Composition for treating atopic dermatitis

Abstract

The invention relates to the use of a composition in a method for treating atopic dermatitis, or a method for treating atopic dermatitis wherein the composition is topically applied to the skin at least twice a day wherein the composition has a pH value in the range of 2.7 to 5.0, and comprises a zinc salt of a polyhydroxy acid and a conjugated base thereof, and a method for treating atopic dermatitis wherein the composition is applied topically to the skin at least twice a day wherein the composition has a pH value in the range of 2.7 to 5.0. Wherein the polyhydroxy acid is selected from lactobionic acid, glucolactone, or a combination of lactobionic acid and glucolactone; a partition coefficient enhancer selected from the group consisting of propylene glycol, butanediol, pentanediol, hexanediol, 1, 5-pentanediol, or a combination thereof; and a diffusion coefficient enhancer selected from the group consisting of C12 to C14 linear fatty acids or C14 linear primary alcohols. The treatment method is particularly suitable for the treatment of moderate atopic dermatitis and / or the topical treatment of the skin for 10 to at most 28 days.

Description

Background Art

[0001] Atopic dermatitis, also known as eczema, is the most common inflammatory skin disease in the world. The condition is characterized by one or more of dry, cracked or swollen skin, itching, redness, and blisters. Atopic dermatitis usually begins in infancy and affects up to 20% of children, but children of other ages can also be affected.

[0002] However, most current treatments for atopic dermatitis, particularly moderate and severe atopic dermatitis, rely on the application of steroid creams. However, these treatments usually require the advice of a doctor or medical practitioner and are not recommended for very young children in some cases. The use of steroid creams is often accompanied by side effects such as burning or stinging, and long-term use can lead to stretch marks or thinning of the skin, which is undesirable because the skin barrier of patients with atopic dermatitis is already damaged. Other common topical compositions for atopic dermatitis include ointments. These creams are anti-inflammatory and immunomodulatory agents, for example containing calcineurin inhibitors, or anti-allergic agents such as antihistamines. However, ointments can also cause skin irritation, leading to thinning of the skin, vasodilation, increased skin fragility and increased risk of infection. Long-term use is generally not recommended.

[0003] Some moisturizing creams or body lotions are recommended for the treatment and prevention of mild atopic dermatitis to reduce the likelihood of rashes on skin prone to eczema. However, some of these treatments have been shown to be minimally effective, requiring frequent applications and / or requiring or recommending extended treatment of at least 4 weeks to see any meaningful improvement. For the treatment of moderate or severe atopic dermatitis, moisturizing creams or body lotions can only be used as part of a combination therapy with different medications, such as steroids (see Hebert et al, American Journal of Clinical Dermatology, (2020), 21: 641-655). Summary of the invention

[0004] According to a first aspect of the present invention, there is provided a composition for use in a method of treating moderate atopic dermatitis (and / or atopic dermatitis with a local SCORAD score of at least 6 points), wherein the composition is topically applied to the skin of a subject at least twice a day, wherein the pH value of the composition is in the range of 2.7 to 5.0, and comprises

[0005] A zinc salt of a polyhydroxy acid and its conjugate base, wherein the polyhydroxy acid is selected from lactobionic acid, gluconolactone, or a combination of lactobionic acid and gluconolactone,

[0006] a partition coefficient enhancer selected from propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, 1,5-pentanediol or a combination thereof, and

[0007] A diffusion coefficient enhancer selected from C12 to C14 straight chain fatty acids or C14 straight chain primary alcohols.

[0008] According to a second aspect of the present invention, there is provided a method for treating moderate atopic dermatitis (and / or atopic dermatitis with a local SCORAD score of at least 6), wherein the method comprises topically applying a composition to the skin of a subject at least twice a day for 10 days to a maximum of 28 days, wherein the pH value of the composition is in the range of 2.7 to 5.0, and comprises

[0009] A zinc salt of a polyhydroxy acid and its conjugate base, wherein the polyhydroxy acid is selected from lactobionic acid, gluconolactone, or a combination of lactobionic acid and gluconolactone,

[0010] a partition coefficient enhancer selected from propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, 1,5-pentanediol or a combination thereof,

[0011] A diffusion coefficient enhancer selected from C12 to C14 straight chain fatty acids or C14 straight chain primary alcohols.

[0012] According to the first or second aspect, in some embodiments, the treatment method can last from about 5 to up to 28 days, or 10 to up to 28 days, or about 10 to 25 days, or 10 to 20 days, or 11 to 18 days, or 12 to 16 days. In some embodiments, the treatment method can last less than 28 days, or less than 25 days, or less than 22 days, or less than 20 days, or less than 18 days, or less than 16 days, or about 14 days.

[0013] According to a third aspect of the present invention, there is provided a use of a composition in a method for treating atopic dermatitis, wherein the composition is topically applied to the skin of a subject at least twice a day for 10 days to a maximum of 28 days, wherein the pH value of the composition is in the range of 2.7 to 5.0, and comprises

[0014] A zinc salt of a polyhydroxy acid and its conjugate base, wherein the polyhydroxy acid is selected from lactobionic acid, gluconolactone, or a combination of lactobionic acid and gluconolactone,

[0015] a partition coefficient enhancer selected from propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, 1,5-pentanediol or a combination thereof,

[0016] A diffusion coefficient enhancer selected from C12 to C14 straight chain fatty acids or C14 straight chain primary alcohols.

[0017] According to a fourth aspect of the present invention, there is provided a method for treating atopic dermatitis, wherein the method comprises topically applying a composition to the skin at least twice a day for 10 days to a maximum of 28 days, wherein the pH value of the composition is in the range of 2.7 to 5.0, and comprises

[0018] A zinc salt of a polyhydroxy acid and its conjugate base, wherein the polyhydroxy acid is selected from lactobionic acid, gluconolactone, or a combination of lactobionic acid and gluconolactone,

[0019] a partition coefficient enhancer selected from propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, 1,5-pentanediol or a combination thereof,

[0020] A diffusion coefficient enhancer selected from C12 to C14 straight chain fatty acids or C14 straight chain primary alcohols.

[0021] According to the third or fourth aspect, in some embodiments, the atopic dermatitis may be mild, mild-moderate, moderate, moderate-severe or severe atopic dermatitis. In some embodiments, the atopic dermatitis is moderate atopic dermatitis. According to the third or fourth aspect, in some embodiments, the treatment method may last for about 10 to 25 days, or 10 to 20 days, or 11 to 18 days, or 12 to 16 days. In some embodiments, the treatment method may last for less than 28 days, or less than 25 days, or less than 22 days, or less than 20 days, or less than 18 days, or less than 16 days, or about 14 days. The atopic dermatitis may be characterized by a local SCORAD score of at least 6 points, or between 6 and 12 points. The atopic dermatitis may be moderate, moderate-severe or severe atopic dermatitis.

[0022] Also disclosed herein is a use of a composition in a method of treating atopic dermatitis, or a method of treating atopic dermatitis, wherein the atopic dermatitis is characterized by a local SCORAD score of at least 6 at the start of treatment, wherein the composition is topically applied to the skin of a subject at least twice a day, wherein the pH value of the composition is in the range of 2.7 to 5.0, and comprises

[0023] A zinc salt of a polyhydroxy acid and its conjugate base, wherein the polyhydroxy acid is selected from lactobionic acid, gluconolactone, or a combination of lactobionic acid and gluconolactone,

[0024] a partition coefficient enhancer selected from propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, 1,5-pentanediol or a combination thereof, and

[0025] A diffusion coefficient enhancer selected from C12 to C14 straight chain fatty acids or C14 straight chain primary alcohols.

[0026] Also disclosed herein is a use of a composition for preparing a medicament for treating atopic dermatitis (e.g., moderate atopic dermatitis, or atopic dermatitis characterized by a local SCORAD score of at least 6, e.g., 6 to 12), wherein the composition is topically applied to the skin of a subject at least twice a day, wherein the pH value of the composition is in the range of 2.7 to 5.0, and comprises

[0027] Zinc salts of polyhydroxy acids and their conjugate bases, wherein the polyhydroxy acid is selected from lactobionic acid, gluconolactone or a combination of lactobionic acid and gluconolactone,

[0028] a partition coefficient enhancer selected from propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, 1,5-pentanediol or a combination thereof, and

[0029] A diffusion coefficient enhancer selected from C12 to C14 straight chain fatty acids or C14 straight chain primary alcohols.

[0030] Also disclosed herein is a composition comprising

[0031] 4-6% w / w of a zinc salt of a polyhydroxy acid and its conjugate base, wherein the polyhydroxy acid is lactobionic acid;

[0032] 15-20% w / w of a partition coefficient enhancer, i.e., butanediol;

[0033] 1-2% w / w of a diffusion coefficient enhancer, preferably tetradecanol, and

[0034] 10-20% w / w of an emollient, preferably hydrogenated polydecene;

[0035] 4.5-12% w / w of a surfactant, wherein the surfactant preferably comprises one or more of methyl glucose sesquistearate, PEG-20 methyl glucose sesquistearate, glyceryl stearate or a combination thereof,

[0036] 40-60% w / w water, and

[0037] Up to 3% w / w of a humectant, preferably glycerol, and

[0038] a co-surfactant, preferably in an amount of up to 6% w / w of the composition;

[0039] Ceramide, in an amount of up to 0.5% to 1.5% w / w of the composition;

[0040] Cholesterol, preferably in an amount of up to 0.5% w / w of the composition;

[0041] Fatty acids, preferably in an amount of up to 0.5% w / w of the composition;

[0042] PEG / HDI copolymer, preferably PEG-240 / HDI copolymer didecyltetradeceth-20 ether, preferably used in an amount of 1% w / w of the composition;

[0043] Acrylates / C10-C30 alkyl acrylate copolymer, preferably present in an amount of up to 0.5% w / w of the composition, and

[0044] optional preservatives, preferably in an amount up to 1% w / w of the composition;

[0045] The pH value of the composition is between 3.0 and 3.5.

[0046] Beneficial Effects of the Invention

[0047] The present invention provides a composition for use in an improved method of treatment, which provides statistically significant improvement for patients with atopic dermatitis, particularly moderate atopic dermatitis and / or atopic dermatitis with a local SCORAD score of at least 6 points. The composition can be used for patients with moderate atopic dermatitis, and the symptoms are significantly improved in a very short period of time, which shows that the cream shows better effects compared with other moisturizing creams on the market. As shown in the submitted examples of the present application (see Example 1), the topical use of the composition in clinical trials reduced the local SCORAD score from an average of 8 points (indicating moderate eczema) to an average of 4 points (indicating mild eczema) in just 2 weeks. As far as the inventors know, this is the first time that a topical composition has been able to provide such a good effect without steroids, especially in such a short period of time. Without the use of steroids, other moisturizing creams usually require at least 4 weeks of treatment to see meaningful improvements.

[0048] The use of the composition or the method of treatment described herein results in a more significant reduction in one or more of dryness, erythema / redness, edema and papules, exudation and crusting, and lichen sclerosis after 2 weeks of treatment compared to the start / baseline of treatment. In most patients, the use of the composition or the method of treatment results in a significant reduction in multiple symptoms after 2 weeks of treatment compared to the start / baseline of treatment.

[0049] Although similar compositions have been reported before, there is no indication that the compositions can be used to treat moderate atopic dermatitis patients before, let alone in such a short time. There is no indication that similar compositions can be used to successfully treat moderate atopic dermatitis, particularly in such a short time, the effect is significantly improved, particularly in the absence of other pharmaceutically active substances, such as hydrocortisone. The statistically significant improvement of the local SCORAD score of the patient suffering from moderate atopic dermatitis is not expected, particularly in the absence of other pharmaceutically active substances, such as steroids or hydrocortisone / hydrocorticosteroid treatment. Therefore, the present invention provides the use of the compositions to a new patient group (i.e., a patient suffering from moderate atopic dermatitis, or a SCORAD score of at least 6 points, preferably a patient of 6 to 12 points), which was not expected or expected before. In certain embodiments or aspects, the present invention also provides a new dosage regimen, wherein the compositions are applied in a specific time period, i.e. up to 4 weeks, and preferably within a shorter time range, such as about 2 weeks. In certain embodiments or aspects, the uses of the compositions and methods of treatment disclosed herein can provide a milder and less irritating treatment compared to other treatment methods used in the prior art, such as treatment methods involving other pharmaceutically active substances or steroid treatments.

[0050] The composition can significantly reduce the pH value of the skin and improve the skin barrier.

[0051] The composition also has improved results in use compared to previously disclosed compositions. The advantages of the composition for treating atopic dermatitis can be attributed to the specific combination of ingredients. In addition, unlike previously disclosed compositions, the use of butylene glycol is less restrictive for young infants and is found to be less irritating than other partition coefficient enhancers (e.g., propylene glycol). The use of the improved formula shows improved stability and texture of the composition. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Figure 1 The distribution of treatment sites used on the arms in the study detailed in Example 1 is shown, although these sites could equally be applied to the legs. A = untreated lesional skin, B = treated lesional skin.

[0053] Figure 2 Shown are regional SCORAD bar graphs containing the means and 95% confidence intervals for total scores (n=29) between baseline (Day 1) and D15 (Day 15) when applied to A=untreated lesional skin or B-treated lesional skin.

[0054] Figure 3Shown are bar graphs containing the means and 95% confidence intervals for the differences in local SCORAD between baseline (Day 1) and D15 (Day 15) when applied to A = untreated lesional skin or B - treated lesional skin.

[0055] Figure 4 Shown is a bar graph containing the mean of the difference in skin pH between baseline (Day 1) and D15 (Day 15) when applied to A = untreated lesional skin or B - treated lesional skin.

[0056] Figure 5 Shown is a bar graph containing the mean of the difference in skin hydration between Baseline (Day 1) and D15 (Day 15) when applied to A = untreated lesional skin or B - treated lesional skin.

[0057] Figure 6 Photographs of an infant patient with atopic dermatitis are shown before treatment and after 5 days of treatment with an exemplary composition according to the present disclosure. DETAILED DESCRIPTION

[0058] The SCORAD (scoring of atopic dermatitis) referred to herein is a well-known clinical tool for assessing the extent and severity of eczema. The extent is measured by the percentage of the body affected. Severity is determined by the intensity of each of the following signs, assessed as absent (0), mild (1), moderate (2), or severe (3): dryness; erythema (i.e., also known as redness); edema and papules (i.e., swelling); exudation and crusting (i.e., also known as oozing and crusting); scaling (e.g., scratching of the skin, determined by scratching); and lichenification (i.e., also known as thickening of the skin). Subjective symptoms of itching and sleep deprivation may also be included. (See https: / / dermnetnz.org / topics / scorad; Journal of Cutaneous Medicine and Surgery 2018, Vol. 22 (1S) 10S–16S “Approach to the Assessment and Management of Adult Patients with Atopic Dermatitis: A consensus Document. Section II: Tools for Assessing the Severity of Atopic Dermatitis” and Dermatology. 1993; 186 (1): 23-31. doi: 10.1159 / 000247298), all of which are incorporated herein by reference in their entirety. Local SCORAD refers to the SCORAD assessment of the intensity of a sign applied to a local site or test area on the skin. The intensity scores are then added together to give a score between 0 = minimum and 18 = maximum. This may also be referred to as the SCORAD intensity score for a specific or local area.

[0059] Atopic dermatitis, as referred to in this article, is a skin condition that causes itchy, cracked, and painful patches of skin. Atopic dermatitis may also be called atopic eczema.

[0060] Severe atopic dermatitis is defined as atopic dermatitis characterized by widespread dryness, persistent itching, redness (with or without bruising, widespread skin thickening, bleeding, oozing, cracking, and pigmentation changes); severe limitation in daily activities and psychosocial functioning, and insufficient nighttime sleep, as determined by the United Kingdom's National Institute of Health and Care Excellence. Severe atopic dermatitis may be characterized by a local SCORAD score greater than 12.

[0061] Moderate atopic dermatitis as referred to herein is atopic dermatitis characterized by dry skin, frequent itching, redness (with or without abrasions and localized skin thickening); moderate impact on daily activities and psychosocial well-being, with frequent disruption of sleep, as determined, for example, by the UK National Institute for Health and Care Excellence. Moderate atopic dermatitis may be characterized by atopic dermatitis with a localized SCORAD score of 6 to 12.

[0062] Mild atopic dermatitis as referred to in this article may be atopic dermatitis characterized by dry skin with minimal impact on daily activities, sleep, and psychosocial well-being, as determined by the National Institute for Health and Care Excellence in the United Kingdom. Mild atopic dermatitis may also be referred to as eczema with a localized SCORAD score of less than 6 points.

[0063] The compositions used in the present invention are formulated for topical administration to the skin.Topical administration refers to a method of administration in which the composition is applied directly to a specific part of the body surface (eg, the skin, more specifically, the affected skin in this context).

[0064] As used herein, "pre-treatment" is considered to be a measurement prior to the start of treatment, eg, prior to the first administration of the composition on Day 1.

[0065] The terms "treat" and "treatment" herein refer to an approach for obtaining beneficial or desired results in a subject, including prophylactic benefits and optionally also therapeutic benefits. In some embodiments, "treat" refers to therapeutic benefit.

[0066] A "preventive benefit" means delaying or eliminating the appearance of the disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping or reversing the progression of a disease or condition, or any combination thereof.

[0067] "Therapeutic benefit" refers to eradication or amelioration of the underlying disease being treated. In addition, therapeutic benefit is achieved by eradication or amelioration of one or more physiological symptoms associated with the underlying disease, such that an improvement is observed in the subject, notwithstanding that the patient may still be afflicted with the underlying disease.

[0068] When ranges are used herein, all combinations and subcombinations of ranges and specific embodiments thereof are intended to be included. When referring to a number or a numerical range, the term "about" means that the number or numerical range referred to is an approximation within the experimental variability (or statistical experimental error), and therefore the number or numerical range may vary. For example, typical experimental variability may arise from changes and adjustments required during the expansion from laboratory experiments to large-scale production environments.

[0069] Features of any dependent claims may readily be combined with features of any independent claim or other dependent claims.

[0070] It must be noted that as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0071] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. Unless otherwise specified, the abbreviations used herein have their conventional meanings in the chemical and biological fields.

[0072] The term "subject" refers to any suitable subject, including any animal, such as a mammal. In one embodiment, the subject is a human. In this article, the subject may also be referred to as a patient. In some embodiments, the subject is an adult subject (i.e., 18 years of age or older). In some embodiments, the subject is a pediatric subject (e.g., a subject less than 18 years of age, or a subject less than 15 years of age, or a subject less than 12 years of age, or a subject less than 10 years of age, or a subject less than 5 years of age).

[0073] The term "comprising" (and related terms such as "including" or "containing" or "having" or "having") includes those embodiments, for example, embodiments of any composition of matter, composition, method or process, etc., that "consists of" or "consists essentially of the described features." The terms "containing" or "including" can be used interchangeably with "comprising."

[0074] Use of the composition in a method of treatment / treatment

[0075] In one or more of the above aspects, the compositions disclosed herein are used to treat atopic dermatitis. The atopic dermatitis can be mild, mild to moderate, moderate, moderate to severe or severe atopic dermatitis. In a preferred embodiment, the atopic dermatitis is moderate atopic dermatitis, or a local SCORAD score of at least 6 points, or atopic dermatitis of 6 to 12 points at the beginning of treatment.

[0076] In one or more aspects described herein, the patient is preferably a human. In some embodiments, the human is an infant, a teenager or an adult.

[0077] In one or more of the above aspects, the composition is applied at least twice a day. In some embodiments, the composition is applied twice a day. In some embodiments, the composition is applied every 6 to 18 hours, or every 8 to 14 hours, or about every 12 hours. In some embodiments, the composition is applied twice a day, or at least 3 times a day, or at least 4 times a day, or at least 5 times a day, or at least 6 times a day, or at least 7 times a day, or at least 8 times a day, or at least 9 times a day, or at least 10 times a day. In a preferred embodiment, the composition is applied twice a day. This is more convenient for patients, so that they do not have to repeatedly apply the cream in a day.

[0078] In one or more of the above aspects, the method for treating dermatitis may not include treatment with a pharmaceutically active substance (i.e., different from treatment with a composition comprising a zinc salt of a polyhydroxy acid and its conjugate base as described herein). In a preferred embodiment, the method for treating atopic dermatitis is steroid-free or corticosteroid-free (e.g., the method for treating atopic dermatitis is steroid-free / cor ... In a preferred embodiment, the method for treating atopic dermatitis does not contain a biological agent. In a preferred embodiment, the method for treating does not contain an antipruritic (e.g., hydrocortisone, menthol, pramoxine hydrochloride, menthoxypropylene glycol, colloidal oatmeal). In a preferred embodiment, the method for treating does not contain lactic acid, PCA (pyrrolidone carboxylic acid) or urea. Even in the absence of other active pharmaceutical ingredients including steroids (e.g., hydrocortisone), the composition used for the present invention can also significantly alleviate the symptoms of atopic dermatitis, for example, even in a short period of time, the local SCORAD score can be significantly reduced. This can be achieved in the absence of other active pharmaceutical ingredients, which may be more irritating, have greater side effects and are more expensive than using the composition described herein. As described herein, a calcineurin inhibitor is any drug that inhibits the action of calcineurin. Calcineurin is an enzyme that activates immune system T cells. In some embodiments, the calcineurin inhibitor is pimecrolimus or tacrolimus.

[0079] In one or more aspects, the composition can be topically applied for any suitable length of time. In one or more aspects, the composition can be topically applied for up to 28 days (i.e., less than or equal to 4 weeks), or up to 25 days, or up to 22 days, or up to 20 days, or up to 19 days, or up to 18 days, or up to 17 days, or up to 16 days, or up to 15 days, or up to 14 days. In some embodiments, the composition can be topically applied for at least 5 days, or at least 8 days, or at least 10 days, or at least 11 days, or at least 12 days, or at least 13 days, or at least 14 days. In some embodiments, the composition can be topically applied for 5 days to 28 days, or 10 days to 28 days, or 12 days to 20 days, or 14 days to 18 days, or 12 days to 16 days, or about 14 days. For the patient, preferably significantly relieve symptoms with a shorter treatment period.

[0080] In one or more aspects above, the composition can be topically applied in an amount of 0.25 g to 5 g, or about 0.5 g to 3 g, or about 0.75 g to 2 g. The amount of the composition applied can depend on the size of the lesion. In some embodiments, the composition can be applied in an amount of 1 fingertip unit (FTU) to 7 FTU (wherein 1 FTU corresponds to 0.5 g), or about 2 FTU, or about 3 FTU, or about 4 FTU, or about 5 FTU, or about 6 FTU. Depending on the age / size of the subject and the skin area to be treated, the recommended dosage will vary (e.g., for adult subjects, the dosage may be 1 FTU for hands, 1 FTU for elbows, 1 FTU for knees, 1 FTU for feet, 2.5 FTU for face and back of neck, 4 FTU for arms, 6 FTU for legs, 7 FTU for chest and abdomen, 7 FTU for back and buttocks; while for pediatric subjects, the dosage may be 1 to 2 FTU for face and back of neck, 1 to 2.5 FTU for arms and hands, 1.5 to 4.5 FTU for legs and feet, 1 FTU and 3.5 FTU for chest and abdomen, 1.5 to 5 FTU for back and buttocks). In some embodiments, the composition administered is less than 500 grams per week, or less than 400 grams per week, or less than 300 grams per week.

[0081] In one or more of the above aspects, the composition can be topically applied to one or more of the face, neck, legs, feet, chest / abdomen, back, buttocks, hands, elbows, knees, genitals, and feet.

[0082] In one or more of the above aspects, at the start of treatment, the local SCORAD score of the atopic dermatitis is at least 6, or at least 7, or at least 8, or at least 9, or at least 10, or at least 11, or at least 12. In some embodiments, the local SCORAD score of the atopic dermatitis is less than 12. In some embodiments, the local SCORAD score of the atopic dermatitis is less than 11, or less than 10, or less than 9, or less than or equal to 8. In some embodiments, the local SCORAD score of the atopic dermatitis is at least 6, or preferably 6 to 12, or 6 to 11, or 6 to 10, or 6 to 9, or 6 to 8. In one or more of the above aspects, at the start of treatment, the local SCORAD score of the atopic dermatitis is greater than or equal to 6, or 7, or 8, or 9, or 10, or 11, or 12.

[0083] In one or more of the above aspects, the treatment method involves identifying a patient with moderate atopic dermatitis, for example, by a local SCORAD score, and determining that the local SCORAD score is at least 6 points, for example, 6 to 12 points. In some embodiments, the identification is performed by a doctor or dermatologist. In some embodiments, after identifying a patient with moderate atopic dermatitis, the treatment method involves prescribing a composition disclosed herein for use. In some embodiments, the method further includes measuring the local SCORAD score after a period of time and determining whether further treatment is needed. In some embodiments, the measurement is performed by a doctor or dermatologist. In some embodiments, the time period is less than 4 weeks, or less than or equal to 3 weeks, or less than or equal to 2 weeks, for example, 2 weeks.

[0084] In one or more of the above aspects, the method of treatment involves identifying atopic dermatitis patients with a local SCORAD score of less than 12 points, or less than 11 points, or less than 10 points, or less than 9 points, or less than or equal to 8 points. In some embodiments, the identification is performed by a doctor or dermatologist. In some embodiments, after identifying the patient, the method of treatment involves prescribing a composition disclosed herein for use. In some embodiments, the method further includes measuring the local SCORAD score after a period of time and determining whether further treatment is needed. In some embodiments, the measurement is performed by a doctor or dermatologist. In some embodiments, the time period is less than 4 weeks, or less than or equal to 3 weeks, or less than or equal to 2 weeks, for example, 2 weeks.

[0085] In one or more of the above aspects, the method of treatment involves identifying a patient with atopic dermatitis with a local SCORAD score of at least 6, or 6 to 12, or 6 to 11, or 6 to 10, or 6 to 8. In some embodiments, the identification is performed by a doctor or dermatologist. In some embodiments, after identifying the patient, the method of treatment involves prescribing a composition disclosed herein for use. In some embodiments, the method further comprises measuring the local SCORAD score after a period of time and determining whether further treatment is needed. In some embodiments, the measurement is performed by a doctor or dermatologist. In some embodiments, the time period is less than 4 weeks, or less than or equal to 3 weeks, or less than or equal to 2 weeks, for example, 2 weeks.

[0086] In one or more of the above aspects, the treatment method may result in a reduction in the local SCORAD score (ΔSCORAD) of at least 1 point, or at least 2 points, or at least 3 points, or at least 4 points compared to the baseline local SCORAD at the start of treatment. In some embodiments, the local SCORAD score reduction is obtained in less than 4 weeks, or less than or equal to 3 weeks, or less than 18 days, or less than or equal to 2 weeks. In some embodiments, the local SCORAD score reduction is obtained in 5 to a maximum of 28 days, or 10 to a maximum of 28 days, or 10 to 25 days, or 10 to 21 days, or 12 to 18 days, or 12 to 16 days. In the examples disclosed herein, the treatment method across the average sample reduces the local SCORAD score by about 4 points after 14 days (± 2 days).

[0087] In one or more of the above aspects, the treatment method may result in a decrease in one or more of the scores for dryness, erythema, edema and papules, exudation and crusting, desquamation, and lichenification compared to before treatment. "Score" refers to each score evaluating dryness, erythema, edema and papules, exudation and crusting, desquamation, and lichenification as part of the local SCORAD assessment, where 0=none, 1=mild, 2=moderate, and 3=strong. In some embodiments, the treatment method may result in a decrease in two or more of dryness, erythema, edema and papules, exudation and crusting, desquamation, and lichenification compared to before treatment; the treatment method may result in a decrease in three or more of dryness, erythema, edema and papules, exudation and crusting, desquamation, and lichenification compared to before treatment, or four or more, or five or more of dryness, erythema, edema and papules, exudation and crusting, desquamation, and lichenification compared to before treatment.

[0088] In one or more of the above aspects, the treatment methods may result in a reduction in dryness scores compared to before treatment. In one or more of the above aspects, the treatment methods may result in a reduction in erythema scores compared to before treatment. In one or more of the above aspects, the treatment methods may result in a reduction in edema and papule scores compared to before treatment. In one or more of the above aspects, the treatment methods may result in a reduction in exudate and crust scores compared to before treatment. In one or more of the above aspects, the treatment methods may result in a reduction in desquamation scores compared to before treatment. In one or more of the above aspects, the treatment methods may result in a reduction in lichen sclerosis scores compared to before treatment.

[0089] In one or more of the above aspects, the treatment method may result in a decrease in skin pH compared to before treatment. In some embodiments, the treatment method results in a decrease in skin pH of at least 0.5, or at least 0.6, or at least 0.7, or at least 0.8, compared to before treatment. In one or more of the above aspects, the treatment method may result in a decrease in skin pH of 0.5 to 0.8, or between 0.55 and 0.75, or 0.6 to 0.7, compared to before treatment. The pH of the skin can be measured by a skin pH meter.

[0090] In one or more of the above aspects, the treatment method may increase skin hydration compared to before treatment. It can be measured by capacitance, for example, using a corneometer to measure skin hydration. In some embodiments, the treatment method increases skin hydration by at least 2 a.u. skin capacitance, or at least 3 a.u. skin capacitance, or at least 4 a.u. skin capacitance compared to before treatment. In some embodiments, the treatment method increases skin hydration by 2 to 6 a.u. skin capacitance compared to before treatment, or the treatment method increases skin hydration by 3 to 5.5 au skin capacitance compared to before treatment, or at least increases skin capacitance by 4 to 5 a.u.

[0091] Composition

[0092] Unless otherwise stated, amounts expressed herein as % w / w of a composition refer to the total composition.

[0093] The composition used in the present invention includes zinc salts of polyhydroxy acids and their conjugate bases. These can be referred to as active ingredients of the composition. In certain embodiments, the active ingredient can be in the water-glycol phase of the composition. In some embodiments, the polyhydroxy acid can be selected from lactobionic acid, gluconolactone / gluconic acid, or a combination of lactobionic acid and gluconolactone / gluconic acid, or a salt thereof. In a preferred embodiment, the polyhydroxy acid is lactobionic acid or a salt thereof. The salt can include one or more of zinc, calcium, potassium, sodium, magnesium or iron salts. The composition of the present invention includes zinc ions (Zn2+ ). Zinc ions can provide antimicrobial and antibacterial effects, which are beneficial in the treatment of atopic dermatitis.

[0094] In an embodiment, the polyhydroxy acid is lactobionic acid, the zinc salt of its conjugate base is zinc lactobionic acid, and the composition comprises a mixture of zinc lactobionic acid and lactobionic acid. In an embodiment, the composition comprises a mixture of zinc lactobionic acid and lactobionic acid in a ratio of about 1:2 to 1:6, or about 1:4. In an example, the zinc salt is derived from zinc oxide (i.e., zinc oxide is used as an ingredient to form the zinc salt). The zinc salt can be from any suitable zinc-containing compound. However, it is preferred that the composition used in the present invention does not contain or use zinc pyridone as an ingredient (i.e., an ingredient sometimes used in unrelated anti-dandruff shampoo formulations).

[0095] The amount of polyhydroxy acid used to prepare the composition may comprise 2.0-10.0% w / w of the composition. The amount of zinc oxide used to prepare the composition may be greater than 0.05% w / w, or at least about 0.1% w / w. The zinc oxide component may be used in an amount of 0.05-0.5% w / w, 0.05-0.2% w / w, preferably about 0.1% w / w.

[0096] In a preferred embodiment, the composition does not include any further active substances or drugs. In a preferred embodiment, the composition does not contain steroids (e.g., hydrocortisone). In a preferred embodiment, the composition does not contain calcineurin inhibitors. In a preferred embodiment, the composition does not contain colloidal oatmeal. In a preferred embodiment, the composition does not contain antibodies. In a preferred embodiment, the composition does not contain antihistamines.

[0097] The composition of the present invention may comprise 2.0–10.0% w / w (percent by weight) of the composition of the zinc salt of a polyhydroxy acid and its conjugate base, or 3.0–8.0% w / w or 4–6.0% w / w of the composition of the zinc salt of a polyhydroxy acid and its conjugate base. The composition of the present invention may comprise greater than or equal to 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0% w / w of the composition of the zinc salt of a polyhydroxy acid and its conjugate base. The composition of the present invention may comprise less than or equal to 9.5, 9.0, 8.5, 8.0, 7.5%, 7%, 6%, or 5.0% w / w of the composition of the zinc salt of a polyhydroxy acid and its conjugate base. The amount of polyhydroxy acid in the composition of the present invention may be about 2.0-10% w / w, 3.0-6.5, or 3.5-6.0, or 4.0-5.5, or about 5% w / w of the composition.

[0098] The composition of the present invention may also include water, and the composition may include 30-60% w / w water, or 35%-60% w / w water, or 40%-60% w / w water, or 40-50% w / w water, such as 44-46% w / w water. In some embodiments, the composition of the present invention includes greater than 40% w / w water, or greater than 41% w / w water, or greater than 42% w / w water, or greater than 43% w / w water, or greater than 44% w / w water. In some embodiments and examples, water is deionized water (e.g., no salt is dissolved in the water). In an embodiment, the salt is dissolved in the water of the composition of the present invention. The salt may include a Group 1 metal anion, such as sodium. The salt may include a halogen cation, such as chloride. The salt may be sodium chloride. The salt may be present in the water of the water-glycol phase at 0.1-3% or 0.5-2.0%).

[0099] The composition of the present invention includes a partition coefficient enhancer. The partition coefficient enhancer can be in the water-glycol phase of the composition. The partition coefficient enhancer can be selected from propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, 1,5-pentanediol or a combination thereof. In a preferred embodiment, the partition coefficient enhancer is butylene glycol. It was found that butylene glycol is less relevant to skin irritation. In an alternative example, the partition coefficient enhancer is propylene glycol. The content of the partition coefficient enhancer can be 15-30% w / w, 15-25% w / w. In some embodiments, the content of the partition coefficient enhancer can account for about 15-20% w / w, 16-18% w / w or about 17.5% w / w of the composition (e.g., butylene glycol).

[0100] The composition of the present invention can also include one or more emollients, which can be present in the oil phase of the composition. The content of one or more emollients can account for 10-30% w / w of the composition. In some embodiments, the emollient is a high molecular weight hydrocarbon, preferably selected from mineral oil, vaseline, paraffin and mixtures thereof. The emollient can be selected from hydrogenated polydecene, hydrogenated didecene, hydrogenated polyisobutene and mixtures thereof. In embodiments, the emollient is hydrogenated polydecene. The composition of the present invention can include 10-30% w / w, 10-25% w / w, 10-19% w / w, 12-16% w / w or about 15% w / w of emollient.

[0101] The composition of the present invention includes a diffusion coefficient enhancer selected from C12 to C14 straight chain fatty acids or C14 straight chain primary alcohols. The diffusion coefficient enhancer can be in the oil phase of the composition. The diffusion coefficient enhancer can be 1-tetradecanol or myristic acid. In an embodiment, the diffusion coefficient enhancer is 1-tetradecanol. 1-tetradecanol is also called myristyl alcohol. The content of the diffusion coefficient enhancer can be 1.0-2.0% w / w or 1.2-2.0% w / w, 1.2-1.8% w / w or about 1.5% w / w of the composition. In some embodiments, the content of the diffusion coefficient enhancer is greater than 1.2% w / w of the composition, or greater than 1.4% w / w, or greater than or equal to 1.5% w / w. The diffusion coefficient enhancer is generally saturated or close to saturation (i.e., at least 95% saturation).

[0102] The composition of the present invention has a low or acidic pH. The pH of the composition of the present invention is in the range of 2.7–5.0. More preferably, the pH of the composition is less than 5.0, or less than 4.5, or less than 4.0, or less than 3.5. The pH of the composition may be in the range of 3.0 to 4.5, or in the range of 3.0 to 4.0, or in the range of 3.0 to 3.5, or about 3.2. The composition of the present invention may contain an acid or a base to adjust the pH of the composition. An acid that can be used to adjust the pH of the composition is citric acid. An alkali that can be used is sodium hydroxide. In some embodiments, the composition comprises a 10% sodium hydroxide solution. In some embodiments, the composition comprises about 0.2% w / w of a 10% sodium hydroxide solution. Unlike previous compositions, a pH between 3.0-3.5 (e.g., about 3.2) gives the composition a more sustained skin pH / lowering ability within 12 hours compared to compositions having a higher pH (e.g., pH 4.0). The pH described herein refers to the pH of the entire composition. pH can be measured using standard methods, for example, using a pH meter.

[0103] The composition of the present invention may also include one or more surfactants and / or co-surfactants. The composition may include 3-15% w / w, 6-14% w / w, 8-13.5% w / w, or 9-13% w / w or about 11% w / w of one or more surfactants and / or co-surfactants. The surfactant stabilizes the viscosity or interface of the water-glycol phase and the oil phase. The composition may include a primary surfactant or a primary surfactant system.

[0104] The composition may comprise 2-10% w / w, 2.5-9% w / w, or about 3-8% w / w, or about 5-7% w / w, or about 6% w / w of the primary surfactant or primary surfactant system. The primary surfactant system may comprise methyl glucose sesquistearate (Glucamate SS) and PEG methyl glucose sesquistearate, such as PEG-20 methyl glucose sesquistearate (Glucamate SSE-20). In some embodiments, the composition may comprise methyl glucose sesquistearate and PEG methyl glucose sesquistearate (e.g., PEG-20 methyl glucose sesquistearate) in a ratio of 5:1 to 1:5, more preferably 5:1 to 1:1, or about 3:1.

[0105] In one embodiment, the composition may include 2.5-7% w / w methyl glucose sesquistearate, or about 3% to 6% w / w methyl glucose sesquistearate, or about 4.5% w / w methyl glucose sesquistearate. In some embodiments, the composition may include at least 1% w / w, or at least 2% w / w, or at least 3% w / w, or at least 4% w / w methyl glucose sesquistearate. In one embodiment, the composition may include 0.5-4% w / w PEG-20 methyl glucose sesquistearate, or 1% to 2% w / w PEG-20 methyl glucose sesquistearate. In some embodiments, the composition may include less than 2% w / w PEG-20 methyl glucose sesquistearate.

[0106] The composition may further comprise a co-surfactant, which may be otherwise referred to as a second surfactant. The co-surfactant may be a C16 to C22 alcohol, more preferably a C20 to C22 alcohol. In some embodiments, the C16 to C22 alcohol is behenyl alcohol. In some embodiments, the composition may comprise 2.0-5.5% w / w, 2.5-7.5% w / w, or about 4-6% w / w, or about 4.5-6% w / w, or about 5% w / w of the co-surfactant. In some embodiments, the co-surfactant is behenyl alcohol.

[0107] The composition may include one or more of ceramide, cholesterol, and fatty acids. In some embodiments, the composition may include ceramide. In some embodiments, the ceramide is present in an amount of 0.4-2% w / w, or about 0.5-1.5% w / w, or about 0.75-1.25% w / w, or about 1.0% w / w of the composition.

[0108] In some embodiments, the composition may include a fatty acid. The fatty acid may be a polyunsaturated fatty acid. In some embodiments, the fatty acid may be a C16 to C20 fatty acid, such as a C18 fatty acid. In some embodiments, the fatty acid is linoleic acid. In some embodiments, the linoleic acid is present in an amount between 0.2 and 0.5% w / w of the composition, or between 0.3 and 0.4% w / w of the composition, preferably about 0.33% w / w.

[0109] In some embodiments, the composition may comprise cholesterol. In some embodiments, the cholesterol is present in an amount between 0.2 and 0.5% w / w of the composition, or between 0.3 and 0.4% w / w of the composition, preferably about 0.33% w / w.

[0110] In some embodiments, the fatty acid may be linoleic acid. In an embodiment, the composition comprises ceramide, cholesterol, and fatty acid in a ratio of about 3:1:1. In an embodiment, the fatty acid may be linoleic acid. These ingredients may act as a skin barrier repair system.

[0111] The composition of the present invention may further comprise a PEG copolymer. In some embodiments, the PEG copolymer is a PEG / HDI copolymer didecyltetradecyl alcohol polyether-20 ether. In some embodiments, the PEG is PEG240. This can act as a viscosity modifier. In some embodiments, the composition further comprises a C12-C14 ether. In some embodiments, the C12-C14 ether is a PEG ether. In some embodiments, the C12-C14 ether comprises a PEG ether of tridecanol. This can act as a viscosity modifier.

[0112] In some embodiments, the composition further comprises an acrylate / C10-C30 alkyl acrylate crosspolymer. This may act as a viscosity modifier.

[0113] In some embodiments, the composition comprises a PEG copolymer that is a PEG / HDI copolymer bis-decyltetradecyl ether-20 ether (e.g., PEG-240 / HDI copolymer bis-decyltetradecyl ether-20 ether), a PEG ether of tridecanol, and an acrylate / C10-C30 alkyl acrylate copolymer. Together, these can act as viscosity modifiers and can improve the texture and stability of the composition.

[0114] The composition used in the present invention may further include a stabilizer, a preservative, a salt or a buffer. The water-ethylene glycol phase may contain a stabilizer. Stabilizers include xanthan gum or a crystal growth inhibitor. In some embodiments, the composition used does not contain xanthan gum or a crystal growth inhibitor.

[0115] In some embodiments, the composition for use according to the preceding claims comprises

[0116] 4-6% w / w of a zinc salt of a polyhydroxy acid and its conjugate base, wherein the polyhydroxy acid is lactobionic acid;

[0117] 15-20% w / w of a partition coefficient enhancer, preferably butanediol;

[0118] 1-2% w / w of a diffusion coefficient enhancer, preferably tetradecanol, and

[0119] 10-20% w / w of an emollient, preferably hydrogenated polydecene;

[0120] 3-12% w / w of a surfactant (i.e., a primary surfactant), wherein the surfactant preferably comprises one or more of methyl glucose sesquistearate, PEG-20 methyl glucose sesquistearate, glyceryl stearate, or a combination thereof, preferably comprising 3-6% w / w methyl glucose sesquistearate and 1-2% w / w PEG-20 methyl glucose sesquistearate;

[0121] 40-60% w / w water, and

[0122] Up to 3% w / w of a humectant, preferably glycerol, and

[0123] an optional co-surfactant, preferably used in an amount of up to 6% w / w of the composition;

[0124] optional ceramide, preferably in an amount up to 1.5% w / w of the composition;

[0125] optionally cholesterol, preferably in an amount up to 0.5% w / w of the composition;

[0126] optional fatty acids, preferably in an amount up to 0.5% w / w of the composition;

[0127] optional PEG copolymer, preferably in an amount up to 1% w / w of the composition;

[0128] optional acrylates / C10-C30 alkyl acrylate copolymers, preferably present in an amount of up to 0.5% w / w of the composition, and;

[0129] optional preservatives, preferably in an amount up to 1% w / w of the composition;

[0130] Wherein, the pH value of the composition is between 3.0 and 3.5.

[0131] In some embodiments, the composition for use according to the preceding claims comprises

[0132] 4-6% w / w of a zinc salt of a polyhydroxy acid and its conjugate base, wherein the polyhydroxy acid is lactobionic acid;

[0133] 15-20% w / w butanediol;

[0134] 1-2% w / w of a diffusion coefficient enhancer, preferably tetradecanol, and

[0135] 10-19% w / w of an emollient, preferably hydrogenated polydecene;

[0136] 3-6% w / w of methyl glucose sesquistearate and

[0137] 1-2% w / w PEG-20 methyl glucose sesquistearate;

[0138] 40-60% w / w water, and

[0139] Up to 3% w / w of a humectant, preferably glycerol, and

[0140] An optional co-surfactant, preferably used in an amount up to 6% w / w of the composition;

[0141] optional ceramide, preferably in an amount up to 1.5% w / w of the composition;

[0142] optionally cholesterol, preferably in an amount up to 0.5% w / w of the composition;

[0143] optional fatty acids, preferably in an amount up to 0.5% w / w of the composition;

[0144] optional PEG copolymer, preferably in an amount up to 1% w / w of the composition;

[0145] optional acrylates / C10-C30 alkyl acrylate copolymers, preferably present in an amount up to 0.5% w / w of the composition, and

[0146] optional preservatives, preferably in an amount up to 1% w / w of the composition;

[0147] Wherein, the pH value of the composition is between 3.0 and 3.5.

[0148] Embodiments of the present invention include:

[0149] A. Use of a composition for treating moderate atopic dermatitis, wherein the composition is topically applied to the skin at least twice a day, wherein the pH value of the composition is in the range of 2.7 to 5.0, and comprises

[0150] A zinc salt of a polyhydroxy acid and a conjugate base thereof, wherein the polyhydroxy acid is selected from lactobionic acid, gluconolactone, or a combination of lactobionic acid and gluconolactone,

[0151] a partition coefficient enhancer selected from propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, 1,5-pentanediol or a combination thereof,

[0152] A diffusion coefficient enhancer selected from C12 to C14 straight chain fatty acids or C14 straight chain primary alcohols.

[0153] B. A method of treating moderate atopic dermatitis, wherein the method comprises topically applying a composition to the skin at least twice a day for 10 days to a maximum of 28 days, wherein the pH value of the composition is in the range of 2.7 to 5.0, and comprises

[0154] A zinc salt of a polyhydroxy acid and a conjugate base thereof, wherein the polyhydroxy acid is selected from lactobionic acid, gluconolactone, or a combination of lactobionic acid and gluconolactone,

[0155] a partition coefficient enhancer selected from propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, 1,5-pentanediol or a combination thereof,

[0156] A diffusion coefficient enhancer selected from C12 to C14 straight chain fatty acids or C14 straight chain primary alcohols.

[0157] C. Use of a composition in a method for treating atopic dermatitis, wherein the composition is topically applied to the skin at least twice a day for 10 days to a maximum of 28 days, wherein the pH value of the composition is in the range of 2.7 to 5.0, and comprises

[0158] A zinc salt of a polyhydroxy acid and a conjugate base thereof, wherein the polyhydroxy acid is selected from lactobionic acid, gluconolactone, or a combination of lactobionic acid and gluconolactone,

[0159] a partition coefficient enhancer selected from propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, 1,5-pentanediol or a combination thereof,

[0160] A diffusion coefficient enhancer selected from C12 to C14 straight chain fatty acids or C14 straight chain primary alcohols.

[0161] D. A method of treating atopic dermatitis, wherein the method comprises topically applying a composition to the skin at least twice a day for 10 days to a maximum of 28 days, wherein the pH value of the composition is in the range of 2.7 to 5.0, and comprises

[0162] A zinc salt of a polyhydroxy acid and a conjugate base thereof, wherein the polyhydroxy acid is selected from lactobionic acid, gluconolactone, or a combination of lactobionic acid and gluconolactone,

[0163] a partition coefficient enhancer selected from propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, 1,5-pentanediol or a combination thereof,

[0164] A diffusion coefficient enhancer selected from C12 to C14 straight chain fatty acids or C14 straight chain primary alcohols.

[0165] E. Use of the composition according to embodiment C or D, wherein the atopic dermatitis is moderate or mild atopic dermatitis.

[0166] F. Use of a composition according to any preceding embodiment, wherein the composition is administered twice a day.

[0167] G. Use of a composition according to any of the preceding embodiments, wherein the composition is free of steroids, topical calcineurin inhibitors.

[0168] H. Use of a composition according to the preceding embodiments, wherein the method of treatment of atopic dermatitis does not comprise treatment with steroids, topical calcineurin inhibitors or other pharmaceutically active substances.

[0169] I. Use of a composition according to any of the preceding embodiments, wherein the composition is topically applied for between 12 and 20 days, such as about 14 days.

[0170] J. Use of a composition according to any of the preceding embodiments, wherein the atopic dermatitis has a local SCORAD score of at least 6, preferably between 6 and 12, such as between 6 and 10 at the start of treatment.

[0171] K. Use of the composition according to any of the preceding embodiments, wherein the method involves identifying patients with moderate atopic dermatitis by measuring a local SCORAD score, wherein the local SCORAD score is determined to be at least 6, more preferably between 6 and 12.

[0172] L. Use of the composition according to embodiment K, wherein the method further comprises measuring the local SCORAD score after a period of time and determining whether further treatment is required.

[0173] M. Use of the composition according to embodiment L, wherein the time period is less than 4 weeks, or less than or equal to 3 weeks, or less than or equal to 2 weeks.

[0174] N. Use of a composition according to the preceding embodiments, wherein the treatment method results in a reduction in the local SCORAD score (ΔSCORAD) of at least 1 point, or at least 2 points, or at least 3 points, or at least 4 points compared to the baseline local SCORAD at the start of treatment.

[0175] O. Use of the composition according to embodiment N, wherein the local SCORAD score reduction is obtained in less than 4 weeks, or less than or equal to 3 weeks, or less than or equal to 2 weeks.

[0176] P. Use of a composition according to any of the preceding embodiments, wherein the pH of the composition is between 3.0 and 4.0, more preferably between 3.0 and 3.5, even more preferably about 3.2.

[0177] Q. Use of a composition according to any preceding embodiment, wherein the partition coefficient enhancer is butanediol.

[0178] R. Use of a composition according to any preceding embodiment, wherein the content of the partition coefficient enhancer is 15-30% w / w of the composition, or 15-25% w / w of the composition, or 15-20% w / w of the composition.

[0179] S. Use of a composition according to any of the preceding embodiments, wherein the content of the diffusion coefficient enhancer is 1.0-2.0% w / w of the composition, or 1.2-1.8% w / w or about 1.5% w / w of the composition.

[0180] T. Use of a composition according to any of the preceding embodiments, said composition further comprising ceramide, wherein preferably the amount of said ceramide is 0.5-1.5% w / w of said composition.

[0181] U. Use of a composition according to any of the preceding embodiments, wherein the composition comprises 3-6% w / w methyl glucose sesquistearate and 1-2% w / w PEG-20 methyl glucose sesquistearate.

[0182] V. Use of a composition according to any of the preceding embodiments, further comprising PEG-240 / HDI copolymer bis-decyltetradeceth-20 ether.

[0183] W. Use of a composition according to any of the preceding embodiments, further comprising an acrylate / C10-C30 alkyl acrylate copolymer.

[0184] X. Use of a composition according to any of the preceding embodiments, comprising 4-6% w / w of a polyhydroxy acid and its conjugate base

[0185] Zinc salt, wherein the polyhydroxy acid is lactobionic acid;

[0186] 15-20% w / w of a partition coefficient enhancer, preferably butanediol;

[0187] 1-2% w / w of a diffusion coefficient enhancer, preferably tetradecanol, and

[0188] 10-20% w / w of an emollient, preferably hydrogenated polydecene;

[0189] 3-12% w / w of a surfactant, wherein the surfactant preferably comprises one or more of methyl glucose sesquistearate, PEG-20 methyl glucose sesquistearate, glyceryl stearate or a combination thereof,

[0190] 40-60% w / w water, and

[0191] Up to 3% w / w of a humectant, preferably glycerol, and

[0192] an optional co-surfactant, preferably used in an amount of up to 6% w / w of the composition;

[0193] optional ceramide, preferably in an amount up to 1.5% w / w of the composition;

[0194] optionally cholesterol, preferably in an amount up to 0.5% w / w of the composition;

[0195] optional fatty acids, preferably in an amount up to 0.5% w / w of the composition;

[0196] Optional PEG-240 / HDI copolymer bis-decyltetradeceth-20 ether, preferably in an amount up to 1% w / w of the composition;

[0197] optional acrylates / C10-C30 alkyl acrylate copolymers, preferably present in an amount up to 0.5% w / w of the composition, and

[0198] optional preservatives, preferably in an amount up to 1% w / w of the composition;

[0199] Wherein, the pH value of the composition is between 3.0 and 3.5.

[0200] Example

[0201] Example 1: Moderate atopic dermatitis treatment trial

[0202] Materials and Methods

[0203] Table 1 - Test Materials

[0204]

[0205]

[0206] Example 1 Compositions used in the study

[0207]

[0208] Unlike previously disclosed example compositions, the compositions used in this study included butylene glycol as a partition coefficient enhancer because butylene glycol was found to be less associated with skin irritation and is more suitable for very young children.

[0209] Furthermore, unlike the previously disclosed exemplary compositions, the amount of methyl glucose sesquistearate is relatively high, while the amount of PEG-20 methyl glucose sesquistearate is relatively low.

[0210] In addition, the present composition includes other components intended to increase the viscosity of the composition, including PEG / HDI copolymer, trideceth-6, and acrylates / C10-30 alkyl acrylate copolymer. These ingredients were found to enhance the stability and texture of the formula compared to previous compositions.

[0211] Unlike previous compositions, a pH of 3.2 was found to provide a composition with a longer lasting skin pH lowering ability over 12 hours compared to compositions with a higher pH (eg, pH 4.0).

[0212] Subjects

[0213] The inclusion, exclusion criteria and instructions mentioned below were checked for all subjects by questionnaires before and during the study. Situations arising during the study listed in the exclusion criteria and instructions, as well as deviations from the protocol, do not necessarily lead to the exclusion of subjects.

[0214] Inclusion Criteria

[0215] Written informed consent from the subject, or for minor subjects (<16 years old), written informed consent from the parent / legal guardian for the child to participate in the study

[0216] Willing to actively participate in the study and attend scheduled visits

[0217] · Parents / legal guardians are willing to actively support participation in the study and accompany their child to scheduled visits

[0218] Female or male

[0219] 4 to 65 years old (no fixed age group ratio)

[0220] · Subjects have atopic dermatitis with at least two similar lesions (local SCORAD mean of at least 6 for both lesions), diagnosed by a dermatologist, preferably in contralateral locations (in single cases this may not be the case).

[0221] Exclusion criteria

[0222] Female subjects: Pregnant or lactating

[0223] ·Drug addicts, alcoholics

[0224] AIDS, HIV positive or infectious hepatitis (if known to the subject)

[0225] Conditions that exclude participation or may affect test response / evaluation

[0226] Participating in similar cosmetic and / or pharmaceutical research or in a waiting period after participation

[0227] Active skin disease in the test area (except atopic dermatitis)

[0228] Any of the following conditions that may require regular systemic medication: insulin-dependent diabetes, cancer, rheumatic disease

[0229] ·Record of allergies to cosmetics and / or ingredients

[0230] The test area may have moles, tattoos, scars, inflamed skin, hair, etc. that may affect the investigation

[0231] Regular use of sunbeds in the past 2 years

[0232] Systemic treatment with immunosuppressive drugs (e.g., corticosteroids) and / or antihistamines (e.g., allergy medications) within the last 30 days before the start of the study

[0233] Topical corticosteroids used on the test area within the last 2 weeks before the start of the study

[0234] · Received supportive treatment for atopic dermatitis (ultraviolet therapy, probiotic homeopathy, etc.) within the last 2 weeks before the start of the study

[0235] Use of disinfectant or antibacterial detergents or topical products within 4 weeks before the start of the study

[0236] Instructions to trial participants before the study begins:

[0237] The subject or the subject's parent / legal guardian was informed not to...

[0238] Smoking within the last 2 hours before the instrument measurement

[0239] Drinking any caffeinated beverages (e.g. coffee, cola) within the last 2 hours before instrument measurement

[0240] Use of any cosmetic products (e.g., creams, lotions, oil-based cleansing products) on the test area within the last 7 days before the start of the study

[0242] Use of any cleaning agents (e.g., soap, shampoo, bath and shower products) on the testing area 24 hours prior to the scheduled visit

[0244] The subject or the subject's parent / legal guardian is informed...

[0245] · 24 ± 2 hours before the start of the study, clean the test area with water only

[0246] Avoid contact of the test area with water (e.g. no bathing, no swimming, no

[0247] Shower only)

[0248] Instructions for trial participants during the study:

[0249] Subjects or their parents / legal guardians were informed not to:

[0250] Smoking within the last 2 hours before the instrument measurement

[0251] Drinking any caffeinated beverages (e.g. coffee, cola) within the last 2 hours before instrument measurement

[0252] · Use any product with the same efficacy as the test product on the test area throughout the study

[0253] Use of any cosmetics (e.g., creams, lotions, oil-based cleansing products) on the test area throughout the study

[0254] Use of any cleaning agents (e.g., soap, shampoo, bath and shower products) on the testing area within 24 hours prior to the scheduled visit

[0256] · Use of any disinfectant / antimicrobial detergents or topical products during the entire study

[0257] The subject or the subject's parent / legal guardian is informed

[0258] Clean the test area with water only 24 ± 2 hours before the scheduled visit

[0259] Avoid contact of the test area with water (e.g. no bathing, no swimming, no

[0260] Shower only)

[0261] Apply the test product to the test area at the following frequency: 2 times a day (morning and evening) throughout the study

[0262] The test area is a randomly selected atopic lesion and surrounding nonlesional skin (e.g., arm or leg)

[0263] · The last application of the test product to the test area was within 3-12 hours before the last study visit. · Continue to use the test area with the usual cleansing agents (e.g., soap, shampoo, body wash and

[0264] shower products), but do not change brands or use new products

[0265] Avoid any sun exposure, UV treatments, and / or artificial tanning in the testing area throughout the study

[0266] Table 2: Test schedule

[0267]

[0268]

[0269] Climate conditions

[0270] Instrumental measurements were performed in an air-conditioned room at a temperature of 22 ± 2 °C and a relative humidity of 50 ± 7.5%. Subjects stayed in the climate-controlled room for at least 30 minutes before the measurements.

[0271] Test Procedure Description

[0272] Day 1: Subjects came to the study site. They were informed about the study and gave written consent. Local SCORAD was assessed by a dermatologist and the lesion site (arm or leg) was located.

[0273] Test products were given to subjects and they were instructed to use them in the designated test area. Test products were assigned according to the randomization scheme. Products were used for the first time under the guidance of the technician. Subjects used them further at home.

[0274] Days 1 to 14: Subjects used the test product as described above (see “Mode of Use”).

[0275] The last use of the product should be within 3-12 hours before the next visit to the study site.

[0276] Day 15: Subjects returned to the study site. After acclimation for at least 30 minutes, a dermatologist assessed local SCORAD.

[0277] A deviation of ±2 days was acceptable as it was not expected to substantially affect the study results.

[0278] Research Methods

[0279] The following research methods were used:

[0280] Visual Assessment

[0281] Local SCORAD (scoring of atopic dermatitis): objective skin condition of atopic lesions (erythema, edema and papules, exudation and crusting, desquamation, lichenification, dryness*) was assessed at the above assessment times according to the following scale:

[0282] 0 = None

[0283] 1 = Mild

[0284] 2 = Moderate

[0285] 3 = Strong

[0286] *Dryness was assessed in non-lesional areas.

[0287] The local SCORAD for each test area is the sum of all scores for all six parameters listed above (minimum = 0, maximum = 18). Objective assessment is performed by a dermatologist or trained physician. The scores are entered directly into a PC system using an appropriate computer program.

[0288] This is in accordance with well-known established procedures, for example as outlined in Dermatology. 1993; 186(1):23-31. doi:10.1159 / 000247298.

[0289] Data List

[0290] Raw data and calculated values ​​for all parameters are presented by parameter, skin area, treatment, and assessment time.

[0291] Local SCORAD: The total score of the local SCORAD was the sum of the scores of the above individual items and was used for further analysis. In addition, the difference from baseline was calculated based on the total score.

[0292] Descriptive Data Analysis

[0293] Local SCORAD:

[0294] · Give the N, mean, standard deviation, median, minimum, maximum and

[0295] Raw data with 95% confidence intervals, and differences from baseline.

[0296] The mean value of the raw data for each parameter and the difference from the baseline are displayed in the form of a bar graph according to the treatment and assessment time.

[0297] The confidence interval is 95%.

[0298] Local SCORAD (single item):

[0299] Raw data including N, mean, standard deviation, median, minimum and maximum values ​​are provided by treatment, assessment time and item.

[0300] For each treatment, assessment time, and item, the raw data presents individual score counts and score counts greater than 0.

[0301] Statistical data analysis

[0302] A significance level of 0.05 (alpha) was chosen for statistical analysis. Due to the exploratory nature of the study, no adjustment for multiplicity was performed.

[0303] Local SCORAD:

[0304] Treatment comparisons (A vs. B) were performed by paired t-test for each assessment time and for differences from baseline in parameters.

[0305] Statistical data were calculated using commercially available statistical software (SAS for Windows).

[0306] result

[0307] Table 3: Number of people and exit

[0308]

[0309] Local SCORAD

[0310] Topical SCORAD by a dermatologist or trained physician

[0311] Table 4 presents the mean and standard deviation of the total local SCORAD scores of the dermatologists for the two diseased skin test areas, untreated (code A) and treated with moisturizer (code B), and the results of treatment comparisons of the differences from baseline by paired t-tests. The local SCORAD represents the sum of the scores of all parameters assessed in this evaluation, with the lowest possible value of "0" and the highest possible value of "18". The lower the local SCORAD value, the better the skin condition.

[0312] Table 4: Regional SCORAD - means, standard deviations and treatment comparisons of differences from baseline by paired t-test

[0313]

[0314]

[0315] Rating: 0 = lowest possible score; ...; 18 = highest possible score

[0316] The local SCORAD mean values ​​decreased for both treatment codes A and B at Day 15 compared to Day 1 (baseline), showing a greater decrease in the treated test area (code B). Treatment comparisons of the difference from baseline unexpectedly showed a statistically significant decrease in the mean local SCORAD value for the area treated with the test product (code B) compared to the untreated area.

[0317] Figure 2 and Figure 3 The total score of the local SCORAD mean and standard deviation are shown, as well as the difference from baseline (Day 1). The count scores of the local SCORAD are also shown in Table 5.

[0318] Table 5: Local SCORAD score counts by dermatologists or trained physicians

[0319]

[0320] For parameters with counts > 0, the differences in score counts between D15 and BL were: dryness – A = 0, B = 9; erythema – A = 2, B = 6; edema and papules – A = 9, B = 13; exudation and crusting – A = 2, B = 5; desquamation – A = -1, B = 2; and lichenification – A = -2, B = 5.

[0321] For parameters with a count > 1, the differences in score counts between D15 and BL were: dryness – A = 6, B = 18; erythema – A = 6, B = 13; edema and papules – A = 5, B = 8; exudation and crusting – A = 4, B = 8; desquamation – A = 1, B = 2; lichenification – A = 7, B = 16.

[0322] The local SCORAD scores showed an improvement in the skin condition (in terms of the parameters assessed) in the affected areas after 2 weeks of application of the test product compared to the baseline values ​​in both untreated and treated test areas. A significant improvement in skin condition was observed after 2 weeks of application of the test product compared to the untreated test areas. The decrease in SCORAD in the untreated areas over time could be explained by changes in a single individual, as atopic dermatitis naturally changes over time.

[0323] The count scores also showed improvement in dryness, erythema, edema and papules, exudation and crusting, desquamation, and lichenification after 2 weeks. In addition, no adverse reactions were observed in this study.

[0324] The trial also showed that treatment resulted in a decrease in skin pH of >0.5 units after 2 weeks (see Figure 4), and after 2 weeks, skin hydration was significantly increased compared with the untreated arm (see Figure 5 ).

[0325] Example 2: Composition treatment after 5 days

[0326] It was also found that the composition for treating atopic dermatitis showed significant improvement in an infant patient with severe atopic dermatitis after only 5 days.

[0327] The composition used is as follows:

[0328]

[0329]

[0330] The results can be clearly seen through visual assessment. Figure 6 Shown is the improvement in skin condition after only 5 days, with the left image showing skin condition before treatment and the right image showing skin condition after treatment.

[0331] in conclusion

[0332] The result of the present invention is the provision of compositions that are effective for the treatment of atopic dermatitis, including moderate atopic dermatitis, unexpectedly without the need for combination therapy with other active substances, such as steroid therapy. The compositions used showed significant improvements in topical SCORAD scores even after a relatively short 2 weeks of treatment. Thus, the present invention provides an improved alternative to steroid therapy, which is associated with many side effects. The present invention is also suitable for pediatric patients. The results are surprising because at the time of filing the application, although it was recommended to use only moisturizing or emollient creams to treat atopic dermatitis and prevent flare-ups of eczema-prone skin, it was recommended to use other ointments or medications at the same time, especially in moderate and severe atopic dermatitis. Even when used alone, it was recommended to use other moisturizing creams, or longer treatment times were required to observe any meaningful improvement in symptoms.

[0333] Appendix - Raw data for Example 1

[0334] Table A1: Descriptive statistics of raw data of local SCORAD by dermatologists or trained physicians

[0335]

[0336] Dryness was assessed in nonlesional areas and scored as 0 – none, 1 – mild, 2 – moderate, 3 – strong.

[0337] Table A2: Descriptive statistics of total score, local SCORAD

[0338]

[0339] Table A3: Descriptive statistics of the difference in local SCORAD from baseline (Day 1) to Day 15

[0340]

[0341] Table A4: Local SCORAD - means, standard deviations and treatment comparisons for differences from BL by paired t-test

[0342]

[0343] Bold - p value: significant (p≤0.05).

Claims

1. A composition for use in a method of treating moderate atopic dermatitis with a local SCORAD score of at least 6, wherein the composition is topically applied to the skin at least twice a day, wherein the pH value of the composition is in the range of 2.7 to 5.0, and comprises A zinc salt of a polyhydroxy acid and its conjugate base, wherein the polyhydroxy acid is selected from lactobionic acid, gluconolactone, or a combination of lactobionic acid and gluconolactone, a partition coefficient enhancer selected from propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, 1,5-pentanediol or a combination thereof, a diffusion coefficient enhancer selected from C12 to C14 straight chain fatty acids or C14 straight chain primary alcohols, Furthermore, the composition is free of steroids.

2. A method for treating moderate atopic dermatitis with a local SCORAD score of at least 6, wherein the method comprises topically applying a composition to the skin at least twice a day, wherein the pH of the composition is in the range of 2.7 to 5.0, and comprises A zinc salt of a polyhydroxy acid and its conjugate base, wherein the polyhydroxy acid is selected from lactobionic acid, gluconolactone, or a combination of lactobionic acid and gluconolactone, a partition coefficient enhancer selected from propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, 1,5-pentanediol or a combination thereof, a diffusion coefficient enhancer selected from C12 to C14 straight chain fatty acids or C14 straight chain primary alcohols, Furthermore, the composition is free of steroids.

3. A composition for use in a method of treating atopic dermatitis, wherein the composition is topically applied to the skin at least twice a day for 10 days to a maximum of 28 days, wherein the pH value of the composition is in the range of 2.7 to 5.0, and comprises A zinc salt of a polyhydroxy acid and its conjugate base, wherein the polyhydroxy acid is selected from lactobionic acid, gluconolactone, or a combination of lactobionic acid and gluconolactone, a partition coefficient enhancer selected from propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, 1,5-pentanediol or a combination thereof, a diffusion coefficient enhancer selected from C12 to C14 straight chain fatty acids or C14 straight chain primary alcohols, and wherein the composition is free of steroids.

4. A method of treating atopic dermatitis, wherein the method comprises topically applying a composition to the skin at least twice a day for 10 days to a maximum of 28 days, wherein the pH of the composition is in the range of 2.7 to 5.0, and comprises A zinc salt of a polyhydroxy acid and its conjugate base, wherein the polyhydroxy acid is selected from lactobionic acid, gluconolactone, or a combination of lactobionic acid and gluconolactone, a partition coefficient enhancer selected from propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, 1,5-pentanediol or a combination thereof, a diffusion coefficient enhancer selected from C12 to C14 straight chain fatty acids or C14 straight chain primary alcohols, Furthermore, the composition is free of steroids.

5. Use of the composition according to claim 3 or the method according to claim 4, wherein the atopic dermatitis is moderate or mild atopic dermatitis.

6. Use of a composition according to any preceding claim or a method according to any preceding claim, wherein the composition is administered twice daily.

7. Use of a composition according to any preceding claim or a method according to any preceding claim, wherein the composition does not contain a topical calcineurin inhibitor.

8. Use of a composition according to any preceding claim or a method according to any preceding claim, wherein The method of treating atopic dermatitis does not include treatment with topical calcineurin inhibitors or other pharmaceutically active substances.

9. Use of a composition according to any preceding claim or a method according to any preceding claim, wherein the composition is topically applied for between 12 and 20 days, such as about 14 days.

10. Use of a composition according to any preceding claim or a method according to any preceding claim, wherein the local SCORAD score of the atopic dermatitis at the start of treatment is at least 6, preferably between 6 and 12, such as between 6 and 10.

11. Use of a composition according to any preceding claim or a method according to any preceding claim, wherein The method involves identifying patients with moderate atopic dermatitis by measuring a local SCORAD score, determining a local SCORAD score of at least 6, more preferably between 6 and 12.

12. Use of a composition according to claim 11 or a method according to claim 11, wherein the method further comprises measuring the local SCORAD score after a period of time and determining whether further treatment is required.

13. Use of a composition according to claim 12 or a method according to claim 12, wherein the time period is less than 4 weeks, or less than or equal to 3 weeks, or less than or equal to 2 weeks.

14. Use of a composition according to any preceding claim or a method according to any preceding claim, wherein The treatment method results in a decrease in the local SCORAD score (ΔSCORAD) of at least 1 point, or at least 2 points, or at least 3 points, or at least 4 points, compared to the baseline local SCORAD at the start of treatment.

15. Use of a composition according to claim 14 or a method according to claim 14, wherein the local SCORAD score reduction is obtained in less than 4 weeks, or less than or equal to 3 weeks, or less than or equal to 2 weeks.

16. Use of a composition according to any preceding claim or a method according to any preceding claim, wherein the pH of the composition is between 3.0 and 4.0, more preferably between 3.0 and 3.5, even more preferably about 3.

2.

17. Use of a composition according to any preceding claim or a method according to any preceding claim, wherein the partition coefficient enhancer is butanediol.

18. Use of a composition according to any preceding claim or a method according to any preceding claim, wherein the partition coefficient enhancer is present in an amount of 15-30% w / w of the composition, or 15-25% w / w of the composition, or 15-20% w / w of the composition.

19. Use of a composition according to any preceding claim or a method according to any preceding claim, wherein the diffusion coefficient enhancer is present in an amount of 1.0-2.0% w / w of the composition, or 1.2-1.8% w / w or about 1.5% w / w of the composition.

20. Use of a composition according to any preceding claim or a method according to any preceding claim, further comprising ceramide, wherein preferably the amount of ceramide is 0.5-1.5% w / w of the composition.

21. Use of a composition according to any preceding claim or a method according to any preceding claim, wherein The composition comprises 3-6% w / w methyl glucose sesquistearate and 1-2% w / w PEG-20 methyl glucose sesquistearate.

22. Use of a composition according to any preceding claim or a method according to any preceding claim, wherein the composition further comprises PEG-240 / HDI copolymer didecyltetradeceth-20 ether.

23. Use of a composition according to any preceding claim or a method according to any preceding claim, wherein the composition further comprises an acrylate / C10-C30 alkyl acrylate copolymer.

24. Use of a composition according to any preceding claim or a method according to any preceding claim, wherein the composition comprises 4-6% w / w of a zinc salt of a polyhydroxy acid and its conjugate base, wherein the polyhydroxy acid is lactobionic acid; 15-20% w / w of a partition coefficient enhancer, preferably butanediol; 1-2% w / w of a diffusion coefficient enhancer, preferably tetradecanol, and 10-20% w / w of an emollient, preferably hydrogenated polydecene; 3-12% w / w of a surfactant, wherein the surfactant preferably comprises one or more of methyl glucose sesquistearate, PEG-20 methyl glucose sesquistearate, glyceryl stearate or a combination thereof, 40-60% w / w water, and Up to 3% w / w of a humectant, preferably glycerol, and an optional co-surfactant, preferably used in an amount of up to 6% w / w of the composition; optional ceramide, preferably in an amount up to 1.5% w / w of the composition; optionally cholesterol, preferably in an amount up to 0.5% w / w of the composition; optional fatty acids, preferably in an amount up to 0.5% w / w of the composition; Optional PEG-240 / HDI copolymer didecyltetradeceth-20 ether, preferably in an amount up to 1% w / w of the composition; optional acrylates / C10-C30 alkyl acrylate copolymers, preferably present in an amount up to 0.5% w / w of the composition, and optional preservatives, preferably in an amount up to 1% w / w of the composition; The pH value of the composition is between 3.0 and 3.5.

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