Topical preparations containing benzoyl peroxide and azelaic acid and uses thereof

Abstract

Compositions are provided that include benzoyl peroxide, azelaic acid, strontium salts, and methylsulfonylmethane (MSM), and are formulated into one or more dosage forms, with at least one dosage form including both benzoyl peroxide and azelaic acid.These compositions are formulated as cosmetic or pharmaceutical products useful for treating skin diseases, disorders, or conditions in which topical co-administration of BPO and azelaic acid may be beneficial.These skin care products provide a dermal shield against neurogenic inflammation, stinging, itching, burning, redness, irritation, and / or other sensations and feelings associated with topical application of BPO and / or azelaic acid.

Description

Detailed Description of the Invention

[0001] [Technical field] The present disclosure relates to formulations combining benzoyl peroxide, azelaic acid, strontium, and methylsulfonylmethane (MSM) for the treatment of certain skin diseases and conditions.

[0002] [Background technology] Various skin diseases and conditions are best treated by topical application of multiple active agents. For example, acne vulgaris and rosacea are multifactorial skin diseases that are treated by multiple drugs or active agents. Separate application of multiple drugs, sometimes in succession with a limited time interval, often causes some discomfort, burden, and / or bother to the patient. Moreover, in many cases, the combination of two or more active agents enhances or intensifies undesirable side effects that would otherwise be low if each of the active agents were administered separately. Thus, the inability of the patient to tolerate such side effects outweighs the benefits and benefits of combination therapy.

[0003] Benzoyl peroxide (BPO) is a well-known ingredient for fighting acne. The ingredient is available in over-the-counter (OTC) gels, cleansers, and spot treatments in various concentrations for mild to moderate breakouts. High-concentration benzoyl peroxide products contain up to 10% BPO by weight, while facial products typically contain up to 4% BPO. Benzoyl peroxide works to treat and prevent acne by killing bacteria under the skin as well as helping pores expel dead skin cells and excess sebum (oil). Benzoyl peroxide is considered safe for most people, but it can cause serious side effects in the area of ​​application, including dryness, redness, excessive peeling, itching, and general irritation. People with sensitive skin should not use BPO.

[0004] Azelaic acid is a naturally occurring acid found in grains such as barley, wheat, and rye. It has antibacterial and anti-inflammatory properties, making it effective in treating skin conditions such as acne and rosacea. Prescription topical azelaic acid is available in gels, foams, and creams that contain at least 15% azelaic acid by weight. Over-the-counter products contain lesser amounts. Azelaic acid helps clear pores of bacteria that can cause irritation or breakouts, reduces inflammation and reduces the appearance of acne, reduces redness and inflammation, and promotes cell turnover, which allows the skin to heal faster and minimizes scarring.

[0005] The acid has side effects such as a burning or stinging sensation of the skin, dryness, redness, and peeling at the application site. Azelaic acid is often prescribed with other acne medications because it acts slowly. Some studies have reported that azelaic acid creams can be as effective in treating acne as benzoyl peroxide and tretinoin (Retin A).

[0006] There is no literature on the combined use of BPO and azelaic acid for the treatment of skin lesions. There is an unmet need for innovative topical formulations and skin care products that combine two or more active agents, such as BPO and azelaic acid, which may be advantageous in certain skin conditions but are not used together in current practice due to the substantial and extensive cumulative skin damage that may be promoted by these combinations.

[0007] Summary of the Invention Benzoyl peroxide (BPO) and azelaic acid are two commonly used anti-acne active agents, each of which is known to cause various side effects when applied alone, and even more so when applied together in any combination. The present disclosure is based on the discovery by the inventors that BPO and azelaic acid, when provided in combination with strontium and / or methylsulfonylmethane (MSM), can nevertheless be applied as a single unit dosage form. Moreover, such combination has been proven to be highly effective in reducing, preventing and / or eliminating the onset, incidence and severity of neurogenic inflammation commonly associated with topical application of benzoyl peroxide and azelaic acid in cosmetics and / or pharmaceuticals, such as anti-acne and / or anti-rosacea products.

[0008] In one embodiment, the disclosure relates to a composition including benzoyl peroxide, azelaic acid, a strontium salt, MSM and a dermatologically acceptable carrier, wherein the composition is formulated as one or more dosage forms, such that at least one dosage form includes both benzoyl peroxide and azelaic acid.

[0009] In the compositions disclosed herein, the concentration of benzoyl peroxide is 0.1-10% by weight, and the concentration of azelaic acid is 0.1-20% by weight.

[0010] The strontium salt can be strontium chloride, strontium acetate, strontium nitrate, or strontium chloride hexahydrate.

[0011] Contemplated compositions may further include active ingredients such as, but not limited to, alpha-hydroxy acids (AHA), beta-hydroxy acids (BHA), retinoids, alpha-keto acids, dicarboxylic acids, arbutin, resorcinol, hydroquinone, kojic acid, myristic acid, sodium laureth sulfate, disodium laureth sulfosuccinate, sulfur, vitamin C, vitamin C derivatives, cannabinoids, azelaic acid derivatives, salts and / or prodrugs, diaryl peroxides, alkylaryl peroxides, and / or cycloalkylaryl peroxides.

[0012] Any of the compositions disclosed herein may be formulated or made into a cosmetic or skin care product for topical application, or a medicinal product, using appropriate excipients, carriers, penetration enhancers, etc. Non-limiting examples of skin care / pharmaceutical formulations or products contemplated herein include ointments, creams, spreads, lotions, oils, solutions, emulsions, nanoemulsions, gels, pastes, milks, aerosols, powders, or foams.

[0013] The cosmetic or pharmaceutical product is physically and / or chemically stable for at least three months in an environment between 4 and 40°C.

[0014] In another aspect, the present disclosure relates to methods of treatment using any of the compositions and / or cosmetic or pharmaceutical agents disclosed herein.

[0015] In some embodiments, contemplated methods are useful for treating, preventing, improving and / or alleviating skin diseases, disorders or conditions that may benefit from topical co-administration of BPO and azelaic acid. Skin diseases, disorders or conditions that may be treated include, but are not limited to, acne, rosacea or seborrhea.

[0016] In some embodiments, contemplated methods are useful for treating, preventing, ameliorating, alleviating and / or reducing neurogenic inflammation.

[0017] In some embodiments, contemplated methods are useful for treating, preventing, ameliorating, relieving and / or reducing one or more of the stinging, itching, burning, redness, irritation, and / or other sensations and feelings associated with the topical application of BPO and azelaic acid. [Full Disclosure]

[0018] The present disclosure relates to the surprising discovery by the inventors that simultaneous topical application of benzoyl peroxide and azelaic acid, either alone or in any combination thereof, at concentrations common to common dermatological products, in combination with application of strontium salts and / or MSM, substantially reduces the severe side effects, such as irritation, itching, erythema, burning sensation, etc., associated with topical application of benzoyl peroxide and / or azelaic acid. The soothing, irritation-reducing effect of the concurrent application of strontium and MSM over the topical combination of benzoyl peroxide and azelaic acid was immediate and effective, preventing the stinging, itching, burning, erythema, and other sensations and feelings associated with neurogenic inflammation over an extended period of time.

[0019] As such, the inventors have envisioned that the application of strontium and / or MSM may allow for the combination of two or more active agents to treat a variety of skin diseases and conditions that have previously been avoided due to significant side effects on the skin.

[0020] There remains a need for innovative topical formulations that combine two or more active agents that are not combined in current embodiments, or that can be formulated as a single product, such as a cream or ointment, and delivered to a subject in need thereof as a stable composition characterized by excellent cosmetic and / or therapeutic properties and minimal undesirable side effects. This need remains unmet for certain combinations of active agents that, although providing enhanced and improved therapeutic / cosmetic results when combined, are not combined due to accumulated intolerable side effects.

[0021] Benzoyl peroxide (molecular formula: C 14 H 10 Benzoyl peroxide (O4; molecular weight: 242.23 g / mol) is an organic peroxide with the structural formula (C6H5-C(=O)O-)2 (often abbreviated as (BzO)2 or BPO) and is available as a white granular crystalline solid with a faint odor of benzaldehyde. The peroxide exhibits antibacterial, irritant, keratolytic, acneolytic, and / or anti-inflammatory properties. As a drug, benzoyl peroxide is most often used to treat acne, either alone or in combination with other treatments. Benzoyl peroxide works to treat and prevent acne by killing bacteria under the skin and helping to expel dead skin cells and excess sebum (oil) from pores. This anti-acne active is particularly effective in inflammatory acne such as acne vulgaris, which is characterized by white spots and red pus-filled bumps (pustules, papules, cysts, and nodules) instead of blackheads. Benzoyl peroxide, through its stimulating effect, increases the rate of epithelial cell turnover, exfoliating the skin and promoting the disappearance of comedones. It has also been suggested that BPO improves the residual hyperkeratosis of the inner bottom hair follicle. For example, topical medications containing 2.5-10% BPO for the treatment of acne vulgaris and / or rosacea are widely used in Asian countries such as Korea, Singapore, and Hong Kong, as well as in Europe and the United States, where medical guidelines recognize BPO as the standard treatment for acne vulgaris. However, application of these products to the skin often results in intolerable side effects such as burning, stinging, irritation, inflamed skin, peeling, and / or redness at the treatment site. Due to these frequent side effects, the use of such products is only marginally effective, and patients often fail to complete the treatment regimen.

[0022] Therefore, the development of a BPO product with improved efficacy and tolerability has been a challenge. Sol-gel technology has been used to develop a microencapsulated formulation of BPO (E-BPO) for the treatment of rosacea, which may alleviate some of the severe side effects caused by the free active agent. Commercially available E-BPO creams (5% formulations) encapsulate BPO within a porous silica shell. This capsule forms a barrier between the skin and the BPO crystals or other components, allowing the active agent to be released in a timely manner (sustained release), resulting in less skin irritation and much better tolerability and compliance of the drug in patients. However, the therapeutic effects of encapsulated BPO are very slow: improvement in rosacea symptoms progresses slowly over several months (e.g., 40-52 weeks).

[0023] Azelaic acid, a dihydroxy acid (HOOC(CH2)7COOH), is a naturally occurring saturated dicarboxylic acid that has been shown to be effective in treating comedonal acne, inflammatory acne (papular pustular acne, nodular acne, and nodular cystic acne) when applied topically (usually as a 20% cream). It has also been shown to be effective in treating various skin pigmentation disorders characterized by melanocyte hyper / dysfunction, such as melasma and lentigo maligna. In addition, azelaic acid has antiproliferative and cytotoxic effects on human malignant melanocytes and may inhibit the progression of cutaneous malignant melanoma. The anti-inflammatory and antipigmentation effects of azelaic acid against acne are attributed to its ability to inhibit tyrosinase. In controlled trials, topical azelaic acid has been shown to be as effective against acne as topical tretinoin, benzoyl peroxide, erythromycin, and oral tetracycline, and in patients with melasma, azelaic acid has proven to be at least as effective as topical hydroquinone.Products containing azelaic acid in concentrations of 15-25% by weight are known, for example, for the treatment of acne vulgaris and / or rosacea.

[0024] Azelaic acid can be used alone or in combination with other soothing and whitening ingredients such as niacinamide, hydroxy acids, or antioxidants. Azelaic acid is often combined with hyaluronic acid to provide moisture and / or with moisturizers and gentle cleansers or sulfur cleansers to treat acne or rosacea. Azelaic acid in combination with other ingredients is usually highly recommended, as it is a very stable molecule and combination therapy is much more effective than azelaic acid monotherapy.

[0025] Well-known azelaic acid products include, for example, facial serums and acid boosters. Facial serums are often used to treat pigmentation and often contain a combination of azelaic acid with other powerful active ingredients such as retinol, vitamin C, and / or sundew extract. Acid boosters provide at least 10% azelaic acid, sometimes combined with salicylic acid, to lighten dark spots and even out skin tone. Further products include acne treatment and / or skin lightening gels formulated with azelaic acid (e.g., 2% by weight), niacinamide, salicylic acid, and / or hyaluronic acid; soothing gel masks containing azelaic acid, green tea extract, and aloe leaf juice to absorb excess oil without stripping the skin of moisture, and to soothe and reduce redness.

[0026] Azelaic acid is generally poorly tolerated, and subjects with sensitive skin may experience mild irritation and redness. In some cases, use of azelaic acid products is associated with more severe side effects, such as moderate burning, stinging, and / or irritation.

[0027] Both BPO and azelaic acid are well known for their therapeutic effects on skin diseases and conditions such as acne, rosacea, and seborrhea, but there have been no practical successes in combining both active agents in a single topical formulation. Canadian Patent No. 2,362,343 discloses a method for treating acne vulgaris using two topical compositions, the first containing benzoyl peroxide and the second containing azelaic acid. Although these compositions showed some improved efficacy over the state-of-the-art compositions known at the time, they were applied sequentially rather than topically at the same time, presumably to avoid the severe overall side effects of both benzoyl peroxide and azelaic acid.

[0028] The combination of strontium and MSM in a topical formulation has previously been shown by the inventors to be useful in reducing the onset, incidence and severity of irritation and erythema associated with topically applied skin irritants, for example, in skin treatment products (International Application Publication No. WO2019 / 198067).

[0029] Strontium salts and MSM are known to rapidly suppress acute sensory irritation (e.g., tingling, burning, pain, and / or itch) caused, for example, by neurological inflammation, chemical irritants, environmental irritants, allergies, illness, etc. It is theorized that strontium's anti-irritant activity may be related to its ability to selectively suppress activation of C-type nociceptors (TCNs), the only sensory nerves responsible for generating and transmitting sensations such as tingling, burning, pain, and itch.

[0030] It is known that benzoyl peroxide and azelaic acid cause various side effects when applied alone, and even more so when applied together in any combination.Nevertheless, it is demonstrated herein that when provided with strontium, for example in the form of strontium salts, and / or in combination with MSM, it can be applied as a single unit dosage form in various topical products.It is further demonstrated herein that such combination is useful for reducing, preventing and / or eliminating the onset, incidence and severity of neurogenic inflammation commonly associated with the topical application of benzoyl peroxide and azelaic acid in cosmetics and / or pharmaceuticals, such as anti-acne and / or anti-rosacea products.

[0031] Surprisingly, a synergistic effect was obtained by combining the two materials, BPO and azelaic acid, in the presence of strontium salts and MSM. That is, a higher, stronger, and more significant effect was observed than would be expected from the simple sum of the effects of BPO and azelaic acid alone. Because it may be desirable to use small amounts of BPO and / or azelaic acid, the synergistic effect allows the use of small, effective combinations of these active agents that would otherwise be ineffective.

[0032] Neurogenic inflammation involves functional changes in sensory neurons induced by inflammatory mediators. Neurogenic inflammation induces enhanced local release of neuropeptides, such as substance P, calcitonin gene-related peptide (CGRP), neurokinin A (NKA), and endothelin-3 (ET-3), from sensory nerve terminals. The release of these inflammatory mediators is thought to be triggered by the activation of ion channels, which are the primary detectors of harmful environmental stimuli.

[0033] Neurogenic inflammation may be caused, for example, by one or more of skin diseases, disorders and conditions, allergic reactions, reactions to local skin irritants, drug applications, chemicals, temperature changes, eczema, environmental exposures, bacterial, fungal, viral, or parasitic infections, changes in pH, beauty and cleansing products, lasers and other light-based treatments, radiofrequency (RF) and ultrasound treatments, bites, or poisonous plants. Neurogenic inflammation may cause localized pain, irritation, stinging, burning, itching, swelling, erythema, unpleasant sensations, and other side effects.

[0034] Tests conducted by the present inventors have demonstrated that a combination of strontium salts and MSM, when topically co-applied with a combination of BPO and azelaic acid, can immediately and effectively prevent the manifestations of neurological inflammatory responses and associated symptoms as defined herein, as well as other sensations and moods associated with skin irritation products containing BPO or azelaic acid.

[0035] [Composition and formulation] In one aspect, the disclosure relates to a composition comprising benzoyl peroxide, azelaic acid, strontium, methylsulfonylmethane (MSM) and a dermatologically acceptable carrier, wherein the composition is formulated as one or more dosage forms, at least one dosage form comprising both benzoyl peroxide and azelaic acid.

[0036] The term "dosage form" as used in the context of this disclosure, sometimes used interchangeably with the term "unit dose", refers to a pharmaceutical and / or cosmetic composition in a form intended for use (application, administration) and / or marketing, containing a specific mixture of active ingredients and optionally inactive ingredients (excipients) apportioned to a specific dose. Depending on the context, in some embodiments, the term dosage form may refer not only to the formulation of the constituent active substance(s) and any combination of the pharmaceutical / cosmetic composition, but also to the manner or form in which it is ultimately constituted as a consumable product. In this broad interpretation, and depending on the method / route of administration, dosage forms can be of several types, including many types of liquid, solid, and semi-solid dosage forms. Common dosage forms include, but are not limited to, pills, tablets, capsules, or syrups, etc. For example, a liquid dosage form is a liquid form of a dose of a chemical compound or mixture of compounds used as a drug, medication, and / or cosmetic intended to be administered or consumed. Of note, the route of administration (ROA) depends on the dosage form of the substance in question. Since different conditions may justify different routes of administration, various dosage forms may exist for a single particular drug and / or cosmetic composition.

[0037] The disclosed compositions can be formulated as a single dosage form that contains BPO, azelaic acid, strontium and MSM. Alternatively, the disclosed compositions can be formulated as two or more dosage forms. For example, the composition can include two dosage forms, a first dosage form that contains BPO and azelaic acid, and a second dosage form that contains strontium and MSM, for example, in salt form. The disclosed compositions can be formulated as, for example, three dosage forms, where the first dosage form contains BPO and azelaic acid, the second dosage form contains strontium, for example, in salt form, and the third dosage form contains MSM.

[0038] The contemplated compositions may include azelaic acid, as well as various pharma- ceutically acceptable derivatives, salts, and prodrugs of azelaic acid, including, but not limited to, sodium or potassium azelaic acid, azeloglycine, and / or lower alkyl esters, i.e., C1-C6 alkyl esters, such as methyl azelaate. Any one or more of these derivatives, salts, and / or prodrugs may be used in addition to or in place of azelaic acid. Similarly, various pharma-ceutically acceptable derivatives, salts, and prodrugs of BPO may be used in the contemplated compositions, including, but not limited to, aqueous benzoyl peroxide. Also, in some embodiments, various forms of other peroxides, such as, but not limited to, diaryl peroxides, alkylaryl peroxides, and / or cycloalkylaryl peroxides, such as lauroyl benzoyl peroxide and / or cyclohexylcarbanol benzoyl peroxide, may be used in place of or in addition to BPO.

[0039] Azelaic acid and / or a pharma- ceutically acceptable salt, derivative or prodrug thereof (e.g., azeloglycine, sodium salt of azelaic acid, or lower alkyl ester of azelaic acid) can be applied in an amount sufficient to provide from about 0.1 to about 40% by weight (w / w) of the total composition, for example, from about 0.1 to about 2% by weight, from about 1 to about 5% by weight, from about 4 to about 8% by weight, from about 5 to about 10% by weight, from about 10 to about 20% by weight, from about 15 to about 30% by weight, from about 22 to about 28% by weight, from about 25 to about 30% by weight, from about 10 to about 30% by weight, from about 25 to about 35% by weight, from about 25 to about 40% by weight, or from about 30 to about 40% by weight, and any subranges and individual values ​​therebetween.

[0040] In some embodiments, contemplated compositions include azelaic acid in an amount of about 0.5 to about 25% by weight, about 5 to about 30% by weight, about 10 to about 25% by weight, about 15 to about 35% by weight, about 15% by weight, or about 25% by weight.

[0041] Benzoyl peroxide, and / or any pharma- ceutically acceptable derivatives, salts, or substitutes for peroxide, may be present in a total amount sufficient to provide about 0.1 to about 30% by weight (w / w) of the total composition, such as about 0.1 to about 2%, about 1 to about 5%, about 4 to about 8%, about 5 to about 10%, about 8 to about 12%, about 10 to about 15%, about 12 to about 20%, about 15 to about 22%, or about 20 to about 30%, and any subranges and individual values ​​therebetween.

[0042] In some embodiments, contemplated compositions include BPO in an amount of about 2.5 to about 10% by weight, about 5 to about 10% by weight, about 8 to about 15% by weight, about 5% by weight, or about 10% by weight.

[0043] In some embodiments, contemplated compositions may include micronized PBO particles (diameter <10 μm) and micronized azelaic acid particles in a nanoemulsion formulation.

[0044] Micronization is the reduction of the average particle size of a solid substance to a size of a few microns. An active pharmaceutical ingredient (API) is said to be micronized when its particle size is generally less than 50 microns, which is about one-fourth to one-tenth the size of conventional drug particles. Micronization is applied to improve a drug's bioavailability, water solubility, and / or body membrane permeability.

[0045] In some embodiments, benzoyl peroxide and / or azelaic acid are present as finely divided particles uniformly dispersed in a contemplated composition.

[0046] As used herein, the terms "nanoemulsion" and "microemulsion" refer to emulsions having particles or droplets in the nano-size range and micro-size range, respectively.

[0047] Nanoemulsions are thermodynamically stable transparent or translucent colloidal dispersions formed from two immiscible liquids, e.g., oil-in-water (o / w) or water-in-oil (w / o), stabilized by an interfacial membrane of surfactant and cosurfactant molecules, with droplet sizes ranging from 10 to 100 nm. Advantages of nanoemulsions include increased drug loading, as well as improved bioavailability, good stability, rapid digestibility, protection from degradation, and controlled release. The oil phase can be formulated with different types of lipids and oils, such as triglycerides and essential oils, to produce nanoemulsions of various physicochemical and biological properties. The aqueous phase can be manipulated by adding different water-soluble components.

[0048] Examples of dosage forms into which nanoemulsified BPO and / or azelaic acid can be formulated include creams, liquids, sprays, foams, etc. Nanoemulsions can be formulated using a variety of techniques, including high pressure homogenization, sonication, microfluidization, and titration methods.

[0049] In some embodiments, the BPO is encapsulated, for example in silica microcapsules. Concentrations of MSM in contemplated compositions can range from about 0.1 to about 40% by weight, such as about 0.1 to about 3%, about 0.5 to about 2%, about 3 to about 5%, about 0.1 to about 5%, about 5 to about 10%, about 5 to about 7%, about 7 to about 10%, about 6 to about 8%, about 6 to about 9%, about 10 to about 20%, about 10 to about 15%, about 15 to about 20%, about 20 to about 40%, about 20 to about 30%, or about 30 to about 40% by weight, and any subranges and individual values ​​therebetween.

[0050] In several embodiments, the concentration of MSM ranges from about 0.1 to about 20% by weight, such as from about 5 to about 10% by weight. In some embodiments, strontium is provided in the contemplated composition as a strontium salt, where the counter anion may be an inorganic or organic counter anion. In some embodiments, strontium is provided as fluoride (F - ), chloride (Cl - ), bromide (Br - ), iodide (I - ) or in the form of a salt with a counter anion such as nitrate.

[0051] In some embodiments, the strontium is in the form of strontium chloride, hi some embodiments, the strontium is in the form of strontium chloride hexahydrate.

[0052] In some embodiments, the strontium is in the form of a strontium nitrate salt. In some embodiments, the strontium is in the form of an organic salt in which the counter anion is an organic anion derived from, for example, a carboxylic acid, an alkoxylate, an amino acid (particularly lysine, arginine, histidine, ornithine, aspartic acid, glutamic acid, proline, and cysteine), a peptide, a saturated or unsaturated organic acid, or a saturated or unsaturated fatty acid.

[0053] In some embodiments, the organic counter anion is, for example, acetate, lactate, glycolate, tartrate, maleate, benzoate, propionate, salicylate, ascorbate, formate, succinate, folate, aspartate, phthalate, oleate, palmitate, stearate, lauryl sulfate, lanolate, myristate, behenate, caseinate, cyclamate, pantothenate, EDTA or other polyaminopolycarboxylate, saccharin, thioglycolate, laurate, methylparaben, propylparaben, ricinoleate, or sorbate.

[0054] In some embodiments, the strontium is in the form of a strontium acetate salt. In some embodiments, the concentration of elemental strontium in the disclosed compositions ranges from about 0.1 to about 15% by weight, such as about 0.1 to about 2% by weight, about 0.5 to about 1.5% by weight, about 2 to about 4% by weight, about 2 to about 8% by weight, about 4 to about 6% by weight, about 5 to about 7% by weight, about 6 to about 8% by weight, about 7 to about 10% by weight, about 8 to about 10% by weight, about 9 to about 12% by weight, or about 10 to about 15% by weight, and any subranges and individual values ​​therebetween.

[0055] In some embodiments, the concentration of strontium is in the range of about 0.1 to about 10% by weight, such as about 2 to about 8% by weight.

[0056] The higher the concentrations of BPO and / or azelaic acid, the higher the concentrations of strontium and / or MSM are recommended.

[0057] In some embodiments, contemplated compositions may include at least the following ingredients: (i) azelaic acid in an amount of about 0.1 to about 40%, about 0.1 to about 5.0%, about 5.0 to about 15.0%, or about 10 to about 30% by weight; (ii) benzoyl peroxide in an amount of about 2.5 to about 10%, about 5 to about 10%, or about 8 to about 15% by weight; (iii) one or more strontium salts in a total amount of about 0.1 to about 10%, about 2 to about 8% by weight; and (iv) MSM in an amount of about 0.1 to about 20%, or about 5 to about 10% by weight. Any of the compositions disclosed herein can contain at least one additional active ingredient (or active agent), such as, but not limited to, an alpha hydroxy acid (AHA), a beta hydroxy acid (BHA), a retinoid, an alpha keto acid, a dicarboxylic acid, arbutin, resorcinol, hydroquinone, kojic acid, myristic acid, sodium laureth sulfate, disodium laureth sulfosuccinate, sulfur, vitamin C, a vitamin C derivative, or a cannabinoid.

[0058] In some embodiments, the additional active agent is, for example, an alpha-hydroxy acid (AHA) such as glycolic acid, lactic acid, mandelic acid, tartaric acid, malic acid, or citric acid; a beta-hydroxy acid (BHA) such as salicylic acid or citric acid; a retinoid such as retinol, retinoic acid, or other derivatives of vitamin A; an alpha-keto acid such as pyruvic acid; arbutin such as alpha- or beta-arbutin; vitamin C and its derivatives such as ascorbyl tetraisopalmitate or ascorbyl glucoside; sulfur; resorcinol, resorcinol monoacetate; hydroquinone; kojic acid; sodium laureth sulfate, disodium laureth sulfosuccinate; or chamomile distillate extract.

[0059] The amount of any one or more additional active agents may range from 0.1 to 70% by weight, e.g., from about 2 to about 10% by weight, from about 5 to about 15% by weight, from about 12 to about 30% by weight, from about 25 to about 40% by weight, or from about 30 to about 50% by weight, depending on the type of formulation, duration and / or intended use.

[0060] In some embodiments, the additional active ingredient is salicylic acid. In some embodiments, the additional active ingredient is glycolic acid. In some embodiments, the additional active ingredient is retinol and / or its derivatives.

[0061] The disclosed compositions further comprise a dermatologically acceptable carrier. As used herein, "dermatologically acceptable carrier" refers to a carrier that is suitable for topical application to keratinous tissue, is compatible with the active ingredients in the formulation, and does not raise safety or toxicity concerns. Any of the dermatologically acceptable carriers known in the art can be used in accordance with the embodiments described herein, in an amount of about 0.1 to 99.1% by weight.

[0062] The disclosed compositions can be formulated as cosmetics or as pharmaceuticals, i.e., medicines, for the treatment of acne, for example. Contemplated formulations can include one or more dosage forms including benzoyl peroxide, azelaic acid, strontium salts, and MSM. Essentially, at least one dosage form includes BPO and azelaic acid and / or its derivatives, salts, or substitutes. When the formulation is intended for the treatment of acne, the formulation is referred to herein as an "anti-acne formulation" and can include a combination of MSM and strontium, a combination of BPO and azelaic acid, and optionally at least one additional anti-acne active and / or one or more anti-inflammatory actives. For example, an anti-acne formulation can include azelaic acid, BPO, MSM, strontium salts, and one or more of lactic acid, sulfur, azeloglycine, resorcinol, and / or resorcinol monoacetate. Such formulations are useful, for example, in treating bumpy skin with papules and associated redness, and can help reduce discoloration. An exemplary formulation for treating acne is described in Example 1 herein.

[0063] The compositions disclosed herein exhibit excellent physical and chemical stability, characterized as intactness, texture stability, homogeneity, and / or constant viscosity over time, e.g., for at least 3 months, at temperatures ranging from 4 to 40°C.

[0064] All of the compositions and formulations disclosed herein, in addition to the associated active agents and combinations of MSM and strontium, include additional excipients, carriers and additives as would be known to one of ordinary skill in the art. Such excipients include, for example, penetration enhancers, emulsifiers, humectants, solvents, surfactants, preservatives, moisturizers, fragrances, dyes / colorants, viscosity modifiers, emollients, binders, absorbents, buffers, chelating agents, conditioning agents, and the like, at various concentrations ranging from 0.01-70% by weight.

[0065] The disclosed compositions intended for topical application typically include a penetration enhancer. Chemical penetration enhancers or penetration enhancers (CPEs) are molecules that interact with and increase the permeability of the stratum corneum (SC), the outermost and rate-limiting layer of the skin. Chemical penetration enhancement strategies are used in the cosmetics and pharmaceuticals disclosed herein to improve topical drug delivery. Non-limiting examples of chemical penetration enhancers include ethanol, dimethyl sulfoxide, dimethyl isosorbide, fatty acid esters (such as isopropyl myristate (IPM), propylene glycol monocaprylate (PGMC), propylene glycol monolaurate (PGML)), alkyl and benzoic acid esters (e.g., ethyl acetate, octyl salicylate (OS)), ether alcohols (e.g., Transcutol®), amides (e.g., Azone (Laurocapram)), fatty acids (e.g., oleic acid (OA)), glycols such as glycerin and propylene glycol (PG), and the like.

[0066] In some embodiments, contemplated cosmetic or pharmaceutical products may include propylene glycol as a penetration enhancer.

[0067] In the cosmetics and skin care products disclosed herein, propylene glycol can further be used as both moisturizer and conditioner.Propylene glycol acts as a moisturizer at low concentration levels, and it secures and transports moisture to the outer layer of skin.Therefore, the cosmetics containing propylene glycol disclosed herein are also suitable for moisturizing the skin and provide smoothness.

[0068] The disclosed compositions can be formulated in the form of an ointment, cream, lotion, oil, solution (in some embodiments, an aqueous solution), emulsion, nanoemulsion, gel, paste, milk, aerosol, powder, or foam. In some embodiments, the formulation is aqueous-based, such as a gel or aqueous solution. In some embodiments, the formulation is an oil-in-water emulsion, nanoemulsion, microemulsion, oil-in-water cream, foam, lotion, or spray.

[0069] In some embodiments, contemplated compositions are formulated as cosmetic or skin care products and / or pharmaceuticals, for example, in the form of a mask, peel, soap (liquid or solid), shampoo, shaving cream or gel, aftershave, sunscreen, makeup and / or makeup remover.

[0070] The disclosed compositions, formulated as pharmaceutical and / or cosmetic / skin care products, allow for the use of high concentrations of active pharmaceutical and / or cosmetic ingredients at low pH without the typical irritation and side effects (such as redness) that result from chemical irritants or low pH. This is because the compositions described herein contain MSM and strontium salts, which provide a shielding effect. Because both MSM and strontium provide skin protection, they are also referred to herein as "DermaShield."

[0071] The combination of MSM and strontium can be used before or after the application of the combination of BPO and azelaic acid. When MSM and strontium are formulated in a dosage form that does not include BPO and azelaic acid, they may be applied before or after, preferably in close proximity to, the application of a dosage form that includes BPO and azelaic acid to have the desired effect of immediately reducing or neutralizing irritation, erythema and / or neurogenic inflammation.

[0072] The present disclosure provides more effective products for skin treatment without typical side effects such as redness, itching, burning, stinging, etc. Absence or mild side effects increase the effectiveness of the product, as subjects are more likely to use these products as prescribed. In addition, subjects who are administered, for example, anti-acne, anti-rosacea and / or anti-seborrheic treatments are more likely to continue to wear the product for longer if the subject is not in pain or discomfort, and thus benefit from the full effect embodied in the product. Furthermore, the disclosed products allow subjects or practitioners to increase the amount of active ingredients, as side effects such as irritation and redness are eliminated or reduced, and the effectiveness of the active ingredients is not harmed or impaired by the addition of strontium and MSM.

[0073] Typical modes of application of the disclosed cosmetic and / or treatment products include applying or depositing a physical applicator such as a finger, brush, stick, cotton swab, tissue or cloth, or a prepared applicator already containing the formulation, such as a cloth mask.

[0074] [Treatment method] In another aspect, the present disclosure relates to a method for treating, preventing, ameliorating, alleviating, and / or alleviating a skin disease, disorder, or condition that may benefit from topical co-administration of benzoyl peroxide (BPO) and azelaic acid, the method comprising administering an effective amount of a contemplated composition and / or a contemplated formulation as disclosed herein.

[0075] In some embodiments, skin diseases, disorders, or conditions that may benefit from topical co-administration of BPO and azelaic acid include, but are not limited to, acne, rosacea, seborrhea, and / or demodicosis.

[0076] In a further aspect, the present disclosure relates to a method for treating, preventing, ameliorating, alleviating, mitigating and / or reducing one or more of neurogenic inflammation, stinging, itching, burning, redness, irritation, and / or other sensations and feelings associated with topical administration or application of benzoyl peroxide (BPO) and azelaic acid, the method comprising administering an effective amount of a composition as defined and contemplated herein and / or a formulation as contemplated. In some embodiments, BPO and azelaic acid are applied / administered simultaneously (co-application or co-administration).

[0077] In several embodiments, BPO and / or azelaic acid are co-applied with strontium salts and MSM to treat, prevent, and / or reduce neurogenic inflammation.

[0078] In several embodiments, topical or co-administration of BPO and azelaic acid (along with MSM and strontium salts) is for the treatment of, for example, but not limited to, acne, rosacea, seborrhea, and / or demodicosis.

[0079] Acne is a common skin condition characterized by pimples on the face, chest, and back. It occurs when pores become clogged with oil, dead skin cells, and bacteria.

[0080] Acne vulgaris is the medical term for common acne, which is the most common skin disorder. Acne can occur at any age, but it usually begins during puberty and worsens during adolescence. Nearly 85% of people develop acne between the ages of 12 and 25. Up to 20% of women develop mild acne.

[0081] Sebaceous glands (also called sebaceous follicles) are found just below the skin's surface. They secrete an oil called sebum, which is the skin's natural moisturizer. These follicles open into the skin through pores. During puberty, androgen (male hormone) levels rise, causing the sebaceous glands to overproduce sebum. When the excess sebum combines with old, sticky skin cells, hard plugs (comedones) form, blocking the pores. There are two types of mild, non-inflammatory acne: whiteheads and blackheads.

[0082] Moderate and severe inflammatory types of acne develop after a clogged hair follicle is invaded by Propionibacterium acnes, a bacterium that normally lives on the skin. Acne forms when a damaged hair follicle weakens and bursts, releasing sebum, bacteria, skin cells, and white blood cells into the surrounding tissue. Inflamed acne near the surface of the skin is called a papule, and deeper, a pustule. The most severe types of acne consist of cysts (closed pouches) and nodules (hard swellings). Scarring occurs when new skin cells are produced to replace the damaged ones.

[0083] Modern topical medications come in a variety of strengths, including creams, gels, lotions, or pads. Examples include antibiotics, such as erythromycin, clindamycin, and meclocycline (Mecran); comedolytics (agents that loosen hard plugs and open pores), such as vitamin A acid (a derivative of vitamin A, also known as retinoic acid, tretinoin, and retin A), salicylic acid, adapalene (Differin), resorcinol, and sulfur. Medications that act as both comedolytics and antibiotics, such as benzoyl peroxide, azelaic acid (Azelex), or benzoyl peroxide and erythromycin (Benzamycin), are also used. These medications are used for months (at least 2 months) to years to control the disease.

[0084] Based on its oxidizing action, BPO exhibits sufficient preservative activity against Propionibacterium acnes, as well as antibiotic-resistant mutants of Propionibacterium acnes and Staphylococcus epidermidis that arise during the long-term use of antibacterial agents.

[0085] Rosacea is a skin disorder that typically develops in people in their 30s and 40s. It is characterized by facial redness (erythema), flushing of the skin, and the presence of hard pimples (papules) or pus-filled pimples (pustules), and small, visible spider-like veins called telangiectasias, primarily on the face, including the nose, cheeks, forehead, and chin, but occasionally on the back, neck, scalp, arms, and legs. In later stages, the face may swell and the nose may develop a bulbous shape called nasal polyps.

[0086] Similar to acne, the skin develops pimples and papules. However, unlike acne, rosacea sufferers do not develop dark spots. In the early stages of rosacea, patients typically experience recurring flushes of the face. Later, parts of the face become persistently red, telangiectasias appear on the nose and cheeks, and inflammatory papules and pustules appear. Over time, the skin becomes rough and has an orange peel texture.

[0087] In addition to or instead of oral antibiotics, topical medications applied directly to the face can be tried to treat rosacea. Topical antibiotics are useful in controlling the papules and pustules of rosacea, but do not control the redness, flushing, and telangiectasias. Topical vitamin derivatives used to treat acne are also useful in treating rosacea. Accumulating evidence suggests that topical isotretinoin and azelaic acid reduce redness and breakouts. Some patients who use these medications experience skin irritation. In the later stages of the disease, surgery may be needed to improve the appearance of the skin. Dermatologists may use an electric scalpel to destroy the blood vessels to remove the telangiectasias.

[0088] Seborrhea is a disease of the sebaceous glands characterized by excessive or altered quality of sebum, resulting in an oily coating, crusts, or greasy scales or cheese-like plugs on the skin, commonly accompanied by an itchy and / or burning sensation.

[0089] Any of the methods disclosed herein are useful in therapeutic and / or cosmetic treatment of the skin, supporting skin soothing, providing skin calm during treatment and overall skin calming, and / or providing cosmetic benefits to the skin such as improving the appearance of the skin.

[0090] The combination of strontium and MSM with both BPO and azelaic acid in accordance with embodiments disclosed herein significantly extends the duration of the anti-irritation effect associated with topical administration of BPO and / or azelaic acid compared to the absence of strontium and / or MSM. The anti-irritation effect is immediate and real-time, with no waiting period between application of the contemplated compositions and / or formulations and the onset of effect.

[0091] Various embodiments and aspects of the present invention as delineated herein and claimed below find experimental support in the following examples.

[0092] [Example] Reference is now made to the following examples, which together with the above description, non-limitingly illustrate some embodiments of the present disclosure. In general, the nomenclature used herein and the experimental procedures utilized in this disclosure include molecular biological, chemical, biochemical and / or microbiological techniques. Such techniques are thoroughly described in the literature. Other general references are provided throughout this specification. The procedures therein are believed to be well known in the art and are provided for the convenience of the reader.

[0093] Example 1 Acne treatment preparations A formulation for treating acne consisting of BPO, azelaic acid, strontium salts, and MSM was prepared using the ingredients shown in Table 1:

[0094] [Table 1]

[0095] Benzoyl peroxide is provided in the form of a stable nanosuspension (nanoemulsion) such as the commercially available Curoxyl™ BP42 USP, an aqueous-based micronized benzoyl peroxide dispersion (40%) conforming to the U.S. Food and Drug Administration (FDA) monograph for benzoyl peroxide gel. BPO was added at the end of the formulation process at a temperature of 35°C.

[0096] Azelaic acid was provided as micronized particles, at least half of which was dissolved in propylene glycol and propanediol with heating, and half was added at the end of the formulation process, thus preventing the formation of agglomerates that would result in a grainy cream.

[0097] Contemplated compositions formulated as anti-acne formulations may further include one or more of the following excipients: sequestering agents, antioxidants such as alpha-arbutin, fullerenes, vitamin C, Q10, vitamin E, etc.; preservatives; electrolytes; colorants; humectants; penetration enhancers such as propylene glycol, dimethyl isosorbite, etc.; moisturizing agents such as hyaluronic acid; essential oils providing fragrance (fragrance) such as Citrus Medica Limonum peel oil, and limonene; active cosmetic agents such as vitamins (vitamin C, vitamin A (retinol), and / or salicylic acid); fatty acids such as myristic acid, stearic acid, oleic acid, and / or palmitic acid; sphingolipids; silica; soothing and / or protective agents.

[0098] The disclosed anti-acne formulations are carefully designed to combine the essential ingredients that provide the desired anti-acne benefits, and are characterized by concentrations and relative amounts that provide a stable, highly effective product, formulated as a cream or spread.

[0099] Due to the keratolytic and antibacterial properties of BPO and azelaic acid, the formulations described herein are particularly useful in treating various forms of acne, including, but not limited to, acne vulgaris, acne conglobata, cystic acne, comedones, severe nodular acne, papular acne, secondary acne such as actinic acne, and drug-induced acne.

[0100] The disclosed formulations are further effective in treating sebum dysfunction, such as hyperseborrheic acne or simple seborrheic dermatitis, and / or seborrheic dermatitis.

[0101] Example 2 Efficacy of MSM and Strontium in Combination with PBO and Azelaic Acid in Treating Rosacea, Acne, and Seborrhea

[0102] Twenty subjects suffering from rosacea, acne, or seborrhea were administered either the formulation disclosed in Example 1 containing BPO, azelaic acid, strontium salts, and MSM (12 subjects), a similar formulation without MSM and strontium as a control (4 subjects), or a placebo (4 subjects).

[0103] All patients in the test group experienced immediate improvement in their skin condition without any adverse side effects, whereas approximately 90% of the control group experienced severe redness and irritation that prevented them from further use of the preparation.

[0104] These results clearly demonstrate that topical combination of BPO and azelaic acid is practically effective for treating the above-mentioned skin conditions only in combination with MSM and strontium salts.

[0105] Additionally, the combination of MSM and strontium salts with either BPO or azelaic acid resulted in a more rapid onset of therapeutic effect and fewer side effects compared to the use of MSM and strontium-free BPO or azelaic acid alone.

Claims

1. A composition comprising benzoyl peroxide, azelaic acid, a strontium salt, methylsulfonylmethane (MSM) and a dermatologically acceptable carrier, formulated into one or more dosage forms, at least one dosage form containing both benzoyl peroxide and azelaic acid. the concentration of the strontium salt ranges from 0.1 to 10% by weight and the concentration of the MSM ranges from 0.1 to 20% by weight; A composition having a concentration of benzoyl peroxide in the range of 0.1 to 30% by weight and a concentration of azelaic acid in the range of 0.1 to 40% by weight.

2. 2. The composition of claim 1, wherein the concentration of benzoyl peroxide is at least one of the following ranges: 2.5-10% by weight, 5-10% by weight, 8-15% by weight, 5% by weight, or 10% by weight.

3. 2. The composition of claim 1, wherein the concentration of azelaic acid is at least one of the following ranges: 0.5-25% by weight, 5-30% by weight, 10-25% by weight, 15-35% by weight, 15% by weight, or 25% by weight.

4. The composition of claim 3 , wherein the benzoyl peroxide and / or azelaic acid are present as homogeneously dispersed fine particles.

5. 2. The composition of claim 1, wherein the strontium salt is selected from the group consisting of strontium chloride, strontium acetate, strontium nitrate and strontium chloride hexahydrate.

6. The composition of claim 1 further comprising at least one additional active ingredient.

7. 7. The composition of claim 6, wherein the at least one additional active ingredient is selected from the group consisting of alpha hydroxy acids (AHAs), beta hydroxy acids (BHAs), retinoids, alpha keto acids, dicarboxylic acids, arbutin, resorcinol, hydroquinone, kojic acid, myristic acid, sodium laureth sulfate, disodium laureth sulfosuccinate, sulfur, vitamin C, vitamin C derivatives, cannabinoids, azelaic acid derivatives, salts, and / or prodrugs of azelaic acid, diaryl peroxides, alkylaryl peroxides, and cycloalkylaryl peroxides.

8. A cosmetic or pharmaceutical product comprising a composition according to any one of claims 1 to 7.

9. 9. The cosmetic or pharmaceutical product of claim 8, comprising one or more ingredients selected from antioxidants, preservatives, electrolytes, colorants, moisturizers, penetration enhancers, moisturizing essential oils, active cosmetic agents, vitamins, essential fatty acids, fragrances, or soothing and protective agents.

10. 10. A cosmetic or pharmaceutical product according to claim 9, containing propylene glycol as a penetration enhancer.

11. 9. The cosmetic or pharmaceutical product of claim 8, formulated as at least one of an ointment, cream, spread, lotion, oil, solution, emulsion, nanoemulsion, gel, paste, milk, aerosol, powder, or foam.

12. The cosmetic or pharmaceutical product according to claim 8, which is physically and / or chemically stable under conditions of 4 to 40° C. for at least 3 months.

13. A cosmetic method for treating, preventing, improving, or alleviating a skin disease, disorder, or condition, comprising the step of administering to the skin of a subject an effective amount of a composition described in any one of claims 1 to 7, or a cosmetic or pharmaceutical product comprising the same, in which topical simultaneous administration of benzoyl peroxide (BPO) and azelaic acid may be beneficial.

14. The cosmetic method according to claim 13, wherein the skin disease, disorder or condition is at least one of acne, rosacea or seborrhea.