Topical preparations

Abstract

This invention relates to a topical formulation comprising: 1) a dispersed phase comprising 5-15% w / w (weight percentage) nicotinamide; and 10-60% w / w a partition coefficient enhancer (Pc enhancer) having the general formula C. n H 2n+2 O2, where n represents an integer from 3 to 6; and ≤10% water, and 2) a continuous phase, wherein the formulation has a pH greater than 4.0. The present invention also relates to pharmaceutical compositions comprising a topical formulation according to the invention, pharmaceutical compositions for treatment according to the invention, and the use of the topical formulation as a cosmetic.

Description

Technical Field

[0001] This invention relates to topical formulations containing nicotinamide, pharmaceutical compositions comprising topical formulations according to the invention, pharmaceutical compositions for treatment according to the invention, and the use of the topical formulations as cosmetics. Background Technology

[0002] Skin cancer is the most common form of cancer in developed countries, and the number of deaths from aggressive melanoma is increasing daily. Ultraviolet radiation has adverse effects on the skin, disrupting its normal repair and protection mechanisms. Evidence suggests that when effective doses of niacinamide enter the skin, it can reactivate the skin's own natural repair mechanisms to protect against these effects.

[0003] Phase III clinical trials demonstrated that oral nicotinamide had a significant preventive effect against actinic keratosis, and subsequent evidence suggests that oral nicotinamide may also prevent other more life-threatening skin cancers, such as melanoma. When administered orally, the dose of nicotinamide reaching the skin can be calculated from known plasma levels using established procedures. Therefore, the target level of nicotinamide dose required for topical administration (based on the desired flux) can be determined.

[0004] However, oral administration of drugs for local skin diseases has many drawbacks, including a variety of side effects such as stomach upset, the need for relatively large amounts of active agent due to first-pass metabolism, and limitations in bioavailability.

[0005] Providing topical compositions comprising nicotinamide as an alternative to orally administered nicotinamide would be highly beneficial. Previous academic studies have shown that relatively high flux levels of nicotinamide into the skin can be achieved using topical formulations or co-solvent systems with very high doses. However, these studies have been characterized by compositions that are not entirely suitable for actual human use or commercial applications. Despite years of research on topical nicotinamide products, to date no fully formulated topical product with good aesthetics has been achieved that can achieve clinically relevant nicotinamide flux levels—in the context of skin cancer prevention. It is well known that for any topical product used for therapeutic applications, compliance is crucial for achieving therapeutic efficacy. This is most likely to be achieved if the product is pleasant to use and has good user-perceived aesthetics.

[0006] Currently, topical sun protection products primarily rely on the inclusion of a Sun Protection Factor (SPF). However, some argue that these products have limited effectiveness in preventing cancerous skin conditions. Furthermore, such products are often aesthetically unpleasant to use, thus failing to promote adherence, which is crucial for achieving protection. Unmet needs remain.

[0007] To date, while topical administration of nicotinamide is desirable, it has not been successful. This is because, prior to this invention, there were no commercially available formulations that were adequately acceptable to consumers and capable of delivering therapeutic concentrations of nicotinamide to the target site in the skin.

[0008] Therefore, there is a need for a topical product that achieves sufficient serum and / or local tissue levels of nicotinamide, comparable to those achieved with oral administration. Efficient transdermal delivery of nicotinamide from topical formulations is also desirable. Furthermore, such topical formulations typically require favorable aesthetic characteristics associated with high-end topical cosmetics. Summary of the Invention

[0009] The scope of this invention is defined by the appended claims.

[0010] According to a first aspect, a topical formulation is provided, the formulation comprising:

[0011] The dispersed phase comprises:

[0012] Nicotinamide at 5-15% w / w (weight percentage);

[0013] Partition coefficient reinforcing agents (Pc reinforcing agents) of 10-60% w / w, which have the general formula C n H 2n+2 O2, where n represents an integer from 3 to 6; and

[0014] ≤10% water

[0015] and continuous phase,

[0016] The formulation described herein has a pH of 4.0 or higher.

[0017] According to the second aspect, a pharmaceutical composition comprising the formulation according to the first aspect is provided.

[0018] According to the third aspect, a pharmaceutical composition for treatment according to the second aspect is provided.

[0019] According to the fourth aspect, the application of the formulation according to the first aspect as a cosmetic agent is provided.

[0020] This invention provides the possibility of delivering an effective topical product to subjects suffering from actinic keratosis to prevent cutaneous melanoma and to prevent recurrence of melanoma in subjects who have previously received treatment for such cancer. More broadly, the formulation is expected to provide benefits associated with abnormal skin pigmentation, skin aging, and general sun-related damage. Therefore, this invention relates to topical formulations that can be used in cosmetic and / or pharmaceutical compositions.

[0021] Certain embodiments of the present invention may provide one or more of the following advantages:

[0022] -Hoping to avoid possible side effects, such as stomach upset;

[0023] - Hoping to avoid first-pass metabolism and limitations in bioavailability;

[0024] -Hopefully compliance will improve.

[0025] -Directly targets sun-exposed tissues and lesions; and

[0026] - Direct treatment of skin lesions.

[0027] The details, embodiments, and preferences provided in connection with any particular aspect or one of the described aspects of the invention are equally applicable to all aspects of the invention. Unless otherwise stated herein or clearly contradicted by the context, all possible variations of any combination of the implementations, embodiments, and preferences described herein are included in the invention. Attached Figure Description

[0028] Figure 1 The data represent the 0–24 hour permeation profiles of NAM derived from the test formulation in human skin. Each data point represents the mean ± SD, n = 6.

[0029] Figure 2 Steady-state permeation profiles of NAM derived from test formulations 1, 2, and 3, and the commercial control, in human skin over 6–12 hours. Each data point represents the mean ± SD, n = 6. Note that per cm... 2 The unit of osmosis is μmol / cm³ 2 This unit originated from Figure 1 The result was obtained by dividing the mass in μg by the molecular weight of NAM, 122.1.

[0030] Figure 3 The peak plasma concentration of NAM (μmol / mL) was plotted in g / M 2 A graph showing the relationship between oral dosages in units of [unit name missing].

[0031] Figure 4 Permeation curves of NAM derived from test formulations #2.2, #4.2, #6.2 and commercial products TDF, Olay, Paula's Choice, and SolarCare B3 in human skin from 0 to 24 hours. Each data point represents mean ± SD, n = 6.

[0032] Figure 5The 0–24 hour penetration profiles of NAM derived from formulations containing propylene glycol or butylene glycol in human skin are shown. Each data point represents the mean ± SD, n = 6.

[0033] Figure 6 The images show actinic keratosis of the upper cheek of a subject before (left) and after (right) treatment with the formulation of the present invention. Reference markers are also marked in the before and after photos for comparison.

[0034] Figure 7 The images show basal cell carcinoma in the chest of a subject before (left) and after (right) treatment with the formulation of the present invention. Reference markers are also marked in the pre- and post-treatment images for comparison. Detailed Implementation

[0035] The present invention provides an advantageous formulation for topical application to solve the above-mentioned problems.

[0036] This invention is based on the surprising discovery that the claimed topical formulations comprising nicotinamide can effectively penetrate the skin. In numerous embodiments, the topical formulations of this invention have been shown to have bioavailability comparable to oral formulations. Furthermore, the topical formulations of this invention can have good aesthetic characteristics, providing a pleasant sensation on the skin.

[0037] This specification illustrates the subject matter of the invention throughout through specific, but not limiting, implementation methods or embodiments. Each embodiment is provided to explain the invention and not to limit it.

[0038] Unless otherwise stated or explicitly implied by the context of the referenced combination, all combinations of methods or process steps as used herein may be performed in any order.

[0039] While it is believed that those skilled in the art will readily understand the following terms as used herein, definitions are provided to aid in the explanation of the subject matter disclosed herein.

[0040] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of this invention pertains.

[0041] According to long-standing patent law practice, the terms “a,” “an,” and “the” are used in this application (including the claims) to mean “one or more.”

[0042] As used herein, when referring to values ​​or amounts of mass, weight, time, volume, concentration, or percentage, the term “about” is intended to cover variations of ±20%, ±15%, ±10%, ±5%, ±1%, ±0.5%, and ±0.1% in some embodiments, on a specified basis, as such variations are suitable for carrying out the disclosed invention.

[0043] All lists of items, such as ingredient lists, are intended to be interpreted as, and should be interpreted as, Markush groups. Therefore, all lists can be read and interpreted as "selecting items from groups and combinations thereof composed of '...list of items...'".

[0044] As used herein, the terms “comprising” or “including” have an open meaning, allowing for the presence of other unspecified features. This term includes, but is not limited to, the semi-closed term “consistent with…” and the closed term “consisting with…”. Unless the context otherwise requires, the term “comprising” may be replaced with “consistent with…” or “consisting with…”.

[0045] Features of any dependent claim may be readily combined with features of any independent claim or other dependent claims. Unless otherwise expressly stated, features of any embodiment may also be readily combined with features of any other embodiment.

[0046] Two phases

[0047] The formulations of this invention can be considered to comprise "two phases," meaning that, in order to prepare the formulation, a hydrophilic aqueous / diol phase and a predominantly hydrophobic oil phase are mixed. In the context of this invention, "two phases" does not necessarily refer to two distinct phases, and the presence of amphiphilic agents will tend to associate at the interface. For convenience, the two phases according to the invention can be described interchangeably in structural terminology, with the aqueous phase (aqueous / diol phase) defined as the "dispersed phase" and the oil phase defined as the "continuous phase."

[0048] In the two-phase system described above, the content of the dispersed phase in the formulation is about 20% to about 60% w / w, or about 25% to about 50% w / w, or about 35% to about 40% w / w. In some embodiments, the content of the dispersed phase in the formulation is about 20% w / w, or about 30% w / w, or about 40% w / w, or about 50% w / w, or about 60% w / w.

[0049] The formulations of this invention comprise an aqueous phase, which may be referred to herein as the dispersed phase. This phase comprises nicotinamide, a partition coefficient enhancer (Pc enhancer), and water with a pH greater than 4. The phase may also comprise one or more polyhydroxy acids, weak acids, and co-enhancing agents.

[0050] The formulations of the present invention include an oil phase, which may be referred to herein as a continuous phase or a moisturizing phase. This phase may be selected from suitable oil or moisturizing phase components known in the art.

[0051] Residual phase

[0052] The residual phase is a combination of the volatile components of the oil phase and some components that remain on the skin after water evaporation. Residual phase compositions, particularly aqueous / diol components containing active agents or therapeutic agents, are considered to play a crucial role in maximizing delivery to the skin. Unwilling to be bound by theory, high concentrations of components and the properties of the composition are believed to impart favorable thermodynamics, making them energy-efficient for the therapeutic agent to penetrate the skin, facilitated by the penetration-enhancing components. Low water content in the formulation promotes rapid formation of a favorable residual phase, and the entire formulation is effectively pre-designed for efficient residual phase formation.

[0053] Niacinamide

[0054] The formulations of the present invention include nicotinamide as an active agent.

[0055] Nicotinamide is water-soluble and can be present in the aqueous phase of the formulation. In one embodiment, the aqueous phase is referred to as the non-volatile phase.

[0056] Nicotinamide, also known as nicotinamide, is a form of vitamin B3, and its IUPAC name is pyridine-3-carboxamide. In this article, nicotinamide may be abbreviated as NAM (or N).

[0057]

[0058]

[0059] The formulations of the present invention comprise 5 to 15% w / w (weight percentage) of nicotinamide. The formulations of the present invention may comprise about 5 to about 12% w / w of nicotinamide. Optionally, the formulations of the present invention may comprise about 5.5 to about 11% w / w and optionally 6 to 10% w / w of nicotinamide, or 6 to 12% w / w of nicotinamide, or 8 to 10% w / w of nicotinamide. The formulations may comprise about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12% w / w of nicotinamide, preferably about 6, about 8, or about 10% w / w of nicotinamide. The formulations of the present invention may comprise more than 5% w / w of nicotinamide. The formulations of the present invention may comprise more than 6%, 7%, 8%, 9%, or 10% w / w of nicotinamide. The formulations of the present invention may comprise less than 15% w / w of nicotinamide. The formulations of the present invention may include less than 14% w / w, 13% w / w, 12% w / w, 11% w / w or 10% w / w nicotinamide.

[0060] Due to the water solubility of nicotinamide and the requirement for low water content, obtaining a pleasant-to-use topical formulation has proven challenging. Formulations with high oil content are generally considered viscous or greasy and aesthetically unpleasant to use. The stability of nicotinamide is also a challenge. The inventors have discovered that stable nicotinamide formulations can be obtained by controlling the pH above 4. The inventors have also discovered that the two-phase formulation allows for the preparation of a pleasant-to-use topical formulation.

[0061] Partition coefficient enhancer (Pc enhancer)

[0062] Dispersion coefficient enhancers, often described as "penetration enhancers," are used to increase the distribution of active ingredients into the stratum corneum, thereby increasing skin penetration. The increase in penetration is a function of the dosage of the Pc enhancer, due to absorption and clearance from the skin barrier.

[0063] The formulation of the present invention comprises about 10 to about 60% w / w of a partition coefficient enhancer (Pc enhancer) having a structure of the general diol formula: C n H 2n+2 O2, where n represents an integer from 3 to 6. The formulation may include one or more Pc enhancers. The Pc enhancers may be present in an aqueous phase. The formulation may include 15-50, 20-45, 20-50, 25-45, or 30-40% w / w of Pc enhancers. Exemplary Pc enhancers for the formulations of the present invention include propylene glycol, butylene glycol, pentanediol, hexanediol, and 1,5-pentanediol, or combinations thereof. In several embodiments, the formulation comprises propylene glycol or butylene glycol, or a combination of propylene glycol and butylene glycol. In a preferred embodiment, the Pc enhancer is propylene glycol.

[0064] The Pc reinforcing agent used in this invention has a similar structure to propylene glycol, as illustrated below, and has the general formula: C n H 2n+2 O2, where n represents an integer from 3 to 6. Propylene glycol (n=3), butanediol (n=4), pentanediol (n=5, 1,2-pentanediol), 1,5-pentanediol (n=5), and hexanediol (n=6) are all in the same C4- group. n H 2n+2 In O2. These highly similar structures are expected to function in similar ways.

[0065] Polyhydroxy acids and / or weak acids

[0066] Polyhydroxy acids, represented by lactobionic acid and gluconolactone, are highly effective skin moisturizers and anti-aging compounds. et al., 2019, #18915; Grimes et al., 2004, #61971} and achieved these effects without significant skin irritation. -Kostov et al., 2019, #60827}. The fundamental mechanism is a deep-seated acidification of the stratum corneum, such as inhibition of protease activity. Dysfunctional stratum corneum protease activity leads to inhibition of essential stratum corneum lipids and reduces stratum corneum integrity / cohesion due to its impact on intercellular desmosome junctions. These effects are completely complementary to the effects of nicotinamide.

[0067] The formulations of the present invention may include one or more polyhydroxy acids. If a polyhydroxy acid is present, the one or more polyhydroxy acids may provide further activators in the formulation. The polyhydroxy acid may be present in an aqueous phase. The formulation may include 2–10% w / w of polyhydroxy acid. The formulation may include 2–9, 2–7, 2–5, 3–5, or about 4% w / w of a Pc enhancer. Polyhydroxy acids that can be used in the formulations of the present invention include gluconolactone, galactonolactone, glucuronolactone, galacturonolactone, gulonolactone, ribonolactone, gluconicolactone, pantothenicolactone, glucohepanolate, mannolactone, and galactohepanolate; 2-keto acids are present in free acid form. The polyhydroxy acid in the formulation may be selected from gluconolactone, galactose, and lactobionic acid. In some embodiments, the polyhydroxy acid in the formulation is lactobionic acid. In some embodiments, the formulation according to the present invention does not include lactobionic acid.

[0068] The formulations of the present invention may further comprise one or more weak acids for buffering or as additional therapeutic agents. The weak acids according to the present invention are generally partially dissociated acids. The weak acids may be present in an aqueous phase. The formulations may comprise 2–10% w / w of a weak acid. The formulations may comprise 2–9, 2–7, 2–5, 3–5, or about 4% w / w of a weak acid. Weak acids that can be used in the formulations of the present invention include natural fruit acids and α-hydroxy acids. The weak acids in the formulations may be selected from ascorbic acid, citric acid, glycolic acid, lactic acid, malic acid, tartaric acid, and combinations thereof. As part of the present invention, polyhydroxy acids may also be considered as weak acids.

[0069] Co-reinforcing agent

[0070] Co-enhancers can be used to increase the diffusion rate of active substances across the stratum corneum barrier, thereby increasing skin penetration. Co-enhancers are also known as diffusion coefficient enhancers (Dc enhancers). Much lower doses of diffusion co-enhancers are required, but it is believed that the dose is saturated due to slower clearance from the skin barrier.

[0071] In several embodiments, the formulations of the present invention may further comprise a co-enhancing agent. If a co-enhancing agent is present, the inherently amphiphilic co-enhancing agent will exhibit partial solubility in both the aqueous and oil phases, and the solubility balance between the two phases is an important characterization of the agent selected herein. The formulations of the present invention may comprise about 0.5% to about 10% w / w of a co-enhancing agent selected from C 12 ~C 14 Linear fatty acids and C 14 The group consisting of linear primary alcohols. The formulation may contain one or more co-enhancing agents. The formulation may include 0.5–7, 0.5–6, 0.5–5, 1–5, 1–4, or 2–4% w / w of Pc enhancing agent. Exemplary co-enhancing agents for the formulations of the present invention include myristicin (1-tetradecanoic acid), lauric acid (dodecanoic acid), and myristic acid (1-tetradecanoic acid).

[0072] The co-enhancing agent used in the formulations of this invention is typically C. 12 ~C 14 Linear fatty acids and C 14 Straight-chain primary alcohols—they all have structures very similar to 1-tetradecanoic acid, as exemplified below, and therefore all exhibit low solubility similar to 1-tetradecanoic acid in propylene glycol (and other Pc enhancers used herein). Therefore, they are expected to function in a similar manner. More specifically, C6–C… 18 Straight-chain fatty acids and C6-C 18 The activity of linear primary alcohols is related to that of co-enhancing agents. C is used in this invention. 12 ~C 14 Linear fatty acids and C 14 Straight-chain primary alcohols, because they are in formula C n H (2n+2) O2 is soluble in Pc reinforcing agents. The solubility of co-reinforcing agents allows them to reach the desired concentration in solution and be at or near saturation. This requirement for co-reinforcing agents to be at or near saturation is a major determinant of their efficiency as co-reinforcing agents.

[0073] In some embodiments, the formulations according to the invention substantially do not include co-enhancing agents. In some embodiments, the formulations according to the invention substantially do not include myristicin. In these embodiments, "substantially do not" is understood to mean that the co-enhancing agent is present in the formulations according to the invention in an amount of less than 0.4% w / w, or less than 0.3 w / w, or less than 0.2 w / w, or less than 0.1 w / w, or less than 0.5 w / w, or less than 0.25% w / w.

[0074] Dispersed phase

[0075] The formulations of the present invention may include water. In some embodiments, the amount of water in the dispersed phase is about 10% w / w or less. In some embodiments, the amount of water in the dispersed phase is about ≤10%, ≤9%, ≤8%, ≤7%, ≤6%, or ≤5% w / w. Water is typically present in the dispersed phase in an amount of about 5% to about 10% w / w. In some embodiments, the amount of water in the final formulation is about ≤6%, ≤5%, ≤4%, ≤3%, ≤2%, ≤1%, or ≤0.5% w / w. Water is typically present in the final formulation in an amount of about 1% to about 5% w / w.

[0076] The low-water-content formulations of this invention are intended for delivering an effective residual phase with favorable thermodynamics for therapeutic delivery. In this invention, the potential drawbacks of high oil content are overcome by carefully designing the oil-phase composition to produce a cream with pleasant properties during and after use and promoting compliance.

[0077] In the context of this invention, a phase including water is referred to as an "aqueous phase", "aqueous / diol phase" or "dispersed phase".

[0078] continuous phase

[0079] The formulations of the present invention comprise a continuous phase. This phase may be selected from suitable oil phase or emollient phase components known in the art. The continuous phase may be referred to as a "hydrophobic phase" or an "oil phase".

[0080] In several embodiments, the continuous phase primarily comprises a hydrophobic component. In some embodiments, the hydrophobic component may be selected from one or more of silicone elastomers, mineral oils, and vegetable oils.

[0081] In several embodiments, the oil phase may be a phase comprising: a 5-45% w / w mixture of first dimethyl silicone oil macromonomers, comprising dimethyl silicone oil macromonomers and a hydrocarbon methyl siloxane emollient selected from the group consisting of alkyl methyl siloxanes, aryl methyl siloxanes and alkyl aryl methyl siloxanes; and a 5-45% w / w mixture of second dimethyl silicone oil macromonomers, comprising methyl siloxane compounds and crosslinked dimethyl silicone oil macromonomers.

[0082] The first dimethyl silicone oil macromonomer mixture may include polyethylene glycol dimethyl silicone oil macromonomers. The first dimethyl silicone oil macromonomer mixture may include compounds having the following structures:

[0083]

[0084] Where R represents H or a hydrocarbon group, especially C1 to C6 alkyl; Y represents a hydrocarbon group, especially C1 to C6 alkyl; X represents an amine, quaternary ammonium, or acid functional group; M and n independently represent integers from 1 to 50.

[0085] The first dimethyl silicone oil macromonomer mixture may include dimethyl silicone oil macromonomers with a number average molecular weight greater than 1000 (usually greater than 2000) and hydrocarbon methylsiloxanes (usually alkyl methylsiloxanes) with a number average molecular weight less than 500.

[0086] The first dimethyl silicone oil macromonomer mixture may include polyethylene glycol dimethyl silicone oil macromonomers that are crosslinked with polyalkylene oxide compounds (typically polyethylene glycol compounds, polypropylene glycol compounds, or copolymers of ethylene oxide and propylene oxide) or crosslinked with dienes.

[0087] The first dimethyl silicone oil macromonomer mixture may include polyethylene glycol dimethyl silicone oil macromonomers selected from the group consisting of PEG-12 dimethyl silicone oil / PPG cross-linked polymers and PEG-12 dimethyl silicone oil / PPG-20 cross-linked polymers and PEG-12 dimethyl silicone oil diisoalkyl PPG cross-linked polymers.

[0088] The first dimethyl silicone oil macromonomer mixture may include polyethylene glycol dimethyl silicone oil macromonomers, which include one or more side groups from the dimethyl silicone oil backbone, said side groups being polyepoxyalkane groups (typically polyethylene glycol compounds, polypropylene glycol compounds, or copolymers of ethylene oxide and propylene oxide).

[0089] Optionally, the polyethylene glycol dimethyl silicone oil macromonomer includes polyethylene glycol side groups and polypropylene glycol side groups from the dimethyl silicone oil backbone.

[0090] In one embodiment, the formulation comprises a dimethyl silicone oil macromonomer functionalized with pyrrolidone carboxylic acid in the first dimethyl silicone oil macromonomer mixture.

[0091] The formulation may contain a mixture of 5-45% w / w dimethyl silicone oil macromonomers, typically 10-40% w / w, and generally 20-30% w / w.

[0092] The first dimethyl silicone oil macromonomer mixture may contain 5 to 30% w / w of polyethylene glycol dimethyl silicone oil macromonomer, typically 10 to 20% w / w, generally 12 to 19% w / w.

[0093] The second dimethyl silicone oil macromonomer mixture may contain methylsiloxane compounds with a number average molecular weight of less than 1000 and cross-linked polyalkylsiloxane diol dimethyl silicone oil macromonomers with a number average molecular weight of greater than 1000, usually greater than 2000.

[0094] The formulation may contain a mixture of 5-45% w / w dimethyl silicone oil macromonomers, typically 10-40% w / w, and generally 20-30% w / w.

[0095] The second dimethyl silicone oil macromonomer mixture may contain 5-30% w / w crosslinked dimethyl silicone oil macromonomers, typically 10-20% w / w, and generally 12-19% w / w.

[0096] Other characteristics of the oil phase, the first dimethyl silicone oil macromonomer mixture, the second dimethyl silicone oil macromonomer mixture, and the first and second dimethyl silicone oil macromonomer mixtures are described in WO 2016 / 139471, which is incorporated herein by reference.

[0097] pH

[0098] The formulations of the present invention have a pH of 4 or higher. The pH of the formulations of the present invention can be in the range of about 4.0 to about 8.0, or about 4.5 to about 7.5, or about 5.0 to about 7.0, or about 5.0 to about 6.0, or about 5.0 to about 5.5. In several embodiments, the formulation has a pH in the range of about 4.0 to about 6.0. The formulation may have a pH greater than about 4.0, 4.5, or 5.0. The formulation may have a pH less than about 6.0, 5.5, or 5.0. The formulations according to the present invention can be measured using a standard pH probe, such as a P-10 Sentek pH electrode or a Sentek P-11 electrode.

[0099] The inventors discovered that maintaining a pH value above 4.0 is beneficial to the stability of the formulations of this invention. For example, it has been observed that the formulation at pH = 3.8 exhibits a significantly worse stability profile for nicotinamide compared to the formulation at pH = 4.5.

[0100] Other characteristics of the formulation

[0101] In one embodiment, the formulation of the present invention does not include one or more of the following components: tranexamic acid, zinc salt, zinc salt of the conjugate base of a polyhydroxy acid, vitamin D, vitamin D derivatives and vitamin D metabolites, such as calcipotriol.

[0102] In several embodiments, the formulations of the present invention do not include tranexamic acid.

[0103] In several embodiments, the formulations of the present invention do not include zinc salts, and optionally, the formulations do not include zinc salts of conjugate bases of polyhydroxy acids.

[0104] In several embodiments, the formulations of the present invention do not include cannabidiol.

[0105] In several embodiments, the formulations of the present invention do not include vitamin D, vitamin D derivatives, or vitamin D metabolites. In some embodiments, the formulations of the present invention do not include calcipotriol.

[0106] In several embodiments, the formulation includes a sunscreen agent. In some embodiments, the sunscreen agent may also be referred to as a sunblock agent, which can increase the SPF rating. In some embodiments, the sunscreen agent may be a physical agent, a chemical agent, or a mixture thereof.

[0107] In one embodiment, the present invention provides a topical formulation comprising:

[0108] The dispersed phase comprises:

[0109] Nicotinamide at a concentration of 5–12% w / w (weight percentage),

[0110] 2-10% w / w polyhydroxy acids,

[0111] Partition coefficient reinforcing agents (Pc reinforcing agents) of 10-60% w / w have the general formula: C n H 2n+2 O2, where n represents an integer from 3 to 6.

[0112] A diffusion coefficient enhancer (Dc enhancer) of approximately 0.5% to approximately 10% w / w, selected from C 12 ~C 14 Linear fatty acids and C 14 The group consisting of linear primary alcohols, and

[0113] ≤10% water

[0114] and a continuous phase, the continuous phase comprising:

[0115] A mixture of 5-45% w / w first dimethyl silicone oil macromonomers, comprising dimethyl silicone oil macromonomers and hydrocarbon methyl siloxane emollients selected from the group consisting of alkyl methyl siloxanes, aryl methyl siloxanes, and alkylaryl methyl siloxanes, and...

[0116] A mixture of 5-45% w / w second dimethyl silicone oil macromonomers, comprising methylsiloxane compounds and cross-linked dimethyl silicone oil macromonomers.

[0117] In one embodiment, the present invention provides a topical formulation comprising:

[0118] The dispersed phase comprises:

[0119] Nicotinamide at a concentration of 5-15% w / w (weight percentage),

[0120] 2–10% w / w of polyhydroxy acids and / or weak acids,

[0121] 10-60% w / w partition coefficient enhancer (Pc enhancer) propylene glycol

[0122] and

[0123] ≤10% water

[0124] and a continuous phase, wherein the formulation has a pH in the range of 4.0 to 6.0.

[0125] In one embodiment, the present invention provides a topical formulation comprising:

[0126] The dispersed phase comprises:

[0127] Nicotinamide at a concentration of 5-15% w / w (weight percentage),

[0128] 2-10% w / w polyhydroxy acids,

[0129] Partition coefficient enhancer (Pc enhancer) of 10-60% w / w

[0130] 10%–30% w / w of particulate sunscreen / sunblocking agent,

[0131] 1-5% w / w skin integrity enhancer linoleic acid

[0132] and

[0133] ≤10% water

[0134] and a continuous phase, the continuous phase comprising:

[0135] A mixture of 30%–70% octyl polymethylsiloxane, PEG-12 dimethyl silicone oil / PPG-20 cross-linked polymer, cyclopentasiloxane, dimethyl silicone oil cross-linked polymer, and trisiloxane.

[0136] and

[0137] The formulation described herein has a pH in the range of 5.0 to 7.0.

[0138] In one embodiment, the present invention provides a topical formulation comprising:

[0139] The dispersed phase comprises:

[0140] Nicotinamide at a concentration of 5-15% w / w (weight percentage),

[0141] 2-10% w / w polyhydroxy acids,

[0142] 2-10% w / w α-hydroxy acid lactic acid,

[0143] 10-60% w / w partition coefficient enhancer (Pc enhancer) propylene glycol

[0144] and

[0145] ≤10% water

[0146] and a continuous phase, which further includes:

[0147] 10%–30% w / w of light-blocking agent

[0148] and

[0149] The formulation described herein has a pH of 4.0 or higher.

[0150] In one embodiment, the present invention provides a topical formulation comprising:

[0151] The dispersed phase comprises:

[0152] Nicotinamide at a concentration of 5-15% w / w (weight percentage),

[0153] 2-10% w / w polyhydroxy acids,

[0154] Propylene glycol with a partition coefficient enhancement factor of 10-60% w / w (Pc enhancement agent)

[0155] 1-5% w / w palmitoyl pentapeptide anti-aging agent,

[0156] 1-5% w / w n-acetylglucosamine skin integrity enhancer

[0157] 5%–20% w / w particulate sunscreen / sunblocker

[0158] and

[0159] ≤10% water

[0160] and continuous phase

[0161] and

[0162] The formulation described herein has a pH of 4.0 or higher.

[0163] In one embodiment, the present invention provides a topical formulation comprising:

[0164] The dispersed phase comprises:

[0165] Nicotinamide at a concentration of 5-15% w / w (weight percentage),

[0166] 2-10% w / w polyhydroxy acids,

[0167] Propylene glycol with a partition coefficient enhancement factor of 10-60% w / w (Pc enhancement agent)

[0168] 1-5% w / w palmitoyl pentapeptide anti-aging agent

[0169] and

[0170] ≤10% water

[0171] and a continuous phase, which further includes:

[0172] A mixture of 5-50% w / w neopentyl glycol diheptanoate, isodecane, diheptyl succinate, and capryloyl glycerol / sebic acid copolymer.

[0173] and

[0174] The formulation described herein has a pH of 4.0 or higher.

[0175] In one embodiment, the present invention provides a topical formulation comprising:

[0176] The dispersed phase comprises:

[0177] Nicotinamide at a concentration of 5-15% w / w (weight percentage),

[0178] Propylene glycol with a partition coefficient enhancement factor of 10-60% w / w (Pc enhancement agent)

[0179] 10%–30% w / w of particulate sunscreen / sunblocking agent,

[0180] 1-5% w / w skin integrity enhancer linoleic acid

[0181] 1-5% w / w palmitoyl pentapeptide anti-aging agent

[0182] and

[0183] ≤10% water

[0184] and a continuous phase, the continuous phase comprising:

[0185] A mixture of 30%–70% octyl polymethylsiloxane, PEG-12 dimethyl silicone oil / PPG-20 cross-linked polymer, cyclopentasiloxane, dimethyl silicone oil cross-linked polymer, and trisiloxane.

[0186] and

[0187] The formulation described herein has a pH in the range of 5.0 to 7.0.

[0188] The basic principle of the embodiment of the enhancer of the formulation of the present invention

[0189] This invention is partly based on the first provision of nicotinamide for topical application to the skin in an enhancer formulation. The formulation comprises nicotinamide and a penetration or partition coefficient enhancer (Pc enhancer) having the general formula: C n H 2n+2 O2, where n represents an integer from 3 to 6. Topical formulations may also include ingredients selected from C.12 ~C 14 Linear fatty acids and C 14 A co-enhancing agent consisting of a group of linear primary alcohols. Typically, the formulation comprises 5–12% w / w (weight percentage) nicotinamide. Typically, the formulation comprises 10–60% w / w Pc enhancer. Typically, if a co-enhancing agent is present, the formulation comprises about 0.5–about 10% w / w co-enhancing agent.

[0190] The formulation includes water. Typically, the formulation contains about 10% w / w or less water. Typically, the aqueous phase contains about 10% w / w or less water.

[0191] The formulation may also include polyhydroxy acids. Typically, if polyhydroxy acids are present, the formulation contains 2 to 10% w / w of polyhydroxy acids.

[0192] It is assumed that the formulation does not contain tranexamic acid. It is also assumed that the formulation does not contain zinc salts, for example, zinc salts of conjugate bases of polyhydroxy acids. It is assumed that the formulation does not contain vitamin D, vitamin D derivatives, or vitamin D metabolites such as calcipotriol.

[0193] This invention is based on the surprising and beneficial properties of the formulations of this invention, which allow for the application of topical formulations to the skin with an eye toward the prevention and / or treatment of skin cancer or as a cosmetic.

[0194] The nicotinamide formulations in the enhancer system of the present invention are carefully designed to achieve a flux of nicotinamide from a topical formulation into the skin, thereby matching the nicotinamide delivery levels previously achieved by oral delivery of nicotinamide in studies demonstrating the prevention and / or treatment of skin cancer. Evidence of achieving the desired flux levels of nicotinamide into human skin using the formulations of the present invention is described below. The nicotinamide formulations of the present invention have been designed to achieve this nicotinamide delivery level, wherein the nicotinamide in the formulation has a clinically relevant dose: i.e., 5–15% w / w, or 5–12% w / w, or 6–10% w / w of nicotinamide. The nicotinamide formulations of the present invention have been designed to achieve this nicotinamide delivery level in a formulation that is aesthetically acceptable and provides a pleasant experience during use, in order to allow for acceptable long-term use and facilitate easier patient compliance.

[0195] It should be noted that previously reported experimental formulations, which achieved similar nicotinamide penetration fluxes to those required herein upon topical application, either contained higher levels of nicotinamide, thus rendering them clinically inappropriate, or contained solvents unacceptable for prolonged use on human skin, thus rendering them unsuitable for commercial use. Furthermore, as described below, the formulations of the present invention have demonstrated surprisingly good clinical efficacy.

[0196] Because nicotinamide is a water-soluble component, achieving the desired low-water-content topical formulation with the benefits discussed in this invention is known to be a challenge in the art. The inventors have discovered that the combination of nicotinamide with a small amount of water in the two-phase topical system results in a combination of excellent delivery properties and additionally favorable aesthetic characteristics of the formulation. Not wishing to be bound by theory, compositions of two-phase systems are thought to promote subject / patient compliance with the formulation through the advantageous aesthetics of the continuous phase. Simultaneously, the relatively concentrated aqueous phase containing a Pc enhancer (e.g., propylene glycol) and the active agent nicotinamide, through its designed composition, produces an effective “residual phase” with favorable thermodynamic properties for enhanced delivery. Crucially, determining the pH range that keeps nicotinamide stable in such a formulation and that the overall composition remains stable in terms of consistency and appearance is also considered a key factor. This combination of properties results in a formulation with good stability, favorable properties for promoting compliance during and after use, and efficient delivery of nicotinamide to the skin upon application. This efficiency of transdermal delivery is particularly evident when using propylene glycol as a Pc enhancer.

[0197] Enhancer for topical application

[0198] Co-enhancing topical dermatological drug delivery techniques can be defined as those based on Fick's first law of diffusion, using a combination of partition / penetration and diffusion coefficient enhancers. For optimal results, both the active pharmaceutical ingredient and the diffusion coefficient enhancer should be at or near saturation solubility in a non-volatile, and therefore residual, phase. Co-enhancing gels formulated as single-phase solution systems comprise a non-volatile co-enhancing residual phase, which is itself a single-phase, volatile solvent, and gelled with a suitable cellulose or acrylate polymer, as is well known, for example, as described in Reckitt Benckiser Healthcare WO 2011 / 070318 A2 and Futura Medical Developments US 8,541,470.

[0199] Despite their significant advantages in drug delivery, co-enhancing formulations such as those described in WO 2011 / 070318 A2 and US 8,541,470 are associated with poorer rubbing and a poorer skin feel, which are related to stickiness and dry skin. Adherence to such topical dermatological products is disappointingly low. Dr. Steven Feldman, an American dermatologist, concluded in the February 2018 issue of *Practical Dermatology* that, overall, adherence to topical dermatological products is “painful.”

[0200] UK patent application GB 2549418, “Topical formulations comprising dimethyl silicone oil macromonomers,” describes a topical formulation technology designed to address all compliance factors related to formulation design, thereby improving adherence to treatment of topical dermatological conditions.

[0201] Because the formulation of this invention is required to be a cream rather than a gel for aesthetic reasons, it includes an oil component by definition. Furthermore, because the oil is required not to excessively dissolve the diffusion coefficient enhancer and thus inhibit its enhancing effect, the selected oils are organosilicon hybrid chemicals, as described in GB 2549418. Due to the chemical properties of such chemicals and general silicone oils, they are immiscible with typical diol partition coefficient enhancers (e.g., propylene glycol typically constitutes 20–40% w / w of the total formulation), thus these design requirements necessitate a two-phase design.

[0202] The aqueous phase of the cream

[0203] In the formulations of this invention, the aqueous dispersion phase comprises a miscible functional partitioning enhancer (diol, such as propylene glycol) and optionally a diffusion coefficient enhancer. Other miscible nonvolatile cosolvents may be added to ensure that the active pharmaceutical ingredient and the diffusion coefficient enhancer are at or near saturation solubility. Water, as a “volatile” solvent or non-solvent, may be added up to 10% w / w. Despite its volatility, due to its polarity, it partitions into the diol-dominated “non-volatile” phase.

[0204] Oil phase of cream

[0205] Silicone-based continuous phases typically comprise a mixture of three silicone oils with varying volatility: broadly rapid, moderately volatile, and persistent. Typical silicone oils are octamethyltrisiloxane, cyclopentasiloxane, and the emollient octylpolymethylsiloxane, with evaporation half-lives of approximately 10–60 seconds, 15–30 minutes, and 1–2 hours, respectively. Octylpolymethylsiloxane may be part of the continuous phase, with an evaporation rate consistent with twice-daily application. Due to this chemical property, diffusion coefficient enhancers, typically C12–14 acids or C14 alcohols, are partitioned between the diol and silicone phases, ideally saturating both.

[0206] Cream structure

[0207] The cream can be structurally defined as an aqueous / silicone diol / oil dispersant; therefore, PEG-12 dimethyl silicone oil / PPG-20 type cross-linking polymers are typically used to disperse droplets of the aqueous / diol phase in a hydrophobic oil / silicone oil. Dimethyl silicone oil cross-linking polymers are also usually added to modify the viscosity (lightness of the feel) of the final cream. When applied to the skin, consumers experience a soft, silky feel from the mixed silicone elastomer-silicone oil / oil continuous phase. The volatile silicones are rapidly lost, giving the impression of being absorbed into the skin.

[0208] General steps for preparing the formulation

[0209] In summary, the manufacture of the formulation of the present invention includes preparing a first premix comprising nicotinamide, a Pc enhancer, and water, optionally including a polyhydroxy acid, and, if present, a co-enhancing agent. The first premix represents the aqueous dispersion phase of the formulation. The components are mixed together, and if the polyhydroxy acid and co-enhancing agent are present, slow heating (>35°C) may be used to ensure the dissolution of the polyhydroxy acid and co-enhancing agent. A second premix comprising the components of the oil continuous phase is added to the other components of the oil phase and mixed together. The first premix comprising the components of the aqueous / diol phase is slowly added to the second premix comprising the components of the continuous phase while vigorous stirring until a hard cream is formed.

[0210] Treatment with formulations

[0211] The present invention provides a method for preventing and / or treating skin cancer, the method comprising applying the preparation of the present invention topically to the skin.

[0212] This invention provides formulations of the invention for treatment. This invention also provides methods for using the formulations of the invention for the prevention and / or treatment of skin cancer. This invention provides methods for the topical application of the formulations of the invention for the prevention and / or treatment of skin cancer.

[0213] The present invention also provides the use of the formulations of the present invention in the preparation of medicaments for the prevention and / or treatment of skin cancer.

[0214] The present invention also provides pharmaceutical compositions comprising the formulations of the present invention for the prevention or treatment of skin cancer.

[0215] The skin cancers that can be prevented or treated include actinic keratosis, basal cell carcinoma, squamous cell carcinoma, and melanoma.

[0216] Therefore, the present invention i) provides a method, ii) provides an formulation for the method, iii) provides the use of the formulation in the preparation of a medicament, and / or iv) provides a pharmaceutical composition comprising the formulation for the prevention of actinic keratosis, the treatment of actinic keratosis, the prevention of melanoma, the prevention of melanoma recurrence, the treatment of melanoma, the achievement of complete or partial remission of melanoma, the prevention of squamous cell carcinoma, the prevention of basal cell carcinoma, the treatment of squamous cell carcinoma, the treatment of basal cell carcinoma, the achievement of complete or partial remission of squamous cell carcinoma, and the achievement of complete or partial remission of basal cell carcinoma.

[0217] One advantage of the formulation is that it may only need to be applied to the skin once or twice a day, so the method may include, consist primarily of, or be composed of application to the skin once or twice a day.

[0218] The formulation is intended for topical application to the skin. It is assumed that the skin in question is human skin.

[0219] In some embodiments, the topical formulation and / or pharmaceutical composition may have one or more of the following effects:

[0220] -Including stable topical formulations containing nicotinamide;

[0221] - Niacinamide transfers well to the skin;

[0222] - An aesthetically pleasing formulation;

[0223] - A formulation that is pleasant to use;

[0224] - Sunscreen;

[0225] - Effectively delivers nicotinamide to the site of treatment;

[0226] - Effective treatment for skin cancer; and

[0227] - Effectively treats skin lesions.

[0228] This invention can be described by one or more of the following paragraphs:

[0229] A. A formulation for topical application and for methods of preventing and / or treating skin cancer,

[0230] The formulation includes:

[0231] The non-volatile residual phase includes:

[0232] Nicotinamide at a concentration of 5–12% w / w (weight percentage),

[0233] 2-10% w / w polyhydroxy acids,

[0234] Partition coefficient reinforcing agents (Pc reinforcing agents) of 10-60% w / w have the general formula: C n H 2n+2 O2, where n represents an integer from 3 to 6.

[0235] A diffusion coefficient enhancer (Dc enhancer) of approximately 0.5% to approximately 10% w / w, selected from C 12 ~C 14 Linear fatty acids and C 14 The group consisting of linear primary alcohols, and

[0236] ≤10% water

[0237] And the moisturizing phase, which includes:

[0238] A mixture of 5-45% w / w first dimethyl silicone oil macromonomers, comprising dimethyl silicone oil macromonomers and hydrocarbon methyl siloxane emollients selected from the group consisting of alkyl methyl siloxanes, aryl methyl siloxanes, and alkylaryl methyl siloxanes, and...

[0239] A mixture of 5-45% w / w second dimethyl silicone oil macromonomers, comprising methylsiloxane compounds and cross-linked dimethyl silicone oil macromonomers.

[0240] B. A formulation for use according to paragraph A, wherein the formulation comprises 5.5 to 11% w / w nicotinamide, optionally comprising 6 to 10% w / w nicotinamide.

[0241] C. A formulation for use according to paragraph A or B, wherein the Pc enhancer is selected from the group consisting of propylene glycol, butanediol, pentanediol, hexanediol, and 1,5-pentanediol and combinations thereof.

[0242] D. A formulation for use according to any one of paragraphs A to C, wherein the formulation comprises 15 to 50, 20 to 45, 25 to 45, or 30 to 40% w / w of a Pc enhancer.

[0243] E. A formulation for use according to any one of the preceding paragraphs, wherein the Dc enhancer is selected from the group consisting of myristol (1-tetradecyl alcohol), myristic acid, and lauric acid (dorsodic acid).

[0244] F. A formulation for application according to any of the preceding paragraphs, wherein the Dc enhancer is 0.5–5, 1–5, or 2–4% w / w (weight percentage) of the formulation.

[0245] G. Formulations for use according to any of the preceding paragraphs, wherein the formulation comprises 2–9, 2–7, 2–5, 3–5, or about 4% w / w of a polyhydroxy acid.

[0246] H. A formulation for use according to any of the preceding paragraphs, wherein the polyhydroxy acid is selected from gluconolactone, galactose, and lactobionic acid.

[0247] I. The formulation for use as described in any of the preceding paragraphs, wherein the first dimethyl silicone oil macromonomer mixture comprises polyethylene glycol dimethyl silicone oil macromonomer.

[0248] J. Formulations for the application described in any of the preceding paragraphs, wherein the first dimethyl silicone oil macromonomer mixture comprises compounds having the following structure:

[0249]

[0250] R represents H or a hydrocarbon group, especially a C1 to C6 alkyl group.

[0251] Y represents a hydrocarbon group, especially a C1-C6 alkyl group;

[0252] X represents an amine, quaternary ammonium, or acid functional group.

[0253] M and n independently represent integers from 1 to 50.

[0254] K. The formulation for application as described in any of the preceding paragraphs, wherein the first dimethyl silicone oil macromonomer mixture comprises dimethyl silicone oil macromonomers with a number average molecular weight greater than 1000 (typically greater than 2000) and a hydrocarbon methylsiloxane emollient (typically an alkyl methylsiloxane) with a number average molecular weight less than 500.

[0255] L. Formulations for use according to any of the preceding paragraphs, wherein the first dimethyl silicone oil macromonomer mixture comprises polyethylene glycol dimethyl silicone oil macromonomers crosslinked with polyalkylene oxide compounds (typically polyethylene glycol compounds, polypropylene glycol compounds, or copolymers of ethylene oxide and propylene oxide) or crosslinked with dienes.

[0256] M. The formulation for application according to paragraph L, wherein the first dimethyl silicone oil macromonomer mixture comprises polyethylene glycol dimethyl silicone oil macromonomer selected from the group consisting of PEG-12 dimethyl silicone oil / PPG crosspolymer, preferably PEG-12 dimethyl silicone oil / PPG-20 crosspolymer, and PEG-12 dimethyl silicone oil diisoalkyl PPG crosspolymer.

[0257] N. A formulation for the application described in any of the preceding paragraphs, wherein the first dimethyl silicone oil macromonomer mixture comprises polyethylene glycol dimethyl silicone oil macromonomers comprising one or more side groups from the dimethyl silicone oil backbone, said side groups being polyalkylene oxide groups (typically polyethylene glycol compounds, polypropylene glycol compounds, or copolymers of ethylene oxide and propylene oxide).

[0258] O. Formulations for use according to any of the preceding paragraphs, wherein the polyethylene glycol dimethyl silicone oil macromonomer comprises polyethylene glycol side groups and polypropylene glycol side groups from the dimethyl silicone oil backbone.

[0259] P. A formulation for use according to any one of paragraphs J to O, said formulation comprising a dimethyl silicone oil macromonomer functionalized with pyrrolidone carboxylic acid.

[0260] Q. The formulation for the application described in any of the preceding paragraphs comprises a mixture of 5-45% w / w dimethyl silicone oil macromonomers, typically 10-40% w / w, generally 20-30% w / w.

[0261] R. A formulation for use according to any of the preceding paragraphs, wherein the second dimethyl silicone oil macromonomer mixture comprises a methylsiloxane compound with a number average molecular weight less than 1000 and a crosslinked polyalkylsiloxane diol dimethyl silicone oil macromonomer with a number average molecular weight greater than 1000, typically greater than 2000.

[0262] S. A formulation for the application described in any of the preceding paragraphs, the formulation comprising a mixture of 5 to 45% w / w dimethyl silicone oil macromonomers, typically 10 to 40% w / w, generally 20 to 30% w / w.

[0263] T. Formulations for use as described in any of the preceding paragraphs, wherein the first dimethyl silicone oil macromonomer mixture contains 5 to 30% w / w polyethylene glycol dimethyl silicone oil macromonomer, typically 10 to 20% w / w, generally 12 to 19% w / w.

[0264] U. Formulations for use according to any of the preceding paragraphs, wherein the second dimethyl silicone oil macromonomer mixture comprises 5 to 30% w / w crosslinked dimethyl silicone oil macromonomers, typically 10 to 20% w / w, generally 12 to 19% w / w.

[0265] V. A formulation for use as described in any of the preceding paragraphs, wherein said formulation does not include tranexamic acid.

[0266] W. A formulation for use according to any of the preceding paragraphs, wherein the formulation does not include zinc salts, and optionally the formulation does not include zinc salts of conjugate bases of polyhydroxy acids.

[0267] X. A formulation for use according to any of the preceding paragraphs, wherein the skin cancer is selected from actinic keratosis, basal cell carcinoma, squamous cell carcinoma, and melanoma.

[0268] Y. The formulation used according to any of the preceding paragraphs, wherein the method of preventing and / or treating skin cancer is selected from the methods of preventing actinic keratosis, treating actinic keratosis, preventing melanoma, preventing melanoma recurrence, 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.

[0269] Z. A formulation for application according to any of the preceding paragraphs, wherein the method consists of application to the skin once or twice daily.

[0270] AA. Use of a formulation in the preparation of a medicament for the prevention and / or treatment of skin cancer, said formulation comprising:

[0271] a. A non-volatile residual phase, comprising:

[0272] i.5-12% w / w (weight percentage) nicotinamide,

[0273] ii. 2-10% w / w polyhydroxy acids,

[0274] iii. A partition coefficient reinforcing agent (Pc reinforcing agent) of 10–60% w / w, having the general formula: C n H 2n+2 O2, where n represents an integer from 3 to 6.

[0275] iv. Approximately 0.5% to approximately 10% w / w of a diffusion coefficient enhancer (Dc enhancer), selected from C 12 ~C 14 Linear fatty acids and C 14 The group consisting of straight-chain primary alcohols, and ≤10% water.

[0276] b. and a moisturizing phase, which includes:

[0277] i.5–45% w / w of a first dimethyl silicone oil macromonomer mixture, comprising dimethyl silicone oil macromonomers and a hydrocarbon methyl siloxane emollient selected from the group consisting of alkyl methyl siloxanes, aryl methyl siloxanes, and alkylaryl methyl siloxanes, and

[0278] ii.5–45% w / w of a mixture of second dimethyl silicone oil macromonomers, comprising methylsiloxane compounds and cross-linked dimethyl silicone oil macromonomers.

[0279] BB. The application described in paragraph AA, wherein the formulation is further defined as in paragraphs B-W.

[0280] CC. According to the application described in paragraph AA, the skin cancer mentioned is selected from actinic keratosis, basal cell carcinoma, squamous cell carcinoma, and melanoma.

[0281] DD. According to the application described in paragraph AA, the prevention and / or treatment of skin cancer is selected from the methods of preventing actinic keratosis, treating actinic keratosis, preventing melanoma, preventing melanoma recurrence, 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.

[0282] EE. The application according to any one of paragraphs AA to DD, wherein the treatment and / or prevention consists of application to human skin once or twice a day.

[0283] FF. A method for preventing and / or treating skin cancer, the method comprising applying topically to the skin a formulation comprising:

[0284] a. Non-volatile residual phases, including:

[0285] i.5-12% w / w (weight percentage) nicotinamide,

[0286] ii. 2-10% w / w polyhydroxy acids,

[0287] iii. A partition coefficient reinforcing agent (Pc reinforcing agent) of 10–60% w / w, having the general formula: C n H 2n+2 O2, where n represents an integer from 3 to 6.

[0288] iv. Approximately 0.5% to approximately 10% w / w of a diffusion coefficient enhancer (Dc enhancer), selected from C 12 ~C 14 Linear fatty acids and C 14 The group consisting of straight-chain primary alcohols, and ≤10% water.

[0289] b. and moisturizing phases, which include:

[0290] i.5–45% w / w of a first dimethyl silicone oil macromonomer mixture, comprising dimethyl silicone oil macromonomers and a hydrocarbon methyl siloxane emollient selected from the group consisting of alkyl methyl siloxanes, aryl methyl siloxanes, and alkylaryl methyl siloxanes, and

[0291] ii.5–45% w / w of a mixture of second dimethyl silicone oil macromonomers, comprising methylsiloxane compounds and cross-linked dimethyl silicone oil macromonomers.

[0292] GG. According to the method described in paragraph FF, the skin cancer is selected from the group consisting of actinic keratosis, basal cell carcinoma, squamous cell carcinoma and melanoma.

[0293] HH. According to the method described in paragraph FF, the prevention and / or treatment are selected from the group consisting of methods for preventing actinic keratosis, treating actinic keratosis, preventing melanoma, preventing melanoma recurrence, 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.

[0294] II. The method according to paragraph FF, wherein the method consists of applying to the skin once or twice daily.

[0295] JJ. According to the method described in paragraph FF, the skin mentioned is human skin.

[0296] KK. The method according to paragraph FF, wherein the formulation comprises 5.5 to 11% w / w nicotinamide, optionally comprising 6 to 10% w / w nicotinamide.

[0297] LL. According to the method described in paragraph FF, the Pc enhancer is selected from the group consisting of propylene glycol, butanediol, pentanediol, hexanediol and 1,5-pentanediol and combinations thereof.

[0298] MM. According to the method described in paragraph FF, the formulation includes 15-50, 20-45, 25-45, or 30-40% w / w of Pc enhancer.

[0299] NN. According to the method described in paragraph FF, the Dc enhancer is selected from the group consisting of myristol (1-tetradecyl alcohol), myristic acid, and lauric acid (dorsodic acid).

[0300] OO. According to the method described in paragraph FF, the Dc enhancer is 0.5-5, 1-5, or 2-4% w / w (weight percentage) of the formulation.

[0301] PP. According to the method described in paragraph FF, the formulation comprises 2-9, 2-7, 2-5, 3-5, or about 4% w / w of a polyhydroxy acid.

[0302] QQ. According to the method described in paragraph FF, the polyhydroxy acid is selected from gluconolactone, galactose, and lactobionic acid.

[0303] RR. According to the method described in paragraph FF, the first dimethyl silicone oil macromonomer mixture comprises polyethylene glycol dimethyl silicone oil macromonomer.

[0304] SS. According to the method described in paragraph FF, the first dimethyl silicone oil macromonomer mixture comprises compounds having the following structure:

[0305]

[0306] R represents H or a hydrocarbon group, especially a C1 to C6 alkyl group.

[0307] Y represents a hydrocarbon group, especially a C1-C6 alkyl group;

[0308] X represents an amine, quaternary ammonium, or acid functional group.

[0309] M and n independently represent integers from 1 to 50.

[0310] TT. According to the method described in paragraph FF, the first dimethyl silicone oil macromonomer mixture comprises dimethyl silicone oil macromonomers with a number average molecular weight greater than 1000 (typically greater than 2000) and hydrocarbon methylsiloxane emollients (typically alkyl methylsiloxanes) with a number average molecular weight less than 500.

[0311] UU. According to the method described in paragraph FF, the first dimethyl silicone oil macromonomer mixture includes polyethylene glycol dimethyl silicone oil macromonomers that are crosslinked with polyepoxyalkane compounds (typically polyethylene glycol compounds, polypropylene glycol compounds, or copolymers of ethylene oxide and propylene oxide) or crosslinked with dienes.

[0312] VV. According to the method described in paragraph FF, the first dimethyl silicone oil macromonomer mixture comprises polyethylene glycol dimethyl silicone oil macromonomers selected from the group consisting of PEG-12 dimethyl silicone oil / PPG crosslinked polymers, preferably PEG-12 dimethyl silicone oil / PPG-20 crosslinked polymers, and PEG-12 dimethyl silicone oil diisoalkyl PPG crosslinked polymers.

[0313] WW. According to the method described in paragraph FF, the first dimethyl silicone oil macromonomer mixture comprises polyethylene glycol dimethyl silicone oil macromonomer, which includes one or more side groups from the dimethyl silicone oil backbone, said side groups being polyepoxyalkane groups (typically polyethylene glycol compounds, polypropylene glycol compounds, or copolymers of ethylene oxide and propylene oxide).

[0314] XX. According to the method described in paragraph FF, the polyethylene glycol dimethyl silicone oil macromonomer includes polyethylene glycol side groups and polypropylene glycol side groups from the dimethyl silicone oil backbone.

[0315] YY. According to the method described in paragraph FF, the method includes a dimethyl silicone oil macromonomer functionalized with pyrrolidone carboxylic acid.

[0316] ZZ. According to the method described in paragraph FF, the method includes a mixture of 5-45% w / w first dimethyl silicone oil macromonomers, typically 10-40% w / w, generally 20-30% w / w.

[0317] AAA. According to the method described in paragraph FF, the second dimethyl silicone oil macromonomer mixture comprises methylsiloxane compounds with a number average molecular weight of less than 1000 and crosslinked polyalkylsiloxane diol dimethyl silicone oil macromonomers with a number average molecular weight of greater than 1000, typically greater than 2000.

[0318] BBB. According to the method described in paragraph FF, the method comprises a mixture of 5-45% w / w second dimethyl silicone oil macromonomers, typically 10-40% w / w, generally 20-30% w / w.

[0319] CCC. According to the method described in paragraph FF, the first dimethyl silicone oil macromonomer mixture contains 5 to 30% w / w of polyethylene glycol dimethyl silicone oil macromonomer, typically 10 to 20% w / w, generally 12 to 19% w / w.

[0320] According to the method described in paragraph FF, the second dimethyl silicone oil macromonomer mixture contains 5-30% w / w crosslinked dimethyl silicone oil macromonomers, typically 10-20% w / w, generally 12-19% w / w.

[0321] EEE. The method described in paragraph FF, wherein the formulation does not include tranexamic acid.

[0322] FFF. The method according to paragraph FF, wherein the formulation does not include zinc salts, and optionally the formulation does not include zinc salts of conjugate bases of polyhydroxy acids.

[0323] This invention can be described by one or more of the following paragraphs:

[0324] a. A topical preparation comprising:

[0325] The aqueous phase includes:

[0326] i.5-15% w / w (weight percentage) nicotinamide,

[0327] ii. A partition coefficient reinforcing agent (Pc reinforcing agent) of 10-60% w / w, having a general formula: C n H 2n+2 O2, where n represents an integer from 3 to 6.

[0328] iii. and

[0329] iv. ≤10% water

[0330] And oil phase,

[0331] The formulation has a pH in the range of 4.0 to 6.0.

[0332] b. The formulation according to paragraph a, wherein the formulation comprises 5-12% w / w nicotinamide, 5.5-11% w / w nicotinamide, and optionally 6-10% w / w nicotinamide.

[0333] c. The formulation according to paragraph a or paragraph b, wherein the Pc enhancer is selected from the group consisting of propylene glycol, butylene glycol, pentanediol, hexanediol and 1,5-pentanediol and combinations thereof.

[0334] d. The formulation according to any one of paragraphs a to c, wherein the formulation comprises 15 to 50% w / w, 20 to 45% w / w, 25 to 45% w / w or 30 to 40% w / w of a Pc enhancer.

[0335] e. The formulation according to any of the preceding paragraphs, wherein the formulation further comprises about 0.5 to about 10% w / w of a diffusion coefficient enhancer (Dc enhancer), selected from C 12 ~C 14 Linear fatty acids and a C 14 A group composed of straight-chain primary alcohols.

[0336] Optionally, the Dc enhancer is selected from the group consisting of myristol (1-tetradecyl alcohol), myristic acid and lauric acid (dorsodic acid).

[0337] f. The formulation according to paragraph e, wherein the Dc enhancer is 0.5–5, 1–5, or 2–4% w / w (weight percentage) of the formulation.

[0338] g. The formulation according to any of the preceding paragraphs, wherein the formulation further comprises 2-10% w / w of a polyhydroxy acid.

[0339] Optionally, the formulation comprises 2–9, 2–7, 2–5, 3–5, or about 4% w / w of a polyhydroxy acid.

[0340] h. The preparation according to paragraph g, wherein the polyhydroxy acid is selected from gluconolactone, galactose and lactobionic acid.

[0341] i. The formulation according to any of the preceding paragraphs, wherein the oil phase of the formulation is a skin-moisturizing phase, comprising:

[0342] A mixture of 5-45% w / w first dimethyl silicone oil macromonomers, comprising dimethyl silicone oil macromonomers and hydrocarbon methyl siloxane emollients selected from the group consisting of alkyl methyl siloxanes, aryl methyl siloxanes, and alkylaryl methyl siloxanes, and...

[0343] A mixture of 5-45% w / w second dimethyl silicone oil macromonomers, comprising methylsiloxane compounds and cross-linked dimethyl silicone oil macromonomers.

[0344] j. The formulation described in any of the preceding paragraphs, wherein the formulation does not include tranexamic acid.

[0345] k. The formulation according to any of the preceding paragraphs, wherein the formulation does not include zinc salts, and optionally the formulation does not include zinc salts of conjugate bases of polyhydroxy acids.

[0346] l. The preparations used for treatment as described in any of paragraphs a to k.

[0347] m. A preparation for the prevention and / or treatment of skin cancer as described in any of paragraphs a to k.

[0348] n. The preparation used in paragraph m, wherein the skin cancer is selected from actinic keratosis, basal cell carcinoma, squamous cell carcinoma and melanoma.

[0349] o. The formulation used in paragraph m, wherein the method of preventing and / or treating skin cancer is selected from the methods of preventing actinic keratosis, treating actinic keratosis, preventing melanoma, preventing melanoma recurrence, 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.

[0350] p. The preparation used in any of paragraphs 1 to 0, wherein the method consists primarily of application to the skin once or twice daily.

[0351] q. The preparation used in any of paragraphs l to o, wherein the skin is human skin.

[0352] r. A method for preventing and / or treating skin cancer, the method comprising applying the preparation of paragraph a topically to the skin.

[0353] s. The method according to paragraph r, wherein the skin cancer is selected from the group consisting of actinic keratosis, basal cell carcinoma, squamous cell carcinoma and melanoma.

[0354] t. Use of the preparation of the formulation described in any of paragraphs a to k in the preparation of a medicament for the prevention and / or treatment of skin cancer.

[0355] u. According to the application described in paragraph t, the skin cancer mentioned is selected from actinic keratosis, basal cell carcinoma, squamous cell carcinoma, and melanoma.

[0356] v. A pharmaceutical composition comprising the preparations for the prevention and / or treatment of skin cancer as described in paragraphs a to k.

[0357] w. The pharmaceutical composition according to paragraph v, wherein the skin cancer is selected from actinic keratosis, basal cell carcinoma, squamous cell carcinoma and melanoma.

[0358] Example

[0359] Exemplary method examples for preparing 6-10% nicotinamide formulations

[0360] Table 1:

[0361]

[0362] process

[0363] In a 500g laboratory scale, this batch was made using two premixes.

[0364] V1 (400 ml): Premix 1

[0365] Sodium chloride + deionized water + lactobionic acid + gluconolactone + glycerin + propylene glycol + nicotinamide (as raw materials for 6 ingredients) + phenoxyethanol + myristol (C14 alcohol, also known as tetradecyl alcohol); slowly heat to 35°C to dissolve; cool to <25°C.

[0366] V2 (100 ml): Premix 2

[0367] Carbomer + trisiloxane; mix and disperse and add V3

[0368] V3 (Kenwood mixing bowl) - final mix with the whisk blade

[0369] Add EL-7040 (octyl polymethylsiloxane (and) PEG-12 dimethyl silicone oil / PPG-20 crosslinked polymer) to the Kenwood mixing bowl.

[0370] - Start at a low speed and increase the speed, add the contents of V2 (carbomer + trisiloxane), then run at the maximum speed #6 for 2 minutes to form "syrup".

[0371] - Add V1 dropwise / slowly in strips over approximately 10–12 minutes at a rate of #6 (maximum). When running at #6, the phase will reverse as the serum reaches its peak and hardens.

[0372] Clean the sides to the center, add ST-E (cyclopentasiloxane (and) dimethyl silicone oil crosspolymer / 9040 silicone elastomer), stir at speed #6 for 3 minutes, clean the sides to the center, and stir at speed #6 for another 3 minutes.

[0373] -Pour into a 500g sealed container.

[0374] Precautions regarding premix 1:

[0375] - The order of addition is as follows

[0376] - After adding nicotinamide, tumble and mix to form a clear solution.

[0377] - After adding gluconolactone, tumble and mix to form a clear solution.

[0378] - After adding lactobionic acid, tumble and mix to form a clear solution.

[0379] - If necessary, heat slowly to dissolve any remaining traces of lactobionic acid (10% polyhydroxy acid only).

[0380] Then add phenoxyethanol and myristol (C14 alcohol, also known as tetradecanol) to complete premix 1.

[0381] Other exemplary formulations of 6-10% nicotinamide

[0382] Table 2: Example of a production batch formula (actual batch weight)

[0383]

[0384]

[0385] 1 Octyl polymethylsiloxane (and) PEG-12 dimethyl silicone oil / PPG-20 crosspolymer

[0386] 2-cyclopentasiloxane (and) dimethyl silicone oil crosslinking polymer

[0387] Treatment and prevention of skin cancer and conditions related to ultraviolet damage

[0388] The formulations described herein are part of this invention and are used for treatment. The formulations of this invention are used for methods of preventing and / or treating skin conditions induced by ultraviolet (UV) radiation, or for preventing and / or treating skin cancer. UV damage to the skin can include discoloration and age-related brown spots (abnormal melanin production or deposition caused by UV exposure), which can potentially lead to cancer. More severe UV damage can include lesion formation and precancerous lesions. Skin cancer can include actinic keratosis, basal cell carcinoma, squamous cell carcinoma, and melanoma. Therefore, the formulations of this invention can be used for methods of treating or preventing actinic keratosis, basal cell carcinoma, squamous cell carcinoma, and melanoma. Specifically, the formulations of this invention are used for methods of preventing actinic keratosis, treating actinic keratosis, preventing melanoma, preventing melanoma recurrence, treating melanoma, preventing squamous cell carcinoma, preventing basal cell carcinoma, treating squamous cell carcinoma, and treating basal cell carcinoma.

[0389] This invention further includes the use of the formulations of this invention in the preparation of medicaments for treating or preventing skin conditions induced by ultraviolet radiation or for treating or preventing skin cancer. Treatment or prevention of skin cancer may include prevention of actinic keratosis, treatment of actinic keratosis, prevention of melanoma, prevention of melanoma recurrence, treatment of melanoma, prevention of squamous cell carcinoma, prevention of basal cell carcinoma, treatment of squamous cell carcinoma, or treatment of basal cell carcinoma.

[0390] This invention provides a method for treating or preventing skin conditions induced by ultraviolet radiation by topically applying the formulation of this invention to the skin. This invention further provides a method for treating or preventing skin conditions induced by ultraviolet radiation, the method comprising topically applying the formulation of this invention to the skin. This invention also provides a method for preventing actinic keratosis, treating actinic keratosis, preventing melanoma, preventing melanoma recurrence, treating melanoma, preventing squamous cell carcinoma, preventing basal cell carcinoma, treating squamous cell carcinoma, and treating basal cell carcinoma, the method comprising topically applying the formulation of this invention to the skin.

[0391] In several embodiments, the formulations of the present invention need to be applied to the skin only once or twice daily. Typically, the skin is human skin.

[0392] The convenience of once-daily application has been widely appreciated by users. As described in this article, the skin penetration-enhancing effect of the Pc enhancer increases over time with increasing dosage, thus providing the ability to administer once or twice daily.

[0393] Cosmetic and medical uses of niacinamide in dermatology

[0394] Nicotinamide (NAM) has been used in cosmetic and medical dermatology nearly 50 years ago, administered topically or orally, and has been documented in several major references (1–6).

[0395] In most cases, NAM is used topically for cosmetic purposes. Regardless of in vitro concentrations, it is used at levels as low as 1–10 μmol / L. -1 At concentrations of 75%–100% of the maximum response, or when applied topically in vivo, NAM significantly increases the biosynthesis of ceramides and other stratum corneum lipids to enhance skin barrier function (7). Consistent with this, Soma Y et al. found that 2% NAM cosmetic cream was a more effective moisturizer than standard petrolatum in a group of 28 patients with atopic dermatitis (8). Similarly, Draelos ZD et al. (9) reported that a facial moisturizer containing 2% NAM improved the skin barrier in a treatment-naïve, controlled study. Furthermore, Kawada A et al. (10) demonstrated the anti-wrinkle effect of cosmetics containing 4% NAM on the face compared to a placebo control. Finally, Wohlrab and Kreft (4) summarized in their review that the antipruritic effect of NAM is primarily based on its barrier protective effect.

[0396] The efficacy of NAM in treating medicinal inflammatory skin diseases such as bullous pemphigoid (11), psoriasis (12), pemphigus vulgaris (13), and rosacea (14) can be partly attributed to its inhibitory effect on nucleopolysaccharide (ADP-ribose) polymerase-1 (PARP-1). NFκB-mediated trans-inhibition of ADP-ribose polymerase-1 (PARP-1) is crucial for reducing the expression of adhesion molecules and pro-inflammatory mediators such as IL-12, TNF-α, IL-1, and nitric oxide.

[0397] Ultraviolet radiation-induced skin cancer is a global public health problem (15), including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma (MEL). The carcinogenic mechanisms include direct DNA damage, suppression of skin immunity, and energy depletion within the skin, all of which can be reversed by NAM (16). Surjana et al. (17) reported two placebo-controlled studies in 2012 involving immunocompetent volunteers with the precancerous skin condition actinic keratosis (AK). A total of 37 patients received oral NAM (Study 1: 500 mg twice daily, or Study 2: 500 mg once daily) for more than 4 months. At the end of 4 months, a highly statistically significant reduction in AK relative to baseline was observed in the nicotinamide group compared to the placebo group (Study 1: 35%; Study 2: 29%). However, Moloney et al. (35) found no difference in AK scores after 6 months of topical treatment with 1% nicotinamide cream or placebo. Given the findings of Surjana et al. (17), low-dose application (and delivery efficiency) of 1% NAM cream may result in a lack of effect on AK in the case of high oral doses of oral NAM.

[0398] As a continuation of the oral NAM program, Chen et al. (18) published the results of the ONTRAC study in 2015, which involved participants selected based on having had at least two non-melanoma skin cancers within the past five years. 386 participants were randomized over a treatment period exceeding 12 months to receive either oral NAM 500 mg twice daily or a placebo. At the 12-month evaluation, the NAM group showed a statistically significant 23% reduction in the incidence of new non-melanoma skin cancers compared to the placebo group, demonstrating efficacy against both BCC and SCC cancers. The publication of the ONTRAC study generated considerable scientific interest (19)(20).

[0399] Recently, researchers at ONTRAC focused on using NAM for the prevention of melanoma (MEL) (21). The 2015 ONTRAC study was not intended to report the role of oral NAM in the prevention of MEL. However, during the 12-month ONTRAC study, a total of 6 cases of in situ melanoma and 4 cases of invasive melanoma occurred in the oral NAM group and the placebo group. It was reported that, compared to placebo, the oral NAM group showed increased CD4+ in the tumor microenvironment of melanomas. + Helper T cells and cytotoxic CD8 +A significant increase in T cells was observed (22). Our preliminary studies in subjects provided evidence of consumer acceptability (see below) that a topical dermatological formulation of 6%–10% NAM with a diol co-enhanced silicone dispersant (GCSD) could prevent and treat sun-induced lesions and skin cancer to restore normal skin. Based on these observations, we now present a scientific analysis of in vivo and in vitro human epidermal pharmacokinetic studies and modeling of oral NAM to support our finding of unexpected clinical efficacy of NAM GCSD formulations in the treatment and prevention of skin cancer.

[0400] Pharmacokinetic-pharmacodynamic (PK-P) analysis of the potential of topical NAM for the effective treatment and prevention of skin cancer. PD analysis

[0401] As mentioned earlier, the publication of ONTRAC studies on the significant preventive effects of NAM at oral doses ranging from 500 to 1000 mg / day against BCC and SCC cancers has generated considerable scientific interest. Furthermore, NAM at such doses does not exhibit significant systemic side effects. Even so, users still prefer targeted local therapy.

[0402] A key advantage of topical therapy is the ability to achieve and maintain steady-state free NAM concentrations at the epidermal target site for 6–8 hours. This contrasts with oral administration, where rapid systemic clearance of NAM may necessitate frequent redosing 4–6 times throughout the day under optimal conditions. If topical therapy can achieve therapeutic free NAM concentrations at the basal epidermal target site and maintain these concentrations for approximately the same duration as the dosing interval, it may offer a significant advantage over oral therapy.

[0403] Skin penetration of NAM in diol co-enhancing silicone dispersant (GCSD) - 1

[0404] NAM is a small molecule with a relatively low melting point. Therefore, although NAM has a low octanol-water partition coefficient, it can penetrate the lipophilic stratum corneum barrier. Its permeability can be improved by using single skin penetration enhancers (23, 24) or co-enhancing agents (25, 26).

[0405] Table 1 shows examples of the GCSD cream formulations of the present invention. The example formulations were blinded as Test 1, Test 2 and Test 3 (as labeled in Table 1) and sent for independent in vitro human skin penetration analysis.

[0406] The NAM permeability of four formulations was tested: Test 1, Test 2, and Test 3 (6%, 8%, and 10% NAM, respectively) and a commercially available control cream containing 8% NAM. This study was conducted under limited dosage conditions (10 μL / cm²). 2The permeation studies were performed on human skin using Franz diffusion cells at 32±1°C for 24 hours. Abdominal skin from a donor (female, Caucasian) following plastic surgery was obtained from an institutionally approved tissue bank (Research Ethics Committee Reference No. 07 / H1306 / 98). Human skin was prepared by thermal separation, and its integrity was confirmed by resistivity assessment (TM-22 Digitron digital thermometer, RSComponents, UK) prior to use. Samples were collected at time points 0, 2, 4, 6, 8, 10, 12, and 24 hours by removing 200 μL of recipient media and replacing it with an equal volume of fresh PBS solution. At the end of the permeation studies, mass balance studies were performed following previously validated procedures. The amount of NAM in all samples was quantified using HPLC.

[0407] Figure 1 The permeation profiles of NAM derived from the test formulations in human skin from 0 to 24 hours are shown. Each data point represents the mean ± SD, n = 6. The results show the cumulative NAM receptor concentrations of the four formulations over 24 hours.

[0408] From Test 1 to Test 3, the cumulative penetration of NAM exhibited a dose-response relationship over time. This was driven by increasing the concentration of propylene glycol (partition coefficient enhancer) from 30% to 35% and then to 40%, respectively (see Table 1). NAM was increased from 6% to 8% and then to 10%, respectively, to maintain its saturation in solution. The diffusion coefficient enhancer was a saturated solution in all three test formulations. Addressing these three principles is crucial for optimizing the design of co-enhancing agent technologies.

[0409] Figure 2 Steady-state permeation curves of NAM derived from the test formulation in human skin over 6–12 hours are shown. Each data point represents the mean ± SD, n = 6. Note that per cm... 2 The unit of osmosis is μmol / cm³ 2 This unit originated from Figure 1 The flux was obtained by dividing the mass in μg by the molecular weight of NAM, 122.1. The results showed that the steady-state flux over 6–12 hours was expressed as μmol / cm³. 2 Its origin Figure 1 It is obtained by dividing the mass in μg by the molecular weight of NAM.

[0410] from Figure 2 The steady-state fluxes over 6–12 hours (for tests 1–3 and the commercial control, respectively) were calculated to be 0.046, 0.064, 0.091, and 0.027 μmol / cm³, respectively. 2 / Hour.

[0411] Predicting the concentration of free NAM in the basal epidermis from steady-state flux values

[0412] For this prediction, it is assumed that the target of BCC, SCC, and MEL is the basal epidermis. The concept of C* was originally developed using the antiviral drug acyclovir (27, 28), which links the free drug concentration at the skin target to the in vivo efficacy of the topical formulation and has been very successful in predicting in vivo efficacy in animal models, as well as closely correlated with clinical outcomes.

[0413] C* is calculated from Equation 1. P D It is calculated based on equations 2 and 3 (29) recently revised by Pensado et al. (30).

[0414] C*=J / P D (1)

[0415] P D =D D / h D (2)

[0416] Dd=-4.15-(0.655×log MW) (3)

[0417] Where J is the in vitro skin flux, and P... D It is the dermal permeability coefficient, D D It is the dermal diffusion coefficient, h D It is the thickness of the uninfused upper dermis. The permeability coefficient of NAM in the dermis is estimated using equation (2), where the dermal diffusion coefficient of free NAM is D. D Estimated by equation (4).

[0418] LogD DNAM = -4.15 - (0.655 × log MW) NAM (4)

[0419] Inputting the NAM molecular weight of 122.12 into equation (4) yields D. DNAM The value is 3.04 × 10 -6 cm 2 s -1 The thickness h of the uninjected upper dermis D Using the value (30) of 100 μm (0.01 cm), P D The calculated value is approximately 1.08 cm h. -1 For clarity, 3.04 × 10 -6 ×60×60 / 0.01=1.08cmh -1 .

[0420] As mentioned above, according to Figure 2Steady-state flux calculations (for tests 1–3 and the commercial control) were 0.046, 0.064, 0.091, and 0.027 μmol / cm³, respectively. 2 / Hour.

[0421] Therefore, according to equation (1), J (steady-state flux in μmol / cm) 2 / hour in units) divided by P D The predicted free NAM concentrations C* at the target basal epidermal sites were obtained, and were therefore 0.043, 0.059, 0.084, and 0.025 μmol / cm³. 3 This corresponds to Test 1, Test 2, and Test 2 cream, as well as the commercial control. From μmol / cm 3 Convert to μmol L -1 43, 59, 84 and 25 μmol / L were obtained. -1 These concentrations are much higher than those as low as 1–10 μmol / L. -1 The high NAM concentration significantly increased the biosynthesis of ceramides and other stratum corneum lipids, thereby improving the skin barrier function during cosmetic application.

[0422] Free NAM concentration associated with anti-skin cancer efficacy

[0423] Figure 3 The peak plasma concentration of NAM (μmol / mL) and its expression in g / M were shown. 2 A graph showing the relationship between oral doses in units of 1. Figure 3 Provided by Stratford et al. (31) to healthy volunteers with g / M 2 Peak plasma concentration (μmol / mL (cm)) after oral administration of NAM 3 The image is shown.

[0424] 1g (approximately 0.5g / M) 2 The mean peak plasma concentration of the dose was 0.127 μmol / mL (127 μmol L). -1 The range is 81–158 μmol / L. -1 In the oral NAM study on the prevention of AK (17) and the ONTRAC study on BCC and SCC (18), the maximum oral dose of 500 mg NAM twice daily was used, assuming linearity, and was expected to reach approximately 63.5 μmol / L. -1 μg / cm 3 Peak plasma concentration; ranging from approximately 40 to 80 μmol / L. -1Under steady state, due to the poor binding of NAM to proteins, similar NAM concentrations are expected to be reached in the basal epidermal tissue, and these NAM concentrations can provide a numerical target concentration to be achieved after local administration.

[0425] As described above, the GCSD cream and the commercial control cream in Tests 1, 2, and 3 are expected to reach 43, 59, 84, and 25 μmol / L, respectively. -1 The baseline steady-state epidermal concentrations were within the efficacy-related range found in the ONTRAC study.

[0426] Therefore, the test cream having the formulation of the present invention, after topical application to the skin, achieves a concentration higher than 40 μmol / L. -1 The peak plasma concentration of nicotinamide. Typically, the test creams and formulations of this invention, after topical application to the skin, achieve a concentration of approximately 40 to approximately 80 μmol / L. -1 The peak plasma concentration of nicotinamide was significantly higher than that of any other commercially available topical formulation.

[0427] Skin penetration of NAM in diol co-enhancing silicone dispersant (GCSD) -2

[0428] Table 2 shows examples of the GCSD cream formulations of the present invention. The example formulations were blinded as Test #2.2, Test #4.2 and Test #6.2 (as labeled in Table 2) and sent for independent in vitro human skin penetration analysis with four commercially available niacinamide-containing skin care products: Olay, Paula's Choice, TDF and SolarCare B3.

[0429] The NAM content of each formulation was evaluated, and the results are shown in Table 3.

[0430] Table 3: NAM content in each test formulation (mean ± SD, n = 5)

[0431]

[0432] The penetration of NAM was tested as described above.

[0433] Figure 4 The cumulative NAM penetration of formulations #2.2, 4.2, 6.2, TDF, Olay, Paula's Choice, and SolarCare B3 is shown. Each data point represents mean ± SD, n = 6. The results show the cumulative NAM receptor concentrations of the seven formulations over 24 hours.

[0434] Table 4 summarizes the results of the quality balance study. For all seven formulations, more than 80% of the applied NAM remained on the skin surface after 24 hours of penetration and was recovered by washing. No statistically significant differences were detected in these percentages recovered by washing (p > 0.05). The cumulative penetration of NAM from the evaluated formulations ranged from 4% to 17% of the applied dose. The penetration percentages of formulations #6.2 and #4.2 were significantly higher than those of commercial products TDF, Olay, Paula's Choice, and SolarCare B3 (p < 0.05). This indicates that the formulations of the present invention provide significantly better skin penetration than commercial products tested in the same manner. There were no differences in NAM retention in the skin for formulations #6.2 (3.0 ± 0.9%), 4.2 (2.4 ± 0.4%), and 2.2 (2.8 ± 0.4%, p > 0.05). However, formulations #6.2, #4.2, and #2.2 showed significantly higher NAM retention rates compared to the results from Olay, Paula's choice, and SolarCare B3 (p < 0.05). Overall recoveries for all seven formulations were determined to be between 93.8% and 103.1%. These results are consistent with the OECD's quality balance standard of 90–110%.

[0435] Table 4: Results of the nicotinamide penetration study of formulations #6.2, 4.2, 2.2, TDF, Olay, Paula's Choice, and SolarCareB3 (n=6, mean ± SD)

[0436]

[0437] Figure 5 The cumulative NAM penetration of formulations #7.1, #6.2, and #9.1 is shown. Each data point represents mean ± SD, n = 6. The results show the cumulative NAM receptor concentrations of the three formulations over 24 hours.

[0438] The results showed that formulations #7.1 and #6.2 containing propylene glycol had greater NAM penetration than formulation #9.1 containing butanediol. This result remained consistent despite the use of more Pc enhancer in #9.1 (50%) than in #7.1 or #6.2 (both 40%). These data indicate that propylene glycol is significantly superior to butanediol as a Pc enhancer.

[0439] In vitro analysis of skin irritation risk

[0440] The risk of skin irritation from the formulations listed in Table 2 was also independently assessed in vitro. This method used the validated testing system EpiDerm. TM Reconstructing a tissue model based on raw material-induced tissue vitality (ET)50 This method reduces the effective time by 50%. It involves topically applying 100 μL of pure test material to the surface of an EpiDerm skin model. The test material was exposed to the skin model for 1, 5, 18, 24, and 48 hours. For the negative control, the skin model was left untreated for up to 5 hours. For the positive control, (100 μL Triton X-100 1%) was applied for 3, 6, and 18 hours.

[0441] ET 50 Measurements were performed. After standardizing the negative control (i.e., the untreated negative control), percentage activity values ​​were plotted on a semi-logarithmic graph with the x-axis, and ET was measured. 50 .

[0442] benchmark ET 50 The values ​​and groupings are shown in Table 5: As a general guideline, the following groupings are used based on ET obtained using EPI-200. 50 The results were distributed according to the expected in vivo stimulus response.

[0443] Table 5:

[0444] <![CDATA[ET 50 (h)]]> Expected internal irritation ＜0.5 Strong / Severe, Possible Corrosive Concentration 0.5～4 moderate 4～12 Moderate to mild 12～24 Very mild 24 Non-irritating

[0445] Table 6 shows the ET of this experiment. 50 And corresponding skin irritation classifications.

[0446] Table 6:

[0447] Test formulation <![CDATA[ET 50 (hours) Classification Positive control 9.02h Moderate to mild stimulation #2.2 24.00 Non-irritating #4.2 18.00 Very mild #6.2 24.00 Non-irritating #7.1 18.00 Very mild #9.1 9.06 Moderate to mild stimulation

[0448] In this test, the positive control ET 50 The value was 9.02h, which was correctly classified as moderate to mild irritation. Formulations #2.2, #4.2, and #6.2 of the present invention were all classified as non-irritating or very mildly irritating. Therefore, the ET obtained from testing formulations #2.2, #4.2, and #6.2 was... s0 The values ​​fall between those obtained by this method, and are therefore comparable to those of baby sunscreen. Therefore, the formulation of the present invention can be expected to be non-irritating and suitable for long-term use, such as for several years. Extended use is recommended for the prevention and treatment of conditions caused by ultraviolet radiation and skin cancer.

[0449] in conclusion

[0450] Therefore, it has been demonstrated that the formulation of the present invention achieves a flux of nicotinamide into the skin after topical application, which matches the nicotinamide delivery levels achieved by oral delivery of nicotinamide in previous experiments demonstrating prevention and / or treatment of skin cancer. Therefore, it has been demonstrated that the formulation of the present invention is promising for the effective prevention and / or treatment of skin cancer. It can be concluded that the inventors have developed a topical formulation for the prevention and / or treatment of skin cancer selected from actinic keratosis, basal cell carcinoma, squamous cell carcinoma, and melanoma. It can be concluded that the inventors have developed a topical formulation for the prevention of actinic keratosis, treatment of actinic keratosis, prevention of melanoma, prevention of melanoma recurrence, treatment of melanoma, achieving complete or partial remission of melanoma, prevention of squamous cell carcinoma, prevention of basal cell carcinoma, treatment of squamous cell carcinoma, achieving complete or partial remission of squamous cell carcinoma, and achieving complete or partial remission of basal cell carcinoma.

[0451] Usage Example - Preliminary Study

[0452] The formulations containing 6%–10% NAM described herein can be structurally described as aqueous / diol co-reinforcing dispersants in a mixed organosilicon elastomer-silicone oil continuous phase (GCSD). Known examples include, for instance, propylene glycol and C2O2 as partition coefficient reinforcing agents. 12～14 Diol co-enhancing gels with diffusion coefficient enhancers can effectively increase the skin penetration of active agents, but they are associated with poor rubbing and skin feel, adhesiveness and skin dryness (32).

[0453] When the diol co-reinforcing silicone dispersant (GCSD) is applied to the skin, consumers experience a soft, silky feel from the blend of silicone elastomer and silicone oil continuous phases. The volatile silicone is rapidly lost, giving the impression of being absorbed into the skin.

[0454] In order to obtain feedback on this design aesthetic, informal beauty studies were conducted on many topics.

[0455] Feedback: Moisturizing

[0456] As a group of participants, feedback from young subjects indicated that GCSD products containing 6–10% niacinamide are excellent moisturizers. This can be expected from the design elements outlined above.

[0457] Feedback: Age spots (solar freckles), sun spots, and liver spots

[0458] These conditions occurred after prolonged exposure to ultraviolet radiation and are therefore associated with older subjects.

[0459] Female subject SJD

[0460] SJD reported having sunspots on her hands due to spending a lot of time outdoors. She voluntarily agreed to participate in a study in which her left hand received treatment, while her right hand served as an untreated control. The cream formulation of this invention, containing 8% niacinamide, was applied once daily to her left hand for four weeks. After two weeks, a significant lightening of the color and a marked reduction in the number of dark brown spots were reported. The product was reported to be quickly absorbed by the skin, leaving it feeling silky soft.

[0461] Female subject JW

[0462] JW requested a sample of the 6% niacinamide cream of this invention for treating dry skin on her hands and face. After approximately four weeks of treatment, she voluntarily sent photos of her hands. Her comment was that sunspots were significantly reduced compared to before treatment.

[0463] Feedback: Actinic keratosis

[0464] Feedback on actinic keratosis (AK) is scarce due to the informality and remoteness of these studies, and because they are often mistaken for sunspots or age spots. Surjana et al. (17) reported in 2012 two placebo-controlled studies in immunocompetent volunteers with actinic keratosis (AK) in which a statistically significant reduction in AK relative to baseline was observed in the NAM group (500 mg orally twice daily or once daily) compared to the placebo group (Study 1: 35%; Study 2: 29). However, Moloney et al. (35) found no difference in AK scores after 6 months of topical treatment with 1% nicotinamide cream or placebo. Given the subsequent findings of Surjana et al. (17), low-dose application (and delivery efficiency) of 1% NAM cream may lead to a lack of effect on AK compared to high-dose oral NAM.

[0465] Feedback: Actinic keratosis

[0466] A 60-year-old white male volunteered to test the cream containing 10% niacinamide of this invention. Figure 6 As shown on the left side, the subject had suffered from actinic keratosis on the left side of his face, near the upper cheekbone, for over a year. The lesions were characterized by irregularly shaped areas of red, peeling skin, approximately 0.5 cm in diameter, with a raised center. The subject frequently experienced burning or stinging sensations due to the lesions. He tried a range of emollients, moisturizers, and ointments to alleviate the symptoms, but without success.

[0467] The subject began applying a high dose of the test cream twice daily to the lesion site, but after two days reported stinging and redness at the site, questioning whether the product was too irritating. He stopped using the cream for a day and noticed the area had calmed significantly, so he resumed applying the cream only once daily for the remainder of the week. Observing no further irritation and improvement in the lesion, he resumed twice-daily administration. Significant improvement was observed over the next few weeks; the lesion gradually shrank, and its surface smoothed to the level of the surrounding tissue. Figure 6 As shown on the right.

[0468] Approximately two months later, the lesion had shrunk to a size only slightly larger than the area of ​​skin that was slightly darker. The subject discontinued the cream shortly after admitting that he believed the lesion had resolved and required no further treatment. However, when the area was examined a few weeks later, the lesion was barely noticeable. No signs of worsening or recurrence were observed in the area over the next 12 months.

[0469] Feedback: Basal cell carcinoma

[0470] The same 61-year-old white male volunteer from the aforementioned example of actinic keratosis began to notice changes in what he initially perceived as a small, harmless "freckle" on the upper right side of his chest. He initially noticed it gradually increasing in diameter to about one centimeter, with irregularly broken edges. Over time, the lesion formed a raised area across its surface and changed color. The area also began to scab, and some bleeding was observed when drying with a towel after showering. The subject also began to notice signs of nighttime bleeding on his sheets.

[0471] As the lesion developed a more menacing appearance, the subject finally decided to see his general practitioner, who immediately referred him to a consultant dermatologist specializing in skin cancer. During a subsequent specialist examination, he was diagnosed with basal cell carcinoma and referred for surgical removal of the lesion. Basal cell carcinoma lesions are as follows... Figure 7 As shown on the left.

[0472] While awaiting surgery, and without any temporary treatment, the subject decided to begin applying the 10% nicotinamide cream of this invention, a sample he had retained from a previous test for actinic keratosis. He admitted he wasn't very confident the cream would be effective in this case, but felt there was no harm in trying, as the lesion would eventually be surgically removed.

[0473] He began applying the cream twice daily and noticed that the early lesions became quite patchy, but the redness did not increase at all. Over the next month, he saw the lesions gradually shrink, flatten, and become continuous with the surrounding normal skin. After about two months, the original small "freckles" were the most prominent feature, with a halo around the "normal-looking" skin, but slightly lighter than the surrounding previously unaffected skin. The subject was pleased and surprised by the progress achieved, and importantly, he avoided potentially disfiguring surgery and saved some money on medical services in the process. The subject continued treatment for about three more months until it was determined that the lesions had completely disappeared. After 12 months of treatment, the halo around the lesions was almost undetectable after treatment, except for the obvious original "freckles." Figure 7 As shown on the right.

[0474] Feedback: Melanoma

[0475] Fortunately, as expected, no spontaneous reports on the effects on MEL were obtained. However, as described in this article, a cream containing 6%–10% NAM as a diol co-enhancing silicone dispersant (GCSD) is expected to be effective in preventing and treating MEL lesions, thereby restoring normal skin.

[0476] in conclusion

[0477] Therefore, it has been demonstrated that, in the case of an aesthetically acceptable and comfortable formulation, the formulations of the present invention advantageously deliver therapeutic levels of nicotinamide into the skin. Thus, while effective, the formulations of the present invention are also acceptable for long-term use, meaning easier patient compliance. Furthermore, the formulations of the present invention have shown surprisingly good efficacy against skin cancer and other skin conditions caused by ultraviolet damage.

[0478] The formulations of this invention represent the first consumer-acceptable (and commercially viable) topical nicotinamide product that achieves the target throughput delivery levels required for the prevention of actinic keratosis and cancerous skin conditions.

[0479] The formulations of the present invention achieve this at a commercial level containing 6-10% nicotinamide.

[0480] The formulation of this invention achieves this while showcasing a high-end aesthetic aesthetic, which is rare in sunscreen products, thus encouraging user compliance is crucial to realizing therapeutic potential.

[0481] The formulations of this invention also have synergistic benefits by containing effective levels of polyhydroxy acids, which are known to provide a range of benefits to the skin, including moisturizing and maintaining the skin's natural barrier function. In short, SOL can encourage continuous daily use as part of a routine skincare routine (therefore it represents more than just a sunscreen product for problem-solving).

[0482] Based on known evidence, the formulations of the present invention hold promise for providing protection against sun damage caused by ultraviolet radiation. However, quite unexpectedly, the formulations of the present invention have been found to treat several cases of previously sun-induced damage, including brown spots and actinic keratosis, as well as diagnosed cases of basal cell carcinoma. This is a surprising and very important discovery, extending the value of the formulations of the present invention to both treatment and prevention.

[0483] Research Summary

[0484] In our initial cosmetic studies of many of the topics described in this article, in order to obtain aesthetic feedback on GCSD creams, we also spontaneously received feedback that these creams are very effective in treating sunspots and age spots, and are also effective in treating skin cancer, especially BCC. Given that NAM has been used topically for nearly 50 years, primarily for cosmetic purposes, but also for medicinal purposes, why is this?

[0485] Over the past few decades, the concentration of NAM used in cosmetics has increased from 1-2% to 10%, but we have not heard of any reports of topical NAM treatment or reversal of BCC, SCC, or MEL skin cancer. This focus on increasing the concentration of active ingredients to enhance skin penetration has been a major issue in the design of topical formulations. Unfortunately, the standard form of the Fickian penetration equation is:

[0486] J∝Cv*Pc*Dc

[0487] Where J is flux, i.e., the rate of skin infusion, Cv is the concentration of NAM in the solution, Pc is the partition coefficient, and Dc is the diffusion coefficient. However, as Cv in the solution increases, for example by adding NAM solvent, Pc decreases proportionally, so J does not increase net. Increasing the NAM concentration from 1 to 10% does not itself increase NAM permeability.

[0488] NAM penetration can be increased by adding a single skin penetration enhancer (23, 24). The commercial control used in our in vitro human skin penetration study was developed by a major company with a global presence in its market and contained 8% NAM and a single skin penetration enhancer, octyl salicylate. The steady-state basal cell concentration was expected to be approximately 25 μmol / L. -1A recent article (36) on a commercially available single-enhanced 4% NAM and two 3% NAM test formulations allows for a prediction range of approximately 9.50–17 μmol L. -1 The steady-state basal cell concentration.

[0489] Recently, Zang Y et al. (25) described a “simple” co-enhancing agent formulation containing 5% NAM in 2019, which combined partition and diffusion coefficient enhancers, such as propylene glycol and oleic acid or linoleic acid, showing that the penetration efficiency of NAM was very similar to that of the co-enhancing agent GCSD cream (predicted basal cell concentration of 35 μmol / L under the limited dose conditions studied). -1 ).

[0490] However, these “simple” solvent mixtures are not complete formulations, and these research prototypes are unlikely to be used on human skin, at least for a long period of time, to confirm our findings on the potential of NAM co-enhancing agent formulations to effectively treat skin cancer.

[0491] ONTRAC researchers Malesu et al. (22) published an article in 2020 on the potential of oral NAM for chemoprevention of MEL. In their discussion, and based on data from Stratford et al. (31) to infer the best-fit line (see this article) Figure 3 They concluded that oral administration of 500 mg NAM could achieve approximately 80 μmol / L. -1 The peak plasma concentration. In a previously published article (37), the group reported (see reference (37)) Figure 6 In vitro, NAM showed a dose-dependent inhibitory effect on PARP-1 at a concentration of 50 μmol / L. -1 The inhibition rate was 60%. PARP-1 inhibitors based on the nicotinamide structure are currently undergoing clinical trials as a targeted therapy for breast cancer, uterine cancer, colorectal cancer, and ovarian cancer.

[0492] As we have described, the NAM-containing diol co-reinforcing silicone dispersant (GCSD) is expected to achieve and maintain up to approximately 80 μmol / L. -1 The steady-state concentration of free NAM has been shown to significantly inhibit PARP-1. Furthermore, the ability of topical administration of a diol co-enhanced silicone dispersant (GCSD) cream containing 6%–10% NAM to maintain a steady-state concentration over 12 hours may be an important benefit of the topical route, since oral NAM is rapidly cleared from the plasma (16).

[0493] While we believe the above pharmacokinetic-pharmacodynamic arguments reasonably support the potential of using NAM-containing diol co-enhancing organosilicon dispersants (GCSD) for the effective prevention and treatment of skin cancer, compliance factors may also contribute to revealing unexpected efficacy.

[0494] As discussed earlier, studies on the causes of low adherence rates have identified slow response and adverse reactions to treatment, the incidence of local and systemic adverse drug reactions or fear of their incidence (especially fear of topical corticosteroids), treatment regimens inconsistent with lifestyle, and, specifically, poor aesthetics and user experience of topical skincare products as major contributing factors. The table below (Table 7) summarizes the different dimensions influencing adherence.

[0495] Table 7: Different Dimensions of Compliance

[0496]

[0497] Of particular relevance to this discussion are the design factors for pharmaceutical cosmeceuticals and biopharmaceuticals, which can be summarized as 1) efficacy, 2) the potential for local and systemic adverse reactions, 3) the time and effort required for use (as described by the WHO) and 4) especially the consumer experience during use.

[0498] When the diol co-reinforcing silicone dispersant (GCSD) is applied to the skin, consumers experience a soft, silky feel from the blend of silicone elastomer and silicone oil continuous phases. The volatile silicone is rapidly lost, giving the impression of being absorbed into the skin.

[0499] Compared to currently available commercial NAM formulations, GCSD formulations (as shown in Figure 1 and Figure 2 of this paper) Figure 2 and Figure 4 (As shown) It is excellent in delivering NAM. However, just as important as delivering NAM to the target site is the experience of using NAM GCSD cream being the same as using a premium cosmetic; without adherence, there is no therapeutic effect.

[0500] References

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[0538] More references

[0539] · “由于20世纪70年代包价旅游的兴起以及近期廉价航班的激增,年轻和老年患者的皮肤癌发病率在十年内飙升了45%”,瓦妮莎·查尔默斯,《每日邮报在线版》,2019年7月18日 https: / / www,dailymail,co.uk / health / article-7257449 / Skin-cancer-rates-soared- 45-10-years-package-holidays-cheap-flights.html

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[0542] ·A Phase 3Randomized Trial of Nicotinamide for Skin-CancerChemoprevention. Chen AC , Martin AJ , Choy B , Fernández- P , Dalziell RA , McKenzie CA , Scolyer RA , Dhillon HM , Vardy JL , Kricker A , St. George G , Chinniah N , Halliday GM , Damian DL .N Engl J Med.2015Oct 22;373(17):1618-26

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[0546] ·Nicotinamide for skin cancer chemoprevention,Diona L Damian,Australasian Journal of Dermatology(2017)58,174-180

[0547] ·Nicotinamide for skin cancer chemoprevention:effects ofnicotinamide on melanoma in vitro andin 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

Claims

1. A topical formulation, said topical formulation comprising: The dispersed phase comprises: 5-15% w / w nicotinamide; A partition coefficient enhancer of 10-60% w / w, wherein the partition coefficient enhancer is selected from the group consisting of propylene glycol, butanediol and pentanediol and combinations thereof; 2–10% w / w of polyhydroxy acids; said polyhydroxy acids are selected from gluconolactone and lactobionic acid; and ≤10% water; and a continuous phase, the continuous phase comprising: A 5-45% w / w mixture of first dimethyl silicone oil macromonomers, comprising dimethyl silicone oil macromonomers and a hydrocarbon methyl siloxane emollient selected from the group consisting of alkyl methyl siloxanes, aryl methyl siloxanes, and alkylaryl methyl siloxanes, and... A mixture of 5-45% w / w second dimethyl silicone oil macromonomers, the second dimethyl silicone oil macromonomer mixture comprising methylsiloxane compounds and cross-linked dimethyl silicone oil macromonomers; The formulation described herein has a pH of 4.0 or higher.

2. The formulation according to claim 1, wherein the partition coefficient enhancer is propylene glycol.

3. The formulation according to claim 1 or 2, wherein the formulation does not include one or more of the following components: tranexamic acid, zinc salt, vitamin D, and calcipotriol.

4. The formulation according to claim 1 or 2, wherein the formulation does not include zinc salts of conjugate bases of polyhydroxy acids.

5. The formulation according to claim 1 or 2, wherein the formulation comprises a sunscreen, a sunblock agent, or a combination thereof.

6. A pharmaceutical composition comprising a formulation according to any one of claims 1 to 5.

7. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is used for treatment.

8. Use of the pharmaceutical composition according to claim 6 in the preparation of a medicament for the prevention and / or treatment of skin cancer.

9. The application according to claim 8, wherein the prevention and / or treatment of skin cancer is selected from the prevention of actinic keratosis, treatment of actinic keratosis, prevention of melanoma, prevention of melanoma recurrence, prevention of squamous cell carcinoma, and prevention of basal cell carcinoma.

10. The application according to claim 8 or 9, wherein the prevention and / or treatment consists of application to the skin once or twice daily.

11. The application of the formulation according to any one of claims 1 to 5 as a cosmetic agent.

12. The application according to claim 11, for improving abnormal skin pigmentation or skin aging.

13. The application according to claim 11, for improving symptoms of sun-related damage.

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