CN116685302A - topical composition - Google Patents
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- CN116685302A CN116685302A CN202280010269.0A CN202280010269A CN116685302A CN 116685302 A CN116685302 A CN 116685302A CN 202280010269 A CN202280010269 A CN 202280010269A CN 116685302 A CN116685302 A CN 116685302A
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Abstract
A topical composition for application to skin, the topical composition comprising a NO donor and a NO counter-agent that balances the effect of the NO donor in the skin.
Description
Technical Field
The present invention relates to a topical composition comprising a first agent and a second agent, the first agent being a nitric oxide donor, the second agent having the property of inhibiting the action of NO; and methods of using such compositions for topical treatment.
Background
Nitric oxide ("NO") is a small gaseous molecule, also known as nitric oxide (nitrogen monoxide), of the formula NO, which has been shown to be a very important signaling molecule in organisms including the human body (and in particular the skin and underlying tissues).
In skin, NO enhances skin microcirculation, it participates in skin pigmentation through uv-induced melanogenesis, it is reported to promote wound healing through cell proliferation and angiogenesis, and has antimicrobial properties against microorganisms. NO also plays an important role in T cell mediated skin diseases and, depending on its concentration, cell type and availability of other substrates, it has both pro-apoptotic and anti-apoptotic properties.
Thus, it is beneficial to apply NO into the skin; however, it is impractical to apply gaseous NO to the skin in a manner that will promote such biological effects or impart therapeutic effects, and therefore, the use of certain NO donors has been proposed.
Although NO has beneficial effects as described above, it also has the potential to produce significant skin side effects due to its powerful pro-inflammatory properties. NO is known to mediate skin edema and inflammation and may result in impaired skin barrier function.
Thus, the need to apply an effective amount of NO to the skin while inhibiting its adverse pro-inflammatory properties remains unmet.
Disclosure of Invention
One aspect of the present invention relates to a topical composition for application to skin comprising a NO donor and a NO agent (counter-NO agent) that balances the effect of the NO donor in the skin.
In one or more embodiments, the NO donor is selected from the group consisting of: inorganic nitrite, inorganic nitrate, organic nitrite, organic nitrate, sodium nitroprusside (sodium nitroprusside), molsidomine, diazeniumdiolate (diazeniumdiolates), S-nitrosothiols, mesoionic oxazoles (mesoionic oxatriazole), iron-thionitrosyl (iron-sulphur nitrosyls), cilitrodil (Sinitrodil), L-arginine and L-citrulline; and the cosmetically or pharmaceutically acceptable salts, isomers, analogs and derivatives thereof.
In one or more embodiments, the NO donor is nitroglycerin.
In one or more embodiments, the concentration of nitroglycerin is selected from the group consisting of about 4% to about 12%, about 4% to 8%, and about 8% to 12%.
In one or more embodiments, the NO donor is selected from the group of L-arginine and salts, isomers, analogs, and derivatives thereof.
In one or more embodiments, the concentration of arginine is selected from the group consisting of about 6% to about 25%, about 6% to 8%, about 8% to 10%, about 10% to 14%, about 14% to 18%, and about 18% to 25%.
In one or more embodiments, the NO donor is selected from the group of L-citrulline and salts, isomers, analogs and derivatives thereof.
In one or more embodiments, the concentration of citrulline is selected from the group consisting of about 4% to about 20%, about 4% to 6%, about 6% to 10%, about 10% to 14%, and about 14% to 20%.
In one or more embodiments, the NO counteractant is selected from the group consisting of: NOS inhibitors, eNOS inhibitors, iNOS inhibitors, nNOS inhibitors, inhibitors of cell expression of eNOS, and inhibitors of NOS production.
In one or more embodiments, the NO counteractant is selected from the group consisting of: L-NG-nitroarginine, NG-nitro-L-arginine methyl and NG-monomethyl-L-arginine, NG-nitro-L-arginine methyl ester, L-NG-nitroarginine, NG-amino-L-arginine, NG.NG-dimethyl-arginine, S-ethylisothiourea diethylphosphate, L-thiocitrulline, S-methyl-L-thiocitrulline, agmatine, 7-bromonitroindazole, 1- [2- (trifluoromethyl) phenyl-imidazole, S- (2-aminoethyl) isothiourea, methylene blue, 1H- [1,2,4] oxadiazol [4,3-a ] quinoxalin-1-one.
In one or more embodiments, the NO counteractant is selected from the group consisting of: nicotinamide and salts, isomers, analogs and derivatives thereof.
In one or more embodiments, the concentration of nicotinamide is from about 1% to about 2%, or from about 2% to about 4%, or from about 4% to about 6%, or from about 6% to about 8%, or from about 8% to about 10%.
In one or more embodiments, the ratio of the NO donor and the NO counteractant in the topical composition is about 1:2 to 8:1, or 1:2 to 1:1, or about 1:1 to 2:1, or about 2:1 to 4:1, or about 4:1 to 8:1
In one or more embodiments, when the NO donor is arginine and the NO counter-acting agent is nicotinamide, wherein the ratio of the arginine to nicotinamide in the topical composition is about 2:1 to 8:1, or about 2:1 to 4:1, or about 4:1 to 6:1, or about 6:1 to 8:1.
In one or more embodiments, when the NO donor is citrulline and the NO counter-reactant is nicotinamide, wherein the ratio of citrulline to nicotinamide in the topical composition is about 2:1 to 8:1, or about 2:1 to 4:1, or about 4:1 to 6:1, or about 6:1 to 8:1.
In one or more embodiments, the composition exerts a tolerable stinging effect when applied topically to the skin.
Another aspect of the invention relates to a method of treating, alleviating or preventing a skin condition comprising topically applying to the skin an effective amount of a composition as disclosed herein.
Yet another aspect of the invention relates to a composition as disclosed herein for treating, alleviating or preventing a skin condition comprising topically applying to the skin of a subject an effective amount of a composition as disclosed herein.
In one or more embodiments, the skin condition is associated with skin aging.
In one or more embodiments, the skin condition includes at least one of the following: photo-induced skin aging, increased transepidermal water loss, dry skin, fine lines, wrinkles, hyperpigmentation, and skin discoloration.
In one or more embodiments, the NO donor is arginine and the NO counteractant is nicotinamide, wherein the application is concurrent with skin application of the neurotoxin.
In one or more embodiments, the concentration of arginine in the composition is selected from the group consisting of about 6% to about 25%, about 6% to 8%, about 8% to 10%, about 10% to 14%, about 14% to 18%, and about 18% to 25%.
In one or more embodiments, the concentration of nicotinamide in the composition is from about 1% to about 2%, or from about 2% to 4%, or from about 4% to 6%, or from about 6% to 8%, or from about 8% to 10%.
In one or more embodiments, the ratio of arginine to nicotinamide in the topical composition is about 2:1 to 8:1, or about 2:1 to 4:1, or about 4:1 to 6:1, or about 6:1 to 8:1.
In one or more embodiments, the NO donor is citrulline and the NO counteractant is nicotinamide, wherein the application is concurrent with skin application of the neurotoxin.
In one or more embodiments, the concentration of citrulline in the composition is selected from the group consisting of about 4% to about 20%, about 4% to 6%, about 6% to 10%, about 10% to 14%, and about 14% to 20%, and the concentration of nicotinamide is about 1% to about 2%, or about 2% to 4%, or about 4% to 6%, or about 6% to 8%, or about 8% to 10%.
In one or more embodiments, the application of the composition increases the supply of oxygen and nutrients to the skin tissue.
In one or more embodiments, the use of the composition enhances the effect of the neurotoxin and/or extends the duration of the effect of the neurotoxin.
In one or more embodiments, the application of the composition is performed continuously prior to the administration of the neurotoxin, or after the administration of the neurotoxin.
In one or more embodiments, the use of the composition reduces inflammation and/or atrophy induced upon administration of the neurotoxin.
In one or more embodiments, the form of the composition is selected from the group consisting of: liquids, solutions, emulsions, lotions, creams (stream), gels, foams, lipsticks, facial masks and essences.
Detailed Description
Although the following detailed description contains many specifics for the purpose of illustration, persons of ordinary skill in the art will appreciate that many variations and alterations to the following details are possible and are considered to be included herein. Accordingly, the following embodiments are set forth without any loss of generality to, and without imposing limitations upon, any claims set forth. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
The present invention relates to topical compositions comprising a NO donor and a NO counteractant that balances the effect of NO in the skin.
The invention further relates to a method of treating, alleviating or preventing a dermatological, cosmetic or mucosal condition comprising topically administering to a subject suffering from said condition a therapeutically effective amount of any of the compositions described herein.
Nitric oxide donors
Nitric oxide having the formula NO is a very small molecule that can migrate rapidly and reach its target site after release from the composition. Nitric oxide is a very versatile biological messenger. The chemical nature of NO is critical to determining its biological role, both as a transcellular signal in the cardiovascular and nervous system and as a cytotoxic anti-pathogenic agent released during the inflammatory response. In other properties, NO is considered an antibiotic. The term "antibiotic" as used herein includes, but is not limited to, destructive or inhibitory effects on the growth of bacteria; or inhibiting the growth of bacteria or destroying the ability of bacteria. Also, NO is known to be effective in eradicating fungi, yeasts, molds and viruses. NO may further have anti-inflammatory and skin rejuvenation effects, and it is also known to enhance wound healing. It can be further used for treating various skin diseases and keratosis.
Upon penetration into and penetration through the skin, NO can cause peripheral vasodilation, also known as enhanced blood flow in the skin, which helps improve the supply of oxygen and nutrients to the subcutaneous tissue (dermis and epidermis).
Peripheral vasodilation is also known to reduce systolic and diastolic pressures.
Various compounds are known as NO donors. In one exemplary embodiment, the NO donor may be selected from several classes including, but not limited to, inorganic nitrites and nitrates (e.g., sodium nitrite and sodium nitrate), organic nitrites and nitrates, sodium nitroprusside, molsidomine and its metabolites, diazeniumdiolate, S-nitrosothiols, mesoionic oxatriazoles and derivatives thereof, iron-thionitrosyls, certols and derivatives thereof, and the amino acids L-arginine and L-citrulline. For clarification purposes, nitrite is NO 2 - And the nitrate is NO 3 - 。
In one embodiment of the invention, the organic NO donor comprises at least one organic nitrite which comprises an ester of nitric acid and may be an acyclic or cyclic compound. For example, the organic nitrate may be nitroglycerin, ethylene glycol dinitrate; isopropyl nitrate; amyl nitrite, amyl nitrate, ethyl nitrite, butyl nitrite, isobutyl nitrite, octyl nitrite, glycerol-1-mononitrate, glycerol-1, 2-dinitrate, glycerol-1, 3-dinitrate, butane-1, 2, 4-triol-trinitrate; erythritol tetranitrate; pentaerythritol tetranitrate; sodium nitroprusside, chloronitrate (clonitrate), erythritol tetranitrate, isosorbide mononitrate, isosorbide dinitrate, mannitol hexanitrate, pentaerythritol tetranitrate, pentenetriol, triethanolamine trinitrate, triethanolamine phosphate (trolnitrate phosphate) (triethanolamine trinitrate diphosphate), propiniter (propatylinite), nitrite of sugar, nitrate of sugar, nitrite of polyol, nitrate of polyol, nicorandil (nicorandil), aprinine (aprese), diazoxide (diazoxide), hydralazine (hydrazine), hydrochlorothiazide, minoxidil (minoxidil), pentaerythritol, tolazoline (tolazoline), scoparone (6, 7-dimethoxycoumarin), pharmaceutically acceptable salts, isomers, analogues and derivatives thereof.
As an example, the following equation shows the equilibrium reaction of nitrite to form nitric oxide:
in this case, the NO donor is a nitrite (MN 02), such as sodium nitrite.
In one embodiment, arginine is the NO donor, and NO is produced from arginine in the skin in a reaction catalyzed by nitric oxide synthase, as follows:
according to us patent 5,895,658, topical application of 12.5% of an arginine formulation helps to induce hair growth, however, when applied to cool skin, an increase in skin temperature of up to 10 ℃ is noted, which can be inconvenient for the subject and, therefore, non-compliance with the treatment.
L-arginine and L-citrulline may be used as the free base or as a salt (e.g., hydrochloride), or any salt, isomer, analogue, and derivative that is converted to arginine by chemical or enzymatic processes.
In one embodiment of the invention, the NO donor is arginine (arginine, 1-arginine, and L-arginine are used interchangeably herein); and in another embodiment, the NO donor is citrulline (citrulline, L-citrulline and L-citrulline are used interchangeably herein).
In one embodiment, the NO donor is attached to the polymer. In another embodiment, the NO donor is N-diazeniumdiolate (N-diazeniumdiolate). In yet another embodiment, the NO donor comprises an N-diazeniumdiolate bound to the polymer; and in further embodiments, the NO donor comprises a polysiloxane polymer backbone containing covalently bound N-diazeniumdiolate nitric oxide donors throughout the polymer structure, as shown in the examples below.
In this case, the NO donor is bound to the polymer and gradually releases NO when applied to the skin, as described above. In this case, the NO donor is nitrite (MN 0 2 Where M is a cationic metal), such as sodium nitrite.
Yet another example of an NO donor is a corticosteroid linked to an NO releasing moiety. An example of such an NO donor is a derivative of hydrocortisone, encoded as "NCX1022", having the structure:
any other compound capable of releasing NO in the skin layer upon application to the skin is suitable as NO precursor or NO donor according to the present invention.
Because of the above-mentioned properties of NO, it may be beneficial when it is present in the skin in a biologically effective concentration, it may have a beneficial effect on skin diseases or conditions. For example, NO has antimicrobial properties, i.e., antibacterial, antifungal and antiviral properties, and thus it has potential for treating skin infections including, but not limited to:
bacterial infections such as cellulitis, impetigo, boils and leprosy;
viral infections such as shingles (shingles), varicella, molluscum contagiosum, warts, measles, hand-foot-and-mouth disease;
Fungal infections such as tinea pedis, yeast infections, tinea, nail fungi and oral thrush (oral thrush), and diaper rash.
Symptoms of skin infection vary according to type. Common symptoms include redness of the skin and rash. Other symptoms may also occur in infected persons, such as itching, pain and tenderness. Signs of severe infection include pus, blisters, skin sloughing, cracking, darkening of the skin, appearance of necrotic skin, or skin discoloration and pain.
Acne is a disease involving infection with the anaerobic bacterial species propionibacterium acnes (Cutibacterium acnes) (also known as propionibacterium acnes (Propionibacterium acnes)); and rosacea is also associated with microbial infections, such as those caused by bacillus vegetables (Bacillus oleronius).
Other skin conditions that may involve microbial infection include, but are not limited to, atopic dermatitis, eczema, and psoriasis.
Thus, topical application of a composition comprising a sufficient amount of NO donor has the potential to treat any of the above-described skin infections and/or their corresponding symptoms.
Also, NO donors or topical application of NO donors have the potential to treat certain skin conditions, which are considered "cosmetic".
Skin dryness is the result of an impaired moisture loss barrier of the skin, which is a characteristic feature of damaged skin, as in the case of atopic dermatitis and skin aging. Topical treatment of patients with atopic dermatitis with arginine hydrochloride has been shown to significantly increase urea in the stratum corneum and increase skin moisture, and thus improve the clinical symptoms of skin dryness. One of the most disturbing consequences of skin dryness is the formation of wrinkles, which can spread over the entire surface (especially on the face, throat and chest), and thus preventing the impairment of the skin barrier function can further prevent the formation of wrinkles. In addition, since NO induces peripheral blood flow, it can mobilize increased levels of oxygen and nutrients to the skin layers, thereby promoting tissue remodeling and reducing the appearance of wrinkles.
As described above, high concentrations of NO in the skin can lead to heating and inflammation of the skin, with redness (erythema), swelling (edema) and burning sensations of the skin. These are considered adverse effects, which may prevent the use of the product by a person in need thereof, despite the potential benefits of the product.
NO counteractant
Surprisingly, it has been found that the combination of an NO donor with an agent that inhibits NO can retain the beneficial effects of NO while reducing unwanted side effects. Such agents are referred to herein as "NO counteractants.
In one embodiment of the invention, the NO counteractant is an agent that inhibits the activity of nitric oxide synthase ("NOs"). There are three isoforms of NOS: brain or neuronal forms ("nNOS"), endothelial forms ("eNOS") and induced forms ("iNOS"). The more common form of NOS in skin is eNOS, and examples of eNOS inhibitors include, but are not limited to, l-N G -nitroarginine (NArg), NG-nitro-L-arginine methyl ester (L-NAME) and NG-monomethyl-1-arginine (1-NMMA), NG-nitro-L-arginine methyl ester (NAME), L-N G Nitroarginine (NNA), NG-amino-L-arginine (NAA), N G .N G -dimethyl-arginine (asymmetric dimethylarginine, ADMA). S-ethylisothiouronium diethyl phosphate (trade name Difetur) is another exemplary eNOS inhibitor that has proven to be safe for topical application.
SDMA (NG, NG' -dimethyl-L-arginine), L-thiocitrulline, S-methyl-L-thiocitrulline, agmatine (1-amino-4-guanidinobutane), L-nionδ - (iminoethyl) -L-ornithine, vinyl-L-NIO, ethyl-L-NIO, 7-NI (7-nitroindazole), 7-NI-Br (7-bromonitroindazole), 1- [2- (trifluoromethyl) phenyl-imidazole), S- (2-aminoethyl) isothiourea, methylene blue, [1H- [1,2,4] oxadiazol [4,3-a ] quinoxalin-1-one ] (from Pharmaceuticals (Basel).2010 Jan;3 (1): 273-299.Nitric Oxide Synthase Inhibitors as Antidepressants by Gregers Wegener,and Vallo Volke).
However, another approach to reduce the activity of eNOS is to inhibit the expression of eNOS by cells, thereby limiting their synthesis and reducing the amount of NO in tissues. A non-limiting example is nicotinamide (a form of vitamin B3) which reduces expression of NOS protein and reduces release of NO from cells.
Notably, niacinamide is known to exert a variety of benefits when applied to skin, including, but not limited to, repair of light-induced skin aging (it helps prevent UV and blue light damage, reduces appearance of fine lines and wrinkles, improves skin elasticity, rebalancing uneven skin tone and reduces discoloration; it helps restore skin barrier function and reduces transepidermal water loss, which is a potential factor in inducing skin aging).
Nicotinamide has also been shown to be effective in preventing and/or treating skin diseases, including but not limited to treating acne and rosacea, alleviating itching (itch), and also has been shown to have chemopreventive effects in non-melanoma skin cancers.
Any salts, isomers, analogs and derivatives of nicotinamide having NO-reactive properties are suitable for use in the context of the present invention.
Concentration of NO donor and NO counteractant in composition
The concentration of NO donor in the topical composition of the present invention is determined by the amount sufficient to increase the NO level in the skin when the composition is topically applied. Because it is impractical to measure NO levels in humans, this increase can be observed by the appearance of redness (erythema), swelling (edema) and burning sensation in the skin, which is exacerbated by the increasing concentration.
For example, in the case of nitroglycerin, 2% is insufficient. At higher concentrations, from about 4%, a slight burning sensation was noted. This sensation is enhanced with increasing nitroglycerin concentration. Thus, in certain embodiments, the concentration of nitroglycerin as a NO donor is from about 4% to about 12%; and in other embodiments it may be about 4% to 8%, or about 8% to 12%.
In the case of arginine, 5% is insufficient. At higher concentrations, from about 6%, a slight burning sensation was noted, with a tingling sensation. This sensation is enhanced with increasing arginine concentration. Thus, in certain embodiments, the concentration of arginine as a NO donor is from about 6% to about 25%; and in other embodiments it may be about 6% to 8%, or about 8% to 10%, or about 10% to 14%, or about 14% to 18%, or about 18% to 25%.
Also, in the case of citrulline, in certain embodiments, the concentration of citrulline is from about 4% to about 20%; and in other embodiments it may be about 4% to 6%, or about 6% to 10%, or about 10% to 14%, or about 14% to 20%.
The concentration of the NO counteractant is determined so as to reduce or eliminate redness (erythema), swelling (edema) and burning sensation of the skin caused by the NO donor. For example, in the case of nicotinamide, 0.5% is insufficient. In certain embodiments, the concentration of nicotinamide as a NO-reactivating agent is from about 1% to about 2%; and in other embodiments it may be about 2% to 4%, or about 4% to 6%, or about 6% to 8%, or about 8% to 10%.
In one observation trial, when subjects topically applied a composition comprising 10% arginine and 2% nicotinamide, several subjects felt very slight warmth or slight tingling to the skin, while the remaining subjects did not have any such sensation. Notably, the very slight warmth or slight tingling of the skin is not considered prohibited by the subject, who means "feel as if the product is functioning".
Thus, in certain embodiments, the ratio between the NO donor and the NO counter-reactant in the topical composition is about 1:2 to 8:1; and in other embodiments it may be about 1:2 to 1:1, or about 1:1 to 2:1, or about 2:1 to 4:1, or about 4:1 to 8:1.
In one embodiment, when the NO donor is arginine or a salt, isomer, analog or derivative thereof and the NO counter-agent is nicotinamide or a salt, isomer, analog or derivative thereof, the ratio between the NO donor and the NO counter-agent in the topical composition is about 2:1 to 8:1; and in other embodiments it may be about 2:1 to 4:1, or about 4:1 to 6:1, or about 6:1 to 8:1.
In one embodiment, the concentration of arginine is about 7.5% to 12.5%, and the concentration of nicotinamide is about 1% to 10%. In further embodiments, the concentration of arginine is about 10% and the concentration of nicotinamide is about 2%.
Synergistic effect
In some cases, in addition to the NO inhibitory effect, NO counteractants have a beneficial effect on the target site of application.
One example is nicotinamide and its salts, isomers, analogs and derivatives, which as mentioned above have therapeutic effects themselves. In such cases, the therapeutic effect of the NO donor (e.g., arginine) and the therapeutic effect of the NO counteractant (e.g., nicotinamide) are synergistically combined to obtain improved results over each individual agent; and without the inherent side effects of its high concentration of NO donor.
Stinging effect
As mentioned above, high concentrations of NO donors can cause redness (erythema), swelling (edema) and burning sensations of the skin, which can make such compositions intolerable. The combination of the NO donor with the NO counteractant reduces the intensity of these side effects and in many cases a slight stinging effect is noted, which is well tolerated and even considered as positive sign by the subjects applying such compositions. In our human test, several subjects expressed "feel as if the product was functional", continued use of the product, and experienced positive therapeutic results.
Thus, in one embodiment, the present invention relates to a topical composition comprising a NO donor and a NO counteractant, which produces a tolerable stinging effect upon topical application.
Additional therapeutic agents
Several pathologies involve a combination of some of the causative factors affected by NO and other causative factors that require additional treatment modalities. For example, psoriasis may be treated with NO as well as steroid drugs, so a combination therapy would be beneficial. Likewise, acne involving microbial infection, excessive keratin production, excessive sebum production and inflammation may benefit from treatment with a combination of NO and an additional therapeutic agent selected from the group consisting of: anti-inflammatory agents, antibiotic agents, sebum inhibitors, and keratolytic agents. Thus, in many cases, the inclusion of additional therapeutic agents in the composition contributes to the clinical activity of NO.
Suitable additional therapeutic agents include, but are not limited to, active herbal extracts, herbal oils, herbal tinctures, acaricides, senile plaques and keratoses, allergens, analgesics, anti-acne agents, antiallergic agents, anti-aging agents, antibacterial agents, antibiotics, antipyrotic agents, anticancer agents, anti-dandruff agents, antidepressants, anti-dermatitis agents, anti-edema agents, antihistamines, anthelmintics, anti-hyperkeratosis agents, anti-inflammatory agents, anti-irritants, anti-hyperlipidemic agents, antimicrobial agents, antifungal agents, antiproliferatives, antioxidants, anti-wrinkle agents, antipruritics, anti-psoriasis agents, anti-rosacea agents, anti-seborrheic agents, preservatives, anti-swelling agents antiviral agents, antiyeast agents, astringents, topical cardiovascular agents, chemotherapeutic agents, corticosteroids, dicarboxylic acids, disinfectants, fungicides, hair growth regulators, hormones, hydroxy acids, immunosuppressants, immunomodulators, insecticides, insect repellents, keratolytic agents, lactams, metals, local anesthetics, metal oxides, mitocides, neuropeptides, non-steroidal anti-inflammatory agents, oxidizing agents, pediculicides, photodynamic therapeutic agents, retinoids, scabies killers, self tanning agents, skin whitening agents, vasoconstrictors, vasodilators, vitamins, vitamin D derivatives, wound healing agents and wart removers. As known to those of skill in the art, in some cases, a particular active agent may have more than one activity, function, or effect.
Form of the composition
The composition of the invention comprises a carrier, an NO donor and an NO counteractant. While the composition may have various rheological characteristics, the following non-limiting examples of the form of the composition are provided for purposes of illustration.
In one embodiment, the composition is a liquid. The liquid composition is flowable.
In one embodiment, the composition is an aqueous liquid, wherein the NO donor and NO counteractant are in solution or in suspension.
In further embodiments, the composition is semi-solid. In certain embodiments, the composition has a viscosity of greater than about 5000Cps, and it may have a viscosity selected from the group consisting of: about 5000Cps to about 100000Cps, about 5000Cps to about 20000Cps, about 20000Cps to about 60000Cps, and about 60000Cps to about 100000Cps.
In one embodiment, the composition is a gel. The viscosity of the gel may be obtained using conventional polymeric or gelling agents. Exemplary polymeric or gelling agents include, in a non-limiting manner, naturally occurring polymeric materials such as locust bean gum, sodium alginate, sodium caseinate, egg albumin, gelatin agar, carrageenan, sodium alginate, xanthan gum, papaya seed extract, tragacanth gum, guar gum, cationic guar gum, hydroxypropyl guar gum, starches, amine-containing polymers such as chitosan; acidic polymers obtainable from natural sources, such as alginic acid and hyaluronic acid; chemically modified starch, etc., carboxyvinyl polymers, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid polymers, polymethacrylic acid polymers, polyvinyl acetate polymers, polyvinyl chloride polymers, polyvinylidene chloride polymers, etc.
Additional exemplary polymeric agents include semisynthetic polymeric materials such as cellulose ethers, e.g., methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, methyl hydroxyethyl cellulose, methyl hydroxypropyl cellulose, hydroxyethyl carboxymethyl cellulose, carboxymethyl cellulose carboxymethyl hydroxyethyl cellulose, and cationic cellulose. Polyethylene glycols having a molecular weight of 1000 or greater (e.g., PEG 1000, PEG 4000, PEG 6000, and PEG 10000) also have gelling ability, and while they are referred to herein as "second polar solvents," they are also referred to herein as polymeric agents, as detailed herein.
Mixtures of the above polymeric agents are contemplated.
In one embodiment, the composition is an aqueous gel, i.e. a gel containing water, wherein the NO donor and the NO counter-agent are in solution or in suspension.
However, in further embodiments, the composition is an emulsion, or microemulsion, or nanoemulsion, comprising an aqueous phase and an organic carrier phase. Examples of topical dosage forms comprising emulsions are creams, lotions and emulsion-based sprays and foams.
However, in other embodiments, lipsticks have in the past focused primarily on imparting decorative benefits (hue, gloss) to the lips. Our lipstick provides functional benefits such as rejuvenation, increasing natural vitality, and providing nutrients and therapeutic agents.
The agent will also slow/eliminate the enzymatic degradation of injected hyaluronic acid and other lip-rounding agents.
In contrast to creams (see forms and compositions), lipsticks contain pigments (colorants), oils and waxes. Many oils are available for lipstick, such as castor oil, mineral oil and hydrogenated vegetable oil. The viscosity of oils ranges from liquid to nearly waxy, and they function as dispersants for colorants and cohesion enhancers in lipsticks. Typical oil concentrations are in the range of 6% to 10%.
The most commonly used waxes in lipsticks are beeswax and carnauba wax. Waxes are used to increase the viscosity of the lipstick and balance the effects of oil and esters. Waxes are harder ingredients and they raise the melting point of the formulation. This control of the melting temperature of the lipstick also controls the return of the lipstick, i.e. the amount of product transferred from the lipstick to the lips. Typical wax concentrations range from 8% to 18%.
Finally, polymers may be added to impart film-forming properties to the lipstick, as well as to aid in the cohesion of the film formed. Another benefit of the polymer is enhanced abrasion resistance. Typically, high molecular weight polymers are used for film adhesion and flexibility to follow the movement of the lips, while low molecular weight branched polymers can create a three-dimensional local network within the film and capture the colorant. Examples of polymers: acrylic ester/C12-22 alkyl methacrylate copolymer
The organic vehicle is selected from the group consisting of hydrophobic organic vehicles (also referred to herein as "hydrophobic vehicles"), emollients, and mixtures thereof.
In one or more embodiments, the hydrophobic carrier is an oil, such as a mineral oil. According to one or more embodiments, the hydrophobic carrier is an oil derived from a plant, marine or animal source. As examples, the vegetable oil may be olive oil, corn oil, soybean oil, rapeseed oil, cottonseed oil, coconut oil, sesame oil, sunflower oil, borage seed oil (borage seed oil), clove oil (syzigium aromaticum oil), hemp seed oil, herring oil, cod liver oil, salmon oil, linseed oil, wheat germ oil, evening primrose oil, or mixtures thereof in any proportion.
Suitable hydrophobic carriers also include polyunsaturated oils containing, for example, omega-3 and omega-6 fatty acids. Examples of such polyunsaturated fatty acids are linoleic and linolenic acids, gamma-linoleic acid (GLA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Such unsaturated fatty acids are known for their skin conditioning effect, which may contribute to the therapeutic benefit of NO.
In the context of the present invention, an oil having therapeutically beneficial properties is referred to as a "therapeutically active oil".
Silicone oils may also be used. Suitable silicone oils include nonvolatile silicones such as polyalkylsiloxanes, polyarylsiloxanes, polyalkylarylsiloxanes and polyether siloxane copolymers, polydimethylsiloxanes (dimethicones) and poly (dimethylsiloxane) - (diphenylsiloxane) copolymers. These are selected from cyclic or linear polydimethylsiloxanes containing from about 3 to about 9, preferably from about 4 to about 5, silicon atoms. Volatile silicones such as cyclomethicones (cyclomethicones) may also be used. Silicone oils are also considered therapeutically active oils due to their barrier retaining and protective properties.
The organic vehicle may comprise a mixture of two or more of the above hydrophobic vehicles in any ratio.
Another class of organic vehicle includes "emollients" that have a softening or soothing effect, especially when applied to body parts such as skin and mucosal surfaces. Emollients are not necessarily hydrophobic. Examples of suitable emollients include hexylene glycol, propylene glycol, isostearic acid derivatives, isopropyl palmitate, isopropyl isostearate, diisopropyl adipate, diisopropyl dimer acid (diisopropyl dimerate), maleated soybean oil, octyl palmitate, cetyl lactate, cetyl ricinoleate, tocopheryl acetate, acetylated lanolin alcohol, cetyl acetate, phenyl trimethicone, glyceryl oleate, tocopheryl linoleate, wheat germ glyceride, arachidyl propionate, myristyl lactate, decyl oleate, propylene glycol ricinoleate, isopropyl lanolate, pentaerythritol stearate, neopentyl glycol dicaprylate/dicaprate, isononyl isononanoate, isotridecyl isononanoate, myristyl myristate, triisocetyl citrate, octyldodecyl alcohol, sucrose esters of fatty acids, octyl hydroxystearate, and mixtures thereof.
Surfactants (also known as "surfactants") include any agent that links oil and water in an emulsion in a composition. The hydrophilic/lipophilic balance (HLB) of a surfactant describes the affinity of an emulsifier for water or oil. The HLB scale is in the range of 1 (fully lipophilic) to 20 (fully hydrophilic), where 10 represents an equivalent balance of the two properties. The lipophilic emulsion forms a water-in-oil (w/o) emulsion; the hydrophilic surfactant forms an oil-in-water (o/w) emulsion. The HLB of a mixture of two emulsifiers is equal to the weight fraction of emulsifier A times its HLB value plus the weight fraction of emulsifier B times its HLB value (weighted average).
According to one or more embodiments of the invention, the surfactant has a hydrophilic-lipophilic balance (HLB) of from about 9 to about 14, which is the HLB required for a hydrophobic carrier or oil (HLB required to stabilize an O/W emulsion of a given oil). Thus, in one or more embodiments, the composition contains a single surfactant having an HLB value of from about 9 to 14, and in one or more embodiments, the composition contains more than one surfactant, and the weighted average of their HLB values is from about 9 to about 14. However, in other embodiments, when a water-in-oil emulsion is desired, the composition contains one or more surfactants having an HLB value of from about 2 to about 9.
The surfactant is selected from the group consisting of anionic surfactants, cationic surfactants, nonionic surfactants, zwitterionic surfactants, amphoteric (amphoteric) surfactants, and ampholytic (ampholytic) surfactants, and mixtures of these surfactants. Such surfactants are well known to those skilled in the art of therapeutic and cosmetic formulations. Non-limiting examples of possible surfactants include polysorbates, such as polyoxyethylene (20) sorbitol monostearate (tween 60) and polyoxyethylene (20) sorbitol monooleate (tween 80); poly (oxyethylene) (POE) fatty acid esters such as Myrj 45, myrj 49, myrj 52 and Myrj 59; poly (oxyethylene) alkyl ethers such as poly (oxyethylene) cetyl ether, poly (oxyethylene) palmityl ether, polyethylene oxide cetyl ether, polyethylene glycol cetyl ether, brij 38, brij 52, brij 56 and brij Wl; partial esters of sucrose esters, sorbitol and anhydrides thereof, such as sorbitan monolaurate and sorbitan monolaurate; monoglycerides or diglycerides, isocetyl polyether-20 (isocetyl-20), sodium methyl cocoyl taurate, sodium methyl oleoyl taurate, sodium lauryl sulfate, triethanolamine lauryl sulfate, and betaine.
In one embodiment, the composition of the present invention is a serum.
In one embodiment, the composition of the present invention is a foam.
In one embodiment, the composition of the invention is adhered to a mask for application to the skin for occlusive treatment; and is removed after application for an extended period of time.
Treatment/therapy
The terms "therapy" and "treatment" as used interchangeably herein encompass any treatment of a disease or disorder or cosmetic condition, and include, for example:
-cure of a disease or disorder or cosmetic condition;
-preventing the disease or disorder or cosmetic condition from occurring in a subject who may be susceptible to the disease but has not yet been diagnosed as having the disease;
-inhibiting a disease or disorder or a cosmetic condition;
-alleviation of a disease or disorder or a cosmetic condition;
-causing regression of the disease or cosmetic condition;
-improving the effect of a therapeutic agent known to affect a disease or disorder or cosmetic condition;
-providing a beneficial immune effect;
-improving the quality of life of a subject suffering from a disease or disorder; and, in the case of cosmetic treatments
Cleaning, beautifying, improving attraction or changing appearance without affecting the structure or function of the body. Hereinafter, some non-limiting examples and experiments will be described in detail. The invention is not limited to these examples and experiments. Many variations will suggest themselves within the full intended scope of the appended claims.
Pharmaceutical application field
By including a suitable NO donor that produces NO, the compositions of the present invention may be used to treat patients suffering from any of a variety of skin conditions (also referred to as "skin disorders") such as, in a non-limiting exemplary manner, according to the following components: dermatitis including contact dermatitis, atopic dermatitis, seborrheic dermatitis, coin dermatitis, chronic dermatitis of hands and feet, generalized exfoliative dermatitis, stasis dermatitis; chronic simple moss; diaper rash; bacterial infections including cellulitis, acute lymphangitis, lymphadenitis, erysipelas, skin abscesses, necrotizing subcutaneous infections, staphylococcal scalded skin syndrome, folliculitis, furuncles, hidradenitis suppurativa, carbuncles, paronychia infections, erythema; fungal infections, including dermatophyte infections, yeast infections; parasitic infections including scabies, pediculosis, and rash; viral infection; disorders of hair follicles and sebaceous glands including acne, rosacea, perioral dermatitis, hirsutism (hirsutism), alopecia, male pattern alopecia, alopecia areata, generalized alopecia (alopecia universalis), and alopecia totalis; pseudofolliculitis barbae (pseudofolliculitis barbae), keratocyst; squamous papular disease including psoriasis, pityriasis rosea, lichen planus, pityriasis rubra pilaris; benign tumors including nevi, dysplastic nevi (dysregulated nevi), skin tags (skin tags), lipomas, hemangiomas, suppurative granulomas, seborrheic keratosis, cutaneous fibromas, keratoacanthomas, keloids; malignant tumors including basal cell carcinoma, squamous cell carcinoma, melanoma, paget's nipple disease (page's disease of the nipples), kaposi's sarcoma; reactions to sunlight, including sunburn, chronic effects of sunlight, photosensitivity; bullous diseases including pemphigus, bullous pemphigoid (bullous pemphigoid), dermatitis herpetiformis, linear immunoglobulin a diseases; pigmentation disorders including hypopigmentation, vitiligo, albinism, hypopigmentation after inflammation, hyperpigmentation after inflammation, melasma, chloasma, drug-induced hyperpigmentation; keratosis, including ichthyosis, keratosis pilaris, calluses, corns, and actinic keratosis; pressure sores; perspiration disorders; inflammatory reactions, including drug eruptions, toxic epidermonecrosis lysis; erythema multiforme, erythema nodosum, granuloma annulare.
In one embodiment, the NO donor is arginine.
In one embodiment, when the NO donor is arginine and the NO counteractant is nicotinamide, the compositions of the invention are useful for treating skin conditions selected from the group consisting of: skin infection, acne, rosacea, atopic dermatitis, eczema and psoriasis.
In one embodiment, the NO donor is citrulline.
In one embodiment, when the NO donor is citrulline and the NO counteractant is nicotinamide, the composition of the invention may be used to treat a skin condition selected from the group consisting of: skin infection, acne, rosacea, atopic dermatitis, eczema and psoriasis.
In further embodiments, when the NO donor is arginine and the NO counteractant is nicotinamide, the compositions of the invention are useful for treating signs of skin aging, including photo-induced skin aging, increased transepidermal water loss (TEWL), dry skin, fine lines, wrinkles, hyperpigmentation, and skin discoloration.
However, in further embodiments, when the NO donor is arginine and the NO counteractant is nicotinamide, the compositions of the invention may be used for simultaneous application with skin administration of a neurotoxin, such as botulinum toxin a ("BTX"). Intradermal injection of botulinum toxin A has been reported to eliminate cutaneous vasodilation (Brett et al, TEMPERRATURE 2017; 4/1:41-59); and by doing so BTX reduces the supply of oxygen and nutrients to the skin tissue. It has also been found that topical application of NO donors enhances the muscle relaxing effect of BTX (Lysy at al., gut 2001; 48:221-224).
Thus, the composition of the present invention releasing NO into the skin may promote an increased supply of oxygen and nutrients to the skin tissue, enhance the effect of BTX and extend the duration of the effect. The composition may be administered prior to BTX injection and then continuously following BTX injection. The composition can also be used for alleviating inflammation caused by injection of BTX.
The composition of the present invention containing NO donors can be further used to alleviate atrophy of the skin due to BTX injection.
The compositions of the present invention are useful for treating non-skin conditions responsive to the local/transdermal delivery of an active agent. By way of example, such conditions include localized pain and/or general pain, as well as joint pain, muscle pain, back pain, rheumatic pain, arthritis, osteoarthritis, and acute soft tissue injury and sports injury. Such other disorders include conditions responsive to hormonal therapies such as hormone replacement therapy, transdermal nicotine administration, and other corresponding disorders known in the art of drug delivery.
Thus, the compositions of the present invention may be used to treat patients suffering from any of a variety of gynaecological disorders, for example, in a non-limiting exemplary manner according to the following categories of components: pelvic pain, including premenstrual syndrome (PMS), inter-menstrual pain (severe metaphase pain due to ovulation), dysmenorrhea (pain associated with the menstrual cycle), endometriosis, ectopic pregnancy, ovarian cysts and masses, acute pelvic inflammatory disease, pelvic congestion syndrome and vulvodynia; vulvovaginal infections including bacterial vaginosis, candidal vaginitis, trichomonas vaginalis, herpes simplex genital ulcers and warts, pelvic inflammatory disease, cervicitis, acute and chronic salpingitis; endometriosis; gynecological tumors including endometrial, ovarian, cervical, vulvar, vaginal, fallopian tube, and gestational trophoblastic diseases; benign tumors; sexually transmitted diseases; sexual dysfunction conditions responsive to drug therapy, including sexual arousal conditions, female orgasmic conditions, dyspareunia, and colposses; and various gynecological disorders responsive to hormonal therapy.
Rectal applications include, for example, anal abscess/fistula, anal cancer, anal warts, hemorrhoids, anal and perianal itching, pain, bruise, anal Zhou E aphtha, anal fissure, fecal incontinence, constipation, crohn's disease, inflammatory bowel disease, and colonic and rectal polyps.
The compositions of the application are further useful for intravaginal and intrarectal treatment of sexually transmitted and non-sexually transmitted infectious diseases (STDs).
In one or more embodiments, the present application provides a method of treating a disease or condition of the skin, mucosa, anus, rectum, gastrointestinal system, vagina, penile urethra, eye, respiratory system (including oral cavity, nasal cavity, sinuses, pharynx, larynx, trachea, bronchi, and lungs), dental system, and ear canal, comprising topically administering a composition of the present application, thereby topically administering a therapeutically effective concentration of one or more NO donors to the affected area.
As used in this written description, the singular forms "a," "an," and "the" include explicit support for plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a gas" includes a plurality of such gases.
In the present application, "include", "contain" and "having" etc. may have the meanings given to them by the U.S. patent laws, and may mean "include", "include" and the like, and are generally interpreted as open-ended terms. The term "consisting of … …" or "consisting of … …" is a closed term and includes only the components, structures, steps, etc. specifically listed in conjunction with such terms and in compliance with the U.S. patent statute. "consisting essentially of … … (consisting essentially of)" or "consisting essentially of … … (consists essentially of)" has the meaning commonly given to them by U.S. patent law. In particular, such terms are generally closed terms except to the extent that they allow for the inclusion of additional items, materials, components, steps, or elements that do not materially affect the basic and novel characteristics or functions of the item in which it is used in conjunction. For example, trace elements present in a composition that do not affect the properties or characteristics of the composition would be permitted if present in a language "consisting essentially of … …" even if not explicitly recited in the list of items following such terms. When open terms (such as "comprising" or "including") are used in this written description, it should be understood that direct support in the language "consisting essentially of … …" and the language "consisting of … …" should also be given as if explicitly stated, and vice versa.
The terms "first," "second," "third," "fourth" and the like in the description and in the claims, if any, are used for distinguishing between similar elements and not necessarily for describing a particular sequential or chronological order. It is to be understood that any terms so used are interchangeable under appropriate circumstances such that the embodiments described herein are, for example, capable of operation in sequences other than those illustrated or otherwise described herein. Similarly, if a method is described herein as comprising a series of steps, the order of such steps as presented herein is not necessarily the only order in which such steps can be performed, and some of the described steps may be omitted and/or some other steps not described herein may be added to the method.
The terms "left", "right", "front", "back", "top", "bottom", "above … …", "below … …", and the like in the description and in the claims, if any, are used for descriptive purposes and not necessarily for describing permanent relative positions. It is to be understood that the terms so used are interchangeable under appropriate circumstances such that the embodiments described herein are, for example, capable of operation in other orientations than those illustrated or otherwise described herein. The term "coupled", as used herein, is defined as directly or indirectly connected in an electrical or non-electrical manner. Objects described herein as being "adjacent" to each other may be in physical contact with each other, in close proximity to each other, or in the same general area or region as each other, as appropriate for the context in which the phrase is used. The appearances of the phrase "in one embodiment" or "in one aspect" in this document are not necessarily all referring to the same embodiment or aspect.
As used herein, comparative terms such as "increased," "decreased," "better," "worse," "higher," "lower," "enhanced," "maximized," "minimized," and the like refer to a property of a device, component, or activity that is measurably different from surrounding or adjacent areas, in a single device or in multiple comparable devices, in one group or class, other devices, components, or activities in multiple groups or classes, or as compared to the known state of the art. For example, a process with an "increased" therapeutic effect or outcome may refer to an improved outcome or efficacy obtained by that process as compared to a similar or different process intended to treat the same condition or experience.
As used herein, the term "substantially" refers to a complete or nearly complete range or degree of action, feature, characteristic, state, structure, item, or result. For example, an object that is "substantially" closed will mean that the object is completely closed or nearly completely closed, and in some cases the precise degree of permission for deviations from absolute completeness may depend on the particular context. However, in general, the proximity to the integrity will have the same overall result as if absolute and overall integrity were obtained. The use of "substantially" as used in a negative connotation refers to the complete or nearly complete absence of an effect, feature, characteristic, state, structure, item, or result. For example, a composition that is "substantially free" of particles will be completely free of particles, or almost completely free of particles, which will be the same effect as completely free of particles. In other words, a composition that is "substantially free" of an ingredient or element may still actually contain such items, so long as there is no measurable effect thereof.
As used herein, the term "about" is used to provide flexibility in the endpoints of a numerical range by providing that the given value may be "slightly above" or "slightly below" the endpoint. The use of the term "about" in accordance with a particular numerical value or range of numerical values should also be understood to provide support for such numerical terms or ranges without the term "about" unless otherwise indicated. For example, for convenience and brevity, a numerical range of "about 50 angstroms to about 80 angstroms" should also be understood to provide support for a range of "50 angstroms to 80 angstroms". Furthermore, it should be understood that in this specification, support for actual numerical values is provided even when the term "about" is used in conjunction therewith. For example, a recitation of "about" 30 should be understood to provide support not only for values slightly above and slightly below 30, but also for actual values of 30.
As used herein, a plurality of items, structural elements, compositional elements, and/or materials may be presented in a common list for convenience. However, these lists should be construed as though each element of the list is individually identified as a separate and distinct element. Thus, individual components of such a list should not be understood to be actually equivalent to any other component of the same list, based solely on their presentation in a common group, in the absence of an indication contrary to the following.
Concentrations, amounts, and other numerical data may be expressed or presented herein in a range format. It is to be understood that such a range format is used for convenience and brevity and thus should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. By way of illustration, a numerical range of "about 1 to about 5" should be interpreted to include not only the explicitly recited values of about 1 to about 5, but also include individual values and subranges within the indicated range. Thus, included within this numerical range are individual values, such as 2, 3, and 4, and subranges, such as 1-3, 2-4, and 3-5, and the like, and 1, 2, 3, 4, and 5, individually.
This same principle applies to ranges reciting only one numerical value, such as the minimum or maximum value. Moreover, such interpretation should apply regardless of the breadth of the range or the characteristics being described.
The term "subject" refers to a human or non-human mammal.
Reference throughout this specification to "an example" means that a particular feature, structure, or characteristic described in connection with the example is included in at least one embodiment. Thus, the appearances of the phrase "in one example" appearing in various places throughout the specification are not necessarily all referring to the same embodiment.
EXAMPLE 1 cream composition
Composition #1 comprising L-arginine and nicotinamide (nicotinamide)
Preparation procedure
Phase A
O water and EDTA were combined, mixed to dissolve EDTA, veegum plus was slowly dispersed into the whipped water.
O slowly disperse KELTROL into phase a, start heating the batch to 75 ℃, add the remaining phase a ingredients.
Phase a was homogenized for 2 minutes at about 3500 rpm.
Phase B
O combining phase B ingredients and heating to 75deg.C with mixing
Phase B was slowly added to phase a while mixing phase C, the pH of the batch was adjusted to 6.3-7.5 using phase C, and the batch was cooled to 40 ℃.
Phase D
First the glycine component of phase d was combined in water and mixed until the powder dissolved.
O the remaining ingredients were added, mixed one by one until homogeneous, finally L-leucine was added, then added to the batch with mixing.
Phase E
The ingredients are combined with water and mixed until homogeneous.
O pH was adjusted to 6.74 using citric acid.
Adjusting the pH will change the phase into a clear solution.
O is added to the batch with mixing.
Phase F
O add phase F ingredients to the batch once, mix for 2 minutes between each addition.
Phase G
O the pH of the batch was adjusted to 6.9-7.0 by adding sodium hydroxide solution. The batch was cooled to 30 ℃.
Phase H
O phase H was slowly added to the batch.
Packaging
pH：6.15
Viscosity (Cps): about 60000
Composition #2 comprising L-arginine (free of nicotinamide)
Preparation-analogously to example #1
EXAMPLE 2 treatment of aged skin (preliminary study # 1)
The purpose is as follows: the effect of compositions #1 and #3 on middle aged women after 1 month was determined. The method comprises the following steps: two women over 40 were willing to receive one month of supplies of composition #1 and composition # 2. They were required to use both compositions daily on both sides of the face for 28 days and provided information by a post-use questionnaire.
Results: the results are summarized in the following table.
Conclusion:
1. composition #1, which contained 10% arginine +2% niacinamide, was very effective in tightening and lifting skin and reducing wrinkles. Composition #2, which contained 10% arginine but no nicotinamide, was slightly less effective.
2. Composition #2 caused a pronounced burning sensation that made both subjects moderately or poorly tolerated. In contrast, composition #1 was highly tolerated with a slight tingling sensation, which was not inhibitory for both subjects.
EXAMPLE 3 treatment of aged skin (study # 2)
The purpose is as follows: to determine the effect of composition #1 on middle aged women after 28 days of continuous use.
The method comprises the following steps: 20 women over 40 years old in 3 countries (united states, italy and israel) were willing to receive a one month supply of composition #1 for use as their day cream. They were asked to use the cream daily for 28 days and provided a non-instructional input (free form)
Results: 13 of the 20 women provided feedback, which is summarized in the table below.
Summarizing:
1. all subjects given their feedback noted that composition #1 met or exceeded their expectations for day cream. They noted high efficacy in treating the symptoms of skin aging.
2. In particular, the composition significantly reduces the appearance of wrinkles.
3. The addition of nicotinamide solves the problems of previous burning and excessive stinging (study # 1).
Example 4: gel formulations comprising arginine or citrulline and nicotinamide
| Composition of the components | #3 | #4 | #5 | #6 | #7 | #8 |
| Arginine (Arg) | 8％ | 10％ | - | 10％ | 10％ | |
| Citrulline | 12％ | 12 | ||||
| Nicotinamide | 2％ | 2％ | 2％ | 4％ | 2％ | 2％ |
| Carbopol 940 | 0.4％ | 0.5％ | 0.6％ | - | - | - |
| Methylcellulose and process for producing the same | - | - | - | 1％ | 3％ | 6％ |
| Propylene glycol | 10％ | 10％ | 10％ | 10％ | 10％ | 10％ |
| Triethanolamine salt | 0.5％ | 0.5％ | 0.5％ | 0.5％ | 0.5％ | 0.5％ |
| Preservative agent | 0.3％ | 0.3％ | 0.3％ | 0.3％ | 0.3％ | 0.3％ |
| Purified water is filled up to | 100％ | 100％ | 100％ | 100％ | 100％ | 100％ |
Example 5: essence formulation comprising arginine or citrulline and nicotinamide
| Composition of the components | #9 | #10 | #11 | #12 | #13 |
| Arginine (Arg) | 8％ | 10％ | - | 10％ | |
| Citrulline | 12％ | 10％ | |||
| Nicotinamide | 2％ | 2％ | 2％ | 4％ | 2％ |
| Hyaluronic acid HMW | 0.2％ | 0.2％ | 0.2％ | 0.2％ | 0.2％ |
| Glycerol | 5％ | 5％ | 5％ | 5％ | 5％ |
| PEG 12 polydimethylsiloxane | 3％ | 3％ | 3％ | 3％ | 3％ |
| Sodium diacrylate | 1％ | 1％ | 1％ | 1％ | 1％ |
| Phenoxyethanol | 1％ | 1％ | 1％ | 1％ | 1％ |
| Purified water is filled up to | 100％ | 100％ | 100％ | 100％ | 100％ |
Example 6: day cream preparation
Claims (44)
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| US63/137,732 | 2021-01-15 | ||
| US202163138702P | 2021-01-18 | 2021-01-18 | |
| US63/138,702 | 2021-01-18 | ||
| PCT/IL2022/050056 WO2022153308A1 (en) | 2021-01-15 | 2022-01-13 | Topical composition |
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| CN116685302A true CN116685302A (en) | 2023-09-01 |
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| CN (1) | CN116685302A (en) |
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