×10 -4 In some embodiments, such individual doses are repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times per day.

[0152] Yes The dosage and frequency of administration of the active ingredient vary depending on the sex, age and weight of the patient, the symptoms to be treated, the desired therapeutic effect, the administration route and the duration of treatment. To people When to administer , conversion The concentration of the formulation containing the compound of the present invention is about 0.0001 to 10.0 W / V%, about 0.005 to 10.0 W / V%, about 0.01 to 10.0 W / V%, about 0.05 to 10.0 W / V%, about 0.1 to 10.0 W / V%, about 0.5 to 10.0 W / V%, about 1.0 to 10.0 W / V%, about 20 to 10.0 W / V%, about 3.0 to 10.0 W / V%, about 4.0 to 10.0 W / V%, or about 5.0 to 10.0 W / V%. One embodiment of the present invention has a formulation containing the compound of the present invention at about 1.0 to 10.0 W / V%. . one In the embodiment, about 0.01 to 10.0 W / V% The The compound has a formulation . one The embodiment is , conversion The compound has a composition of about 5.0 to 10.0 W / V %. 、1 It can be done several times a day, 1-10 times, 1-4 times, or once a day.

[0153] When used in the above composition , medicine A therapeutically effective amount may be employed in pure form or in the form of a pharma- ceutically acceptable salt, ester or prodrug, if such forms exist.

[0154] Usage example The following examples illustrate the currently most well-known embodiment of the present disclosure. However, the following are merely illustrative of the application of the principles of the present disclosure. Numerous modifications and alternative compositions, methods, and systems can be devised by those skilled in the art without departing from the spirit and scope of the present disclosure. The appended claims are intended to cover such modifications and arrangements. Thus, although the present disclosure has been specifically described above, the following examples provide further details in connection with what is currently considered to be the most practical and preferred embodiment of the present disclosure.

[0155] Example 1 The materials used in preparing the topical sensitizing agents described herein can be produced by known methods or are commercially available. It is also possible to utilize variants that are known per se to those skilled in the art, but are not mentioned in more detail. Those skilled in the art, given the literature and this disclosure, are fully equipped to prepare the formulations of this application.

[0156] teenager A topical preparation for general use is called a "broad" ,oh Call " Narrower " in amounts ranging from 0.1 to 0.25, as shown in Tables 1 and 2 below.

[0157] [Table 1]

[0158] [Table 2]

[0159] Use of the topical solution as described in Example 1 provides the following benefits to subjects:

[0160] Example 2 Subject 1 For several years, I have been suffering from the intermittent effects of Guillain-Barré Syndrome (GBS), which mainly affects my athletic ability. A 44-year-old Asian man 1 Over a 5-year period, he had noticed a decrease in sensitivity during sex and a progressive delay in ejaculation, averaging 40-50 minutes. Made ofAfter applying the agent (described in Example 1) daily to the entire penis, including the head (glans), shaft, and scrotum, for two weeks, the subject noticed that the time between ejaculations was shortened by an average of 30 minutes. His orgasms were noticeably more intense.

[0161] Example 3 Subject 2 was 68 years old. There was. The subjects A topical preparation as described in Example 1 was applied once daily late at night to the head (glans) and shaft of the penis for eight weeks. After two weeks, the subject noticed a significant and qualitatively improved positive difference in sensation during intercourse. Although the subject did not believe that sensitivity was reduced, after three weeks of treatment, he found that there was a significant improvement in sensitivity, intensity, speed of response, urgency, and duration to baseline levels of stimulation. No negative side effects were noted, and sensation continued to improve after four weeks. Ta The subject stated that he had not realized how much sensation he had lost until it returned. The subject used tadalafil 10 mg before intercourse, which improved sensitivity, duration, and hardness. 、5 The dosage was reduced to mg.

[0162] Example 4 Subject 3 was a 49-year-old non-diabetic Asian male in good health who had had difficulty reaching ejaculation for approximately three years with ongoing deterioration. Subject 3 used the provided topical medication inconsistently, on average once a week for three months. During that time, subject saw a tremendous improvement in his ability to reach orgasm; he had never experienced such an instance since beginning treatment for his inability to reach orgasm. Subject 3 reported increased occurrence of early morning erections upon awakening and increased sexual sensitivity.

[0163] Example 5 Subject 4 was a 61-year-old male of Caucasian descent diagnosed with type 2 diabetes in July 2010. The subject reported that he had experienced a decrease in sexual response over several years and had occasionally treated his function with Cialis, but had not continued due to side effects. The subject began topical pirenzepine application to the penis and after 2 days had an increase in sexual response and function. Subject 4 reported that after 3 days of typical application, typically applied twice a week, nocturnal erections occurred. The subject experienced a noticeable sensation after application around the scrotum where the penis resides. The subject reported functional improvement in his ability to achieve erection and penetrative intercourse. Ejaculation was similar to what the patient experienced with Cialis, but was not accompanied by headaches.

[0164] It should be noted that in the above examples, the various skin contact areas, contact times of the analgesic system, methods of treating specific conditions, etc. are provided by way of example only. Methods and Compositions Although the present invention has been described with reference to specific embodiments, those skilled in the art will appreciate that the present invention is Disclosure It is understood that various modifications, changes, omissions, and substitutions may be made without departing from the spirit of 。

Claims

1. A method for improving sexual sensation disorders in a subject by applying to the anogenital area of ​​the subject an effective amount of a composition comprising a therapeutically effective amount of pirenzepine or a pharma- ceutically acceptable salt thereof.

2. 10. The method of claim 1, comprising improving anogenital sensitivity in the subject.

3. 3. The method of claim 2, comprising increasing anogenital sensitivity of the subject.

4. 3. The method of claim 2, comprising decreasing anogenital sensitivity of the subject.

5. 5. The method of claim 4, comprising reducing anogenital pain.

6. 13. The method of claim 1, which reverses, prevents or delays sexual dysfunction symptoms.

7. The method of claim 1 , wherein the composition is applied to the anogenital skin.

8. 8. The method of claim 7, wherein the subject is male.

9. 9. The method of claim 8, wherein the skin is on the penis and / or anus.

10. 10. The method of claim 9, wherein the subject is female.

11. 11. The method of claim 10, wherein the composition is applied to the external genitalia, cervix, vagina, vulva, labia, meatus, clitoris, urethral meatus, urethral folds, vulvar vestibule, perineum, and / or anus.

12. 13. The method of claim 1, wherein the composition comprises pirenzepine, or a pharma- ceutically acceptable salt, in a concentration of about 1% to about 15% by weight.

13. 13. The method of claim 1, wherein the composition comprises pirenzepine, or a pharma- ceutically acceptable salt, in a concentration of about 1% to about 6% by weight.

14. The method of claim 1 , wherein the composition is formulated for topical, transdermal or transmucosal administration.

15. 15. The method of claim 14, wherein the composition is in the form of a gel, cream, lotion, solution, suspension, emulsion, ointment, powder, crystal, spray, foam, ointment, paste, plaster, paint, bioadhesive, suppository, tampon, body wipe, wound dressing, skin patch, genital pad, or transdermal patch.

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