IL292632A - Methods and compositions for treating, ameliorating, prevention and recurrence-prevention of anorectal disorders - Google Patents
Methods and compositions for treating, ameliorating, prevention and recurrence-prevention of anorectal disordersInfo
- Publication number
- IL292632A IL292632A IL292632A IL29263222A IL292632A IL 292632 A IL292632 A IL 292632A IL 292632 A IL292632 A IL 292632A IL 29263222 A IL29263222 A IL 29263222A IL 292632 A IL292632 A IL 292632A
- Authority
- IL
- Israel
- Prior art keywords
- composition
- formulation
- oil
- acmella
- genital
- Prior art date
Links
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Description
METHODS AND COMPOSITIONS FOR TREATING, AMELIORATING, PREVENTION AND RECURRENCE-PREVENTION OF ANORECTAL DISORDERS FIELD OF INVENTION The present invention relates to methods and compositions for treating, preventing, ameliorating and recurrence-preventing of anal fissures, hemorrhoids and genital disorders. More specifically, it relates to compositions comprising an N-alkylamide of a plurality of N-alkylamides for local administration.
BACKGROUND OF INVENTION Anorectal disorders are very common among a wide population of patients and have been an ongoing problem for millennia. Because patients may be embarrassed about the anatomic location of their symptoms, they may present to care late in the course of their illness. Although anorectal disorders such as anal fissures, and hemorrhoids and abscess, are typically outpatient problems, they also occur in the critically ill patient population, where their presentation and management are more difficult, see Bach, H. H., Wang, N., & Eberhardt, J. M. (2014). Common Anorectal Disorders for the Intensive Care Physician. Journal of intensive care medicine, 29(6), 334-341.) Anal fissures, caused by a small tear in the lining of the anus are a common problem in routine medical care with a lifetime risk of over 75% (see Douglas J. MacKay (2001). Hemorrhoids and Varicose Veins: A Review of Treatment Options. Alternative Medicine Review, Volume 6, Number 2, 2001, pp. 126). Patients’ quality of life can be significantly reduced due to massive discomfort. Complications from a lack or inadequacy of treatment include abscess, fistula and incontinence. Thus, it is important to have therapeutic options that are efficient and safe. Lateral internal sphincterotomy (LIS) is often claimed to be the gold standard therapy for chronic anal fissures; however a recent meta-analysis indicated that LIS is the most efficacious treatment but is compromised by a high rate of postoperative incontinence, see Ebinger, S. M., Hardt, J., Warschkow, R., Schmied, B. M., Herold, A., Post, S., & Marti, L. (2017). Operative and medical treatment of chronic anal fissures-a review and network meta-analysis of randomized controlled trials. Journal of gastroenterology, 52(6), 663-676.
Despite the high prevalence of anal fissure, there is not much to offer the patients change in life style with high fiber diets, exercising and sitz bath, medications that often provide only temporary relive and painful invasive treatments, such as botulinum toxin injections and surgery. The limited arsenal of therapeutic medications includes the nitric oxide donor nitroglycerin and calcium channel blocking drugs, mainly nifedipine with/without anesthetics. The efficacy of both is limited and is associated with significant side effects.
Hemorrhoids are common, affecting up to one quarter of all adults according to some estimates. Hemorrhoids are a result of increased pressure gradient within the hemorrhoid plexus. This typically results from increased intra-abdominal pressure experienced in scenarios such as prolonged straining during defecation or during pregnancy and labor. Numerous interventions exist for their management, ranging from topical and medical therapies to outpatient treatments and surgical interventions that aim to fix or excise. The clinical manifestations of symptomatic hemorrhoids vary with the extent of the disease process. Current treatment of hemorrhoids includes dietary and lifestyle modification, pharmacological approach, office-based procedures and specific operations and surgeries for hemorrhoids (such as hemorrhoidectomy and other non-excisional invasive or semi-invasive surgical methods).
Non-operative approaches for treating hemorrhoids comprise dietary and lifestyle modification such as fiber supplementation. However, although fiber supplementation was associated with significant reductions in the risk of persistent symptoms and the risk of rectal bleeding, the effects of fiber supplementation on mucosal prolapse, pain, and itching were not significant. Furthermore, clinical experience indicates that use of topical glucocorticoids, vasoconstrictors (e.g., phenylephrine-based creams or suppositories), or analgesics may provide temporary relief of some symptoms, but data from randomized trials on long-term efficacy and side effects are lacking. See Jacobs, D. (2014). Hemorrhoids. New England Journal of Medicine, 371(10), 944-951. Surgery is indicated for high-graded hemorrhoids, or when non-operative approaches have failed, or complications have occurred. Despite advances in office-based procedures and better surgical approaches, post-procedural pain and disease recurrence remain the most challenging problems in the treatment of hemorrhoids; see Lohsiriwat, V. (2015).
Treatment of hemorrhoids: A coloproctologist’s view. World Journal of Gastroenterology: WJG, 21(31), 9245–9252.
Many different systems, devices and procedures have been provided over the years in an attempt to alleviate/reduce the pain and/or reduce the symptoms associated with anorectal disorders and improve the patients’ quality of life. However, even after these many years of trying, there has gone unmet a need for effective treatments that are simple, usable by the common person, and effective at alleviating both symptoms and discomfort associated with hemorrhoids and other conditions. The present compositions and methods remedy one or more of these long-felt needs.
SUMMARY OF THE INVENTION: It is hence one object of the present invention to disclose a local composition as defined above, for treating, ameliorating, preventing and recurrence-preventing anorectal disorders in a mammalian subject, wherein said composition comprises at least one N-alkylamide.
It is another object of the present invention to disclose a composition as defined above, wherein said N-alkylamide is spilanthol.
It is another object of the present invention to disclose a composition, as defined above, wherein said anorectal disorders are selected from a group consisting at least one of hemorrhoids, anal fissures, fecal incontinence, proctalgia fugax, excessive perineal descent, pruritus ani, anal abscess, fistula, and any combination thereof.
It is another object of the present invention to disclose a composition, as defined above,wherein said composition is additionally useful for treating, ameliorating, preventing and recurrence-preventing genital disorders, said genital disorders are selected from a group consisting genital itch in males or females, , vaginal discharge in females, genital lesions in males or females, , pruritus ani, balanitis, dermatitis , lichen simplex, atopic dermatitis, seborrheic dermatitis , irritant contact dermatitis, balanitis, intertrigo, allergic contact dermatitis;, pruritus vulvae, eczema, seborrheic dermatitis, irritant contact dermatitis vulvitis, intertrigo, allergic contact dermatitis , psoriasis , lichen sclerosis , lichen planus, vaginitis, vaginal or genital malodour, desquamative vaginitis, vulval skin lesions, angiokeratomas , hidradenitis suppurativa ,hailey hailey , labial adhesions , sebaceous adenitis, milia, pilar and epidermal cysts,, vulval intraepithelial neoplasia, bowenoid papulosis, penile intraepithelial neoplasia, bowen disease of penis, erythroplasia of quyerat, anal intraepithelial neoplasia , invasive squamous cell carcinoma including vulval cancer and anal cancer, vulval cancer, extramammary paget disease, genital melanotic macules, melanosis, mucosal melanoma ,pearly penile papules, peyronie disease, and any combination thereof.
It is another object of the present invention to disclose a composition, as defined above,wherein said mammalian subject is an animal or human.
It is another object of the present invention to disclose a composition, as defined above, wherein said N-alkylamide is extracted of a plant family selected from a group consisting of acanthaceae, amaranthaceae, Acanthaceae, amaranthaceae, aristolochiaceae, asteraceae, brassicaceae, bromeliaceae, caryophyllaceae, convolvulaceae, ephedraceae, euphorbiaceae, fabaceae, hippocastanaceae, lauraceae, liliaceae, malvaceae, meliaceae, menispermacea, piperaceae, poaceae, rhamnaceae, rosaceae, rutaceae, salicaceae, scrophulariaceae, solanaceae, zygophyllaceae and any combination thereof.
It is another object of the present invention to disclose a composition, as defined above, wherein said N-alkylamide is a synesthetic or modified N-alkylamide.
It is another object of the present invention to disclose a composition, as defined above, where said composition additionally comprises complexing and formulation agents such as cyclodextrin, polyethylene glycol (PEG).
It is another object of the present invention to disclose a composition, as defined above, wherein at least one of said N-alkylamide is encapsulated.
It is another object of the present invention to disclose a composition, as defined above,wherein said spilanthol is extracted of a plant selected from a group consisting of Acmella oleracea, Acmella spilanthes, Acmella ciliate, Acmella oppositifolia, Acmella radicans, Acmella brachyglossa, Acmella ciliate, Acmella oleracea, Acmella paniculata, Acmella uliginosa, Welelia parviceps , Heliopsis longipes and any combination thereof.
It is another object of the present invention to disclose a composition, as defined above, wherein said spilanthol is a synesthetic spilanthol. It is another object of the present invention to disclose a composition, as defined above,wherein said composition is configured to be administrable in a manner selected from a group consisting of topical or dermal and any combination thereof.
It is another object of the present invention to disclose a composition, as defined above, wherein said composition is provided in a form selected from a group consisting of liquid, solution, capsule, gel, dissolving capsule, capsule comprising a filter, infusion, cream, ointment, electroporation formulation, foam, suspension, emulsion, lotion, microspheres, microbeads, mud, oil, paste, nanospheres, liposomes, powder, roller stick, soap, surfactant, spray, suppositories (anal or vaginal), vaginal tablets, washing or bathing preparations, tampons, patches , plasters, local injections, liniments, lotions, drops, injection, ointment Pessary (vaginal suppository) vaginal ring, vaginal douche, Intrauterine device (IUD), extra-amniotic infusion,, intravesical infusion, enema solution ,hydrogel liposomes balm, shampoo, dermal patch, transdermal patch, transdermal spray, jet injector and any combination thereof.
It is another object of the present invention to disclose a composition, as defined above, wherein said composition is in a form selected from a pharmaceutical product or a cosmetic product or a medical device.
It is another object of the present invention to disclose a composition, as defined above , said composition comprises two formulations, Formulation 1 and Formulation 2, wherein said Formulation 1 is a lipophilic Formulation and said Formulation 2 is a hydrophilic formulation; further wherein said Formulation 1 is administered to said mammalian subject before said Formulation 2.
It is another object of the present invention to disclose a composition, as defined above, wherein said Formulation 1 comprises spilanthol microcapsules and at least one of coconut oil, olive oil, lanolin alcohol, obliphica oil, almond oil, alchemilla roots ethanolic extract, clove oil, lavender oil, aloe vera, and any combination thereof.
It is another object of the present invention to disclose a composition, as defined above,wherein said Formulation 2 comprises spilanthol microcapsule, and at least one of evodia rutaecarpa, sophora japonica, alchemilla mollis, horse chestnut, centella asiatica, malva sylvestris, ranunculus (or Ratanhia, licorice, aloe vera, allantoin, hyaluronic acid, red algae, rutin , pomegranate seed oil, carum carvi essential oil, calendula oil, honey, sea buckthorn oil, beeswax, cocconut oil, lanolin alcohol, brij 72, brij 721, grapefruit seed extract (GSE) and any combination thereof.
It is another object of the present invention to disclose a composition, as defined above, wherein said plant is extracted by one of solvents of a group consisting of: organic solvents, hydrophilic solvents, hydrophobic solvents, water, ethanol, petroleum ether, cold water extraction (CWE), methanol, chloroform, hexane, ethyl acetate, methanol, and any combination thereof.
It is hence one object of the present invention to disclose a method of treating, ameliorating, preventing and recurrence-preventing anorectal disorders in a mammalian subject comprising steps of locally applying a composition, wherein said composition comprises at least one N-alkylamide.
It is another object of the present invention to disclose a method as defined above, wherein said method is additionally useful for treating, ameliorating, preventing and recurrence-preventing of genital disorders.
It is another object of the present invention to disclose a method as defined above, wherein said N-alkylamide is spilanthol.
It is another object of the present invention to disclose a method as defined above, wherein said anorectal disorders wherein said anorectal disorders are selected from a group consisting at least one of hemorrhoids, anal fissures, fecal incontinence, proctalgia fugax, excessive perineal descent, pruritus ani, anal abscess, fistula, and any combination thereof.
It is another object of the present invention to disclose a method as defined above, wherein said composition is additionally useful for treating, ameliorating, preventing and recurrence-preventing of genital disorders, said genital disorders are selected from a group consisting genital itch in males or females, , vaginal discharge in females, genital lesions in males or females, , pruritus ani, balanitis, dermatitis , lichen simplex, atopic dermatitis, seborrheic dermatitis , irritant contact dermatitis , balanitis, intertrigo, allergic contact dermatitis;, pruritus vulvae, eczema, , seborrheic dermatitis, irritant contact dermatitis vulvitis, intertrigo, ,allergic contact dermatitis , psoriasis , lichen sclerosis , lichen planus, vaginitis, vaginal or genital malodour, desquamative vaginitis, vulval skin lesions, angiokeratomas , hidradenitis suppurativa ,hailey hailey , labial adhesions , sebaceous adenitis, milia, pilar and epidermal cysts,, vulval intraepithelial neoplasia, bowenoid papulosis, penile intraepithelial neoplasia, bowen disease of penis, erythroplasia of quyerat, anal intraepithelial neoplasia , invasive squamous cell carcinoma including vulval cancer and anal cancer, vulval cancer, extramammary paget disease, genital melanotic macules, melanosis, mucosal melanoma ,pearly penile papules, peyronie disease, and any combination thereof.
It is another object of the present invention to disclose a method as defined above, wherein said mammalian subject is an animal or human.
It is another object of the present invention to disclose a method as defined above, wherein said N-alkylamide is extracted of a plant family selected from a group consisting of acanthaceae, amaranthaceae, Acanthaceae, amaranthaceae, aristolochiaceae, asteraceae, brassicaceae, bromeliaceae, caryophyllaceae, convolvulaceae, ephedraceae, euphorbiaceae, fabaceae, hippocastanaceae, lauraceae, liliaceae, malvaceae, meliaceae, menispermacea, piperaceae, poaceae, rhamnaceae, rosaceae, rutaceae, salicaceae, scrophulariaceae, solanaceae, zygophyllaceae and any combination thereof.
It is another object of the present invention to disclose a method as defined above, wherein said plant is extracted by one of solvents of a group consisting of: organic solvents, hydrophilic solvents, hydrophobic solvents, water, ethanol, petroleum ether, chloroform, cold water extraction (CWE), methanol, hexane, ethyl acetate, methanol, and any combination thereof.
It is another object of the present invention to disclose a method as defined above, wherein said N-alkylamide is a synesthetic N-alkylamide.
It is another object of the present invention to disclose a method as defined above, wherein said spilanthol is extracted of a plant selected from a group consisting of Acmella oleracea, Acmella spilanthes, Acmella ciliate, Acmella oppositifolia, Acmella radicans, Acmella brachyglossa, Acmella ciliate, Acmella oleracea, Acmella paniculata, Acmella uliginosa, Welelia parviceps , Heliopsis longipes and any combination thereof.
It is another object of the present invention to disclose a method as defined above, wherein said spilanthol is a synesthetic spilanthol.
It is another object of the present invention to disclose a method as defined above, wherein said composition is configured to be administrable in a manner selected from a group consisting of topical , dermal, intravenous, intramuscular, and subcutaneous, transmucosal (buccal, vaginal, and rectal), transdermal and any combination thereof.
It is another object of the present invention to disclose a method as defined above, wherein said composition is provided in a form selected from a group consisting of liquid, solution, capsule, gel, dissolving capsule, capsule comprising a filter, infusion, cream, ointment, electroporation formulation, foam, suspension, emulsion, lotion, microspheres, microbeads, mud, oil, paste, nanospheres, liposomes, powder, roller stick, soap, surfactant, spray, suppositories (anal or vaginal), vaginal tablets, washing or bathing preparations, tampons, patches , plasters, local injections, liniments, lotions, drops, injection, ointment Pessary (vaginal suppository) vaginal ring, vaginal douche, Intrauterine device (IUD), extra-amniotic infusion,, intravesical infusion, enema solution ,hydrogel liposomes balm, shampoo, dermal patch, transdermal patch, transdermal spray, jet injector and any combination thereof.
It is another object of the present invention to disclose a method as defined above, wherein said composition is in a form selected from a pharmaceutical product or a cosmetic product. The method of claim 19, said composition comprises two formulations, Formulation 1 and Formulation 2, wherein said Formulation 1 is a lipophilic formulation and said Formulation 2 is a hydrophilic formulation; further wherein said Formulation 1 is administered to said mammalian subject before said Formulation 2.
It is another object of the present invention to disclose a method as defined above, wherein said Formulation 1 or Formulation 2 comprises spilanthol microcapsules, and at least one of coconut oil, olive oil, lanolin alcohol, obliphica oil, almond oil, alchemilla roots ethanolic extract, clove oil, ranunculus ficaria, lavender oil, aloe vera, evodia rutaecarpa or rutaecarpine, sophora japonica, alchemilla mollis, horse chestnut, centella asiatica, malva sylvestris, ratanhia, licorice, allantoin, hyaluronic acid, red algae, rutin, troxerutin, pomegranate seed oil, carum carvi essential oil , calendula oil, honey, sea buckthorn oil, beeswax, brij 72, brij 721, Grapefruit seed extract (GSE) and any combination thereof.
It is hence one object of the present invention to disclose a method for locally treating, ameliorating, preventing and recurrence-preventing of anorectal disorders in a mammalian subject, said method comprises steps of: a. administering Formulation 1 for at least one day to said mammalian subject, said Formulation 1 is a water-free lipophilic formulation, b. administering said Formulation 1 and Formulation 2, for at least one additional day; said Formulation 2 is a hydrophilic formulation; wherein said Formulation 2 is administered to said mammalian subject following said Formulation 1.
It is another object of the present invention to disclose a method as defined above, wherein said Formulation 1 or Formulation 2 comprises spilanthol microcapsule , and at least one of coconut oil, olive oil, lanolin alcohol, obliphica oil, almond oil, alchemilla roots ethanolic extract, clove oil, ranunculus ficaria, lavender oil, aloe vera, evodia rutaecarpa or rutaecarpine, sophora japonica, alchemilla mollis, horse chestnut, centella asiatica, malva sylvestris, Rathania, licorice, allantoin, hyaluronic acid, red algae, rutin, troxerutin, pomegranate seed oil, carum carvi essential oil , calendula oil, honey, sea buckthorn oil, beeswax, brij 72, brij 721, grapefruit seed extract (GSE)and any combination thereof.
It is hence one object of the present invention to disclose a kit for a local treatment, amelioration, prevention and recurrence-prevention of anorectal disorders or genital disorders in a mammalian, wherein said kit comprises; a. a container comprising at least one topical composition, said composition comprises at least one N-alkylamide, and b. instructions for administration of said composition to said mammalian subject.
BRIEF DESCRIPTION OF THE FIGURES The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the principles of the invention.
Figure 1 Liquid extract of acmella.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS The following description is provided, alongside all chapters of the present invention, so as to enable any person skilled in the art to make use of the invention and sets forth the best modes contemplated by the inventor of carrying out this invention. Various modifications, however, are adapted to remain apparent to those skilled in the art, since the generic principles of the present invention have been defined specifically to provide compositions and methods for treating, ameliorating, prevention and recurrence-prevention of anorectal disorders.
The term local administration or local treatment or local therapy or local application refer hereinafter to application of composition or compositions to a specific location; treatment that is directed to a specific organ or limited area of the body,. Examples of local therapy or local administration, include inter alia, injection, intradermal, subcutaneous, transdermal implant, intracavernous intravenous, intramuscular, topical therapy (medicine in a lotion or cream that is applied to the skin).
The term topical administration or topical treatment or topical therapy or topical application refer hereinafter to application to body surfaces such as the skin or mucous membranes to treat ailments via a large range of classes including, for example ,creams, foams, gels, lotions, and ointments. Many topical medications are epicutaneous, meaning that they are applied directly to the skin. Topical routes of administration may also be inhalational, such as asthma medications, or applied to the surface of tissues other than the skin, such as transmucosal routes, rectal enteral or vaginal, to the mucus of vagina or rectum.
The term anorectal disorders refers hereafter to one or more of hemorrhoids, anal fissures, fecal incontinence, proctalgia fugax, excessive perineal descent, pruritus ani, anal abscess or fistula.
The term anal fissures refers hereinafter to longitudinal tears in the squamous epithelium of the anal canal distal to the dentate line. Fissures are classified into internal and external fissures based on their location at the sphincter is a smooth muscle that is the most distal extension of the inner circular smooth muscle of the colon and the rectum and the external anal sphincter which is striated muscle that forms a circular tube around the anal canal, respectively.
In up to 90% of cases they are located on the posterior midline. Fissures are classified into an acute and a chronic form and into primary and secondary fissures based on their pathogenesis. Chronic fissures are defined by both or either chronology and morphology. The criteria are duration of symptoms for longer than 8 weeks, the presence of a sentinel pile, a skin tag or an ulcer with exposed internal sphincter fibers. The exact pathogenesis of primary fissures remains uncertain, but a core point is hypertonicity of the internal anal sphincter, which leads to local ischemia. Furthermore, inflammation and pain induce ongoing hypertonicity, giving rise to a vicious circle. Therefore, the aim of treatment strategies is to reduce the sphincter tone with either medical agents, such as glyceryl trinitrate (GTN, also called nitroglycerine), calcium channel blockers (CCBs) and botulinum toxin, or surgical interventions, such as lateral internal sphincterotomy (LIS).
The term hemorrhoids or pathologic hemorrhoids refer hereinafter to an abnormal mass of dilated and engorged blood vessels in swollen tissue that occurs internally in the anal canal or externally around the anus, that may be marked by bleeding, pain, or itching, and that when occurring internally often protrude through the outer sphincter of the anus and when occurring externally may lead to thrombosis. Hemorrhoids is recognized as one of the most common medical conditions in general population. The most common complications of hemorrhoids are heavy bleeding, chronic unremitting prolapse of mucosal tissue, strangulation, ulceration, and thrombosis.
Hemorrhoids of Grade 1 are hemorrhoid protruded into the anal canal but does not prolapse outside the anus, hemorrhoids of Grade 2 are hemorrhoid protrudes through the anus during straining or evacuation but returns spontaneously, hemorrhoids of Grade 3 are hemorrhoid protrudes through the anus during straining or evacuation but needs to be manually returned to position and of Grade 4 are hemorrhoid that remains prolapsed outside of the anus.
The terms N-alkylamides or NAAs refer hereinafter to a group of natural secondary metabolites plant-derived amides, found in different plant genera, mostly contain a poly-unsaturated aliphatic fatty acid chain and a shorter substituent at the amine side. Both might include cyclic systems and/or hetero-molecules (nitrogen, sulfur, oxygen). At the core is the amide bond, which resembles the peptide link –C(QO)NH– as observed in polypeptides and proteins. Due to its resonance characteristics, amide bonds are planar and relatively stable, possess partial double bond characters and are at the origin of its large dipole moment. Up till now, NAAs are found in 26 different plant families comprising more than 100 plant species. NAAs are mainly found in the plant genera Echinacea, Zanthoxylum, Heliopsis and Spilanthes. Accordingly, Table 1 lists non-limiting examples of plant origins for NAAs.
Table 1: Plant origins of NAAs Acanthaceae + Hydrangeae • Aphelandra - squarrosa Nees Amaranthaceae + Gomphreneae • Gomphrena - globosa L. Aristolochiaceae + Asareae • Asarum - forbesii Maxim. - heterotropoides F.Schmidt Asteraceae + Anthemideae • Achillea - ageratifolia - asiatica Serg. - aspleniifolia Vent. - biebersteinii Afan. - collina (Becker ex Rchb.f.) Heimerl - crithmifolia - falcata L - grandifolia Friv. - lanulosa Nutt. - latiloba Ledeb. ex Nordm. - ligustica All. - lycaonica Boiss. & Heldr. - macrophylla L. (Achillea) - millefolium L. - nana L. - pannonica Scheele [nom. illeg.] - ptarmica L. - setacea - spinulifolia Fenzl ex Boiss. - tomentosa L - wilhelmsii K.Koch • Anacyclus - monanthos (L.) - pyrethrum (L.) • Artemisia - dracunculus L. • Chrysanthemum - frutescens L. • Leucocyclus - formosus Boiss. • Otanthus - maritimus + Heliantheae • Echinacea - angustifolia DC. - pallida (Nutt.) - purpurea (L.) • Helianthus - annuus L. • Heliopsis - buphthalmoides (Jacq.) - helianthoides (L.) - longipes (A.Gray) • Salmea - scandens (L.) Liliaceae + Lilieae • Lilium - sp. (Lilium) Malvaceae + Gossypieae • Gossypium - hirsutum L. + Hibisceae • Abelmoschus - esculentus (L.) Meliaceae + Aglaieae • Aglaia - tenuicaulis Hiern Menispermacea + Menispermeae • Cissampelos - glaberrima A.St.-Hil. Piperaceae + Pipereae • Piper - aduncum L - amalago L - arboreum Aubl. - demeraranum (Miq.) - longum L. - nigrum L. - retrofractum Vahl - sarmentosum Roxb. - sylvaticum Roxb. - tuberculatum Jacq. Poaceae + Andropogoneae • Zea - mays L. + Bambuseae • Phyllostachys - bambusoides + Paniceae • Pennisetum - americanum (L.) Rhamnaceae + Phyliceae • Phylica - pubescens Phylica Rosaceae + Pyreae • Pyrus - communis L. (Pyrus) + Rubeae • Rubus - idaeus L. Rutaceae + Amyrideae • Amyris - balsamifera L.
• Spilanthes - acmella (L.) L. - alba - callimorpha - ciliata Kunth - oppositifolia var. oppositifolia (Lam.) - radicans Schrad. ex DC + Senecioneae • Senecio - erechthithoides F.Muell. Brassicaceae + Brassiceae • Arabidopsis - thaliana (L.) • Brassica - oleracea L. + Lepidieae • Lepidium - meyenii Walp. Bromeliaceae + Ananaseae • Ananas - comosus (L.) Caryophyllaceae + Diantheae • Dianthus - caryophyllus L. Convolvulaceae + Ipomoeeae • Ipomoea - aquatica Forssk. - nil (L.) - obscura (L) - quinquefolia Ephedraceae + Ephedreae • Ephedra - aphylla Forssk. Euphorbiaceae + Acalypheae • Acalypha - indica L. (Acalypha) • Ricinus - communis L. (Ricinus) Extraction artefacts Fabaceae + Aeschynomeneae • Arachis - hypogaeal. + Phaseoleae • Glycine - max (L.) Merr. + Vicieae • Pisum - savitum L. • Vicia - faba L. Hippocastanaceae + Aesculeae • Aesculus - hippocastanum L. Lauraceae + Perseeae • Persea - gratissima + Clauseneae • Clausena - indica (Dalzell) - lansium (Lour.) • Glycosmis - chlorosperma (Blume) Spreng. - calcicola - parviflora - cyanocarpa - mauritiana + Pilocarpeae • Pilocarpus - trachyllophus + Zanthoxyleae • Zanthoxylum - ailanthoides var. ailanthoides - armatum - beecheyanum - bungeanum - gilletii - heitzii - fagara (L.) - integrifolium (Merr.) - lemairie - macrophylla - piperitum (L.) DC. - planispinum - rubescens - schinifolium - setulosum - simulans - thomense Salicaceae + Saliceae • Salix - sp. Scrophulariaceae + Antirrhineae • Chaenorhinum - minus (L.) • Schweinfurthia - papilionacea Boiss. Solanaceae + Capsiceae • Capsicum - annuum L. - pubescens + Nicotianeae • Nicotiana - tabacum L. + Solaneae • Solanum - lycopersicum Lam. Synthetic Zygophyllaceae + Tribuleae • Tribulus - terrestris L. See: Boonen,J.,et al.(2012), Alkamid database: Chemistry, occurrence and functionality of plant N-alkylamides. Journal of Ethnopharmacology (2012).
The term extraction refers hereinafter to a separation process consisting in the separation of a substance from a matrix. It includes inter alia liquid-liquid extraction based on solubility, solid phase extraction based on different chemical and/or physical characteristics, supercritical fluid extraction, pressurized liquid extraction, chromatographs, pressurized hot water extraction, microwave assisted extraction, subcritical CO 2 extraction, membrane-assisted solvent extraction, solid phase micro extraction and stir-bar sorptive extraction. The distribution of a solute between two phases is an equilibrium condition described by partition theory. This is based on exactly how the analyte move from the water into an organic layer.
Plant parts are extracted dry, or wet, using, inter alia the following solvents: organic solvents, hydrophilic solvents, hydrophobic solvents, water, ethanol, petroleum ether, cold water extraction (CWE), methanol, chloroform, hexane, ethyl acetate, methanol. Plant parts are extracted, in whole or in part, including inter alia seeds, fruits, root, flowers, stems, foliage and leaves.
The terms Spilanthol or Affinin refer hereinafter to s a fatty acid amide, a highly abundant and biologically potent triene NAA. Spilanthol’s IUPAC name is: (2E,6Z,8E)-N-Isobutyl-2,6,8-decatrienamide; deca-2E,6Z,8E-trienoic acid isobutylamide; F3M1 according to the FxMy classification of NAAs. Spilanthol’s CAS Number is 25394-57-4. Spilanthol is found in Asteracea plants such as Spilanthes acmella. Specifically, spilanthol is found in plants comprising inter alia, Acmella oleracea, or Acmella spilanthes or Acmella ciliate, or Acmella oppositifolia, or Acmella radicans, or Acmella brachyglossa, or Acmella ciliate, or Acmella oleracea, or Acmella paniculata, or Acmella uliginosa, or Welelia parviceps or Heliopsis longipes and any combination thereof.
The current invention also relates to synthetic N-alkylamides or modified N-alkylamides. The current invention discloses topical and transdermal compositions and methods for treatment, ameliorate, prevention and recurrence-prevention of anorectal and genital disorders in mammalian subjects. The anorectal disorders comprising, inter alia one of hemorrhoids, anal fissures, fecal incontinence, proctalgia fugax, excessive perineal descent, pruritus ani, anal abscess or fistula.
The current invention is additionally useful for treating, ameliorating, preventing and recurrence-preventing and ameliorating genital skin or dermal disorders comprising of, inter alia, one of genital itch in males or females, , vaginal discharge in females, , genital lesions in males or females, and any combination thereof.
Genital skin or dermal disorders comprise, inter alia: 1. Genital itch in males: such as a. Pruritus ani (itchy anus), b. Balanitis (inflammation of the glans penis in males), c. Dermatitis (eczema), including: Lichen simplex (dermatitis due to localised itch-scratch-itch response and resulting in thickened skin on scrotum), Atopic dermatitis (eczema), Seborrheic dermatitis (usually affects scalp as well), Irritant contact dermatitis (from wetness, incontinence, vigorous cleansing) the most common cause of nonspecific balanitis (in males), Intertrigo (in skin folds), and Allergic contact dermatitis (most often due to fragrances, preservatives or rubber). 2. Genital itch in females a. Itchy anus (pruritus ani), b. Itchy vulva (pruritus vulvae) in adult women, c. Itchy vulva (pruritus vulvae) in prepubertal girls, d. Dermatitis (eczema), including: Lichen simplex (dermatitis due to localised itch-scratch-itch response and resulting in thickened skin on labia majora, Atopic dermatitis (eczema), Seborrheic dermatitis (usually affects scalp as well), Irritant contact dermatitis (from wetness, incontinence, vigorous cleansing) the most common cause of vulvitis, Intertrigo (in skin folds),Allergic contact dermatitis (most often due to fragrances, preservatives or rubber), e. Psoriasis (persistent, well-defined, red, scaly or moist patches), f. Lichen sclerosis (white scarred patches), and g. Lichen planus. 3. Vaginal discharge a. Vaginitis, b. Vaginal or genital malodour, and c. Desquamative vaginitis. 4. Genital skin lesions Non-infectious skin lesions and miscellaneous conditions that are commonly found in the genital area include: a. Vulval skin lesions, b. Angiokeratomas (red/purple spots), c. Hidradenitis suppurativa (boil-like lumps in skin folds), d. Hailey Hailey (blisters in skin folds), e. Labial adhesions in prepubertal girls, f. Labial adhesions in adults, g. Sebaceous adenitis (inflamed papules on labia minora), h. Milia, pilar and epidermal cysts, i. Vulval intraepithelial neoplasia or VIN (also called vulval squamous cell carcinoma in situ), which includes Bowenoid papulosis, j. Penile intraepithelial neoplasia or PIN (also called penile squamous cell carcinoma in situ, Bowen disease of penis, erythroplasia of Quyerat), k. Anal intraepithelial neoplasia or AIN (also called anal squamous cell carcinoma in situ), l. Invasive squamous cell carcinoma including vulval cancer and anal cancer (arising from genital warts). Vulval cancer can also arise from lichen sclerosis or lichen planus), m. Extramammary Paget disease, n. Genital melanotic macules or melanosis (harmless brown marks in which there is more pigment in the skin cells), o. Mucosal melanoma (a rare form of skin cancer in which there is uncontrolled proliferation of pigment cells) p. Pearly penile papules q. Peyronie disease, in which a fibrous band appears on the penis N-alkyamides are extracted from at least one of the plants listed in Table 1.
The extraction products or the synthetic or modified N-alkyamides are formulated with additional acceptable carriers, solvents, dispersing agents, surfactants, lubricants, fillers, thickening agents, diluting agents, local anesthetic agents, antibiotics, NO donors, CCBs, relaxation agents, vasoactive agents and relaxing smooth muscles agents, cGMP increasing agents, protein kinase activation agents, phosphodiesterase type 5 (PDE5) inhibitors, cAMP mediators, guanylate cyclase activators, L-arginase inhibitors, dichloromethane or dimethyl sulfoxide (DMSO), antimycotic- and anti-viral agents, to be applied locally in order to treat, ameliorate, prevent and prevent recurrence.
The current invention also relates to the extraction products or the synthetic or modified N-alkyamides, where the N-alkyamides is with complexing or formulating agents such as cyclodextrin and/or polyethylene glycol (PEG).
The formulation of the composition is prepared in a form of liquid, solution, capsule, gel, dissolving capsule, capsule comprising a filter, infusion, cream, ointment, electroporation formulation, foam, suspension, emulsion, lotion, microspheres, microbeads, mud, oil, paste, nanospheres, liposomes, powder, roller stick, soap, surfactant, spray, suppositories (anal or vaginal), vaginal tablets, washing or bathing preparations, tampons, patches , plasters, local injections, liniments, lotions, drops, injection, ointment Pessary (vaginal suppository) vaginal ring, vaginal douche, Intrauterine device (IUD), extra-amniotic infusion,, intravesical infusion, enema solution ,hydrogel liposomes balm, shampoo, dermal patch, transdermal patch, transdermal spray, jet injector and any combination thereof.
The formulation/ composition of the current invention is applied locally in the diseased area of the mammalian subject. The routes of administration for this formulation/composition comprise, inter alia, topical, dermal, intravenous, intramuscular, and subcutaneous, transmucosal (buccal, vaginal, and rectal), transdermal and any combination thereof.
EXAMPLE 1: Reference is now made to an embodiment of the present invention disclosing the composition mentioned above, the composition discloses spilanthol, liquid extracted of acmella plant (Figure 1).
EXAMPLE 2: Reference is now made to an embodiment of the present invention disclosing the composition mentioned above, the composition discloses formulations for treating anorectal disorders. The method of treatment, ameliorate, prevention and recurrence-prevention comprise two steps: a. Local application of a water-free, lyophilic oil formulation (Formulation 1) for several days, at least one a day; followed by: b. Local application of a hydrophilic, cream formulation (Formulation 2) for several days, at least one a day.
Formulation 1 is the first treatment, ameliorate, prevention and recurrence-prevention for hemorrhoids and fissures; an oil formulation. This is a water-free lipophilic formulation. This formulation is used a first treatment-stage for anorectal disorders, specifically fissures and hemorrhoids and genital disorders. The formation is non-aqueous (or water free) in order to avoid pain associated with water sensation in diseases area. Table 2 discloses the ingredients of Formulation 1.
Table 2: The ingredients of oil formulation (Formulation 1).
# Ingredient Concertation (%) Range (%) 1. Coconut Oil 16 10 – 2. Olive Oil 5 2 – 3. Lanolin Alcohol 3 1 – 4. Obliphica Oil 4 1 – 5. Almond Oil 16 10 – 6. Alchemilla roots ethanolic extract 3.5 1 – 10 7. Affinin Roots extract complexed with hydroxypropyl-β-cyclodextrin (HPβCD) 2.8 1 – 8. Clove Oil 1.1 0.15 – 9. Lavender Oil 3 1 – 10. Aloe vera 200:1 1.5 0.5 – Formulation 2 is the second treatment-stage; a cream formulation. This is applied following Formulation 1 (oil formulation) administration for the treatment, amelioration, prevention and recurrence-prevention of anorectal disorders, specifically fissures and hemorrhoids and genital disorders. Table 3 discloses the ingredients of Formulation 1.
Table 3: The ingredients of cream formulation (Formulation 2). [ Range (%) Concertation (%) Ingredient # 1 – 90 1.2 Affinin 0.1 – 2 0.6 Evodia Rutaecarpa 1 – 5 1.7 Sophora Japonica D.E. 1 – 10 2.9 Alchemilla Mollis D.E. 1 – 10 3 Horse Chestnut D.E. 1 – 10 2.5 Centella Asiatica 70% 1 – 10 3.3 Malva Sylvestris D.E. 1 – 5 3.6 Ranunculus (or Ratanhia) D.E 1 – 5 2.5 Licorice D.E. 1 – 5 1.2 Aloe Vera 200:1 1 – 15 4.8 Allantoin 1 – 10 4 Hyaluronic Acid (1%Sol.) 1 – 10 1.6 Red Algae 1 – 10 2.7 Rutin (Troxerutin) 1 – 15 2.6 Pomegranate Seed Oil 0.5 – 6 1.5 Carum Carvi essential oil 16 1 – 10 4.5 Calendula Oil 5 – 40 20.4 Honey 1 – 10 3.6 Sea Buckthorn Oil 5 – 15 8.3 Beeswax 5 – 20 12.5 Coconut Oil 1 – 10 3.6 Lanolin Alcohol 0.15 – 8 1.8 Brij 72 0.5 – 8 1.3 Brij 721 0.1 – 10 0.5 Grapefruit seed extract (GSE) D.E. - Dry Extract; T.M. - Mother Tincture.
EXAMPLE 3: Reference is now made to an embodiment of the present invention disclosing the compositions and methods mentioned above; the compositions and methods disclose an open label clinical trial evaluating the efficacy of two of the compositions of the current invention in the treatment, amelioration, prevention and recurrence-prevention of anal fissures accompanied with severe pain in human patients.
Three hundred (300) patients, comprising men women and children in various ages, were treated for anal fissures and for hemorrhoids. The anal fissures were diagnosed in various serveries: either superficial, or deep; while hemorrhoids were diagnosed as stages 1 to 4.
Patients were treated in two phases: Phase A: patients were instructed to apply the oil formulation (Formulation 1 as disclosed in EXAMPLE 2), for 2-4 days every two hours.
Phase B: following completion of Phase A treatment, patients were instructed to apply the cream formulation (Formulation 2 as disclosed in EXAMPLE 2), 3 times a day, after application of the oil formulation (Formulation 1 as disclosed in EXAMPLE 2), for 10-days.
Results: After two days of applying the oil, pain subsided profoundly and bleeding stopped. After 10-14 days of applying the oil formulation following by the cream formulation, overall significant improvement in the patients’ condition was observed.
Comparison of the treatment disclosed by the present embodiment, of the oil formulation, followed by the cream-oil formulation (refers hereinafter to a combined herbal formulation) to a standard medical gel containing nifedipine 0.2% revealed that the combined herbal formulation was superior to the medical nifedipine 0.2% treatment, and that observed improvement was better and faster. No side effects were detected in patients treated by the combined herbal formulation; including patients suffering from diabetes, cardiac disorders or high blood pressure. Furthermore, the use of the combined herbal formulation reduced or even eliminated the need for hemorrhoids and anal fissures surgery in 46% of the patients.
ABSTRACT The present invention provides compositions and methods for treating, ameliorating, preventing and recurrence-preventing anorectal disorders and genital disorders in a mammalian subject. In accordance with various aspects of the present invention, the current invention discloses methods and compositions for local administration, which comprise at least one N-alkylamide. The current invention also relates to synthetic N-alkylamides or modified N-alkylamides.
Claims (21)
1. A local composition for treating, ameliorating, preventing and recurrence-preventing anorectal disorders in a mammalian subject, wherein said composition comprises at least one N-alkylamide.
2. The composition of claim 1, wherein said N-alkylamide is spilanthol.
3. The composition of claim1, wherein said anorectal disorders are selected from a group consisting at least one of hemorrhoids, anal fissures, fecal incontinence, proctalgia fugax, excessive perineal descent, pruritus ani, anal abscess, fistula, and any combination thereof.
4. The composition of claim 1, wherein said composition is additionally useful for treating, ameliorating, preventing and recurrence-preventing genital disorders, said genital disorders are selected from a group consisting genital itch in males or females, , vaginal discharge in females, genital lesions in males or females, , pruritus ani, balanitis, dermatitis , lichen simplex, atopic dermatitis, seborrheic dermatitis, irritant contact dermatitis, balanitis, intertrigo, allergic contact dermatitis, pruritus vulvae, eczema, seborrheic dermatitis, irritant contact dermatitis vulvitis, intertrigo, allergic contact dermatitis , psoriasis , lichen sclerosis, lichen planus, vaginitis, vaginal or genital malodour, desquamative vaginitis, vulval skin lesions, angiokeratomas , hidradenitis suppurativa ,hailey hailey, labial adhesions , sebaceous adenitis, milia, pilar and epidermal cysts,, vulval intraepithelial neoplasia, bowenoid papulosis, penile intraepithelial neoplasia, bowen disease of penis, erythroplasia of quyerat, anal intraepithelial neoplasia, invasive squamous cell carcinoma including vulval cancer and anal cancer, vulval cancer, extramammary paget disease, genital melanotic macules, melanosis, mucosal melanoma ,pearly penile papules, peyronie disease, and any combination thereof.
5. The composition of claim 1, wherein said mammalian subject is an animal or human.
6. The composition of claim 1, wherein said N-alkylamide is extracted of a plant family selected from a group consisting of acanthaceae, amaranthaceae, Acanthaceae, amaranthaceae, aristolochiaceae, asteraceae, brassicaceae, bromeliaceae, caryophyllaceae, convolvulaceae, ephedraceae, euphorbiaceae, fabaceae, hippocastanaceae, lauraceae, liliaceae, malvaceae, meliaceae, menispermacea, piperaceae, poaceae, rhamnaceae, rosaceae, rutaceae, salicaceae, scrophulariaceae, solanaceae, zygophyllaceae and any combination thereof.
7. The composition of claim 1, wherein said N-alkylamide is a synesthetic or modified N-alkylamide.
8. The composition of claim 1, where said composition additionally comprises complexing and formulation agents such as cyclodextrin, polyethylene glycol (PEG).
9. The composition of claim 1, wherein at least one of said N-alkylamide is encapsulated.
10. The composition of claim 2, wherein said spilanthol is extracted of a plant selected from a group consisting of Acmella oleracea, Acmella spilanthes, Acmella ciliate, Acmella oppositifolia, Acmella radicans, Acmella brachyglossa, Acmella ciliate, Acmella oleracea, Acmella paniculata, Acmella uliginosa, Welelia parviceps , Heliopsis longipes and any combination thereof.
11. The composition of claim 2, wherein said spilanthol is a synesthetic spilanthol.
12. The composition of claim 1, wherein said composition is configured to be administrable in a manner selected from a group consisting of topical or dermal and any combination thereof.
13. The composition of claim 1, wherein said composition is provided in a form selected from a group consisting of liquid, solution, capsule, gel, dissolving capsule, capsule comprising a filter, infusion, cream, ointment, electroporation formulation, foam, suspension, emulsion, lotion, microspheres, microbeads, mud, oil, paste, nanospheres, liposomes, powder, roller stick, soap, surfactant, spray, suppositories (anal or vaginal), vaginal tablets, washing or bathing preparations, tampons, patches, plasters, local injections, liniments, lotions, drops, injection, ointment Pessary (vaginal suppository) vaginal ring, vaginal douche, Intrauterine device (IUD), extra-amniotic infusion,, intravesical infusion, enema solution ,hydrogel liposomes balm, shampoo, dermal patch, transdermal patch, transdermal spray, jet injector and any combination thereof.
14. The composition of claim 1, wherein said composition is in a form selected from a pharmaceutical product or a cosmetic product or a medical device.
15. The composition of claim 1, said composition comprises two formulations, Formulation 1 and Formulation 2, wherein said Formulation 1 is a lipophilic Formulation and said Formulation 2 is a hydrophilic formulation; further wherein said Formulation 1 is administered to said mammalian subject before said Formulation 2.
16. The composition of claim 15, wherein said Formulation 1 comprises spilanthol microcapsules and at least one of coconut oil, olive oil, lanolin alcohol, obliphica oil, almond oil, alchemilla roots ethanolic extract, clove oil, lavender oil, aloe vera, and any combination thereof.
17. The composition of claim 15, wherein said Formulation 2 comprises spilanthol microcapsule, and at least one of evodia rutaecarpa, sophora japonica, alchemilla mollis, horse chestnut, centella asiatica, malva sylvestris, ranunculus (or Ratanhia, licorice, aloe vera, allantoin, hyaluronic acid , red algae, rutin , pomegranate seed oil, carum carvi essential oil, calendula oil, honey, sea buckthorn oil, beeswax, cocconut oil, lanolin alcohol, brij 72, brij 721, grapefruit seed extract (GSE) and any combination thereof.
18. The composition of claim 10, wherein said plant is extracted by one of solvents of a group consisting of: organic solvents, hydrophilic solvents, hydrophobic solvents, water, ethanol, petroleum ether, cold water extraction (CWE), methanol, chloroform, hexane, ethyl acetate, methanol, and any combination thereof.
19. Use of a composition in the preparation of a topical medicament for treating, ameliorating, preventing and recurrence-preventing anorectal disorders in a mammalian subject wherein said composition comprises at least one N-alkylamide.
20. The composition of claim 19, wherein said composition is additionally useful for treating, ameliorating, preventing and recurrence-preventing of genital disorders.
21. A kit for a local treatment, amelioration, prevention and recurrence-prevention of anorectal disorders or genital disorders in a mammalian, wherein said kit comprises; c. a container comprising at least one topical composition, said composition comprises at least one N-alkylamide, and d. instructions for administration of said composition to said mammalian subject.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201962927139P | 2019-10-29 | 2019-10-29 | |
| PCT/IL2020/051124 WO2021084534A1 (en) | 2019-10-29 | 2020-10-29 | Methods and compositions for treating, ameliorating, prevention and recurrence-prevention of anorectal disorders |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IL292632A true IL292632A (en) | 2022-07-01 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL292632A IL292632A (en) | 2019-10-29 | 2020-10-29 | Methods and compositions for treating, ameliorating, prevention and recurrence-prevention of anorectal disorders |
Country Status (2)
| Country | Link |
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| IL (1) | IL292632A (en) |
| WO (1) | WO2021084534A1 (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4192866A (en) * | 1978-10-10 | 1980-03-11 | Ralph Anderson | Anorectal medication |
| RS50883B (en) * | 2004-01-01 | 2010-08-31 | Panacea Boitec Ltd. | Pharmaceutical compositions comprising an extract of euphorbia prostrata |
| WO2017037508A1 (en) * | 2015-09-03 | 2017-03-09 | Moradi Asghar | An anti hemorrhoid herbal composition for targetting hemorrhoids and a method of synthesizing the same |
-
2020
- 2020-10-29 IL IL292632A patent/IL292632A/en unknown
- 2020-10-29 WO PCT/IL2020/051124 patent/WO2021084534A1/en active Application Filing
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| WO2021084534A1 (en) | 2021-05-06 |
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