Topical formulations of dual pi3k / mtor inhibitors

Abstract

The present invention relates to topical compositions comprising a compound of formula (I) as defined herein: (I). The present invention also relates to the use of said topical compositions for the treatment of a disease or disorder alleviated by the inhibition of PI3K and / or mTOR in a subject, preferably a human, in particular for the treatment of skin lesions and / or skin conditions.

Description

[0001] This invention relates to topical compositions comprising compounds of formula (I) as defined herein. The invention also relates to the use of said topical compositions for treating a disease or disorder (particularly for treating skin lesions and / or skin conditions) in a subject (preferably a human) that is relieved by inhibition of PI3K and / or mTOR. Background Technology

[0002] The mammalian target of rapamycin (mTOR) is a large serine / threonine-specific protein kinase that binds to a protein-binding chaperone to form one of two functionally distinct mTOR complexes (mTORC1 and mTORC2) to regulate different cellular processes. mTOR can be inhibited by inhibiting upstream kinases (e.g., PI3K and / or AKT), by allosteric changes (e.g., via rapamycin), or by directly inhibiting mTOR kinases via ATP site-directed inhibitors (Saxton RA, Sabatini DM Cell, (2017) 168:960-976).

[0003] Evidence suggests that PI3K / mTOR signaling plays a role in the progression of skin diseases. For example, PI3K / mTOR signaling is associated with non-melanoma skin cancer (NMSC), particularly with the progression of actinic keratosis (AK) and cutaneous squamous cell carcinoma (cSCC) (Ayli EE et al., J. Cutaneous Pathology (2008) 35:273-277). Recent advances in understanding the mTOR signaling pathway and its downstream effects in angiogenesis have further expanded the clinical application of mTOR inhibitors to many challenging hereditary skin diseases, such as tuberous sclerosis, congenital pachyonychia, complex vascular malformations, and inflammatory skin diseases (AL Fogeld et al., J. Am. Acad. Dermatol., (2015) 72:879-89, and the references cited therein).

[0004] Bimiralisib is a dual PI3K / mTOR inhibitor that has shown activity in mouse models of skin diseases such as AK and cSCC (WO 2017 / 198347).

[0005] In humans and pigs, the stratum corneum (SC) is the outermost layer of the epidermis. It forms a protective barrier containing dead tissue. When topical formulations of drugs are applied, the SC can act as a reservoir, isolating the active ingredients of the topical formulation and thus limiting its ability to penetrate deeper into the skin, such as the epidermis and dermis. This limits the effectiveness of such topical drug formulations.

[0006] WO 2019 / 087158 teaches a formulation comprising an oxazolidin-2-one-pyrimidine compound. However, attempts to prepare topical galenine compositions comprising this compound have been challenging because the compound exhibits limited solubility, which is a significant factor affecting drug loading. Furthermore, the compound has been found to be unstable in the presence of solvents such as PEG400 (WO 2019 / 087158). Therefore, the topical drug compositions taught in WO 2019 / 087158 contain only up to 0.3% of the active compound, providing a skin concentration of only 1.12 µg / g after two weeks of once-daily administration in miniature pig studies. It should be noted that the value of 1.12 µg / g was obtained without prior removal of the stratum corneum, and therefore represents the drug concentration in the skin, including the concentration in the stratum corneum. As mentioned above, the stratum corneum can act as a reservoir, isolating the active agent from, for example, the epidermis and dermis. Therefore, there is a need for clinically acceptable topical formulations of PI3K and / or dual PI3K / mTOR inhibitors that can penetrate the stratum corneum to reach the epidermis and dermis of human skin. Summary of the Invention

[0007] This invention relates to topical pharmaceutical compositions comprising compounds of formula (I). As described below, it has been found that the topical pharmaceutical compositions of the present invention comprise a mixture of solvent and excipient (e.g., polyethylene glycol and diethylene glycol monoethyl ether), which unexpectedly dissolves an increased amount of the compound of formula (I) in a synergistic manner. Therefore, a greater amount of the compound of formula (I) is soluble in the topical pharmaceutical compositions of the present invention compared to amounts predicted based on the solubility of the compound of formula (I) in the individual solvent and excipient alone. The increased solubility of the compound of formula (I) at the topical pharmaceutical concentrations of the present invention thus contributes to greater skin penetration of the compound of formula (I) in human and porcine skin models. Without wishing to be bound by theory, it is anticipated that the increased penetration of the stratum corneum and into the epidermis and dermis by the compound of formula (I) will lead to more favorable clinical outcomes in patients with skin lesions, including AK and cSCC. Furthermore, it has been found that the compound of formula (I) is stable under most conditions of accelerated degradation. When formulated into the topical pharmaceutical compositions of the present invention disclosed herein, compounds of formula (I) were found to be stable under accelerated degradation conditions.

[0008] Similarly, surprisingly, other formulations tested did not synergistically dissolve compounds of formula (I) in increased amounts. For example, compositions containing less than 50% polyethylene glycol (e.g., less than 45%, less than 30% polyethylene glycol) were able to dissolve fewer compounds of formula (I) than expected based on the solubility of compounds of formula (I) in individual solvents and individual excipients.

[0009] Other features and advantages of this technology are described in the following detailed embodiments.

[0010] On one hand, the present invention provides a topical pharmaceutical composition comprising:

[0011] At least 0.1% by weight of the compound of formula (I):

[0012] Formula (I),

[0013] In the formula:

[0014] W is H or F.

[0015] Y is either N or CH.

[0016] R 1 and R 2 Each is independently a morpholino group of formula (II).

[0017] Equation (II),

[0018] In the formula, R 3 and R 4 Each is independently H or C1-C3 alkyl, or R 3 and R 4 They combine to form divalent C1-C3 alkylene residues;

[0019] At least 30% by weight of polyalkylene glycol, preferably at least 45% by weight of polyalkylene glycol; and

[0020] At least 10% by weight of diethylene glycol monoethyl ether, preferably at least 15% by weight of diethylene glycol monoethyl ether.

[0021] On one hand, the present invention provides a topical pharmaceutical composition comprising:

[0022] At least 0.3% by weight of the compound of formula (I):

[0023] Formula (I),

[0024] In the formula:

[0025] W is H or F.

[0026] Y is either N or CH.

[0027] R 1 and R 2 Each is independently a morpholino group of formula (II).

[0028] Equation (II),

[0029] In the formula, R 3 and R 4Each is independently H or C1-C3 alkyl, or R 3 and R 4 They combine to form divalent C1-C3 alkylene residues;

[0030] At least 30% by weight of polyalkylene glycol, preferably at least 45% by weight of polyalkylene glycol; and

[0031] At least 10% by weight of diethylene glycol monoethyl ether, preferably at least 15% by weight of diethylene glycol monoethyl ether.

[0032] On one hand, the present invention provides a topical pharmaceutical composition comprising:

[0033] At least 0.5% by weight of the compound of formula (I):

[0034] Formula (I),

[0035] In the formula:

[0036] W is either H or F;

[0037] Y is either N or CH;

[0038] R 1 and R 2 Each is independently a morpholino group of formula (II).

[0039] Equation (II),

[0040] In the formula R 3 and R 4 Each is independently H or C1-C3 alkyl, or R 3 and R 4 They combine to form divalent C1-C3 alkylene residues;

[0041] At least 30% by weight of polyalkylene glycol, preferably at least 45% by weight of polyalkylene glycol; and

[0042] At least 10% by weight of diethylene glycol monoethyl ether, preferably at least 15% by weight of diethylene glycol monoethyl ether.

[0043] On one hand, the present invention provides a topical pharmaceutical composition comprising:

[0044] At least 0.9% by weight of the compound of formula (I):

[0045] Formula (I),

[0046] In the formula:

[0047] W is either H or F;

[0048] Y is either N or CH;

[0049] R 1 and R 2 Each is independently a morpholino group of formula (II).

[0050] Equation (II),

[0051] In the formula, R 3 and R 4 Each is independently H or C1-C3 alkyl, or R 3 and R 4 They combine to form divalent C1-C3 alkylene residues;

[0052] At least 45% by weight of polyalkylene glycols; and

[0053] At least 15% by weight of diethylene glycol monoethyl ether.

[0054] On one hand, the present invention provides a topical pharmaceutical composition comprising:

[0055] At least 1.5% by weight of the compound of formula (I):

[0056] Formula (I),

[0057] In the formula:

[0058] W is either H or F;

[0059] Y is either N or CH;

[0060] R 1 and R 2 Each is independently a morpholino group of formula (II).

[0061] Equation (II),

[0062] In the formula, R 3 and R 4 Each is independently H or C1-C3 alkyl, or R 3 and R 4 They combine to form divalent C1-C3 alkylene residues;

[0063] At least 45% by weight of polyalkylene glycols; and

[0064] At least 15% by weight of diethylene glycol monoethyl ether.

[0065] On one hand, the present invention provides a topical pharmaceutical composition comprising:

[0066] At least 1.9% by weight of the compound of formula (I):

[0067] Formula (I),

[0068] In the formula:

[0069] W is H or F.

[0070] Y is either N or CH.

[0071] R 1 and R 2 Each is independently a morpholino group of formula (II).

[0072] Equation (II),

[0073] In the formula, R 3 and R 4 Each is independently H or C1-C3 alkyl, or R 3 and R 4 They combine to form divalent C1-C3 alkylene residues;

[0074] At least 45% by weight of polyalkylene glycols; and

[0075] At least 15% by weight of diethylene glycol monoethyl ether.

[0076] On one hand, the present invention provides the use of the topical pharmaceutical composition described herein in a method of treating a subject’s skin lesions or skin conditions; preferably, said skin lesions or skin conditions are actinic keratosis (AK). Attached Figure Description

[0077] Figure 1 This is a schematic diagram of a static Franz cell used to evaluate the release characteristics of compound 1 across a synthetic cellulose membrane (for the ten experimental formulations tested in Example 3).

[0078] Figure 2 Compound 1 was transferred from the ten formulations tested in Example 3 through the synthetic cellulose membrane into the receiving solution (in 2% Brij in 50 / 50 ethanol / water) between one and seven hours. ® Average cumulative release per unit area (µg / cm²) 2 The data is presented as mean ± standard deviation (n=6). The order of the formulation labels from top to bottom in the legend on the right corresponds to (2.65). 2 The cumulative amount of compound 1 released after hours is in the same order from top to bottom, that is, the highest amount of compound 1 is released by NA03 and the lowest amount is released by AG18.

[0079] Figure 3This is a schematic diagram of a diffusion cell used to test the ex vivo skin penetration of the selected formulation as described in Example 4.

[0080] Figure 4 This is a graph showing the amount of compound 1 recovered from human skin (epidermis and dermis) as described in Example 4.

[0081] Figure 5 This is a schematic diagram showing the location where the test preparation was applied to the back of a domestic pig as described in Example 5.

[0082] Figure 6 The graph shows the mean tissue concentration (±SD; n = 6) of the 11 test formulations administered in vivo to domestic pigs as described in Example 5, as a function of time.

[0083] Figure 7 This is a bar graph showing the total amount of compound 1 isolated from pig skin biopsies after in vivo administration of 11 test formulations (integrated at time points of 6, 9, and 12 hours).

[0084] Figure 8 This is a schematic diagram showing the location where the test preparation was applied to the back of a domestic pig as described in Example 6.

[0085] Figure 9 The mean (mean ± SEM) concentration of compound 1 in the skin of domestic pigs after administration of all formulations is shown (integrated at all time points (6h, 9h, 12h)).

[0086] Figure 10 This is a schematic diagram of the clinical trial protocol design described in Example 7. Detailed Implementation

[0087] This invention relates to topical pharmaceutical compositions comprising compounds of formula (I). The topical pharmaceutical compositions of the present invention comprise a mixture of a solvent and an excipient (e.g., at least 45 wt% of a polyalkylene glycol and at least 15 wt% of diethylene glycol monoethyl ether), said mixture being capable of synergistically dissolving an increased amount of the compound of formula (I). In other words, a composition comprising at least 45 wt% of a polyalkylene glycol (e.g., polyethylene glycol) and at least 15 wt% of diethylene glycol monoethyl ether is capable of dissolving an amount of the compound of formula (I) greater than expected based on the solubility of the compound of formula (I) in the individual solvent and individual excipient. Surprisingly, other formulations tested did not synergistically dissolve the increased amount of the compound of formula (I), and in some cases, the amount of the compound of formula (I) dissolved was less than predicted based on the solubility of the compound of formula (I) in the individual solvent and individual excipient.

[0088] As shown in the examples, based on the solubility of compound 1 in the individual solvents and excipients contained in NA03, it is expected that formulation NA03 will dissolve 1.85 g of compound 1 per 100 g of total formulation. Surprisingly, NA03 is able to dissolve up to 7.88 g of compound 1. This represents a co-solubility factor of 4.26. Similarly, based on the solubility of compound 1 in the individual solvents and excipients contained in AG20, it is expected that formulation AG20 will dissolve 1.89 g of compound 1 per 100 g of total formulation. Surprisingly, AG20 is able to dissolve up to 4 g of compound 1. This represents a co-solubility factor of 2.11.

[0089] Conversely, formulation CR01, containing less than 45% (wt / wt) PEG 400, is expected to dissolve 1.7 g of compound 1 per 100 g of total formulation, based on the solubility of compound 1 in the individual solvents and excipients contained in CR01. However, CR01 is only able to dissolve at most 1.375 g of compound 1 per 100 g of total formulation. This represents a solubility factor of 0.8.

[0090] The increased solubility of compounds of formula (I) at the local drug concentrations of this invention facilitates greater skin penetration of compounds of formula (I) into the stratum corneum and into the epidermis and dermis in human and porcine skin models. For example, as further illustrated in the examples and figures, the non-aqueous gel (NA03) exhibited the fastest release rate of compound 1 across the synthetic membrane, representing an increase of approximately 2 to 5 times compared to all other tested formulations. Formulations AG20, EG01, and AG21 all had statistically similar release rates, ranking as the second-highest release rates after NA03.

[0091] Similarly, as further illustrated in the examples and figures, in in vitro experiments using a porcine skin model, formulation NA03 delivered 1.7 to 17 times more compound 1 to the epidermis compared to all other tested formulations. For dermal delivery, formulation NA03 also ranked third highest. In the tested aqueous gels, formulations AG20 and AG21 delivered the highest amounts of compound 1 to both the dermis and epidermis.

[0092] As further illustrated in the examples and figures, in in vivo experiments using live pigs, among the tested experimental compounds, formulations NA03 and AG20 produced the highest concentrations of compound 1 in the skin. Figure 7 As shown, when integrals were performed at the three time points tested (i.e., 6 h, 9 h, and 12 h), the amounts of compound 1 delivered by formulations NA03 and AG20 after a single administration were higher than the IC50 for inhibiting phosphoS6. 90 .

[0093] As further illustrated in the examples and figures, formulation NA03 (containing 6.3% wt / wt of compound 1) even when administered in low doses (e.g., as low as 1.0 mg / cm³) 2 When administered, it still delivered a clinically effective dose (i.e., higher than the IC50 for inhibiting phosphoS6) after a single skin application. 90 Even when formulation NA03 contains a low concentration of compound 1 (e.g., as low as 2%), it is still able to deliver a clinically relevant amount of compound 1 after a single administration.

[0094] Furthermore, the compound of formula (I) was found to be stable under forced degradation conditions designed to accelerate degradation. As shown in Table 4, compound 1 was stable under all test conditions except for 0.1N HCl at 90 °C.

[0095] Without being bound by theory, and as described in the examples below, the increased permeability of the compound of formula (I) through the stratum corneum and into the epidermis and dermis enables patients with skin lesions and / or skin conditions (including AK and cSCC as well as hereditary skin diseases) to achieve more favorable clinical outcomes.

[0096] definition

[0097] As used herein, the term "about" should have a meaning of + / - 10%. For example, about 50% should mean 45% to 55%. Preferably, the term "about" as used herein should have a meaning of + / - 5%. For example, about 50% should mean 47.5% to 52.5%. In a preferred embodiment, the term "about" refers to any value within the range of -10% to +10% of the value it refers to. In a preferred embodiment, the term "about" refers to any value within the range of -8% to +8% of the value it refers to. In a preferred embodiment, the term "about" refers to any value within the range of -7% to +7% of the value it refers to. In a preferred embodiment, the term "about" refers to any value within the range of -5% to +5% of the value it refers to. In a preferred embodiment, the term "about" refers to any value within the range of -4% to +4% of the value it refers to. In a preferred embodiment, the term "about" refers to any value within the range of -3% to +3% of the value it refers to. In a preferred embodiment, the term "about" refers to any value within the range of -2% to +2% of the value it refers to. In a preferred embodiment, the term "about" refers to any value within the range of -1% to +1% of the value it refers to. In some embodiments, the term "about" refers to the exact value.

[0098] As used herein, the phrase "between value X and value Y" shall refer to values ​​X and Y, and any value in between. For example, the phrase "between 0.01 mg and 50 mg" refers to 0.01 mg and 50 mg, and any value in between. The same applies to the phrase "between approximately value X and approximately value Y" (with further consideration for variations in the term "approximately"). Similarly, as used herein, the phrase "value X to value Y" shall refer to values ​​X and Y, and any value in between. For example, the phrase "between 65% and 75%" refers to 65% and 75%, and any value in between. The same applies to the phrase "approximately value X to approximately value Y" (with further consideration for variations in the term "approximately").

[0099] As used herein, the terms “% (w / w)”, “% (wt / wt)”, or “weight %” refer to (mass of a component / total mass of the composition) x 100. For example, 70 wt% PEG400 means 70 g of PEG400 per 100 g of composition.

[0100] When the terms “a” or “an” are used herein, they mean “at least one” unless otherwise stated.

[0101] As used herein, the terms “locally” and “partially” refer to the application of the composition of the invention to the skin surface of a subject (preferably a human). Therefore, as used herein, the term “local application” refers to application to the skin of a subject (preferably a human), preferably for the treatment of skin lesions.

[0102] As used herein, the term "topical composition" refers to a composition suitable for topical application and applicable to the skin of a subject (preferably a human).

[0103] As used herein, the terms “treatment,” “cure,” “treatment,” or “perform treatment” refer to preventative methods and / or therapies. In one embodiment, the terms “treatment,” “cure,” “treatment,” or “perform treatment” refer to therapeutic treatment. In another embodiment, the terms “treatment,” “cure,” “treatment,” or “perform treatment” refer to preventative treatment. Preferably, the beneficial or desired clinical outcomes of the treatment include, but are not limited to, symptom relief, reduction in the severity of the disease or condition, stabilization of the disease or condition (i.e., no worsening), delay or slowing of disease or condition progression, and improvement or reduction of the disease or condition.

[0104] As used herein, the term "effective amount" refers to an amount necessary or sufficient to achieve the desired biological effect. Preferably, the term "effective amount" refers to an amount of the compound of formula (I) of the present invention that (i) treats or prevents a particular disease or condition, (ii) reduces, improves, or eliminates one or more symptoms of a particular disease or condition, or (iii) prevents or delays the onset of one or more symptoms of a particular disease or condition, as described herein. The effective amount of the compound of formula (I) of the present invention, or the topical composition, or the pharmaceutical composition will be the amount required to achieve the selected result, and such amounts can be determined routinely by those skilled in the art. More preferably, the term "effective amount" as used herein refers to an amount necessary or sufficient to inhibit PI3K and / or mTOR (e.g., 50%, 90%, or more of PI3K and / or mTOR activity). The effective amount can vary depending on the specific composition administered and the size of the subject. A particular effective amount of the compound of formula (I) of the present invention, or the topical composition, or the pharmaceutical composition can be determined empirically by those skilled in the art without extensive experimentation.

[0105] The term "mammal" as used herein includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cattle, pigs, and sheep. The term "mammal" as used herein preferably refers to humans. The term "subject" as used herein includes, but is not limited to, humans and mammals. The term "subject" as used herein preferably refers to humans.

[0106] The term "AG" stands for aqueous gel. Formulations described herein that begin with the letters AG are understood to be aqueous gels. As used herein, aqueous gels are understood to be topical pharmaceutical compositions in gel form containing at least 5% water (wt / wt), preferably at least 9% water (wt / wt).

[0107] The term "EG" stands for emulsion gel. Formulations described herein that begin with the letters EG are understood to be emulsion gels.

[0108] The term "NA" stands for non-aqueous gel. Formulations described herein that begin with the letters NA are understood to be non-aqueous gels. Non-aqueous gels as used herein are understood to be topical pharmaceutical compositions in a substantially anhydrous gel form.

[0109] As used herein, the term "substantially anhydrous" should be understood to mean that the topical pharmaceutical composition does not contain added water, and that the solvents and excipients used to prepare the topical pharmaceutical composition do not contain water. In some embodiments, a "substantially anhydrous" topical pharmaceutical composition may contain trace amounts of water (e.g., less than about 1% wt / wt, preferably less than about 0.1% wt / wt). These trace amounts of water can be absorbed from the environment, for example, by diffusion from atmospheric moisture into the topical pharmaceutical composition (e.g., a non-aqueous gel) (e.g., during the preparation and / or storage of the topical pharmaceutical composition (e.g., a non-aqueous gel). However, those skilled in the art will understand that a "substantially anhydrous" topical pharmaceutical composition is a composition that does not contain added water and does not require water.

[0110] In some embodiments, the non-aqueous gel is anhydrous. In some embodiments, the non-aqueous gel contains 0.0% water.

[0111] The term "CR" stands for "cream". Preparations described in this article that begin with the letters CR are understood to be creams.

[0112] As used herein, when a formulation is represented by a descriptor followed by a hyphen and a percentage, the percentage refers to the amount of compound I (preferably compound 1) in the formulation. For example, formulation “NA03-2.0%” contains 2.0% of formula I, while formulation “NA03-3%” contains 3% of compound 1. Formulation “AG20-3.2%” contains 3.2% of compound 1. Unless otherwise stated, formulation “NA03” contains 6.3% of compound 1.

[0113] The compounds of formula (I) included in the partial compositions of this invention comprise pharmaceutically acceptable salts of said compounds. Specifically, the term "pharmaceutically acceptable salt" as used herein refers to a pharmaceutically acceptable organic or inorganic salt, particularly an acid addition salt, of the compounds of this invention. Exemplary salts include, but are not limited to, salts of physiologically acceptable inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid), or salts of organic acids (e.g., methanesulfonic acid, p-toluenesulfonic acid, lactic acid, malic acid, tartaric acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid, and salicylic acid). Other examples of pharmaceutically acceptable salts of compounds of formula (I) are alkali metal and alkaline earth metal salts (e.g., sodium, potassium, lithium, calcium, or magnesium salts), ammonium salts, or salts of organic bases (e.g., methylamine, dimethylamine, triethylamine, piperidine, ethylenediamine, lysine, choline hydroxide, meglumine, morpholine, or arginine). Other examples of pharmaceutically acceptable salts of compounds of formula (I) include hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, nitrate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, benzenesulfonate, p-toluenesulfonate, etc.

[0114] As used herein, the term "lower monoaliphatic alcohol" refers to a saturated organic compound containing a single hydroxyl group and one to six carbon atoms, wherein the lower monoaliphatic alcohol does not contain an ether bond. Examples are methanol, ethanol, propanol (e.g., isopropanol), butanol (e.g., isobutanol or tert-butanol), pentanol (e.g., isoamyl alcohol), and hexanol (e.g., isohexanol). For the avoidance of ambiguity, diethylene glycol monoethyl ether is not considered a lower monoaliphatic alcohol.

[0115] As used herein, the term "aliphatic monoaliphatic alcohol" refers to a saturated, monounsaturated, or diunsaturated organic compound containing a single hydroxyl group and at least seven carbon atoms. Preferred aliphatic monoaliphatic alcohols contain 15 to 25 carbon atoms.

[0116] As used in this article, the term "polyalkylene glycol" refers to a substance with the chemical formula H-[O-CHR-CH2]. m Polymers with -H groups, where "m" represents the average number of repeating oxyethylene groups and R represents -H or C1-C6 alkyl groups. Preferred polyalkylene glycols are polyethylene glycol, polypropylene glycol, and polybutanediol.

[0117] The term "PEG" refers to polyethylene glycol, which has the chemical formula H-[O-CH2-CH2]. m -H polymers, where "m" represents the average number of repeating oxyethylene groups.

[0118] Those skilled in the art will understand that PEG can be prepared in various molecular weights, all of which are considered in this disclosure. Furthermore, those skilled in the art will understand that, as polymers, even purified PEG compositions do not necessarily contain the exact same molecular weight or number of repeating oxyethylene groups. Rather, PEG compositions can typically contain a range of average molecular weights, and can be characterized by the average number of repeating oxyethylene groups, “m”.

[0119] For example, Handbook of Pharmaceutical Excipients (6th Edition), RC Rowe, PJ Sheskey, ME Quinn, Pharmaceutical Press (2009) teaches the following common PEG polymers (this should not be interpreted as an exhaustive list):

[0120]

[0121] The term "Transcutol" ® "P" is a registered trademark. Transcutol ® P refers to the trade name of diethylene glycol monoethyl ether, which is also abbreviated as "DEGEE" in this article.

[0122] The term "DIPA" used in this article refers to diisopropyl adipate.

[0123] In some embodiments, the pharmaceutical composition of the present invention comprises polyacrylic acid. In a preferred embodiment, the polyacrylic acid is crosslinked with allyl sucrose or allyl pentaerythritol. In a preferred embodiment, the polyacrylic acid is marketed under the trade name "Carbopol". ® "Sales, preferably Carbopol" ® 974 or Carbopol ® 980.

[0124] In some embodiments, the pharmaceutical compositions of the present invention comprise polyethylene glycol alkyl ethers. In a preferred embodiment, the polyethylene glycol alkyl ether is a dialkylene glycol alkyl ether, for example, of formula C. n H 2n+1 (OCH2CH2) m A compound of polyethylene glycol (OH) in which "n" is an integer between 1 and 24, and "m" is the average number of repeating ethylene oxide units, preferably m is about 2 to about 20. In a preferred embodiment, the polyethylene glycol alkyl ether is marketed under the trade name "Brij". ® "Sales. In a preferred embodiment, the polyethylene glycol alkyl ether is Brij." ® S2, namely diethylene glycol octadecyl ether (C 18 H 37 (OCH2CH2)2OH). In a preferred embodiment, the polyethylene glycol alkyl ether is Brij. ® S20, or polyethylene glycol octadecyl ether (C 18 H 37 (OCH2CH2) m OH), where m is approximately 20.

[0125] In this article, "GTCC" refers to caprylic / capric triglyceride.

[0126] As used herein, the term "pharmaceuticalally acceptable excipient" includes any physiologically inert additive routinely used in pharmaceutical dosage forms. Pharmaceutically acceptable excipients are selected from binders, diluents, carriers, lubricants, flow aids, coating additives, or combinations thereof.

[0127] As used herein, the term "solubility synergist" refers to a measure of the increase in solubility of a compound of formula (I) (e.g., compound 1) in the topical pharmaceutical compositions of the present invention by a factor of the expected solubility of the compound based on formula (I) in individual solvents and individual excipients.

[0128] As used herein, the term "hyperkeratosis" is understood to mean thickening of the stratum corneum. In some implementations, hyperkeratosis is associated with the presence of an abnormal amount of keratin. Skin exhibiting hyperkeratosis is described herein as "hyperkeratotic." Skin not exhibiting hyperkeratosis is described as "non-hyperkeratotic."

[0129] As used in this article, the term "hypertrophy" is understood to refer to an increase in the volume of an organ or tissue due to the enlargement of its constituent cells. When used in the context of skin lesions (such as actinic keratosis), lesions exhibiting hypertrophy are described as "hypertrophic." Cells that do not exhibit hypertrophy are described as "non-hypertrophic."

[0130] The formulation of the present invention

[0131] On one hand, the present invention provides a topical pharmaceutical composition comprising:

[0132] At least 0.5% by weight of the compound of formula (I):

[0133] Formula (I),

[0134] In the formula:

[0135] W is either H or F;

[0136] Y is either N or CH;

[0137] R 1 and R 2 Each is independently a morpholino group of formula (II).

[0138] Equation (II),

[0139] In the formula, R 3 and R 4 Each is independently H or C1-C3 alkyl, or R 3 and R 4 They combine to form divalent C1-C3 alkylene residues;

[0140] At least 30% by weight, preferably at least 45% by weight, of polyalkylene glycols; and

[0141] At least 10% by weight, preferably at least 15% by weight, of diethylene glycol monoethyl ether.

[0142] On one hand, the present invention provides a topical pharmaceutical composition comprising:

[0143] At least 0.9% by weight of the compound of formula (I):

[0144] Formula (I),

[0145] In the formula:

[0146] W is either H or F;

[0147] Y is either N or CH;

[0148] R 1 and R 2 Each is independently a morpholino group of formula (II).

[0149] Equation (II),

[0150] In the formula, R 3 and R 4 Each is independently H or C1-C3 alkyl, or R 3 and R 4 They combine to form divalent C1-C3 alkylene residues;

[0151] At least 30% by weight, preferably at least 45% by weight, of polyalkylene glycols; and

[0152] At least 10% by weight, preferably at least 15% by weight, of diethylene glycol monoethyl ether.

[0153] On one hand, the present invention provides a topical pharmaceutical composition comprising:

[0154] At least 1.5% by weight of the compound of formula (I):

[0155] Formula (I),

[0156] In the formula:

[0157] W is either H or F;

[0158] Y is either N or CH;

[0159] R 1 and R 2 Each is independently a morpholino group of formula (II).

[0160] Equation (II),

[0161] In the formula, R 3 and R 4 Each is independently H or C1-C3 alkyl, or R 3 and R 4 They combine to form divalent C1-C3 alkylene residues;

[0162] At least 30% by weight, preferably at least 45% by weight, of polyalkylene glycols; and

[0163] At least 10% by weight, preferably at least 15% by weight, of diethylene glycol monoethyl ether.

[0164] On one hand, the present invention provides a topical pharmaceutical composition comprising:

[0165] At least 1.9% by weight of the compound of formula (I):

[0166] Formula (I),

[0167] In the formula:

[0168] W is either H or F;

[0169] Y is either N or CH;

[0170] R 1 and R 2 Each is independently a morpholino group of formula (II).

[0171] Equation (II),

[0172] In the formula, R 3 and R 4 Each is independently H or C1-C3 alkyl, or R 3 and R 4 They combine to form divalent C1-C3 alkylene residues;

[0173] At least 30% by weight, preferably at least 45% by weight, of polyalkylene glycols; and

[0174] At least 10% by weight, preferably at least 15% by weight, of diethylene glycol monoethyl ether.

[0175] In some embodiments, the topical pharmaceutical composition contains less than about 5% by weight of water. In some embodiments, the topical pharmaceutical composition contains less than about 4% by weight of water. In some embodiments, the topical pharmaceutical composition contains less than about 3% by weight of water. In some embodiments, the topical pharmaceutical composition contains less than about 2% by weight of water. In some embodiments, the topical pharmaceutical composition contains less than about 1% by weight of water. In some embodiments, the topical pharmaceutical composition contains less than about 0.5% by weight of water. In some embodiments, the topical pharmaceutical composition contains less than about 0.4% by weight of water. In some embodiments, the topical pharmaceutical composition contains less than about 0.3% by weight of water. In some embodiments, the topical pharmaceutical composition contains less than about 0.2% by weight of water. In some embodiments, the topical pharmaceutical composition contains less than about 0.1% by weight of water. In some embodiments, the topical pharmaceutical composition is substantially anhydrous, as defined above.

[0176] In some embodiments, the topical pharmaceutical composition is anhydrous. In some preferred embodiments, the topical pharmaceutical composition contains 0.0% by weight of water.

[0177] Not wanting to be bound by theory, the inclusion of DMSO in a topical formulation can facilitate the penetration of compounds dissolved therein through the subject's skin and into the systemic circulation. Therefore, in a preferred embodiment, the topical pharmaceutical composition does not contain DMSO. In some embodiments, the topical pharmaceutical composition contains less than about 1% by weight of DMSO. In some embodiments, the topical pharmaceutical composition contains less than about 0.9% by weight of DMSO. In some embodiments, the topical pharmaceutical composition contains less than about 0.8% by weight of DMSO. In some embodiments, the topical pharmaceutical composition contains less than about 0.7% by weight of DMSO. In some embodiments, the topical pharmaceutical composition contains less than about 0.6% by weight of DMSO. In some embodiments, the topical pharmaceutical composition contains less than about 0.5% by weight of DMSO. In some embodiments, the topical pharmaceutical composition contains less than about 0.4% by weight of DMSO. In some embodiments, the topical pharmaceutical composition contains less than about 0.3% by weight of DMSO. In some embodiments, the topical pharmaceutical composition contains less than about 0.2% by weight of DMSO. In some embodiments, the topical pharmaceutical composition contains less than about 0.1% by weight of DMSO. In some preferred embodiments, the topical pharmaceutical composition does not contain DMSO, that is, the topical pharmaceutical composition contains 0.0% by weight of DMSO.

[0178] In some embodiments, the topical pharmaceutical composition comprises less than about 1% by weight of a lower monoaliphatic alcohol. In some embodiments, the topical pharmaceutical composition comprises less than about 0.9% by weight of a lower monoaliphatic alcohol. In some embodiments, the topical pharmaceutical composition comprises less than about 0.8% by weight of a lower monoaliphatic alcohol. In some embodiments, the topical pharmaceutical composition comprises less than about 0.7% by weight of a lower monoaliphatic alcohol. In some embodiments, the topical pharmaceutical composition comprises less than about 0.6% by weight of a lower monoaliphatic alcohol. In some embodiments, the topical pharmaceutical composition comprises less than about 0.5% by weight of a lower monoaliphatic alcohol. In some embodiments, the topical pharmaceutical composition comprises less than about 0.4% by weight of a lower monoaliphatic alcohol. In some embodiments, the topical pharmaceutical composition comprises less than about 0.3% by weight of a lower monoaliphatic alcohol. In some embodiments, the topical pharmaceutical composition comprises less than about 0.2% by weight of a lower monoaliphatic alcohol. In some embodiments, the topical pharmaceutical composition comprises less than about 0.1% by weight of a lower monoaliphatic alcohol. In some preferred embodiments, the topical pharmaceutical composition does not contain monoaliphatic alcohols, that is, the topical pharmaceutical composition contains 0.0% by weight of lower monoaliphatic alcohols.

[0179] In some embodiments, the topical pharmaceutical composition contains less than about 1% by weight of ethanol. In some embodiments, the topical pharmaceutical composition contains less than about 0.9% by weight of ethanol. In some embodiments, the topical pharmaceutical composition contains less than about 0.8% by weight of ethanol. In some embodiments, the topical pharmaceutical composition contains less than about 0.7% by weight of ethanol. In some embodiments, the topical pharmaceutical composition contains less than about 0.6% by weight of ethanol. In some embodiments, the topical pharmaceutical composition contains less than about 0.5% by weight of ethanol. In some embodiments, the topical pharmaceutical composition contains less than about 0.4% by weight of ethanol. In some embodiments, the topical pharmaceutical composition contains less than about 0.3% by weight of ethanol. In some embodiments, the topical pharmaceutical composition contains less than about 0.2% by weight of ethanol. In some embodiments, the topical pharmaceutical composition contains less than about 0.1% by weight of ethanol. In some embodiments, the topical pharmaceutical composition does not contain ethanol, that is, the topical pharmaceutical composition contains 0.0% by weight of ethanol.

[0180] In some embodiments, the topical pharmaceutical composition comprises polyacrylic acid. In some embodiments, the composition comprises about 0.1 wt% to about 10 wt% of polyacrylic acid. In some embodiments, the composition comprises about 0.5 wt% to about 5 wt% of polyacrylic acid. In some embodiments, the composition comprises about 0.5 wt% to about 2.5 wt% of polyacrylic acid. In some embodiments, the composition comprises about 0.5 wt% to about 1.5 wt% of polyacrylic acid.

[0181] In some embodiments, the composition comprises at least 1% by weight of polyacrylic acid. In some embodiments, the composition comprises at most 1% by weight of polyacrylic acid. In some embodiments, the composition comprises about 1% by weight of polyacrylic acid.

[0182] In some embodiments, the polyacrylic acid is Carbopol ® 974. In some embodiments, the polyacrylic acid is Carbopol. ® 980.

[0183] In some embodiments, the topical pharmaceutical composition comprises less than about 1% by weight of polyacrylic acid, preferably less than about 0.1% by weight of polyacrylic acid. In some embodiments, the topical pharmaceutical composition does not contain polyacrylic acid, i.e., the topical pharmaceutical composition comprises 0.0% by weight of polyacrylic acid.

[0184] In some embodiments, the topical pharmaceutical composition comprises a preservative. Preservatives are known to those skilled in the art and include, for example, benzyl alcohol, benzoic acid, phenol, m-cresol, methylparaben, propylparaben, or combinations thereof. In a preferred embodiment, the preservative is benzyl alcohol.

[0185] In some embodiments, the amount of preservative present is from about 0.01% (w / w) to about 5% (w / w) based on the total weight of the partial composition, preferably from about 0.1% (w / w) to about 5% (w / w), more preferably from about 1% (w / w) to about 3% (w / w).

[0186] In a preferred embodiment, the topical composition comprises one or more other preservatives, wherein the preservative is benzyl alcohol, and the amount of benzyl alcohol present, based on the total weight of the topical composition, is about 0.01% (w / w) to about 5% (w / w), preferably about 0.1% (w / w) to about 5% (w / w), more preferably about 1% (w / w) to about 3% (w / w), and even more preferably about 2% (w / w). In a preferred embodiment, the topical composition comprises a preservative, wherein the preservative is benzyl alcohol, and the amount of benzyl alcohol present, based on the total weight of the topical composition, is about 0.01% (w / w) to about 5% (w / w), preferably about 0.1% (w / w) to about 5% (w / w), more preferably about 1% (w / w) to about 3% (w / w), and even more preferably about 2% (w / w).

[0187] In some embodiments, the topical pharmaceutical composition does not contain any preservatives, that is, the topical pharmaceutical composition contains 0.0% by weight of preservatives.

[0188] In a preferred embodiment, the topical composition comprises benzyl alcohol, and the amount of benzyl alcohol present is from about 0.01% (w / w) to about 5% (w / w) based on the total weight of the topical composition, preferably from about 0.1% (w / w) to about 5% (w / w), more preferably from about 1% (w / w) to about 3% (w / w), and even more preferably from about 2% (w / w).

[0189] In some embodiments, the topical pharmaceutical composition does not contain benzyl alcohol.

[0190] In a preferred embodiment, the topical pharmaceutical composition comprises an aliphatic alcohol, more preferably the aliphatic alcohol comprising 15 to 25 carbon atoms. In a preferred embodiment, the aliphatic alcohol is fully saturated or comprises one or two olefins, more preferably one olefin. In some embodiments, the topical composition does not comprise an aliphatic alcohol.

[0191] In a preferred embodiment, the aliphatic alcohol is oleyl alcohol. In a preferred embodiment, the oleyl alcohol is present in an amount of about 1% to about 5% by weight, more preferably about 1% to about 4% by weight, more preferably about 1% to about 3% by weight, more preferably about 1% to about 2% by weight, and even more preferably about 1.5% by weight. In some embodiments, the topical composition does not contain oleyl alcohol.

[0192] In some embodiments, the topical pharmaceutical composition comprises a thickener. Thickeners are known to those skilled in the art and include cellulose derivatives, polyvinylpyrrolidone, carbomer polymers, carbomer derivatives, maltodextrin, polydextrose, glucose dextrorates, carboxylated polymethylene, polyvinyl alcohol, poloxamer, and mixtures thereof. In a preferred embodiment, the thickener is used to increase the final viscosity of the topical composition, preferably ensuring and increasing the residence time of the topical composition on the subject's skin (e.g., at sites of skin lesions and / or skin conditions).

[0193] In a preferred embodiment, the thickener is selected from: carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (“HPC”), sodium hyaluronate, and polyvinylpyrrolidone. In a preferred embodiment, the thickener is carboxymethyl cellulose. In a preferred embodiment, the thickener is hydroxyethyl cellulose. In a preferred embodiment, the thickener is hydroxypropyl cellulose. In a preferred embodiment, the thickener is sodium hyaluronate. In a preferred embodiment, the thickener is polyvinylpyrrolidone. The term “HPC HF” as used herein is understood to refer to pharmaceutical grade hydroxypropyl cellulose. The abbreviation “HPC” as used herein is understood to refer to “hydroxypropyl cellulose”, and the abbreviation “HF” is understood to indicate that the HPC is pharmaceutical grade HPC. In a preferred embodiment, the HPC HF is Klucel… TM HCF HF.

[0194] In some embodiments, the composition comprises about 0.1 wt% to about 10 wt% of a thickener. In some embodiments, the composition comprises about 0.5 wt% to about 5 wt% of a thickener. In some embodiments, the composition comprises about 0.5 wt% to about 2.5 wt% of a thickener. In some embodiments, the composition comprises about 0.5 wt% to about 1.5 wt% of a thickener.

[0195] In some embodiments, the composition contains at least 1% by weight of a thickener. In some embodiments, the composition contains at most 1% by weight of a thickener. In some embodiments, the composition contains about 1% by weight of a thickener.

[0196] In some embodiments, the composition comprises about 0.1% by weight to about 10% by weight of hydroxypropyl cellulose. In some embodiments, the composition comprises about 0.5% by weight to about 5% by weight of hydroxypropyl cellulose. In some embodiments, the composition comprises about 0.5% by weight to about 2.5% by weight of hydroxypropyl cellulose. In some embodiments, the composition comprises about 0.5% by weight to about 1.5% by weight of hydroxypropyl cellulose.

[0197] In some embodiments, the composition comprises at least 1% by weight of hydroxypropyl cellulose. In some embodiments, the composition comprises at most 1% by weight of hydroxypropyl cellulose. In some embodiments, the composition comprises about 1% by weight of hydroxypropyl cellulose.

[0198] In some embodiments, the topical pharmaceutical composition comprises about 0.1 wt% to about 8 wt% of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises about 0.2 wt% to about 8 wt% of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises about 0.3 wt% to about 8 wt% of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises about 0.4 wt% to about 8 wt% of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises about 0.5 wt% to about 8 wt% of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises about 0.9 wt% to about 8 wt% of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises about 1.0 wt% to about 8 wt% of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises about 1.5 wt% to about 8 wt% of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises about 1.5 wt% to about 7.9 wt% of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises about 1.9 wt% to about 7.5 wt% of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises about 1.9 wt% to about 7 wt% of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises about 1.9 wt% to about 6.5 wt% of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises about 1.9 wt% to about 6 wt% of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises about 1.9 wt% to about 5 wt% of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises about 1.9 wt% to about 4 wt% of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises about 1.9 wt% to about 3 wt% of a compound of formula (I). In a preferred embodiment, the topical pharmaceutical composition comprises about 1.5 wt% to about 2.5 wt% of a compound of formula (I). In a preferred embodiment, the topical pharmaceutical composition comprises about 1.9% to about 2.5% by weight of a compound of formula (I). In a very preferred embodiment, the topical pharmaceutical composition comprises about 1.9% to about 2.1% by weight of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises about 2.0% by weight of a compound of formula (I).

[0199] In some embodiments, the topical pharmaceutical composition comprises at least about 0.1% by weight of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises at least about 0.2% by weight of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises at least about 0.3% by weight of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises at least about 0.4% by weight of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises at least about 0.5% by weight of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises at least about 0.9% by weight of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises at least about 1% by weight of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises at least about 1.5% by weight of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises at least about 1.6% by weight of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises at least about 1.7% by weight of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises at least about 1.8% by weight of a compound of formula (I). In a preferred embodiment, the topical pharmaceutical composition comprises at least about 1.9% by weight of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises at least about 2.0% by weight of a compound of formula (I). In some embodiments, the composition comprises at least about 2.5% by weight of a compound of formula (I). In some embodiments, the composition comprises at least about 3.0% by weight of a compound of formula (I). In some embodiments, the composition comprises at least about 3.5% by weight of a compound of formula (I). In some embodiments, the composition comprises at least about 4.0% by weight of a compound of formula (I). In some embodiments, the composition comprises at least about 4.5% by weight of a compound of formula (I). In some embodiments, the composition comprises at least about 5.0% by weight of a compound of formula (I). In some embodiments, the composition comprises at least about 5.5% by weight of a compound of formula (I). In some embodiments, the composition comprises at least about 6.0% by weight of a compound of formula (I). In some embodiments, the composition comprises at least about 6.3% by weight of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises at least about 6.5% by weight of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises at least about 7.0% by weight of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises at least about 7.5% by weight of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises at least about 7.7% by weight of a compound of formula (I).In some embodiments, the topical pharmaceutical composition comprises at least about 7.8% by weight of a compound of formula (I). In some embodiments, the topical pharmaceutical composition comprises at least about 7.9% by weight of a compound of formula (I).

[0200] In some embodiments, the topical pharmaceutical composition comprises about 0.1 wt% to about 8 wt% of compound 1. In some embodiments, the topical pharmaceutical composition comprises about 0.2 wt% to about 8 wt% of compound 1. In some embodiments, the topical pharmaceutical composition comprises about 0.3 wt% to about 8 wt% of compound 1. In some embodiments, the topical pharmaceutical composition comprises about 0.4 wt% to about 8 wt% of compound 1. In some embodiments, the topical pharmaceutical composition comprises about 0.5 wt% to about 8 wt% of compound 1. In some embodiments, the topical pharmaceutical composition comprises about 0.9 wt% to about 8 wt% of compound 1. In some embodiments, the topical pharmaceutical composition comprises about 1.0 wt% to about 8 wt% of compound 1. In some embodiments, the topical pharmaceutical composition comprises about 1.5 wt% to about 8 wt% of compound 1. In some embodiments, the topical pharmaceutical composition comprises about 1.5 wt% to about 7.9 wt% of compound 1. In some embodiments, the topical pharmaceutical composition comprises about 1.9 wt% to about 7.5 wt% of compound 1. In some embodiments, the topical pharmaceutical composition comprises about 1.9 wt% to about 7 wt% of compound 1. In some embodiments, the topical pharmaceutical composition comprises about 1.9 wt% to about 6.5 wt% of compound 1. In some embodiments, the topical pharmaceutical composition comprises about 1.9 wt% to about 6 wt% of compound 1. In some embodiments, the topical pharmaceutical composition comprises about 1.9 wt% to about 5 wt% of compound 1. In some embodiments, the topical pharmaceutical composition comprises about 1.9 wt% to about 4 wt% of compound 1. In some embodiments, the topical pharmaceutical composition comprises about 1.9 wt% to about 3 wt% of compound 1. In a preferred embodiment, the topical pharmaceutical composition comprises about 1.5 wt% to about 2.5 wt% of compound 1. In a preferred embodiment, the topical pharmaceutical composition comprises about 1.9 wt% to about 2.5 wt% of compound 1. In a very preferred embodiment, the topical pharmaceutical composition comprises about 1.9 wt% to about 2.1 wt% of compound 1.

[0201] In some embodiments, the topical pharmaceutical composition comprises at least about 0.1% by weight of compound 1. In some embodiments, the topical pharmaceutical composition comprises at least about 0.2% by weight of compound 1. In some embodiments, the topical pharmaceutical composition comprises at least about 0.3% by weight of compound 1. In some embodiments, the topical pharmaceutical composition comprises at least about 0.4% by weight of compound 1. In some embodiments, the topical pharmaceutical composition comprises at least about 0.5% by weight of compound 1. In some embodiments, the topical pharmaceutical composition comprises at least about 0.9% by weight of compound 1. In some embodiments, the topical pharmaceutical composition comprises at least about 1% by weight of compound 1. In some embodiments, the topical pharmaceutical composition comprises at least about 1.5% by weight of compound 1. In some embodiments, the topical pharmaceutical composition comprises at least about 1.6% by weight of compound 1. In some embodiments, the topical pharmaceutical composition comprises at least about 1.7% by weight of compound 1. In some embodiments, the topical pharmaceutical composition comprises at least about 1.8% by weight of compound 1. In a preferred embodiment, the topical pharmaceutical composition comprises at least about 1.9% by weight of compound 1. In some embodiments, the topical pharmaceutical composition comprises at least about 2.0% by weight of compound 1. In some embodiments, the composition comprises at least about 2.5% by weight of compound 1. In some embodiments, the composition comprises at least about 3.0% by weight of compound 1. In some embodiments, the composition comprises at least about 3.5% by weight of compound 1. In some embodiments, the composition comprises at least about 4.0% by weight of compound 1. In some embodiments, the composition comprises at least about 4.5% by weight of compound 1. In some embodiments, the composition comprises at least about 5.0% by weight of compound 1. In some embodiments, the composition comprises at least about 5.5% by weight of compound 1. In some embodiments, the composition comprises at least about 6.0% by weight of compound 1. In some embodiments, the composition comprises at least about 6.3% by weight of compound 1. In some embodiments, the topical pharmaceutical composition comprises at least about 6.5% by weight of compound 1. In some embodiments, the topical pharmaceutical composition comprises at least about 7.0% by weight of compound 1. In some embodiments, the topical pharmaceutical composition comprises at least about 7.5% by weight of compound 1. In some embodiments, the topical pharmaceutical composition comprises at least about 7.7% by weight of compound 1. In some embodiments, the topical pharmaceutical composition comprises at least about 7.8% by weight of compound 1. In some embodiments, the topical pharmaceutical composition comprises at least about 7.9% by weight of compound 1.

[0202] In some embodiments, the polyalkylene glycol is selected from polyethylene glycol (PEG), polypropylene glycol, and polybutanediol, and combinations thereof. In a preferred embodiment, the polyalkylene glycol is polyethylene glycol. In some embodiments, the polyethylene glycol is selected from PEG 200, PEG 300, PEG 400, PEG 540, PEG 600, PEG 900, PEG 1000, PEG 1450, PEG 1540, PEG 2000, PEG 3000, PEG 3350, PEG 4000, PEG 4600, PEG 8000, or combinations thereof. In some embodiments, the polyethylene glycol is selected from PEG 200, PEG 300, PEG 400, PEG 540, PEG 600, PEG 900, PEG 1000, or combinations thereof. In some embodiments, the polyethylene glycol is selected from PEG 200, PEG 300, PEG 400, PEG 540, PEG 600, or combinations thereof. In some embodiments, the polyethylene glycol is selected from PEG 300, PEG 400, PEG 540, or combinations thereof. In a preferred embodiment, the polyethylene glycol is selected from PEG 400.

[0203] In some embodiments, the topical pharmaceutical composition comprises at least 30% by weight of a polyalkylene glycol, preferably polyethylene glycol. In some embodiments, the topical pharmaceutical composition comprises at least 35% by weight of a polyalkylene glycol, preferably polyethylene glycol. In some embodiments, the topical pharmaceutical composition comprises at least 40% by weight of a polyalkylene glycol, preferably polyethylene glycol. In some embodiments, the topical pharmaceutical composition comprises at least 45% by weight of a polyalkylene glycol, preferably polyethylene glycol. In some embodiments, the topical pharmaceutical composition comprises at least 50% by weight of a polyalkylene glycol, preferably polyethylene glycol. In some embodiments, the topical pharmaceutical composition comprises at least 55% by weight of a polyalkylene glycol, preferably polyethylene glycol. In some embodiments, the topical pharmaceutical composition comprises about 57.81% by weight of a polyalkylene glycol, preferably polyethylene glycol.

[0204] In some embodiments, the topical pharmaceutical composition comprises about 30% to about 80% by weight of polyalkylene glycol. In some embodiments, the topical pharmaceutical composition comprises about 35% to about 80% by weight of polyalkylene glycol. In some embodiments, the topical pharmaceutical composition comprises about 40% to about 80% by weight of polyalkylene glycol. In some embodiments, the topical pharmaceutical composition comprises about 45% to about 80% by weight of polyalkylene glycol. In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of polyalkylene glycol. In some embodiments, the topical pharmaceutical composition comprises about 45% to about 70% by weight of polyalkylene glycol. In some embodiments, the topical pharmaceutical composition comprises about 45% to about 65% by weight of polyalkylene glycol. In some preferred embodiments, the topical pharmaceutical composition comprises about 50% to about 60% by weight of polyalkylene glycol. In some preferred embodiments, the topical pharmaceutical composition comprises about 53% to about 60% by weight of polyalkylene glycol. In some preferred embodiments, the topical pharmaceutical composition comprises about 55% to about 60% by weight of polyalkylene glycol.

[0205] In some embodiments, the topical pharmaceutical composition comprises at least 45% by weight of PEG 400. In some embodiments, the topical pharmaceutical composition comprises at least 50% by weight of PEG 400. In some embodiments, the topical pharmaceutical composition comprises at least 55% by weight of PEG 400. In some embodiments, the topical pharmaceutical composition comprises about 57.8% by weight of PEG 400.

[0206] In some embodiments, the topical pharmaceutical composition comprises about 45 wt% to about 80 wt% of PEG 400. In some embodiments, the topical pharmaceutical composition comprises about 45 wt% to about 75 wt% of PEG 400. In some embodiments, the topical pharmaceutical composition comprises about 45 wt% to about 70 wt% of PEG 400. In some embodiments, the topical pharmaceutical composition comprises about 45 wt% to about 65 wt% of PEG 400. In some preferred embodiments, the topical pharmaceutical composition comprises about 50 wt% to about 60 wt% of PEG 400. In some preferred embodiments, the topical pharmaceutical composition comprises about 53 wt% to about 60 wt% of PEG 400. In some preferred embodiments, the topical pharmaceutical composition comprises about 55 wt% to about 60 wt% of PEG 400.

[0207] In some embodiments, the topical pharmaceutical composition comprises about 10% to about 35% by weight of diethylene glycol monoethyl ether. In some embodiments, the topical pharmaceutical composition comprises about 15% to about 35% by weight of diethylene glycol monoethyl ether. In some embodiments, the topical pharmaceutical composition comprises about 15% to about 30% by weight of diethylene glycol monoethyl ether. In some embodiments, the topical pharmaceutical composition comprises about 19% to about 30% by weight of diethylene glycol monoethyl ether. In some embodiments, the topical pharmaceutical composition comprises about 20% to about 30% by weight of diethylene glycol monoethyl ether. In some embodiments, the topical pharmaceutical composition comprises about 20% to about 25% by weight of diethylene glycol monoethyl ether. In some embodiments, the topical pharmaceutical composition comprises about 22% to about 25% by weight of diethylene glycol monoethyl ether.

[0208] In some embodiments, the topical pharmaceutical composition comprises at least 10% by weight of diethylene glycol monoethyl ether. In some embodiments, the topical pharmaceutical composition comprises at least 15% by weight of diethylene glycol monoethyl ether. In some embodiments, the topical pharmaceutical composition comprises at least 19% by weight of diethylene glycol monoethyl ether. In a preferred embodiment, the composition comprises at least 20% by weight of diethylene glycol monoethyl ether. In a preferred embodiment, the composition comprises at least 21% by weight of diethylene glycol monoethyl ether. In a preferred embodiment, the composition comprises at least 22% by weight of diethylene glycol monoethyl ether. In a preferred embodiment, the composition comprises at least 23% by weight of diethylene glycol monoethyl ether. In a preferred embodiment, the composition comprises about 24.5% by weight of diethylene glycol monoethyl ether.

[0209] In some embodiments, the topical pharmaceutical composition comprises diisopropyl adipate. In some embodiments, the composition comprises about 1% to about 20% by weight of diisopropyl adipate. In some embodiments, the composition comprises about 1% to about 15% by weight of diisopropyl adipate. In some embodiments, the composition comprises about 5% to about 15% by weight of diisopropyl adipate. In some embodiments, the composition comprises about 7% to about 13% by weight of diisopropyl adipate. In some embodiments, the composition comprises about 9% to about 11% by weight of diisopropyl adipate.

[0210] In some embodiments, the composition comprises at least about 5% by weight of diisopropyl adipate. In some embodiments, the composition comprises at least about 6% by weight of diisopropyl adipate. In some embodiments, the composition comprises at least about 7% by weight of diisopropyl adipate. In some embodiments, the composition comprises at least about 8% by weight of diisopropyl adipate. In some embodiments, the composition comprises at least about 9% by weight of diisopropyl adipate. In some embodiments, the composition comprises at least about 9.3% by weight of diisopropyl adipate. In some embodiments, the composition comprises about 9.36% by weight of diisopropyl adipate. In some embodiments, the composition comprises about 9.8% by weight of diisopropyl adipate.

[0211] In some embodiments, the topical pharmaceutical composition comprises glycerin. In some embodiments, the composition comprises about 1% to about 10% by weight of glycerin. In some embodiments, the composition comprises about 3% to about 8% by weight of glycerin. In some embodiments, the composition comprises about 4% to about 6% by weight of glycerin.

[0212] In some embodiments, the composition contains at least 3% by weight of glycerol. In some embodiments, the composition contains at least 4% by weight of glycerol. In some embodiments, the composition contains at least 4.5% by weight of glycerol. In some embodiments, the composition contains at least 5% by weight of glycerol. In some embodiments, the composition contains 3% by weight of glycerol. In a preferred embodiment, the composition contains 4% by weight of glycerol. In some embodiments, the composition contains 5% by weight of glycerol. In some embodiments, the composition contains about 4.89% by weight of glycerol.

[0213] In some embodiments, the composition comprises about 0.1% by weight to about 10% by weight of hydroxypropyl cellulose. In some embodiments, the composition comprises about 0.5% by weight to about 5% by weight of hydroxypropyl cellulose. In some embodiments, the composition comprises about 0.5% by weight to about 2.5% by weight of hydroxypropyl cellulose. In some embodiments, the composition comprises about 0.5% by weight to about 1.5% by weight of hydroxypropyl cellulose.

[0214] In some embodiments, the composition comprises at least 1% by weight of hydroxypropyl cellulose. In some embodiments, the composition comprises at most 1% by weight of hydroxypropyl cellulose. In some embodiments, the composition comprises about 1% by weight of hydroxypropyl cellulose.

[0215] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 80% by weight of polyalkylene glycol and about 15% to about 35% by weight of diethylene glycol monoethyl ether. In some embodiments, the topical pharmaceutical composition comprises about 45% to about 80% by weight of polyalkylene glycol and about 15% to about 30% by weight of diethylene glycol monoethyl ether. In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of polyalkylene glycol and about 15% to about 30% by weight of diethylene glycol monoethyl ether. In some embodiments, the topical pharmaceutical composition comprises about 45% to about 65% by weight of polyalkylene glycol and about 15% to about 30% by weight of diethylene glycol monoethyl ether. In some embodiments, the topical pharmaceutical composition comprises about 45% to about 65% by weight of polyalkylene glycol and about 19% to about 30% by weight of diethylene glycol monoethyl ether. In some embodiments, the topical pharmaceutical composition comprises about 45% to about 65% by weight of polyalkylene glycol and about 20% to about 30% by weight of diethylene glycol monoethyl ether. In some embodiments, the topical pharmaceutical composition comprises about 50% to about 60% by weight of polyalkylene glycol and about 20% to about 25% by weight of diethylene glycol monoethyl ether.

[0216] In some embodiments, the topical pharmaceutical composition comprises about 45 wt% to about 80 wt% PEG, preferably PEG400, and about 15 wt% to about 35 wt% diethylene glycol monoethyl ether. In some embodiments, the topical pharmaceutical composition comprises about 45 wt% to about 80 wt% PEG, preferably PEG400, and about 15 wt% to about 35 wt% diethylene glycol monoethyl ether. In some embodiments, the topical pharmaceutical composition comprises about 45 wt% to about 75 wt% PEG, preferably PEG400, and about 15 wt% to about 30 wt% diethylene glycol monoethyl ether. In some embodiments, the topical pharmaceutical composition comprises about 45 wt% to about 65 wt% PEG, preferably PEG400, and about 15 wt% to about 30 wt% diethylene glycol monoethyl ether. In some embodiments, the topical pharmaceutical composition comprises about 45 wt% to about 65 wt% PEG, preferably PEG400, and about 19 wt% to about 30 wt% diethylene glycol monoethyl ether. In some embodiments, the topical pharmaceutical composition comprises about 45% to about 65% by weight of PEG, preferably PEG400, and about 20% to about 30% by weight of diethylene glycol monoethyl ether. In some embodiments, the topical pharmaceutical composition comprises about 50% to about 60% by weight of PEG, preferably PEG400, and about 20% to about 25% by weight of diethylene glycol monoethyl ether.

[0217] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 80% by weight of a polyalkylene glycol; about 15% to about 35% by weight of a diethylene glycol monoethyl ether; and about 0.1% to about 8% by weight of a compound of formula (I).

[0218] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 80% by weight of a polyalkylene glycol; about 15% to about 35% by weight of a diethylene glycol monoethyl ether; and about 0.5% to about 8% by weight of a compound of formula (I).

[0219] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 80% by weight of a polyalkylene glycol; about 15% to about 35% by weight of a diethylene glycol monoethyl ether; and about 0.9% to about 8% by weight of a compound of formula (I).

[0220] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of a polyalkylene glycol; about 15% to about 30% by weight of diethylene glycol monoethyl ether; and about 1% to about 7.9% by weight of a compound of formula (I).

[0221] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of a polyalkylene glycol; about 15% to about 30% by weight of diethylene glycol monoethyl ether; and about 1.9% to about 7% by weight of a compound of formula (I).

[0222] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of a polyalkylene glycol; about 15% to about 30% by weight of diethylene glycol monoethyl ether; and about 1.9% to about 5% by weight of a compound of formula (I).

[0223] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of a polyalkylene glycol; about 15% to about 30% by weight of a diethylene glycol monoethyl ether; and about 1.9% to about 2.5% by weight of a compound of formula (I).

[0224] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 65% by weight of a polyalkylene glycol; about 19% to about 30% by weight of a diethylene glycol monoethyl ether; and about 1.9% to about 2.5% by weight of a compound of formula (I).

[0225] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 65% by weight of a polyalkylene glycol; about 20% to about 30% by weight of a diethylene glycol monoethyl ether; and about 1.9% to about 2.5% by weight of a compound of formula (I).

[0226] In some embodiments, the topical pharmaceutical composition comprises about 50% to about 60% by weight of a polyalkylene glycol; about 20% to about 25% by weight of a diethylene glycol monoethyl ether; and about 1.9% to about 2.5% by weight of a compound of formula (I).

[0227] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 80% by weight of PEG, preferably PEG400; about 15% to about 35% by weight of diethylene glycol monoethyl ether; and about 0.1% to about 8% by weight of compound 1.

[0228] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 80% by weight of PEG, preferably PEG400; about 15% to about 35% by weight of diethylene glycol monoethyl ether; and about 0.5% to about 8% by weight of compound 1.

[0229] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 80% by weight of PEG, preferably PEG400; about 15% to about 35% by weight of diethylene glycol monoethyl ether; and about 0.9% to about 8% by weight of compound 1.

[0230] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of PEG, preferably PEG400; about 15% to about 30% by weight of diethylene glycol monoethyl ether; and about 1% to about 7.9% by weight of compound 1.

[0231] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of PEG, preferably PEG400; about 15% to about 30% by weight of diethylene glycol monoethyl ether; and about 1.9% to about 7% by weight of compound 1.

[0232] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of PEG, preferably PEG400; about 15% to about 30% by weight of diethylene glycol monoethyl ether; and about 1.9% to about 5% by weight of compound 1.

[0233] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of PEG, preferably PEG400; about 15% to about 30% by weight of diethylene glycol monoethyl ether; and about 1.9% to about 2.5% by weight of compound 1.

[0234] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 65% by weight of PEG, preferably PEG400; about 19% to about 30% by weight of diethylene glycol monoethyl ether; and about 1.9% to about 2.5% by weight of compound 1.

[0235] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 65% by weight of PEG, preferably PEG400; about 20% to about 30% by weight of diethylene glycol monoethyl ether; and about 1.9% to about 2.5% by weight of compound 1.

[0236] In some embodiments, the topical pharmaceutical composition comprises about 50% to about 60% by weight of PEG, preferably PEG400; about 20% to about 25% by weight of diethylene glycol monoethyl ether; and about 1.9% to about 2.5% by weight of compound 1.

[0237] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 80% by weight of polyalkylene glycol; about 15% to about 35% by weight of diethylene glycol monoethyl ether; about 1% to about 20% by weight of diisopropyl adipate; and about 0.1% to about 8% by weight of a compound of formula (I).

[0238] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 80% by weight of polyalkylene glycol; about 15% to about 35% by weight of diethylene glycol monoethyl ether; about 1% to about 20% by weight of diisopropyl adipate; and about 0.5% to about 8% by weight of a compound of formula (I).

[0239] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 80% by weight of polyalkylene glycol; about 15% to about 35% by weight of diethylene glycol monoethyl ether; about 1% to about 20% by weight of diisopropyl adipate; and about 0.9% to about 8% by weight of a compound of formula (I).

[0240] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of polyalkylene glycol; about 15% to about 30% by weight of diethylene glycol monoethyl ether; about 1% to about 15% by weight of diisopropyl adipate; and about 1% to about 7.9% by weight of a compound of formula (I).

[0241] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of polyalkylene glycol; about 15% to about 30% by weight of diethylene glycol monoethyl ether; about 1% to about 15% by weight of diisopropyl adipate; and about 1.9% to about 7% by weight of a compound of formula (I).

[0242] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of polyalkylene glycol; about 15% to about 30% by weight of diethylene glycol monoethyl ether; about 5% to about 15% by weight of diisopropyl adipate; and about 1.9% to about 5% by weight of a compound of formula (I).

[0243] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of polyalkylene glycol; about 15% to about 30% by weight of diethylene glycol monoethyl ether; about 5% to about 15% by weight of diisopropyl adipate; and about 1.9% to about 2.5% by weight of a compound of formula (I).

[0244] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 65% by weight of polyalkylene glycol; about 19% to about 30% by weight of diethylene glycol monoethyl ether; about 7% to about 13% by weight of diisopropyl adipate; and about 1.9% to about 2.5% by weight of a compound of formula (I).

[0245] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 65% by weight of polyalkylene glycol; about 20% to about 30% by weight of diethylene glycol monoethyl ether; about 7% to about 13% by weight of diisopropyl adipate; and about 1.9% to about 2.5% by weight of a compound of formula (I).

[0246] In some embodiments, the topical pharmaceutical composition comprises about 50% to about 60% by weight of polyalkylene glycol; about 20% to about 25% by weight of diethylene glycol monoethyl ether; about 9% to about 11% by weight of diisopropyl adipate; and about 1.9% to about 2.5% by weight of a compound of formula (I).

[0247] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 80% by weight of PEG, preferably PEG400; about 15% to about 35% by weight of diethylene glycol monoethyl ether; about 1% to about 20% by weight of diisopropyl adipate; and about 0.1% to about 8% by weight of compound 1.

[0248] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 80% by weight of PEG, preferably PEG400; about 15% to about 35% by weight of diethylene glycol monoethyl ether; about 1% to about 20% by weight of diisopropyl adipate; and about 0.5% to about 8% by weight of compound 1.

[0249] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 80% by weight of PEG, preferably PEG400; about 15% to about 35% by weight of diethylene glycol monoethyl ether; about 1% to about 20% by weight of diisopropyl adipate; and about 0.9% to about 8% by weight of compound 1.

[0250] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of PEG, preferably PEG400; about 15% to about 30% by weight of diethylene glycol monoethyl ether; about 1% to about 15% by weight of diisopropyl adipate; and about 1% to about 7.9% by weight of compound 1.

[0251] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of PEG, preferably PEG400; about 15% to about 30% by weight of diethylene glycol monoethyl ether; about 1% to about 15% by weight of diisopropyl adipate; and about 1.9% to about 7% by weight of compound 1.

[0252] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of PEG, preferably PEG400; about 15% to about 30% by weight of diethylene glycol monoethyl ether; about 5% to about 15% by weight of diisopropyl adipate; and about 1.9% to about 5% by weight of compound 1.

[0253] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of PEG, preferably PEG400; about 15% to about 30% by weight of diethylene glycol monoethyl ether; about 5% to about 15% by weight of diisopropyl adipate; and about 1.9% to about 2.5% by weight of compound 1.

[0254] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 65% by weight of PEG, preferably PEG400; about 19% to about 30% by weight of diethylene glycol monoethyl ether; about 7% to about 13% by weight of diisopropyl adipate; and about 1.9% to about 2.5% by weight of compound 1.

[0255] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 65% by weight of PEG, preferably PEG400; about 20% to about 30% by weight of diethylene glycol monoethyl ether; about 7% to about 13% by weight of diisopropyl adipate; and about 1.9% to about 2.5% by weight of compound 1.

[0256] In some embodiments, the topical pharmaceutical composition comprises about 50% to about 60% by weight of PEG, preferably PEG400; about 20% to about 25% by weight of diethylene glycol monoethyl ether; about 9% to about 11% by weight of diisopropyl adipate; and about 1.9% to about 2.5% by weight of compound 1.

[0257] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 80% by weight of polyalkylene glycol; about 15% to about 35% by weight of diethylene glycol monoethyl ether; about 1% to about 20% by weight of diisopropyl adipate; about 1% to about 10% by weight of glycerol; and about 0.1% to about 8% by weight of a compound of formula (I).

[0258] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 80% by weight of polyalkylene glycol; about 15% to about 35% by weight of diethylene glycol monoethyl ether; about 1% to about 20% by weight of diisopropyl adipate; about 1% to about 10% by weight of glycerol; and about 0.5% to about 8% by weight of a compound of formula (I).

[0259] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 80% by weight of polyalkylene glycol; about 15% to about 35% by weight of diethylene glycol monoethyl ether; about 1% to about 20% by weight of diisopropyl adipate; about 1% to about 10% by weight of glycerol; and about 0.9% to about 8% by weight of a compound of formula (I).

[0260] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of polyalkylene glycol; about 15% to about 30% by weight of diethylene glycol monoethyl ether; about 1% to about 15% by weight of diisopropyl adipate; about 1% to about 10% by weight of glycerin; and about 1% to about 7.9% by weight of a compound of formula (I).

[0261] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of polyalkylene glycol; about 15% to about 30% by weight of diethylene glycol monoethyl ether; about 1% to about 15% by weight of diisopropyl adipate; about 1% to about 10% by weight of glycerin; and about 1.9% to about 7% by weight of a compound of formula (I).

[0262] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of polyalkylene glycol; about 15% to about 30% by weight of diethylene glycol monoethyl ether; about 5% to about 15% by weight of diisopropyl adipate; about 3% to about 8% by weight of glycerol; and about 1.9% to about 5% by weight of a compound of formula (I).

[0263] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of polyalkylene glycol; about 15% to about 30% by weight of diethylene glycol monoethyl ether; about 5% to about 15% by weight of diisopropyl adipate; about 3% to about 8% by weight of glycerol; and about 1.9% to about 2.5% by weight of a compound of formula (I).

[0264] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 65% by weight of polyalkylene glycol; about 19% to about 30% by weight of diethylene glycol monoethyl ether; about 7% to about 13% by weight of diisopropyl adipate; about 3% to about 8% by weight of glycerol; and about 1.9% to about 2.5% by weight of a compound of formula (I).

[0265] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 65% by weight of polyalkylene glycol; about 20% to about 30% by weight of diethylene glycol monoethyl ether; about 7% to about 13% by weight of diisopropyl adipate; about 4% to about 6% by weight of glycerol; and about 1.9% to about 2.5% by weight of a compound of formula (I).

[0266] In some embodiments, the topical pharmaceutical composition comprises about 50% to about 60% by weight of polyalkylene glycol; about 20% to about 25% by weight of diethylene glycol monoethyl ether; about 9% to about 11% by weight of diisopropyl adipate; about 4% to about 6% by weight of glycerol; and about 1.9% to about 2.5% by weight of a compound of formula (I).

[0267] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 80% by weight of PEG, preferably PEG400; about 15% to about 35% by weight of diethylene glycol monoethyl ether; about 1% to about 20% by weight of diisopropyl adipate; about 1% to about 10% by weight of glycerol; and about 0.1% to about 8% by weight of compound 1.

[0268] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 80% by weight of PEG, preferably PEG400; about 15% to about 35% by weight of diethylene glycol monoethyl ether; about 1% to about 20% by weight of diisopropyl adipate; about 1% to about 10% by weight of glycerol; and about 0.5% to about 8% by weight of compound 1.

[0269] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 80% by weight of PEG, preferably PEG400; about 15% to about 35% by weight of diethylene glycol monoethyl ether; about 1% to about 20% by weight of diisopropyl adipate; about 1% to about 10% by weight of glycerol; and about 0.9% to about 8% by weight of compound 1.

[0270] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of PEG, preferably PEG400; about 15% to about 30% by weight of diethylene glycol monoethyl ether; about 1% to about 15% by weight of diisopropyl adipate; about 1% to about 10% by weight of glycerol; and about 1% to about 7.9% by weight of compound 1.

[0271] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of PEG, preferably PEG400; about 15% to about 30% by weight of diethylene glycol monoethyl ether; about 1% to about 15% by weight of diisopropyl adipate; about 1% to about 10% by weight of glycerol; and about 1.9% to about 7% by weight of compound 1.

[0272] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of PEG, preferably PEG400; about 15% to about 30% by weight of diethylene glycol monoethyl ether; about 5% to about 15% by weight of diisopropyl adipate; about 3% to about 8% by weight of glycerol; and about 1.9% to about 5% by weight of compound 1.

[0273] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of PEG, preferably PEG400; about 15% to about 30% by weight of diethylene glycol monoethyl ether; about 5% to about 15% by weight of diisopropyl adipate; about 3% to about 8% by weight of glycerol; and about 1.9% to about 2.5% by weight of compound 1.

[0274] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 65% by weight of PEG, preferably PEG400; about 19% to about 30% by weight of diethylene glycol monoethyl ether; about 7% to about 13% by weight of diisopropyl adipate; about 3% to about 8% by weight of glycerol; and about 1.9% to about 2.5% by weight of compound 1.

[0275] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 65% by weight of PEG, preferably PEG400; about 20% to about 30% by weight of diethylene glycol monoethyl ether; about 7% to about 13% by weight of diisopropyl adipate; about 4% to about 6% by weight of glycerol; and about 1.9% to about 2.5% by weight of compound 1.

[0276] In some embodiments, the topical pharmaceutical composition comprises about 50% to about 60% by weight of PEG, preferably PEG400; about 20% to about 25% by weight of diethylene glycol monoethyl ether; about 9% to about 11% by weight of diisopropyl adipate; about 4% to about 6% by weight of glycerol; and about 1.9% to about 2.5% by weight of compound 1.

[0277] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 80% by weight of polyalkylene glycol; about 15% to about 35% by weight of diethylene glycol monoethyl ether; about 1% to about 20% by weight of diisopropyl adipate; about 1% to about 10% by weight of glycerin; about 0.1% to about 10% by weight of hydroxypropyl cellulose; and about 0.1% to about 8% by weight of a compound of formula (I).

[0278] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 80% by weight of polyalkylene glycol; about 15% to about 35% by weight of diethylene glycol monoethyl ether; about 1% to about 20% by weight of diisopropyl adipate; about 1% to about 10% by weight of glycerin; about 0.1% to about 10% by weight of hydroxypropyl cellulose; and about 0.5% to about 8% by weight of a compound of formula (I).

[0279] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 80% by weight of polyalkylene glycol; about 15% to about 35% by weight of diethylene glycol monoethyl ether; about 1% to about 20% by weight of diisopropyl adipate; about 1% to about 10% by weight of glycerin; about 0.1% to about 10% by weight of hydroxypropyl cellulose; and about 0.9% to about 8% by weight of a compound of formula (I).

[0280] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of polyalkylene glycol; about 15% to about 30% by weight of diethylene glycol monoethyl ether; about 1% to about 15% by weight of diisopropyl adipate; about 1% to about 10% by weight of glycerin; about 0.1% to about 10% by weight of hydroxypropyl cellulose; and about 1% to about 7.9% by weight of a compound of formula (I).

[0281] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of polyalkylene glycol; about 15% to about 30% by weight of diethylene glycol monoethyl ether; about 1% to about 15% by weight of diisopropyl adipate; about 1% to about 10% by weight of glycerin; about 0.5% to about 5% by weight of hydroxypropyl cellulose; and about 1.9% to about 7% by weight of a compound of formula (I).

[0282] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of polyalkylene glycol; about 15% to about 30% by weight of diethylene glycol monoethyl ether; about 5% to about 15% by weight of diisopropyl adipate; about 3% to about 8% by weight of glycerin; about 0.5% to about 5% by weight of hydroxypropyl cellulose; and about 1.9% to about 5% by weight of a compound of formula (I).

[0283] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of polyalkylene glycol; about 15% to about 30% by weight of diethylene glycol monoethyl ether; about 5% to about 15% by weight of diisopropyl adipate; about 3% to about 8% by weight of glycerin; about 0.5% to about 2.5% by weight of hydroxypropyl cellulose; and about 1.9% to about 2.5% by weight of a compound of formula (I).

[0284] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 65% by weight of polyalkylene glycol; about 19% to about 30% by weight of diethylene glycol monoethyl ether; about 7% to about 13% by weight of diisopropyl adipate; about 3% to about 8% by weight of glycerin; about 0.5% to about 2.5% by weight of hydroxypropyl cellulose; and about 1.9% to about 2.5% by weight of a compound of formula (I).

[0285] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 65% by weight of polyalkylene glycol; about 20% to about 30% by weight of diethylene glycol monoethyl ether; about 7% to about 13% by weight of diisopropyl adipate; about 4% to about 6% by weight of glycerin; about 0.5% to about 1.5% by weight of hydroxypropyl cellulose; and about 1.9% to about 2.5% by weight of a compound of formula (I).

[0286] In some embodiments, the topical pharmaceutical composition comprises about 50% to about 60% by weight of polyalkylene glycol; about 20% to about 25% by weight of diethylene glycol monoethyl ether; about 9% to about 11% by weight of diisopropyl adipate; about 4% to about 6% by weight of glycerin; about 0.5% to about 1.5% by weight of hydroxypropyl cellulose; and about 1.9% to about 2.5% by weight of a compound of formula (I).

[0287] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 80% by weight of PEG, preferably PEG400; about 15% to about 35% by weight of diethylene glycol monoethyl ether; about 1% to about 20% by weight of diisopropyl adipate; about 1% to about 10% by weight of glycerol; about 0.1% to about 10% by weight of hydroxypropyl cellulose; and about 0.1% to about 8% by weight of compound 1.

[0288] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 80% by weight of PEG, preferably PEG400; about 15% to about 35% by weight of diethylene glycol monoethyl ether; about 1% to about 20% by weight of diisopropyl adipate; about 1% to about 10% by weight of glycerol; about 0.1% to about 10% by weight of hydroxypropyl cellulose; and about 0.5% to about 8% by weight of compound 1.

[0289] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 80% by weight of PEG, preferably PEG400; about 15% to about 35% by weight of diethylene glycol monoethyl ether; about 1% to about 20% by weight of diisopropyl adipate; about 1% to about 10% by weight of glycerol; about 0.1% to about 10% by weight of hydroxypropyl cellulose; and about 0.9% to about 8% by weight of compound 1.

[0290] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of PEG, preferably PEG400; about 15% to about 30% by weight of diethylene glycol monoethyl ether; about 1% to about 15% by weight of diisopropyl adipate; about 1% to about 10% by weight of glycerin; about 0.1% to about 10% by weight of hydroxypropyl cellulose; and about 1% to about 7.9% by weight of compound 1.

[0291] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of PEG, preferably PEG400; about 15% to about 30% by weight of diethylene glycol monoethyl ether; about 1% to about 15% by weight of diisopropyl adipate; about 1% to about 10% by weight of glycerol; about 0.5% to about 5% by weight of hydroxypropyl cellulose; and about 1.9% to about 7% by weight of compound 1.

[0292] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of PEG, preferably PEG400; about 15% to about 30% by weight of diethylene glycol monoethyl ether; about 5% to about 15% by weight of diisopropyl adipate; about 3% to about 8% by weight of glycerol; about 0.5% to about 5% by weight of hydroxypropyl cellulose; and about 1.9% to about 5% by weight of compound 1.

[0293] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 75% by weight of PEG, preferably PEG400; about 15% to about 30% by weight of diethylene glycol monoethyl ether; about 5% to about 15% by weight of diisopropyl adipate; about 3% to about 8% by weight of glycerol; about 0.5% to about 2.5% by weight of hydroxypropyl cellulose; and about 1.9% to about 2.5% by weight of compound 1.

[0294] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 65% by weight of PEG, preferably PEG400; about 19% to about 30% by weight of diethylene glycol monoethyl ether; about 7% to about 13% by weight of diisopropyl adipate; about 3% to about 8% by weight of glycerol; about 0.5% to about 2.5% by weight of hydroxypropyl cellulose; and about 1.9% to about 2.5% by weight of compound 1.

[0295] In some embodiments, the topical pharmaceutical composition comprises about 45% to about 65% by weight of PEG, preferably PEG400; about 20% to about 30% by weight of diethylene glycol monoethyl ether; about 7% to about 13% by weight of diisopropyl adipate; about 4% to about 6% by weight of glycerol; about 0.5% to about 1.5% by weight of hydroxypropyl cellulose; and about 1.9% to about 2.5% by weight of compound 1.

[0296] In some embodiments, the topical pharmaceutical composition comprises about 50% to about 60% by weight of PEG, preferably PEG400; about 20% to about 25% by weight of diethylene glycol monoethyl ether; about 9% to about 11% by weight of diisopropyl adipate; about 4% to about 6% by weight of glycerol; about 0.5% to about 1.5% by weight of hydroxypropyl cellulose; and about 1.9% to about 2.5% by weight of compound 1.

[0297] In some embodiments, the weight ratio of polyalkylene glycol to diethylene glycol monoethyl ether in the topical pharmaceutical composition is about 5:1. In some embodiments, the weight ratio of polyalkylene glycol to diethylene glycol monoethyl ether in the topical pharmaceutical composition is about 4.5:1. In some embodiments, the weight ratio of polyalkylene glycol to diethylene glycol monoethyl ether in the topical pharmaceutical composition is about 4:1. In some embodiments, the weight ratio of polyalkylene glycol to diethylene glycol monoethyl ether in the topical pharmaceutical composition is about 3.5:1. In some embodiments, the weight ratio of polyalkylene glycol to diethylene glycol monoethyl ether in the topical pharmaceutical composition is about 3:1. In some embodiments, the weight ratio of polyalkylene glycol to diethylene glycol monoethyl ether in the topical pharmaceutical composition is about 2.5:1. In some embodiments, the weight ratio of polyalkylene glycol to diethylene glycol monoethyl ether in the topical pharmaceutical composition is about 2.4:1. In some embodiments, the weight ratio of polyalkylene glycol to diethylene glycol monoethyl ether in the topical pharmaceutical composition is about 2:1.

[0298] In some embodiments, the weight ratio of polyalkylene glycol to diethylene glycol monoethyl ether in the topical pharmaceutical composition is from about 1:1 to about 5:1. In some embodiments, the weight ratio of polyalkylene glycol to diethylene glycol monoethyl ether in the topical pharmaceutical composition is from about 1.5:1 to about 4.5:1. In some embodiments, the weight ratio of polyalkylene glycol to diethylene glycol monoethyl ether in the topical pharmaceutical composition is from about 2:1 to about 4:1. In some embodiments, the weight ratio of polyalkylene glycol to diethylene glycol monoethyl ether in the topical pharmaceutical composition is from about 2:1 to about 3.5:1. In some embodiments, the weight ratio of polyalkylene glycol to diethylene glycol monoethyl ether in the topical pharmaceutical composition is from about 2:1 to about 3:1.

[0299] In some embodiments, the weight ratio of PEG 400 to diethylene glycol monoethyl ether in the topical pharmaceutical composition is about 5:1. In some embodiments, the weight ratio of PEG 400 to diethylene glycol monoethyl ether in the topical pharmaceutical composition is about 4.5:1. In some embodiments, the weight ratio of PEG 400 to diethylene glycol monoethyl ether in the topical pharmaceutical composition is about 4:1. In some embodiments, the weight ratio of PEG 400 to diethylene glycol monoethyl ether in the topical pharmaceutical composition is about 3.5:1. In some embodiments, the weight ratio of PEG 400 to diethylene glycol monoethyl ether in the topical pharmaceutical composition is about 3:1. In some embodiments, the weight ratio of PEG 400 to diethylene glycol monoethyl ether in the topical pharmaceutical composition is about 2.5:1. In some embodiments, the weight ratio of PEG 400 to diethylene glycol monoethyl ether in the topical pharmaceutical composition is about 2:1.

[0300] In some embodiments, the weight ratio of PEG 400 to diethylene glycol monoethyl ether in the topical pharmaceutical composition is from about 1:1 to about 5:1. In some embodiments, the weight ratio of PEG 400 to diethylene glycol monoethyl ether in the topical pharmaceutical composition is from about 1.5:1 to about 4.5:1. In some embodiments, the weight ratio of PEG 400 to diethylene glycol monoethyl ether in the topical pharmaceutical composition is from about 2:1 to about 4:1. In some embodiments, the weight ratio of PEG 400 to diethylene glycol monoethyl ether in the topical pharmaceutical composition is from about 2:1 to about 3:1.

[0301] In some preferred embodiments, the composition comprises:

[0302] At least about 6.0% by weight of compound 1;

[0303] At least about 55% by weight of polyethylene glycol, preferably PEG400;

[0304] At least about 23% by weight of diethylene glycol monoethyl ether;

[0305] At least approximately 4.5% by weight of glycerin;

[0306] At least about 9% by weight of diisopropyl adipate; and

[0307] About 1% by weight of hydroxypropyl cellulose. In a preferred embodiment, the composition contains less than 1% water, preferably less than 0.1% water. In a preferred embodiment, the composition contains less than 1% ethanol, preferably less than 0.1% ethanol.

[0308] In some preferred embodiments, the composition comprises:

[0309] 6.3% by weight of compound 1;

[0310] 55.25% by weight of polyethylene glycol, preferably PEG400;

[0311] 23.41% by weight of diethylene glycol monoethyl ether;

[0312] 4.68% by weight of glycerin;

[0313] 9.36% by weight of diisopropyl adipate; and

[0314] 1% by weight of hydroxypropyl cellulose. In a preferred embodiment, the composition contains less than 1% water, preferably less than 0.1% water. In a preferred embodiment, the composition contains less than 1% ethanol, preferably less than 0.1% ethanol.

[0315] In some preferred embodiments, the composition comprises:

[0316] At least about 2.0% by weight of compound 1;

[0317] At least about 55% by weight of polyethylene glycol, preferably PEG400;

[0318] At least about 23% by weight of diethylene glycol monoethyl ether;

[0319] At least approximately 4.5% by weight of glycerin;

[0320] At least about 9% by weight of diisopropyl adipate; and

[0321] About 1% by weight of hydroxypropyl cellulose. In a preferred embodiment, the composition contains less than 1% water, preferably less than 0.1% water. In a preferred embodiment, the composition contains less than 1% ethanol, preferably less than 0.1% ethanol.

[0322] In some preferred embodiments, the composition comprises:

[0323] 2.0 wt% of compound 1;

[0324] 57.81% by weight of polyethylene glycol, preferably PEG400;

[0325] 24.50% by weight of diethylene glycol monoethyl ether;

[0326] 4.89% by weight of glycerol (anhydrous);

[0327] 9.80% by weight of diisopropyl adipate; and

[0328] 1% by weight of hydroxypropyl cellulose. In a preferred embodiment, the composition contains less than 1% water, preferably less than 0.1% water. In a preferred embodiment, the composition contains less than 1% ethanol, preferably less than 0.1% ethanol. In a preferred embodiment, the composition does not contain DMSO.

[0329] In some preferred embodiments, the composition comprises:

[0330] About 1.5% by weight to about 2.5% by weight, preferably about 1.9% by weight to about 2.5% by weight of compound 1;

[0331] About 45% to about 75% by weight of polyethylene glycol, preferably PEG400;

[0332] From about 15% by weight to about 30% by weight of diethylene glycol monoethyl ether;

[0333] From about 1% to about 10% by weight of glycerin;

[0334] about 5% by weight to about 15% by weight of diisopropyl adipate; and

[0335] Hydroxypropyl cellulose, approximately 0.1% to approximately 10% by weight.

[0336] On the one hand, this disclosure provides a topical aqueous pharmaceutical composition.

[0337] In some embodiments, the topical aqueous pharmaceutical composition comprises about 45% to about 80% by weight of polyalkylene glycol; about 10% to about 30% by weight of diethylene glycol monoethyl ether; about 1% to about 10% by weight of diisopropyl adipate; about 1% to about 10% by weight of glycerol; about 1% to about 20% by weight of water; and about 0.1% by weight (preferably about 0.5% by weight) to about 8% by weight of a compound of formula (I).

[0338] In some embodiments, the topical aqueous pharmaceutical composition comprises about 45% to about 80% by weight of polyalkylene glycol; about 10% to about 30% by weight of diethylene glycol monoethyl ether; about 1% to about 10% by weight of diisopropyl adipate; about 1% to about 10% by weight of glycerol; about 1% to about 20% by weight of water; and about 0.9% to about 8% by weight of a compound of formula (I).

[0339] In some embodiments, the topical aqueous pharmaceutical composition comprises about 45% to about 75% by weight of polyalkylene glycol; about 10% to about 30% by weight of diethylene glycol monoethyl ether; about 1% to about 10% by weight of diisopropyl adipate; about 1% to about 10% by weight of glycerol; about 1% to about 20% by weight of water; and about 1% to about 7.9% by weight of a compound of formula (I).

[0340] In some embodiments, the topical aqueous pharmaceutical composition comprises about 45% to about 75% by weight of polyalkylene glycol; about 10% to about 30% by weight of diethylene glycol monoethyl ether; about 1% to about 10% by weight of diisopropyl adipate; about 1% to about 10% by weight of glycerin; about 1% to about 15% by weight of water; and about 1.9% to about 7% by weight of a compound of formula (I).

[0341] In some embodiments, the topical aqueous pharmaceutical composition comprises about 45% to about 75% by weight of polyalkylene glycol; about 10% to about 30% by weight of diethylene glycol monoethyl ether; about 2% to about 8% by weight of diisopropyl adipate; about 3% to about 8% by weight of glycerol; about 1% to about 15% by weight of water; and about 1.9% to about 5% by weight of a compound of formula (I).

[0342] In some embodiments, the topical aqueous pharmaceutical composition comprises about 45% to about 75% by weight of polyalkylene glycol; about 15% to about 25% by weight of diethylene glycol monoethyl ether; about 2% to about 8% by weight of diisopropyl adipate; about 3% to about 8% by weight of glycerol; about 5% to about 15% by weight of water; and about 1.9% to about 4% by weight of a compound of formula (I).

[0343] In some embodiments, the topical aqueous pharmaceutical composition comprises about 45% to about 65% by weight of polyalkylene glycol; about 15% to about 25% by weight of diethylene glycol monoethyl ether; about 2% to about 9% by weight of diisopropyl adipate; about 3% to about 8% by weight of glycerol; about 5% to about 15% by weight of water; and about 1.9% to about 4% by weight of a compound of formula (I).

[0344] In some embodiments, the topical aqueous pharmaceutical composition comprises about 45% to about 65% by weight of polyalkylene glycol; about 15% to about 25% by weight of diethylene glycol monoethyl ether; about 3% to about 6% by weight of diisopropyl adipate; about 4% to about 6% by weight of glycerol; about 9% to about 11% by weight of water; and about 1.9% to about 4% by weight of a compound of formula (I).

[0345] In some embodiments, the topical aqueous pharmaceutical composition comprises about 50% to about 60% by weight of polyalkylene glycol; about 18% to about 22% by weight of diethylene glycol monoethyl ether; about 3% to about 6% by weight of diisopropyl adipate; about 4% to about 6% by weight of glycerol; about 9% to about 11% by weight of water; and about 1.9% to about 4% by weight of a compound of formula (I).

[0346] In some embodiments, the topical aqueous pharmaceutical composition comprises about 45% to about 80% PEG, preferably PEG400; about 10% to about 30% diethylene glycol monoethyl ether; about 1% to about 10% diisopropyl adipate; about 1% to about 10% glycerol; about 1% to about 20% water; and about 0.1% (preferably about 0.5%) to about 8% compound 1.

[0347] In some embodiments, the topical aqueous pharmaceutical composition comprises about 45% to about 80% PEG, preferably PEG400; about 10% to about 30% diethylene glycol monoethyl ether; about 1% to about 10% diisopropyl adipate; about 1% to about 10% glycerol; about 1% to about 20% water; and about 0.9% to about 8% compound 1.

[0348] In some embodiments, the topical aqueous pharmaceutical composition comprises about 45% to about 75% by weight of PEG, preferably PEG400; about 10% to about 30% by weight of diethylene glycol monoethyl ether; about 1% to about 10% by weight of diisopropyl adipate; about 1% to about 10% by weight of glycerol; about 1% to about 20% by weight of water; and about 1% to about 7.9% by weight of compound 1.

[0349] In some embodiments, the topical aqueous pharmaceutical composition comprises about 45% to about 75% by weight of PEG, preferably PEG400; about 10% to about 30% by weight of diethylene glycol monoethyl ether; about 1% to about 10% by weight of diisopropyl adipate; about 1% to about 10% by weight of glycerol; about 1% to about 15% by weight of water; and about 1.9% to about 7% by weight of compound 1.

[0350] In some embodiments, the topical aqueous pharmaceutical composition comprises about 45% to about 75% by weight of PEG, preferably PEG400; about 10% to about 30% by weight of diethylene glycol monoethyl ether; about 2% to about 8% by weight of diisopropyl adipate; about 3% to about 8% by weight of glycerol; about 1% to about 15% by weight of water; and about 1.9% to about 5% by weight of compound 1.

[0351] In some embodiments, the topical aqueous pharmaceutical composition comprises about 45% to about 75% by weight of PEG, preferably PEG400; about 15% to about 25% by weight of diethylene glycol monoethyl ether; about 2% to about 8% by weight of diisopropyl adipate; about 3% to about 8% by weight of glycerol; about 5% to about 15% by weight of water; and about 1.9% to about 4% by weight of compound 1.

[0352] In some embodiments, the topical aqueous pharmaceutical composition comprises about 45% to about 65% by weight of PEG, preferably PEG400; about 15% to about 25% by weight of diethylene glycol monoethyl ether; about 2% to about 9% by weight of diisopropyl adipate; about 3% to about 8% by weight of glycerol; about 5% to about 15% by weight of water; and about 1.9% to about 4% by weight of compound 1.

[0353] In some embodiments, the topical aqueous pharmaceutical composition comprises about 45% to about 65% by weight of PEG, preferably PEG400; about 15% to about 25% by weight of diethylene glycol monoethyl ether; about 3% to about 6% by weight of diisopropyl adipate; about 4% to about 6% by weight of glycerol; about 9% to about 11% by weight of water; and about 1.9% to about 4% by weight of compound 1.

[0354] In some embodiments, the topical aqueous pharmaceutical composition comprises about 50% to about 60% by weight of PEG, preferably PEG400; about 18% to about 22% by weight of diethylene glycol monoethyl ether; about 3% to about 6% by weight of diisopropyl adipate; about 4% to about 6% by weight of glycerol; about 9% to about 11% by weight of water; and about 1.9% to about 4% by weight of compound 1.

[0355] In some embodiments, the topical aqueous pharmaceutical composition comprises:

[0356] At least about 3% by weight of compound 1;

[0357] At least approximately 9% by weight water;

[0358] At least about 54% by weight of polyethylene glycol, preferably PEG400;

[0359] At least about 19% by weight of diethylene glycol monoethyl ether;

[0360] At least approximately 4% by weight of glycerin;

[0361] At least about 4% by weight of diisopropyl adipate;

[0362] At least about 2% by weight of benzyl alcohol; and

[0363] About 1% by weight of polyacrylic acid. In a preferred embodiment, the composition contains less than about 1% ethanol, preferably less than about 0.1% ethanol.

[0364] In some embodiments, the topical aqueous pharmaceutical composition comprises:

[0365] 3.2% by weight of compound 1;

[0366] 9.64% by weight water;

[0367] 54.9% by weight of polyethylene glycol, preferably PEG400;

[0368] 19.26% by weight of diethylene glycol monoethyl ether;

[0369] 5% by weight of glycerin;

[0370] 5% by weight of diisopropyl adipate;

[0371] 2% by weight of benzyl alcohol; and

[0372] 1% by weight of polyacrylic acid. In a preferred embodiment, the composition contains less than 1% ethanol, preferably less than 0.1% ethanol.

[0373] In some embodiments, the topical aqueous pharmaceutical composition comprises:

[0374] At least about 3% by weight of compound 1;

[0375] At least approximately 9% by weight water;

[0376] At least about 57% by weight of polyethylene glycol, preferably PEG400;

[0377] At least about 21% by weight of diethylene glycol monoethyl ether;

[0378] Approximately 3% by weight of glycerin;

[0379] Approximately 1.5% by weight of oleyl alcohol;

[0380] Approximately 2% by weight of benzyl alcohol; and

[0381] Approximately 1% by weight of polyacrylic acid. In a preferred embodiment, the composition contains less than 1% ethanol, preferably less than 0.1% ethanol.

[0382] In some embodiments, the topical aqueous pharmaceutical composition comprises:

[0383] 3.4% by weight of compound 1;

[0384] 9.52% by weight water;

[0385] 57.67% by weight of polyethylene glycol, preferably PEG400;

[0386] 21.91% by weight of diethylene glycol monoethyl ether;

[0387] 3% by weight of glycerin;

[0388] 1.5% by weight of oleyl alcohol;

[0389] 2% by weight of benzyl alcohol; and

[0390] 1% by weight of polyacrylic acid. In a preferred embodiment, the composition contains less than 1% ethanol, preferably less than 0.1% ethanol.

[0391] In some preferred embodiments, the composition comprises:

[0392] (i) at least about 1.9% by weight of compound 1;

[0393] At least about 55% by weight of polyethylene glycol, preferably PEG400;

[0394] At least about 23% by weight of diethylene glycol monoethyl ether;

[0395] At least approximately 4.5% by weight of glycerin;

[0396] At least about 9% by weight of diisopropyl adipate; and

[0397] Approximately 1% by weight of hydroxypropyl cellulose;

[0398] (ii) at least about 3% by weight of compound 1;

[0399] At least approximately 9% by weight water;

[0400] At least about 54% by weight of polyethylene glycol, preferably PEG400;

[0401] At least about 19% by weight of diethylene glycol monoethyl ether;

[0402] At least approximately 4% by weight of glycerin;

[0403] At least about 4% by weight of diisopropyl adipate;

[0404] At least about 2% by weight of benzyl alcohol; and

[0405] Approximately 1% by weight of polyacrylic acid; or

[0406] (iii) at least about 3% by weight of compound 1;

[0407] At least approximately 9% by weight water;

[0408] At least about 57% by weight of polyethylene glycol, preferably PEG400;

[0409] At least about 21% by weight of diethylene glycol monoethyl ether;

[0410] Approximately 3% by weight of glycerin;

[0411] Approximately 1.5% by weight of oleyl alcohol;

[0412] Approximately 2% by weight of benzyl alcohol; and

[0413] Approximately 1% by weight of polyacrylic acid. In a preferred embodiment, the composition contains less than 1% ethanol, preferably less than 0.1% ethanol.

[0414] In some preferred embodiments, the composition comprises:

[0415] (i) at least about 1.9% by weight of compound 1;

[0416] At least about 55% by weight of polyethylene glycol, preferably PEG400;

[0417] At least about 23% by weight of diethylene glycol monoethyl ether;

[0418] At least approximately 4.5% by weight of glycerin;

[0419] At least about 9% by weight of diisopropyl adipate; and

[0420] Approximately 1% by weight of hydroxypropyl cellulose; or

[0421] (ii) at least about 3% by weight of compound 1;

[0422] At least approximately 9% by weight water;

[0423] At least about 54% by weight of polyethylene glycol, preferably PEG400;

[0424] At least about 19% by weight of diethylene glycol monoethyl ether;

[0425] At least approximately 4% by weight of glycerin;

[0426] At least about 4% by weight of diisopropyl adipate;

[0427] At least about 2% by weight of benzyl alcohol; and

[0428] Approximately 1% by weight of polyacrylic acid. In a preferred embodiment, the composition contains less than 1% ethanol, preferably less than 0.1% ethanol.

[0429] In some preferred embodiments, the composition comprises:

[0430] (i) at least about 1.9% by weight of compound 1;

[0431] At least about 55% by weight of polyethylene glycol, preferably PEG400;

[0432] At least about 23% by weight of diethylene glycol monoethyl ether;

[0433] At least approximately 4.5% by weight of glycerin;

[0434] At least about 9% by weight of diisopropyl adipate; and

[0435] Approximately 1% by weight of hydroxypropyl cellulose; or

[0436] (ii) at least about 3% by weight of compound 1;

[0437] At least approximately 9% by weight water;

[0438] At least about 57% by weight of polyethylene glycol, preferably PEG400;

[0439] At least about 21% by weight of diethylene glycol monoethyl ether;

[0440] Approximately 3% by weight of glycerin;

[0441] Approximately 1.5% by weight of oleyl alcohol;

[0442] Approximately 2% by weight of benzyl alcohol; and

[0443] Approximately 1% by weight of polyacrylic acid. In a preferred embodiment, the composition contains less than 1% ethanol, preferably less than 0.1% ethanol.

[0444] In some preferred embodiments, the composition comprises:

[0445] (i) at least about 3% by weight of compound 1;

[0446] At least approximately 9% by weight water;

[0447] At least about 54% by weight of polyethylene glycol, preferably PEG400;

[0448] At least about 19% by weight of diethylene glycol monoethyl ether;

[0449] At least approximately 4% by weight of glycerin;

[0450] At least about 4% by weight of diisopropyl adipate;

[0451] At least about 2% by weight of benzyl alcohol; and

[0452] Approximately 1% by weight of polyacrylic acid; or

[0453] (ii) at least about 3% by weight of compound 1;

[0454] At least approximately 9% by weight water;

[0455] At least about 57% by weight of polyethylene glycol, preferably PEG400;

[0456] At least about 21% by weight of diethylene glycol monoethyl ether;

[0457] Approximately 3% by weight of glycerin;

[0458] Approximately 1.5% by weight of oleyl alcohol;

[0459] Approximately 2% by weight of benzyl alcohol; and

[0460] Approximately 1% by weight of polyacrylic acid. In a preferred embodiment, the composition contains less than 1% ethanol, preferably less than 0.1% ethanol.

[0461] In some preferred embodiments, the composition comprises:

[0462] (i) 2.0 wt% of compound 1;

[0463] 57.81% by weight of polyethylene glycol, preferably PEG400;

[0464] 23.41% by weight of diethylene glycol monoethyl ether;

[0465] 4.68% by weight of glycerin;

[0466] 9.36% by weight of diisopropyl adipate; and

[0467] 1% by weight of hydroxypropyl cellulose;

[0468] (ii) 3.2% by weight of compound 1;

[0469] 9.64% by weight water;

[0470] 54.9% by weight of polyethylene glycol, preferably PEG400;

[0471] 19.26% by weight of diethylene glycol monoethyl ether;

[0472] 5% by weight of glycerin;

[0473] 5% by weight of diisopropyl adipate;

[0474] 2% by weight of benzyl alcohol; and

[0475] 1% by weight of polyacrylic acid; or

[0476] (iii) 3.4% by weight of compound 1;

[0477] 9.52% by weight water;

[0478] 57.67% by weight of polyethylene glycol, preferably PEG400;

[0479] 21.91% by weight of diethylene glycol monoethyl ether;

[0480] 3% by weight of glycerin;

[0481] 1.5% by weight of oleyl alcohol;

[0482] 2% by weight of benzyl alcohol; and

[0483] 1% by weight of polyacrylic acid. In a preferred embodiment, the composition contains less than 1% ethanol, preferably less than 0.1% ethanol.

[0484] In some preferred embodiments, the composition comprises:

[0485] (i) 2.0 wt% of compound 1;

[0486] 57.81% by weight of polyethylene glycol, preferably PEG400;

[0487] 23.41% by weight of diethylene glycol monoethyl ether;

[0488] 4.68% by weight of glycerin;

[0489] 9.36% by weight of diisopropyl adipate; and

[0490] 1% by weight of hydroxypropyl cellulose; or

[0491] (ii) 3.2% by weight of compound 1;

[0492] 9.64% by weight water;

[0493] 54.9% by weight of polyethylene glycol, preferably PEG400;

[0494] 19.26% by weight of diethylene glycol monoethyl ether;

[0495] 5% by weight of glycerin;

[0496] 5% by weight of diisopropyl adipate;

[0497] 2% by weight of benzyl alcohol; and

[0498] 1% by weight of polyacrylic acid.

[0499] In a preferred embodiment, the composition contains less than 1% ethanol, preferably less than 0.1% ethanol.

[0500] In some preferred embodiments, the composition comprises:

[0501] (i) 3.2% by weight of compound 1;

[0502] 9.64% by weight water;

[0503] 54.9% by weight of polyethylene glycol, preferably PEG400;

[0504] 19.26% by weight of diethylene glycol monoethyl ether;

[0505] 5% by weight of glycerin;

[0506] 5% by weight of diisopropyl adipate;

[0507] 2% by weight of benzyl alcohol; and

[0508] 1% by weight of polyacrylic acid; or

[0509] (ii) 3.4% by weight of compound 1;

[0510] 9.52% by weight water;

[0511] 57.67% by weight of polyethylene glycol, preferably PEG400;

[0512] 21.91% by weight of diethylene glycol monoethyl ether;

[0513] 3% by weight of glycerin;

[0514] 1.5% by weight of oleyl alcohol;

[0515] 2% by weight of benzyl alcohol; and

[0516] 1% by weight of polyacrylic acid. In a preferred embodiment, the composition contains less than 1% ethanol, preferably less than 0.1% ethanol.

[0517] In some preferred embodiments, the composition comprises:

[0518] (i) 2.0 wt% of compound 1;

[0519] 57.81% by weight of polyethylene glycol, preferably PEG400;

[0520] 23.41% by weight of diethylene glycol monoethyl ether;

[0521] 4.68% by weight of glycerin;

[0522] 9.36% by weight of diisopropyl adipate; and

[0523] 1% by weight of hydroxypropyl cellulose;

[0524] or

[0525] (ii) 3.4% by weight of compound 1;

[0526] 9.52% by weight water;

[0527] 57.67% by weight of polyethylene glycol, preferably PEG400;

[0528] 21.91% by weight of diethylene glycol monoethyl ether;

[0529] 3% by weight of glycerin;

[0530] 1.5% by weight of oleyl alcohol;

[0531] 2% by weight of benzyl alcohol; and

[0532] 1% by weight of polyacrylic acid. In a preferred embodiment, the composition contains less than 1% ethanol, preferably less than 0.1% ethanol.

[0533] In some embodiments, the composition comprises:

[0534] 58.94% by weight of polyethylene glycol 400 (PEG400);

[0535] 24.98% by weight of diethylene glycol monoethyl ether (Transcutol P®);

[0536] 9.99% by weight of diisopropyl adipic acid;

[0537] 4.99% by weight of glycerin, preferably anhydrous glycerin;

[0538] 0.10 wt% of compound 1; and

[0539] 1.00% by weight of hydroxypropyl cellulose. In a preferred embodiment, the composition contains less than 1% water, preferably less than 0.1% water. In a preferred embodiment, the composition contains less than 1% ethanol, preferably less than 0.1% ethanol. In a preferred embodiment, the composition does not contain DMSO.

[0540] In some embodiments, the composition comprises:

[0541] 58.70% by weight of polyethylene glycol 400 (PEG400);

[0542] 24.88% by weight of diethylene glycol monoethyl ether (Transcutol P®);

[0543] 9.95% by weight of diisopropyl adipic acid;

[0544] 4.97% by weight of glycerol, preferably anhydrous glycerol;

[0545] 0.50 wt% of compound 1; and

[0546] 1.00% by weight of hydroxypropyl cellulose. In a preferred embodiment, the composition contains less than 1% water, preferably less than 0.1% water. In a preferred embodiment, the composition contains less than 1% ethanol, preferably less than 0.1% ethanol. In a preferred embodiment, the composition does not contain DMSO.

[0547] In some embodiments, the composition comprises:

[0548] 57.22% by weight of polyethylene glycol 400 (PEG400);

[0549] 24.24% by weight of diethylene glycol monoethyl ether (Transcutol P®);

[0550] 9.70% by weight of diisopropyl adipate;

[0551] 4.84% by weight of glycerol, preferably anhydrous glycerol;

[0552] 3.00 wt% of compound 1; and

[0553] 1.00% by weight of hydroxypropyl cellulose. In a preferred embodiment, the composition contains less than 1% water, preferably less than 0.1% water. In a preferred embodiment, the composition contains less than 1% ethanol, preferably less than 0.1% ethanol. In a preferred embodiment, the composition does not contain DMSO.

[0554] In some embodiments, the topical pharmaceutical composition further comprises one or more other excipients, the pharmaceutically acceptable excipients being selected from: thickeners, stabilizers, antioxidants, chelating agents, oily materials, emulsifiers, penetration enhancers, pH adjusters, preservatives, antimicrobial agents, opacifiers, fragrances, colorants, gelling agents, humectants, surfactants, and combinations thereof.

[0555] In one embodiment, the topical composition comprises one or more other pharmaceutically acceptable excipients selected from: thickeners, stabilizers, antioxidants, pH adjusters, preservatives, antimicrobial agents, and combinations thereof.

[0556] The pharmaceutically acceptable excipients used in the topical compositions of the present invention can function in more than one manner. For example, thickeners can also act as gelling agents.

[0557] In a preferred embodiment, the topical composition comprises one or more other pharmaceutically acceptable excipients, one of which is a thickener. In a preferred embodiment, the topical composition comprises a thickener.

[0558] In a preferred embodiment, the topical composition comprises one or more other pharmaceutically acceptable excipients, one of which is an antioxidant. In a preferred embodiment, the topical composition comprises an antioxidant.

[0559] Antioxidants are known to those skilled in the art, including, for example, butylated hydroxyanisole, butylated hydroxytoluene, vitamin C, vitamin E, vitamin A, lutein, lycopene, retinyl palmitate, potassium metabisulfite, sodium metabisulfite, sodium thiosulfate pentahydrate, 3,4-dihydroxybenzoic acid, propyl gallate, alpha-lipoic acid, ascorbyl palmitate, sodium metabisulfite, ubiquinone, selenium, or combinations thereof.

[0560] In a preferred embodiment, the topical composition comprises one or more excipients selected from antioxidants such as butylated hydroxyanisole, butylated hydroxytoluene, vitamin C, vitamin E, vitamin A, lutein, lycopene, retinyl palmitate, potassium metabisulfite, sodium metabisulfite, sodium thiosulfate pentahydrate, 3,4-dihydroxybenzoic acid, propyl gallate, α-lipoic acid, ascorbyl palmitate, sodium metabisulfite, ubiquinone, selenium, or combinations thereof.

[0561] In some embodiments, the antioxidant is present in an amount of about 0.001% (w / w) to about 0.1% (w / w) based on the total weight of the partial composition, preferably about 0.001% (w / w) to about 0.01% (w / w), more preferably about 0.002% (w / w) to about 0.008% (w / w).

[0562] In some embodiments, the topical pharmaceutical composition further comprises a buffer, preferably a phosphate buffer.

[0563] In a preferred embodiment, the local composition comprises a buffer (preferably a phosphate buffer) with a pH of about 6.5 to about 7.5, more preferably a buffer (preferably a phosphate buffer) with a pH of about 6.5 to about 7.0, and even more preferably a buffer (preferably a buffer) with a pH of about 6.7.

[0564] In a preferred embodiment, the local composition is in the form of a non-aqueous gel, wherein the local composition contains a phosphate buffer, preferably, the local composition contains a phosphate buffer with a pH of about 6.5 to about 7.5, more preferably a phosphate buffer with a pH of about 6.5 to about 7.0, and even more preferably a phosphate buffer with a pH of about 6.7.

[0565] In a preferred embodiment, the local composition is in the form of an aqueous gel, wherein the local composition comprises an aqueous phosphate buffer, preferably, the local composition comprises an aqueous phosphate buffer with a pH of about 6.5 to about 7.5, more preferably an aqueous phosphate buffer with a pH of about 6.5 to about 7.0, and even more preferably an aqueous phosphate buffer with a pH of about 6.7.

[0566] In a preferred embodiment, the buffer (preferably the phosphate buffer) has a molar concentration of about 10 to about 15 mM (preferably about 12 mM). In a preferred embodiment, the buffer is a phosphate buffer, wherein the phosphate buffer has a molar concentration of about 10 to about 15 mM (preferably about 12 mM).

[0567] Compound of formula (I)

[0568] On the one hand, the pharmaceutical composition of the present invention comprises a compound of formula (I):

[0569] Formula (I),

[0570] In the formula:

[0571] W is either H or F;

[0572] Y is either N or CH;

[0573] R 1 and R 2 Each is independently a morpholino group of formula (II).

[0574] Equation (II),

[0575] In the formula, R 3 and R 4 Each is independently H or -C1-C3 alkyl; or, R 3 and R 4They combine to form divalent C1-C3 alkylene residues.

[0576] In some implementations, R 1 and R 2 Selected independently from:

[0577] , , , , , , , , as well as .

[0578] In some implementations, R 1 and R 2 Selected independently from:

[0579] , , , as well as .

[0580] In some embodiments, the compounds of formula (I) are selected from:

[0581] 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridine-2-amine (Compound 1);

[0582] 4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine (compound 2);

[0583] 5-(4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridine-2-amine (compound 3);

[0584] (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridine-2-amine (compound 4); and

[0585] 4-(difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridine-2-amine (compound 5).

[0586] In some embodiments, the compound of formula (I) is 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridine-2-amine (compound 1), also known as “PQR309” and “bimiralisib”:

[0587] .

[0588] In some embodiments, the compound of formula (I) is 4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine (compound 2):

[0589] .

[0590] In some embodiments, the compound of formula (I) is 5-(4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridine-2-amine (compound 3):

[0591] .

[0592] In some embodiments, the compound of formula (I) is (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridine-2-amine (compound 4):

[0593] .

[0594] In some embodiments, the compound of formula (I) is 4-(difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine (compound 5):

[0595] .

[0596] Treatment

[0597] As used herein, the term "for use in the treatment of a disease" in the phrase "topical pharmaceutical composition, for use in the treatment of a disease" should also disclose the corresponding treatment method and the use of the corresponding formulation in the manufacture of a medicament for the treatment of a disease.

[0598] Therefore, in one respect, the present invention provides the use of the topical pharmaceutical composition of the present invention as a medicament.

[0599] As shown in the examples below, a randomized phase 2 clinical trial demonstrated that the topical pharmaceutical composition of the present invention is safe and effective for treating skin lesions such as actinic keratosis. The safety profile of the topical pharmaceutical composition of the present invention indicates good tolerability, with most associated adverse events being grade 1. For example, adverse events such as lesion erosion, crusting, and erythema resolved rapidly after treatment. No significant additional toxicity was observed with a four-week treatment period compared to a two-week treatment period. In the group of 42 patients treated, only one patient discontinued treatment before completing the entire course.

[0600] The topical pharmaceutical composition of the present invention has shown a high level of efficacy, with 60% of patients showing complete or partial elimination of lesions at the 4-week follow-up (70% in group B and 50% in group A of the phase 2 trial).

[0601] On one hand, the present invention provides the use of the topical pharmaceutical composition of the present invention for the prevention or treatment of skin lesions or skin conditions in a subject, wherein the topical pharmaceutical composition of the present invention is applied topically to the subject.

[0602] In a preferred embodiment, the topical pharmaceutical composition of the present invention is administered to the subject once daily. In some embodiments, the topical composition of the present invention is administered once daily for two or four weeks. In some embodiments, the topical composition of the present invention is administered once daily for two weeks. In some embodiments, the topical composition of the present invention is administered once daily for four weeks.

[0603] On one hand, the present invention provides the use of the topical pharmaceutical composition of the present invention for the prevention or treatment of skin lesions or skin conditions in a subject, wherein the topical pharmaceutical composition of the present invention is applied once daily.

[0604] On one hand, the present invention provides the use of the topical pharmaceutical composition of the present invention for the prevention or treatment of actinic keratosis in a subject, wherein the topical pharmaceutical composition of the present invention is applied once daily.

[0605] On one hand, the present invention provides a topical pharmaceutical composition for the prevention or treatment of squamous cell carcinoma of the skin in a subject, wherein the topical pharmaceutical composition of the present invention is applied once daily.

[0606] On one hand, the present invention provides a method for treating skin lesions or skin conditions in a subject in need, the method comprising applying the disclosed topical pharmaceutical composition of the present invention topically to the subject, preferably, the topical pharmaceutical composition being applied once daily.

[0607] On one hand, the present invention provides the use of the topical pharmaceutical composition of the present invention in the manufacture of a medicament for the topical treatment of a subject’s skin lesions or skin conditions, preferably, the topical pharmaceutical composition is for once-daily application.

[0608] In one embodiment, a topical pharmaceutical composition comprising a compound of formula (I) according to the invention (preferably compound 1) is provided for use in preventing or treating skin lesions of a subject, wherein the topical pharmaceutical composition comprising the compound of formula (I) is applied topically (preferably once daily) to the subject.

[0609] In one embodiment, a topical pharmaceutical composition comprising a compound of formula (I) according to the invention (preferably compound 1) is provided for use in the prevention or treatment of a skin lesion in a subject, preferably said skin lesion being non-melanoma skin cancer (NMSC), cutaneous lymphoma, or their pre-invasive forms.

[0610] In a preferred embodiment of the invention, the skin lesion is a pre-invasive form of non-melanoma skin cancer (NMSC).

[0611] In another preferred embodiment of the invention, the skin lesion is non-melanoma skin cancer (NMSC).

[0612] In another preferred embodiment of the invention, the skin lesion is cutaneous lymphoma.

[0613] In other embodiments, a topical pharmaceutical composition comprising a compound of formula (I) according to the invention (preferably compound 1) is provided for use in the prevention or treatment of a subject with non-melanoma skin cancer (NMSC), which is squamous cell carcinoma (cSCC) or basal cell carcinoma.

[0614] In a preferred embodiment, a topical pharmaceutical composition comprising a compound of formula (I) according to the invention (preferably compound 1) is provided for use in the prevention or treatment of cutaneous squamous cell carcinoma (cSCC) in a subject.

[0615] In other embodiments, a topical pharmaceutical composition comprising a compound of formula (I) according to the invention (preferably compound 1) is provided for use in the prevention or treatment of a subject with cutaneous squamous cell carcinoma (cSCC), said cutaneous squamous cell carcinoma (cSCC) being invasive cSCC.

[0616] In other embodiments, a topical pharmaceutical composition comprising a compound of formula (I) according to the invention (preferably compound 1) is provided for use in the prevention or treatment of cutaneous squamous cell carcinoma (cSCC) in a subject, wherein the cutaneous squamous cell carcinoma (cSCC) is metastatic cSCC.

[0617] In one embodiment, a topical pharmaceutical composition comprising a compound of formula (I) according to the invention (preferably compound 1) is provided for use in the prevention or treatment of basal cell carcinoma in a subject.

[0618] In other embodiments, a topical pharmaceutical composition comprising a compound of formula (I) according to the invention (preferably compound 1) is provided for use in the prevention or treatment of basal cell carcinoma in a subject, wherein the basal cell carcinoma is selected from: superficial basal cell carcinoma (also known as "basal cell carcinoma in situ" or "superficial multicentric basal cell carcinoma"), invasive basal cell carcinoma, and nodular basal cell carcinoma.

[0619] In a preferred embodiment, a topical pharmaceutical composition comprising a compound of formula (I) according to the invention (preferably compound 1) is provided for use in the prevention or treatment of basal cell carcinoma in a subject, wherein the basal cell carcinoma is superficial basal cell carcinoma (also known as "basal cell carcinoma in situ" or "superficial multicentric basal cell carcinoma").

[0620] In other preferred embodiments, a topical pharmaceutical composition comprising a compound of formula (I) according to the invention (preferably compound 1) is provided for use in the prevention or treatment of basal cell carcinoma in a subject, wherein the basal cell carcinoma is invasive basal cell carcinoma.

[0621] In other preferred embodiments, a topical pharmaceutical composition comprising a compound of formula (I) according to the invention (preferably compound 1) is provided for use in the prevention or treatment of basal cell carcinoma in a subject, wherein the basal cell carcinoma is nodular basal cell carcinoma.

[0622] In one embodiment, a topical pharmaceutical composition comprising a compound of formula (I) according to the invention (preferably compound 1) is provided for use in the prevention or treatment of basal cell carcinoma in a subject, wherein the basal cell carcinoma is selected from: cystic basal cell carcinoma, scarring basal cell carcinoma (also known as "scleroderma-like basal cell carcinoma" or "morphological scleroderma-like basal cell carcinoma"), micronodular basal cell carcinoma, pigmented basal cell carcinoma, rodent ulcer (also known as "Jacob ulcer"), Pinkus fibroepithelialoma, polypoid basal cell carcinoma, pore-like basal cell carcinoma, and aberrant basal cell carcinoma.

[0623] In other embodiments, a topical pharmaceutical composition comprising a compound of formula (I) according to the invention (preferably compound 1) is provided for use in the prevention or treatment of a subject’s pre-invasive form of non-melanoma skin cancer (NMSC), wherein the pre-invasive form is selected from: squamous cell carcinoma in situ (cSCCis, also known as “Bowen’s disease”), precancerous actinic keratosis (AK), and chronic UV damage.

[0624] In a preferred embodiment, a topical pharmaceutical composition comprising a compound of formula (I) according to the invention (preferably compound 1) is provided for use in the prevention or treatment of a pre-invasive form of non-melanoma skin cancer (NMSC), wherein the pre-invasive form is squamous cell carcinoma in situ (cSCCis, also known as "Bowen's disease").

[0625] In other preferred embodiments, a topical pharmaceutical composition comprising a compound of formula (I) according to the invention (preferably compound 1) is provided for use in the prevention or treatment of a subject’s pre-invasive form of non-melanoma skin cancer (NMSC), wherein the pre-invasive form is precancerous actinic keratosis (AK).

[0626] In other preferred embodiments, a topical pharmaceutical composition comprising a compound of formula (I) according to the invention (preferably compound 1) is provided for use in the prevention or treatment of a subject’s pre-invasive form of non-melanoma skin cancer (NMSC), wherein the pre-invasive form is chronic UV damage.

[0627] In one embodiment, a topical pharmaceutical composition comprising a compound of formula (I) according to the invention (preferably compound 1) is provided for use in preventing or treating actinic keratosis (AK) (e.g., precancerous actinic keratosis (AK)) in a subject, wherein the AK is field cancerization.

[0628] In some embodiments, a topical pharmaceutical composition comprising a compound of formula (I) according to the invention (preferably compound 1) is provided for the prevention or treatment of actinic keratosis (AK), preferably comprising at least three actinic keratotic lesions, preferably the at least three actinic keratotic lesions being Olsen grade 1 or 2. In a preferred embodiment, the at least three actinic keratotic lesions are non-hypertrophic. In a preferred embodiment, the at least three actinic keratotic lesions are non-hyperkeratotic. In a preferred embodiment, the at least three actinic keratotic lesions are contained within a contiguous treatment area, preferably with a total area of ​​about 100 cm². 2More preferably, the at least three actinic keratosis lesions are located on the subject's face, scalp, and / or the back of his / her hand.

[0629] In some embodiments, a topical pharmaceutical composition comprising a compound of formula (I) according to the invention (preferably compound 1) is provided for the prevention or treatment of actinic keratosis (AK), wherein the actinic keratosis comprises at least three Olsen grade 1 or 2 actinic keratotic lesions, wherein the actinic keratotic lesions are non-hypertrophic and non-hyperkeratotic, and comprise a total area of ​​approximately 100 cm² on the subject's face, scalp, and / or back of the hands. 2 Within the continuous treatment area.

[0630] In a preferred embodiment, a topical pharmaceutical composition comprising a compound of formula (I) according to the invention (preferably compound 1) is provided for use in the prevention or treatment of cutaneous lymphoma in a subject, wherein the cutaneous lymphoma is cutaneous T-cell lymphoma (CTCL) or cutaneous B-cell lymphoma (CBCL).

[0631] In another preferred embodiment, a topical pharmaceutical composition comprising a compound of formula (I) according to the invention (preferably compound 1) is provided for use in the prevention or treatment of cutaneous T-cell lymphoma (CTCL) in a subject.

[0632] In another preferred embodiment, a topical pharmaceutical composition comprising a compound of formula (I) according to the invention (preferably compound 1) is provided for the prevention or treatment of cutaneous lymphoma in a subject, wherein the cutaneous lymphoma is cutaneous B-cell lymphoma (CBCL).

[0633] In a preferred embodiment, a topical pharmaceutical composition comprising a compound of formula (I) according to the invention (preferably compound 1) is provided for use in the prevention or treatment of a skin condition in a subject. In a preferred embodiment, the skin condition is a hereditary skin disease. In other preferred embodiments, the hereditary skin disease is selected from tuberous sclerosis (TSC), Birt-Hogg-Dubé (BHD), phosphatase and tensin homolog (PTEN) hamartoma syndrome, and hereditary keratinopathy; preferably, the hereditary skin disease is selected from skin conditions associated with tuberous sclerosis (TSC), skin conditions associated with Birt-Hogg-Dubé (BHD), phosphatase and tensin homolog (PTEN) hamartoma syndrome, and hereditary keratinopathy.

[0634] In other preferred embodiments, the hereditary skin disease is tuberous sclerosis (TSC). In other preferred embodiments, the hereditary skin disease is tuberous sclerosis minus (TSC-). In other preferred embodiments, the hereditary skin disease is Birt-Hogg-Dubé (BHD, or also known as hereditary fibroma). In other preferred embodiments, the hereditary skin disease is phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS). In other preferred embodiments, the hereditary skin disease is hereditary keratosis. In other preferred embodiments, the hereditary skin disease is hereditary keratosis, wherein the hereditary keratosis is congenital pachyonychia. In other preferred embodiments, the hereditary skin disease is a skin condition associated with tuberous sclerosis (TSC). In other preferred embodiments, the hereditary skin disease is a skin condition associated with Birt-Hogg-Dubé (BHD).

[0635] In other preferred embodiments, the skin condition associated with tuberous sclerosis (TSC) is angiofibroma (AF). In a very preferred embodiment, the skin condition associated with TSC is facial angiofibroma. In other preferred embodiments, the skin condition associated with TSC is hamartoma. In other preferred embodiments, the skin condition associated with TSC is periungual fibroma. In yet another preferred embodiment, the skin condition associated with Birt-Hogg-Dubé (BHD) is fibrofollicular tumor of BHD. In other preferred embodiments, the skin condition is hereditary keratosis. In other preferred embodiments, the skin condition is congenital pachyonychia.

[0636] In other preferred embodiments, the PTEN hamartoma tumor syndrome (PHTS) is selected from Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-associated Proteus syndrome (PS), Lhermitte-Duclos syndrome, and Proteus-like syndrome. In other preferred embodiments, the PTEN hamartoma tumor syndrome (PHTS) is Cowden syndrome (CS). In other preferred embodiments, the PTEN hamartoma tumor syndrome (PHTS) is Bannayan-Riley-Ruvalcaba syndrome (BRRS). In other preferred embodiments, the PTEN hamartoma tumor syndrome (PHTS) is PTEN-associated Proteus syndrome (PS). In other preferred embodiments, the PTEN hamartoma tumor syndrome (PHTS) is Lhermitte-Duclos syndrome. In other preferred embodiments, the PTEN hamartoma tumor syndrome (PHTS) is Proteus-like syndrome. In other preferred embodiments, a hereditary keratosis, preferably congenital pachyonychia.

[0637] In other preferred embodiments, the skin condition is PTEN hamartomatoma syndrome (PHTS), preferably selected from Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-associated Proteobacterium syndrome (PS), Lhermitte-Duclos syndrome, and Proteobacterium-like syndrome. In other preferred embodiments, the skin condition is Cowden syndrome (CS). In other preferred embodiments, the skin condition is Bannayan-Riley-Ruvalcaba syndrome (BRRS). In other preferred embodiments, the skin condition is PTEN-associated Proteobacterium syndrome (PS). In other preferred embodiments, the skin condition is Lhermitte-Duclos syndrome. In other preferred embodiments, the skin condition is Proteobacterium-like syndrome. In other preferred embodiments, the skin condition is skin fibrosis. In other preferred embodiments, the skin condition is hamartoma. In other preferred embodiments, the skin condition is periungual fibroma.

[0638] In other preferred embodiments, the skin condition is a hereditary skin disease selected from tuberous sclerosis (TSC), Birt-Hogg-Dubé (BHD), phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS), and hereditary keratosis.

[0639] In other preferred embodiments, the skin condition is a vascular abnormality selected from port-wine stains (PWS), infantile hemangiomas, blue rubber blister syndrome, and complex vascular abnormalities.

[0640] In a preferred embodiment, the skin condition is a vascular abnormality. In other preferred embodiments, the vascular abnormality is selected from port-wine stains (PWS), infantile hemangiomas, blue rubber blister hemangiomas syndrome, and complex vascular abnormalities. In other preferred embodiments, the vascular abnormality is port-wine stains (PWS, or also Sturge Weber syndrome). In other preferred embodiments, the vascular abnormality is infantile hemangiomas. In other preferred embodiments, the vascular abnormality is blue rubber blister hemangiomas syndrome. In other preferred embodiments, the vascular abnormality is a complex vascular abnormality. In other preferred embodiments, the vascular abnormality is a complex vascular abnormality, specifically Kaposi's angioendothelioma.

[0641] In other preferred embodiments, the skin condition is selected from port-wine stains (PWS), infantile hemangiomas, blue rubber blister syndrome, and complex vascular abnormalities. In other preferred embodiments, the skin condition is a port-wine stain (PWS, or also Sturge Weber syndrome). In other preferred embodiments, the skin condition is an infantile hemangioma. In other preferred embodiments, the skin condition is blue rubber blister syndrome. In other preferred embodiments, the skin condition is a complex vascular abnormality. In other preferred embodiments, the skin condition is a complex vascular abnormality, wherein the complex vascular abnormality is Kaposi's angioendothelioma. In other preferred embodiments, the skin condition is Kaposi's angioendothelioma.

[0642] In other preferred embodiments, the skin condition is selected from scleroderma, scleroderma-associated chronic graft-versus-host disease, sclerosing lichen, lichen planus, lichen planus, and scars, preferably hypertrophic scars.

[0643] In a preferred embodiment, the skin condition is scleroderma. In other preferred embodiments, the skin condition is scleroderma-associated chronic graft-versus-host disease. In other preferred embodiments, the skin condition is lichen sclerosus. In other preferred embodiments, the skin condition is lichen planus. In other preferred embodiments, the skin condition is lichen planus. In other preferred embodiments, the skin condition is scarring. In other preferred embodiments, the skin condition is hypertrophic scarring.

[0644] In other highly preferred embodiments, the skin condition is selected from: skin conditions associated with tuberous sclerosis (TSC) or Birt-Hogg-Dubé (BHD), angiofibroma (AF) (preferably facial angiofibroma), fibrofollicular tumor of BHD, phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS), Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-associated Proteus syndrome (PS), Lhermitte-Duclos syndrome, Proteus-like syndrome, hereditary keratosis, congenital pachyonychia, vascular abnormalities, skin fibrosis, hamartoma, periungual fibroma, vascular abnormalities, port-wine stains (PWS), infantile hemangioma, blue rubber blister hemangioma syndrome, complex vascular abnormalities, Kaposi's hemangioendothelioma, scleroderma, scleroderma-associated chronic graft-versus-host disease, sclerosing lichen, lichen planus, lichen planus, and scars, preferably hypertrophic scars.

[0645] In a very preferred embodiment, the skin condition is angiofibroma (AF). In other very preferred embodiments, the skin condition is facial angiofibroma.

[0646] In a highly preferred embodiment, a topical pharmaceutical composition comprising a compound of formula (I) according to the invention (preferably compound 1) is provided for use in the prevention or treatment of a skin condition in a subject, said skin condition being a hereditary skin disease selected from tuberous sclerosis (TSC), Birt-Hogg-Dubé (BHD), phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS), and hereditary keratosis, wherein the compound of formula (I) is applied topically to the subject.

[0647] In other preferred embodiments, a topical pharmaceutical composition comprising a compound of formula (I) according to the invention (preferably compound 1) is provided for use in preventing or treating a skin condition in a subject, said skin condition being a vascular abnormality selected from port-wine stains (PWS), infantile hemangiomas, blue rubber blister syndrome, and complex vascular abnormalities, said topical pharmaceutical composition being applied topically to the subject.

[0648] In other preferred embodiments, a topical pharmaceutical composition comprising a compound of formula (I) according to the invention (preferably compound 1) is provided for use in the prevention or treatment of a skin condition in a subject, said skin condition being selected from: skin conditions associated with tuberous sclerosis (TSC) or Birt-Hogg-Dubé (BHD), angiofibroma (AF) (preferably facial angiofibroma), fibrofollicular tumors of BHD, phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS), Cowden syndrome (CS), Bannayan-Riley-Ruva syndrome, etc. The topical pharmaceutical composition is used topically on a subject for the following conditions: lbaba syndrome (BRRS), PTEN-associated Proteus syndrome (PS), Lhermitte-Duclos syndrome, Proteus-like syndrome, hereditary keratosis, congenital pachyonychia, vascular abnormalities, cutaneous fibrosis, hamartoma, periungual fibroma, vascular abnormalities, port-wine stains (PWS), infantile hemangioma, blue rubber blister hemangioma syndrome, complex vascular abnormalities, Kaposi's hemangioendothelioma, scleroderma, sclerodermic chronic graft-versus-host disease, lichen sclerosus, lichen planus, lichen planus erythroplasia, and scars (preferably hypertrophic scars).

[0649] In other preferred embodiments, a topical pharmaceutical composition comprising a compound of formula (I) according to the invention (preferably compound 1) is provided for use in preventing or treating a skin condition in a subject, said skin condition being angiofibroma (AF), preferably facial angiofibroma, said topical pharmaceutical composition being applied topically to the subject.

[0650] In some embodiments, the topical pharmaceutical composition of the present invention has a solubility synergy factor of at least 1.1. In some embodiments, the topical pharmaceutical composition of the present invention has a solubility synergy factor of at least 1.5. In some embodiments, the topical pharmaceutical composition of the present invention has a solubility synergy factor of at least 2.0. In some embodiments, the topical pharmaceutical composition of the present invention has a solubility synergy factor of at least 2.5. In some embodiments, the topical pharmaceutical composition of the present invention has a solubility synergy factor of at least 3.0. In some embodiments, the topical pharmaceutical composition of the present invention has a solubility synergy factor of at least 3.5. In some embodiments, the topical pharmaceutical composition of the present invention has a solubility synergy factor of at least 4.0. In some embodiments, the topical pharmaceutical composition of the present invention has a solubility synergy factor of at least 4.5.

[0651] In some embodiments, the topical pharmaceutical composition of the present invention provides a clinically relevant concentration of compound (I) to the patient's skin, preferably after a single application to the patient.

[0652] In some embodiments, the clinically relevant concentration of the compound of formula (I) is higher than the clinical IC50 for inhibiting pAKT. 90 For example, the clinically relevant concentration of the compound of formula (I) is higher than 1,000 ng / g, preferably achieved after a single application of the topical pharmaceutical composition of the present invention.

[0653] In some embodiments, the clinically relevant concentration of the compound of formula (I) is higher than the clinical IC50 for inhibiting pS6. 90 For example, the clinically relevant concentration of the compound of formula (I) is higher than 3,000 ng / g, preferably achieved after a single application of the topical pharmaceutical composition of the present invention.

[0654] In some embodiments, the topical pharmaceutical composition of the present invention provides a clinically relevant concentration of the formula (I) compound to the dermis and / or epidermis of a patient, preferably after a single application to the patient.

[0655] In some embodiments, the clinically relevant concentrations of the compound of formula (I) in the patient's dermis and / or epidermis are higher than the clinical IC50 for inhibiting pAKT. 90 For example, the clinically relevant concentration of the compound of formula (I) is higher than 1,000 ng / g, preferably achieved after a single application of the topical pharmaceutical composition of the present invention.

[0656] In some embodiments, the clinically relevant concentrations of the compound of formula (I) in the patient's dermis and / or epidermis are higher than the clinical IC50 for inhibiting pS6. 90 For example, the clinically relevant concentration of the compound of formula (I) is higher than 3,000 ng / g, preferably achieved after a single application of the topical pharmaceutical composition of the present invention.

[0657] In some embodiments, the topical pharmaceutical composition of the present invention provides a clinically relevant concentration of compound (I) to the dermis of a patient, preferably after a single application to the patient.

[0658] In some embodiments, the clinically relevant concentration of the compound of formula (I) in the patient's dermis is higher than the clinical IC50 for inhibiting pAKT. 90 For example, the clinically relevant concentration of the compound of formula (I) is higher than 1,000 ng / g, preferably achieved after a single application of the topical pharmaceutical composition of the present invention.

[0659] In some embodiments, the clinically relevant concentration of the compound of formula (I) in the patient's dermis is higher than the clinical IC50 for inhibiting pS6. 90For example, the clinically relevant concentration of the compound of formula (I) is higher than 3,000 ng / g, preferably achieved after a single application of the topical pharmaceutical composition of the present invention.

[0660] In some embodiments, the topical pharmaceutical composition of the present invention provides a clinically relevant concentration of compound (I) to the patient's epidermis, preferably after a single application to the patient.

[0661] In some embodiments, the clinically relevant concentration of the compound of formula (I) in the patient's epidermis is higher than the clinical IC50 for inhibiting pAKT. 90 For example, the clinically relevant concentration of the compound of formula (I) is higher than 1,000 ng / g, preferably achieved after a single application of the topical pharmaceutical composition of the present invention.

[0662] In some embodiments, the clinically relevant concentration of the compound of formula (I) in the patient's epidermis is higher than the clinical IC50 for inhibiting pS6. 90 For example, the clinically relevant concentration of the compound of formula (I) is higher than 3,000 ng / g, preferably achieved after a single application of the topical pharmaceutical composition of the present invention.

[0663] In some embodiments, the topical pharmaceutical composition of the present invention delivers a clinically relevant concentration of compound 1 to the patient's skin, preferably after a single application to the patient.

[0664] In some embodiments, the clinically relevant concentration of compound 1 is higher than the clinical IC50 for inhibiting pAKT. 90 For example, the clinically relevant concentration of compound 1 is higher than 1,000 ng / g, preferably achieved after a single application of the topical pharmaceutical composition of the present invention.

[0665] In some embodiments, the clinically relevant concentration of compound 1 is higher than the clinical IC50 for inhibiting pS6. 90 For example, the clinically relevant concentration of compound 1 is higher than 3,000 ng / g, preferably achieved after a single application of the topical pharmaceutical composition of the present invention.

[0666] In some embodiments, the topical pharmaceutical composition of the present invention provides a clinically relevant concentration of compound 1 to the dermis and / or epidermis of a patient, preferably after a single application to the patient.

[0667] In some embodiments, the clinically relevant concentration of compound 1 in the patient's dermis and / or epidermis is higher than the clinical IC50 for inhibiting pAKT.90 For example, the clinically relevant concentration of compound 1 is higher than 1,000 ng / g, preferably achieved after a single application of the topical pharmaceutical composition of the present invention.

[0668] In some embodiments, the clinically relevant concentration of compound 1 in the patient's dermis and / or epidermis is higher than the clinical IC50 for inhibiting pS6. 90 For example, the clinically relevant concentration of compound 1 is higher than 3,000 ng / g, preferably achieved after a single application of the topical pharmaceutical composition of the present invention.

[0669] In some embodiments, the topical pharmaceutical composition of the present invention provides a clinically relevant concentration of compound 1 to the dermis of a patient, preferably after a single application to the patient.

[0670] In some embodiments, the clinically relevant concentration of compound 1 in the patient's dermis is higher than the clinical IC50 for inhibiting pAKT. 90 For example, the clinically relevant concentration of compound 1 is higher than 1,000 ng / g, preferably achieved after a single application of the topical pharmaceutical composition of the present invention.

[0671] In some embodiments, the clinically relevant concentration of compound 1 in the patient's dermis is higher than the clinical IC50 for inhibiting pS6. 90 For example, the clinically relevant concentration of compound 1 is higher than 3,000 ng / g, preferably achieved after a single application of the topical pharmaceutical composition of the present invention.

[0672] In some embodiments, the topical pharmaceutical composition of the present invention provides a clinically relevant concentration of compound 1 to the patient's epidermis, preferably after a single application to the patient.

[0673] In some embodiments, the clinically relevant concentration of compound 1 in the patient's epidermis is higher than the clinical IC50 for inhibiting pAKT. 90 For example, the clinically relevant concentration of compound 1 is higher than 1,000 ng / g, preferably achieved after a single application of the topical pharmaceutical composition of the present invention.

[0674] In some embodiments, the clinically relevant concentration of compound 1 in the patient's epidermis is higher than the clinical IC50 for inhibiting pS6. 90 For example, the clinically relevant concentration of compound 1 is higher than 3,000 ng / g, preferably achieved after a single application of the topical pharmaceutical composition of the present invention. Example

[0675] The present disclosure is further illustrated by the following examples, which should not be construed as limiting the scope or spirit of the disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain implementations and are not intended to limit the scope of the disclosure. It should also be understood that various other implementations, modifications, and equivalents of the teachings can be employed by those skilled in the art without departing from the spirit of the disclosure and / or the scope of the appended claims.

[0676] Table 1 shows the formulation composition tested in the examples below:

[0677] Table 1. Formulations containing compound 1

[0678]

[0679] Table 1 (continued)

[0680]

[0681] Table 1 (continued)

[0682]

[0683] The concentrations of compound 1 in the formulations described in Table 1 represent the upper limit of the total solubility of compound 1 in these formulations (i.e., 80-90%).

[0684] Animal welfare

[0685] All animal studies were conducted under conditions approved by the Austrian Federal Ministry of Science, Research and Economic Affairs.

[0686] Example 1 - Calculation of solubility and solubility factor of compound 1 in a single solvent

[0687] The solubility of compound 1 in various individual solvents and excipients was first tested. Table 2 below shows the solubility of compound 1 in individual solvents and excipients at 25 °C, measured as a weight / weight ratio. For example, for PEG400, a solubility of 1.66% wt / wt means that 1.66 g of compound 1 dissolves in 100 g of PEG400.

[0688] Table 2. Solubility of Compound 1 in individual solvents and excipients (wt / wt)

[0689]

[0690] As measured in Table 2 above, the formulations of the present invention are able to dissolve a greater amount of compound 1 than would have been expected based on the solubility of compound 1 in individual solvents and excipients (i.e., exhibiting synergistic solubility of compound 1).

[0691] Table 3 below shows the solubility synergistic factors observed for formulations NA03, AG20, and CR01. For each tested formulation, the amount of compound 1 added represents 80% of the total amount of compound 1 that can dissolve in that formulation.

[0692] Table 3. Solubility Co-factors of the Tested Formulations

[0693]

[0694] Example 2: Stability of Compound 1 in various solvents

[0695] Forced degradation studies were conducted to determine the stability of compound 1 under various conditions designed to accelerate degradation. The results are shown in Table 4 below.

[0696] Table 4. Stability of Compound 1 in various excipients

[0697]

[0698] Example 3: In vitro drug release test

[0699] Use such as Figure 1 The static Franz cell shown was used for in vitro drug release tests to evaluate the release characteristics of compound 1 across a synthetic cellulose membrane from ten experimental formulations: AG02, AG11, AG12, AG15, AG18, AG20, AG21, NA03, EG01, and CR01. In short, a formulation containing compound 1 was placed on top of a synthetic cellulose membrane and allowed to diffuse across the membrane over time into a receiving solution that initially did not contain compound 1, as shown. Figure 1 As shown.

[0700] Three receiving solutions were initially tested to confirm the stability of compound 1 in the receiving solution. The receiving solution selected was 2% Brij in 50 / 50 ethanol / water. ® Compound 1 was found to be stable in the selected receiving solution at 5, 25, and 32 °C for five days.

[0701] Six membranes were initially tested to evaluate the potential for backdiffusion from the receiver solution to the formulation solution and / or binding of compound 1 to the membrane. Cellulose membranes were chosen because they do not allow any backdiffusion when used with the receiver solution and do not bind to compound 1. The administration area of ​​the Franz pool ranged from 1.9 to 2.4 cm². 2 The volume is 7.5-11 mL.

[0702] In preliminary experiments, an infinite dose (300 mg) of a single batch of formulation AG18 was administered to cellulose membranes mounted in static Franz cells (n=3). A single static cell with a cellulose membrane but without administration served as a blank control. Receiving solutions were collected at seven time points (1, 2, 4, 6, 24, 30, and 48 hours) and analyzed using HPLC-UV. The data indicated that the 1–7 hour time range was optimal for full-scale experiments because the slope was linear when plotted as the square root of time. Backdiffusion was observed only after 24 hours.

[0703] In subsequent full-scale experiments, in vitro release studies were conducted on the ten experimental formulations (AG02, AG11, AG12, AG15, AG18, AG20, AG21, NA03, EG01, and CR01) based on the conditions determined during the small-scale experiments.

[0704] Figure 2 Table 5 shows the amount of Compound 1 released across the synthetic cellulose membrane into the receiving solution over 7 hours. The non-aqueous gel (NA03) showed the fastest release rate of Compound 1 (P < 0.0001 for all formulations), approximately 2–5 times higher than all other formulations. Release rates for the ten tested formulations ranged from 216–1084 µg / cm³. 2 The release rates of compound 1 were between 600 and 600 hr, with the slowest release rates observed in CR01 and AG18. The cumulative amount of compound 1 in the receiver at 7 hours post-dose increased with increasing percentage of compound 1 present in the administered formulation. Formulations AG20, EG01, and AG21 all had statistically similar release rates, ranking as the second highest release rates after NA03.

[0705] Table 5. Cumulative amount of compound 1 released into the receiving liquid across the cellulose membrane (µg / cm³) 2 )

[0706]

[0707] Example 4: Penetration and permeation of isolated human skin

[0708] Ex vivo skin permeation experiments involve the use of diffusion cells designed to simulate the physiological and anatomical conditions of in situ skin. A schematic diagram of the model used to test skin permeation in this embodiment is shown below. Figure 3 As shown, human skin is placed between the donor and recipient chambers. An automated, optimized fluid collection system creates a flow path with small void volumes, forming a localized clearance beneath the sliced ​​skin to generate a precise and detailed flow profile.

[0709] Human skin from a single donor undergoing plastic surgery was used. Subcutaneous fat was removed mechanically, and the skin was cut to a thickness of 500 ± 50 µm using an Integra Life Sciences SB Slimline dermist. When not used immediately, the skin was stored at -80 °C and thawed to room temperature before being placed in a diffusion pool.

[0710] Based on nonspecific binding experiments and the high stability of compound 1 in the receiving solution, a solution containing 0.01% Brij was used. ® The PBS receiving solution was used. The extraction solution used was 90 / 10 (ethanol / water).

[0711] In preliminary experiments, formulation AG11 was used to test experimental conditions. Approximately 100 ng / cm³ was detected in the receiving solution after 24 hours. 2 The accumulation level of compound 1 was determined, and compound 1 was recovered from the epidermis and dermis. Based on these results, the conditions were considered suitable for full-size ex vivo skin permeation and penetration studies.

[0712] Using the above setup, full-size ex vivo skin penetration and permeation studies were conducted with formulations AG02, AG11, AG12, AG15, AG18, AG20, AG21, CR01, EG01, and NA03. For each active formulation, n=5 replicates were performed. Single replicates were performed for the corresponding placebo formulations and blank controls.

[0713] For the full-scale experiment, the recovery of residual formulation from the skin was performed as follows: The drug (compound 1) was recovered from the skin surface using a total of three swabs. After the skin was removed from the diffusion pool, all formulation was removed from the skin surface using a dry, degreased swab, which was then discarded. A second swab was then dipped in the extraction solution and used to wipe the skin surface, after which it was discarded. The last swab was used to dry-wipe the skin surface and was then discarded.

[0714] Compound 1 was removed from the stratum corneum using the following procedure: Adhesive strips (5 strips) were removed from the skin surface to separate the stratum corneum from the epidermis and discarded. The remaining epidermis and a portion of the dermis were thermally separated from each other by placing the skin in a 60 °C incubator for 2 minutes. The epidermis and dermis were placed in their respective tissue homogenizer vials, and 1 mL of extraction solution was added. The tissue homogenizer vials were placed in a bead mill homogenizer and homogenized at 5 m / s for 3 x 30 seconds at ambient laboratory temperature. The vials were then shaken on an orbital shaker at ambient temperature for 0.5–1 hour. The homogenate was then transferred to 96-well plates and centrifuged. The dermal and epidermal samples were analyzed using LC-MS / MS.

[0715] No significant differences in the concentration of compound 1 in the receiving solution were found between any of the test formulations.

[0716] The average amount (ng) of compound 1 recovered from the epidermis and dermis is presented in Figure 4 And as shown in Table 6 below. Compared to all other tested formulations, formulation NA03 delivered 1.7 to 17 times more Compound 1 to the epidermis. For dermal delivery, formulation NA03 also ranked third highest. Among the tested aqueous gels, formulations AG20 and AG21 delivered the highest amounts of Compound 1 to both the dermis and epidermis.

[0717] Table 6. Amount (ng) of Compound 1 recovered from the epidermis and dermis 24 hours after formulation administration and percentage of the administered dose.

[0718]

[0719] Example 5: In vivo porcine skin permeability study

[0720] In in vivo porcine skin studies, biopsy extractions were used to determine the PK characteristics of ten experimental formulations and one control formulation. Prior to biopsy extraction, the stratum corneum was removed using a tape stripping method. Three replicate biopsy samples were taken from each application site (20 x 40 mm). Additionally, three biopsy samples were taken from untreated tape stripping sites (blank samples) for analytical validation. All biopsy samples were stored at -80 °C until analysis. The formulations tested were AG08, AG11, AG13, AG15, AG17, AG20, AG21, NA03, EG01, and CR01. The control formulation contained 1% Compound 1, PG, and a thickener.

[0721] A four-month-old domestic pig weighing 40 kg was used. Three days prior to the study, the hair on the pig's back and flanks was shaved. On the day of the study, the pig was anesthetized. The skin was cleaned with water, and wounds, abrasions, or other changes were examined. Application sites were marked on the skin using a template and surgical marker. A diagram of the application sites is shown below. Figure 5 As shown.

[0722] The dosage for each formulation is 56 mg (7 mg / cm² over an application area of ​​4 x 2 cm). 2 (The formulation). Weigh the dose using an analytical balance and apply with a plastic spatula. Administer the medication sequentially. Exposure times are 6, 9, and 12 hours.

[0723] After the exposure period ended, the pigs were euthanized by preoperative administration of 10 mg / kg ketamine, 0.2 mg / kg midazolam and 2 mg / kg azapiron, as well as excessive amounts of propofol and potassium chloride.

[0724] Before peeling off the tape, clean the application site twice with gauze to remove any remaining preparation. To remove the stratum corneum, apply a strip of tape to the skin of all relevant application sites. Using gloved fingers, press the tape evenly onto the skin surface to ensure uniform contact, and peel it off quickly with a smooth motion. To thoroughly remove the stratum corneum, repeat the tape peeling process 80 times each time using a new strip of tape, alternating between peeling directions (from left to right and from right to left).

[0725] Three duplicate biopsy samples were taken from each application site using a 4.0 mm biopsy needle. Subcutaneous tissue was removed from the biopsy samples. The biopsy samples were placed in 1.8 mL cryovials and weighed. In addition, three blank biopsy samples were taken from untreated sites where the tape had been removed to determine background in the analytical run. Samples were stored in a temperature-monitored freezer at -80 °C until sample shipment.

[0726] LC-MS / MS was used to quantify the concentrations of compound 1 in all ten formulations and the control formulation in all tissue samples. The mean concentration, standard deviation (SD), and coefficient of variation (CV) were calculated for each formulation and time point. The resulting CVs ranged from 6% to 89%.

[0727] The results are presented in Table 7 below. Figure 6 and Figure 7 middle. Figure 6 The concentration of compound 1 in pig skin biopsy samples at each test time point is shown. Figure 7 The amount of compound 1 in the biopsy samples is shown as integrated at three test time points (6, 9, and 12 hours). The dotted line represents the IC50 of compound 1 against phosphoS6. 90 The dashed line indicates that compound 1 has an IC50 saturation of phosphoAKT. 90 .

[0728] Of the experimental compounds tested, formulations NA03 and AG20 showed the highest concentrations of compound 1 in the skin. (For example...) Figure 7 As shown, when integrated at the three time points tested, the amount of compound 1 delivered by formulations NA03 and AG20 was higher than the IC50 for inhibiting phosphoS6. 90 .

[0729] Table 7. Concentration of Compound 1 in skin tissue after in vivo skin penetration study

[0730]

[0731] Example 6: In vivo porcine skin penetration study using different concentrations of formulations NA03 and AG20

[0732] Based on the results of the above embodiments, two formulations, NA03 and AG20, were selected for further study. Five different formulations based on the original NA03 and AG20 formulations but with different concentrations of compound 1 were prepared and administered in vivo to pig skin, as shown in Table 8 below.

[0733] Table 8. Formulations Used

[0734]

[0735] The formulation is at 1.0 mg / cm³. 2 2.0 mg / cm 2 3.5 mg / cm 2 and 7.0 mg / cm 2 Different dosages were applied. The application area was 12 cm². 2 (4 cm x 3 cm).

[0736] A 2.5-month-old domestic pig (weight: 33 kg) was brought to the research site. Four days prior to the study, the hair on the pig's back and both sides of the flanks was shaved off with a clipper. On the day of the study, the pig was anesthetized, its skin was cleaned with water, and wounds, abrasions, and other changes were examined. The application site was marked on the skin using a surgical template and a surgical marker.

[0737] The test formulation containing compound 1 was administered to ten application sites with an exposure time of 6 hours, ten application sites with an exposure time of 9 hours, and another ten application sites with an exposure time of 12 hours. Placebo formulations (i.e., formulations NA03 and AG20, which do not contain compound 1) were administered to two additional application sites for a 12-hour exposure time. The application sites for the formulations to the pigs are as follows... Figure 8 As shown. Apply the preparation using a plastic spatula.

[0738] At the end of the study, the pigs were euthanized. Any remaining experimental preparation at the application site was removed by cleaning the site twice with gauze. Then, the stratum corneum was removed using adhesive tape. The tape was applied to the skin at the application site. Using gloved fingers, the tape was pressed evenly against the skin surface to ensure uniform contact, and then quickly peeled off with a smooth motion. To completely remove the stratum corneum, the tape peeling procedure was repeated 80 times each time, using a new strip of tape, alternating between peeling directions (from left to right and from right to left). The tape peeling procedure for all sites took approximately 70 minutes.

[0739] Biopsy samples consisted of the remaining epidermis and the entire dermis. For application sites treated with a formulation containing compound 1, six duplicate biopsy samples were taken using a biopsy puncture device (4.0 mm), three of which were used to test pharmacokinetic characteristics. For the two application sites treated with placebo cream, three biopsy samples were taken. In addition, three blank biopsy samples were taken from untreated sites where the tape had been removed to determine background in the analytical run. Biopsy samples were placed in 1.8 mL cryovials and weighed. All biopsy samples were stored at -80 °C until analysis.

[0740] Table 9 below shows the concentration of compound 1 in the skin for each of the tested formulations. Figure 9 The average (mean ± SEM) concentration of compound 1 for all formulations is shown at all time points (6 h, 9 h, 12 h). The dotted line represents the IC50 of compound 1 against phosphoS6. 90 The dashed line indicates that compound 1 has an IC50 saturation of phosphoAKT. 90 .

[0741] Table 9. Concentration of Compound 1 in skin tissue after in vivo pharmacokinetic studies

[0742]

[0743] ( Values ​​excluded from further calculations.

[0744] Six to 12 hours after treatment, compound 1 in all applied formulations penetrated into the underlying epidermis and dermis in significant amounts. Formulation NA03-6.3% was present at all applied doses (7.0 mg / cm³). 2 3.5 mg / cm 2 2.0 mg / cm 2 ; and 1.0 mg / cm 2 The highest skin concentrations were observed at all of these levels. Formulation NA03-2% showed clinically relevant skin concentrations.

[0745] Example 7: A randomized phase 2 proof-of-concept study to evaluate the efficacy and safety of topical bimiralisib in patients with actinic keratosis of the face and / or scalp and / or dorsum of the hands during 2-week and 4-week treatment periods.

[0746] A study was conducted to evaluate the efficacy and safety of bimiralisib gel treatment for actinic keratosis of the face and / or scalp and / or back of the hands. This was a multicenter, randomized, open-label, parallel-group study. The study product was applied to the target lesions for 2 or 4 weeks. The study included the following phases: screening (up to 30 days); treatment (2 or 4 weeks); and follow-up (4 weeks).

[0747] Patients were randomly assigned to one of two groups (1:1): (1) Group A: topical bimiralisib gel treatment for 2 weeks; (2) Group B: topical bimiralisib gel treatment for 4 weeks.

[0748] A schematic diagram of clinical trial design is shown below. Figure 10 As shown.

[0749] Age eligibility for research: Applicants must be at least 50 years old (adult, senior adult) at the time of signing the informed consent form. Gender eligibility for research: All. Healthy volunteers are not accepted.

[0750] Qualification Standards

[0751] 1. The person must be at least 50 years old when signing the informed consent form.

[0752] 2. A stable, clinically typical clinical diagnosis of actinic keratosis.

[0753] 3. At least three actinic keratosis lesions (Olsen grade 1 or 2) in a continuous treatment area on the face and / or scalp and / or back of the hand.

[0754] 4. You must agree not to use any products on the treatment area throughout the study, except for investigator-approved cleansers, sunscreens, lotions, and non-medicinal cosmetics.

[0755] 5. Must be willing to comply with sun protection measures for all exposed areas, including using investigator-approved sunscreen and / or hats, limiting sun exposure time, and not using tanning beds.

[0756] 6. Must be in good overall health (ECOG 0-1).

[0757] 7. Patients of childbearing age must agree to use two effective contraceptive methods from the start of screening until 90 days after the end of study treatment.

[0758] 8. Female patients who have had menstrual cycles within the two years prior to screening must have a negative serum pregnancy test at the time of screening and a negative urine pregnancy test on the first day of treatment.

[0759] 9. A signed informed consent form must be provided.

[0760] Exclusion criteria

[0761] 1. Known or suspected allergy to any excipients in bimiralisib gel.

[0762] 2. Clinically atypical and / or rapidly changing actinic keratosis lesions are present in the treatment area.

[0763] 3. Clinical evidence of severe, uncontrolled autoimmune, cardiovascular, gastrointestinal, hematologic, liver, neurological, lung, or kidney disease.

[0764] 4. Participate in any clinical study within 30 days of the baseline visit.

[0765] 5. Within 4 weeks of the baseline visit, cosmetic or treatment procedures (such as laser, skin resurfacing, photodynamic therapy, cryotherapy) were performed within 2 cm of the selected treatment area.

[0766] 6. The presence of other skin diseases (e.g., vitiligo, rosacea, psoriasis, atopic dermatitis, eczema, basal cell carcinoma or squamous cell carcinoma, or albinism) or conditions (e.g., scars, open wounds, tattoos, piercings, sunburn) in the selected treatment area may, in the investigator's opinion, interfere with the conduct or evaluation of the study, or expose participants to unacceptable risks by participating in the study.

[0767] 7. Used tanning lamps, tanning beds, and tanning rooms within 4 weeks prior to the baseline visit, or planned to use them during the study.

[0768] 8. Use of any retinoic acid within 90 days of the baseline visit, or use of systemic corticosteroids, methotrexate, or other antimetabolites or nicotinamide within 28 days of the baseline visit. Topical steroid treatment for non-AK indications is permitted outside the selected treatment area.

[0769] 9. Has undergone any systemic cancer treatment or been diagnosed with cancer within 6 months of the baseline visit.

[0770] 10. Have had any other malignant tumor within the 5 years prior to screening, except for basal cell or squamous cell carcinoma outside the treatment area that has received curative intention-to-treat treatment and has not recurred.

[0771] 11. Other significant uncontrolled or unstable medical conditions or illnesses that the researchers believe would expose the participants to unacceptable risks by participating in the study.

[0772] 12. Known history of human immunodeficiency virus (HIV), chronic hepatitis C, or chronic hepatitis B infection (not mandatory testing).

[0773] 13. Patients receiving immunosuppressive therapy, according to researchers, may experience a risk of developing non-melanoma skin cancer.

[0774] 14. Women who are pregnant, breastfeeding, or planning to become pregnant during the study.

[0775] 15. Patients who are unable to comply with the study requirements for any reason.

[0776] Research Plan

[0777] Primary objective: Treatment. Grouping: Randomized. Intervention model: Parallel assignment. Masking: None (open label).

[0778] Groups and Interventions

[0779]

[0780] The patient is treated with a topical formulation containing compound 1 as described herein, comprising:

[0781] 2.0 wt% of compound 1;

[0782] 57.81% by weight of polyethylene glycol, preferably PEG400;

[0783] 24.50% by weight of diethylene glycol monoethyl ether;

[0784] 4.89% by weight of glycerol (anhydrous);

[0785] 9.80% by weight of diisopropyl adipate; and

[0786] 1% by weight of hydroxypropyl cellulose.

[0787] Apply this topical preparation once daily.

[0788] Main Result Measurement

[0789]

[0790] Response assessment

[0791] Measurement of treatment response to the target lesion: (i) Investigator Global Assessment (IGA), (ii) absolute lesion count, and (iii) change in lesion size from baseline.

[0792] The Investigator Global Assessment (IGA) score was measured using a five-point response scale compared to baseline, and included the following scores:

[0793] 0 (Completely clear)

[0794] 1 (Partial Clearing)

[0795] 2 (Moderate clearance)

[0796] 3 (Mild Removal)

[0797] 4 (No improvement).

[0798] IGA success is defined as an IGA score of 0 or 1 at follow-up.

[0799] Absolute lesion count is characterized by the following: "Complete clearance": No clinically visible or palpable AK lesions are present in the treated area; "Partial clearance": The number of AK lesions in the treated area is reduced by at least 75%.

[0800] The size of the lesion is calculated by measuring the vertical dimension of each selected target lesion and calculating its area, which is then summed as the total area of ​​all selected target lesions.

[0801] Secondary outcomes included safety, tolerability, and the percentage of AK lesion partial clearance.

[0802] Twenty-nine (29) patients were initially recruited. No treatment interruptions occurred. The application of the topical formulation resulted in a significant reduction in AK lesions: 50% (Group A) and 58% (Group B) achieved an IGA score of 0–1, respectively. Related adverse events (AEs) included pruritus (n=5), irritation (n=1), erythema (n=1), and burning sensation (n=1), all of which were mild and resolved. Seven (7) patients had mild erosion of lesions as part of the treatment effect. Thus, topical bimiralisib gel (2%) demonstrated efficacy in the treatment of AK with a favorable safety profile.

[0803] At subsequent time points, 46 adult patients with Olsen grade 1 or 2 actinic keratosis (face and / or scalp and / or back of hands) were randomized in a 1:1 ratio to receive bimiralisib gel treatment for 2 or 4 weeks. Forty-two (42) patients actually received treatment (4 patients withdrew after randomization and before treatment). At patient assessment, 35 patients had completed the initial treatment period and follow-up (18 patients in group A and 17 patients in group B). Two (2) patients were in the initial treatment period. Five (5) patients were in the safety / efficacy follow-up period (4 weeks). Sixteen (16) patients had entered the optional 8-week treatment extension period (provided to patients whose lesion size improved by at least 50% from baseline at the end of the 4-week follow-up period).

[0804] Security

[0805] Adverse events were based on the initial treatment period (2 or 4 weeks) and a 28-day safety follow-up. Table 10 summarizes all adverse events in the 42 treated patients at patient assessment. Table 11 summarizes treatment-related adverse events. Table 12 provides detailed information on treatment-related adverse events.

[0806] Table 10. All Adverse Events

[0807]

[0808] Table 11. Treatment-related adverse events

[0809]

[0810] Table 12. Detailed information on treatment-related adverse events

[0811]

[0812] At the time of patient assessment, most treatment-related adverse events had subsided (two events were ongoing and awaiting follow-up).

[0813] Except for one patient in group B who discontinued the study after 2 weeks due to grade 1 burning sensation in the treated area, all patients completed the initial treatment period without interruption. No significant laboratory abnormalities were found.

[0814] therapeutic effect

[0815] Table 13 summarizes the observed efficacy outcomes in 35 patients who met the primary endpoint at patient assessment (based on Investigator Global Assessment (IGA) compared to baseline).

[0816] Table 13. Summary of therapeutic effects

[0817]

[0818] 60% of patients (70% in group B and 50% in group A) achieved an IGA score of 0 or 1 at the primary endpoint. All 35 patients who achieved the primary endpoint at patient assessment showed some degree of clearance (6 patients with complete clearance, 15 patients with partial clearance, 13 patients with moderate clearance, and 1 patient with mild clearance).

[0819] Example 8: The formulation of the present invention

[0820] The following formulations were prepared:

[0821] Table 14. NA03-0.1%

[0822]

[0823] Table 15. NA03-0.5%

[0824]

[0825] Table 16. NA03-2%

[0826]

[0827] Table 17. NA03-3%

[0828]

[0829] By pre-weighing PEG400, Transcutol P ® To prepare the above formulation, diisopropyl adipate and glycerol were transferred to a glass laboratory container. The mixture was stirred at an appropriate speed to induce flow throughout the container until the solution was visually homogeneous. A pre-weighed amount of compound 1 was transferred to the container while stirring at a speed sufficient to induce flow throughout the container. The mixture was stirred until compound 1 dissolved. A pre-weighed amount of hydroxypropyl cellulose was transferred to the container while stirring at a speed suitable for generating sufficient eddies. Stirring was continued at an appropriate speed to induce flow throughout the container until the hydroxypropyl cellulose was completely dissolved.

[0830] Example 9: Stability testing of non-aqueous gel formulations NA03-2% and NA03-6.3%

[0831] Based on the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) stability testing standards, the non-aqueous gel formulations NA03-2% and NA03-6.3% underwent stability testing for up to 24 months. All procedures were performed in accordance with the current EU GMP guidelines for pharmaceuticals for clinical trials (IMP) as defined in EudraLex Guidelines, Volume 4. QC testing was conducted according to the principles of EU Directives 2001 / 20 / EC, 2003 / 94 / EC, and EudraLex cGMP guidelines.

[0832] Work Plan

[0833] Stability samples were stored in the stability test chamber during the study and removed from the chamber at specified time points for the analyses described below. Each test sample tube corresponding to NA03-2% was filled using a single container containing NA03-2%, and each test sample tube corresponding to NA03-6.3% was filled using a single container containing NA03-6.3%. To ensure thorough mixing of the contents of each container, three sample tubes filled at the beginning, middle, and end of the filling process were tested at the initial time point (T=0). Samples were stored under ambient conditions after being removed from the stability test chamber before and during stability testing.

[0834] The number of samples required for stability testing of each batch of formulation is listed in Table 18.

[0835] Table 18. Test samples for each formulation, based on 15 g filled tubes, placed in a stability test chamber at a specified temperature. The number of tubes (excluding QC release / t=0 tubes).

[0836]

[0837] The formulation was stored and tested in accordance with the ICH stability program, as detailed in Table 19. A specified number of tubes were removed from the stability test chamber and tested using the specific methods summarized below.

[0838] Table 19. Summary of stability storage conditions, time points, and tests based on a 15 g fill weight.

[0839]

[0840] X = Comprehensive testing (macroscopic appearance, microscopic appearance, API determination and related substances, apparent viscosity) — from 3 tubes

[0841] M = Modified Quantitative Test (MQT) test — from 2 tubes.

[0842] P = Preservative efficacy test — from 8 tubes.

[0843] ( ) = Alternative conditions. If unexpected or out-of-trend ("out of specification") results are obtained when testing is performed under 40 °C / 75 % RH storage conditions, then specific testing is performed on the product.

[0844] R = If possible, use batch release data for t=0.

[0845] At each time point, a total of 3 tubes were removed from the stability test chamber for comprehensive testing, as detailed in Table 19. An additional 2 tubes were used for microbial quality testing, and 8 tubes were used for preservative efficacy testing; these were only removed at specified time points, as detailed in Table 19.

[0846] The following analysis was performed on each batch:

[0847] • Determination of compound 1 and related substances.

[0848] • Macroscopic appearance (n=1 replicates per batch under each condition).

[0849] • Microscopic appearance (n=1 replicates per batch under each condition).

[0850] • Apparent viscosity (n=1 replicates per batch under each condition).

[0851] • Microbiological quality testing (n=1 replicates per batch, from 2 additional tubes).

[0852] • Preservative efficacy testing (n=1 replicates per batch, from an additional 8 tubes).

[0853] The formulation was analyzed by HPLC. The HPLC chromatograms were manually compiled using Empower software.

[0854] Table 20. Stability test results of NA03-2.0%.

[0855]

[0856] Table 21. HPLC test results of NA03-2.0%.

[0857]

[0858] Table 22. Microbial test results for NA03-2.0%.

[0859]

[0860] TAMC = Total Aerobic Microorganisms

[0861] TYMC = Total number of yeast / mold cells

[0862] Table 23. Stability test results of NA03-6.3%.

[0863]

[0864] Table 24. HPLC test results of NA03-6.3%.

[0865]

[0866] Table 25. Microbial test results for NA03-6.3%.

[0867]

[0868] TAMC = Total Aerobic Microorganisms

[0869] TYMC = Total number of yeast / mold cells

Claims

1. A topical pharmaceutical composition comprising: At least 0.1% by weight of the compound of formula (I): Equation (I), In the formula: W is H or F. Y is either N or CH. R 1 and R 2 Each is independently a morpholino group of formula (II). Equation (II), In the formula, R 3 and R 4 Each is independently H or C1-C3 alkyl, or R 3 and R 4 They combine to form divalent C1-C3 alkylene residues; At least 30% by weight of polyalkylene glycol, preferably at least 45% by weight of polyalkylene glycol; and At least 10% by weight of diethylene glycol monoethyl ether, preferably at least 15% by weight of diethylene glycol monoethyl ether.

2. The topical pharmaceutical composition according to claim 1, wherein, R 1 and R 2 Selected independently from: , , , , , , , , as well as .

3. The topical pharmaceutical composition according to claim 1, wherein, The compound of formula (I) is 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridine-2-amine: 。 4. The topical pharmaceutical composition according to any one of the preceding claims, wherein, The composition contains less than 1% water.

5. The topical pharmaceutical composition according to any one of the preceding claims, wherein, The composition contains less than 1% DMSO.

6. The topical pharmaceutical composition according to any one of the preceding claims, wherein, The composition comprises diisopropyl adipate, preferably about 1% to about 20% by weight.

7. The topical pharmaceutical composition according to any one of the preceding claims, wherein, The composition contains glycerol, preferably about 1% to about 10% by weight.

8. The topical pharmaceutical composition according to any one of the preceding claims, wherein, The composition comprises hydroxypropyl cellulose, preferably about 0.1% to about 10% by weight of hydroxypropyl cellulose.

9. The topical pharmaceutical composition according to any one of the preceding claims, wherein, The composition comprises about 45% to about 80% by weight of polyethylene glycol.

10. The topical pharmaceutical composition according to any one of the preceding claims, wherein, The composition comprises 15% by weight to about 35% by weight of diethylene glycol monoethyl ether.

11. The topical pharmaceutical composition according to any one of the preceding claims, wherein, The composition comprises at least 1.9% by weight of a compound of formula (I).

12. The topical pharmaceutical composition according to any one of the preceding claims, wherein, The topical pharmaceutical composition comprises about 45% to about 80% PEG, preferably PEG400; about 15% to about 35% diethylene glycol monoethyl ether; about 1% to about 20% diisopropyl adipate; about 1% to about 10% glycerol; about 0.1% to about 10% hydroxypropyl cellulose; and about 0.5% to about 8% compound 1.

13. A topical aqueous pharmaceutical composition, said topical aqueous pharmaceutical composition comprising: From about 45% by weight to about 80% by weight of polyalkylene glycols; From about 10% by weight to about 30% by weight of diethylene glycol monoethyl ether; From about 1% to about 10% by weight of diisopropyl adipate; From about 1% to about 10% by weight of glycerin; water, approximately 1% to approximately 20% by weight; and About 0.9% by weight to about 8% by weight of compounds of formula (I): Equation (I), In the formula: W is H or F. Y is either N or CH. R 1 and R 2 Each is independently a morpholino group of formula (II). Equation (II), In the formula, R 3 and R 4 Each is independently H or C1-C3 alkyl, or R 3 and R 4 They combine to form divalent C1-C3 alkylene residues.

14. Use of the topical pharmaceutical composition according to any one of claims 1-12 as a medicament.

15. Use of the topical pharmaceutical composition of claim 13 as a medicament.

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