GB2597526A

GB2597526A - Topical formulation

Info

Publication number: GB2597526A
Application number: GB2011605.9A
Authority: GB
Inventors: Hammond Kevin
Original assignee: Incanthera R&d Ltd
Current assignee: Incanthera R&d Ltd
Priority date: 2020-07-27
Filing date: 2020-07-27
Publication date: 2022-02-02
Also published as: GB202011605D0

Abstract

A topical formulation comprising nicotinamide provides effective treatment and/or prevention against skin cancers such as actinic keratosis, melanoma, squamous cell carcinoma and basal cell carcinoma. In particular the formulation comprises: a non-volatile residual phase comprising: 5 to 12% w/w nicotinamide, 2 to 10% w/w of a polyhydroxy acid, 10 to 60% w/w of a partition coefficient enhancer as defined therein, about 0.5 to about 10 % w/w of a diffusion coefficient enhancer as defined therein and ≤ 10% water; and an emollient phase comprising: 5 to 45% w/w of a first dimethicone macromer mixture including a dimethicone macromer and a hydrocarbyl methyl siloxane emollient selected from the group consisting of an alkyl methyl siloxane, an aryl methyl siloxane and an alkyl aryl methyl siloxane, and 5 to 45% w/w of a second dimethicone macromer mixture including a methyl siloxane compound and a cross-linked dimethicone macromer.

Description

Topical Formulation

Background

Skin cancers are the most common form of cancers in the developed world, and deaths arising from invasive melanoma are on the increase.

UV light has an adverse effect on skin, acting to deactivate the skin's normal repair and protection mechanisms.

Evidence suggests that effectively dosed into skin, nicotinamide could protect against this effect by reactivating the skin's own natural repair mechanisms.

Orally administered nicotinamide has been shown in Phase 3 Clinical Studies to have significant preventative effects against actinic (solar) keratosis and there has been subsequent evidence that oral nicotinamide may prevent other more life-threatening C\I skin cancers such as melanoma. Oral dosing for targeting localised skin disease suffers a number of disadvantages and a topical product (so far unavailable) would C;) 20 be highly beneficial. ('Si

O The possibility of achieving effective topical dosing of nicotinamide offers a number of advantages over oral administration, notably: -Avoidance of possible side effects, such as gastric upset -Circumvention of first-pass metabolism and limitations on bioavailability.

-Ease of compliance -Direct targeting of sun exposed tissues and lesions.

-Opportunity to introduce additional UV protection through inclusion of SPF agents or blocks.

-Inclusion of effective cosmetic skin care ingredients Current topical products intended to provide protection against sun damage rely primarily on SPF inclusion. However, the effectiveness of such product in preventing cancerous skin conditions is viewed as having limitations. Moreover, such products can often be aesthetically unpleasant to use and therefore do not encourage compliance which is critical in achieving protection. There remains an unmet need.

To date topical administration of nicotinamide, whilst desirable, has not been successful. This is because prior to the present invention a commercially available formulation, with appropriate consumer acceptability, and capability to deliver therapeutic concentrations of nicotinamide to the target site in the skin has not been available.

Summary

The present invention overcomes the challenges noted above and provides a topical formulation comprising nicotinamide that provides effective prevention and treatment for skin cancers including conditions such as actinic keratosis, basal cell carcinoma, squamous cell carcinoma and melanoma.

Phase 3 Clinical Studies have demonstrated significant preventative effects against actinic (solar) keratosis for orally administered nicotinamide. More recent literature evidence from the same workers has suggested that effectively dosed oral nicotinamide may also prevent the more serious forms of skin cancer including C\I melanoma.

The dosing of nicotinamide into skin when administered via an oral route can be calculated from known plasma levels using established procedures. The target level

CD

of dosing of nicotinamide -in terms of required flux -required from topical dosing can therefore be established.

Academic studies have previously shown relatively high flux levels of nicotinamide into skin is achievable using very high doses or co-solvent systems. But such studies were characterised by compositions wholly unsuitable for practical human use or commercial application A fully formulated topical product with good aesthetic properties that can achieve the clinically relevant nicotinamide flux levels -in the context of skin cancer prevention -has hitherto not been achieved in spite of the many years of research into topical nicotinamide products.

It is well established that for any topical product intended for therapeutic use, compliance is critical to achieving therapeutic benefits. This is most likely to be achieved if products are pleasant to use and have good user-perceived aesthetic properties.

The invention described herein addresses and overcomes a key challenge with a topicalty administened product, namely That of achieving sufficient serum and/or local tissue levels of the active comparable to those found with oral dosing. The formulation used in the present invention is capable of both highly effective trans-dermal nicotinamide delivery and has aesthetic properties typically associated with high-end topical cosmetic products. This opens up the possibility of delivering an effective topical product for skin melanoma prevention in subjects suffering from solar keratosis and in preventing recurrence of melanoma in subjects who have previously been treated for such cancers. More broadly, this formulation is expected to provide benefits relating to abnormal skin pigmentation, skin ageing and general damage associated with sun exposure.

The present invention provides a method of preventing and/or treating a skin cancer, C\I the method comprising topical application to skin of a formulation as described herein.

The present invention provides a formulation for topical application and for use in a (\I 20 method of preventing and/or treating a skin cancer.

The present invention also provides use of a formulation in the manufacture of a medicament for the prevention and/or treatment of a skin cancer.

The skin cancer to be prevented or treated can be selected from actinic keratosis, basal cell carcinoma, squamous cell carcinoma and melanoma.

Therefore present invention i) provides a method of, fi) provides a formulation for use in a method of, and/or iii) provides use of a formulation in the manufacture of a medicament for preventing actinic keratosis, treating actinic keratosis, preventing melanoma, preventing recurrence of melanoma, treating melanoma, achieving complete or partial remission of melanoma, preventing squamous cell carcinoma, preventing basal cell carcinoma, treating squamous cell carcinoma, treating basal cell carcinoma, achieving complete or partial remission of squamous cell carcinoma, and achieving complete or partial remission of basal cell carcinoma.

A benefit of the formulation is that it may only need to be applied to skin once or twice a day and hence the method may consist of application to skin once or twice a day.

The formulation is for topical application to skin. It is envisaged that the skin is human skin.

The present invention embraces a topical formulation. The formulation used in the present invention comprises: a non-volatile residual phase comprising: to 12% w/w (percentage weight/weight) nicotinamide, 2 to 10% w/w of a polyhydroxy acid, to 60% w/w of a partition coefficient enhancer (Pc enhancer), having a structure of the general formula: C,H2n.202 where n represents an integer from 3 to 6 inclusive, about 0.5 to about 10 % w/w of a diffusion coefficient enhancer (Dc enhancer), selected from the group consisting of a C12 to C14 straight chain C\I fatty acid and a 014 straight chain primary alcohol, and 10% w/w water and an emollient phase comprising: C\I 5 to 45% w/w of a first dimethicone macromer mixture including a dimethicone macromer and a hydrocarbyl methyl siloxane emollient selected from the group consisting of an alkyl methyl siloxane, an aryl methyl siloxane and an alkyl aryl methyl siloxane, and to 45% w/w of a second dimethicone macromer mixture including a methyl siloxane compound and a cross-linked dimethicone macromer.

The formulation may comprise 5.5 to 11% w/w, and optionally 6 to 10% w/w nicotinamide.

The Pc enhancer of the formulation may be selected from the group consisting of propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, and 1,5 pentane diol and a combination thereof The formulation may comprise 15-50, 20-45, 25-45, or 30 -40 % w/w of the Pc enhancer.

Dc enhancer of the formulation can be selected from the group consisting of myristyl alcohol (1-Tetradecanol), myristic acid, and lauric acid (dodecanoic acid).

The Dc enhancer can be 0.5 -5, 1 -5, 2 -4 % w/w (percentage weight/weight) of the composition.

The formulation may comprise 2 to 9, 2 to 7, 2 to 5, 3 to 5 or about 4 % w/w of a polyhydroxy acid.

The polyhydroxy acid in the formulation may be selected from gluconolactone, galactose and lactobionic acid.

The first dimethicone macromer mixture of the formulation may include a polyglycol dimethicone macromer.

The first dimethicone macromer mixture of the formulation may include a compound r C\I of the following structure: N*** R R R R 0 11 1 1 C\I R-Si-O+Si-01 [ Si-O+Si-R 0 1 1 n 1 m 1

R R Y R

Where R represents H or hydrocarbyl group, in particular Cl to C6 alkyl Y represents a hydrocarbyl group in particular Cl to C6 alkyl group; X represents an amine, a quaternary amino group or acid functionality. M and n independently represent an integer from 1 to 50.

The first dimethicone macromer mixture may include a dimethicone macromer having a number average molecular weight of more than 1000 (typically more than 2000) and a hydrocarbyl methyl siloxane emollient (generally an alkyl methyl siloxane) having a number average molecular weight of less than 500.

The first dimethicone macromer mixture may include a polyglycol dimethicone macromer cross-linked with a polyalkylene oxide compound (generally a polyethylene glycol compound, a polypropylene glycol compound or a copolymer of ethylene oxide and propylene oxide) or cross-linked with a diene.

Optionally, the first dimethicone macromer mixture can include a polyglycol dimethicone macromer selected from the group consisting of PEG dimethicone PPG crosspolymer, preferably PEG-12 dimethicone/PPG-20 crosspolymer, and PEG dimethicone bis-isoalkyl PPG crosspolymer.

The first dimethicone macromer mixture of the formulation may include a polyglycol dimethicone macromer comprising one or more pendant groups from the dimethicone backbone, said pendant group(s) being a polyalkylene oxide group (generally a polyethylene glycol compound, a polypropylene glycol compound or a copolymer of ethylene oxide and propylene oxide).

Optionally the polyglycol dimethicone macromer can include a polyethylene glycol pendant group and a polypropylene glycol pendant group from the dimethicone backbone.

In embodiment the formulation comprises pyrrolidone carboxylic acid functionalized C\I dimethicone macromer.

CD The formulation may comprise 5 to 45 % w/w first dimethicone macromer mixture, typically 10 to 40% w/w, generally 20 to 30 % w/w.

CD The second dimethicone macromer mixture of the formulation may include a methyl siloxane compound having a number average molecular weight of less than 1000 and a cross-linked polyalkylsiloxane diol dimethicone macromer having a number average molecular weight of more than 1000, generally of more than 2000.

The formulation may comprise 5 to 45 % w/w second dimethicone macromer mixture, typically 10 to 40% w/w, generally 20 to 30 % w/w.

The first dimethicone macromer mixture of the formulation may comprise 5 to 30 % w/w polyglycol dimethicone macromer, typically 10-20% w/w generally 12-19% w/w.

The second dimethicone macromer mixture of the formulation may comprise 5 to 30% w/w cross-linked dimethicone macromer, typically 10-201%w/w generally 12-19% w/w.

In embodiments the formulation does not comprise tranexamic acid.

In embodiments the formulation does not comprise a zinc salt, optionally the formulation does not comprise a zinc salt of a conjugate base of the polyhydroxy acid.

Brief Description of Figures

Figure 1 Permeation profiles of NAM 0-24 hours from tested formulations in human skin. Each data point represents the mean ± SD, n=6.

Figure 2. Steady state permeation profiles of NAM 6-12 hours from tested formulations in human skin. Each data point represents the mean ± SD, n=6. NOTE that mass units permeated per cm2 are in pmol/cm2derived from Figure 1 by dividing mass in ug by 122.1 the molecular weight of NAM.

Figure 3: Plot of peak plasma concentration, pmoliml, of NAM plotted versus oral dose in g/M2. C\I

Figure 4. The images show an actinic keratosis lesion on the upper cheek of a O subject before treatment (left hand panel) and after treatment (right hand panel) with a formulation of the present invention. Reference markings are identified in both the before and after photographs for comparison purposes.

Figure 5: The images show a basal cell carcinoma on the chest of a subject before treatment (left hand panel) and after treatment (right hand panel) with a formulation of the present invention. Reference markings are identified in both the before and after photographs for comparison purposes.

General description

The present invention is based on the first provision of nicotinamide in a coenhancer formulation for topical application to skin. The formulation comprises nicotinamide, a partition coefficient enhancer (Pc enhancer), having a structure of the general formula: CRH2n+202 where n represents an integer from 3 to 6 inclusive, and a diffusion coefficient enhancer (Dc enhancer), selected from the group consisting of a Ci2 to C14 straight chain fatty acid and a C14 straight chain primary alcohol.

Generally the formulation comprises 5 to 12% w/w (percentage weight/weight) nicotinamide. Generally the formulation comprises 10 to 60% w/w of a Pc enhancer. Generally the formulation comprises about 0.5 to about 10 % w/w of a Dc enhancer.

The formulation comprises water. Generally the formulation has about 10% w/w or less of water.

The formulation also comprises a polyhydroxy acid. Generally the formulation has 2 to 10% w/w of a polyhydroxy acid.

It is envisioned that the formulation does not comprise tranexamic acid. It is also envisioned that the formulation does not comprise a zinc salt, for example the formulation does not comprise a zinc salt of the conjugate base of the polyhydroxy acid.

The present invention is based on the surprising and beneficial properties of the present formulation which make it valuable in preventing and/or treating skin cancers. The present formulation of nicotinamide in a coenhancer system has been carefully designed to achieve flux of nicotinamide into skin from a topical formulation to match N*** the nicotinamide delivery levels previously achieved via oral delivery of nicotinamide in experiments showing prevention and/or treatment of skin cancers. Demonstration C\I of achieving the required level of flux of nicotinamide into human skin with the present formulation is described below. The present formulation of nicotinamide has been designed to achieve this delivery level of nicotinamide with clinically relevant doses of nicotinamide in the formulation: namely 5 to 12% w/w, or 6 to 10% w/w of nicotinamde. The present formulation of nicotinamide has been designed to achieve this delivery level of nicotinamide in the context of a formulation that is aesthetically acceptable and has nice feel in use so that it is acceptable for long term use and patient compliance is more readily achieved. It should be noted that experimental formulations have been reported which allegedly achieve flux of nicotinamide into the skin at similar levels to that required herein following topical application, but such formulations either contain much higher levels of nicotinamide and so these are not clinically relevant doses, or contain solvents which are unacceptable for long term use on human skin and hence cannot be marketable products. Additionally, as described below the present formulation has been demonstrated to show surprisingly good clinical effects.

Coenhancer topical formulation Coenhancer topical dermatological drug delivery technology may be defined as use of a combination of partition and diffusion coefficient enhancers, based on Fick's First Law of diffusion. For optimal effectiveness, both the active drug and the diffusion coefficient enhancer should be at, or near, saturated solubility in a non-volatile, thus residual, phase. Coenhancer gels, formulated as a single-phase solution system comprising a nonvolative coenhancer residual phase, itself a single phase, volatile solvents and gelled with a suitable cellulose or acrylate polymers are well known, for example; as described in WO 201 1/070318 A2 to Reckitt Benckiser Healthcare and US 8,541,470 ri5Vito Futura Medical Developments.

Despite their significant drug delivery benefits, coenhancer formulations such as those described in WO 2011/070318 A2 and US 8,541,470 are associated with poor rub-in and skin feel, being associated with tackyness and skin drying. Adherence to such topical dermatological medicinal products is disappointingly low. The American dermatologist Dr Steven Feldman concluded in the February 2018 edition of Practical C\I Dermatology that adherence to topical dermatological, in general, is "miserable".

The UK patent application GB 2549418 "Topical formulations comprising dimethicone macromers" describes a topical formulation technology which aims to address all formulation design-related adherence factors, thus to improve adherence to topical dermatological treatments Because formulations of the present invention were required for aesthetic reasons to be creams, rather than gels, thus by definition to contain an emollient, and also because it was required that the emollient would not over solubilise the diffusion coefficient enhancer, thus to inhibit enhancement effects, the emollient class chosen was of silicone-hybrid chemistry, as described in GB 2549418. Because the chemistry of this class, and silicone fluids in general, are such that they are not miscible with typical glycol partition coefficient enhancers (for example propylene glycol typically at 20-40% w/w of the total formulation) these design requirements force a two-phase design. As within simple coenhancer gels, the two phases are broadly a non-volatile residual phase and a volatile solvent phase, but these immiscible within the cream formulation.

Nonvolatile residual phase of the cream The essential formulation requirements are that the non-volatile residual phase comprises miscible functional partition (a glycol, such as propylene glycol) and diffusion coefficient enhancers. Other miscible nonvolatile cosolvents may be added to ensure that both the active drug and the diffusion coefficient enhancer are at, or near, saturated solubility. Water, as a volatile solvent or nonsolvent may be added at up to 10%w/w. Although volatile, it will partition into the glycol-dominated "nonvolatile" phase, because of its polarity.

Volatile phase of the cream The silicone-based volatile phase comprises a blend typically of three silicone fluids of different volatilities; broadly rapid, intermediate and sustained. Typical silicone fluids are octamethyltrisiloxane, cyclopentasiloxane and the hybrid emollient caprylyl methicone with half lives of evaporation broadly in the range 10-60 seconds, 15-30 minutes and 1-2 hours, respectively. The Emollient, caprylyl methicone is part of the volatile phase and with an evaporation rate consistent with twice-a-day application.

N*** The diffusion coefficient enhancer, typically a C12.14 acid or C14 alcohol will, because of this chemistry, partition between the glycol and silicone phases and will be, ideally, C\I saturated in both.

Structuring of the Cream The cream is structurally defined as a glycol-in-silicone dispersion; thus with droplets of the glycol phase dispersed in the volatile silicone fluids by use of, typically, PEG-12 Dimethicone/ PPG-20 type Crosspolymer. Typically a dimethicone crosspolymer will also by added to modify the viscosity (lightness of touch) of the final cream. On application to the skin of glycol-coenhancer-in-silicone dispersions, the consumer experiences the soft and silky skin feel of the mixed silicone elastomer-silicone fluid/emollient continuous phase. Loss of volatile silicones occurs quickly to give the perception of absorption into the skin.

Nicotinamide The formulation of the present invention comprises nicotinamide as active agent. Nicotinamide., also known as niacinarnide, is a form of vitamin B3 with IUP.AC name pyridine-3-carboxarnide. Nicotinamide may be abbreviated as NAM for N) herein.

Physicochemical properties of NAM Chemical structure Molecular weight 122.1 Da Solubility 1 in 1 of water -1 in 5 in propylene glycol 22°C -1 in 3 in propylene glycol 32°C Log P (octanol/water) -0.4 Melting point 128°C Formulations of the present invention comprise about 510 about 12% wisiv nicotinarnide, Optionally, formulations of the present invention can comprise about O 5.5 to about 11% w/w, and optionally 6 to 10% w/w nicotinamide. Formulations can comprise about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12% w/w of nicotinamide and preferably optionally about 6, about 8 or about 10% w/w nicotinamide.

Polyhydroxy acid Polyhydroxy acids, as typified by lactobionic acid and gluconolactone, are very effective skin moisturisers and antiaging compounds {Algiert-Zielinska et al., 2019, #18915; Grimes et al., 2004, #61971} and achieve these effects without significant skin irritation {Tasit-Kostov et al., 2019, #60827}. The fundamental mechanism is one of acidification deep into the stratum corneum, for example to inhibit protease activity. Dysfunctional stratum corneum protease activity leads to inhibition of essential stratum corneum lipids and also to reduced stratum corneum integrity/cohesion due to effects on corneodesmosome linking between cells. These effects are entirely complementary with those of nicotinamide.

The formulation of the present invention can comprise one or more polyhydroxy acids. The one or more polyhydroxy acids can provide a further active agent in the formulation. The formulation can comprise 2 to 10% w/w of a polyhydroxy acid. The formulation can comprise 2 to 9, 2 to 7, 2 to 5, 3 to 5 or about 4 % w/w of a polyhydroxy acid. Polyhydroxy acids that may be used in the formulation of the present invention include gluconolactone, galactonolactone, glucuronolactone, galacturonolactone, gulonolactone, ribonolactone, saccharic acid lactone, pantoyllactone, glucoheptonolactone, mannonolactone, and galactoheptonolactone; 2-ketoacids present as free acid.

Partition coefficient enhancer (Pc enhancer) Partition coefficient enhancers are used to increase the solubility of the active in the stratum corneum barrier layer, thus to increase skin penetration. Increase in penetration is a function of dose of the Pc enhancer due to uptake and clearance from the skin barrier C\I Formulations of the present invention comprise about 10 to about 60% w/w of a N*** partition coefficient enhancer (Pc enhancer), having a structure of the general glycol formula: CnH2n+202 where n represents an integer from 3 to 6 inclusive. Formulations C\I can comprise one or more Pc enhancers. Formulation can comprise 15-50, 20-

O

45, 25-45, or 30 -40 % w/w of Pc enhancer. Exemplary Pc enhancers for the formulations of the present invention include propylene glycol, butylene glycol, pentylene glycol, hexylene glycol and 1,5 pentane diol or a combination thereof In embodiments the formulations comprise propylene glycol or butylene glycol or a combination of propylene glycol and butylene glycol.

The Pc enhancers used in the present invention have similar structures to propylene glycol which has been exemplified below and have a general formula: CnH2n+202 where n represents an integer from 3 to 6 inclusive. Propylene glycol (n=3), butylene glycol (n=4), pentylene glycol (n=5, 1,2 pentane diol), 1,5 pentane diol (n=5) and hexylene glycol (n=6) are in the homologous series CnH2n+202. Such highly similar structures would be expected to function in a similar way.

Diffusion coefficient enhancer (Dc enhancer) Diffusion coefficient enhancers are used to increase the diffusivity of the active through the stratum corneum barrier layer, thus to increase skin penetration. Much lower doses of the Dc enhancer are required, (but at saturation) believed due to slow clearance from the skin barrier Formulations of the present invention comprise about 0.5 to about 10 % w/w of a diffusion coefficient enhancer (Dc enhancer), selected from the group consisting of a C12 to C14 straight chain fatty acid and a C14 straight chain primary alcohol.

Formulations can comprise one or more Dc enhancers. Formulations can comprise 0.5 to 7, 0.5 to 6, 0.5 to 5, 1 to 5, 1 to 4, 2 to 4 % w/w of Pc enhancer. Exemplary Dc enhancers for the formulations of the present invention include myristyl alcohol (1-tetradecanol), lauric acid (dodecanoic acid) and myristic acid (1-tetradecanoic acid).

The Dc enhancers used in formulations of the present invention are generally 012 to C14 straight chain fatty acids and C14 straight chain primary alcohols -all have a very similar structure to 1-tetradecanol which has been exemplified below and thus all have a low solubility in propylene glycol (and the other Pc enhancers used herein) O 20 similar to that of 1-tetradecanol. Therefore, they should also be expected to function C\I in a similar way. In more detail, 06 to 018 straight chain fatty acids and Cs to Cis straight chain primary alcohols are known to be associated with Dc enhancer activity. In the present invention, C12 to C14 straight chain fatty acids and 014 straight chain primary alcohols are used due to their solubility in Pc enhancers of the formula CnH(2n+2)02. The solubility of the Dc enhancers allows them to achieve the required concentration in solution and to be at or near saturation. This requirement for the Dc enhancer to be at or near saturation is the primary determinant of its efficiency as a co-enhancer. Water

The formulation of the present invention can comprise water and generally in an amount of about 10% w/w or less. Water can be present in an amount of 10%, 9%, 8%, 7%, 6 % or 5 %. Water is generally present in an amount of about 5 35 to about 10 % w/w.

Emollient phase The formulation of the present invention comprises an emollient phase comprising: 5 to 45% w/w of a first dimethicone macromer mixture including a dimethicone macromer and a hydrocarbyl methyl siloxane emollient selected from the group consisting of an alkyl methyl siloxane, an aryl methyl siloxane and an alkyl aryl methyl siloxane, and 5 to 45% w/w of a second dimethicone macromer mixture including a methyl siloxane compound and a cross-linked dimethicone macromer.

The first dimethicone macromer mixture can include a polyglycol dimethicone macromer. The first dimethicone macromer mixture can include a compound of the following structure: 1 1 1 1 R-Si-O+Si-01 Si-O+Si-R 1 1 11 1 mR1 C\I O where R represents H or hydrocarbyl group, in particular Cl to C6 alkyl Y represents C\I 15 a hydrocarbyl group in particular Cl to 06 alkyl group; X represents an amine, a quaternary amino group or acid functionality; and M and n independently represent an integer from 1 to 50. The first dimethicone macromer mixture can include a dimethicone macromer having a number average molecular weight of more than 1000 (typically more than 2000) and a hydrocarbyl methyl siloxane emollient (generally an alkyl methyl siloxane) having a number average molecular weight of less than 500. The first dimethicone macromer mixture can include a polyglycol dimethicone macromer cross-linked with a polyalkylene oxide compound (generally a polyethylene glycol compound, a polypropylene glycol compound or a copolymer of ethylene oxide and propylene oxide) or cross-linked with a diene. The first dimethicone macromer mixture can include a polyglycol dimethicone macromer selected from the group consisting of PEG dimethicone PPG crosspolymer, preferably PEG-12 dimethicone/PPG-20 crosspolymer, and PEG dimethicone bisisoalkyl PPG crosspolymer. The first dimethicone macromer mixture can include a polyglycol dimethicone macromer comprising one or more pendant groups from the dimethicone backbone, said pendant group(s) being a polyalkylene oxide group (generally a polyethylene glycol compound, a polypropylene glycol compound or a copolymer of ethylene oxide and propylene oxide). Optionally the polyglycol dimethicone macromer includes a polyethylene glycol pendant group and a polypropylene glycol pendant group from the dimethicone backbone. Optionally the formulation comprises pyrrolidone carboxylic acid functionalized dimethicone macromer.

The formulation can comprise 5 to 45 % w/w of the first dimethicone macromer mixture, typically 10 to 40 % w/w, generally 20 to 30 % w/w.

The first dimethicone macromer mixture comprises 5 to 30 % w/w polyglycol dimethicone macromer, typically 10-20 % w/w generally 12-19 % w/w.

The second dimethicone macromer mixture can include a methyl siloxane compound having a number average molecular weight of less than 1000 and a cross-linked polyalkylsiloxane diol dimethicone macromer having a number average molecular weight of more than 1000, generally of more than 2000.

The formulation can comprise 5 to 45 % w/w of the second dimethicone macromer mixture, typically 10 to 40 % w/w, generally 20 to 30 % w/w. C\I

The second dimethicone macromer mixture can comprise 5 to 30% w/w cross-linked dimethicone macromer, typically 10-20%w/w generally 12-19% w/w. ('Si

Further features of the emollient phase, the first dimethicone macromer mixture, the second dimethicone macromer mixture and first and second dimethicone macromer mixtures are described on WO 2016/139471 which is incorporated herein by reference.

Further features of the formulation In embodiments the formulation of the present invention does not comprise tranexamic acid.

In embodiments the formulation of the present invention does not comprise a zinc salt, optionally the formulation does not comprise a zinc salt of a conjugate base of the polyhydroxy acid.

General process for manufacturing the formulation In summary the manufacture of a formulation of the present invention involves preparation of a first pre-mix which comprises the nicotinamide, the polyhydroxy acid, the Pc enhancer, water and, finally, the Dc enhancer. The first pre-mix represents the aqueous, "non-volatile" residual phase of the formulation. The components are mixed together and may also be gently heated (>35°C) to ensure the polyhydroxy acid and Dc enhancer are dissolved. A second pre-mix comprises components of the emollient phase and is added to further components of the emollient phase and mixed together. The first pre-mix, comprising components of the non-volatile phase, is added slowly and with vigorous mixing to the second pre-mix, comprising components of the emollient phase until a firm cream has been formed.

Example of method for making exemplary formulations of 6-10% Nicotinamide

CV

N-('Si

Table 1

Material % w/w Serum #2 500g % w/w Serum #2 500g actual 150.0 % w/w Serum #4 500g actual % w/w Serum #6 500g % w/w Serum #6 500g actual Process Order Test 1 Test 2 Test 3 Lactobionic Acid (LBA) 22.50 22.50 30.00 30.00 37.50 37.49 7 Gluconolactone (GLA) 7.50 7.51 10.00 10.03 12.50 12.51 6 % Polyhydroxy acid (PHA) 6.00 8.00 10.00 Nicotinamide (N) 30.00 30.00 40.00 39.99 50.00 50.02 5 % N 6.00 8.00 10.00 NaCI 2.00 2.00 2.00 2.00 2.00 2.0 1 Glycerol (G) 17.50 17.49 2.50 2.52 0.00 0.00 3 Propylene 150.00 150.00 175.00 175.02 200.00 200.03 4 glycol (PG) % PG 30.00 35.00 40.00 De-ionized water (DI H20) 28.50 28.51 28.50 28.51 8.50 8.53 2 (16.81%) (5.01%) Myristyl alcohol 7.50 7.55 7.50 7.58 7.50 7.53 8 Phenoxyethanol 2.50 2.51 2.50 2.50 2.50 2.50 9 Trisiloxane 50.00 50.04 45.00 45.01 35.00 35.00 11 Carbomer 2.00 2.00 2.00 2.00 2.00 2.01 12 EL-7040 120.00 120.24 103.00 103.23 94.50 94.58 10 ST-Elastomer/9040 Silicone Elastomer 60.00 60.36 52.00 52.32 48.00 48.25 13 Total 500.00 500.71 500.00 500.71 500.00 500.45 pH 3.827 3.828 3.931 Process: At the 500g lab scale the batch is made using two premixes V1 (400mI): Premix 1 NaCI + DI H20 + LBA +GLA +G +PG +Nicotinamide (as a 6 ingredient stock) +Phenoxyethanol + Myristyl alcohol (C14 alcohol aka tetradecanol); gentle heat to 35°C to dissolve; cool to <25°C.

V2 (100m1): Premix 2 Carbomer + trisiloxane-mix to disperse and also on addition to V3 V3 (Kenwood bowl) Final mix with beater blade EL-7040 (Caprylyl Methicone (and) PEG-12 Dimethicone/ PPG-20 Crosspolymer into Kenwood bowl add contents of V2 (Carbomer + trisiloxane) from low speed increasing speed, then speed at #6 max 2 minutes to form "syrup".

- Add V1 dropwise/slow ribbon over -10-12 minutes, speed at #6 (max). Phase is inverted when the serum is peaked and firm when running at #6.

Clean sides to middle, add ST-E (Cyclopentasiloxane (and) Dimethicone Crosspolymer/9040 Silicone Elastomer, mix speed #6, 3 minutes, clean sides C\I to middle, #6 further 3 minutes.

-Pack into 500g sealed buckets Note on Premix 1: CD Order of addition as shown - After Niacinamide addn, tumble mixed into clear solution After GLA addn, tumble mixed into clear solution After LBA addn, tumble mixed into clear solution - Gentle heat to dissolve last traces of LBA if required (10% PHA only) Then add Phenoxyethanol and Myristyl alcohol (C14 alcohol, aka tetradecanol) to complete Premix 1 Further exemplary formulations of 6-10% Nicotinamide Table 2: Formulation examples from manufacturing batch sheets (actual batch weights) Material Cream #2.2 g/500g actual Cream Cream #6.2 g/500g actual DOM: 26-30/04/2020 Cream Cream #9.I g/500g actual DOM: 2630/04/2020 DOM: 26- #4.2 #7.1 30/04/2020 g/500g actual DOM: 26-30/04/2020 g/500g actual DOM: 26-30/04/2020 Lactobionic Acid 22.50 30.01 37.50 22.51 15.00 Gluconolactone 7.52 10.00 12.53 7.50 5.01 % PHA (polyhydroxy acid) 6.00 8.00 10.00 6.00 4.00 Nicotinamide (N) 30.02 40.00 50.02 50.02 50.02 %Nicotinamide 6.00 8.00 10.00 10.00 10.00 Sodium chloride solid 2.00 2.00 2.02 2.00 2.02 Glycerol 17.51 2.50 0.00 0.00 0.00 Propylene glycol 150.02 175.11 200.01 200.02 Butylene glycol - - - - 200.03 % prop / butylene glycol 30.00 35.00 40.00 40.00 40.00 DI H20 28.52 28.53 8.49 8.53 50.00 Myristyl alcohol 7.53 7.50 7.51 7.49 -Lauric acid - - - - 7.49 Phenoxyethanol 2.51 2.51 2.52 2.53 2.51 25% LA NH3 (liquid ammonia) 2.00 2.01 2.00 1.00 1.20 (state after LA NH3) Clear Clear Clear Clear Clear Octamethyltrisiloxane 48.03 43.07 33.02 44.01 20.01 Carbomer 2.00 2.00 1.99 2.00 2.00 EL-7040Hydro Elastomer blend' 120.09 103.20 94.65 101.77 96.14 9040 Elastomer blend2 60.15 52.16 48.20 50.85 48.12 Total 500.40 500.60 500.46 500.23 499.55 pH after LA NH3 4.471 4.423 4.610 4.592 4.460 pH serum (4.4-4.6) 4.490 Pass 4.480 Pass 4.514 Pass 4.495 Pass 4.447 Pass Caprylyl Methicone (and) PEG-12 Dimethicone/ PPG-20 Crosspolymer 2 Cyclopentasiloxane (and) Dirnethicone Crosspolyme Treatment and prevention of skin cancers and conditions associated with UV damage Formulations described herein are part of the invention and are for use in therapy.

Formulations of the present invention are for use in a method of preventing and/or treating an ultraviolet (UV) radiation-induced skin condition, or for preventing and/or treating a skin cancer. UV damage to skin can include discolouration, and age-related brown spots (abnormal production or deposition of melanin arising from UV exposure) which may lead to cancers. More severe UV damage can include lesion formation and pre-cancerous lesions. Skin cancers can include actinic keratosis, basal cell carcinoma, squamous cell carcinoma and melanoma. Therefore, the formulation of the present invention is for use in a method of treating or preventing actinic keratosis, basal cell carcinoma, squamous cell carcinoma and melanoma. In particular the formulation of the present invention is for use in a method for use in a method of preventing actinic keratosis, treating actinic keratosis, preventing melanoma, preventing recurrence of melanoma, treating melanoma, preventing squamous cell carcinoma, preventing basal cell carcinoma, treating squamous cell carcinoma and treating basal cell carcinoma.

The present invention further includes use of the formulation of the present invention in the manufacture of a medicament for the treatment or prevention of an ultraviolet radiation-induced skin condition, or the treatment or prevention of a skin cancer. Treatment or prevention of a skin cancer can include prevention of actinic keratosis, treatment of actinic keratosis, prevention of melanoma, prevention of the recurrence of melanoma, treatment of melanoma, prevention of squamous cell carcinoma, prevention of basal cell carcinoma, treatment of squamous cell carcinoma or treatment of basal cell carcinoma.

The present invention provides a method of treating or preventing an ultraviolent radiation-induced skin by topical application to skin of a formulation of the present invention. The present invention further provides a method of treating or preventing an ultraviolent radiation-induced skin condition, the method comprising topical application to skin of a formulation of the present invention. The present invention also provides a method of preventing actinic keratosis, treating actinic keratosis, preventing melanoma, preventing recurrence of melanoma, treating melanoma, preventing squamous cell carcinoma, preventing basal cell carcinoma, treating squamous cell carcinoma and treating basal cell carcinoma comprising topical application to skin of a formulation of the present invention.

In embodiments formulations of the present invention need only be applied to skin once or twice a day. Generally the skin is human skin.

The convenience of once-a day application is widely appreciated by users. As described herein, as the dose of the Pc enhancer is increased its effect to increase skin penetration is extended over time, thus providing the ability to achieve once or twice-a-day dosing.

The cosmetic and medicinal use of Nicotinamide in Dermatoloav The use of Nicotinamide (NAM) in cosmetic and medicinal dermatology, via topical or oral administration, extends back nearly 50 years and has been documented in C\I several major reviews (1-6).

Mostly, NAM is used topically and for cosmetic purposes. NAM, both in vitro, and at C\I concentrations as low as 1-10 pmol L-1(75%-100% of maximum response), and in vivo topically in man, very significantly increases the biosynthesis of ceramides and other stratum corneum lipids to increase skin barrier function (7). Consistent with this, Soma Y et al. found that 2% NAM cosmetic cream was a more effective moisturisier than standard petrolatum in a group of 28 patients with atopic dermatitis (8).

Similarly, Draelos ZD et al. (9) reported that a 2% NAM-containing facial moisturizer improved skin barrier in subjects with rosacea in a non-treated controlled study. Also, Kawada A et al. (10) demonstrated facial anti-wrinkle effects of a cosmetic containing 4% NAM compared with a placebo control. Finally, in their review, Wohlrab and Kreft (4) conclude that the antipruritic effects of NAM are mainly based on barrier-protective effects.

The efficacy of NAM in medicinal inflammatory dermatological conditions such as bullous pemphigoid (11), psoriasis (12), pemphigus vulgaris (13) and rosacea (14) may be due in part to its inhibition of the nuclear poly(ADP-ribose) polymerase-1 (PARP-1). Nuclear poly(ADP-ribose) polymerase-1 (PARP-1) NFK13-mediated transrepression is important in reducing the expression of adhesion molecules and pro-inflammatory mediators such as IL-12, TNF-a, IL-1 and nitric oxide.

Ultraviolet radiation-induced skin cancers, including basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and melanoma (MEL) are a global public health issue (15). Oncogenic mechanisms include direct damage to DNA, suppression of the skin's immunity and energy depletion within the skin, all of which are reversed by NAM (16). In 2012, Surjana et al, (17) reported on two placebo-controlled studies in immune-competent volunteers with the pre-cancerous skin condition actinic keratoses (AK). In total, 37 patients each per active NAM or placebo treatment were treated over 4 months with either oral NAM (500 mg twice daily, study 1, or 500 mg once daily, study 2). At the end of 4 months, highly statistically significant reductions in AK versus baseline (35% study 1; 29% study 2) were seen with the Nicotinamide groups compared with placebo. However, Moloney et al. (35) found no difference in AK scores after 6 months topical treatment with 1% Nicofinamide cream or placebo.

Given the finding of Surjana et al, (17) with oral high dose oral NAM it seems likely that the low dose applied (and delivery efficiency) from the 1% NAM cream may have C\I contributed to the lack of effect in AK.

In a continuation of the oral NAM program, in 2015, Chen et al. (18) published the o results of the ONTRAC study on participants selected on the basis of having had at least two nonmelanoma skin cancers in the last five years. The 386 participants were randomly assigned to receive oral NAM 500 mg twice a day or placebo over a 12 months treatment period. At 12 months assessment, the rate of new nonmelanoma skin cancers was statistically significantly lowered by 23% in the NAM group compared with placebo group, with effects in both BCC and SCC cancers. The ONTRAC study publication generated considerable scientific interest (19) (20).

Recently, the ONTRAC associates have focused on the use of NAM for the prevention of MEL (21). The 2015 ONTRAC study was not designed to report on the effect of oral NAM in prevention of MEL. However, during the ONTRAC 12 months study period, a total of six in situ and four invasive melanomas developed in the oral NAM and placebo groups. A significant increase in CD4+ helper T cells, and cytotoxic CD8+ T cells in the tumour microenvironment was reported in melanomas arising in the oral NAM group compared with placebo (22).

We have found evidence from consumer acceptability studies on Family and Friends that glycol-coenhancer silicone dispersion (GCSD) topical dermatological formulations of 6%-10% NAM are able to prevent and treat sun-induced lesions and skin cancers to restore a normal skin. A scientific analysis, based on the observations described above, of NAM oral in-vivo and in vitro human skin epidermal pharmacokinetic studies and modelling is now presented to support our finding of unexpected clinical effects of GCSD formulations of NAM in treating and preventing skin cancers.

PK-PD analysis of the potential for topical dermatological NAM to be effective to treat and prevent skin cancers As we have commented, the ONTRAC study publication on the effect of oral doses of NAM in the range 500-1,000mg/day to significantly prevent both BCC and SCC cancers generated considerable scientific interest. Also, NAM at such doses is without significant systemic adverse effects. Even so, there is a preference of users to use C\I targeted topical therapy.

One particular advantage of topical therapy is that steady-state free concentrations CD may be achieved and sustained over a 6-8 hour period at the epidermal target site.

This is in contrast to oral dosing where the rapid systemic clearance of NAM is such that, optimally, frequent re-dosing 4-6 times throughout the day may be required. If topical therapy can achieve therapeutic free NAM concentration at the basal epidermal target site, and sustain these over times approximating the dose interval, there may be significant advantage over oral therapy.

Skin permeation of NAM from qlycol-coenhancer silicone dispersions (GCSD) NAM is a small molecule with a relatively low melting point and so, although it has a low octanol water partition coefficient, it penetrates through the lipophilic stratum corneum barrier, the rate of which may be increased by use of skin penetration mono-enhancer (23, 24) or co-enhancer technologies (25, 26).

Table 1 shows examples of GCSD cream formulations of the present invention. Example formulations were blinded as Test 1, Test 2 and Test 3 (as labelled in Table 1) and sent for independent analysis of in vitro permeation across human skin.

The permeation of NAM was tested for four formulations, namely Test 1, Test 2, Test 3 (respectively 6%, 8% and 10% NAM) and an 8% NAM commercial control cream. The study was conducted using Franz diffusion cells in human skin under finite dose conditions (10 pL/cm2) at 32±1 °C up to 24 h. The human (female, Caucasian) abdominal skin from one donor following plastic surgery was obtained from a tissue bank with institutional approval (Research Ethics Committee reference 07/H1306/98).

The human skin was prepared by heat separation and skin integrity was confirmed by evaluation of electrical resistance (TM-22 Digitron digital thermometer, RS Components, UK) before use. Samples were collected at 0, 2, 4, 6, 8, 10, 12 and 24 h by withdrawing 200 pt of receptor medium and replacing with an equal volume of fresh PBS solution. At the end of the permeation study, the mass balance study was C\I conducted following a procedure validated previously. The amounts of NAM in all samples were quantified using HPLC.

Figure 1 shows permeation profiles of NAM 0-24 hours from tested formulations in o 20 human skin. Each data point represents the mean ± SD, n=6. The results show the cumulative receptor concentrations of NAM from the four formulations over 24 hours.

There is a dose-response of cumulative permeation of NAM with time from Test 1 through to Test 3. This is driven (see Table 1) by increasing the concentration of propylene glycol, (the partition coefficient enhancer) from 30% to 35% to 40%, respectively. NAM is increased from 6% to 8% to 10% respectively, to maintain its degree of saturation in solution. The diffusion coefficient enhancer is a saturated solution in all three Test formulations. Addressing these three principles is essential for optimisation of the co-enhancer technology design.

Figure 2 shows the steady state permeation profiles of NAM 6-12 hours from tested formulations in human skin. Each data point represents the mean ± SD, n=6. NOTE that mass units permeated per cm2 are in pmol/cm2derived from Figure 1 by dividing mass in ug by 122.1 the molecular weight of NAM.The results show the 6-12 hour steady state flux expressed as pmol/cm2derived from Figure 1 by dividing mass in ug by the molecular weight of NAM.

From Figure 2 the steady state flux over 6-12 hour may be calculated to be (Tests 1-3, commercial control respectively) 0.046, 0.064, 0.091 and 0.027 pmol/cm2/hour.

Estimation of free NAM concentrations in the basal epidermis from steady state flux values For this estimation it was assumed that the target site for BCC, SCC and MEL is the basal epidermis. The C star (C") concept, relating the free drug concentration at the skin target site and the in vivo effectiveness of a topical formulation, was first developed using the antiviral acyclovir (27, 28) and was very successful in predicting in-vivo efficacy in animal models and also correlates well with clinical outcomes.

C* was calculated from equation 1. PD was calculated from equations 2 and 3 (29) as recently modified by Pensado et al. (30).

C* = J/Po PD = DD /hD Dd = -4.15 -(0.655 x log MVV) Where J is in vitro skin flux, PD is the dermal permeability coefficient, Do is the dermal diffusion coefficient and ho is the thickness of the unperfused upper dermis. The permeability coefficient of NAM in the dermis was estimated using equation (2) where DD, the dermal diffusion coefficient for free NAM was estimated from equation (4).

LogDoNAm --4.15 -(0.655 x log MWNAm) (4) Inputting the molecular weight of NAM of 122.12 into equation (4) gives a value for DoNAm of 3.04 x 10-6 cm2 s-1. A value of 100 pm (0,01cm) was used for ha the thickness of the unperfused upper dermis (30) and Po calculated to be approximately 1.08 cm hi For clarity of communication 3.04 x106 x 60 x 60/0.01 = 1.08 cm hi As previously described, from Figure 2, the steady state flux was calculated to be (Tests 1-3, commercial control respectively) 0.046, 0.064, 0.091 and 0.027 pmolicm2/hour.

Thus, from equation (1), C*, the predicted free NAM concentrations at the target basal epidermal site are given by J, steady state flux in pmoles/cm2/hour, divided by Po, thus are 0.043, 0.059, 0.084 and 0.025 pmol/cm3 for Test 1, Test 2 and Test 2 creams and the commercial control. Conversion from pmol/cm3 to pmol Llgives 43, 59, 84 and 25 pmol L-1. These concentrations are considerably higher than the concentrations of NAM, as low as 1-10 pmole L-1, that very significantly increases the biosynthesis of ceramides and other stratum corneum lipids to increase skin barrier function in cosmetic applications.

Free NAM concentrations associated with efficacy aqainst skin cancers C\I Figure 3 shows a plot of peak plasma concentration, prnolirnl, of NAM plotted versus oral dose in g/f02. Figure 3 provides a plot of peak plasma concentrations, o prnollml(enta), following oral doses of NAM in g1M2 administered to healthy volunteers by Stratford et al. (31).

Mean peak plasma concentrations from the 1g (-0.5 g/M2) dose were 0.127 prnolinil (127 pmol L-1); range 81-158 pmol L-1) in the studies on oral NAM in the prevention of AK (17) and the ONTRAC study on BCC and SCC (18) a maximum oral dose of 500mg of NAM twice a day was used which, assuming linearity, would be predicted to achieve peak plasma concentrations of approximately 63.5 pmol L-1 ug/cm3; range -40-80 pmol L-1. At steady state, and because NAM is poorly protein bound, similar concentrations of NAM are also predicted to be achieved in basal epidermal tissue and may provide a numerical target concentration to be achieved following topical administration.

As described, the Test 1, Test 2, Test 3 GCSD creams and the commercial control cream are predicted to achieve basal steady state epidermal concentrations of 43, 59, 84 and 25 pmol L1 respectively, which are in the range associated with the efficacy found in the ONTRAC study.

Conclusions

Therefore it has been demonstrated that the present formulation achieves flux of nicotinamide into skin, following topical application, which matches the nicotinamide delivery levels previously achieved via oral delivery of nicotinamide in experiments showing prevention and/or treatment of skin cancers. Consequently, it has been demonstrated that the present formulation is expected to be effective in the prevention and/or treatment of skin cancers. It can be concluded that the present inventors have developed a topical formulation that is useful for preventing and/or treating a skin cancer selected from actinic keratosis, basal cell carcinoma, squamous cell carcinoma and melanoma. It can be concluded that the present inventors have developed a topical formulation for preventing actinic keratosis, treating actinic keratosis, preventing melanoma, preventing recurrence of melanoma, treating melanoma, achieving complete or partial remission of melanoma, preventing squamous cell carcinoma, preventing basal cell carcinoma, treating squamous cell carcinoma, treating basal cell C\I carcinoma, achieving complete or partial remission of squamous cell carcinoma, and achieving complete or partial remission of basal cell carcinoma.

C\I Exemplification -Informal Studies on Family and Friends (F&F) The formulations containing 6%-10% NAM described herein may be structurally described as glycol-coenhancer dispersions in a mixed silicone elastomer-silicone fluid continuous phase (GCSD). Glycol-coenhancer gels comprising, for example, propylene glycol as partition coefficient enhancer and a C12.14 diffusion coefficient enhancer are known to be effective to increase skin penetration of an active but are associated with poor rub in and skin feel, tackiness and skin drying (32).

On application to the skin of glycol-coenhancer silicone dispersions (GCSD), the consumer experiences the soft and silky skin feel of the mixed silicone elastomer-silicone fluid continuous phase. Loss of volatile silicones occurs quickly to give the perception of absorption into the skin.

In order to get feedback on the aesthetics of this design, informal cosmetic studies on Family and Friends (F&F) were undertaken.

Feedback: Moisturisation As a group, younger F&F members feedback was that GCSD products containing 610% Nicotinamide were exceptionally good moisturises. This is to be expected from the design elements outline above.

Feedback: Age Spots (Solar Lentigines), Sunspots and Liver spots These conditions occur after long-term exposure to UV light and so are associated with older F&F members.

Female family member SJD C\I SJD reported sunspots on her hands due her time spent on many outdoor activities.

She volunteered to undertake a study in which her left hand was treated and the right o used as an untreated control. A cream formulation of the current invention containing 8% Nicotinamide was applied once a day up to 4 weeks to the left hand. After two weeks a noticeable evening of colour was reported with a significant reduction in the

CD

number of darker brown spots. The product was reported to be absorbed very quickly into the skin and left the skin feeling silky and soft.

Female friend JW JW requested samples of a 6% Nicotinamide cream of the current invention for treatment of dry skin on hands and face. After approximately 4 weeks treatment she spontaneously mailed images of both hands. Her comment was that the sun spots had been very significantly reduced compared to pre-treatment.

Feedback: Actinic keratoses Because of the informal and distant nature of these studies, and because of they are often mistaken for sunspots or age spots, it was not possible to get feedback on actinic keratoses (AK) In 2012, Suriana et al, (17) reported on two placebo-controlled studies in immune-competent volunteers actinic keratoses (AK) where statistically significant reductions in AK versus baseline (35% study 1; 29% study 2) were seen with the NAM groups (500mg orally twice or once a day) compared with placebo. However, Moloney et al. (35) found no difference in AK scores after 6 months topical treatment with 1% Nicotinamide cream or placebo. Given the subsequent finding of Surjana et al, (17) with oral high dose oral NAM it seems likely that the low dose applied (and delivery efficiency) from the 1% NAM cream may have contributed to the lack of effect in AK.

Feedback: Actinic Keratosis A 60-year-old white male volunteered to test a 10% nicotinamide containing cream of the present invention. The subject had been suffering for over a year with a solar keratosis lesion positioned on the left-hand side of his face in the vicinity of the upper side of the cheek bone as shown in Figure 4 left hand panel. The lesion was characterised by an irregular edged area of reddish flaking skin around 0.5 cm in diameter with an elevated centre. The subject had often experienced a stinging or C\I tingling sensation from the lesion. He had tried a range of emollients, moisturisers and medicated creams to alleviate the condition without any success.

The subject began by applying a liberal dose of the test cream to the lesion twice a O day, but after two days reported that the lesion had started to sting and redden and he questioned if the product might be a bit too aggressive. He halted use of the cream for a day and noticing the area had calmed significantly he began re-applying the cream more sparingly only once per day for the rest of the week. Observing that no further irritation had occurred and that the lesion had improved, he resumed dosing twice a day. Significant improvement was observed over the next few weeks with the lesion gradually shrinking and the surface of the lesion smoothing to the level of the surrounding tissue as shown in Figure 4 right hand panel.

After around two months the lesion had been reduced to little more than an area of slightly darker skin. The subject ceased use of the cream shortly after admitting that he assumed the lesion had been resolved and so he didn't need to bother further treatment. Nevertheless, on checking the area a few weeks later he was barely able to detect where the lesion had been. No deterioration of the area or evidence of reoccurrence was observed over the following twelve months.

Feedback: Basal Cell Carcinoma The same white male volunteer from the above Actinic Keratosis Example above, now 61 years of age, had begun to notice changes in what he considered a small innocuous freckle' on the upper right-hand side of his chest. Initially he noticed that it began to gradually increase in diameter to around one centimetre with an irregular broken edge. As time progressed the lesion developed raised areas and colour variations across the lesion. Crusting of areas also began to occur and some bleeding was noticed on towel drying after showering. The subject also began to notice evidence of overnight bleeding on bed linen.

As the lesion progressed to develop a more sinister appearance the subject finally decided to visit his general medical practitioner, who promptly referred him to a consultant dermatologist specialising in skin cancer. On subsequent examination by the specialist a 'basal cell carcinoma' was diagnosed and the subject referred for C\I surgical removal of the lesion. The basal cell carcinoma lesion is shown in Figure 5 left hand panel.

Whilst waiting for surgery, and in the absence of any interim treatment, the subject o decided to begin applying the 10% nicofinamide cream of the present invention, a sample of which he had retained from his previous testing on an actinic keratosis lesion. He admitted having no great confidence that the cream would do anything in this case, but felt he had nothing to lose in trying it as ultimately the lesion would be surgically removed.

He proceeded to apply the cream twice a day, noting in the early days that the lesion became rather flaky, but the level of redness did not increase at all. Over the next month he saw the lesion gradually shrink in size and become flattened and continuous with the surrounding normal skin. After around two months the original small 'freckle' was the most visible feature with a halo of 'normal-looking' skin but slightly lighter than the surrounding previously unaffected skin. The subject was pleased and surprised by the improvement achieved, and importantly he had avoided potentially disfiguring surgery and saved the health service some money in the process. The subject continued treatment for around three months before deciding that the lesion had been fully resolved. Twelve months on from treatment, aside from the obvious original 'freckle', the halo of the treated lesion remained barely detectable as shown in Figure 5 right hand panel.

Feedback: Melanoma Fortunately, and as might be anticipated, no spontaneous reports of effect on MEL were obtained. However, as described herein it is expected that glycol-coenhancer silicone dispersion (GCSD) creams containing 6%-10% NAM may be effective to prevent and treat, to restore to normal skin, MEL lesions.

Conclusions

Therefore it has been demonstrated that the present formulation advantageously delivers therapeutically effective levels of nicotinamide into the skin in the context of a C\I formulation that is aesthetically acceptable and feels nice use. Therefore, whilst being effective the present formulation is also acceptable for long term use meaning that o patient compliance is more readily achieved. Additionally, the present formulation has been demonstrated to show surprisingly good effects on skin cancers and other skin conditions caused by UV damage.

CD

The present formulation represents the first consumer acceptable (and commercially viable) topical nicotinamide containing product that can achieve the target flux delivery levels required for the prevention of actinic keratosis and cancerous skin conditions.

The present formulation achieves this at commercially practical levels 01 6-10% nicotinamide inclusion.

The present formulation achieves this whilst demonstrating high-end cosmetic aesthetics, rarely found in sun protection products, thus encouraging user compliance critical in achieving therapeutic potential.

The present formulation also incorporates synergistic benefits through inclusion of effective levels of Polyhydroxy acids which are known to deliver a range of benefits to skin, including moisturising and maintenance of the skin's natural barrier function. In short, SOL can encourage sustained daily use as part of an everyday skincare routine (so it represents much more than a product reserved for problem-solution sun protection).

The present formulation would be expected to provide protection against sun UV damage based on the known evidence, but totally unexpectedly, SOL has been found to be able to treat some cases of previous sun induced damage including brown-spot and actinic keratosis lesions and a diagnosed case of a basal cell carcinoma lesion.

This is a surprising and very significant finding and extends the value of SOL into treatment as well as prevention.

Summary of studies

In informal cosmetic studies on Family and Friends described herein and undertaken to C\I obtain feedback on the aesthetics of GCSD creams, we have in addition, and spontaneously, received feedback that these creams are exceptionally effective in o treating sunspots and age spots and may be effective in treating skin cancers, particularly BCC. Why is this, as NAM has been applied topically, mainly in cosmetic use but also in medicinal use, for almost 50 years?

CD

Concentration of NAM used in cosmetics have increased from 1-2% to up to 10% over the last decades, yet we know of no reports of efficacy of topical NAM to treat, to reverse, BCC, SCC or MEL skin cancers. This focus on increase in concentration of the active to increase skin permeation has been a major issue in topical formulation design. Unfortunately, the normal form of the Fickian permeation equation is: J o Cv *Pc *Dc Where J is the flux, skin input rate, Cv is the concentration in solution in the vehicle and Pc and Dc are partition and diffusion coefficient terms. However, as Cv in solution is increased, for example by addition of a solvent for NAM, Pc is proportionally decreased, so that there is no net increase in J. Increasing concentration of NAM from 1-10% will not, on its own, increase NAM permeation. C\I

CD ('Si CD 20

NAM permeation may be increased by addition of skin penetration mono-enhancers (23, 24). The commercial control used in our in vitro human skin penetration study, developed by a major expert Global Player in this market, contains 8% NAM and the mono-skin penetration enhancer Octyl salicylate. Steady state basal cell concentration are predicted to be -25 pmol L-1. A recent publication on a commercial mono-enhanced 4% NAM and two test 3% NAM formulations (36) allows steady state basal cell concentration in the range -9.50 to 17 pmol L-1 to be predicted.

Very recently, Zang Y et al. 2019 (25) have described "simple" co-enhancer formulations of 5% NAM, in a combination of partition and diffusion coefficient enhancers such as propylene glycol and oleic acid or linoleic acid which show very similar efficiency of permeation of NAM to the co-enhancer GCSD creams (predicted basal cell concentrations of 35 pmol L1 under the finite dose conditions studied). However, these "simple" solvent mixtures are not, yet, complete formulations and it is unlikely that these research prototypes will have been used in vivo on human skin, at least for extended periods of time, such as to confirm our finding of the potential for NAM co-enhancer formulations to be effective to treat skin cancers.

In 2020 Malesu et al., the ONTRAC associates, (22) published on the potential of oral NAM to be chemoprevention on MEL. In their discussion, and from extrapolating the best line of fit to the data of Stratford et al. (31) (see Figure 3 herein) they conclude that oral administration of 500mg of NAM would achieve peak plasma concentrations of -80 pmol L-1. In a previous publication (37) this group reported (see Figure 6 of publication (37)) that in vitro NAM showed a dose-dependent inhibition of PARP-1 with 60% inhibition at a concentration of 50 pmol 12. PARP-1 inhibitors, based on nicotinamide structure, are currently undergoing clinical trials as targeted treatment modalities in the treatment of breast, uterine, colorectal and ovarian cancer.

As we have described, NAM containing glycol-coenhancer silicone dispersions (GCSD) are predicted to be able to achieve and sustain steady state free NAM concentrations of up to -80 pmol L-1, a concentration that has been shown to significantly inhibit PARP-1. Also, the ability of topical administration of glycol-coenhancer silicone dispersion (GCSD) creams containing 6%-10% NAM to sustain steady-state concentration over a period of 12 hours may be an important benefit of the topical route as oral NAM is rapidly cleared from plasma (16).

While we believe that the above pharmacokinetic-pharmacodynamic arguments to support the potential for use of NAM containing glycol-coenhancer silicone dispersions (GCSD) to be effective in the prevention and treatment of skin cancers are sound, there may also be an adherence factor that contributes to the unexpected efficacy seen.

As discussed previously research into the reasons for low rates of adherence identifies that slow and poor response to treatment, incidence of or fear of incidence of local and systemic drug adverse effects (especially the phobia of topical corticosteroids), treatment regimens inconsistent with lifestyle and, specific to topical products, the poor aesthetics and experience in use of topical dermatological products, are main causal factors. The table below (Table 3) shows a summary of various dimensions effecting adherence.

Table 3-Dimensions of Adherence Patient social, economic and psychological factors HOP-HO system-related factors Disease-related factors Formulation design-related factors Age, gender, marital status, employment, drug and alcohol abuse Communication, disease education, motivation Visual (facial lesions, disease severity Dissatisfaction with Efficacy, local and systemic AEs, excessive time and effort, poor sensory and perceptive experience in use Especially relevant to this discussion are the formulation cosmeceufical and biopharmaceutical design factors, briefly 1) efficacy, 2) local and systemic adverse effects potential, 3) time and effort in use (all as described by WHO) and 4) particularly the consumer experience in use.

GCSD formulations, as shown in Figures 1 and 2 herein, are exceptional in delivery of NAM when compared to current commercial NAM formulations. However, as important as NAM delivery to the target site is the experience in use of NAM GCSD creams equivalent to that experienced with Premium cosmetics; without adherence, there can be no therapeutic effect.

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Chen, AC, Damian, DL. Nicotinamide and the skin. Australas J Dermatol.

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4 Wohlrab, J, Kreft, D. Niacinamide -mechanisms of action and its topical use in dermatology. Skin Pharmacol Physiol. 2014;27(6):311-315.

S. Rolfe, HM. A review of nicotinamide: treatment of skin diseases and potential side effects.

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6 Namazi, MR. Nicotinamide in dermatology: a capsule summary. Int J Dermatol.

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7 Tanno, 0, Ota, Y, Kitamura, N, Katsube, T, Inoue, S. Nicotinamide increases biosynthesis of ceramides as well as other stratum corneum lipids to improve the epidermal permeability barrier. Br J Dermatol. 2000;143(3):524-531.

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20. Barton, MK. Nicotinamide found to reduce the rate of nonmelanoma skin cancers in high-risk patients. CA Cancer J Clin. 2016;66(2):91-92.

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Pharmacokinetics of nicotinamide and its effect on blood pressure, pulse and body temperature in normal human volunteers. Radiother Oncol. 1992;25(1):37-42.

32. AF, KAAD. Topical Formulation tf i WO 2011 / 070318 A2. RECKITT BENCKISER HEALTHCARE INTERNATIONAL LIMITED.

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35. Moloney, F, Vestergaard, M, Radojkovic, B, Damian, D. Randomized, double-blinded, placebo controlled study to assess the effect of topical 1% nicotinamide on actinic keratoses. Br J Dermatol. 2010;162(5):1138-1139.

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Further references * Skin cancer rates have soared by 45% in ten years in both young and old patients because of rise of package holidays in the 1970s and a more recent surge in cheap flights', Vanessa Chalmers MAILONLINE 18 July 2019, e-frosf.Avvvvv.claiipnaii.co.0 cer-rates-s, 0-years-

S

caoicg.ie-ficifidays-ctieav-fliani, * Skin Cancer Facts & Statistics, 2020 The Skin Cancer Foundation, https://www.skincancer.org/skin-cancer-information/skin-cancer-facts/ * The Good, the Bad, and the Ugly of Sunscreens M Berwick, Clinical pharmacology & Therapeutics, p 31-33 VOLUME 89 NUMBER 1, JANUARY 2011 * A Phase 3 Randomized Trial of Nicotinamide for Skin-Cancer Chemoprevention. Chen AC, Marlin Ai, Choy B, Fern.andez-Panes P Dalziell RA, McKenzie CA, Scolyer RA Oh//ion HM Varciv JL Kricker A St George G Chinniah N Halliday GM, Damian DL. N Engl J Med. 2015 Oct 22;373(17):1618-26 * New and current preventive treatment options in actinic keratosis P. Arenberger and fill. Arenbergerova in JEADV 2017, 31 (Suppl. 5), 13-17 * Could vitamin B-3 help to prevent melanoma? Honor Whiteman, Medical News Today, 9th Aug, 2017 pttlIsilvwmegcalaew§lodgi.colniailice.V310M.Ww: * Melanoma and nonmelanoma skin cancer chemoprevention: A role for nicotinamide? Rashi Minocha, Diona L. Damian and Gary M. Halliday, Photodermatol Photoimmunol Photomed. 2017;1-8 * Nicotinamide for skin cancer chemoprevention, Diona L Damian, Australasian Journal of Dermatology (2017) 58, 174-180 Ne* 25 * Nicotinamide for skin cancer chemoprevention: effects of nicotinamide on melanoma in vitro and in vivo, Rashi Malesu, Andrew J. Martin, J. Guy Lyons, Richard A. Scolyer, Andrew C. Chen, Catriona A. McKenzie, Jason Madore, Gary M. Halliday and Diona L. Damian, Photochem. Photobiol. Sci., 2020,19, 171-179 ('Si

Claims

Claims 1.
A formulation for topical application and for use in a method of preventing and/or treating a skin cancer, the formulation comprising: a non-volatile residual phase comprising: 5 to 12% w/w (percentage weight/weight) nicotinamide, 2 to 10% w/w of a polyhydroxy acid, to 60% w/w of a partition coefficient enhancer (Pc enhancer), having a structure of the general formula: CnH2n+202 where n represents an integer from 3 to 6 inclusive, C\I N* about 0.5 to about 10% w/w of a diffusion coefficient enhancer (Dc enhancer), selected from the group consisting of a C12 to C14 straight chain fatty acid and a C14 straight chain primary alcohol, and 10% water and an emollient phase comprising: to 45% w/w of a first dimethicone macromer mixture including a dimethicone macromer and a hydrocarbyl methyl siloxane emollient selected from the group consisting of an alkyl methyl siloxane, an aryl methyl siloxane and an alkyl aryl methyl siloxane, and to 45% w/w of a second dimethicone macromer mixture including a methyl siloxane compound and a cross-linked dimethicone macromer.;2.
The formulation for the use according to claim 1, wherein the formulation comprises 5.5 to 11% w/w, and optionally 6 to 10% w/w nicotinamide.;3.
The formulation for the use according to claim 1 or 2, wherein the Pc enhancer is selected from the group consisting of propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, and 1,5 pentane diol and a combination thereof.;4.
The formulation for the use according to any one of claims 1 to 3, wherein the formulation comprises 15-50, 20-45, 25-45, or 30 -40 % w/w of the Pc enhancer.;5.
The formulation for the use according to any one of the preceding claims, wherein the Dc enhancer is selected from the group consisting of myristyl alcohol (1-Tetradecanol), myristic acid, and lauric acid (dodecanoic acid).;6.
The formulation for the use according to any one of the preceding claims, C\I wherein the Dc enhancer is 0.5 -5, 1 -5, 2 -4 % w/w (percentage weight/weight) of the formulation.wherein the formulation comprises 2 to 9, 2 to 7, 2 to 5, 3 to 5 or about 4 % w/w of a;CDpolyhydroxy acid.;
8. The formulation for the use according to any one of the preceding claims, wherein the polyhydroxy acid is selected from gluconolactone, galactose and lactobionic acid.
9. The formulation for the use according to any of the preceding claims wherein the first dimethicone macromer mixture includes a polyglycol dimethicone macromer.;7. The formulafion for the use according to any one of the preceding claims,
10. The formulation for the use according to any of the preceding claims wherein the first dimethicone macromer mixture includes a compound of the following structure: R-SIi-O-SIi-01 SIi-OSIi-R Where R represents H or hydrocarbyl group, in particular Cl to C6 alkyl Y represents a hydrocarbyl group in particular Cl to C6 alkyl group; X represents an amine, a quaternary amino group or acid functionality.;M and n independently represent an integer from 1 to 50.;
11. The formulation for the use according to any of the preceding claims wherein the first dimethicone macromer mixture includes a dimethicone macromer having a number average molecular weight of more than 1000 (typically more than 2000) and a hydrocarbyl methyl siloxane emollient (generally an alkyl methyl siloxane) having a number average molecular weight of less than 500. C\I;
12. The formulation for the use according to any of the preceding claims wherein the first dimethicone macromer mixture includes a polyglycol dimethicone macromer cross-linked with a polyalkylene oxide compound (generally a polyethylene glycol compound, a polypropylene glycol compound or a copolymer of ethylene oxide and propylene oxide) or cross-linked with a diene.;
13. The formulation for the use according to claim 12, wherein the first dimethicone macromer mixture includes a polyglycol dimethicone macromer selected from the group consisting of PEG dimethicone PPG crosspolymer, preferably PEG-12 dimethicone/PPG-20 crosspolymer, and PEG dimethicone bis-isoalkyl PPG crosspolymer.;
14. The formulation for the use according to any of the preceding claims wherein the first dimethicone macromer mixture includes a polyglycol dimethicone macromer comprising one or more pendant groups from the dimethicone backbone, said pendant group(s) being a polyalkylene oxide group (generally a polyethylene glycol compound, a polypropylene glycol compound or a copolymer of ethylene oxide and propylene oxide).;I 1I nl imI
15. The formulation for the use according to claim 14 wherein the polyglycol dimethicone macromer includes a polyethylene glycol pendant group and a polypropylene glycol pendant group from the dimethicone backbone.;
16. The formulation for the use according to any one of claims 10 to 15 comprising pyrrolidone carboxylic acid functionalized dimethicone macromer.;
17. The formulation for the use according to any of the preceding claims comprising 5 to 45 % w/w first dimethicone macromer mixture, typically 10 to 40 % w/w, generally 20 to 30 % w/w.;
18. The formulation for the use according to any of the preceding claims wherein the second dimethicone macromer mixture includes a methyl siloxane compound having a number average molecular weight of less than 1000 and a cross-linked polyalkylsiloxane diol dimethicone macromer having a number average molecular weight of more than 1000, generally of more than 2000.;C\I
19. The formulation for the use according to any of the preceding claims comprising 5 to 45 % w/w second dimethicone macromer mixture, typically 10 to 40% o w/w, generally 20 to 30 % w/w.;
20. The formulation for the use according to any of the preceding claims where O the first dimethicone macromer mixture comprises 5 to 30 % w/w polyglycol dimethicone macromer, typically 10-20 % w/w generally 12-19 % w/w.;
21. The formulation for the use as claimed in any preceding claim where the second dimethicone macromer mixture comprises 5 to 30% w/w cross-linked dimethicone macromer, typically 10-20%w/w generally 12-19% w/w.;
22. The formulation for the use according to any of the preceding claims wherein the formulation does not comprise tranexamic acid.;
23. The formulation for the use according to any of the preceding claims wherein the formulation does not comprise a zinc salt, optionally the formulation does not comprise a zinc salt of a conjugate base of the polyhydroxy acid.;
24. The formulation for the use according to any of the preceding claims wherein the skin cancer is selected from actinic keratosis, basal cell carcinoma, squamous cell carcinoma and melanoma.;
25. The formulation for the use according to any of the preceding claims wherein the method of preventing and/or treating a skin cancer is selected from a method of preventing actinic keratosis, treating actinic keratosis, preventing melanoma, preventing recurrence of melanoma, treating melanoma, achieving complete or partial remission of melanoma, preventing squamous cell carcinoma, preventing basal cell carcinoma, treating squamous cell carcinoma, treating basal cell carcinoma, achieving complete or partial remission of squamous cell carcinoma, and achieving complete or partial remission of basal cell carcinoma.;
26. The formulation for the use of any one of the preceding claims, wherein the method consists of application to skin once a day or twice a day. C\ICDCD;
27. Use of a formulation in the manufacture of a medicament for the prevention and/or treatment of a skin cancer, the formulation comprising: a non-volatile residual phase comprising: to 12% w/w (percentage weight/weight) nicotinamide, 2 to 10% w/w of a polyhydroxy acid, to 60% w/w of a partition coefficient enhancer (Pc enhancer), having a structure of the general formula: CnH2n+202 where n represents an integer from 3 to 6 inclusive, about 0.5 to about 10% w/w of a diffusion coefficient enhancer (Dc enhancer), selected from the group consisting of a C12 to C14 straight chain fatty acid and a C14 straight chain primary alcohol, anth 10% water and an emollient phase comprising: to 45% w/w of a first dimethicone macromer mixture including a dimethicone macromer and a hydrocarbyl methyl siloxane emollient selected from the group consisting of an alkyl methyl siloxane, an aryl methyl siloxane and an alkyl aryl methyl siloxane, and to 45% w/w of a second dimethicone macromer mixture including a methyl siloxane compound and a cross-linked dimethicone macromer.;
28. The use according to claim 27, wherein the formulation is as further defined in claims 2 to 23.;
29. The use according to claim 27, wherein the skin cancer is selected from actinic keratosis, basal cell carcinoma, squamous cell carcinoma and melanoma.;
30. The use according to claim 27, wherein the prevention and/or treatment of a skin cancer is selected from a method of preventing actinic keratosis, treating actinic C\I keratosis, preventing melanoma, preventing recurrence of melanoma, treating melanoma, achieving complete or partial remission of melanoma, preventingCDsquamous cell carcinoma, preventing basal cell carcinoma, treating squamous cell carcinoma, treating basal cell carcinoma, achieving complete or partial remission of CD squamous cell carcinoma, and achieving complete or partial remission of basal cell carcinoma.;
31. The use according to any one of claims 27 to 30, wherein the treating and/or preventing consists of application to human skin once a day or twice a day.;
32. A method of preventing and/or treating a skin cancer, the method comprising topical application to skin of a formulation comprising: 25 a non-volatile residual phase comprising: to 12% w/w (percentage weight/weight) nicotinamide, 2 to 10% w/w of a polyhydroxy acid, to 60% w/w of a partition coefficient enhancer (Pc enhancer), having a structure of the general formula: CnH2,202 where n represents an integer from 3 to 6 inclusive, about 0.5 to about 10% w/w of a diffusion coefficient enhancer (Dc enhancer), selected from the group consisting of a C12 to C14 straight chain fatty acid and a C14 straight chain primary alcohol, and 10% water and an emollient phase comprising: to 45% w/w of a first dimethicone macromer mixture including a dimethicone macromer and a hydrocarbyl methyl siloxane emollient selected from the group consisting of an alkyl methyl siloxane, an aryl methyl siloxane and an alkyl aryl methyl siloxane, and C\I 5 to 45% w/w of a second dimethicone macromer mixture including a methyl siloxane compound and a cross-linked dimethicone macromer.;
33. The method according to claim 32, wherein the skin cancer is selected from CD 20 the group consisting of actinic keratosis, basal cell carcinoma, squamous cell carcinoma and melanoma.;
34. The method according to claim 32, wherein the preventing and/or treating is selected from the group consisting of a method of preventing actinic keratosis, treating actinic keratosis, preventing melanoma, preventing recurrence of melanoma, treating melanoma, achieving complete or partial remission of melanoma, preventing squamous cell carcinoma, preventing basal cell carcinoma, treating squamous cell carcinoma, treating basal cell carcinoma, achieving complete or partial remission of squamous cell carcinoma, and achieving complete or partial remission of basal cell carcinoma.;
35. The method according to claim 32, wherein the method consists of application to skin once or twice a day.;
36. The method according to claim 32, wherein the skin is human skin.;
37. The method according to claim 32, wherein the formulation comprises 5.5 to 11% w/w, and optionally 6 to 10% w/w nicotinamide.;
38. The method according to claim 32, wherein the Pc enhancer is selected from the group consisting of propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, and 1,5 pentane diol and a combination thereof.;
39. The method according to claim 32, wherein the formulation comprises 15 - 50, 20 -45, 25-45, or 30 -40 % w/w of the Pc enhancer.;
40. The method according to claim 32, wherein the Dc enhancer is selected from the group consisting of myristyl alcohol (1-Tetradecanol), myrisfic acid, and lauric acid (dodecanoic acid).C;
41. The method according to claim 32, wherein the Dc enhancer is 0.5 -5, 1 -CD 5, 2 -4 % w/w (percentage weight/weight) of the formulation.o
42. The method according to claim 32, wherein the formulation comprises 2 to 9, 2 to 7, 2 to 5, 3 to 5 or about 4 % w/w of a polyhydroxy acid.
43. The method according to claim 32, wherein the polyhydroxy acid is selected from gluconolactone, galactose and lactobionic acid.
44. The method according to claim 32, wherein the first dimethicone macromer mixture includes a polyglycol dimethicone macromer.
45. The method according to claim 32, wherein the first dimethicone macromer mixture includes a compound of the following structure: R-SIi-O-SIi-01 SIi-OSIi-R Where R represents H or hydrocarbyl group, in particular Cl to C6 alkyl Y represents a hydrocarbyl group in particular Cl to C6 alkyl group; X represents an amine, a quaternary amino group or acid functionality.M and n independently represent an integer from 1 to 50.
46. The method according to claim 32, wherein the first dimethicone macromer mixture includes a dimethicone macromer having a number average molecular weight of more than 1000 (typically more than 2000) and a hydrocarbyl methyl siloxane emollient (generally an alkyl methyl siloxane) having a number average molecular weight of less than 500 C\I
47. The method according to claim 32, wherein the first dimethicone macromer mixture includes a polyglycol dimethicone macromer cross-linked with a polyalkylene oxide compound (generally a polyethylene glycol compound, a polypropylene glycol compound or a copolymer of ethylene oxide and propylene oxide) or cross-linked with a diene.
48. The method according to claim 32, wherein the first dimethicone macromer mixture includes a polyglycol dimethicone macromer selected from the group consisting of PEG dimethicone PPG crosspolymer, preferably PEG-12 dimethicone/PPG-20 crosspolymer, and PEG dimethicone bis-isoalkyl PPG crosspolymer.
49. The method according to claim 32, wherein the first dimethicone macromer mixture includes a polyglycol dimethicone macromer comprising one or more pendant groups from the dimethicone backbone, said pendant group(s) being a polyalkylene oxide group (generally a polyethylene glycol compound, a polypropylene glycol compound or a copolymer of ethylene oxide and propylene oxide).I 1I nl imI
50. The method according to claim 32, wherein the polyglycol dimethicone macromer includes a polyethylene glycol pendant group and a polypropylene glycol pendant group from the dimethicone backbone.
51. The method according to claim 32, comprising pyrrolidone carboxylic acid functionalized dimethicone macromer.
52. The method according to claim 32, comprising 5 to 45 % w/w first dimethicone macromer mixture, typically 10 to 40 % w/w, generally 20 to 30 % w/w.
53. The method according to claim 32, wherein the second dimethicone macromer mixture includes a methyl siloxane compound having a number average molecular weight of less than 1000 and a cross-linked polyalkylsiloxane diol dimethicone macromer having a number average molecular weight of more than 1000, generally of more than 2000.
54. The method according to claim 32, comprising 5 to 45 % w/w second C\I dimethicone macromer mixture, typically 10 to 40 % w/w, generally 20 to 30 % w/w.
55. The method according to claim 32, where the first dimethicone macromer mixture comprises 5 to 30% w/w polyglycol dimethicone macromer, typically 10-20 ok w/w generally 12-19 % w/w.
56. The method according to claim 32, where the second dimethicone macromer mixture comprises 5 to 30% w/w cross-linked dimethicone macromer, typically 10-20%w/w generally 12-19% w/w.
57. The method according to claim 32, wherein the formulation does not comprise tranexamic acid.
58. The method according to claim 32, wherein the formulation does not comprise a zinc salt, optionally the formulation does not comprise a zinc salt of a conjugate base of the polyhydroxy acid.*