Topical formulation containing jak inhibitor and laureth-4

Abstract

To provide a composition to enhance penetration of a topical pharmaceutical formulation into the subject's skin.SOLUTION: A topical pharmaceutical composition contains about 0.1 to 1.0% w / w of SHR0302, about 0.5 to 5.0% w / w of laureth-4, and a solvent.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 057,503, filed July 28, 2020, the disclosure of which is incorporated by reference in its entirety into this specification.

[0002] FIELD OF THEINVENTION

[0002] The subject matter disclosed herein generally relates to topical formulations containing laureth-4. Specifically, the present disclosure addresses the surprising discovery that laureth-4 acts as a penetration enhancer in the currently disclosed and claimed topical formulations. [Background technology]

[0003]

[0003] The epidermal barrier has several functions, including maintaining moisture balance, reducing oxidative stress, protecting against foreign substances such as microorganisms and antigens, and protecting against UV damage. Although the entire epidermis is involved in the epidermal barrier, the stratum corneum is primarily responsible for many of these functions. Many topically administered drugs do not have the ability to fully penetrate the stratum corneum to achieve maximum clinical efficacy. In these cases, it is necessary to regulate the skin penetration profile of these drugs and regulate the skin barrier. Enhancement of skin penetration can be achieved either chemically, physically, or by using appropriate formulations.

[0004]

[0004] Enhancement of skin penetration can be achieved mechanically by optimizing the properties of the drug and vehicle and / or by modifying the stratum corneum (HAE Benson, “Transdermal Drug Delivery Penetration Enhancement Techniques” Current Drug Delivery 2 , 23-33, 2005). Optimization of the vehicle properties involves selecting the most potent active substances in a pharmacological class with molecular weights closer to 300 Daltons than 500 Daltons. オクタノール / 水 <2.5) The synthesis of prodrugs for active substances or the formation of ion pairs with charged active substances to facilitate distribution into the stratum corneum are additional examples of strategies to optimize drug and vehicle properties. Strategies similar to the formation of ion pairs include the development of eutectic systems, complexation of drugs with materials such as cyclodextrins, or the formulation of complex vehicles such as liposomes, vesicles, or nanotechnology formulations. One of the earliest recognized strategies to optimize topical drug and vehicle properties was the use of solvents, particularly propylene glycol (PG), to maximize the drug's chemical potential, i.e., thermodynamic driving force, while balancing the concentration of dissolved active substances in the formulation.

[0005]

[0005] Solvents such as propylene glycol (PG), N-methylpyrrolidone (NMP), ethanol and dimethyl sulfoxide (DMSO) have long been used to optimize drug-vehicle properties to enhance both penetration into the stratum corneum and penetration across the stratum corneum into the viable epidermis. Since 2005, diethylene glycol monoethyl ether (DEGEE) has been added to the list of solvents that optimize drug-vehicle properties for topical formulation products that have been established as safe and effective by the US Food and Drug Administration. It has also long been recognized that these solvents easily penetrate and modify the stratum corneum. Although solvents can be effectively used to enhance skin penetration / permeation of drugs, it is necessary to blend the solvent with a fatty alcohol, fatty acid or fatty acid ester adjuvant, such as a non-ionic surfactant, in order to maximize the amount of drug that crosses the skin.

[0006]

[0006] This synergistic skin penetration was first reported in 1976 for PG (U.S. Pat. No. 3,934, It was described in 2011 for NMP (WO 2011 / 07629 A2, Petersson, published June 30, 2011) and in 1973 for DMSO (U.S. Pat. No. 3,711,602 A, Herschler, published January 16, 1973). A 2018 paper (DW Osborne and J Musakhanian, AAPS Pharm SciTech. 19(8):3512-3533 (2018) DOI: 10.1208 / s12249-018-1196-8) described the use of fatty alcohol, fatty acid or fatty acid ester adjuvants as glycerides. A comprehensive review of the skin penetration enhancement literature of DEGEE when combined with BANT was provided.

[0007] During a review of published data on skin penetration enhancers, it becomes apparent that an experimental artifact in in vitro permeation testing (IVPT) has often been mistaken for enhanced skin penetration. This artifact occurs when excised skin is mounted in an in vitro diffusion cell (typically a Franz vertical diffusion cell) with an infinite volume of a liquid or semisolid. For our purposes, we define the infinite volume as 1 cm of skin surface area. 2We define an infinite dose as any amount exceeding 20 μl of formulation per cm. The artifact is caused by the applied dose extracting barrier lipids from the stratum corneum over the time course of the experiment (typically 24-48 hours). Thus, the barrier properties of the tissue are reduced by applying too much product to the surface of the skin. This results in the reported skin permeation enhancement factor for a formulation being exaggerated, sometimes by a factor of 20-100. The extent of this artifact is further increased when an infinite dose is applied to excised rodent or rabbit skin compared to mounting of human skin (typically cut with a dermatome to a thickness of approximately 500 microns) on an IVPT diffusion cell. Topical solvents and fatty acid ester surfactants are topical excipients that can greatly exaggerate IVPT flux values ​​when applied as infinite doses. While any clinically non-relevant dose (>20 μl) can cause this artifact, a dose of 100 μl / cm of a liquid or semi-solid formulation containing a solvent or surfactant is not sufficient to cause this artifact. 2 Doses above this level will rapidly and efficiently extract skin barrier lipids and exaggerate the appearance of active agent in the receptor solution of an in vitro diffusion cell.

[0008]

[0008] In part because this artifact was so prevalent in the 1980s and 1990s skin penetration enhancer literature, the FDA's Dermatology Division did not accept IVPT results as supporting data for topical product registration before about 2010. In January 2012, four of the Food and Drug Administration's leading scientists published a paper entitled "Generic Development of Topical Dermatologic Products: Formulation Development, Process Development, and Testing of Topical Dermatologic Products." In one seminal publication, the authors state: "...finite dose techniques (i.e., approximately 3-5 mg / cm 2) is considered more appropriate than an infinite dose design because it better represents the clinical situation for a topical drug product...Data arising from in vitro permeation studies using excised human skin give good predictions of in vivo bioavailability and bioequivalence and provide a practical surrogate to clinical bioequivalence studies”.

[0009] In the 1997 publication Skin Penetration Enhancers Cited in the Technical Literature, Laureth-4 (listed as Brij 30) has two citations: a citation in Shen 1976 (WW Shen et.al. J.Pharm Sci 65(12)1780-1783 (1976) doi.org / 10.1002 / jps.2600651222) and a citation in Aungst 1986 (BJ Aungst et.al. International journal of pharmaceuticals 33 (1-3) 225-234 (1986) doi.org / 10.1016 / 0378-5173(86)90057-8). Shen et al. Fifteen different nonionic surfactants (10% w / w) incorporated into a white petrolatum USP ointment base containing 10% (w / w) dimethyl sulfoxide (DMSO) with 10% (w / w) salicylic acid were tested. 5.0 grams of ointment was applied to a 6.4 × 12.7 cm area of ​​skin. 2 In the area of Percutaneous absorption was determined from blood salicylate levels in New Zealand white rabbits at regular intervals for 8 hours after application. Percutaneous absorption of salicylic acid was significantly increased when sorbitan monopalmitate, sorbitan trioleate, poloxamer 231, poloxamer 182, polyoxyethylene 4 lauryl ether (laureth-4), polyoxyethylene 2 oleyl ether or polyoxyl 8 stearate was added to an ointment containing dimethyl sulfoxide, salicylic acid and white petrolatum. It should be noted that Shen used an in vivo test after infinite dosing on rabbit skin.

[0010]

[0010] Aungst et al. Various chemicals were screened as penetration enhancers by adding fatty acids and fatty alcohols. Fatty acids and fatty alcohols were very effective enhancers of naloxone flux. The maximum flux was 235.2 μg / cm for the acid (lauric acid). 2 -hr) and alcohol (45.8 μg / cm for lauryl alcohol 2 In both the 18:2-hr) series, the adjuvant was C12 saturated and the adjuvant was C18 unsaturated (linoleic acid 18:2, 103.0 μg / cm 2 -hr) and alcohol (116.3 μg / cm for linolenyl alcohol) 2 -hr) adjuvant. Another effective skin penetration enhancer was pelargonic acid (201.9 ± 65.4 μg / cm 2 -hr), capric acid (187.9±67.5μg / cm 2 -hr), propylene glycol laurate (43.8±5.5μg / cm 2 -hr) and laureth-4 (34.5 ± 8.3 μg / cm 2 The excised human skin experiments included an infinite dose (278 μl / cm 2 ) to compare 64 adjuvants for their ability to increase the in vitro flux of naloxone from PG. The PG alone (no adjuvant) control was 1.6±0.4 μg / cm2 The naloxone flux value was 0.001-hr.

[0011]

[0011] S-laureth-4 was shown to increase the percutaneous absorption of salicylic acid in rabbits. In the 44 years since hen's first publication, one photodynamic drug / device combination product and three topical drug products containing laureth-4 have been approved by the FDA. None of the three topical drug products use laureth-4 as a skin permeation enhancer. LAC-HYDRIN Cream (1.1% Laureth-4) and LAC-HYDRIN Lotion (1.3% Laureth-4) are designed to treat dry skin (xeroderma) and are not designed to enhance delivery beyond the stratum corneum, the target tissue for treating dry skin. The third approved product is VELTIN Gel (3% Laureth-4), a dual-active gel for the treatment of acne that combines clindamycin phosphate and tretinoin. Laureth-4 and propylene glycol are used in this product to increase the solubility of tretinoin to 0.025%. Clindamycin phosphate is readily soluble in water without the addition of laureth-4 as a solubilizer. Due to a clear warning in the VELTIN Gel label that systemic absorption of clindamycin can cause severe colitis that may result in death, formulators will not add skin penetration enhancers to topical clindamycin. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] U.S. Patent No. 3,934,013 [Patent Document 2] International Publication No. 2011 / 07629 A2 [Patent Document 3] U.S. Patent No. 3,711,602A [Non-patent literature]

[0013] [Non-Patent Document 1] HAE Benson “Transdermal Drug Delivery Penetration Enhancement Techniques” Current Drug Delivery 2, 23-33, 2005 [Non-Patent Document 2] DW Osborne and J Musakhanian, AAPS Pharm SciTech. 19(8):3512-3533 (2018) DOI: 10.1208 / s12249-018-1196-8 [Non-Patent Document 3] Generic Development of Topical Dermatologic Products: Formulation Development, Process Development, and Testing of Topical Dermatologic Products. [Non-Patent Document 4] Skin Penetration enhancers Cited in the Technical Literature [Non-Patent Document 5] WW Shen et.al. J.Pharm Sci 65(12)1780-1783 (1976) doi.org / 10.1002 / jps.2600651222 [Non-Patent Document 6] BJ Aungst et.al. International journal of pharmaceuticals 33(1-3) 225-234 (1986) doi.org / 10.1016 / 0378-5173(86)90057-8 Summary of the Invention

[0014] In accordance with one aspect of the present invention, a topical formulation of the novel JAK inhibitor SHR0302 is It has been surprisingly discovered that the addition of laureth-4 significantly increases the skin permeation of SHR0302. In some instances, the increase is a 5-fold to 30-fold increase in skin permeation compared to topical formulations without laureth-4.

[0015] In certain embodiments of the present invention, a method for treating a pulmonary arthritis (PTA) comprising administering to the patient a therapeutically effective amount of a JAK inhibitor, laureth-4, and a solvent. In a preferred embodiment, the JAK inhibitor is SHR0302 (also known as ARQ-250).

[0016]

[0014] The pharmaceutical composition comprises a JAK inhibitor in an amount of about 0.1 to about 1.0% w / w. The pharmaceutical composition may include laureth-4 in an amount of about 0.5 to about 5% w / w. The pharmaceutical composition may further include dimethyl sulfoxide. In addition, the pharmaceutical composition may include an antioxidant, a preservative, an emulsifier, a moisturizer, or a thickener.

[0017]

[0015] Topical pharmaceutical compositions include oil-in-water emulsions, water-in-oil emulsions, microemulsions, and the like. The emulsion may be selected from the group consisting of a microemulsion, a nanoemulsion, a foam, a spray, a hydrophilic ointment or a hydrophobic ointment.

[0018]

[0016] The topical pharmaceutical composition may comprise a corticosteroid, timolol, methotrexate or or cyclosporine.

[0019]

[0017] The topical pharmaceutical composition contains laureth-4 as determined by an in vitro permeation test. It is possible to enhance skin permeation by 5 to 30 times compared to topical pharmaceutical formulations that do not contain

[0020] In certain aspects of the present invention, a method for treating an inflammatory skin disease in a subject in need thereof is provided. A method of treating a disease, disorder or condition is provided comprising topically administering to a subject a pharmaceutical composition comprising a JAK inhibitor, laureth-4 and a solvent.

[0021]

[0019] The inflammatory skin disease, disorder or condition is atopic dermatitis, rosacea, psoriasis, seborrhea, The condition can be one of the following: eczema, vitiligo, eczema or alopecia areata.

[0022]

[0020] The pharmaceutical composition may be administered to the subject one or more times per day.

[0023] The method may include administration of SHR0302, a JAK inhibitor. The AK inhibitor can be present in the pharmaceutical composition in an amount of about 0.1 to about 1.0% w / w. The laureth-4 can be present in the pharmaceutical composition in an amount of about 0.5 to about 5% w / w. The method of administration can include administering a pharmaceutical composition comprising dimethyl sulfoxide. Additionally, the pharmaceutical composition can further comprise a corticosteroid, timolol, methotrexate or cyclosporine.

[0024]

[0022] The method of administration to a subject is one that is effective in preventing laureth-related inflammatory responses as measured by in vitro permeation testing. This can result in 5- to 30-fold enhanced skin penetration of the topical pharmaceutical composition compared to a topical pharmaceutical formulation not containing -4.

[0025] In certain embodiments, to enhance skin penetration of a topical pharmaceutical formulation in a subject, A method is provided for treating a topical pharmaceutical composition comprising administering to a subject a therapeutically effective amount of a JAK inhibitor, comprising preparing a formulation comprising a JAK inhibitor, laureth-4, and a solvent, wherein skin penetration of the topical pharmaceutical composition is enhanced 5-fold to 30-fold compared to a topical pharmaceutical formulation not comprising laureth-4.

[0026]

[0024] The accompanying drawings, which are incorporated in this specification and form a part of this disclosure, illustrate the invention in a simplified form. It further serves to help explain the various embodiments and, together with the description, to describe the invention to enable one of ordinary skill in the relevant art to make and use the embodiments disclosed herein. [Brief description of the drawings]

[0027] [Figure 1]

[0025] Figure 1 illustrates the results of IVPT comparing exemplary SHR0302 formulations with and without laureth-4. The x-axis depicts time (in hours) and the y-axis depicts ng / mL cumulative SHR0302 in the receptor solution. The results show that the addition of laureth-4 significantly enhances skin penetration in formulations containing SHR0302 and DMSO. [Diagram 2]

[0026] Figure 2 illustrates the IVPT results comparing three exemplary SHR0302 formulations with varying concentrations of xanthan gum and laureth-4. The x-axis depicts time (in hours) and the y-axis depicts ng / mL cumulative SHR0302 in the receptor solution. The results show that the addition of laureth-4 significantly enhances skin penetration in formulations containing SHR0302 and NMP. [Diagram 3]

[0027] Figure 3 illustrates the results of an IVPT comparing exemplary SHR0302 formulations with and without laureth-4. The x-axis depicts time (in hours) and the y-axis depicts ng / mL cumulative SHR0302 in the receptor solution. The results show that the addition of laureth-4 significantly enhances skin penetration in formulations containing SHR0302. [Figure 4]

[0028] Figure 4 illustrates IVPT results comparing exemplary SHR0302 formulations with and without Laureth-4. The x-axis depicts time (in hours) and the y-axis depicts cumulative SHR0302 in ng / mL in the receptor solution. The results show that the addition of Laureth-4 significantly enhances skin penetration in formulations containing SHR0302. [Diagram 5]

[0029] Figure 5 illustrates IVPT results comparing exemplary SHR0302 formulations with and without Laureth-4. The x-axis depicts time (in hours) and the y-axis depicts cumulative SHR0302 in ng / mL in the receptor solution. The results show that the addition of Laureth-4 significantly enhances skin penetration in formulations containing SHR0302. [Figure 6]

[0030] Figure 6 illustrates IVPT results comparing exemplary SHR0302 formulations with and without Laureth-4. The x-axis depicts time (in hours) and the y-axis depicts cumulative SHR0302 in ng / mL in the receptor solution. The results show that the addition of Laureth-4 significantly enhances skin penetration in formulations containing SHR0302. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028]

[0031] Before the present invention is described in detail below, the present invention is first described with reference to the specific It should be understood that the present invention is not limited to the specific methodology, protocols, and reagents, as these may vary. The terminology used herein is for the purpose of describing particular embodiments. It should also be understood that these terms are for purposes of illustration only and are not intended to limit the scope of the present invention, which will be limited only by the scope of the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0029]

[0032] All publications, patents and patent applications cited herein are hereby incorporated by reference in their entirety. Unless otherwise specified, the term is incorporated herein by reference in its entirety. Where the same term is defined in a publication, patent or patent application and in this disclosure incorporated herein by reference, the definition in this disclosure represents the controlling definition. With respect to publications, patents and patent applications referenced to describe a particular type of compound, chemistry, etc., the portion related to such compound, chemistry, etc. is the portion of the document incorporated herein by reference.

[0030]

[0033] As used herein, the singular forms "a," "an," and "the" refer to It is noted that plural references are included unless the context clearly dictates otherwise. Thus, for example, "active ingredient" includes a single ingredient as well as two or more different ingredients, "solvent" refers to a single solvent as well as two or more different solvents or complex mixtures of solvents, and "sulfate" includes a single sulfate salt as well as two or more different sulfate salts.

[0031]

[0034] The terms "ARQ-250" or "SHR0320" are used unless otherwise specified. It refers to (3aR,5S,6aS)-N-(3-methoxyl-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide and its salts.

[0032]

[0035] The term "about" when used in connection with a numerical value means a value less than 5% of the stated numerical value. It is meant to encompass values ​​within the range having a lower limit and an upper limit that is 5% greater than the stated value.

[0033]

[0036] "Pharmaceutical acceptable" means a substance that is generally safe for administration to humans or animals. Preferably, a pharma- ceutically acceptable component is one that is approved by a federal or state regulatory agency or is listed in the United States Pharmacopeia, published by the United States Pharmacopeial Convention (Rockville, Md.), or other generally recognized pharmacopoeias, for use in animals, and more particularly in humans.

[0034]

[0037] A "pharmaceutical composition" according to the invention may comprise different active ingredients and diluents and / or The combinations or combination preparations may be in the form of compositions in which the carriers are mixed with one another or in the form of combined preparations in which the active ingredients are present in partially or completely different forms. An example of such a combination or combined preparation is a kit of parts.

[0035]

[0038] As used herein, the term "subject" or "patient" refers most preferably to a human The term "subject" or "patient" can include any mammal that can benefit from the compounds described herein.

[0036]

[0039] A "therapeutic amount" or "therapeutically effective amount" means an amount sufficient to achieve its intended purpose. The effective amount of a given therapeutic agent will vary depending on factors such as the nature of the agent, the route of administration, the size of the subject to receive the therapeutic agent, and the purpose of administration. The effective amount in each individual case can be empirically determined by those skilled in the art according to established methods in the art.

[0037]

[0040] The term "topical" in reference to administration of a drug or composition refers to administration to the skin or cornea. "Topical application" refers to the application of such a drug or composition to epithelial surfaces outside the body, including the epithelial surfaces of the skin, eyes, and the skin. With respect to this application, application inside a body orifice, such as the mouth, nose, or ears, is not considered to be topical application.

[0038]

[0041] As used herein, "treating" or "treating a disease or disorder" refers to " or "treatment" thereof means accomplishing one or more of the following: (a) reducing the severity and / or duration of the disorder; (b) limiting or preventing the occurrence of symptoms characteristic of the disorder(s) being treated; (c) inhibiting the worsening of symptoms characteristic of the disorder(s) being treated; (d) limiting or preventing the recurrence of the disorder(s) in patients who previously had the disorder(s); and (e) limiting or preventing the recurrence of symptoms in patients who previously had symptoms related to the disorder(s).

[0039]

[0042] The abbreviation "w / w" refers to the relative concentrations of components in a composition by volume or other amount. The ingredients are expressed on a "weight by weight" basis (i.e., percentages refer to percentages of total weight).

[0040]

[0043] Laureth-4 (CAS number 5274-68-0) is a tetraethylene glycol It is also known as lauryl alcohol monododecyl ether, 3,6,9,12-tetraoxatetracosan-1-ol, lauryl alcohol tri(oxyethylene)ethanol, PEG-4 lauryl ether, polyethylene glycol 200 lauryl ether, polyoxyethylene (4) lauryl ether and tetraethylene glycol dodecyl ether. The compound has the molecular formula C 20 H 42 O5 and has a molecular weight of 362.5 g / mol. The structure of Laureth-4 is as follows:

[0041] [ka]

[0042] .

[0043]

[0044] Laureth-4 is found in cosmetics, shampoos, soaps, deodorants and moisturizing products Laureth-4 is a synthetic polymer that is commonly used as a surfactant and emulsifier in some personal care products. For the past 45 years, Laureth-4 has only been known in scientific literature as a nominal penetration enhancer. However, in the present invention, Laureth-4 surprisingly functions as a penetration enhancer. In particular, it has been surprisingly found that Laureth-4 acts as a skin penetration enhancer in the topical formulation of the present invention.

[0044]

[0045] Janus kinase inhibitors (JAK inhibitors) are kinase inhibitors that inhibit the JAK family (e.g., JA JAK inhibitors are a class of compounds that function by inhibiting the activity of one or more enzymes (JAK1, JAK2, JAK3 or Tyk2). These compounds are believed to function by inhibiting the JAK-STAT signaling pathway, which plays a central role in immune system function. Many inflammatory cytokines and other signaling molecules rely on the JAK pathway, particularly JAK1. Inhibition of JAK1 has previously been shown to treat a range of inflammatory diseases, including rheumatoid arthritis, psoriasis, Crohn's disease and eczema. There is particular interest in developing topical formulations of JAK inhibitors for the treatment of inflammatory skin conditions.

[0045]

[0046] In a preferred embodiment, the JAK1 inhibitor is Particularly preferred are the inhibitors disclosed in U.S. Pat. No. 9,527,851. In one embodiment, the JAK1 inhibitor is (3aR,5S,6aS)-N-(3-methoxyl-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide (also known as SHR0302 or ARQ-250).

[0046] The structure of SHR0302 is as follows:

[0047] [ka]

[0048] .

[0049] SHR0302 has high selectivity for JAK1 over JAK2. SHR0302 is a potent small molecule inhibitor of JAK1 that has been shown to have potent anti-inflammatory properties, and thus has the potential to treat inflammatory diseases without causing the deleterious effects of the hematopoietic system, such as anemia, thrombocytopenia, and neutropenia, associated with JAK2 inhibition. Topical formulations containing SHR0302 may be effective in treating inflammatory skin diseases, disorders, and conditions, including, but not limited to, atopic dermatitis, rosacea, psoriasis, seborrheic dermatitis, vitiligo, eczema, and alopecia areata.

[0050] Other JAK inhibitors are also useful for treating inflammatory skin diseases, disorders, and conditions. It is also contemplated that the JAK inhibitor may be incorporated into the topical formulation of the present invention, and thus may be incorporated into the topical formulation of the present invention. Examples of JAK inhibitors that may be incorporated into the formulation of the present invention include ruxolitinib, tofacitinib, ocalcitinib, baricitinib, peficitinib, fedratinib, upadacitinib, filgotinib, cerduratinib, gandotinib, lestaurtinib, momelotinib, pacritinib, abrocitinib, cucurbitacin I, decernotinib, solcitinib, CHZ868, CYT387, TG101348, AZD1480, R348, VX-509, GLPG0634, SKD2586148, AC-430, BMS-911543 or PF-04965842.

[0051] The topical formulation of the present invention comprises a JAK inhibitor, laureth-4 and a solvent. In a preferred embodiment, the JAK inhibitor is SHR0302. In a preferred embodiment, the JAK inhibitor is about 0.01 to about 1.0% w / w, about 0.05 to about 1.0% w / w, about 0 In preferred embodiments, laureth-4 is present in an amount of about 0.05 to about 8% w / w, about 0.1 to about 6% w / w, about 0.5 to about 5% w / w, or about 1.0 to about 4% w / w.

[0052]

[0050] Preferably, the topical formulation of the present invention is in one of the following forms: Oil-in-water emulsion: The product is a separate phase of hydrophobic components as well as water and The emulsions may be emulsions that contain a continuous aqueous phase that contains one or more polar hydrophilic excipients, as well as solvents, co-solvents, salts, surfactants, emulsifiers and other ingredients. These emulsions may contain water-soluble or water-swellable polymers that help stabilize the emulsion.

[0053]

[0052] Water-in-oil emulsion: The composition comprises a continuous phase of hydrophobic components and water and The emulsions may be emulsions that contain an aqueous phase containing an oil-soluble or oil-swellable polymer and optionally one or more emulsifiers that help stabilize the emulsion.

[0054]

[0053] Hydrophilic or hydrophobic ointments: The compositions are prepared in a hydrophobic base (e.g., petrolatum, thickening or Hydrophilic ointments are generally formulated with a water-insoluble phase (such as a gel or water-insoluble oil) and may have a minor amount of a water-soluble phase. Hydrophilic ointments generally contain one or more surfactants or humectants.

[0055] Microemulsions: These are often a mixture of oil, water and a surfactant. It is a clear, thermodynamically stable, isotropic liquid system that contains in combination with a surfactant. Microemulsions can be water-continuous, oil-continuous, or bicontinuous mixtures. The formulations can also optionally contain up to 60% water by weight. Higher levels may be appropriate in some compositions.

[0056] Nanoemulsions: These are isotropic dispersions containing water, oil, and an emulsifier. Nanoemulsions are systems that can be oily systems dispersed in aqueous systems or aqueous systems dispersed in oily systems forming nanometer-sized droplets or oily phases. Nanoemulsions often have a higher loading capacity for lipophilic active ingredients than microemulsions. Hydrophobic and hydrophilic active ingredients can also be incorporated into nanoemulsions. Nanoemulsions can be formed by any suitable method known in the art, including high pressure homogenization, microfluidization, and phase transition temperature.

[0057] Aerosol foam or spray: The product is an aerosol containing emulsified wax. The foam concentrates may be coal / solvent-based solutions or emulsions that contain a discrete phase of hydrophobic components and a continuous aqueous phase that includes water and optionally one or more polar hydrophilic excipients as well as solvents, co-solvents, surfactants, emulsifiers and other components. These solvent or emulsion foam concentrates may contain water-soluble or water-swellable polymers that help stabilize the emulsion and corrosion inhibitors to improve compatibility between the formulation and the package. Hydrocarbon, hydrochlorofluorocarbon (HCFC) or chlorofluorocarbon (CFC) aerosol propellants may be added to the solvent or emulsion foam concentrates in a package designed to maintain pressure until the foam or spray product is dispensed for application.

[0058] Solvent

[0058] The composition according to the present invention is effective in preventing skin permeation or the activity of other excipients contained in the formulation. The solvent may include one or more solvents or co-solvents that modify the properties of the solvent. Solvents include acetone, ethanol, Examples of suitable ethanol include, but are not limited to, ethanol, benzyl alcohol, butyl alcohol, diethyl sebacate, diethylene glycol monoethyl ether, diisopropyl adipate, dimethyl isosorbide, dimethyl sulfoxide, ethyl acetate, isopropyl alcohol, isopropyl isostearate, isopropyl myristate, N-methyl pyrrolidione, polyethylene glycol, glycerol, propylene glycol, and SD alcohol.

[0059]

[0059] Surfactants

[0060] The compositions according to the invention contain one or more surfactants or co-surfactants. Surfactants include, but are not limited to, short chain alcohols, alkanediols and triols, alkyl phosphate esters, polyethylene glycols and glycol ethers, polyethylene stearyl ethers (including those sold under the trade names Brij S2, Brij S20, Brij 721, Brij 38, Brij 52, Brij 56, and Brij W1), pyrrolidine derivatives, bile salts, sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty acid esters.

[0060]

[0061] Moisturizer

[0062] The compositions according to the present invention may contain one or more preservatives to increase the level of hydration. The moisturizer may include a humectant. The moisturizer can be a hydrophilic material including a humectant, or it can be a hydrophobic material including an emollient. Suitable moisturizers include, but are not limited to, the following moisturizers: 1,2,6-hexanetriol, 2-ethyl-1,6-hexanediol, butylene glycol, glycerin, polyethylene glycol 200-8000, butyl stearate, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, cetyl palmitate, cocoa butter, coconut oil, cyclomethicone, dimethicone, docosanol, elastomers, ethylhexyl hydroxystearate, fatty acids, glyceryl isostearate, glyceryl laurate, monostearate, glyceryl oleate ... Glyceryl stearate, glyceryl oleate, glyceryl palmitate, glycol distearate, glycol stearate, isopropyl palmitate, isostearic acid, isostearyl alcohol, lanolin, mineral oil, limonene, medium chain triglycerides, menthol, myristyl alcohol, octyldodecanol, oleic acid, oleyl alcohol, oleyl oleate, olive oil, paraffin, peanut oil, petrolatum, Plastibase-50W, polypropylene glycol stearyl ethers and stearyl alcohol.

[0061]

[0063] Polymers and Thickeners

[0064] Soluble, swellable or insoluble organic polymeric thickeners depending on the particular application It may be desirable to formulate products thickened with, for example, natural and synthetic polymers or inorganic thickeners such as acrylate copolymers, carbomer 1382, carbomer copolymer type B, carbomer homopolymer type A, carbomer homopolymer type B, carbomer homopolymer type C, acrylamide / sodium acryloyldimethyltaurate copolymer, carboxyvinyl copolymers, carboxymethylcellulose, carboxypolymethylene, carrageenan, guar gum, xanthan gum, hydroxyethylcellulose, hydroxypropylcellulose, microcrystalline wax and methylcellulose.

[0062]

[0065] Additional components

[0066] The compositions according to the present invention contain additional ingredients conventionally found in cosmetic and pharmaceutical topical products. The components may be formulated with, for example, fillers, carriers and excipients. Antifoaming agents, preservatives (e.g., p-hydroxybenzoic acid esters, benzyl alcohol, phenylmercuric salts, chlorocresol, methylparaben, propylparaben), antioxidants (e.g., Additional components may be added to the composition including, but not limited to, BHT, BHA, ascorbic acid, tocopherol, citric acid, propyl gallate, sodium metabisulfite), sequestering agents, stabilizers, buffers, pH adjusters (preferably agents that result in an acidic pH, including but not limited to gluconolatone, citric acid, lactic acid, and alpha hydroxy acids), skin penetration enhancers, skin protectants (including but not limited to petrolatum, paraffin wax, dimethicone, glyceryl monoisostearate, isopropyl isostearate, isostearyl isostearate, cetyl alcohol, potassium cetyl phosphate, cetyl behenate, and behenic acid), chelating agents, film formers, suspending agents (e.g., xantham gum), dyes, pigments, diluents, bulking agents, fragrances, aerosol forming agents, and other excipients to enhance stability or aesthetics.

[0063]

[0067] The compositions according to the invention may be administered in combination with additional active agents depending on the condition being treated. Exemplary additional active agents for combination topical drug products include the following agents: corticosteroids (e.g., clobetasol, betamethasone, halobetasol, or triamcinolone), beta-andrenergic antagonists (e.g., timolol), calcineurin inhibitors (e.g., tacrolimus or pimecrolimus), methotrexate, or cyclosporine.

[0064]

[0068] Administration and Dosage

[0069] Compositions according to the present invention may be administered by any of a variety of routes, including, but not limited to, subcutaneous (topical), transdermal and mucosal administration. The composition can be administered by any suitable route of administration, without limitation. In a preferred embodiment, the composition is administered topically. The composition can be administered once or more per month, once or more per week, or once or more per day. In a preferred embodiment, the composition is administered once, twice, or three times per day.

[0065]

[0070] Topical formulations containing laureth-4 as disclosed herein result in improved The topical formulation containing laureth-4 can provide a skin permeation increase of more than 5-fold, more than 8-fold, more than 10-fold, more than 15-fold, or more than 20-fold compared to the same topical formulation without laureth-4, as measured by in vitro permeation test (IVPT).In some cases, the increase is a 5-fold to 30-fold increase in skin permeation compared to the same topical formulation without laureth-4, as measured by in vitro permeation test (IVPT).In preferred embodiments, the topical formulation containing laureth-4 provides a 5-fold increase, more than 8-fold increase, more than 10-fold increase, more than 15-fold increase, or more than 20-fold increase in skin permeation compared to the same topical formulation without laureth-4. EXAMPLES

[0066]

[0071] Although various embodiments have been described herein, they have been presented by way of example only. It should be understood that these are presented as illustrative and not limiting. Thus, the breadth and scope of the present disclosure should in no way be limited by any of the above-described exemplary embodiments. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the present disclosure unless otherwise indicated herein or otherwise clearly contradicted by context.

[0067]

[0072] Experimental Example 1

[0073] A formulation was prepared with the following composition:

[0068] [Table 1]

[0069]

[0074] Experimental Example 2

[0075] IVPT results comparing prototype SHR0302 formulations were Human cadaver skin was used, cut with a dermatome to Cron's target thickness, received frozen from a US tissue bank and stored at -20°C until use. Skin was loaded onto a vertical Franz cell with a spreading area of ​​0.503 cm2 (8 mm diameter) and a receptor chamber filled with 3.0 ml of 4% bovine serum albumin (BSA) in water containing 0.01% gentamicin sulfate, thermostated at 32°C. A positive displacement pipette was used to Five microliters of cream were administered onto each Franz cell (10 mg per square centimeter of skin). The appearance of the active substance in the receptor solution (average of four replicates) was determined using LC / MS / MS.

[0070]

[0076] This study was performed to determine the effect of 100 mg / mL of SHR0302 on the receptor solution. The results of the study are shown in Table 1 and depicted in Figure 1. The addition of laureth-4 to a topical formulation containing DMSO showed a surprising and significant increase in skin penetration when compared to a nearly identical formulation without laureth-4. These results demonstrate the effectiveness of laureth-4 as a skin penetration enhancer in the topical formulation of the present invention.

[0071] [Table 2]

[0072]

[0077] Experimental Example 3

[0078] A formulation was prepared having the following composition:

[0073] [Table 3]

[0074]

[0079] Experimental Example 4

[0080] IVPT results comparing prototype SHR0302 formulations were Human cadaver skin was used, cut with a dermatome to the target thickness of Cron's, received frozen from a US tissue bank and stored at -20°C until use. The skin was loaded onto a vertical Franz cell with a diffusion area of ​​0.503 cm2 (diameter 8 mm) and a receptor chamber filled with 3.0 ml of 4% BSA in water containing 0.01% gentamicin sulfate thermostated at 32°C. Using a positive displacement pipette, 5 microliters of cream was dispensed onto each Franz cell (10 mg per square centimeter of skin). The appearance of the active substance in the receptor solution (average of four replicates) was determined using LC / MS / MS.

[0075]

[0081] This study was performed to determine the effect of 100 mg / mL of SHR0302 on the receptor solution. The results of the study are shown in Table 2 and depicted in Figure 2. The addition of Laureth-4 to topical formulations containing NMP demonstrated a surprising and significant increase in skin penetration when compared to nearly identical formulations containing minimal amounts of Laureth-4. These results support the conclusion that the skin penetration of topical formulations of the present invention is The effectiveness of laureth-4 as a penetration enhancer has been demonstrated.

[0076] [Table 4]

[0077]

[0082] Experimental Example 5

[0083] A formulation was prepared having the following composition:

[0078] [Table 5]

[0079]

[0084] Experimental Example 6

[0085] IVPT results comparing prototype SHR0302 formulations were Human cadaver skin was used, cut with a dermatome to the target thickness of Cronbach's, received frozen from a tissue bank in the United States and stored at -20°C until use. The skin was cut into a 0.503 cm2 (8 mm diameter) diffusion area and placed in a 32°C hood containing 0.01% gentamicin sulfate. The cream was loaded onto a vertical Franz cell with the receptor chamber filled with 3.0 ml of 4% bovine serum albumin (BSA) in water. Using a positive displacement pipette, 5 microliters of cream was dispensed onto each Franz cell (10 mg per square centimeter of skin). The appearance of the active substance in the receptor solution (average of four replicates) was determined using LC / MS / MS.

[0080]

[0086] This study was performed to determine the effect of 100 mg / mL of SHR0302 on the receptor solution. The results of the study are shown in Table 3 and depicted in Figure 3. The addition of laureth-4 to a topical formulation containing a 1:1:1 ratio of DMSO:DMI:DEGEE demonstrated a surprising and significant increase in skin penetration when compared to a nearly identical formulation without laureth-4. These results demonstrate the effectiveness of laureth-4 as a skin penetration enhancer in the topical formulations of the present invention.

[0081] [Table 6]

[0082]

[0087] Experimental Example 7

[0088] A formulation was prepared having the following composition:

[0083] [Table 7]

[0084]

[0089] Experimental Example 8

[0090] IVPT results comparing prototype SHR0302 formulations were Human cadaver skin was used, cut with a dermatome to the target thickness of Cron, received frozen from a US tissue bank and stored at -20°C until use. Skin was loaded onto vertical Franz cells with a diffusion area of ​​0.503 cm2 (diameter 8 mm) and a receptor chamber filled with 3.0 ml of 4% bovine serum albumin (BSA) in water containing 0.01% gentamicin sulfate thermostated at 32°C. Five microliters of cream was dispensed onto each Franz cell (10 mg per square centimeter of skin) using a positive displacement pipette. The appearance of active substance in the receptor solution (average of four replicates) was monitored using the LC / Determined using MS / MS.

[0085]

[0091] This study was performed to determine the effect of 100 mg / mL of SHR0302 on the receptor solution. The results of the study are shown in Table 4 and depicted in Figure 4. The addition of laureth-4 to a topical formulation containing a 1:1:1 ratio of DMSO:DMI:DEGEE demonstrated a surprising and significant increase in skin penetration when compared to a nearly identical formulation without laureth-4. These results demonstrate the effectiveness of laureth-4 as a skin penetration enhancer in the topical formulations of the present invention.

[0086] [Table 8]

[0087]

[0092] Experimental Example 9

[0093] A formulation was prepared having the following composition:

[0088] [Table 9]

[0089]

[0094] Experimental Example 10

[0095] IVPT results comparing prototype SHR0302 formulations were Human cadaver skin was cut with a skin harvester to the target thickness of Cron and then transferred to the US Histology Center. They were received frozen from the bank and stored at -20°C until use. The skin was loaded onto vertical Franz cells with a diffusion area of ​​0.503 cm2 (diameter 8 mm) and a receptor chamber filled with 3.0 ml of 4% bovine serum albumin (BSA) in water containing 0.01% gentamicin sulfate thermostated at 32°C. Using a positive displacement pipette, 5 microliters of cream was administered onto each Franz cell (10 mg per square centimeter of skin). The appearance of the active substance in the receptor solution (average of four replicates) was determined using LC / MS / MS.

[0090]

[0096] This study was performed to determine the effect of 100 mg / mL of SHR0302 on the receptor solution. The results of the study are shown in Table 5 and depicted in Figure 5. The addition of laureth-4 to a topical formulation containing DMSO showed a surprising and significant increase in skin penetration when compared to a nearly identical formulation without laureth-4. These results demonstrate the effectiveness of laureth-4 as a skin penetration enhancer in the topical formulation of the present invention.

[0091] [Table 10]

[0092]

[0097] Experimental Example 11

[0098] A formulation was prepared having the following composition:

[0093] [Table 11]

[0094]

[0099] Experimental Example 12 [000100] IVPT results comparing the prototype SHR0302 formulation used human cadaver skin cut with a dermatome to a target thickness of 500 microns, received frozen from a US tissue bank and stored at -20°C until use. Skin was loaded onto a vertical Franz cell with a diffusion area of ​​0.503 cm2 (8 mm diameter) and a receptor chamber filled with 3.0 ml of 4% bovine serum albumin (BSA) in water containing 0.01% gentamicin sulfate thermostated at 32°C. Using a positive displacement pipette, 5 microliters of cream was dispensed onto each Franz cell (10 mg per square centimeter of skin). The appearance of active substance in the receptor solution (average of four replicates) was monitored using LC / mL. Determined using MS / MS.

[0095] [000101] The results of this experiment (reported as ng / mL cumulative SHR0302 in the receptor solution) are shown in Table 6 and depicted in Figure 6. The addition of laureth-4 to a topical formulation containing DMSO showed a surprising and significant increase in skin penetration when compared to a nearly identical formulation without laureth-4. These results demonstrate the effectiveness of laureth-4 as a skin penetration enhancer in the topical formulations of the present invention.

[0096] [Table 12]

[0097] [000102] Example 13 [000103] A formulation was prepared having the following composition:

[0098] [Table 13]

[0099] [000104] Formulation #7 was prepared as follows: 38.93 grams of purified water was placed in the main manufacturing vessel. 0.50 grams of sodium phosphate, monobasic, anhydrous was added to the water in the main manufacturing vessel and mixed until a clear solution was obtained. In a separate container labeled "Part B", 10.04 grams of dimethyl sulfoxide, 10.16 grams of diethylene glycol monoethyl ether (Transcutol P®) and 10.14 grams of dimethyl isosorbide were blended together. Two preservatives (0.10 grams) were added to the main manufacturing vessel. 0.021 grams of methylparaben and 0.021 grams of propylparaben, and 0.62 grams of the JAK inhibitor SHR0302 were added to "Part B" and mixed until completely dissolved. The entire contents of the container labeled "Part B" was added to the main manufacturing vessel and mixed until a clear solution was obtained. Polysorbate 60 (10.15 grams) was added to the main manufacturing vessel and mixed to form a hazy, viscous liquid. Hydroxypropylcellulose (0.51 grams) was added to the main manufacturing vessel and mixed to form a hazy, viscous liquid. In a separate container labeled "Part E", 10.15 grams of white petrolatum, 10.16 grams of Crodafos™ CES, and 4.0 grams of Laureth-4 were combined and heated to 66°C. The main manufacturing vessel was heated to 68°C. Using a homogenizer (25 mm head set, 10, 230 rpm), the entire contents of "Part E" was added to the main manufacturing vessel and homogenized for 5 minutes. Dimethicone (1.01 grams) was added to the main manufacturing vessel and homogenized for an additional 2 minutes. Purified water (0.76 grams) was added to the batch sufficient to bring it to 100%.

[0100] [000105] Formulation #9 was prepared as follows: 38.63 grams of purified water was placed in the main manufacturing vessel. Glycerin (5.1 grams) and 0.50 grams of sodium phosphate, monobasic anhydrous were added to the water in the main manufacturing vessel and mixed until a clear solution was obtained. Xanthan gum (0.2 grams) was added to the main manufacturing vessel and mixed for 59 minutes. In a separate vessel labeled "Part D", 10.08 grams of dimethyl sulfoxide, 10.10 grams of diethylene glycol monoethyl ether (Transcutol P®) were added. 0.06 grams of dimethyl isosorbide, 0.10 grams of methylparaben, 0.020 grams of propylparaben, 0.052 grams of butylhydroxytoluene, and 0.62 grams of the JAK inhibitor SHR0302 were combined and mixed until a clear solution was obtained. In a third separate container labeled "Part C," 5.15 grams of polyethylene (2) stearyl ether, 5.06 grams of polyethylene (21) stearyl ether, 5.06 grams of PPG 15 stearyl ether, 6.10 grams of cetostearyl alcohol, and 4.06 grams of laureth-4 were combined and heated to 72°C. The main manufacturing vessel was heated to 74°C. Using a homogenizer (25 mm head set at 9800 rpm), the entire contents of "Part C" were added to the main manufacturing vessel and homogenized for 3 minutes. While homogenization continued, the entire contents of "Part D" were slowly added to the main manufacturing vessel. Total homogenization time was 5 minutes. Not enough additional purified water was used to bring this particular batch to 100%.

[0101] [000106] The foregoing description has been presented for purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed. Those skilled in the art will appreciate that modifications and substitutions to the description of the basic invention may be made.

Claims

1. A topical pharmaceutical composition comprising a JAK inhibitor, laureth-4 and a solvent.

2. 2. The topical pharmaceutical composition of claim 1, wherein the JAK inhibitor is SHR0302.

3. 3. The topical pharmaceutical composition of claim 2, wherein the JAK inhibitor is present in an amount of about 0.1 to about 1.0% w / w.

4. 10. The topical pharmaceutical composition of claim 1, wherein laureth-4 is present in an amount of about 0.5 to about 5% w / w.

5. 10. The topical pharmaceutical composition of claim 1, further comprising dimethyl sulfoxide.

6. 10. The topical pharmaceutical composition of claim 1, further comprising an antioxidant, a preservative, an emulsifier, a humectant, or a thickener.

7. 10. The topical pharmaceutical composition of claim 1, wherein the composition is selected from the group consisting of an oil-in-water emulsion, a water-in-oil emulsion, a microemulsion, a nanoemulsion, a foam, a spray, a hydrophilic ointment, or a hydrophobic ointment.

8. 10. The topical pharmaceutical composition of claim 1, further comprising a corticosteroid, timolol, methotrexate or cyclosporine.

9. 10. The topical pharmaceutical composition of claim 1, wherein the skin penetration of the topical pharmaceutical composition is enhanced 5-30 fold compared to a topical pharmaceutical formulation not containing Laureth-4 as measured by an in vitro permeation test.

10. 1. A method of treating an inflammatory skin disease, disorder or condition in a subject in need thereof, comprising the steps of: topically administering to said subject a pharmaceutical composition comprising a JAK inhibitor, laureth-4 and a solvent; The method includes:

11. 11. The method of claim 10, wherein the inflammatory skin disease, disorder or condition is atopic dermatitis, rosacea, psoriasis, seborrheic dermatitis, vitiligo, eczema or alopecia areata.

12. 11. The method of claim 10, wherein the pharmaceutical composition is administered to the subject one or more times per day.

13. 11. The method of claim 10, wherein the JAK inhibitor is SHR0302.

14. 11. The method of claim 10, wherein the JAK inhibitor is present in the pharmaceutical composition in an amount of about 0.1 to about 1.0% w / w.

15. 11. The method of claim 10, wherein the laureth-4 is present in the pharmaceutical composition in an amount of about 0.5 to about 5% w / w.

16. 11. The method of claim 10, wherein the pharmaceutical composition further comprises dimethyl sulfoxide. method.

17. 11. The method of claim 10, wherein the pharmaceutical composition further comprises a corticosteroid, timolol, methotrexate or cyclosporine.

18. 11. The method of claim 10, wherein the skin penetration of the topical pharmaceutical composition is enhanced 5-30 fold compared to a topical pharmaceutical formulation not containing Laureth-4 as measured by an in vitro permeation test.

19. 1. A method for enhancing skin penetration in a subject of a topical pharmaceutical formulation, comprising the steps of: A formulation is prepared comprising a JAK inhibitor, Laureth-4 and a solvent; wherein skin penetration of the topical pharmaceutical composition is enhanced 5- to 30-fold compared to a topical pharmaceutical formulation not containing Laureth-4.

20. 20. The method of claim 19, wherein the JAK inhibitor is SHR0302.

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