Skin delivery of the compound

Abstract

The topical skin delivery formulations of pharmaceutical, cosmeceutical, or cosmetic active ingredients containing functional co-enhancer delivery systems contain a primary active in combination with a supplemental user adherence-improving skin barrier repair system containing nicotinamide and polyhydroxy acid. The formulations generally contain a water-soluble solvent and C in combination with a blend of hydrocarbylmethylsiloxanes, other volatile silicones, and silicone elastomers. 12 Or C 14 Fatty acids or C 14 Contains alcohol.

Description

[Technical Field]

[0001] The present invention relates to formulations suitable for use in the topical dermal delivery of active agents. [Background technology]

[0002] In a 2003 report on medication adherence, the World Health Organization (WHO) asserted that "enhancing the effectiveness of adherence interventions would have a much greater impact on population health than improving specific therapies." In this report, the WHO primarily addressed major systemic diseases and subsequent, primarily oral, therapies. Several treatment-related factors were found to contribute to poor adherence, including slow or low onset of efficacy, actual or perceived unwanted effects, and treatment plans that are not compatible with lifestyle.

[0003] Applying medications topically to the skin to treat conditions and diseases of the skin and subcutaneous tissue is a straightforward therapeutic concept and makes sense. Topical products are widely and enthusiastically used by consumers, as evidenced by the $145 billion in annual sales of skin care products in the global cosmetic beauty market in 2020.

[0004] Since this 2003 WHO report, several studies have been conducted on the occurrence and drivers of adherence to topical skin medications. However, adherence to recommended or prescribed topical skin medication products remains disappointingly low. In the February 2018 edition of "Practical Dermatology," American dermatologist Dr. Steven Feldman concluded that adherence to topical medications is "dismal."

[0005] Similar to the WHO report, investigations into the reasons for this low adherence rate have found that the main causes include slow and inadequate response to treatment, the occurrence or concern of local and systemic drug side effects (particularly fear of topical corticosteroids), treatment regimens that do not fit into lifestyle, and the unsightly and uncomfortable effects inherent to topical products (Zschocke et al., Venereol. 2014 May;28 Suppl 2:4-9; Tan et al., Expert Opin Drug Deliv. 2012 Oct;9(10):1263-71; Devaux et al., Acad Dermatol. 2012 May;26 Suppl 3:61-7).

[0006] The table below provides an overview of the various dimensions that govern adherence. Particularly relevant in this context are biologic and cosmetic design factors, briefly: 1) efficacy, 2) potential for local and systemic side effects, 3) time and effort of use (all described by the WHO), and 4) consumer experience of use. [Table 1]

[0007] Passive topical drug delivery technology: Coenhancer gel technology Co-enhancer technology can be defined as incorporating functional ingredients into topical formulations with enhanced partition and diffusion coefficients, thereby enhancing the skin penetration of the active agent.

[0008] More recent passive delivery coenhancer technology considers all of the principles embodied in Fick's first law of diffusion and incorporates the following elements: -An effective amount of one or more active substances that is saturated or nearly saturated with the non-volatile residual phase (N-VRP); the phase that remains after evaporation of the volatile substances to an equilibrium state -Inclusion of a partition coefficient enhancer within N-VRP at an effective dose -Inclusion of a diffusion coefficient enhancer in the N-VRP at an effective dose and at or near saturation in the non-volatile residual phase.

[0009] U.S. Pat. No. 8,541,470 discloses a co-enhancer gel composition for topical application of an NSAID, comprising an NSAID solution in a carrier system containing a polyhydric alcohol, a glycol ether, and an ester of a high fatty acid, the carrier system existing as a single phase at ambient temperature. The NSAID can be diclofenac, i.e., diclofenac acid. The polyhydric alcohol can be a glycol such as propylene glycol, and the glycol ether can be a diethylene glycol ether such as diethylene glycol monoethyl ether. The high fatty acid ester is typically isopropyl myristate.

[0010] The formulations described in US 8,541,470 are designed with a non-volatile single residual phase containing a co-enhancer excipient with an active and functional partition coefficient (e.g., propylene glycol) and a diffusion coefficient (e.g., isopropyl myristate) together with a co-solvent (diethylene glycol monoethyl ether). The formulation-dependent skin penetration of the active ingredient is primarily influenced by the following factors: -Dosage of partition coefficient enhancers -Dose and saturation of the active ingredient in the non-volatile monophasic residual phase -Dose and saturation of diffusion coefficient enhancers in the non-volatile monophasic residual phase

[0011] To complete the co-enhanced gel formulation, a highly volatile solvent such as ethanol, isopropyl alcohol, and optionally water, and a gelling polymer can be added to the non-volatile residual phase to ensure single-phase solubility and a suitable macroviscosity for ease of application during use. Upon application to the skin as a thin film, the highly volatile solvent evaporates, rapidly modifying the physical and chemical properties of the non-volatile single-phase residual phase.

[0012] While it is well known to take into account the degree of saturation of the active ingredient, US 8,541,470 first describes the importance of the dosage and degree of saturation of the diffusion coefficient enhancer, in this case isopropyl myristate, in the non-volatile residual phase. Figure 1 of US 8,541,470 is a three-phase diagram showing the composition of the non-volatile mono-phase residual phase when the diffusion coefficient enhancer is saturated. When the degree of saturation of the diffusion coefficient enhancer is low, a significant decrease in the penetration of the diffusion coefficient enhancer, and therefore the drug, into the stratum corneum is observed.

[0013] Despite their drug delivery benefits, coenhancer formulations such as those described in U.S. Patients reportedly experience poor application and skin discomfort, leading to stickiness and dry skin. It is widely recognized that aesthetic concerns, particularly skin discomfort, reduce adherence to medical treatments involving topical formulations. Patients consistently report a preference for creams over gels or ointments. Coenhancer systems formulated as emollient creams address all of the formulation-related factors that contribute to poor adherence. However, the addition of surfactants and an emollient oil phase to the cream vehicle tends to affect the performance of the included coenhancer system, reducing the ability of the active substance to penetrate the skin barrier and thereby reducing delivery of the active substance to the target site. Therefore, a limitation of current topical coenhancer technology is the inability to incorporate an emollient, maintain high saturation of the key active ingredient, and optimize skin penetration.

[0014] Without being bound by any particular theory, it is hypothesized that this is because the emollient oil phase of the cream adversely affects the performance of the co-enhancer system. In particular, emollient oil phase components containing hydrocarbon structural elements may be more effective than diffusion coefficient enhancing excipients, such as C8-C 22Excipients containing alcohol, acid, or ester derivatives of hydrocarbons can be expected to enhance solubility. Ideally, the diffusion coefficient enhancer should be saturated in the non-volatile residual phase (N-VRP) of the formulation. Emollient excipients increase the solubility of the diffusion coefficient enhancer in the residual non-volatile emollient oil phase of the vehicle, resulting in a predominantly subsaturated state of the diffusion coefficient enhancer, which can adversely affect its partitioning into the stratum corneum barrier and reduce the skin penetration of incorporated active ingredients by 5-10 times.

[0015] Passive topical drug delivery technology: Coenhancer silicone cream technology GB Patent No. 2549418B, "Topical formulations comprising dimethicone macromers," describes a topical formulation technology that aims to address all four formulation-related adherence factors. The first three are biopharmaceutical factors related to the absorbed dose, applied dose, and rate of absorbed dose, respectively. These requirements are met through the use of a co-enhancer system that includes partition coefficient and diffusion coefficient enhancers.

[0016] The fourth factor is satisfied by dispersing a glycol coenhancer system within a silicone elastomer silicone-fluid-silicone emollient continuous phase to form a cream. When the glycol-coenhancer silicone dispersion is applied to the skin, the consumer experiences the soft, smooth feel of the mixed silicone elastomer-silicone emollient fluid continuous phase. The loss of the volatile silicone occurs rapidly, allowing for the perception of absorption into the skin.

[0017] In vitro skin penetration studies on human skin demonstrate that the co-enhancer silicone cream technology effectively penetrates the stratum corneum barrier. 14The partitioning of alcohol diffusion coefficient enhancers is not impaired by the inclusion of a silicone emollient such as caprylyl methicone. Figure 1 shows the effect of C8-C6 in propylene glycol and the silicone emollient caprylyl methicone. 22 The solubility of fatty alcohol, fatty acid, and fatty acid ester diffusion coefficient enhancers is shown in Table 1. 10 The fatty acid and alcohol diffusion coefficient enhancers of C are highly soluble in propylene glycol, so their penetration into the skin barrier is minimal. 12 and C 14 Acid and C 14 Only alcohol has adequate solubility in both propylene glycol and caprylyl methicone and is therefore a suitable diffusion coefficient enhancer. Figure 3 shows the diffusion coefficient enhancer C in caprylyl methicone for a range of common emollient esters and silicone emollients. 14 This shows the solubility of alcohol in common emollient esters. 14 The high solubility of alcohols allows them to penetrate the stratum corneum barrier. 14 This is quite consistent with the hypothesis that alcohol partitioning is impaired to such an extent that it reduces the skin penetration ability of the incorporated active ingredient by a factor of 5-10.

[0018] British Patent No. 2549418B describes a topical cream formulation with high skin penetration, capable of efficiently and predictably delivering active ingredients to target areas of the skin. Furthermore, when a glycol-coenhancer silicone emollient / elastomer cream is applied to the skin, consumers experience a soft, smooth feel from the mixed silicone elastomer-silicone fluid emollient continuous phase. The disappearance of the volatile silicone occurs rapidly, leading to the perception of absorption into the skin. This cosmetic technology is widely used in premium brand cosmetic skin creams. However, our consumer research revealed that, although consumers recognize and appreciate the soft, smooth feel and perceive skin penetration when the volatile material disappears, they add, "But I'm not sure if it's really good."

[0019] Described herein are formulations containing primary active(s) with a supplemental user adherence improving skin barrier repair system containing nicotinamide and polyhydroxy acid, in addition to improved skin penetration and exceptional aesthetics, to not only restore the skin to its natural healthy state but also give the user reason to believe in their treatment and motivation to continue adhering to their primary treatment regimen.

[0020] Nicotinamide, logP O / W -0.38 and polyhydroxy acid (lactobionic acid / gluconolactone, logP O / W -4.8) are both hydrophilic compounds, so e.g., C 14 They have little or no ability to dissolve diffusion coefficient enhancers, such as alcohols with logP O / W>+4.00. For the same reason, both are distributed in the glycol dispersed phase and have very low solubility in the continuous silicone phase. Both have a pKa of about pH 3.5, which means that by definition, they are 50% non-ionized, thus providing greater skin penetration. However, as the pH decreases, the proportion of non-ionized polyhydroxy acids increases and decreases for nicotinamide. As the pH increases, the opposite occurs. As demonstrated in our examples, this allows for flexibility in optimizing the pH, for example, depending on the chemical nature of the primary active substance(s). In addition, our N-VRP formulation concept can optionally use volatile buffer technology to achieve different, individually optimized in-pack equilibrium phase pHs, as described in US Pat. No. 10,028,927.

[0021] In view of the above-mentioned problems, various proposals have been made, but there remains a need for improved formulations that address one or more of the problems presented by prior art configurations. In this regard, the present invention seeks to provide a formulation that preferably addresses one or more of the problems presented by prior art configurations. Summary of the Invention

[0022] According to a first aspect of the present invention, there is provided a formulation for topical application, said formulation comprising a main active ingredient for the topical treatment of the skin, a skin barrier repair combination that improves user adherence of 1.0 to 5% w / w of nicotinamide and 1.0 to 5% w / w of a polyhydroxy acid, and a compound of the general formula: C n H 2n+2 O2 (where n is an integer of 3 to 5), and a 10 to 60% w / w partition coefficient enhancer (PC enhancer) having the structure C 12 ~C 14 Straight-chain fatty acids and C 14 The formulation comprises: a diffusion coefficient enhancer (DC enhancer) selected from the group consisting of linear primary alcohols; a first dimethicone macromer mixture comprising a dimethicone macromer and a hydrocarbyl methyl siloxane emollient selected from the group consisting of alkyl methyl siloxanes, aryl methyl siloxanes, and alkylaryl methyl siloxanes; and a second dimethicone macromer mixture comprising a methyl siloxane compound and a crosslinked dimethicone macromer, wherein the formulation comprises less than 15% by weight of water.

[0023] Suitably, the formulation comprises one or more active substances.

[0024] The formulations of the present invention incorporate a functional co-enhancer active ingredient delivery system while retaining the aesthetics associated with the use of superior cosmetic and cosmeceutical technology. Additionally, the skin barrier repair combination, which includes nicotinamide and polyhydroxy acid, improves user adherence by restoring the skin surface to a natural, healthy state, which is perceived by the user with continued use, promoting user adherence. Increased patient adherence to treatments involving application of the formulations also improves medical outcomes.

[0025] According to another aspect of the present invention, there is provided a cosmetic formulation comprising a formulation described herein and one or more pharmaceutically acceptable carriers or excipients.

[0026] The formulations disclosed herein are provided for use in therapy.

[0027] According to another aspect of the present invention, there is provided a method for preventing, reducing the likelihood of, alleviating or treating a medical condition in the human or animal body, comprising topical administration of a therapeutically effective amount of the formulations described herein.

[0028] According to another aspect of the present invention there is provided a formulation according to the present invention for use in the prevention, alleviation or treatment of a medical condition in the human or animal body.

[0029] The medical condition may be selected from the group consisting of pain and / or inflammation, pigmentation, pruritus, acne, blistering skin conditions such as eczema, psoriasis, rosacea, bullous pemphigoid, diaper rash, dry skin, bacterial conditions including fungal and / or skin infections such as yeast infections and dermatophyte infections, viral infections of the skin or mucous membranes, warts, dry or aging skin, androgen deficiency, immune conditions, freckles, actinic keratosis, basal cell and squamous cell skin cancer and melanoma, alopecia, and radiation therapy dermatitis. The medical condition is typically treated by topical application.

[0030] According to another aspect of the present invention, there is provided a method of forming the formulations described herein, which formulations are generally applied to biological membranes, particularly the skin of the human or animal body, including the mucous membranes of the human or animal body. [Brief explanation of the drawings]

[0031] The invention will now be further described, by way of example only, with reference to the accompanying drawings in which:

[0032] [Figure 1] 1 shows the solubility of C8-C22 fatty alcohol, fatty acid, and fatty acid ester diffusion coefficient enhancers in propylene glycol and the silicone emollient caprylyl methicone. [Figure 2]Only the C12 and C14 acids and C14 alcohols have adequate solubility in both propylene glycol and caprylyl methicone, and therefore are shown to be suitable diffusion coefficient enhancers. [Figure 3] 1 shows the solubility of a suitable diffusion coefficient enhancer, C14 alcohol, in common emollient esters and the silicone emollient, caprylyl methicone. [Figure 4] The dose response of ceramide synthesis to NAM added to human keratinocytes in vitro (FIG. 4a) and the dose response of PARP-1 to NAM in vitro (FIG. 4b) are shown. [Figure 5] Data are shown for steady-state flux (n=6) achieved after a lag period of 8-24 hours. [Figure 6] 1 shows the results of a questionnaire that investigated the subjects' experience when using the cream; cosmetic properties, ease of application, efficacy, and tolerance. [Figure 7] The materials used are shown below. [Figure 8] The chemical structure and stability of nicotinamide (Figure 8a) and the results of storage at 40°C for 6 months (Figure 8b) are shown. DETAILED DESCRIPTION OF THE INVENTION

[0033] It will be understood that the aspects, embodiments, and preferred features of the invention have been described in a manner that enables the specification to be written clearly and concisely. However, unless circumstances specifically indicate otherwise, the aspects, embodiments, and preferred features may be variously combined or separated in accordance with the present invention. Thus, preferably, the present invention provides a device having features of two or more, three or more, or four or more of the aspects described herein. In one preferred embodiment, a device according to the present invention includes all aspects of the present invention.

[0034] Within the context of this specification, the term "about" means ±20%, more preferably ±10%, even more preferably ±5%, and most preferably ±2%.

[0035] Within the context of this specification, the term "substantially" preferably means at least 90%, more preferably 95%, even more preferably 98%, and most preferably 99%.

[0036] Within the context of this specification, the term "comprises" means "particularly comprises" and should not be interpreted as meaning "consisting only of".

[0037] Within the context of this specification, the term "active agent" means a molecule that has pharmaceutical activity. This term includes pharmacologically active compounds.

[0038] An "effective" amount or "therapeutically effective amount" means a sufficient amount of one or more active agents to provide the desired effect without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment.

[0039] All values ​​presented preferably incorporate less than 10% by weight and more than 10% by weight of the presented value.

[0040] The partition coefficient is the ratio of the amounts of a substance in a mixture of two immiscible phases at equilibrium. The partition coefficient can be calculated using the following formula:

[0041] K partition =[X (phase1) ] / [X (phase2) ] where K is the partition coefficient, X is the substance, and X (phase1) is the amount of material in the first phase, and X (phase2) is the amount of material in the second phase.

[0042] As used herein, a partition coefficient (PC) enhancer increases the partition coefficient of an active agent between the non-volatile residual phase of the formulation and the stratum corneum barrier of the skin, enhancing the penetration of the active agent into the target site on or under the skin.

[0043] As used herein, a diffusion coefficient (DC) enhancer increases the diffusion coefficient of an active agent through the stratum corneum barrier of the skin, enhancing penetration of the active agent into the target site in the skin or subcutaneously.

[0044] Partition coefficient (PC) enhancers and diffusion coefficient (DC) enhancers affect the penetration of active agents into the cutaneous or subcutaneous target site as defined by Fick's first law of diffusion:

[0045] F=Cv*PC*DC / h where F is the flux, i.e., the mass of substance passing through the stratum corneum per unit time and unit area, CV is the concentration of the active ingredient in solution in the non-volatile residual phase, PC refers to the partition coefficient enhancer effect, DC refers to the diffusion coefficient enhancer effect, and h is the thickness of the stratum corneum barrier.

[0046] Preferably, a modification of Fick's first law of diffusion is used in the design of the following formulations.

[0047] F=~DSv * sat sol SC * DC / h where F is the flux, i.e., the mass of drug passing through the stratum corneum per unit time and unit area, and DS V is the saturation degree of the active ingredient in the solution of the non-volatile residual phase, sat solSC is the saturated solubility of the active ingredient in the stratum corneum (affected by the partition coefficient enhancer), DC refers to the diffusion coefficient enhancer effect, and h is the thickness of the stratum corneum barrier.

[0048] For purposes of the present invention, the term "highly volatile" refers to liquids such as Dow Corning® Q7-9180 silicone fluid (0.65 cSt hexamethyldisiloxane and 1.0 cSt octamethyltrisiloxane), ethanol, isopropyl alcohol, and water, which have a skin-temperature evaporation half-life of less than 5 minutes. The term "volatile" refers to liquids such as cyclopentasiloxane (D5), which have a skin-temperature evaporation half-life of approximately 1 hour. The term "non-volatile" refers to liquids such as caprylyl methicone and polydimethylsiloxane (Dow Corning Q7-9120 silicone fluid), which have a skin-temperature evaporation half-life of approximately 6 to 24 hours. The formulations of the present invention are intended to be applied once or twice daily.

[0049] The phrase "non-volatile residual phase" refers to the composition of the formulation remaining after evaporation of volatile solvents such as Dow Corning Q7-9180 silicone fluid (0.65 cSt and 1.0 cSt), ethanol, isopropyl alcohol, and water, and generally includes actives, PC enhancers, DC enhancers, and medium and high molecular weight materials. As used herein, alkylmethylsiloxanes such as nominally volatile Silicone ST, Cyclomethicone 5-NF, and Caprylyl Methicone are considered relatively medium / non-volatile within the time frame of topical application and absorption.

[0050] The term "carbinol" is used to refer to a hydroxyl functional group bonded to a carbon atom, which may be bonded to a carbon atom (e.g., a carbon atom that forms part of a hydrocarbon group), a non-carbon atom, such as Si, N, or O.

[0051] The phrase "small alkyl group" refers to an alkyl group having a carbon backbone of from 1 to 6 carbon atoms, typically from 1 to 4 carbon atoms.

[0052] According to a first aspect of the present invention, there is provided a topical formulation comprising a primary active ingredient for the topical treatment of the skin, a skin barrier repair combination that improves user adherence of 1.0 to 5% w / w of nicotinamide and 1.0 to 5% w / w of a polyhydroxy acid, and a compound of the general formula: Cn H2 n+2 O2 (where n is an integer of 3 to 5), and a 10 to 60% w / w partition coefficient enhancer (PC enhancer) having the structure C 12 ~C 14 Straight-chain fatty acids and C 14 The formulation comprises: a diffusion coefficient enhancer (DC enhancer) selected from the group consisting of linear primary alcohols; a first dimethicone macromer mixture comprising a dimethicone macromer and a hydrocarbyl methyl siloxane emollient selected from the group consisting of alkyl methyl siloxanes, aryl methyl siloxanes, and alkylaryl methyl siloxanes; and a second dimethicone macromer mixture comprising a methyl siloxane compound and a crosslinked dimethicone macromer, wherein the formulation comprises less than 15% by weight of water.

[0053] Generally, the formulation is a polyol-in-silicone dispersion cream or serum.

[0054] According to one embodiment, the present invention provides a formulation suitable for topical application of an active compound, the formulation comprising the active compound in a carrier, the carrier comprising a partition coefficient enhancer, C, comprising a secondary or primary alcohol group. 12 ~C 14 Fatty acids and C 14 The composition includes a diffusion coefficient enhancer selected from the group consisting of alcohols, a first dimethicone macromer mixture, and a second crosslinked dimethicone macromer mixture.

[0055] Generally, the formulation will comprise a solution, suspension or dispersion of the active agent in the carrier. Preferably, the active ingredient is in solution.

[0056] The formulations of the present invention achieve and improve the effectiveness of active ingredient delivery and enhance adherence. Specifically, the formulations of the present invention have higher skin penetration than known formulations, allowing high therapeutic free active substance concentrations to be achieved and maintained at the target site. Typically, the free active substance concentration at the target site greatly exceeds the EC50 (half the maximum effective concentration). The delivery efficiency of the active substance to the target site is maximized, resulting in an effective and reliable dosing regimen. Therefore, severe symptoms can be treated or more reliable clinical responses can be achieved in the general patient population.

[0057] Additionally, adherence to the use of the formulation is enhanced by the use of silicone fluids and silicone emollients, which provide an improved feel and perceived wear. Continued use of the skin barrier repair system, which improves adjunctive user adherence, provides a visible improvement in skin health as well as a reason to trust and maintain adherence over long or intensive treatment periods.

[0058] The absorption range of most skin active ingredients is 1-5% of the dosage applied to intact skin. At permeable skin sites, the absorbed dose increases significantly, leading to local and systemic side effects. The formulations of the present invention not only control the dosage of the active agent, reducing potential side effects, but also improve adherence. Because delivery of the active agent to the target site is optimized through the use of the formulations of the present invention, the amount of active agent contained in the formulation can be reduced, typically to 5-10% of the current dosage. This reduces the risk and concern of side effects, maximizes adherence to the treatment, and reduces waste and associated costs due to overdosing from inefficient drug delivery systems. While this has traditionally been viewed as an economic waste problem, it now also includes environmental pollution issues resulting from excess drug washing and release into the environment. Above all, this is a significant therapeutic issue.

[0059] The formulations of the present invention are effective enough to reduce dosing, reducing the need for application of known formulations two to six times per day to one to three times per day, typically once per day. Once-daily or intermittent treatment regimens are widely understood by patients and consumers and are scientifically supported by drug reservoir structures within the stratum corneum. The formulations of the present invention enable such regimens while maintaining therapeutic efficacy and improving adherence.

[0060] It has been found that users prefer creams over gel and ointment formulations.

[0061] Emollients are the primary functional aesthetic ingredient in creams, typically requiring surfactant and wax co-excipients for effective dispersion. Emollients add spreadability, slip, and smoothness to cosmetic products, promoting adherence. As noted above, most emollients contain hydrocarbon structural elements that are predicted to adversely affect the performance of diffusion coefficient-enhancing excipients by solubilizing them in the residual non-volatile phase of the vehicle.

[0062] The formulations generally include cosmetic, cosmeceutical, or pharmaceutical actives.

[0063] Typically, the compound has the general formula C n H 2n+2 O2 (where n=3 to 5).

[0064] Typically, the formulations include a hydrocarbyl methyl siloxane emollient compound selected from the group consisting of caprylyl methicone, lauryl methicone, stearyl methicone, and caprylyl trimethicone. Preferably, the hydrocarbyl methyl siloxane emollient is caprylyl methicone.

[0065] The formulation may also include a highly volatile solvent selected from the group consisting of hexamethyldisiloxane, octamethyltrisiloxane, ethanol, isopropyl alcohol, and water.

[0066] Hydrocarbylmethylsiloxane Emollient A limitation of current co-enhancer technology is that it is not possible to incorporate an emollient while maintaining a high degree of saturation of the active ingredient as well as a high degree of saturation of the diffusion coefficient enhancer, while ensuring optimal skin penetration.Surprisingly, it has been found that polyol-in-silicone emulsions provide a structural matrix for incorporating chemically different excipients.In particular, the inventors have discovered that the chemical type of the hydrocarbylmethylsiloxane emollient excipient is very important due to its compatibility with silicone oil.

[0067] The formulations of the present invention optionally include a substituted hydrocarbylmethylsiloxane emollient. The emollients used in the formulations of the present invention contain hydrocarbon and methylsiloxane backbone structural elements. The methylsiloxane backbone adds a light, smooth, powdery feel, contributing to improved aesthetics of the resulting formulation. The methylsiloxane backbone can be in the form of a linear, branched, or cyclosiloxane compound. The hydrocarbyl portion of the emollient compound can be saturated or unsaturated and can include alkyl, alkenyl, alkynyl, haloalkyl, carbocyclyl, e.g., heterocyclyl, aryl, or heteroaryl groups. The hydrocarbyl portion of the emollient compound can be linear or branched, substituted or unsubstituted.

[0068] According to one embodiment, one or more carbon or silicon atoms of the hydrocarbylmethylsiloxane group may each be substituted with one or more of the group consisting of small hydrocarbyl groups, typically small alkyl groups (preferably 1 to 6 carbon atoms), cycloalkyl groups, C1 to C6 alkoxyl, halogen, trifluoromethyl, cyano, thio, amino, nitro, oxo, and hydroxyl.

[0069] Typically, the hydrocarbylmethylsiloxane group is substituted with one or more small alkyl groups, halogen groups and / or hydroxyl groups, typically one or more small alkyl groups.

[0070] Generally, the hydrocarbylmethylsiloxane groups are unsubstituted.

[0071] Hydrocarbylmethylsiloxanes generally have the following structure:

[0072] [ka] wherein each R group represents a hydrocarbyl group or hydrogen, at least one R group represents a methyl group, and at least one R group represents a hydrocarbyl group.

[0073] Typically, one to three R groups each represent a hydrocarbyl group containing two or more carbon atoms and are usually selected from the group consisting of alkyl groups having a backbone of two or more carbon atoms, aryl groups, and alkyl groups bonded to aryl groups. Typically, the or each alkyl group is a small alkyl group. Preferably, one or two R groups each represent a hydrocarbyl group containing two or more carbon atoms. Typically, each R group represents a methyl or hydrocarbyl group containing two or more carbon atoms. Preferably, each R group represents a methyl, an alkyl group having a backbone of two or more carbon atoms, an aryl group, or an alkyl group bonded to an aryl group. Typically, the or each alkyl group is a small alkyl group. According to one embodiment, hydrocarbylmethylsiloxane refers to a compound having the structure shown below:

[0074] [ka] [ka] where R represents a hydrocarbyl group, typically an alkyl or aryl group.

[0075] Particular mention may be made of alkylmethylsiloxane, arylmethylsiloxane, and alkylarylmethylsiloxane. According to one embodiment, the emollient is alkylmethylsiloxane or alkylarylmethylsiloxane. Suitable emollients include cetyl dimethicone, stearyl dimethicone, phenyl dimethicone, caprylyl methicone (e.g., TI-2021AMS from Dow Corning), myristyl methicone, stearyl methicone, lauryl methicone (e.g., from Siltec), caprylyl trimethicone (e.g., from Clariant), and decamethylcyclopentasiloxane.

[0076] The primary chemical properties and state of matter of any hydrocarbyl methyl siloxane (including alkyl methyl siloxanes and alkylaryl methyl siloxanes) can be inferred from the ratio of hydrocarbon to methyl siloxane and the hydrocarbon chain length. Therefore, the principles for selecting appropriate alkyl and alkylaryl methyl siloxanes are recognized by those skilled in the art. In general, alkyl methyl siloxanes and alkylaryl methyl siloxanes that are liquid due to their low hydrocarbon content and short hydrocarbon chain length are suitable as emollients. Such liquid alkyl methyl siloxanes include caprylyl methicone, lauryl methicone, stearyl methicone, and caprylyl trimethicone.

[0077] Typically, the hydrocarbylmethylsiloxane compound has a number average molecular weight of less than 1000, preferably less than 800, typically less than 500. According to one embodiment, the hydrocarbylmethylsiloxane compound has a number average molecular weight of 100 to 700, typically 200 to 400.

[0078] The solubility of the active compound and the functional diffusion coefficient (DC) enhancer can be studied to select a suitable hydrocarbylmethylsiloxane emollient for use in the present invention. The formulations of the present invention contain two or more methylsiloxane-containing compounds, particularly two or more hydrocarbylmethylsiloxanes, usually two or more alkyl-, aryl-, or arylalkyl-methylsiloxane compounds (generally having a number average molecular weight of less than 1000).

[0079] Typically the hydrocarbyl methyl siloxane consists of or includes caprylyl methicone.

[0080] Suitably, the formulation comprises one or more cyclomethicone compounds such as cyclopentasiloxane, especially decamethylcyclopentasiloxane.

[0081] The saturated solubility of typical corticosteroids fluticasone propionate (FP) and mometasone furoate (MF) in silicone fluids suitable for use in the present invention, including the alkylmethylsiloxane emollient caprylyl methicone, is sufficiently low that high saturation of the active compound in the non-volatile residual phase can be achieved even with significantly reduced active compound dosages in the presence of the emollient.

[0082] Diffusion Coefficient-Enhancing Excipients As mentioned above, diffusion coefficient enhancing excipients (DC enhancers) are generally C8-C 22 The hydrocarbon alcohol, acid, or ester derivatives are included. Figures 1-3 show the performance of linear saturated C8-C6 hydroxybenzoates in caprylyl methicone, propylene glycol as a partition coefficient enhancer, and hydrocarbon-based emollient esters at 23-25°C. 22 The solubility of alcohols, acid and ester derivatives, and 5-NF (decamethylcyclopentasiloxane, a silicone fluid) is shown.

[0083] In Figure 1 of the acid and alcohol series, the carbon chain length is C 16 As it increases beyond C 18 ~C22 Since the solubility of C8 and C9 in caprylyl methicone drops to less than 0.1% w / w, these larger carbon chain lengths can be considered unsuitable for use as DC enhancers in the formulations of the present invention due to low solubility-dissolution constraints. 10 Alcohols and C8 and C 10 Small carbon chain length acids and alcohols, such as caprylyl methicone, are believed to be highly soluble in hydrocarbyl methyl siloxanes, including caprylyl methicone, thereby adversely affecting their performance as diffusion coefficient enhancing excipients. 14 ~C 16 ) isopropyl esters are highly soluble in hydrocarbyl methyl siloxanes such as caprylyl methicone, enabling their performance as DC enhancers. For both of these types of DC enhancers, up to 50% of the DC enhancer is required to saturate or nearly saturate the non-volatile residual phase. In contrast, C 12 ~C 14 Acid and C 14 Alcohol has suitable solubility in caprylyl methicone. As shown in Figure 3, 14 The alcohol has adequate solubility in both the hydrocarbylmethylsiloxane and 5-NF (decamethylcyclopentanecyclohexane).

[0084] As shown in Figure 1, the partition coefficient (PC) enhancer propylene glycol contains short chain C8-C 10 Fatty acids and short chain C8-C 12 The DC enhancers alcohol and fatty acids would be adversely affected because the solubility of fatty alcohols would be too high. 16 ~C 22 The solubility of C is too low to achieve satisfactory performance. 12 ~C 14 Acid and C 14 The alcohol has suitable solubility in propylene glycol.

[0085] As shown in detail in Figure 2, 12 ~C 14 Acid and C 14Only alcohol has adequate total solubility with propylene glycol and caprylyl methicone.

[0086] Figure 3 shows the C values ​​of suitable diffusion coefficient enhancers in common emollient esters and the silicone emollient caprylyl methicone. 14 This shows the solubility of alcohol in common emollient esters. 14 The high solubility of alcohols allows them to penetrate the stratum corneum barrier. 14 This is quite consistent with the hypothesis that alcohol partitioning is impaired to such an extent that it reduces the skin penetration ability of the incorporated active ingredient by a factor of 5-10.

[0087] Propylene glycol, e.g., C 14 As an example of a rough design for a simple co-enhancer system containing an alcohol diffusion coefficient enhancer and caprylyl methicone, we first consider concentrations of propylene glycol and caprylyl methicone in the final formulation (otherwise comprised of non-solvents) of 25% each. Based on this, we expect the C 14 The total amount of alcohol is 2.44% / 4 + 2.30% / 4 = 1.185%, or approximately 1.2%. Experience has shown that a concentration of diffusion coefficient enhancer in the range of 1-5% w / w is required, thus falling within the optimum range for the chosen diffusion coefficient enhancer.

[0088] The DC enhancers used in the formulations of the present invention generally include C 12 ~C 16 Acids and C12-C 14 Alcohol, usually C 12 ~C 14 Straight-chain fatty acids and C 14 The group of compounds selected is preferably soluble in both the hydrocarbylmethylsiloxane and the partition coefficient enhancer, thereby enabling strong diffusion coefficient enhancement and efficient epidermal delivery of the active agent.

[0089] The fatty acids used in the formulations of the present invention have a carbon backbone of 12 to 16 carbon atoms, preferably 12 to 14 carbon atoms. The alcohols used in the formulations of the present invention have a carbon backbone of 12 to 14 carbon atoms, typically 14 carbon atoms. In some embodiments, the fatty acids / alcohols can include a substituent from the carbon backbone that can include additional carbon atoms. In particular, the fatty acids / alcohols can include a hydrocarbyl substituent containing 1 to 3 carbon atoms.

[0090] Generally, the fatty acids / alcohols used in the formulations of the present invention are not substituted.

[0091] DC enhancers generally comprise substituted Cs that can be optionally saturated or unsaturated. 12 ~C 16 Generally, the fatty acids / alcohols used in the formulations of the present invention are saturated.

[0092] Typically, DC enhancers are saturated fatty acids with a carbon backbone of 12 to 14 carbon atoms.

[0093] According to one embodiment, the fatty acid / alcohol is unsaturated and the two carbon molecules in the carbon backbone adjacent to the or each double bond can be in a cis or trans configuration, generally in a trans configuration.

[0094] Alternatively, the DC enhancer may optionally contain a substituted C, which may be saturated or unsaturated. 14 It may also be an alcohol. Typically, the DC enhancer is a straight chain primary alcohol.

[0095] Typically, the DC enhancer is a saturated alcohol having a carbon backbone of 12 to 14 carbon atoms, typically 14 carbon atoms. According to one embodiment, the acid or alcohol DC enhancer can be substituted. One or more of the carbon atoms can each be substituted with one or more C1-C6 hydrocarbyl groups, typically C1-C4 alkyl groups.

[0096] Suitable Substitute C 12 ~C 16 Acid and C 12 ~C 14 The alcohol can be easily identified by its overall solubility in the hydrocarbylmethylsiloxane and the partition coefficient enhancer.

[0097] According to one embodiment of the present invention, the DC enhancer is C 12 ~C 14 Straight-chain fatty acids and C 12 the group consisting of C to C alcohols, in particular C 12 ~C 14 Straight-chain fatty acids and C 14 The alcohol is selected from the group consisting of straight chain primary alcohols.

[0098] Typically, the DC enhancer is selected from the group consisting of lauric acid, myristic acid, and myristyl alcohol.

[0099] The amount of DC enhancer required will depend on the other ingredients of the formulation, particularly the identity and amount of the hydrocarbyl silicone emollient and PC enhancer used, as discussed above.

[0100] Typically, the formulations of the present invention contain less than about 10% w / w, usually less than about 5% w / w, and preferably less than about 4% w / w of DC enhancer. The formulations contain at least about 0.5% w / w, usually at least about 0.7% w / w, and typically at least about 1% w / w of DC enhancer.

[0101] According to one embodiment, the formulation comprises less than 10% w / w of DC enhancer, typically 1-4% w / w, usually less than 2% w / w, suitably 0.5-2% w / w of DC enhancer.

[0102] Partition coefficient enhancing excipients The inclusion of a partition coefficient enhancer (PC enhancer) improves the solubility of the active in the stratum corneum barrier, increasing skin penetration.

[0103] The formulations of the present invention generally comprise at least one PC enhancer, in particular at least one OH-terminal PC enhancer. Typically, the PC enhancer is a primary or secondary alcohol, in particular a diol or polyol compound. In particular, the PC enhancer is of the general formula C n H 2n+2 O2, where n is an integer of 3 to 6.

[0104] Typically, the PC enhancer has a number average molecular weight of 1500 or less, usually 750 or less, preferably 150 or less.

[0105] Typically, PC enhancers are (common names and IUPAC names): propylene glycol, propane-1,2-diol, n=3; butylene glycol, butane-1,3-diol, n=4; or pentylene glycol, pentane 1,5 diol, n=5.

[0106] Typically, the partition coefficient enhancer is propylene glycol.

[0107] Generally, a second, mutually miscible PC enhancer / cosolvent is present in the formulation to adjust the saturation of the active ingredient in the residual phase. This can take the form of a diol, triol, alcohol, ether alcohol, or alkylpyrrolidone. Suitable diols have the general formula C n H 2n+2 O2 (n≧6). Suitable alcohols have the general formula C n H 2n+2 O where n=2 or 3. Suitable INCI listed ether alcohols have the general formula C n H 2n+2 O3, for example, dipropylene glycol CH 14 O3;Transcutol (diethylene glycol monoethyl ether)C6H 14 O3;ButoxydiglycolC8H 16 O3;Diethylene glycolC4H 10 O3; DimethoxydiglycolC6H 14 O3, methoxydiglycol C5H12 O3. The ether alcohols on the INCI list that are relevant are of the general formula C n H 2n+2 O2, for example, butoxyethanol CH 14 O2; Ethoxyethanol C4H 10 O2; Ethylhexanediol C8H 18 O2;Methoxyethanol C3H8O2,Methoxyisopropanol C4H 10 O2. A suitable alkylpyrrolidone is N-methylpyrrolidone. A suitable triol is glycerol.

[0108] The amount of PC enhancer required will depend on the degree of skin penetration enhancement desired and the identity and amount of the other ingredients in the formulation, particularly the hydrocarbyl silicone emollient and DC enhancer used.

[0109] Typically, the formulations of the present invention contain less than about 70% w / w, preferably less than about 50% w / w, usually less than about 40% w / w, and more preferably less than about 30% w / w of PC enhancer. The formulations preferably contain at least about 10% w / w, usually at least about 20% w / w of PC enhancer.

[0110] According to one embodiment, the formulation comprises 10-60% w / w of PC enhancer.

[0111] First Dimethicone Macromer Mixture The first dimethicone macromer mixture includes a dimethicone macromer and a hydrocarbylmethylsiloxane emollient selected from the group consisting of alkylmethylsiloxanes, arylmethylsiloxanes, and alkylarylmethylsiloxanes.

[0112] The first dimethicone macromer mixture generally includes a polyglycol dimethicone macromer.

[0113] The first dimethicone macromer mixture typically includes a polyglycol dimethicone macromer surfactant having a number average molecular weight greater than 1000 (usually greater than 2000) and a hydrocarbylmethylsiloxane emollient (typically an alkylmethylsiloxane) having a number average molecular weight less than 500.

[0114] The first dimethicone macromer mixture can contain 5-30% w / w, typically 10-20% w / w, and usually 12-19% w / w of polyglycol dimethicone macromer surfactant.

[0115] Typically, the polyglycol dimethicone macromer surfactant comprises one or more polyalkylsiloxane moieties (typically one or more dimethylsiloxane moieties) and one or more oxypropylene or oxyethylene moieties. Preferably, the dimethicone macromer comprises one or more copolymers of ethylene oxide and propylene oxide.

[0116] In particular, the first polyglycol dimethicone macromer surfactant mixture comprises a polyglycol dimethicone macromer crosslinked with a polyalkylene oxide compound (typically a polyethylene glycol compound, a polypropylene glycol compound, or a copolymer of ethylene oxide and propylene oxide).

[0117] The first dimethicone macromer mixture can include a polyglycol dimethicone macromer surfactant selected from the group consisting of PEG dimethicone PPG crosspolymer and PEG dimethicone bis-isoalkyl PPG crosspolymer.

[0118] Generally, dimethicone macromers contain one or more terminal carbinol groups.

[0119] Dimethicone macromers are dihydroxy-terminated block copolymers of varying molecular weights containing various weight percent non-siloxane units, and may have the structure oxyethylene-dimethylsiloxane-oxyethylene; oxypropylene-dimethylsiloxane-oxypropylene, or caprolactone-dimethylsiloxane-caprolactone. Optionally, the block copolymers may contain pendant oxyalkylene groups. Typically, the block copolymers can be crosslinked.

[0120] The dimethicone macromer can have a non-siloxane content of 20-70% by weight.

[0121] The number average molecular weight of the or each dimethicone macromer is generally 800 or more, preferably 1000 or more, usually 1000 to 10000, preferably 2000 to 7000.

[0122] According to one embodiment, the higher the number average molecular weight of the dimethicone macromer, the higher the non-siloxane weight % content.

[0123] Dimethicone macromers can take the form of a dimethicone-containing central linking group attached to 2 to 5 polyoxyalkylene groups, typically 2 to 5 oxypropylene groups. Typically, dimethicone macromers contain 3, 4, or 5 polyoxyalkylene groups.

[0124] Generally, the polyoxyalkylene group is a polymer and / or copolymer of ethylene oxide and / or propylene oxide. The polyoxyalkylene group can contain primary or secondary hydroxyl groups or mixtures thereof.

[0125] According to one embodiment, the dimethicone macromer comprises a dimethicone backbone having one or more pendant polyoxyalkylene groups selected from the group consisting of oxyethylene groups, oxypropylene groups, and copolymers of oxyethylene and oxypropylene. Typically, the pendant polyoxyalkylene groups contain 5 to 50 repeating units, preferably 10 to 30 repeating units, and usually 15 to 20 repeating units.

[0126] Typically, dimethicone macromer surfactants contain a dimethicone backbone with one or more pendant oxyethylene groups and one or more pendant oxypropylene groups.

[0127] For example, the dimethicone macromer can have the following general structure of the pendant polymer PEG / PPG-18 / 18 dimethicone: where m and n each represent an integer between 10 and 30, preferably 18.

[0128] [ka]

[0129] Alternatively or additionally, the dimethicone macromer can comprise a dimethicone backbone with one or more pendant block copolymers of oxyethylene and oxypropylene. For example, a dimethicone macromer may have the following general structure: where m and n are each integers from 10 to 30, preferably m=20 and n=15. Such a macromer is commercially available as Silsoft® SF1540.

[0130] [ka]

[0131] Alternatively or additionally, the dimethicone macromer can include a dimethicone backbone with one or more oxyethylene endblocks, typically one or more PEG endblocks, usually two PEG endblocks. For example, the endblock copolymer bis-PEG-10 dimethicone is shown below. [ka]

[0132] Advantageously, the dimethicone macromer is crosslinked. In particular, the first dimethicone backbone is crosslinked to the second dimethicone backbone through one or more bridging groups, such as substituted or unsubstituted hydrocarbyl groups, particularly substituted or unsubstituted alkylene groups. In particular, the bridging groups can be selected from the group consisting of unsubstituted alkylene groups and oxyalkylene groups, particularly one or more oxyethylene or one or more oxypropylene groups. Typically, the oxyalkylene bridging group contains 5 to 50 repeating groups. The dimethicone macromer can also contain one or more pendant oxyalkylene groups that are not crosslinked to the dimethicone backbone.

[0133] Dimethicone PEG-10 crosspolymer is an example of a polyethylene glycol cross-linked dimethicone macromer. [ka]

[0134] PEG-12 dimethicone crosspolymer is an example of a hydrocarbon diene cross-linked copolymer emulsifier with pendant polyethylene glycol groups. [ka]

[0135] According to one embodiment, the dimethicone copolymer comprises a first dimethicone backbone containing at least one side group containing an oxyalkylene (particularly an oxypropylene or oxyethylene group) and a second dimethicone backbone crosslinked thereto containing at least one side group containing an oxyalkylene (particularly an oxypropylene or oxyethylene group), the crosslinking group comprising an oxyalkylene group (particularly an oxypropylene or oxyethylene group). The repeating oxyalkylene group can be attached to the or each dimethicone backbone through a substituted or unsubstituted hydrocarbyl group, particularly a substituted or unsubstituted alkyl group (generally a C1-4 alkyl group).

[0136] Typically the side groups are oxyethylene groups containing 5 to 50, typically 10 to 15 repeating groups.

[0137] Typically, the bridging group is an oxypropylene group containing 5 to 50 repeating groups, typically 15 to 30 repeating groups.

[0138] PEG-12 dimethicone PPG20 crosspolymer is an example of a suitable silicone polyether used as a dimethicone macromer crosslinked with polypropylene glycol and pendant polyethylene glycol. [ka]

[0139] Further examples of suitable crosslinked silicone polyethers are shown below. [ka]

[0140] These PPG crosslinked PEG-12 pendant dimethicone crosspolymers are dissolved C 12 -C 14 Acid and C 12 It is particularly useful for stabilizing propylene glycol in silicone oil non-aqueous emulsions containing alcohol functional excipients.

[0141] Alternatively or additionally, the dimethicone macromer may comprise a dimethicone backbone with ionic pendant chains of the general structure shown below, where X represents a hydrophilic amine, a quaternary amine, or a functional group. [ka]

[0142] Particularly preferred is the pyrrolidone carboxylic acid functionalized dimethicone macromer, specifically the INCI designation PCA dimethicone. This ionic dimethicone macromer, especially in combination with PPG crosslinked PEG-12 pendant dimethicone crosspolymer, provides dissolved C 12 ~C 14 Acid and C 12 Suitable for stabilizing propylene glycol in silicone oil non-aqueous emulsions containing alcohol functional excipients. [ka]

[0143] According to one embodiment, the formulations of the present invention comprise two or more dimethicone macromers, typically two or more polydialkylsiloxane diol compounds or ionic dimethicone macromer surfactants.

[0144] Generally, the dimethicone macromer is dispersed, dissolved, or suspended in the hydrocarbylmethylsiloxane compound, or vice versa.

[0145] In particular, the or each dimethicone macromer can be dispersed, dissolved or suspended in an alkylmethylsiloxane such as caprylyl methicone, lauryl methicone, stearyl methicone, or caprylyl trimethicone.

[0146] Alternatively or additionally, the or each dimethicone macromer may be dispersed, dissolved or suspended in a methylsiloxane compound, for example, a cyclomethicone such as decamethylcyclopentasiloxane.

[0147] According to one embodiment, the formulations of the present invention comprise two or more siloxane-containing compounds, in particular one or more alkyl-methylsiloxane, aryl-methylsiloxane, and / or alkylaryl-methylsiloxane compounds (generally having a number average molecular weight of less than 1000), and one or more dimethicone macromers (usually having a number average molecular weight of more than 1000, preferably more than 2000), generally two or more polyalkylsiloxane diol compounds.

[0148] Typically, the formulation comprises a mixture of one or more alkylmethylsiloxane compounds and / or alkylarylmethylsiloxane compounds (typically having a number average molecular weight of less than 1000) with one or more dimethicone macromers having a number average molecular weight greater than 1000, the mixture comprising 50-95% w / w of alkyl and / or alkylarylmethylsiloxane compounds having a number average molecular weight of less than 1000 and 5-50% w / w of dimethicone macromer surfactant.

[0149] According to one embodiment, a formulation is provided that includes a hydrocarbylmethylsiloxane compound, an alkylsiloxane compound (generally a methylsiloxane compound, particularly a cyclomethicone compound), and two polyalkylsiloxane macromers.

[0150] The formulations of the present invention can typically include one or more alkyl-methylsiloxane, aryl-methylsiloxane, or alkylaryl-methylsiloxane compounds selected from the group consisting of caprylyl methicone, lauryl methicone, stearyl methicone, caprylyl trimethicone, and decamethylcyclopentasiloxane; and one or more dimethicone macromers, which typically contain one or more polyalkylsiloxane moieties (typically one or more dimethylsiloxane moieties) and one or more oxypropylene or oxyethylene moieties. Typically, the dimethicone macromers contain one or more copolymers of ethylene oxide and propylene oxide.

[0151] According to one embodiment, the formulation of the present invention comprises an alkylmethylsiloxane and / or arylalkylmethylsiloxane having a number average molecular weight of 800 or less and a crosslinked dimethicone macromer having a number average molecular weight of greater than 1000, said dimethicone macromer comprising one or more copolymers of ethylene oxide and propylene oxide.

[0152] Typically, the viscosity of the mixture of hydrocarbylmethylsiloxane compound and dimethicone macromer is greater than 200,000 cSt, typically 250,000 to 1,000,000 cSt.

[0153] The first dimethicone macromer blend can include a blend of caprylyl methicone and polyethylene glycol dimethicone / polypropylene glycol crosspolymer. A suitable formulation is available from Dow Corning under the INCI name Caprylyl Methicone PEG-12 Dimethicone / PPG-20 Crosspolymer (EL-7040 Hydroelastomer Blend).

[0154] The formulations of the present invention may include a mixture of alkylmethylsiloxanes (generally having a number average molecular weight of less than 1000, usually less than 400) and polyalkylsiloxane diol compounds.

[0155] Second Dimethicone Macromer Mixture The formulations of the present invention include a second dimethicone macromer mixture that includes a methylsiloxane compound and a crosslinked dimethicone macromer.

[0156] The formulations of the present invention can include a mixture of alkylsiloxane compounds (usually cyclomethicone compounds, especially alkylcyclomethicone compounds) having a number average molecular weight of less than 1000 and dimethicone macromers, usually crosslinked polyalkylsiloxane diols, having a number average molecular weight of greater than 1000. A suitable formulation is available from Dow Corning under the tradename ST Elastomer 10.

[0157] First and Second Dimethicone Macromer Mixtures According to one embodiment, the formulation of the present invention can comprise a first dimethicone macromer mixture comprising a hydrocarbylmethylsiloxane compound (typically an alkylmethylsiloxane or alkylarylmethylsiloxane) and a polyglycol dimethicone macromer, typically a crosslinked polyalkylsiloxane diol compound; and a second dimethicone macromer mixture comprising a methylsiloxane compound (particularly a methylcyclomethicone compound) and a dimethicone macromer, typically a crosslinked polyalkylsiloxane diol compound.

[0158] According to one embodiment, the formulation of the invention comprises up to 50% w / w of hydrocarbylmethylsiloxane, usually between 10 and 40% w / w, preferably between 20 and 30% w / w.

[0159] According to one embodiment, the formulation comprises less than 40% w / w, typically not more than 20% w / w, and preferably not more than 20% w / w of alkylsiloxane-containing compounds.

[0160] The formulation may contain up to 30% w / w of dimethicone macromers, especially crosslinked polyalkylsiloxane diol compounds.

[0161] According to one embodiment, the formulations of the present invention comprise not more than 30% w / w, usually not more than 20% w / w, and preferably not more than 10% w / w, of a hydrocarbylmethylsiloxane, typically one or more alkylmethylsiloxane or alkylarylmethylsiloxane compounds having a number average molecular weight of not more than 1000.

[0162] According to one embodiment, the formulations of the present invention comprise no more than 30% w / w, usually no more than 20% w / w, and preferably no more than 10% w / w of a dimethicone macromer surfactant having a number average molecular weight greater than 1000, typically greater than 2000.

[0163] According to one embodiment, the second dimethicone macromer mixture comprises a methylsiloxane compound having a number average molecular weight of less than 1000 and a crosslinked polyalkylsiloxane diol dimethicone macromer having a number average molecular weight of greater than 1000, typically greater than 2000.

[0164] In particular, the second dimethicone macromer mixture can contain 5-30% w / w, typically 10-20% w / w, and usually 12-19% w / w of crosslinked dimethicone macromer.

[0165] The formulation may contain 5-45% w / w, usually 10-40% w / w, and typically 20-30% w / w of the second dimethicone macromer mixture.

[0166] Typically, the first and second dimethicone macromers are mixed in a ratio of 3:1 to 0.6:1, ideally 1.5:1.

[0167] The first crosslinked polyalkylsiloxane diol compound can be in the form of a mixture comprising an alkyl or alkylarylmethylsiloxane and a dimethicone macromer, and the second crosslinked polyalkylsiloxane diol can be in the form of a mixture comprising an alkylsiloxane compound, such as an alkylcyclomethicone compound, and a dimethicone macromer.

[0168] According to one embodiment, the first crosslinked polyalkylsiloxane diol compound may be a PEG dimethicone / PPG crosspolymer such as that sold under the tradename EL-7040 Hydroelastomer Blend by Dow Corning, which contains 17.5 to 19.50% PEG-12 dimethicone / PPG-20 crosspolymer.

[0169] Typically, the second dimethicone macromer blend contains a dimethicone crosspolymer swelled in a silicone fluid such as cyclopentasiloxane. Such dimethicone macromer blends tend to provide a dry, smooth, and non-greasy feel on the skin. They help enhance physical stability and reduce creaming and phase separation when concentrating the continuous phase of water-in-silicone or polyol-in-silicone emulsions. The second crosslinked polyalkylsiloxane diol compound can take the form of a blend of cyclopentasiloxane and dimethicone crosspolymer, such as that sold under the tradename ST Elastomer 10 by Dow Corning, which contains 12.5% ​​high molecular weight silicone elastomer in decamethylcyclopentasiloxane.

[0170] Skin barrier repair system containing nicotinamide and polyhydroxy acid to improve supplemental user adherence Niacinamide and skin and cosmetic uses. The use of topical or oral nicotinamide (NAM) in cosmetic and medical dermatology dates back approximately 50 years and has been documented in several major studies.

[0171] NAM is most often used topically for cosmetic purposes. NAM, cultured in vitro in human keratinocytes at low concentrations of 1–10 μM (maximum response 75%–100%, 1–10 μmol L-1; (μM)), and applied topically to humans in vivo, significantly increases the biosynthesis of ceramides and other stratum corneum lipids by up to fivefold, improving skin barrier function. Figure 4a, taken from Tanno O et al. (British Journal of Dermatology 2000;143:524–531), shows the dose response of ceramide synthesis to NAM added to human keratinocytes in vitro.

[0172] Consistent with this, Soma Y et al. (Int J Dermatol. 2005 March;44(3):197-202) found that a 2% NAM cosmetic cream was a more effective moisturizer than standard petrolatum in a group of 28 patients with atopic dermatitis. Similarly, Draelos ZD et al. (J Cosmet Laser Ther. 2006 June;8(2):96-101) reported in a non-treatment controlled study that a facial moisturizer containing 2% NAM improved the skin barrier in subjects with rosacea. Kawada et al. (J Dermatol. 2008 October;35(10):637-42) also demonstrated the anti-wrinkle effect of a cosmetic product containing 4% NAM compared with a placebo control. Finally, in an extensive study, Wohlrab and Kreft (Skin Pharmacol Physiol. 2014;27(6):311-5) concluded that the antipruritic effects of NAM are primarily due to its barrier protective / restorative effects.

[0173] Polyhydroxy acids and skin and cosmetic applications Polyhydroxy acids (PHAs), typified by lactobionic acid and gluconolactone, are highly effective skin moisturizers and anti-aging compounds (Grimes et al., Cutis. 2004 Feb;73(2 Suppl):3-13), achieving these benefits without significant skin irritation (Tasic-Kostov et al., J Cosmet Dermatol. 2019;18(6):1705-1710).

[0174] One of the basic mechanisms is acidification of the deep stratum corneum (SC), which inhibits, for example, serine protease activity. Hachem JP et al. (Acute acidification of the stratum corneum membrane area using polyhydroxy acids improves lipid processing and inhibits corneodesmosome degradation. J Invest Dermatol. 2010 Feb;130(2):500-10) applied 10% PHA (lactobionic acid) to the flank skin of rats and was able to lower the pH at all SC depths by 0.5-1.0 pH units. In GB2562270A, we reported that propylene glycol / myristyl alcohol (C 14 We were able to demonstrate that 5% PHA (lactobionic acid) in a non-silicone cream with an alcohol co-enhancer can lower the pH of human SC by up to 1.5 pH units in vivo. In conclusion, 5% PHA is optimal for inhibiting serine protease activity that occurs in the pH range of 3-4 in the human stratum corneum.

[0175] Increased serine protease activity in the stratum corneum leads to degradation of key lipid processing enzymes, thus inhibiting the synthesis of essential stratum corneum lipids and further reducing the integrity / cohesion of the stratum corneum through the action of corneodesmosomes, which connect cells together.

[0176] These effects perfectly complement the effects of NAM, which acts to enhance ceramide / essential lipid synthesis. Nature teaches that positive and negative feedback loops are required to keep the system under control; for example, when symptoms such as skin redness are present, the positive feedback loop can be increased and the negative feedback loop decreased to restore normalcy.

[0177] Therapeutic potential of topical niacinamide (NAM) (high dose delivery) in dermatology In early 2017, Limeway Pharma Design (LPD) conducted a literature search on the skin treatment potential of NAM, incorporated into the LPD platform's glycol-in-silicone cream co-enhancer technology. Entering the strings (niacinamide or nicotinamide) and (skin or dermatology or whitening or melasma or ultraviolet or actinic radiation or melanoma or eczema or psoriasis) into PubMed yielded 1,787 hits, of which 101 were deemed relevant and entered into the database "nicotinamide."

[0178] The biological effects of topical niacinamide (NAM) (high doses, 7.5–10%) on the skin are that it is the sole substrate for the DNA repair enzyme poly(ADP) ribose polymerase (PARP-1), inhibiting PARP-1 by 66% at a concentration of 50 μM (Park J, Photochem Photobiol. 2010;86(4):942–948). Figure 4b, from Park J, 2010, shows the dose response of PARP-1 inhibition to NAM in vitro. Concentrations of 50–100 μM NAM are predicted to be necessary for significant PARP-1 inhibition. Therefore, at least 5–10 times the concentration range of 1–10 μmol L–1 (μM) are associated with enhanced biosynthesis of ceramides and other stratum corneum lipids to improve skin barrier function and restore healthy skin.

[0179] NAM inhibition of PARP-1 regulates NFκB-mediated transcription and is therefore important for the expression of adhesion molecules and proinflammatory mediators such as IL-12, TNF-α, IL-1, and nitric oxide (Wohlrab and Kreft, Skin Pharmacol Physiol. 2014;27(6):311-5). Ting L et al. (Signal Transduct Target Therap. 2017;2:17023) in their study of inflammatory signaling identified IL-1, IL-2, IL-6, IL-8, IL-12, and TNFα as important NFκB-regulated proinflammatory cytokines. Ungerstedt JS. et al. (Clin Exp Immunol. 2003;131(1):48-52) reported that NAM is a potent inhibitor of proinflammatory cytokines, including IL-1β, IL-6, IL-8, and TNFα, but in an endotoxin-induced model, 2,000 μM NAM was required to achieve significant effects.

[0180] Hwang and Song (Cell Mol Life Sci. 2017;74(18):3347-3362) reported that the IC50 concentration range for NAM to inhibit SIRT1 was 50-180 μM. SIRT1 is a member of the sirtuin family, and its inhibition results in suppression of the MAPK, NF-κB, and STAT3 oxidative stress signaling pathways, downregulation of inflammatory factors, suppression of inflammation and keratinocyte hyperproliferation, and inhibition of angiogenesis.

[0181] Hakosaki et al. (Br J Dermatol. 2002;147(1):20-3; Exp Dermatol. 2005;14(7):498-508) reported the effects of NAM on reducing skin pigmentation and inhibiting melanosome transfer from melanocytes to keratinocytes in vitro during coculture. NAM at 10 mmol L (1 mM) inhibited melanosome transfer in the coculture model by 35-68% (Hakosaki et al. Br J Dermatol. 2002). Using a similar coculture model, Hakosaki et al. (Exp Dermatol. 2005) found that 10 μM NAM inhibited melanosome transfer from melanocytes to keratinocytes, but only by 14% after 3 days of treatment. It is reasonably expected that increasing the skin concentration of NAM above 50 μM will result in increased efficacy in reducing skin pigmentation.

[0182] Thus, NAMs can be expected to exert different pharmacological / therapeutic effects on the skin depending on the dose delivered to the skin.

[0183] As described by Tanno et al. (British Journal of Dermatology. 2000;143:524-531), NAM significantly increases the biosynthesis of ceramides and other stratum corneum lipids by up to fivefold in vitro at low concentrations of 1-10 μM (maximal response 75%-100%, 1-10 μmol L-1; (μM)), improving skin barrier function. Consistent with this, Draelos ZD et al. (J Cosmet Laser Ther. 2006 June;8(2):96-101) reported that a facial moisturizer containing 2% NAM significantly improved the skin barrier in subjects with rosacea in a non-treatment controlled study.

[0184] However, when high doses of NAM are delivered, the PARP-1 and SIRT1 pathways and melanosome signaling are inhibited, leading to downregulation of the associated biology and thus to previously unexplored pharmacological possibilities. This dose-dependence of the induced pharmacology is not a novel idea. Paracelus (1493-1541) said, "All things are poisonous, and nothing is non-poisonous; only the dose makes a thing non-poisonous."

[0185] As a real-world example, aspirin (acetylsalicylic acid) is used orally at doses of less than 100 mg per day for the prevention of heart attacks and strokes. For the temporary relief of mild pain, such as that caused by headaches, arthritis, muscle pain, or toothaches, aspirin is administered at doses of 1,200 to 2,600 mg per day. Many chemicals have different potential therapeutic actions and therefore act as different drugs depending on the dose delivered.

[0186] Pharmacokinetic modeling predicted that a free NAM drug skin concentration of 50 μM could be achieved after topical application of 7.5%–10% NAM in a glycol-coenhancer-in-silicone cream (Zhang Y et al. Pharmaceutics. 2019;11:668-681), so the topical skin therapeutic potential of high-dose NAM was further investigated.

[0187] Therapeutic potential of high-dose topical niacinamide in dermatology; indications Topical nicotinamide (NAM) cream for use in UV-induced skin cancer Of particular scientific relevance is a publication by a research group led by Professor Diana Damian of the School of Dermatology at the University of Sydney, New South Wales, on the potential of oral and topical NAM as a chemoprevention of skin cancer.

[0188] Chemoprevention of skin cancer using NAM In 2008, Damian et al. (J Invest Dematol. 2008;128(2):447-54) demonstrated that topical 5% NAM prevented UV radiation-induced immunosuppression in healthy volunteers and suggested adding NAM to sunscreens and after-sun lotions to improve immunosuppression and skin cancer protection.

[0189] Moloney-Damian et al. (Br J Dermatol, 2010;162(5):1138-9) conducted a vehicle-controlled trial of the use of 1% NAM gel to prevent actinic keratosis (AK) in patients susceptible to AK. AK was significantly reduced at 3 months but not at 6 months. The authors concluded that the use of a higher NAM concentration or a different topical vehicle (more effective NAM delivery) would have led to enhanced efficacy. Consistent with this conclusion, Surjana-Damian et al. reported that high-dose oral NAM significantly reduced actinic keratosis in a Phase II double-blind, randomized, placebo-controlled trial (J. Invest. Dermatol. 2012;132:1497-1500).

[0190] In 2015, Chen-Damian et al. published the "Phase 3 Randomized Trial of Nicotinamide for Chemoprevention of Skin Cancer" (ONTRAC) (N.Engl J Med2015;373(17):161-26), reporting that oral NAM was safe and effective in reducing the rate of new non-melanoma human skin cancers (basal cell carcinoma (BCC), squamous cell carcinoma (SCC)), and actinic keratosis (AK).

[0191] In a further analysis of ONTRAC tissue specimens, Malesu et al. (Photochem Photobiol, February 2020;19(2):171-179) reported on melanomas arising from both the NAM and placebo groups. Peritumoral and tumor-infiltrating CD4+ and CD8+ lymphocytes were statistically significantly increased in melanomas arising from NAM treatment compared with placebo treatment. The authors conclude that NAM's chemopreventive effect against keratinocyte carcinoma, its ability to enhance DNA repair in melanocytes, and its potential to increase tumor-infiltrating lymphocytes support clinical trials on the use of nicotinamide for melanoma chemoprevention. From these studies, it can be concluded that nicotinamide may be useful in preventing AK, BCC, SCC, and melanoma, especially when used in conjunction with broad-spectrum sunscreen.

[0192] Importantly, Malesu et al. (Photochem Photobiol Sci 2020 Feb;19(2):171-179) confirm our 2017 pharmacokinetic analysis that approximately 50-80 μM free drug plasma NAM (at steady state in viable skin tissue) was achieved in the ONTRAC oral dosing study. These predictions support a PARP-1 / SIRT1 mechanism of action for NAM in preventing skin cancer.

[0193] A further Canadian pilot clinical trial (NCT03769285); "Nicotinamide Chemoprevention of Keratinocyte Carcinoma of Solid Organs in Transplant Patients: A Pilot, Placebo-Controlled Randomized Trial" was scheduled to be completed in December 2020.

[0194] Treatment of skin cancer using high-dose NAM Drago et al. (Dept. Dermatology, Genoa, Italy, Eur J, December 2017;27(4):382-385) studied the efficacy of high-dose oral nicotinamide as a treatment for AK in transplant recipients. After 6 months of nicotinamide treatment, AKs significantly reduced in size in 18 / 19 patients (88%). Of these 18 patients, 7 patients (42%) achieved complete clinical resolution, and no patients developed new AKs. Conversely, 91% of controls showed an increase in AK size and / or new AKs developed. Seven existing AKs progressed to squamous cell carcinoma. Drago et al. concluded that nicotinamide appears to be effective in both the prevention and treatment of AKs.

[0195] A recent study, "The Role of Nicotinamide in Cancer Chemoprevention and Treatment" (Biomolecules. Nikas, IP et al. 2020 March;10(3):477-497), included all of the above-mentioned chemoprevention studies and focused on skin cancer. The authors concluded that, in contrast to its role in chemoprevention, there is little evidence for the clinical efficacy of NAM as a chemoprevention treatment regimen. Only the first phase of clinical trials for lymphoma is mentioned. However, NAM inhibits SIRT1 and PARP1 and the oncogenic KRAS / AKT pathway in the skin. Given its predicted effects on vascular mimicry, metastasis, invasion, and proliferation, Nikas, IP et al. included existing melanoma treatment with NAM as a future avenue worthy of clinical trials. Chen A (Chin J Cancer. 2011 July;30(7):463-471) reported the clinical development of a PARP-1 inhibitor for the treatment of existing melanoma.

[0196] The association between the presence of AKs and the potential for future development of NMSCs, particularly BCCs, and the therapeutic efficacy of NAMs in treating existing AKs (Drago et al. (Dept Dernarology, Genoa, Italy, Eur J Dermatol 2017;27(4):382-385)) motivates speculation that NAMs may be effective in treating existing BCCs and SCCs. Nikas, IP et al. also warn that SIRT1 inhibition by NAMs may suppress metabolism, the deregulation of which can lead to tumorigenesis, while PARP1 inhibition may lead to long-term cumulative genetic damage. Therefore, this inference not only seems unwise but may also be dangerous, at least at this time. There are currently no clinical data regarding the use of NAMs in the treatment of NMSCs, and as a search of the US database ClinicalTrials.gov shows, no trials providing this evidence are currently being planned. We believe that there are insufficient data at present to conclude that NAMs are effective in treating existing BCCs and SCCs.

[0197] Topical nicotinamide (NAM) cream used to treat proliferative / inflammatory skin diseases Topical nicotinamide (NAM) cream used to treat psoriasis Namazi MR's seminal study (The Potential of Nicotinamide as a Weapon against Psoriasis. FASAB J. 2003;17(11):1377-9) first described the potential of oral antipsoriatic nicotinamide as an inhibitor of poly(ADP-ribose) polymerase-1 (PARP-1), which plays a key role in the expression of inflammatory cytokines, chemokines, adhesion molecules, and inflammatory mediators through the enhancement of nuclear kappa B-mediated transcription. Unsurprisingly, the skin concentration of nicotinamide required to inhibit PARP-1 was not described. We conclude that a product concentration of 7.5-10.00% w / w in a functional topical coenzyme-activated delivery system is required to significantly inhibit PARP-1 (>50 μM) and be used for the topical treatment of psoriasis.

[0198] Levino D et al. (J AmAcad Dermatol. 2010;63(5):775-81) conducted a 12-week study in patients with psoriasis and found no significant difference between topical calcipotriol 0.05% and calcipotriol 0.05% and 1.4% NAM. Siadat, AH et al. (Adv Biomed R. 2013;2:90) conducted a 12-week study in patients with mild to moderate psoriasis using topical calcipotriol 0.005% or calcipotriol 0.005% and 4.0% NAM. At the end of the 12-week study, PASI scores were significantly reduced with calcipotriol plus NAM compared with calcipotriol alone (83.6±7.9% vs. 77.8±9.7%).

[0199] Topical calcipotriol plus corticosteroid cream is a mainstay of psoriasis treatment, demonstrating the fidelity of this antiproliferative plus anti-(NF-κB-related) inflammatory treatment concept. The high-dose functional topical coenhancer delivery of calcipotriol plus 7.5-10.0% NAM cream, without corticosteroids, should facilitate this medical concept.

[0200] Topical nicotinamide (NAM) cream used to treat dermatitis and inflammatory skin conditions Various studies have demonstrated that topical NAM is effective in treating inflammatory skin diseases. A high oral dose of 2 g / day (target skin concentration of approximately 100 μM) of NAM (with a cyclin antibiotic) (Kolbach DN. et al. BJD 1995;13(1):88-90) was effective in achieving relief of the potentially life-threatening blistering skin condition bullous pemphigoid in 6-8 weeks.

[0201] However, we hypothesize that the relative ineffectiveness of topical NAM for inflammatory skin diseases is due to the inability to deliver sufficient concentrations of NAM to target sites within the skin. For example, Grange et al.'s study, "Nicotinamide Inhibits Propionibacterium acnes-Induced IL-8 Production in Keratinocytes via the NF-κB and MAPK Pathways" (Grange et al. Journal Dermatological Science. 2009;56:106-112), reported that 5.0 μg / ml (approximately 40 μM) of NAM was required to significantly inhibit P. acnes-induced IL-8 mRNA production in keratinocytes. We conclude that a product concentration of 7.5–10.00% w / w of NAM in a functional topical coenhancer delivery system is required to achieve significant anti-inflammatory effects in the treatment of inflammatory skin conditions such as acne, psoriasis, eczema, and rosacea, as well as blistering skin conditions such as bullous pemphigoid.

[0202] Topical nicotinamide (NAM) cream used to treat radiation dermatitis Bowstorm A. et al. (Radiotherapy and Oncology. 2001;59:257-265) reported that mometasone furoate, a topical corticosteroid cream, was significantly more effective than emollient cream alone in reducing acute radiation-induced dermatitis in breast cancer patients. The primary component of this mode of action was postulated to be the inhibition of IL-6. Yanez et al. (2019;9:102-19 https: / / doi.org / 10.1038 / s41598-019-46678-8) used an in vitro LPS-induced inflammatory macrophage model to produce high levels of TNF-α, IL-6, and VEGF. NAM, at 500 μM, the only dose tested, reduced IL-6 production by 88% compared to untreated controls. In conclusion, product concentrations of 7.5–10.00% w / w of NAM are required in functional topical coenhancer delivery systems to achieve significant anti-inflammatory effects in the treatment of dermatitis, including radiation-induced dermatitis.

[0203] Topical nicotinamide (NAM) cream used to treat hyperpigmentation Hakosaki et al. (Exp Dermatol. 2005;14(7):498-508) reported that 10 μM NAM inhibited melanosome transfer from melanocytes to keratinocytes, but only by 14% after 3 days of treatment. A clinical trial was conducted on 79 women with generalized hyperpigmentation. In a split-face design, Group 1 (n = 1 / 4 39) used a 5% NAM moisturizer on one side of the face and a solvent moisturizer (no NAM) on the other side of the face, while Group 2 (n = 1 / 4 40) used a 2% NAM moisturizer and a solvent moisturizer. The authors reported a dose-dependent reduction in hyperpigmentation damage. However, after 8 weeks, the visual difference between 5% NAM and the split-face control, although statistically significant, was only 6%. In conclusion, product concentrations of 7.5-10.00% w / w NAM are required in functional topical coenhancer delivery systems to achieve significant anti-pigmentation effects.

[0204] Penetration of NAM from a topical coenhancer delivery system across human skin in vitro Prediction of human skin permeability to steady state in vitro and free NAM epidermal concentration in vivo: Barrier repair An in vitro 24-hour human skin penetration study was conducted on the cream formulation of Example 46 described in Table 9, containing 5.0% NAM and 5% PHA at a product pH of approximately 4.60 (equilibrium pH of approximately 3.86). Receptor fluid samples were analyzed for NAM at 0, 2, 4, 8, 10, and 24 hours. Figure 5 shows the steady-state flux (n=6) achieved after the lag period from 8 to 24 hours. Average steady-state flux values ​​J (μg / cm) for the input rate to the skin were calculated. 2 / hour)2.28μg / cm 2 / h was calculated. From this, the NAM free drug concentration achieved at the basal epidermal site was estimated. In this study, steady-state flux, and therefore, by definition, steady-state skin tissue concentrations of NAM, were achieved and sustained for at least 16 hours. After oral administration of NAM, peak concentrations in both plasma and skin are predicted to decline with a half-life of approximately 90 minutes (Bongiovanni T et al. Review Proc. Med. Def. Bioscience. 1993;1: Conference Paper).

[0205] Estimation of target site tissue concentrations of basal cells from in vitro skin permeability data. C * The concentration of free NAM at the basal epidermal target site was calculated using formula (1).

[0206] C * =J / P D (1)

[0207] The permeability of NAM in the dermis was estimated using equation (2). The dermal diffusion coefficient of free NAM, D, D was estimated from equation (2).

[0208] D DNAM =-4.15-(0.655×log MW NAM ) (2)

[0209] Entering the molecular weight of NAM, 122.12, into equation (2) gives 3.04 × 10 -6 cm 2 s -1 DD NAM The thickness of the upper unperfused dermis (17) h D For the PD, 100 μm (0.01 cm) was used, and the PD was calculated to be approximately 1.08 cm h-1. Briefly, (3.04 × 10 -6 ×60×60) / 0.01=1.08cmh -1 .

[0210] Finally, from equation (1), C * Concentration of free NAM at the basal epidermal target site = J / P D=2.28 / 1.08=2.11μg / cm 3 , with a molecular weight of 122.12 for NAM, the concentration is approximately 17.50 μM. As mentioned above, Tanno O et al. (British Journal of Dermatology 2000;143:524±531) showed that the in vitro dose response of ceramide synthesis is maximized at approximately 10 μM nicotinamide. For example, creams such as those in Table 10, Examples 49 and 50, containing 2.5% nicotinamide and 5.0% PHA and using lactic acid nonvolatile and liquid ammonia volatile buffers to control the pH within the product and on the skin, are predicted to achieve approximately 9 μM free NAM at the basal epidermal target site. Examples 49 and 50 are predicted to be skin barrier repair candidates with the highest NAM and PHA concentrations.

[0211] Human skin penetration to steady state in vitro and free NAM epidermal concentrations in vivo: PARP-1 / SIRT1 NF-κB-mediated therapeutic potential The cream formulation described in Example 44 in Table 9 and two variations containing 10.0% NAM at an equilibrium pH of approximately 3.80-4.00 were subjected to 24-hour ex vivo human skin penetration studies using abdominal skin from three different donors. Receptor fluid samples were analyzed for NAM at 0, 2, 4, 8, 10, and 24 hours. Average steady-state flux values ​​for the input rate to the skin, J (μg / cm), were calculated. 2 / hour)6.64μg / cm 2 / hr was calculated. From this, the average free NAM drug concentration achieved at the basal epidermal site was estimated to be 50.40 uM using equation (1). The cream formulation described in Example 47 of Table 9, in which the NAM is almost completely deionized using a non-volatile pH adjuster to achieve an equilibrium pH of approximately 5.10, is predicted to achieve an epidermal concentration of NAM of approximately 70.00 uM.

[0212] Penetration of glycol-in-silicone cream into human skin in vitro. As postulated in GB2549418B, including a silicone emollient such as caprylyl methicone in a functional glycol-coenhancer system to form a cream does not adversely affect coenhancer function. For example, a commissioned study of a glycol-coenhancer cream containing 0.1% retinoic acid metabolism blocker achieved peak skin concentrations 10 times higher than conventional creams formulated by an expert skin formulation group.

[0213] Ng SP et al. (J Cosmet Dermatol. 2020;19(10):2656-2662) compared the skin concentration of tranexamic acid, a plasmin inhibitor for the treatment of melasma, with a commercially available 2% cream and a 2% glycol-C solution that also contained 5% PHA and 4% NAM. 14 The skin concentrations of tranexamic acid after application of the coenhancer cream were well within the range required for efficacy at both 6 and 24 hours, whereas the skin concentrations of the commercial cream were within the lower range at only 24 hours, approximately 10-fold lower.

[0214] 2% Plasmin Inhibitor Glycol-C 14 Alcohol-Coenhancer Cream+ (5% PHA 4% NAM): Effectiveness in Melasma (MASI) and Consumer Experience An unpublished dermatologist-investigator-controlled study of 22 subjects aged 42-60 years was conducted over a 12-week period using the formulation tested by Ng SP. et al. applied to facial skin in conjunction with sunscreen.

[0215] After 12 weeks (84 days), MASI scores (Melasma Area and Severity Index) were assessed by dermatologist clinical investigators as follows: All 22 subjects completed the study.

[0216] [Table 2]

[0217] A 2018 study by Bala et al. (Dermatol Surg 2018;44(6):814-825) focused on the use of oral tranexamic acid in the treatment of melasma and concluded that it is a safe and effective treatment for refractory melasma. This conclusion is clearly supported by two very recent double-blind, placebo-controlled trials of oral tranexamic acid in the treatment of melasma, in which 250 mg / day twice daily for 12 weeks reduced melasma (mMASI, MASI) scores by approximately 50%, significantly different from placebo. In contrast, clinical results from topical administration have so far been disappointing, although tranexamic acid glycol-C 14 Our findings regarding the efficacy of topical application of alcohol-coenhancer cream after 12 weeks are encouraging in support of this topical treatment concept.

[0218] In addition, subjects were asked to complete a questionnaire (Figure 6) investigating their experience using the cream, and cosmetic properties, ease of application, efficacy, and tolerance were all rated very highly. All subjects (100%) answered yes to both ratings. -Would you buy this product again (regardless of price)? -Would you recommend this product to a friend?

[0219] These scores, in particular, strongly suggest that the subjects have "reason to trust the product." When the cream's equilibrium pH is 5.00, the pH is nearly optimal for NAM, but the PHA is about 90% ionized, resulting in significantly lower skin penetration. Creams with equilibrium pH values ​​in the range of 3.0-4.0, such as Examples 45, 49, and 50, provide optimal ionization states for skin penetration of both NAM and PHA, thereby promoting adherence to treatment.

[0220] active substance Preferably, the active agents included in the formulations described herein are selected from retinoids, retinoic acid metabolic blockers (RAMBAs), cannabinoids including tetrahydrocannabinol and cannabidiol, alpha and beta-hydroxy acids, polymers and derivatives thereof, in particular lactobionic acid and gluconolactone, immune response modulating compounds, tranexamic acid, vitamin D analogues including calcipotriol (also known as calcipotriene), vitamin B3 analogues including nicotinamide, corticosteroids, antirosacea agents, antihistamines, antibacterial agents, antiacne agents, antifungal agents, antiviral agents, anticytotoxic agents used in actinic keratosis, basal and squamous cell carcinoma and melanoma, psoralens, anti-hair loss agents, antiandrogens, pain relievers, keratolytic agents, skin lightening agents, dithranol, disinfectants, anesthetics, analgesics, neuropathic agents, nonsteroidal anti-inflammatory agents, vasoactive agents, and agents to combat dry and aging skin. In one embodiment, the formulation may include two or more pharmacologically active agents, salts, or derivatives thereof. Suitable concentration ranges for the active agents are from about 0.001 to about 10% by weight of the formulation, depending on the nature of the active agent or combination of active agents.

[0221] Suitable active agents for inclusion in the formulations described herein are selected from retinoids, tranexamic acid, vitamin D analogues, vitamin B analogues including nicotinamide, corticosteroids, immunomodulatory agents, anti-acne agents, antifungal agents, antiviral agents, anticytotoxic agents used in actinic keratosis, basal and squamous cell carcinoma and melanoma, pain relievers, keratolytic agents, skin lightening agents, analgesics, nonsteroidal anti-inflammatory agents, cannabinoids including tetrahydrocannabinol and cannabidiol, and agents that combat dry and aging skin.

[0222] In one embodiment, the therapeutically active substance is a retinoid. Examples of suitable retinoids include, but are not limited to, tazarotene, tretinoin, isotretinoin, acitretin, etretinate, adapalene, bexarotene, alitretinoin, retinol, retinal, retinyl esters including retinyl palmitate, retinyl acetate, retinyl propionate, and retinyl linoleate, ethyl 5-(2-(4,4-dimethylthiochroman-6-yl)ethynyl)thiophene-2-carboxylate, 6-(2-(4,4-dimethylthiochroman-6-yl)ethynyl)-3-pyridinemethanol, and 6-(2-(4,4-dimethylthiochroman-6-yl)ethynyl)pyridine-3-carbaldehyde, salts thereof, derivatives thereof, and mixtures thereof. In one embodiment, the retinoid is tazarotene. In another embodiment, the retinoid is tretinoin. In another embodiment, the retinoid is retinol. In another embodiment, the formulation comprises a retinoid in combination with a second pharmacologically active agent. In one embodiment, the combination is tazarotene and a second pharmacologically active agent. In another embodiment, the combination is tretinoin and a second pharmacologically active agent.

[0223] Preferably, the retinoid is combined with a corticosteroid such as clobetasol propionate, a vitamin D analog such as calcipotriene, or an antibacterial agent such as clindamycin or a pharmacologically acceptable salt thereof (e.g., clindamycin phosphate). Alternatively, in one embodiment, the formulation comprises tretinoin combined with an antibacterial agent such as clindamycin or a pharmacologically acceptable salt thereof (e.g., clindamycin phosphate).

[0224] Suitable concentrations of the retinoid in the formulation range, for example, from about 0.001 to about 1% by weight of the formulation. In one embodiment, the retinoid is present at about 0.01 to about 1% by weight. In another embodiment, the retinoid is present at about 0.025 to about 0.5% by weight. In another embodiment, the retinoid is present at about 0.005 to about 0.025% by weight. In one embodiment, when the retinoid is tazarotene, it is present at about 0.05 or 0.1% by weight. In another embodiment, when the retinoid is tretinoin, it is present at about 0.005, 0.025, 0.05, or 0.1% by weight. In another embodiment, when the retinoid is retinol, it is present at about 0.05% by weight, or 0.1 or 1.0% by weight.

[0225] A suitable retinoic acid metabolism blocker (RAMBA) for use as the pharmacologically acceptable active substance herein is talarozole.

[0226] Suitable cannabinoids include tetrahydrocannabinol and cannabidiol.

[0227] Suitable terpenes include myrcene, limonene, caryophyllene, pinene, ocimene, geraniol, and terpinene, or combinations thereof.

[0228] In another embodiment, the α- and β-hydroxy acids, polymers, and derivatives thereof are alkylhydroxycarboxylic acids, aralkyl 1- and aryl 2-hydroxycarboxylic acids, polyhydroxycarboxylic acids, and hydroxypolycarboxylic acids. The 2-hydroxycarboxylic acids exist in forms other than the acid, such as salts or lactones. Typical lactone forms include, for example, gluconolactone, galactonolactone, glucuronolactone, galacturonolactone, gulonolactone, ribonolactone, saccharinic acid lactone, pantolactone, glucoheptonolactone, mannonolactone, and glucoheptonolactone. The 2-keto acids exist as free acids or esters, or as salts with organic bases or inorganic alkalis. Representative 2-ketocarboxylic acids and their esters are ascorbic acid, quinic acid, isocitric acid, tropic acid (2-phenyl 3-hydroxypropionic acid), trethocanic acid, 3-chloroacetic acid, citramalic acid, agaricic acid, aleuritic acid, pantoic acid, lactobionic acid, and hexulosonic acid.

[0229] As used herein, suitable immune response modulating compounds, immunosuppressants, immunomodulators, and immunoregulators include chemical or biological agents that alter the immune response or function of the immune system (e.g., by stimulating antibody formation and inhibiting white blood cell activity). Exemplary agents or compounds include, but are not limited to, cyclic peptides (such as cyclosporine), tacrolimus, tresperimus, pimecrolimus, sirolimus (rapamycin), verolimus, laflunimus, laquinimod, mycophenolic acid, imidazoquinoline amines such as imiquimod, salts thereof, derivatives thereof, and mixtures thereof.

[0230] Suitable vitamin D analogs include, but are not limited to, calcidiol, calcitriol, calcipotriene, paricalcitol, 22-oxacalcitriol, dihydrotachysterol, calciferol, salts thereof, derivatives thereof, and mixtures thereof.

[0231] Suitable vitamin B3 compounds include nicotinamide (also known as niacinamide).

[0232] Suitable corticosteroids include alclometasone propionate, amcinonide, beclomethasone dipropionate, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, budesonide, clobetasol propionate, clobetasone butyrate, cortisone acetate, desonide, desoximetasone, diflorasone acetate, diflucortolone valerate, flucloron acetonide, flumethasone pivalate, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, and fluprolactone acetate. These include, but are not limited to, redonidene, fludroxycortide, flurandrenolone, fluticasone propionate, halcinonide, halobetasol propionate, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone propionate, hydrocortisone valerate, methylprednisolone acetate, mometasone furoate, pramoxine hydrochloride, prednisone acetate, prednisone valerate, triamcinolone acetonide, prednicarbate, salts thereof, derivatives thereof, and mixtures thereof.

[0233] Suitable hormone replacement agents include testosterone and estradiol.

[0234] Combinations of vitamin D analogs and corticosteroids, such as fluticasone propionate or mometasone furoate with calcipotriene (also known as calcipotriol), are preferred.

[0235] Suitable anti-rosacea compounds include, but are not limited to, clindamycin, erythromycin, metronidazole, nicotinamide, and azelaic acid.

[0236] Suitable antihistamines include, but are not limited to, cetirizine, bapitadine, diphenhydramine, triprolidine, pyrilamine, chlorcyclizine, promethazine, carbinoxamine, tripelennamine, brompheniramine, hydroxyzine, terfenadine, chlorpheniramine, salts thereof, derivatives thereof, and mixtures thereof.

[0237] Suitable antibacterial agents include, but are not limited to, gentamicin, neomycin, streptomycin, cefpodoxime proxetil, clindamycin, lincomycin, erythromycin, bacitracin, gramicidin, vancomycin, doxycycline, minocycline, oxytetracycline, tetracycline, fosfomycin, fusidic acid, mupirocin, sulfacetamide, metronidazole, dapsone, salts thereof, derivatives thereof, and mixtures thereof.

[0238] Suitable antifungal agents include echinocandins such as anidulafunin, caspofungin, and micafungin; polyenes such as amphotericin B, candicidin, filipin, fungiclomin, hachimycin, hamycin, lucensomycin, mepartricin, natamycin, nystatin, paecilomycin, and perimycin; allylamines such as butenafine, naftifine, and terbinafine; imidazoles such as bifonazole, butoconazole, chlormidazole, cloconazole, clotrimazole, econazole, enilconazole, fenticonazole, flutrimazole, isoconazole, ketoconazole, lanoconazole, miconazole, neticonazole, omoconazole, oxiconazole nitrate, sertaconazole, sulconazole, and tioconazole; and thiocalcins such as liranaftate, tricyclate, tolindate, and tolnaftate. triazoles such as albaconazole, fluconazole, itraconazole, posaconazole, ravuconazole, saperconazole, terconazole, and voriconazole; and other antifungal agents such as acrizolysin, amorolfine, biphenamine, bromosalicylchloranilide, buclosamide, calcium propionate, chlorphenesin, ciclopirox, cloxiquin, coporafinate, exalamide, flucytosine, haloprogin, hexetidine, loflucarban, nifuratel, potassium iodide, propionic acid, pyrithione, salicyldianilide, sodium propionate, sulbenzine, tenonitrozole, triacetin, undecylenic acid, zinc propionate, griseofulvin, oligomycin, pyrrolnitrin, siccanin, and viridian, salts thereof, derivatives thereof, and mixtures thereof.

[0239] Suitable antiviral agents include, but are not limited to, acyclovir, descyclovir, carbovir, famciclovir, foscarnet sodium, ganciclovir, interferon, penciclovir, valacyclovir, salts thereof, derivatives thereof, and mixtures thereof.

[0240] Suitable cytotoxic agents include, but are not limited to, azathioprine, cyclophosphamide, cyclosporine, methotrexate, hydroxyurea, thalidomide, bleomycin, diclofenac, fluorouracil, salts thereof, derivatives thereof, and mixtures thereof.

[0241] An exemplary psoralen is methoxsalen. An exemplary anti-hair loss agent is minoxidil.

[0242] Suitable antiandrogens include, but are not limited to, spironolactone, cyproterone, flutamide, finasteride, salts thereof, derivatives thereof, and mixtures thereof.

[0243] Suitable anti-itch agents include, but are not limited to, calamine, camphor, menthol, derivatives thereof, and mixtures thereof. Other suitable anti-itch agents include kappa opioid agonists, protease inhibitors, and PAR-2 ​​inhibitors.

[0244] For example, suitable keratolytic agents for treating acne include, but are not limited to, benzoyl peroxide, salicylic acid, urea, resorcinol, sulfur, salts thereof, derivatives thereof, and mixtures thereof.

[0245] Suitable antiseptics include, but are not limited to, chlorhexidine, cetrimide, povidone-iodine, triclosan, its salts, its derivatives, and mixtures thereof.

[0246] Suitable anesthetics and analgesics include, but are not limited to, benzocaine, lidocaine, prilocaine, choline salicylate, salts thereof, derivatives thereof, and mixtures thereof.

[0247] Suitable nonsteroidal anti-inflammatory agents include, but are not limited to, diclofenac, ibuprofen, ketorolac, ketoprofen, their optical isomers, salicylate esters including methyl salicylate, menthol, camphor, capsaicin, and related agents.

[0248] Suitable nonsteroidal anti-inflammatory agents with specificity for COX-2 over COX-1 include, but are not limited to, celecoxib and rofecoxib.

[0249] Other suitable anti-inflammatory agents include nicotinamide, resveratrol, cumin, and gallate, which are used in treating inflammatory skin conditions such as eczema, psoriasis, and rosacea.

[0250] Suitable vasoactive agents include, but are not limited to, glyceryl trinitrate, alprostadil, and the like.

[0251] Suitable agents for the treatment of dry and aging skin include lactic acid, glycolic acid, lactobionic acid, palmitoyl tri- and tetra-peptides, hyaluronic acid, and its salts, such as resveratrol, curcumin, and natural NF-κB inhibitors such as gallates.

[0252] Suitable UV blocking agents include nano- or microparticles of titanium, zinc, or silicone, or other inorganic oxides.

[0253] The formulations of the present invention are generally in the form of a cream or serum.

[0254] According to one embodiment, the formulation of the present invention is in the form of a serum or gel-like serum.

[0255] According to one embodiment, the formulations of the present invention are in the form of a cream. Polymers, particles, and co-emulsifiers may be included to improve physical stability.

[0256] The active substance and other ingredients form a suspension, solution, or emulsion in a suitable oil or water medium, which may contain formulating agents such as suspending, stabilizing, and / or dispersing agents. If necessary, adjuvants selected from antioxidants, surfactants, other preservatives, film-forming, keratolytic or acne-lytic agents, perfumes, fragrances, and colorants may be added.

[0257] The formulations of the present invention generally contain less than about 50% by weight of water, preferably less than about 15% by weight, more preferably less than about 10% by weight, and most preferably less than 0.05% by weight of water. According to one embodiment, the formulations of the present invention are substantially free of water.

[0258] The formulations of the present invention will generally be self-preserving and usually sterile. Sterile media employed in preparing suitable formulations are readily available by standard techniques well known to those skilled in the art.

[0259] Foams, primarily formulated for application to biological films, can take the form of, for example, creams, milks, gels, dispersions, lotions of various strengths, aerosol formulations (e.g., mists or foams), or lotions. Other conventional forms for this purpose include serums, creams, lotions, and sprays.

[0260] The formulations of the present invention may comprise an aqueous or non-aqueous base containing one or more dispersants, solubilizers, or suspending agents. The liquid mist can be pumped or conveniently extruded from a pressurized pack. Droplets can be delivered via a simple dropper cap bottle, a plastic bottle designed to deliver liquid contents in droplets, or a specially shaped container. Airless pump packs are particularly preferred for cosmetic applications.

[0261] The weight percentage of the therapeutic agent of the invention present in a topical formulation will depend on a variety of factors, but will generally be between 0.005% and 10%, usually between 0.1 and 5% by weight of the total weight of the formulation.

[0262] The active agents referred to herein can exist in various forms, such as free acids, free bases, esters, other prodrugs, salts, tautomers, etc. For example, the present invention includes all variations of the active compounds.

[0263] Also provided are the above products for use in treatment.

[0264] Treatment method According to one aspect of the present invention, there is provided a method of preventing, reducing the likelihood of, alleviating, or treating a medical condition in the human or animal body, comprising topically administering a therapeutically effective amount of the formulations described herein.

[0265] According to another aspect of the present invention there is provided a formulation according to the present invention for use in the prevention, alleviation or treatment of a medical condition in the human or animal body.

[0266] Generally, the methods / uses of the present invention provide localized relief of medical symptoms for at least 4 hours, usually at least 6 hours, and preferably at least 12 hours after administration of the formulation.

[0267] Because the formulations of the present invention are administered locally, their effectiveness is typically associated with a rapid onset: generally, the formulations provide localized relief of a medical condition within 30 minutes of administration, usually within 15 minutes, and preferably within 5 minutes of administration.

[0268] Generally, local relief lasts for 6 to 8 hours, usually at least 12 hours, and preferably 24 hours.

[0269] The method involves topically applying a formulation to the area affected by the condition or disorder and surrounding tissues, which improves the bioavailability of the active pharmaceutical ingredient, allowing for more predictable dosage and reducing the potential for side effects.

[0270] The methods and uses of the present invention are generally topical and generally provide a way to harness the beneficial effects of an active agent or combination of active agents while reducing the dosage required and the risk of side effects.

[0271] The methods / uses of the present invention generally involve application of a formulation to the skin or mucosa of a patient. According to one embodiment, the method / use may involve application of the formulation to the patient's genitals.

[0272] The medical condition may be selected from the group consisting of pain and / or inflammation, pigmentation, pruritus, acne, blistering skin conditions such as eczema, psoriasis, rosacea, bullous pemphigoid, diaper rash, dry skin, bacterial conditions including fungal and / or skin infections such as yeast infections and dermatophyte infections, viral infections of the skin or mucous membranes, warts, dry or aging skin, androgen deficiency, immune conditions, freckles, actinic keratosis, basal cell and squamous cell skin cancer and melanoma, alopecia, and radiation therapy dermatitis.

[0273] Skin conditions suitable for treatment with the formulations of the present invention include vitiligo, eczema, psoriasis, and skin disorders associated with certain lymphomas.

[0274] The method of the present invention can include irradiating the affected area with UV light.

[0275] The medical condition may be a viral, fungal and / or bacterial condition.

[0276] The medical condition may be caused in whole or in part by or associated with a local immune response, particularly histamine, and the formulation may include one or more antihistamines, immunosuppressants, immunomodulators and / or immunoregulators.

[0277] According to one embodiment, the method promotes growth and repair of body tissue and comprises the application of a formulation comprising one or more steroid compounds, in particular one or more corticosteroid compounds.

[0278] Medical conditions may be caused in part or in whole by or related to vitamin D deficiency.

[0279] According to one embodiment, the method treats, alleviates, or prevents the formation of wrinkles, acne, or psoriasis and comprises application of a formulation comprising one or more of the group consisting of a retinoid compound, a retinoic acid metabolism blocker (RAMBA), an alpha and beta-hydroxy acid polymer, and derivatives thereof.

[0280] According to one embodiment, the formulation comprises one or more analgesic or anti-inflammatory compounds, and the condition is localized and / or associated with inflammation.

[0281] Medical conditions are generally treated via topical application. The active substances of the present invention are generally administered topically, usually to the skin or mucous membranes of a patient. The formulations of the present invention are generally administered in an amount effective for the intended treatment, prevention, or palliative, in the form of a pharmaceutical agent adapted for such a route.

[0282] The amount of therapeutically active substance administered and the dosage regimen for treating a condition with a compound and / or combination will vary widely, depending on a variety of factors, including the subject's age, weight, sex, medical condition, severity of the condition, route and frequency of administration, the particular compound employed, and the pharmacokinetic properties of the individual being treated. Generally, when a compound is administered for prophylaxis rather than treatment, the dosage will be relatively low. Such treatment can be provided as frequently as necessary for as long as the treating physician deems necessary. Those skilled in the art will recognize that the dosage regimen or the therapeutically effective amount of inhibitor administered will need to be optimized for the individual.

[0283] The methods / uses of the present invention generally involve application of the formulation 1 to 5 times daily, usually 1 to 2 times daily, preferably once daily.

[0284] The methods of the present invention can be performed on an as-needed basis. Generally, a course of treatment lasts from 1 to 6 months, depending on the nature and severity of the condition being treated.

[0285] The formulations of the present invention are typically applied to humans.

[0286] In particular, prophylactic methods are provided that prevent or minimize the occurrence of symptoms in patients who have previously experienced symptoms of the same medical condition.

[0287] When the method of the present invention is used prophylactically, the course of treatment can last up to six months. However, when the method is used to treat severe symptoms, the method / use can involve an initial administration of a large amount of an active substance or combination thereof, followed by a second, longer period of, for example, one to six months, at a lower dose.

[0288] The total amount of formulation applied in one dose is generally 1 / 4 of the total area of ​​skin to be treated. 2 Approximately 2.5 to 10.00 mg per serving.

[0289] The active agents can be administered simultaneously, sequentially, or separately. The active agents can be provided in a unitary package. The unitary package can include the product of the present invention along with instructions for the simultaneous, separate, or sequential administration of each active agent. For sequential administration, the active agents can be administered in any order.

[0290] The active substances of the methods / uses of the present invention may be provided as pharmaceutical formulations additionally containing one or more pharmaceutically acceptable diluents, excipients and / or carriers, which may be applied in both fixed or loose combinations.

[0291] The phrase "pharmacologically acceptable" is used to refer to compounds, materials, and / or formulations that are, within the scope of sound medical judgment, suitable for use in contact with human tissues or, as the case may be, animals, without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Such carriers are well known in the art and include buffers, fillers, diluents, binders, humectants, disintegrants, absorption enhancers, surfactants, absorption carriers, lubricants, and preservatives.

[0292] The patient is generally a human in some embodiments, although animals can also be treated.

[0293] Formulation Examples: Specific Formulations The invention will now be described, by way of example only, with reference to the accompanying drawings, in which:

[0294] According to one embodiment of the present invention, there is provided a formulation for topical application, the formulation comprising: a. Active substance(s); bc. a skin barrier repair combination that improves user adherence of 1.0-5% w / w nicotinamide and d. 1.0-5% w / w polyhydroxy acid; e. a partition coefficient enhancer, particularly propylene glycol, butylene glycol, pentylene glycol, or hexylene glycol (generally propylene glycol); fC 12 ~C 14 Saturated fatty acids and C 14 a diffusion coefficient enhancer selected from the group consisting of saturated primary alcohols; g. a hydrocarbylmethylsiloxane emollient selected from the group consisting of alkylmethylsiloxane compounds or alkylarylmethylsiloxane compounds, and having a number average molecular weight of less than 500; h. a dimethicone macromer surfactant, generally having a number average molecular weight greater than 1000 and usually comprising a polyalkylsiloxane moiety and one or more copolymers of ethylene oxide and propylene oxide or ionic side groups; i. methylsiloxanes, in particular cyclomethicone compounds having a number average molecular weight of less than 500; j. a crosslinked dimethicone macromer, generally having a number average molecular weight greater than 1000 and generally comprising a polyalkylsiloxane moiety.

[0295] Exemplary formulations of the present invention include: i. 0.001% to about 10% w / w of the active substance; ii. a skin barrier repair combination that improves user adherence of 1.0-5% w / w nicotinamide and iv. 1.0-5% w / w polyhydroxy acid; v. 20 to 70% w / w of propylene glycol, butylene glycol, pentylene glycol, or hexylene glycol (generally propylene glycol); vi.C 12 ~C 14 Saturated straight-chain fatty acids and C 14 0.5-5% w / w of a diffusion coefficient enhancer selected from the group consisting of saturated linear primary alcohols; vii. 10-25% w / w hydrocarbylmethylsiloxane emollient comprising a mixture of alkylarylmethylsiloxane compounds having a number average molecular weight of less than 500 and typically one or more selected from the group consisting of crosslinked dimethicone macromers having a number average molecular weight of greater than 1000 and containing polyalkylsiloxane moieties, one or more copolymers of ethylene oxide and propylene oxide or ionic side groups, and pyrrolidone carboxylic acid functionalized dimethicone macromers, wherein the mixture comprises 10-20% w / w dimethicone macromer; viii. A 10-25% w / w alkylsiloxane emollient comprising a mixture of a cyclomethicone compound having a number average molecular weight of less than 500 and a crosslinked dimethicone macromer having a number average molecular weight of greater than 1000 and comprising a polyalkylsiloxane moiety, the mixture comprising 10-20% w / w silicone macromer.

[0296] Tables 1-7 show examples of skin barrier repair combinations that improve user adherence, including 1.0-5% w / w nicotinamide and 1.0-5% w / w polyhydroxy acid, and formulations containing 0.001% to about 10% w / w active agent, respectively.

[0297] Examples of the present invention include cannabinoids (Examples 1-6), antiviral and antifungal agents (Examples 7-13), retinoids (Examples 14-17), vitamin B3 (Examples 18-24), immunomodulators (Examples 25-26), humectants (Examples 29-34), and corticosteroids (Examples 35-37).

[0298] Process-Related Examples (Nicotinamide-PHA Formulation Process Control) Tables 8-11 (Examples 38-55) are explained after the next section.

[0299] Cream composition technology and manufacturing process (0.5~3.0kg laboratory scale) Glyco-in-silicone cream technology The cosmetic technology of glycol-in-silicone active ingredient emulsions originates from the 1960s work on non-aqueous emulsions, such as glycerin dispersions in olive oil (Peterson RV and Hamil RD. J Soc. Cos. Chem. 1968;19:627-640). Florence AT et al. reported a "novel anhydrous emulsion" using the silicone surfactant systems cyclomethicone / PEG / PPG-18 / 18 dimethicone and cyclopentasiloxane / PEG / PPG-18 / 18 dimethicone to stabilize anhydrous castor oil-in-silicone fluid dispersions. An important breakthrough for cosmetic science was the publication in 1996 by Zombec and Dahms (Dow Corning Corporation) of "Novel Formulations Based on Non-Aqueous Emulsions of Polyol (Propylene Glycol) in Silicone." A stable anhydrous propylene glycol-in-silicone emulsion was prepared using dimethicone copolyol in cyclomethicone and sodium chloride to salt out the surfactant from the glycol phase.

[0300] The co-enhancer-in-silicone cream technology adds a diffusion coefficient enhancer, and optionally an additional glycol / water solvent, to a propylene glycol partition coefficient enhancer, and a hydrocarbyl methyl siloxane emollient such as caprylyl methicone and a silicone elastomer / fluid to a silicone continuous phase.

[0301] Manufacturing process overview The process uses two premix stages: first, an N-VRP diffusion phase premix, and then a silicone continuous phase premix. To avoid trisiloxane loss at small scales, the N-VRP premix is ​​dispersed into the silicone premix, and then, in a final step, on a smaller scale (0.50–3.0 kg), the highly volatile trisiloxane, which is part of the silicone continuous phase, is added. This may not be necessary in closed manufacturing systems. At small scales (0.50–3.0 kg), glycol-in-silicone cream dispersions are formed using a Kenwood Chef Professional Stand Mixer (KVC7300S, 1.5 kW, 4.6 L bowl). These dispersions are white, rather than the gray color often associated with silicone serums. Conventional Silverson-type homogenizers create air bubbles and are not useful for forming these dispersions. However, in-line homogenization, used at larger scales, can further improve the white color of these creams.

[0302] The table below shows a typical list of ingredients, omitting the main active substances. Because each ingredient has a function and some multitasking, typically only 12-13 ingredients are required. The importance of in-process control (IRC) is illustrated in Tables 8-11.

[0303] [Table 3]

[0304] As a general rule, the non-volatile residual phase (N-VRP) materials are added in order of decreasing polarity with the intent of not inducing a sudden change in polarity and causing supersaturation during processing.

[0305] N-VRP Premix Step / Ingredients 1 Sodium chloride Sodium chloride is weighed out on a 0.5 kg scale into a 500 ml Dewar flask weighing vessel.

[0306] Step / Material 2 Deionized water Deionized water is measured into a 500 ml Dewar flask and shaken in the flask for 1 minute to ensure complete solution.

[0307] Step / Material 3: Propylene glycol Propylene glycol is weighed into a 500 ml Dewar flask.

[0308] Step / Material 4 Niacinamide (Figures 7.1a and 7.1b) Niacinamide (sieved) is weighed into a 500 ml Dewar flask and the flask is mixed on a rotating bed until a clear solution is obtained.

[0309] Process / Materials 5 / 6 PHA (Figures 7.2a, 7.2b, and 7.2c) Gluconolactone 5, then lactobionic acid 6 are weighed into a 500 ml Dewar flask and the flask is mixed on a rotating bed until a clear solution is obtained.

[0310] Step / Ingredient 7 Add pH adjuster Add pH adjuster dropwise to the appropriate target pH.

[0311] After addition of N-VRP to N-VRP Step / Material 8 Addition of antibacterial agent Add phenoxyethanol dropwise to the target weight. Phenoxyethanol is completely soluble in N-VRP.

[0312] Step / Material 9 Diffusion Coefficient Enhancer, Myristyl Alcohol (C 14 Addition of alcohol) (Figures 7.3a, 7.3b, and 7.3c) Myristyl alcohol is weighed into a 500 ml Dewar flask. Myristyl alcohol is soluble in up to 50% of its weight in N-VRP and requires heating to approximately 30°C to form a coarse dispersion that facilitates distribution into the silicone continuous phase. At ambient and slightly elevated temperatures, myristyl alcohol is saturated in both phases at approximately equal concentrations.

[0313] Silicone Continuous Phase Premix Process / Materials 10 / 11 / 12 Addition of Silicone Elastomer Blend and Carbomer (Figures 7.4a, 7.4b, 7.4c, 7.4d, and 7.4e) A Kenwood Chef Professional Stand Mixer (KVC7300S, 1.5 kW, 4.6 L bowl capacity) was used to create the glycol-in-silicone cream dispersion. The highest speed setting was used, but accelerated slowly to avoid splashing. The elastomer-silicone fluid blend (EL-7040 hydroelastomer and DC-9040 elastomer) was weighed into the bowl and mixed for 1 minute (Figure 7.4a). The material on the sides of the bowl was scraped down to the center with a silicone spatula (Figure 7.4b), then mixed for 1 minute, scraped down to the center with a silicone spatula, and the carbomer was added. This was followed by another minute of mixing, scraping down the sides of the bowl to the center, and repeating the process (Figures 7.4c, 7.4d, and 7.4e).

[0314] Addition of N-VRP premix to silicone elastomer blend-carbomer premix Increase the mixer speed setting to maximum speed at 1 second intervals and add the Myristyl Alcohol Coarse Dispersion in N-VRP to the silicone elastomer blend-carbomer premix as a "split stream"; on a 0.5 kg scale, this takes approximately 12 minutes to complete (approximately 20 g / min). Scrape the initial glycol-in-silicone emulsion down the sides of the bowl into the center with a silicone spatula, then mix again at maximum speed for 2 minutes.

[0315] Step / Material 13 Addition of Volatile Silicone Fluid Trisiloxane (Figures 7.5a and 7.5b) The trisiloxane is weighed into a Kenwood bowl and added to the first glycol-in-silicone mixture.

[0316] Increase the mixer speed setting to maximum in 1 second intervals and mix for 2 minutes. Then scrape down the sides of the bowl to the center and repeat. The resulting cream was packaged in 500g steam-tight plastic buckets.

[0317] Examples 39 to 54 (Tables 8 to 11) Table 8 shows a series of formulations (Examples 39-43) in which the PHA (lactobionic acid:gluconolactone) ratio varies from 1:0, 3:1, and 1:1. Additionally, in formulations (Examples 41-43), the nicotinamide:total PHA ratio varies from 2:1, 1.5:1, and 1:1. In all of these formulations, only a volatile buffer (aqueous) ammonia is used to bring the glycol phase (Materials 1-7) to a pH of approximately 4.6. Because the continuous silicone phase of the cream is anhydrous, it does not affect the pH of the glycol-silicone cream dispersion, which is therefore approximately 4.6. Upon application of the cream to the skin as a thin film, ammonia is lost by evaporation, and the pH decreases to equilibrium, primarily depending on the nicotinamide:total PHA ratio. In some embodiments of the present invention, a target equilibrium pH of 3.5 is appropriate, as this is the pKa of both nicotinamide (base) and PHA (acid), and therefore functions to jointly optimize the skin penetration of these co-active ingredients. Example 40, containing 5% NAM at a pH of about 4.4, does not reduce the efficacy of NAM over a 6-month period at 40° C. U.S. Patent No. 10,028,927 (invented by Limeway, Futura Medical, UK) describes the use of ammonia, a volatile buffer, to achieve a product pH of about 7.00, which chemically stabilizes diclofenac, but lowers the pKa, pH, to about 4.00, optimizing skin penetration upon application to the skin.

[0318] Table 9 shows a series of formulations (Examples 44-47) in which the nicotinamide:total PHA ratio ranges from 2:1, 1.50:1, and 1:1. The equilibrium pH depends on the nicotinamide:total PHA ratio, with a 2:1 ratio resulting in a pH of approximately 4.00. This equilibrium pH may be optimal if the primary objective is to maximize the skin penetration of the co-active nicotinamide component. Formulation (Example 47) uses a non-volatile base buffer, 25% NaOH, to achieve an equilibrium (and product) pH of approximately 5.00, where nicotinamide is almost completely deionized. Formulations (Examples 44-46) use a volatile buffer (aqueous) ammonia to achieve a pH of approximately 4.6 in the glycol phase (Materials 1-7), which drops to a pH of ≦4.00 upon application to the skin.

[0319] Table 10 shows a series of formulations (Examples 48-51) in which the nicotinamide:total PHA ratio ranges from 1:1 to 0.5:1 (both in duplicate batches). In all of these formulations, nonvolatile buffered lactic acid is used to lower the equilibrium pH. Volatile buffered (aqueous) ammonia is then used to bring the glycol phase (Materials 1-7) to a pH of 4.6. Because the continuous silicone phase of the cream is anhydrous, it does not affect the pH of the glycol-silicone cream dispersion, which is therefore approximately 4.6. When the cream is applied to the skin as a thin film, ammonia is lost by evaporation, and the pH drops to an equilibrium pH ranging from approximately 3.6 to 3.8, depending primarily on the nicotinamide:total PHA ratio and the amount of nonvolatile buffered lactic acid added. Table 10 demonstrates how in-process control / pH tracking is useful in the design and manufacture of these creams. In-process control of weight provides excellent pH reproducibility, particularly for nicotinamide and total PHA.

[0320] Table 11. Cream texture is an important part of the use experience. The texture of the glycol-silicone cream dispersions described herein is determined by the texture of the continuous silicone phase of the cream, which is related to the ratio of elastomeric polymer to low viscosity silicone fluid, particularly trisiloxane. Examples 52-54 show that for a fixed amount of elastomeric polymer, viscosity is proportional to the amount of trisiloxane added.

[0321] The explanations in Tables 8, 9, and 10 above describe how the equilibrium pH achieved in N-VRP after evaporative loss of volatile materials (e.g., water and, if present, volatile buffers) depends on the ratio of nicotinamide to total PHA. Naturally, the addition of acid and / or base nonvolatile buffers can also be used to adjust the equilibrium pH. Additionally, knowledge gained from U.S. Pat. No. 10,028,927 would be beneficial. For example, the use of a volatile base buffer (aqueous) ammonia can increase the product pH to a value of 4.5-6.00, which is associated with NAM chemical stability. However, when applied to the skin as a thin film, the volatile materials, including the liquid ammonia volatile buffer, evaporate, resulting in a pH that is optimal for skin penetration, e.g., in the range of pH 3.0-4.0.

[0322] Modifications and variations of the above-described aspects of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to the specific embodiments described above. Indeed, various modifications of the modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the following claims.

[0323] Chemical structure and stability of nicotinamide cream Nicotinamide (also known as niacinamide) (NAM) is an amide of nicotinic acid, with the chemical structure shown in Figure 8a.

[0324] Although amides as a class are significantly more stable to acid hydrolysis than esters, this remains the primary route of NAM degradation. Finholt and Higuchi (Rate Studies on the Hydrolysis of Niacinamide, J. Pharm Sci., 1962, 51(7); p. 655-661) reported that a minimum first-order rate of NAM hydrolysis was found in the pH range of 4.5 to 6.0 (see Figure 8a for the fitted rate diagram). The cream formulation described in Example 40 of Table 8, containing 5% nicotinamide and 5% PHA at pH 4.402, was stored in sealed glass jars at 5°C and 40°C for 6 months. No significant degradation of NAM was observed. Physical stability was as follows: DOM at 5°C and 40°C for 6 months. Figure 8b shows that slight graying, attributed to PHA, occurred after 6 months of storage at 40°C compared to the center jar stored at 5°C. The jar on the right is a fresh control sample.

[0325] NAM content in the formulation 5% NAM + 5% PHA stored at 5°C and 40°C (mean ± SD, n=5); pH 4.402 (target 4.40-4.80).

[0326] [Table 4]

[0327] NAM content in formulations NAM+PHA2-6 stored at 5°C and 40°C for 6 months (mean ± SD, n=5); pH 4.490, 4.480, 4.514, 4.495, and 4.440 (target 4.40-4.60), respectively; see table below.

[0328] [Table 5]

[0329] NAM+PHA formulations 2-6 were stored in sealed glass jars for 6 months at 5° C. and 40° C. No significant degradation of NAM was observed.

[0330] In contrast, samples held at ambient temperature and at a pH of about 3.8-3.9 showed a progressive loss of about 20% of NAM potency over 24 months; see table below.

[0331] [Table 6]

[0332] NAM is very stable until decomposition, provided that the pH is adjusted to a range of 4.5-6.00. Many options exist for adjusting the pH to this target range using organic or inorganic bases. As mentioned above, a further option is to use volatile buffer technology to achieve different, individually optimized in-pack equilibrium phase pHs, as described in U.S. Pat. No. 10,028,927.

[0333] [Table 7-1] [Table 7-2] [Table 8-1] [Table 8-2]

[0334] [Table 9]

[0335] [Table 10-1] [Table 10-2]

[0336] [Table 11]

[0337] [Table 12]

[0338] [Table 13-1] [Table 13-2]

[0339] [Table 14-1] [Table 14-2]

[0340] [Table 15-1] [Table 15-2]

[0341] [Table 16-1] [Table 16-2]

[0342] [Table 17-1] [Table 17-2]

[0343] It will of course be appreciated that the above-described embodiments are provided by way of example only and that those skilled in the art can make many modifications without departing from the scope of the invention.

Claims

1. A formulation for topical application comprising: a main active substance for topical treatment of the skin; a skin barrier repair combination that improves user adherence, comprising 1.0-5% w / w nicotinamide and 1.0-5% w / w polyhydroxy acid; General formula: C ｎ H ２ｎ＋２ O ２ wherein n is an integer of 3 to 5; and C １２ ~C １４ Straight-chain fatty acids and C １４ a diffusion coefficient enhancer (DC enhancer) selected from the group consisting of straight chain primary alcohols; a first dimethicone macromer mixture comprising a dimethicone macromer and a hydrocarbylmethylsiloxane emollient selected from the group consisting of alkylmethylsiloxanes, arylmethylsiloxanes, and alkylarylmethylsiloxanes; a second dimethicone macromer mixture comprising a methylsiloxane compound and a crosslinked dimethicone macromer; A formulation, wherein the formulation comprises less than 15% by weight of water.

2. The first dimethicone macromer mixture comprises a polyglycol dimethicone macromer comprising a compound of the following structure: 【Chemistry 1】 wherein R represents H or a hydrocarbyl group; Y represents a hydrocarbyl group; X represents an amine, a quaternary amino group, or an acidic functional group; 2. The formulation of claim 1, wherein M and n independently represent integers from 1 to 50.

3. 3. The formulation of claim 1 or 2, wherein the formulation comprises 5-45% w / w of a first dimethicone macromer mixture and / or 5-45% w / w of a second dimethicone macromer mixture, the first dimethicone macromer mixture comprising a dimethicone macromer having a number average molecular weight greater than 1000 and a hydrocarbylmethylsiloxane emollient having a number average molecular weight less than 500.

4. 4. The formulation of claim 1, wherein the first dimethicone macromer mixture comprises a polyglycol dimethicone macromer crosslinked with a polyalkylene oxide compound or crosslinked with a diene, and the first dimethicone macromer mixture comprises a polyglycol dimethicone macromer selected from the group consisting of PEG dimethicone PPG crosspolymer and PEG dimethicone bis-isoalkyl PPG crosspolymer.

5. 4. The formulation of claim 1, wherein the first dimethicone macromer mixture comprises a polyglycol dimethicone macromer containing one or more side groups from the dimethicone backbone, the side group(s) being polyalkylene oxide groups, and the polyglycol dimethicone macromer containing polyethylene glycol and polypropylene glycol side groups from the dimethicone backbone.

6. A formulation according to any one of claims 1 to 5, comprising a pyrrolidone carboxylic acid functionalised dimethicone macromer.

7. 7. The formulation of any one of claims 1 to 6, wherein the second dimethicone macromer mixture comprises a methylsiloxane compound having a number average molecular weight of less than 1000 and a crosslinked polyalkylsiloxane diol dimethicone macromer having a number average molecular weight of greater than 1000.

8. 8. The formulation of any one of claims 1 to 7, wherein the first dimethicone macromer mixture comprises 5 to 30% w / w polyglycol dimethicone macromer and / or the second dimethicone macromer mixture comprises 5 to 30% w / w crosslinked dimethicone macromer.

9. A formulation according to any one of claims 1 to 8, which contains less than 0.05% w / w water or is substantially free of water.

10. A formulation according to any one of claims 1 to 9, wherein the formulation comprises 1 to 10% w / w of polyhydroxy acid.

11. A formulation according to any one of claims 1 to 10, wherein the polyhydroxy acid is selected from lactobionic acid, gluconolactone, or galactose, and mixtures of any of these.

12. General formula C ｎ H ２ｎ＋２ O ２ (where n is an integer of 7 or more), a diol of the general formula C ｎ H ２ｎ＋２ O (where n is an integer of 2 or 3), an alcohol of the general formula C ｎ H ２ｎ＋２ O ３ Or C ｎ H ２ｎ＋２ O ２ 12. The formulation of any one of claims 1 to 11, comprising a second mutually miscible PC enhancer / co-solvent selected from the group consisting of alcohols, ether-alcohols, diols, triols, or alkylpyrrolidones, preferably selected from the group consisting of ether-alcohols of formula (I) where n represents an integer from 1 to 10, or alkylpyrrolidones, wherein said second mutually miscible PC enhancer / co-solvent is glycerol or N-methylpyrrolidone.

13. A formulation according to any one of claims 1 to 12, comprising 25-45% w / w of a PC enhancer and / or less than 10% w / w of a diffusion coefficient enhancer.

14. 14. A formulation according to any one of claims 1 to 13, comprising 25-45% w / w of a PC enhancer and / or 0.5-2% w / w of a diffusion coefficient enhancer, as required to retain the main active substance in the stratum corneum.

15. 15. The formulation of any one of claims 1 to 14, wherein the product pH is in the range of 4.4 to 6.00 and / or the equilibrium pH is in the range of pH 3 to 4.

16. 16. The formulation of any one of claims 1 to 15, comprising a highly volatile solvent selected from the group consisting of hexamethyldisiloxane, octamethyltrisiloxane, cyclopentasiloxane, ethanol, isopropyl alcohol, and water.

17. 17. The formulation of any one of claims 1 to 16, wherein the active agent is selected from the group consisting of retinoids, retinoic acid metabolic blockers (RAMBAs), cannabinoids including tetrahydrocannabinol and cannabidiol, alpha and beta hydroxy acids and polymers and derivatives thereof, immune response modulating compounds, tranexamic acid, vitamin D analogues including calcipotriol (also known as calcipotriene), vitamin B3 analogues including nicotinamide, corticosteroids, anabolic steroids, estrogens, antirosacea agents, antihistamines, antibacterial agents, antiacne agents, antifungal agents, antiviral agents, anticytotoxic agents used in actinic keratosis, basal and squamous cell carcinoma and melanoma, psoralens, anti-depilatory agents, antiandrogens, antipruritic agents, keratolytic agents, skin lightening and depigmenting agents, dithranol, disinfectants, anesthetics, analgesics, neuropathic agents, nonsteroidal anti-inflammatory agents, vasoactive agents, and agents to combat dry and aging skin.

18. 18. The formulation according to any one of claims 1 to 17, wherein the active substance is selected from PARP-1 inhibitors used in the treatment of inflammatory skin diseases such as eczema, psoriasis, acne, bullous pemphigoid, and rosacea.

19. 19. The formulation according to any one of claims 1 to 18, wherein the active substance is selected from PARP-1 inhibitors used in the chemoprevention of actinic keratosis, basal and squamous cell skin cancers and melanoma.

20. 20. The formulation according to any one of claims 1 to 19, wherein the active substance is selected from a PARP-1 inhibitor in combination with a broad-spectrum inorganic or hydrophilic UV blocker for use in the chemoprevention of actinic keratosis, basal and squamous cell skin cancers and melanoma.

21. Formulation according to any one of claims 1 to 20, wherein the active substance is selected from ARP-1 inhibitors used in the treatment of actinic keratosis and melanoma.

22. 22. The formulation according to any one of claims 1 to 21, wherein the active agent is selected from PARP-1 inhibitors in combination with broad-spectrum inorganic or hydrophilic UV blocks used in the treatment of actinic keratosis and melanoma.

23. Formulation according to any one of claims 1 to 22, wherein the active substance is selected from PARP-1 inhibitors used in the chemoprevention of radiation dermatitis.

24. A formulation according to any one of claims 1 to 23, wherein the active substance is selected from melanosome transport inhibitors used in the treatment of skin pigmentation.

25. A formulation according to any one of claims 18 to 24, wherein the active substance is 5 to 10% by weight of nicotinamide.

26. A formulation according to any one of claims 1 to 25, wherein the primary active substance is not tranexamic acid in combination with 1-5% by weight of nicotinamide and 1-5% by weight of PHA.

27. A formulation according to any one of claims 1 to 26 for use in therapy.

28. 27. The formulation of any one of claims 1 to 26 for use in the prevention, alleviation or treatment of a medical condition in the human or animal body caused by or associated with one or more of the following: pain and / or inflammation, pigmentation, pruritus, acne, blistering skin conditions such as eczema, psoriasis, rosacea, bullous pemphigoid, nappy rash, dry skin, bacterial conditions including fungal and / or yeast infections and skin infections such as dermatophyte infections, viral infections of the skin or mucous membranes, warts, dry or aging skin, androgen deficiency, immune conditions, freckles, actinic keratosis, basal cell and squamous cell skin cancer and melanoma, alopecia, and radiation therapy dermatitis.

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