Uracil skin medicine preparation

Abstract

The present disclosure provides topical pharmaceutical formulations and methods of administration comprising uracil and a penetration enhancer. Methods for treating or preventing skin conditions associated with the administration of 5-fluorouracil or its precursors or prodrugs, such as capecitabine, are also provided. The penetration enhancer is selected from the group consisting of dimethyl isosorbide, isopropyl myristate, isopropyl palmitate, octyldodecanol, oleic acid, oleyl alcohol, polyoxylglycerides, pyrrolidone, thymol, tricaprylin, triolein, myristic acid, medium-chain triglycerides, linoleic acid, lauric acid, glycofurol, glyceryl monooleate, ethyl oleate, dimethyl sulfoxide, dibutyl sebacate, and mixtures thereof.

Description

[Technical field]

[0001] The present invention relates to a uracil dermatological pharmaceutical formulation. [Background technology]

[0002] Capecitabine, originally branded XELODA (Roche), is a widely prescribed, orally available prodrug of the chemotherapy agent 5-fluorouracil (5-FU). Capecitabine is indicated in the United States, Canada, and internationally for the treatment of metastatic breast cancer (mBC), adjuvant colon cancer, and metastatic colorectal cancer. It is also commonly used "off-label" to treat patients with cancer, particularly gastric and esophageal cancer.

[0003] Capecitabine is absorbed unchanged from the gastrointestinal tract and is metabolized to 5-FU in three enzymatic steps. Thymidine phosphorylase (TP), found in high concentrations in certain tumors, selectively catalyzes the third metabolic step in the activation of 5-FU to active metabolites that achieve anticancer activity through the interference with RNA synthesis and inhibition of thymidylate synthase.

[0004] The major toxicity associated with capecitabine is hand-foot syndrome (HFS), also known as palmar-plantar erythrodysesthesia, which occurs in 60-70% of patients receiving capecitabine. This adverse effect limits the dose and / or length of time that capecitabine can be administered, thereby preventing patients from receiving the optimal dose or dosing schedule of capecitabine. The incidence, time to onset, and severity of HFS are related to both the dose and duration of capecitabine treatment. As the duration of treatment increases, the severity of HFS characteristically progresses from painless skin changes such as erythema and edema (Grade 1 [NCI Common Terminology Criteria for Adverse Events (AEs) Grading Scale for HFS]) to painful changes that affect daily life (Grade 2), severe changes such as skin peeling, blistering, bleeding (Grade 3), and pain requiring strong analgesics. According to the Xeloda prescribing information (March 2015), grade 3 or higher HFS occurs in 17-24% of patients. Although the pharmacological basis of capecitabine-induced HFS has not yet been fully elucidated, an increase in the rate of basal cell proliferation in the palms and soles of the hands and feet combined with elevated keratinocyte TP levels is thought to be the primary causative mechanism.

[0005]

[0004] Currently, there are no approved therapeutic agents for the treatment or prevention of HFS. The most effective treatment strategy requires interruption or discontinuation of capecitabine treatment. Usually, a change in the capecitabine dosing schedule is performed upon the occurrence of grade 2 HFS, and there is evidence that prolonged treatment interruption or dose reduction may reduce the efficacy of capecitabine in its approved indications. Summary of the Invention

[0006]

[0005] The present invention relates to a pharmaceutical formulation comprising uracil and a penetration enhancer, which, when applied topically, delivers uracil to the skin, thereby significantly delaying the onset and / or progression of HFS.

[0007] In some embodiments, the topical pharmaceutical formulation comprises about 0.05 to about 0.8% w / w uracil, about 2.0 to about 8% w / w of a penetration enhancer, about 0.01 to about 4% w / w of an alkalizing agent, about 0.01 to about 5% w / w of an antimicrobial preservative, about 10 to about 20% w / w of polyethylene glycol, about 10 to about 20% w / w of glycerin, about 0.1 to about 3% w / w of propylene glycol, about 0.01 to about 3% w / w of an acidifying agent, about 0.1 to about 3% w / w of a carbomer, about 1 to about 5% w / w of an oily internal phase vehicle, about 1 to about 5% w / w of an ionic emulsifier, about 0.1 to about 7% w / w of a nonionic emulsifier, and about 40 to about 70% w / w of water.

[0008]

[0007] The present invention also relates to a method of administration, comprising the step of applying about 0.08 to about 1.0 grams of the above-described topical pharmaceutical formulation to a mammal. In another embodiment of the method, about 0.1 to about 0.5 grams of the topical pharmaceutical formulation is applied to the mammal.

[0009]

[0008] The present invention further relates to a method for treating or preventing skin diseases associated with the administration of 5-fluorouracil or a prodrug thereof in a mammal in need thereof by topically administering to the mammal in need thereof the above-described formulation. [Brief description of the drawings]

[0010] [Figure 1] The protective mechanism of the uracil formulation (UTC, composition 7 in Table 3) provided herein for skill cells is shown. Figure 1A shows that in skin cells, 5-fluorouracil (5-FU) is enzymatically converted to a toxic metabolite that causes HFS. Figure 1B shows that composition 7 applied to the palms and soles creates a large local excess of uracil concentration in the skin. Uracil is a natural substrate for the enzyme that catabolizes 5-FU, preventing the formation of local skin toxicity and allowing toxic species to diffuse out of skin cells, reducing the likelihood of HFS. [Diagram 2] In Example 2, the highest grade of HFS observed for each patient in the treatment group (uracil cream - composition 2) and the placebo group (PTC, composition 1 in Table 1) is shown. [Diagram 3] 1 shows a Kaplan-Meier plot of the proportion of patients without grade ≥2 HFS from randomization in each study arm of Example 2. [Figure 4] Figure 1 shows the viability of human epidermal keratinocytes (HPEK) cells cultured in the presence of 5-FU and uracil. The presence of uracil, which protected against 5-FU, induced cell death in cultured HPEK cells. [Diagram 5] 1 shows a plot of the results of a Franz diffusion experiment for uracil topical formulations with increasing concentrations of dimethyl isosorbide (DMI). Formulations containing 0.3% uracil and 5% DMI outperformed all other formulations tested, even when compared to a formulation containing 15% DMI. The total amount of permeated uracil recovered from the receiver compartment at 12 hours was nearly identical when comparing all formulations. The uracil formulation with a penetration enhancer (UTC, composition 7 in Table 3) outperformed a uracil formulation without a penetration enhancer (1UO, composition 2 in Table 1), delivering a 6.5-fold increase in uracil compared to the 1UO formulation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011]

[0014] The present disclosure relates to a pharmaceutical formulation comprising uracil and a penetration enhancer, which, when applied topically, delivers uracil to the skin, thereby significantly delaying the onset and / or progression of HFS, i.e., painful reddening and cracking of the skin of the hands and feet, which can occur with systemic treatment with 5-fluorouracil or its precursors or prodrugs, such as capecitabine, or other chemotherapeutic agents.

[0012]

[0015] Uracil is a natural metabolite and a competitive substrate for enzymes that catabolize capecitabine to toxic metabolites that contribute to hand-foot syndrome (HFS). It has been demonstrated that the severity of HFS correlates positively with the response rate to capecitabine treatment, suggesting that increased drug exposure may improve treatment outcome. See, e.g., Chua et al., Proceedings of ASCO 22 (2003); Chua et al., Jpn J Clin Oncol 38:244-249 (2008); Kurt et al., Acta Oncol 45:625-626 (2006); Yun et al., J Korean Soc Coloproctol 26:287-292 (2010); Zielinski et al., British Journal of Cancer 114:163-170 (2016); and Clark et al., Support Cancer Ther 1:213-218 (2004).

[0013]

[0016] Advantageously, the pharmaceutical formulations of the present disclosure reduce the incidence of HFS, exhibit improved aesthetic properties, and deliver greater amounts of uracil (e.g., 6.5 times more than other formulations) into the skin, i.e., the site of uracil action, without increasing the amount of uracil that penetrates through the skin into the systemic circulation.

[0014]

[0017] Therefore, administration of the formulation allows for a longer administration period of sufficient doses of capecitabine therapeutic agent (or other chemotherapeutic agent) without interfering with the chemotherapeutic effect of capecitabine, thus improving the therapeutic response to capecitabine treatment. Thus, the uracil formulation can improve the quality of life, response rate, progression-free survival, and overall survival of patients.

[0015]

[0018] A further advantage of the formulation is that it can be manufactured on a large scale (eg, 75 kg batch size) with reproducible product specifications, analytical profile, and stability.

[0016]

[0019] In some embodiments, the present disclosure provides a composition comprising about 0.05 to about 0.8% w / w uracil, about 2 to about 8% w / w of a penetration enhancer, about 0.01 to about 4% w / w of an alkalizing agent, about 0 to about 5% w / w of an antimicrobial preservative, about 10 to about 40% w / w of a solvent selected from the group consisting of polyethylene glycol 400, glycerin, propylene glycol, and mixtures thereof, about 0.01 to about 3% w / w of an acidifying agent, about 0.1 to about 3% w / w of a carbomer, polycarbophil, polyvinyl alcohol, povidone, hypromellose, sodium hyaluronate, hyaluronic acid, xanthan gum, pectin, methylcellulose, hydroxypropylcellulose, glyceryl stearate ... The present invention provides a topical pharmaceutical formulation comprising a gel-forming agent selected from the group consisting of propylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, guar gum, dextrin, copovidone, ceratonia, carrageenan, alginic acid, sodium carboxymethylcellulose, calcium carboxymethylcellulose, ammonium alginate, sodium alginate, gum arabic, and potassium alginate, and mixtures thereof, about 1 to about 5% w / w of an oily internal phase vehicle, about 0 to about 5% w / w of an ionic emulsifier, about 0 to about 7% w / w of a non-ionic emulsifier, and about 40 to about 70% w / w of water.

[0017]

[0020] In another embodiment, the present disclosure provides a topical pharmaceutical formulation comprising about 0.05 to about 0.5% w / w uracil, about 3 to about 6% w / w of a penetration enhancer, about 0.01 to about 4% w / w of an alkalizing agent, about 0.01 to about 5% w / w of an antimicrobial preservative, about 10 to about 20% w / w of polyethylene glycol, about 10 to about 20% w / w of glycerin, about 0.1 to about 3% w / w of propylene glycol, about 0.1 to about 3% w / w of an acidifying agent, about 0.1 to about 3% w / w of a carbomer, about 1 to about 5% w / w of an oily internal phase vehicle, about 1 to about 5% w / w of an ionic emulsifier, about 0.1 to about 7% w / w of a non-ionic emulsifier, and about 40 to about 70% w / w of water.

[0018]

[0021] In yet another embodiment, the present disclosure provides a composition comprising about 0.05 to about 0.6% w / w uracil, about 3.0 to about 10% w / w dimethyl isosorbide, about 0.1 to about 2% w / w ammonia solution (about 29%), about 0 to about 2% w / w methylparaben, about 0 to about 2% w / w propylparaben, about 10 to about 20% w / w polyethylene glycol, about 10 to about 20% w / w glycerin, about 0 to about 3% w / w The present invention provides a topical pharmaceutical formulation comprising about 0 to about 3% w / w propylene glycol, about 0 to about 3% w / w hydrochloric acid (about 20%), about 0.1 to about 5% w / w carbomer, about 0.1 to about 2% w / w trolamine, about 1 to about 5% w / w dimethicone, about 1 to about 5% w / w stearic acid, about 0 to about 4% w / w polysorbate, about 0 to about 3% w / w sorbitan monooleate, and about 40 to about 80% w / w water.

[0019]

[0022] In some embodiments, the present disclosure provides an improved formulation comprising about 0.05 to about 0.6% w / w uracil, about 3.0 to about 10% w / w dimethyl isosorbide, about 0.1 to about 2% w / w ammonia solution (about 29%), about 0 to about 2% w / w methylparaben, about 0 to about 2% w / w propylparaben, about 10 to about 20% w / w polyethylene glycol, about 10 to about 20% w / w glyceryl. The present invention provides a topical pharmaceutical formulation comprising about 0 to about 3% w / w of propylene glycol, about 0 to about 3% w / w of hydrochloric acid (about 20%), about 0.1 to about 5% w / w of carbomer, about 0.1 to about 2% w / w of trolamine, about 1 to about 5% w / w of dimethicone, about 1 to about 7% w / w of a nonionic emulsifier, about 0 to about 5% w / w of an ionic emulsifier, and about 40 to about 80% w / w of water.

[0020]

[0023] In other embodiments, the present disclosure provides an aqueous emulsion containing from about 0.05 to about 0.6% w / w uracil, from about 3.0 to about 10% w / w dimethyl isosorbide, from about 0.1 to about 4% w / w alkalizing agent, from about 0.1 to about 2% w / w methylparaben, from about 0.01 to about 1% w / w propylparaben, from about 10 to about 40% w / w polyethylene glycol 400, glycerin, propylene glycol, and mixtures thereof. and about 40 to about 60% w / w of water.

[0021]

[0024] In other embodiments, the present disclosure provides a composition that is an effective amount of uracil at about 0.05 to about 0.5% w / w, dimethyl isosorbide at about 3.0 to about 8% w / w, ammonia solution at about 0.1 to about 2% w / w (about 29%), methylparaben at about 0.1 to about 2% w / w, propylparaben at about 0.01 to about 1% w / w, polyethylene glycol 400 at about 10 to about 20% w / w, glycerin at about 10 to about 20% w / w, A topical pharmaceutical formulation is provided which comprises propylene glycol, about 0.01 to about 3% w / w hydrochloric acid (about 20%), about 0.1 to about 3% w / w carbomer 940, about 0.1 to about 2% w / w trolamine, about 1 to about 5% w / w dimethicone, about 1 to about 5% w / w stearic acid, about 0.5 to about 4% w / w polysorbate 80, about 0.1 to about 3% w / w sorbitan monooleate, and about 40 to about 60% w / w water.

[0022]

[0025] In other embodiments, the present disclosure provides a composition comprising about 0.3% w / w uracil, about 5.0% w / w dimethyl isosorbide, about 0.9 to about 1.1 The present invention provides a topical pharmaceutical formulation comprising about 29% w / w ammonia solution, about 0.4 to about 0.6% w / w methylparaben, about 0.04 to about 0.06% w / w propylparaben, about 14 to about 16% w / w polyethylene glycol 400, about 13 to about 15% w / w glycerin, about 1 to about 2% w / w propylene glycol, about 0.01 to about 0.1% w / w hydrochloric acid (about 20%), about 1 to about 2% w / w carbomer 940, about 0.4 to about 0.6% w / w trolamine, about 3 to about 4% w / w dimethicone, about 2 to about 3% w / w stearic acid, about 1 to about 2% w / w polysorbate 80, about 0.9 to about 2% w / w sorbitan monooleate, and about 50 to about 60% w / w water.

[0023]

[0026] In some embodiments, the formulation comprises about 0.07 to about 0.4% w / w, about 0.08 to about 0.4%, about 0.09 to about 0.38%, about 0.09 to about 0.35%, about 0.1 to about 0.3%, or about 0.1 to about 0.6% uracil.

[0024]

[0027] In some embodiments, the formulation comprises from about 10 to about 60% w / w solvent, from about 15 to about 60%, or from about 20 to about 50%.

[0025]

[0028] In some embodiments, the formulation comprises about 1.0 to about 20%, about 2 to about 15%, about 3 to about 10%, about 3.5 to about 6%, or about 4 to about 5.5%, or about 4% or about 5% w / w of a penetration enhancer.

[0026]

[0029] In some embodiments, the formulation comprises from about 0.1 to about 4%, from about 0.5 to about 3%, or from about 0.9 to about 2% w / w of an alkalizing agent.

[0027]

[0030] In some embodiments, the formulation comprises about 0.01 to about 5%, about 0.1 to about 2%, about 0.2 to about 1.5%, about 0.4 to about 1%, or about 0.4 to about 0.8% w / w of an antimicrobial preservative.

[0028]

[0031] In some embodiments, the formulation comprises from about 0.01 to about 5%, from about 0.01 to about 5%, or from about 0.05 to about 4% w / w of an acidifying agent.

[0029]

[0032] In some embodiments, the formulation comprises about 0.1 to about 5%, about 0.9 to about 4%, or about 1 to about 2% w / w of a gel forming agent.

[0030]

[0033] In some embodiments, the formulation comprises about 1 to about 10%, about 1 to about 3%, or about 3 to about 4% w / w of an oily internal phase vehicle.

[0031]

[0034] In some embodiments, the formulation comprises about 0.5 to about 10%, about 1 to about 5%, about 1 to about 4%, or about 2 to about 4% w / w of an ionic emulsifier.

[0032]

[0035] In some embodiments, the formulation comprises from about 0.1 to about 10%, from about 0.5 to about 5%, or from about 0.9 to about 2% w / w of a non-ionic emulsifier.

[0033]

[0036] In some embodiments, the formulations contain about 0.5 to about 20%, about 1 to about 15%, about 1 to about 10%, about 3.0 to about 6%, about 3.5 to about 5.5%, or about 4 to about 5.5% w / w of dimethyl isosorbide, about 0.1 to about 4%, about 0.5 to about 3%, or about 0.9 to about 1.1 w / w of ammonia solution (about 29%), about 0.1 to about 2% w / w, about 0.3 to about 1%, or about 0.4 to about 0.6% w / w of methylparaben, about 0.01 to about 2% w / w, about 0.03 to about 1%, or about 0.04 to about 0.06% w / w of propylparaben, about 5 to about 20%, about 10 to about 18%, or about 12 to about 16% w / w of Polyethylene glycol 400, about 5 to about 20%, about 10 to about 18%, or about 12 to about 15% w / w glycerin, about 0.1 to about 5%, about 0.5 to about 3%, or about 1 to 2% w / w propylene glycol, about 0.02 to about 3%, about 0.03 to about 2%, about 0.03 to about 1%, or about 0.04 to about 0.06% w / w hydrochloric acid (about 20%), about 0.1 to about 5%, about 0.9 to about 4%, or about 1 to about 2% w / w of Carbomer 940, about 1 to about 5%, about 2 to about 4%, or about 3 to about 4% w / w of Dimethicone, about 0.1 to about 2%, about 0.3 to about 1%, or about 0.4 to about 0.8% w / w of Trolamine, about 1 to about 5%, about 1 to about 4%, or about 2 to about 4% w / w of Stearyl Alcohol, oleic acid, about 1 to about 5%, about 1 to about 4%, about 1 to about 3% w / w, or about 1 to about 2% w / w of polysorbate 80, about 0.1 to about 7%, about 0.5 to about 5%, or about 0.9 to about 2% w / w of sorbitan monooleate, and about 40 to about 70%, about 45 to about 65%, about 50 to about 60%, or about 50 to about 56% w / w of water.

[0034]

[0037] In some embodiments, the penetration enhancer is selected from the group consisting of dimethyl isosorbide (Gransolve DMI), isopropyl myristate, isopropyl palmitate, octyldodecanol, oleic acid, oleyl alcohol, polyoxylglycerides, pyrrolidone, thymol, tricaprylin, triolein, myristic acid, medium chain triglycerides, linoleic acid, lauric acid, glycofurol, glyceryl monooleate, ethyl oleate, dimethyl sulfoxide, dibutyl sebacate, and mixtures thereof.

[0035]

[0038] In some embodiments, the alkalinizing agent is selected from the group consisting of ammonia solution, trolamine, tromethamine, sodium hydroxide, potassium hydroxide, diethanolamine, monoethanolamine, potassium citrate, sodium citrate, sodium bicarbonate, sodium borate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium acetate, sodium phosphate, meglumine, and mixtures thereof.

[0036]

[0039] In some embodiments, the antimicrobial preservative is selected from the group consisting of methylparaben, ethylparaben, propylparaben, butylparaben, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, benzoic acid, potassium benzoate, sodium benzoate, propionic acid, sodium propionate, potassium propionate, phenoxyethanol, phenylethyl alcohol, sorbic acid, sodium lactate, lactic acid, thymol, xylitol, imidurea, hexetidine, EDTA, cresol, chloroxylenol, chlorocresol, chlorobutanol, chlorhexidine, cetrimide, calcium lactate, calcium acetate, butylene glycol, bronopol, boric acid, benzyl alcohol, and mixtures thereof.

[0037]

[0040] In some embodiments, the acidifying agent is selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, nitric acid, citric acid, propionic acid, adipic acid, lactic acid, phosphoric acid, tartaric acid, maleic acid, fumaric acid, calcium chloride, ammonium chloride, and mixtures thereof.

[0038]

[0041] In some embodiments, the oily internal phase medium is selected from the group consisting of dimethicone, various grades of vegetable oils, mineral oil, isopropyl palmitate, octyldodecanol, oleyl alcohol, petrolatum, simethicone, tricaprylin, triolein, myristyl alcohol, medium chain triglycerides, glyceryl monooleate, ethyl oleate, dibutyl sebacate, cyclomethicone, and mixtures thereof.

[0039]

[0042] In some embodiments, the ionic emulsifier is selected from the group consisting of stearic acid, oleic acid, palmitic acid, sodium lauryl sulfate, anionic emulsifying wax, myristic acid, linoleic acid, lecithin, lauric acid, sodium docusate, aluminum monostearate, and mixtures thereof.

[0040]

[0043] In some embodiments, the nonionic emulsifier is selected from the group consisting of sorbitan monooleate; polyoxyethylene alkyl ethers; polysorbates; polyoxyethylene castor oil derivatives; polyoxyethylene stearates; polyoxylglycerides; sorbitan laurate, palmitate, stearate, trioleate, sesquioleate, dioleate, sesquiisostearate, sesquistearate, triisostearate, tristearate, diisostearate, or monoisostearate; nonionic emulsifying wax; myristyl alcohol; medium chain triglycerides; macrogol 15 hydroxystearate; glyceryl monooleate; cholesterol; cetyl alcohol; cetostearyl alcohol; monoglycerides; diglycerides; triton X-100; and mixtures thereof.

[0041]

[0044] In some embodiments, the penetration enhancer is dimethylisosorbide and the ratio of w / w concentrations of uracil to dimethylisosorbide is about 0.3 to 5. In some embodiments, the concentration of uracil is about 0.3% w / w and the concentration of dimethylisosorbide is about 5.0% w / w.

[0042]

[0045] In some embodiments, the amount of uracil permeated from the formulation as measured using IVTP is about 150.6 ng / cm 2 In some embodiments, the permeation of uracil from the formulation as measured using IVTP is less than about 160.0, about 145.0, about 140.0, or about 135.0 ng / cm 2 is less than.

[0043]

[0046] In some embodiments, the topical pharmaceutical formulation does not include a methyl methacrylate polymer.

[0044]

[0047] In other embodiments, the formulation is an emulsion and the viscosity of the formulation is about 100,000 to about 400,000 cps, or about 250,000 to about 320,000 cps. Viscosity can be measured, for example, by a Brookfield LVDV II+ viscometer (Brookfield Engineering Labs, Inc.) with a TF spindle at 2 rpm for 1 minute with the helipath turned on.

[0045]

[0048] As used herein, an active ingredient is a component of a formulation that achieves a desired pharmacological effect at the intended site of action. Active ingredients that may be used in the formulation include uracil.

[0046]

[0049] Solvent as used herein refers to a component of the formulation that dissolves or helps dissolve one or more other components of the formulation.One solvent that can be used in the formulation is water.In addition to water, the formulation can include one or more of the following solvents: propylene glycol, glycerin, various grades of polyethylene glycol (e.g. 200, 300, 400, 540, 600, 900, 1000, 1450, 1540, 2000, 3000, 3350, 4000, 4600, 8000), polyethylene oxide, poloxamer, propylene carbonate, pyrrolidone, sorbitol, xylitol, glycofurol.

[0047]

[0050] As used herein, a penetration enhancer is a component of a formulation that interferes with the normal barrier properties of the skin to increase the rate at which an active ingredient can penetrate the skin. The permeation amount is the amount of drug delivered to and retained in the skin (i.e., the site of action) at a particular time point after topical application of the drug. The permeation amount is the amount of drug that passes through the skin and enters the systemic circulation (a systemic increase in uracil levels is undesirable so that uracil levels do not interfere with chemotherapy) and into the receiver fluid in an in vitro permeation test (IVPT) as described in Example 5. Preferably, the permeation amount of uracil from a topical formulation of the present invention is 150.6 ng / cm over 12 hours. 2 is less than.

[0048]

[0051] The formulation preferably includes one or more penetration enhancers, such as dimethyl isosorbide (Gransorb DMI), isopropyl myristate, isopropyl palmitate, octyldodecanol, oleic acid, oleyl alcohol, polyoxylglycerides, pyrrolidone, thymol, tricaprylin, triolein, myristic acid, medium chain triglycerides, linoleic acid, lauric acid, glycofurol, glyceryl monooleate, ethyl oleate, dimethyl sulfoxide, and dibutyl sebacate.

[0049]

[0052] An alkalizing agent, as used herein, refers to a component of a formulation that increases the pH of the mixture into which it is introduced. Preferably, the formulation includes two alkalizing agents. Preferably, the formulation includes one or more alkalizing agents, such as ammonia solution, trolamine, tromethamine, sodium hydroxide, potassium hydroxide, diethanolamine, monoethanolamine, potassium citrate, sodium citrate, sodium bicarbonate, sodium borate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium acetate, sodium phosphate, and meglumine.

[0050]

[0053] As used herein, antimicrobial preservative refers to a formulation component that, alone or in combination with other components, helps to kill or inhibit the growth of microorganisms such as bacteria, fungi, and / or yeast.Preferably, the formulation comprises one or more antimicrobial preservatives, such as methylparaben, ethylparaben, propylparaben, butylparaben, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, benzoic acid, potassium benzoate, sodium benzoate, propionic acid, sodium propionate, potassium propionate, phenoxyethanol, phenylethyl alcohol, sorbic acid, sodium lactate, lactic acid, thymol, xylitol, imidurea, hexetidine, EDTA, cresol, chloroxylenol, chlorocresol, chlorobutanol, chlorhexidine, cetrimide, calcium lactate, calcium acetate, butylene glycol, bronopol, boric acid, and benzyl alcohol.

[0051]

[0054] An acidifying agent, as used herein, is a component of a formulation that reduces the pH of the mixture in which it is introduced. Preferably, the formulation includes one or more acidifying agents, such as hydrochloric acid, sulfuric acid, acetic acid, nitric acid, citric acid, propionic acid, adipic acid, lactic acid, phosphoric acid, tartaric acid, maleic acid, fumaric acid, calcium chloride, and ammonium chloride.

[0052]

[0055] As used herein, a gel-forming agent is a component of the formulation that forms a viscous gel when dissolved / dispersed in a suitable solvent.Preferably, the formulation includes one or more gel-forming agents, such as carbomer (e.g., carbomer 940, or other grades of carbomer, e.g., 934, 934P, 941, 1342) copolymers, homopolymers, interpolymers), polycarbophil, polyvinyl alcohol, povidone, hypromellose, sodium hyaluronate, hyaluronic acid, xanthan gum, pectin, methylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose, guar gum, dextrin, copovidone, ceratonia, carrageenan, alginic acid, sodium carboxymethylcellulose, calcium carboxymethylcellulose, ammonium alginate, sodium alginate, gum arabic, and potassium alginate.

[0053]

[0056] As used herein, the term "oil-based internal phase (emulsion) vehicle" refers to the hydrophobic component of the formulation that, alone or in combination with other components, constitutes the internal phase (discontinuous phase) of the oil-in-water emulsion.Preferably, the formulation comprises one or more oil-based internal phase (emulsion) vehicles, such as dimethicone, various grades of vegetable oils, mineral oil, isopropyl palmitate, octyldodecanol, oleyl alcohol, petrolatum, simethicone, tricaprylin, triolein, myristyl alcohol, medium chain triglycerides, glyceryl monooleate, ethyl oleate, dibutyl sebacate, and cyclomethicone.

[0054]

[0057] As used herein, an ionic emulsifier refers to a formulation component that (1) contains at least one functional group that is substantially ionized at the pH of the mixture in which the component is used, and (2) serves to form emulsions and / or stabilize emulsion formulations.Preferably, the formulation contains one or more ionic emulsifiers, such as stearic acid, oleic acid, palmitic acid, sodium lauryl sulfate, anionic emulsifying wax, myristic acid, linoleic acid, lecithin, lauric acid, sodium docusate, and aluminum monostearate.

[0055]

[0058] As used herein, a nonionic emulsifier is a formulation component that (1) does not contain functional groups that are substantially ionized at the pH of the mixture in which it is used, and (2) aids in forming emulsions and / or stabilizing the emulsion formulation. The formulation may contain one or more nonionic emulsifiers, such as sorbitan monooleate, polyoxyethylene alkyl ethers, various polysorbate grades (20, 21, 40, 60, 61, 65, 80, 81, 85, and 120), polyoxyethylene castor oil derivatives, polyoxyethylene stearates, polyoxylglycerides, other sorbitan esters (laurate, palmitate, stearate, trioleate, sesquioleate, dioleate, etc.). Preferred emulsifying agents include glyceryl stearate, sesquiisostearic acid ester, sesquistearic acid ester, triisostearic acid ester, tristearate, diisostearate, monoisostearate), nonionic emulsifying wax, myristyl alcohol, medium chain triglycerides, macrogol 15 hydroxystearate, glyceryl monooleate, cholesterol, cetyl alcohol, cetostearyl alcohol, mono- and diglycerides, and Triton X-100.

[0056]

[0059] A non-active ingredient in a formulation can serve more than one function in the formulation.

[0057]

[0060] Solvents (especially water) can also act as diluents, meaning that they reduce the concentration of other ingredients in the formulation. Solvents can also act as humectants. Humectants are ingredients of the formulation that, when applied to the skin, retain moisture in the outer layer of the skin to increase the hydration level of the skin. Some solvents can also act as stabilizers, meaning that they help prevent phase separation in emulsions. Some solvents or oil-based internal phase vehicles can also act as lubricants, meaning that they provide a slippery feel when applied to the skin. Some solvents can also act as coating agents, meaning that they help the formulation to spread evenly across the surface of the skin. Some solvents can also act as emollients, meaning that they soften the skin.

[0058]

[0061] One or more alkalizing agents may also act as solubilizing agents, meaning that they increase the rate and / or extent to which another component in the formulation dissolves in a solvent with which they are in contact.An alkalizing agent may also act as a buffering agent, meaning that they allow a mixture to withstand a change in pH when small amounts of acid or base are added.

[0059]

[0062] Gel formers and some solvents can also act as thickeners, meaning that they increase the viscosity of a mixture into which they are introduced, either alone or in combination with another component.

[0060]

[0063] Some oil-based internal phase vehicles can also act as anti-foaming agents, meaning that they help the formulation to dissipate air bubbles and / or prevent air bubbles from forming.

[0061]

[0064] Some ionic emulsifiers can also act as stiffening agents, meaning that they specifically increase the viscosity of the emulsion.

[0062]

[0065] In some embodiments, the disclosure provides a method of administration comprising applying about 0.08 to about 1.0 grams of the topical pharmaceutical formulation to the mammal. In other embodiments of the method, about 0.1 to about 0.5 grams of the topical pharmaceutical formulation is applied to the mammal.

[0063]

[0066] In some embodiments, the present disclosure provides a method of treating or preventing a skin disease associated with administration of 5-fluorouracil or a prodrug thereof in a mammal in need thereof by topically administering to a mammal in need thereof a topical pharmaceutical formulation as described above.

[0064]

[0067] In some embodiments, the mammal is a human and the formulation is applied to the palms of the human hands. In some embodiments, the mammal is a human and the formulation is applied to the soles of the human feet.

[0065]

[0068] In some embodiments, the amount of the formulation applied is about 0.333 grams to about 0.666 grams. In some embodiments, the amount of the formulation applied is about 0.1 to about 0.7 grams, about 0.3 to about 0.4 grams, or about 0.5 to about 0.7 grams.

[0066]

[0069] In some embodiments, the disclosure provides a method of preventing chemotherapy-associated hand-foot syndrome (HFS), comprising administering the formulation to the palms and / or soles of a mammal in need thereof receiving systemic treatment with a 5-fluoropyrimidine, e.g., 5-fluorouracil, or a precursor or prodrug thereof, e.g., capecitabine. In some embodiments, the mammal is receiving systemic capecitabine. In some embodiments, the mammal is receiving 5-fluorouracil. In some embodiments, the mammal is a human.

[0067]

[0070] In some embodiments, the administering step is performed twice daily while the mammal is undergoing capecitabine treatment. In some embodiments, the administration is initially performed about 5 to about 30 minutes prior to the administration of capecitabine. In some embodiments, the administration is initially performed about 15 minutes prior to the administration of capecitabine. Treatment is preferably initiated at least about 15 minutes prior to the administration of capecitabine, although treatment may be initiated earlier and treatment is continued throughout the use of capecitabine.

[0068]

[0071] In some embodiments, about one-third of a gram of the formulation (containing about 1 mg of uracil) is administered per palm or sole of each foot, hi some embodiments, about 0.8 mg to about 1.2 mg of uracil is administered per palm or sole of each foot.

[0069]

[0072] The formulation is applied topically twice daily (BID) to the palms of both hands and soles of both feet for 21 days per cycle, and in addition, capecitabine 1000 mg / m2 is administered orally (PO) twice daily on days 1-14 of every 21 days.

[0070]

[0073] The formulation is applied on a continuous schedule without interruption in treatment while the mammal is undergoing systemic treatment with a 5-fluoropyrimidine, such as 5-fluorouracil, or a precursor or prodrug thereof, such as capecitabine.

[0071]

[0074] In some embodiments, the formulations of the present invention are for use in treating or preventing skin diseases associated with administration of 5-fluorouracil or a prodrug thereof in a mammal in need thereof, hi other embodiments, the formulations are for use in preventing systemic chemotherapy-associated hand-foot syndrome (HFS) in a mammal in need thereof.

[0072]

[0075] In some embodiments of these uses of the formulation, the mammal is a human and the formulation is applied to the palms or soles of the human's feet. In some embodiments, the amount of formulation applied is about 0.1 to about 0.5 grams. In other embodiments, the amount of formulation applied is about 0.3 to about 0.4 grams, or about 0.5 to about 0.7 grams.

[0073] [Definition]

[0076] As used herein, "a" or "an" means one or more, unless otherwise specified. As used herein, the terms "a" or "an," when used in combination with the term "comprising," means one, or more than one, unless otherwise specified. As used herein, "another" or "further" may mean at least a second or more.

[0074]

[0077] The term "about," when used in conjunction with a numerical value or range, modifies that value or range by extending the boundaries above and below the numerical values ​​set forth. In general, the term "about" is used herein to modify numerical values ​​above and below the set forth value by a variation of 10 percent above or below (high or low) the value in question, i.e., ±10%, unless a different variation (e.g., ±30%, ±20%, ±5%, ±1%, ±0.5%, etc.) is indicated.

[0075]

[0078] As used herein, "percent" or "%" means percent by weight (w / w) unless otherwise specified.

[0076]

[0079] Use of the term "or" in the claims is used to mean "and / or" unless expressly indicated to refer to alternatives only or unless the alternatives are mutually exclusive, however, the present disclosure supports a definition that refers to both alternatives only and "and / or."

[0077]

[0080] As used herein, the terms "comprising" (and any variation or form of comprising, such as "comprise" and "comprises"), "having" (and any variation or form of having, such as "have" and "has"), "including" (and any variation or form of including, such as "includes" and "include"), or "containing" (and any variation or form of containing, such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0078]

[0081] Where features or aspects of the disclosure or claims are described in terms of a Markush group, one of skill in the art will recognize that the disclosure also is described herein in terms of any individual members or subgroups of members of the Markush group.

[0079]

[0082] Moreover, all ranges disclosed herein encompass all possible subranges and combinations of subranges thereof. Any range recited can be readily recognized as fully descriptive and allowing for the range to be divided into at least two, three, four, five, ten, etc. As a non-limiting example, each range described herein can be readily divided into a lower third, a middle third, and an upper third, etc. As one of skill in the art will also appreciate, all terms such as "up to," "at least," "greater than," "less than," etc. are inclusive of the recited numbers and refer to ranges that can be subsequently divided into subranges as described above. Finally, as one of skill in the art will appreciate, a range includes each individual member. For example, a group having 1 to 3 members refers to a group having 1, 2, or 3 members. Similarly, a group having 1 to 5 members refers to a group having 1, 2, 3, 4, or 5 members, and so forth.

[0080]

[0083] As used herein, methyl methacrylate polymer refers to a synthetic polymer of methyl methacrylate (an organic methyl ester) called poly(methyl methacrylate) (PMMA).

[0081]

[0084] The use of the term "for example" and its corresponding abbreviation "eg" (whether italicized or not) means that the particular terms being described are representative examples and embodiments of the present disclosure that are not intended to be limited to the specific examples being mentioned or referenced, unless expressly stated otherwise.

[0082]

[0085] As used herein, "between" refers to a range that includes both ends of the range. For example, a number between x and y specifically includes the numbers x and y, as well as any number that is within the range between x and y.

[0083]

[0086] All references cited herein, including patents, patent applications, articles, textbooks, and the like, and the references cited therein, are hereby incorporated by reference in their entirety, to the extent that they have not already been incorporated. EXAMPLES

[0084]

[0087] The present disclosure is further illustrated in the following examples, which are merely illustrative and do not limit the scope of the present invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present disclosure. The present disclosure is illustrated, but is not limited to, the following examples.

[0085]

[0088] Example 1. Formulation

[0089] Four types of cream formulations were prepared, as shown in Table 1 below. [Table 1]

[0086]

[0090] Each of the formulations described in Table 1 above was prepared according to the following procedure.

[0091] Phase A was prepared by combining the Phase A ingredients in an appropriate sized auxiliary container. The ingredients were mixed until the uracil was completely dissolved. The mixture was warmed slightly to less than 50°C to aid in dissolution. This Phase A auxiliary container then contained the completed Phase A. Phase B was prepared in another appropriate sized auxiliary container (Phase B auxiliary container) by combining the Phase B ingredients and heating to 50-60°C. The ingredients were mixed until most of the parabens were dissolved. Phase A was transferred to the Phase B auxiliary container. The alkalinity of Phase A aided in paraben dissolution. While maintaining the temperature at 50-60°C, Phases A and B were mixed until all ingredients were dissolved. This Phase B auxiliary container then contained the combination of Phase A and Phase B ingredients. Phase C was prepared in another appropriate sized container (Main container) by adding the ingredients in the order listed. The Carbomer 940 was dispersed by very rapid agitation. If gel bodies were present, the mixture was lightly homogenized to achieve uniformity, then the Trolamine was added. After the trolamine was added, phase C became very viscous and clear. Phase C was heated to 50°C and maintained at this temperature. Phase D (in auxiliary container D) and phase E (in auxiliary container E) were prepared in two separate appropriately sized auxiliary containers. Phases D and E were each heated to 80°C, and then phase E was added to phase D, which now contains the combination of phases E and D. The contents of auxiliary container D were cooled to 45-55°C with mixing. The contents of auxiliary container D were added to phase C in the main container, which now contains the combination of phases C, D and E.

[0087]

[0092] While the contents of the main vessel were still warm (approximately 40-55°C), phases A and B from auxiliary vessel B were added to the main vessel, which now contains all phases. The contents were mixed until uniform. A smooth, white, pearlescent cream was formed.

[0088]

[0093] Example 2. Preliminary clinical trials of uracil formulations

[0094] A randomized, double-blind, placebo-controlled, Phase 1-2 clinical trial was conducted in 18 metastatic breast cancer patients being treated with capecitabine to evaluate the efficacy of topical application of uracil, composition no. 2 in Table 1 above. Nine patients were randomized to placebo (PTO, composition no. 1 in Table 1). Patients were instructed to thoroughly rub the formulation (composition no. 2 (uracil) or composition no. 1 (placebo)) into the palms of both hands and the soles of both feet twice daily following each twice-daily capecitabine treatment. Capecitabine was administered at the approved dose of 1250 mg / m twice daily on days 1-14 of each 21-day cycle. 2 Treatment was continued for a maximum of six cycles unless tumor progression was documented, unacceptable toxicity occurred, or consent was withdrawn.

[0089]

[0095] Adverse events (AEs), including hand-foot syndrome (HFS), were evaluated on days 1 and 15 of each treatment cycle and upon completion or discontinuation of the study. The incidence of HFS according to the highest grade (NCI CCTAE scale) in each patient was recorded as a function of study arm.

[0090]

[0096] The resulting distribution of the incidence of HFS according to the highest grade in each patient as a function of study group is shown in Figure 2 . [Table 2]

[0091]

[0097] Table 2 above summarizes the time from randomization for grade 2 or higher HFS in each study group. If a patient did not develop grade 2 or higher HFS, they were removed as event-free at the last follow-up evaluation. Any grade of HFS was observed in 5 patients (55.5%) in the uracil cream (composition 2) group and 7 patients (77.8%) in the placebo group. HFS grade 2 or higher was observed in 4 patients (44.4%) in the uracil cream group and 7 patients (77.8%) in the PTO group. Dose reduction or interruption was required for grade 2 or higher HFS in 2 patients (22.2%) in the uracil cream group and 6 patients (66.7%) in the PTO group. The Xeloda prescribing information specifies that upon the occurrence of grade 2 or higher HFS, capecitabine administration should be interrupted or reduced to avoid the development of severe grade 3 HFS and prolonged treatment interruption. Importantly, patients in the uracil cream group had a significantly longer time to development of grade ≥2 HFS compared with patients in the PTO group (treatment group hazard ratio (HR) = 0.33, p = 0.09).

[0092]

[0098] Figure 3 shows the Kaplan-Meier plot of the proportion of patients without grade 2 or higher HFS from randomization in each study group. Although the small number of study patients does not allow precise quantification of the preventive effect of uracil cream on capecitabine-associated HFS, the study results show that uracil cream delays the onset of clinically significant grade HFS. One patient in each group experienced one AE attributable to the topical cream, and there were no serious adverse events (SAEs) attributable to the study drug. A high proportion of patients in each study group exhibited AEs. It is well known that most AEs are caused by capecitabine and / or the underlying disease.

[0093]

[0099] Thus, the overall incidence of all grades of HFS was similar in the treatment and placebo groups, but a higher proportion of placebo-treated patients experienced higher grade HFS than did uracil cream-treated patients, and higher grade HFS occurred sooner after randomization in the PTO group. HFS accounted for a higher number of capecitabine dose reductions and treatment interruptions in the PTO group compared with the uracil glime group. Uracil cream was generally very well tolerated.

[0094]

[0100] Uracil levels were monitored over time in plasma samples from patients after applying 1 g of uracil cream to the palms and soles of the feet. Plasma uracil concentrations increased slowly from a baseline mean of 19.20 ng / mL. At 2.5 hours, the mean concentration was 45.40 ng / mL. max C of this test was reached. max The values ​​were compared with other reported oral uracil doses (500 mg / m 2 ), the oral route produced uracil concentrations several orders of magnitude higher than those seen in the present study (20 mg / L vs. 45.40 ng / mL). Baseline uracil concentrations were nearly identical to those reported by Bi et al., J Chromatogr B Biomed Sci Appl 738:249-258 (2000), 19.20 ng / mL vs. 19.06 ng / mL. Uracil concentrations remained constant when uracil cream was applied repeatedly for 56 days, suggesting that there was no accumulation of uracil in the patients studied. 2 Capecitabine administered at doses ranging from max (See Reigner et al., Clin Pharmacokinet 40:85-104 (2001)). Any systemic fluctuations in uracil concentrations caused by 1UO application were negligible compared to the systemic activity of capecitabine.

[0095]

[0101] Example 3. Protective effect of uracil against 5-FU in cultured human keratinocytes

[0102] Primary human epidermal keratinocytes (HPEK cells) were cultured in the presence of 10 μM 5-FU, 10 μM 5-FU + 100 μM uracil, or 10 μM 5-FU + 300 μM uracil for 120 hours under standard culture conditions, and cell viability was determined after 120 hours of incubation. As shown in Figure 4, an increase in relative cell viability was observed with increasing uracil concentrations.

[0096]

[0103] Example 4. Uracil Topical Cream Formulation and Manufacturing Information

[0104] Feasibility analysis showed that the 1UO formulation (composition 2 in Table 1), while effective, was not fully optimized. Therefore, several additional formulations were prepared. The formulation optimization efforts focused on developing a formulation that exhibited (1) improved penetration of uracil into the skin with minimal penetration into the systemic circulation, and (2) improved aesthetic properties as measured by improved spreadability, reduced drying time, and improved rheology that was patient-friendly. The formulation was designed to allow for easy and uniform application with minimal friction, as well as excellent coatability and skin adhesion resulting in adequate and efficient absorption. The optimized cream is odorless and leaves no noticeable residue or film on the hands and feet after application. 42 different formulations were investigated, and several lead formulations were tested using an in vitro permeation test (IVPT) on human cadaver skin. Of these formulations, composition 7 in Table 3 below, containing dimethyl isosorbide (DMI), performed best. This formulation was reproducibly prepared at laboratory scale (5 kg) with defined product specifications, analytical profile, and stability. [Table 3]

[0097]

[0105] Each of the formulations described in Tables 1 and 2 above was prepared according to the following procedure.

[0106] Phase A was prepared by combining the Phase A ingredients in an appropriate sized auxiliary container. The ingredients were mixed until the uracil was completely dissolved. The mixture was warmed slightly to less than 50°C to aid in dissolution. This Phase A auxiliary container then contained the completed Phase A. Phase B was prepared in another appropriate sized auxiliary container (Phase B auxiliary container) by combining the Phase B ingredients and heating to 50-60°C. The ingredients were mixed until most of the parabens were dissolved. Phase A was transferred to the Phase B auxiliary container. The alkalinity of Phase A aided in paraben dissolution. While maintaining the temperature at 50-60°C, Phases A and B were mixed until all ingredients were dissolved. This Phase B auxiliary container then contained the combination of Phase A and Phase B ingredients. Phase C was prepared in another appropriate sized container (Main container) by adding the ingredients in the order listed. The Carbomer 940 was dispersed by very rapid agitation. If gel bodies were present, the mixture was lightly homogenized to achieve uniformity, then the Trolamine was added. After the trolamine was added, phase C became very viscous and clear. Phase C was heated to 50°C and maintained at this temperature. Phase D (in auxiliary container D) and phase E (in auxiliary container E) were prepared in two separate appropriately sized auxiliary containers. Phases D and E were each heated to 80°C, and then phase E was added to phase D, which now contains the combination of phases E and D. The contents of auxiliary container D were cooled to 45-55°C with mixing. The contents of auxiliary container D were added to phase C in the main container, which now contains the combination of phases C, D and E.

[0098]

[0107] While the contents of the main vessel were still warm (approximately 40-55°C), phases A and B from auxiliary vessel B were added to the main vessel, which now contains all phases. The contents were mixed until uniform. A smooth, white, pearlescent cream was formed.

[0099] Example 5. In vitro permeation test using Franz cell diffusion apparatus

[0108] Skin permeation testing through human cadaver skin is considered to be the best alternative to in vivo human testing (Abd et al., Clinical Pharmacology 8:163-176 (2016)). Two uracil formulations, Composition 7 (containing the penetration enhancer dimethylisosorbide) and Composition 2 (containing no penetration enhancer), were compared using dermatome-treated human cadaver skin from two donors (60 and 57 years old, 250 μm thick). Each formulation was tested in triplicate on skin from each donor (skin samples from the same cadaver in each triplicate), with untreated skin used as a control for the amount of endogenous uracil. Before mounting in the Franz cell, the skin was thawed to room temperature and cut into pieces 28 mm in diameter. 1.5 mg / cm of each uracil formulation was tested. 2 (calculated based on clinical dose) was applied to the skin surface, and the receiver compartment fluid was sampled at 0.5, 1, 2, 4, 6, 8, 10, and 12 hours, and samples were subjected to mass spectrometry for quantification of the amount of uracil that had permeated the skin. To measure the level of uracil that had penetrated the skin without permeation after 12 hours, the skin was biopsied and subjected to a washing protocol previously validated to remove uracil from the skin surface. Weighed skin was cut into small pieces and uracil was extracted by vortexing in 5 ml of aqueous ammonium hydroxide (pH 9) for 16 hours and centrifuging at 11000 rpm for 10 minutes. The extraction protocol was previously validated by extracting uracil injected into the skin (98±2% recovery).

[0100]

[0109] Of the 42 formulations produced, six were selected for the Franz test, as shown in Table 4 below. Similar permeation was observed regardless of the % uracil in the topical cream (80.1-143.6 ng / cm 2 Range). See Table 4 for % transmission. [Table 4]

[0101]

[0110] As shown in FIG. 5, the formulation with the penetration enhancer (Composition 7) resulted in a 6.5-fold increase in uracil penetrating the skin (p=0.01) compared to the uracil formulation without the penetration enhancer (Composition 2) used in the Phase 1-2 clinical trial. The cumulative amount of penetrating uracil recovered from the receiver compartment at 12 hours was nearly identical when comparing these two different uracil formulations. This suggests that Composition 7 (with the penetration enhancer), like Composition 2, is unlikely to interfere with the efficacy of capecitabine by increasing the patient's systemic uracil levels. As shown in FIG. 5, the formulation containing 0.3% uracil and 5% DMI (Composition 7) outperformed all other formulations tested, even when compared to the formulation containing 15% DMI. Importantly, the total amount of penetrating uracil recovered from the receiver compartment at 12 hours was nearly identical when comparing all formulations. This indicates that similar to composition 2 (without a penetration enhancer), which does not cause systemic changes in uracil levels that would affect the efficacy of capecitabine, composition 7 containing 5% DMI is also unlikely to affect the anticancer activity of capecitabine and its metabolites.

[0102] Example 6. Large-scale batch production of UTC

[0111] Further evaluation is performed on 75 kg batches of uracil topical formulation (UTC). The scaled-up production is tested by HPLC to ensure there is no change in uracil or preservative stability when the batch is scaled up. Accelerated and real-time stability studies are performed at ICH conditions 25°C / 60% RH, 30°C / 65% RH (back-up, no test), and 40°C / 75% RH. Studies include the formulation alone at t=0 and five additional time points over three months, and in the packaging selected for clinical trials. The drug product is also tested for forced degradation by heat, acid, base, oxidation, and light (ambient and ICH conditions).

[0103]

[0112] Evaluate the drug concentration upon impurity / related substance drug extraction required to enable detection of related substances at reporting thresholds (determined based on drug product and dosage form). Validate the precision of the drug extraction method is "fit for purpose" by extracting drug from formulations prepared at 100% of target concentration and calculating percent recovery from each formulation (n=6 each).

[0104]

[0113] Preservative efficacy testing (PET) is performed using one preservative system at the recommended preservative concentration and at a preservative concentration lower than this level (e.g., 90%) (to mimic preservative degradation over shelf life) according to standard procedures (Pharmaceutical Microbiology Manual, 2014). Preservative efficacy testing is performed on single-strength drug-formulated creams and matching placebos (4 batches in total).

[0105] Example 7. Further evaluation of topical uracil cream

[0114] Data from a Phase 1-2 clinical trial of mBC patients receiving capecitabine (described in Examples 2-3) showed that, although the patient numbers were small, the incidence of HFS was reduced in patients treated with 1UO compared to those treated with PTO, and that the safety profile of 1UO was tolerable compared to placebo. The Phase 2 clinical trial is a randomized, double-blind, placebo-controlled study with a sample size of 100 patients with histologically or cytologically confirmed mBC receiving capecitabine.

[0106]

[0115] Since pain is a core symptom of HFS, the primary objective of this study is to evaluate whether co-treatment with UTC (composition 7) in women with mBC treated with capecitabine delays a significant adverse increase in patient-reported pain in the hands or feet (measured as a 100% increase vs. placebo in time to a ≥2 point increase in worst pain in 24 hours in the hands or feet at UTC) that is expected to be associated with the occurrence of HFS. The study utilizes patient-reported outcomes (PROs) of pain based on item 3 of the Brief Pain Questionnaire (BPI) as the primary efficacy endpoint. This study allows confirmation of the PRO outcome of pain intensity associated with HFS, which serves as the primary endpoint in the registrational clinical trial. The time to the appearance of grade ≥2 HFS is evaluated as a secondary endpoint. The safety and PK profile of UTC and capecitabine and its metabolites are investigated in this larger patient population. Patients will be treated with a registration dose of 1250 mg / m 2 rather than 1000 mg / m 2 , but receive capecitabine in the same regimen (twice daily on days 1-14 of a 21-day cycle). 2 at a dose of 1250 mg / m 2 (Leonard et al., Clin Breast Cancer 11:349-356 (2011); Zielinski et al., Ann Oncol 21:2145-2152 (2010)). The approved single-agent starting dose of capecitabine in the United States and Canada and elsewhere is 1250 mg / m 2 is rarely used because it is associated with unacceptably high incidences of HFS, diarrhea, mucositis, and other toxicities.

[0107]

[0116] Besides the patient-reported outcome of pain, patients are also assessed for HFS by physical examination and digital photography. Assessment of HFS severity using the NCI CTCAE criteria is shown in Table 5 below. HFS is assessed on days 1 and 15 of each treatment cycle and at the final visit. In Phase 1-2 studies, UTC appeared to delay the occurrence of clinically significant HFS, although UTC-treated patients appeared to develop a variety of other dose-related capecitabine-associated AEs. Based on the experience with capecitabine in the United States and on days 1-14 of each 21-day cycle, 2 Based on the trend toward the use of capecitabine doses less than twice daily, perhaps the use of lower doses of capecitabine (1000 mg / m on days 1-14 of each 21-day cycle), a dosing regimen that is still associated with cumulative HFS but with a lower incidence of other capecitabine-related AEs, is warranted. 2 The overall therapeutic benefit of UTC in preventing HFS may be greater in patients receiving 100 mg of UTC twice daily. [Table 5]

[0108]

[0117] To assess plasma PK of uracil, capecitabine, and capecitabine metabolites (5'-DFCR, 5'-DFUR, and 5-FU), blood samples are collected from the first 24 patients enrolled in each treatment group: (a) C1D1: before administration of UTC / PTC and capecitabine and 0.5, 1, 2, 4, 6, and 8 hours after capecitabine administration; (b) C1D14: before administration of UTC / PTC and capecitabine and 0.5, 1, 2, 4, 6, and 8 hours after capecitabine administration. Additional blood samples to assess plasma concentrations of uracil, capecitabine, and capecitabine metabolites are collected from all patients remaining in the study during D1C2 and subsequent even-numbered cycles before and 2 hours after administration of UTC / PTC and capecitabine. max , T max , AUC, Cl / F, V z / F,t 1 / 2 AUC, T 1 / 2, Cl, and V d Determine parameters including but not limited to:

Claims

1. About 0.3% w / w uracil, Dimethyl isosorbide at about 5.0% w / w, from about 0.01 to about 4% w / w of an alkalizing agent; from about 0 to about 5% w / w of an antimicrobial preservative; from about 10 to about 40% w / w of a solvent selected from the group consisting of polyethylene glycol 400, glycerin, propylene glycol, and mixtures thereof; from about 0.01 to about 3% w / w of an acidifying agent; from about 0.1 to about 3% w / w of a gel forming agent selected from the group consisting of carbomer, polycarbophil, polyvinyl alcohol, povidone, hypromellose, sodium hyaluronate, hyaluronic acid, xanthan gum, pectin, methylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose, guar gum, dextrin, copovidone, ceratonia, carrageenan, alginic acid, sodium carboxymethylcellulose, calcium carboxymethylcellulose, ammonium alginate, sodium alginate, gum arabic, and potassium alginate, and mixtures thereof; from about 1 to about 5% w / w of an oily internal phase medium; from about 0 to about 5% w / w of an ionic emulsifier; from about 0 to about 7% w / w of a non-ionic emulsifier, and About 40 to about 70% w / w water 13. A topical pharmaceutical formulation comprising:

2. 2. The topical pharmaceutical formulation of claim 1, wherein the alkalizing agent is selected from the group consisting of ammonia solution, trolamine, tromethamine, sodium hydroxide, potassium hydroxide, diethanolamine, monoethanolamine, potassium citrate, sodium citrate, sodium bicarbonate, sodium borate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium acetate, sodium phosphate, meglumine, and mixtures thereof.

3. 3. The topical pharmaceutical formulation of claim 1 or 2, wherein the antimicrobial preservative is selected from the group consisting of methylparaben, ethylparaben, propylparaben, butylparaben, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, benzoic acid, potassium benzoate, sodium benzoate, propionic acid, sodium propionate, potassium propionate, phenoxyethanol, phenylethyl alcohol, sorbic acid, sodium lactate, lactic acid, thymol, xylitol, imidurea, hexetidine, EDTA, cresol, chloroxylenol, chlorocresol, chlorobutanol, chlorhexidine, cetrimide, calcium lactate, calcium acetate, butylene glycol, bronopol, boric acid, benzyl alcohol, and mixtures thereof.

4. 4. The topical pharmaceutical formulation according to any one of claims 1 to 3, wherein the acidifying agent is selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, nitric acid, citric acid, propionic acid, adipic acid, lactic acid, phosphoric acid, tartaric acid, maleic acid, fumaric acid, calcium chloride, ammonium chloride, and mixtures thereof.

5. 5. A topical pharmaceutical formulation according to any one of claims 1 to 4, wherein the oily internal phase vehicle is selected from the group consisting of dimethicone, various grades of vegetable oils, mineral oil, isopropyl palmitate, octyldodecanol, oleyl alcohol, petrolatum, simethicone, tricaprylin, triolein, myristyl alcohol, medium chain triglycerides, glyceryl monooleate, ethyl oleate, dibutyl sebacate, cyclomethicone, and mixtures thereof.

6. 6. A topical pharmaceutical formulation according to any one of claims 1 to 5, wherein the ionic emulsifier is selected from the group consisting of stearic acid, oleic acid, palmitic acid, sodium lauryl sulfate, anionic emulsifying wax, myristic acid, linoleic acid, lecithin, lauric acid, sodium docusate, aluminium monostearate, and mixtures thereof.

7. 7. A topical pharmaceutical formulation according to any one of claims 1 to 6, wherein the non-ionic emulsifier is selected from the group consisting of sorbitan monooleate; polyoxyethylene alkyl ethers; polysorbates; polyoxyethylene castor oil derivatives; polyoxyethylene stearates; polyoxylglycerides; sorbitan laurate, palmitate, stearate, trioleate, sesquioleate, dioleate, sesquiisostearate, sesquistearate, triisostearate, tristearate, diisostearate, or monoisostearate; non-ionic emulsifying wax; myristyl alcohol; medium chain triglycerides; macrogol 15 hydroxystearate; glyceryl monooleate; cholesterol; cetyl alcohol; cetostearyl alcohol; monoglycerides; diglycerides; triton X-100; and mixtures thereof.

8. A topical pharmaceutical formulation according to any one of claims 1 to 7, wherein the formulation is an emulsion and the viscosity of said formulation is from about 100,000 to about 400,000 cps.

9. A topical pharmaceutical formulation according to any one of claims 1 to 7, wherein the formulation is an emulsion and the viscosity of said formulation is from about 250,000 to about 320,000 cps.

10. About 0.3% w / w uracil, Dimethyl isosorbide at about 5.0% w / w, About 0.1 to about 2% w / w ammonia solution (about 29%), methylparaben from about 0 to about 2% w / w; from about 0 to about 2% w / w propylparaben, about 10 to about 20% w / w polyethylene glycol, about 10 to about 20% w / w glycerin, about 0 to about 3% w / w propylene glycol, Hydrochloric acid (about 20%) from about 0 to about 3% w / w; about 0.1 to about 5% w / w of carbomer, about 0.1 to about 2% w / w of trolamine, about 1 to about 5% w / w dimethicone, from about 1 to about 7% w / w of a non-ionic emulsifier; from about 0 to about 5% w / w of an ionic emulsifier, and About 40 to about 80% w / w water 13. A topical pharmaceutical formulation comprising:

11. 11. The topical pharmaceutical formulation of claim 10, wherein the formulation is an emulsion and the viscosity of said formulation is from about 100,000 to about 400,000 cps.

12. 11. The topical pharmaceutical formulation of claim 10, wherein the formulation is an emulsion and the viscosity of said formulation is from about 250,000 to about 320,000 cps.

13. About 0.3% w / w uracil, Dimethyl isosorbide at about 5.0% w / w, from about 0.1 to about 4% w / w of an alkalizing agent; about 0.1 to about 2% w / w methylparaben, about 0.01 to about 1% w / w propylparaben, from about 10 to about 40% w / w of a solvent selected from the group consisting of polyethylene glycol 400, glycerin, propylene glycol, and mixtures thereof; from about 0.01 to about 3% w / w of an acidifying agent; about 0.1 to about 3% w / w of Carbomer 940, about 1 to about 5% w / w dimethicone, about 1 to about 5% w / w stearic acid, about 0.5 to about 4% w / w of polysorbate 80, from about 0.1 to about 3% w / w of sorbitan monooleate, and About 40 to about 60% w / w water 13. A topical pharmaceutical formulation comprising:

14. About 0.3% w / w uracil, Dimethyl isosorbide at about 5.0% w / w, About 0.1 to about 2% w / w ammonia solution (about 29%), about 0.1 to about 2% w / w methylparaben, about 0.01 to about 1% w / w propylparaben, about 10 to about 20% w / w of polyethylene glycol 400, about 10 to about 20% w / w glycerin, about 0.1 to about 3% w / w propylene glycol, Hydrochloric acid (about 20%) from about 0.01 to about 3% w / w; about 0.1 to about 3% w / w of Carbomer 940, about 0.1 to about 2% w / w of trolamine, about 1 to about 5% w / w dimethicone, about 1 to about 5% w / w stearic acid, about 0.5 to about 4% w / w of polysorbate 80, about 0.1 to about 3% w / w of sorbitan monooleate, and About 40 to about 60% w / w water 13. A topical pharmaceutical formulation comprising:

15. About 0.3% w / w uracil, Dimethyl isosorbide at about 5.0% w / w, about 0.9 to about 1.1 w / w ammonia solution (about 29%); about 0.4 to about 0.6% w / w of methylparaben, about 0.04 to about 0.06% w / w propylparaben, about 14 to about 16% w / w of polyethylene glycol 400, about 13 to about 15% w / w glycerin, about 1 to about 2% w / w propylene glycol; Hydrochloric acid (about 20%) from about 0.01 to about 0.1% w / w, about 1 to about 2% w / w of Carbomer 940, about 0.4 to about 0.6% w / w of trolamine, about 3 to about 4% w / w dimethicone, about 2 to about 3% w / w of stearic acid; about 1 to about 2% w / w of polysorbate 80, from about 0.9 to about 2% w / w of sorbitan monooleate, and About 50 to about 60% w / w water 13. A topical pharmaceutical formulation comprising:

16. A topical pharmaceutical formulation according to any one of claims 1 to 10 and 13 which is free of methyl methacrylate polymers.

17. A topical pharmaceutical formulation according to any one of claims 1 to 16 for use in the treatment or prevention of a skin disease associated with the administration of 5-fluorouracil or a prodrug thereof in a mammal in need thereof.

18. 20. The topical pharmaceutical formulation of claim 17, wherein the mammal is a human and the formulation is applied to the palms of the hands or the soles of the feet of the human.

19. The topical pharmaceutical formulation of claim 18, wherein the amount of the formulation applied is from about 0.1 to about 0.5 grams.

20. 19. The topical pharmaceutical formulation of claim 18, wherein the amount of the formulation applied is from about 0.3 to about 0.4 grams, or from about 0.5 to about 0.7 grams.

21. A topical pharmaceutical formulation according to any one of claims 1 to 16 for use in the prevention of hand-foot syndrome (HFS) associated with systemic chemotherapy in a mammal in need thereof.

22. 22. The topical pharmaceutical formulation of claim 21, wherein the mammal is a human and the formulation is applied to the palms of the human hands or the soles of the feet.

23. 23. The topical pharmaceutical formulation of claim 22, wherein the amount of the formulation applied is from about 0.1 to about 0.5 grams.

24. 23. The topical pharmaceutical formulation of claim 22, wherein the amount of the formulation applied is from about 0.3 to about 0.4 grams, or from about 0.5 to about 0.7 grams.

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