Compositions and methods for deep dermal drug delivery

Abstract

To provide pharmaceutical compositions for the topical administration of a drug to the pilosebaceous unit, and to provide methods of treating alopecia areata.SOLUTION: Provided is a pharmaceutical composition comprising: a therapeutically effective amount of SHR0302 or a pharmaceutically acceptable salt thereof, the primary particle size distribution of the SHR0302 being characterized by a D90 value of less than about 20 μm; as well as a silicone selected from the group consisting of dimethicone and cyclomethicone.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 / 114,887, filed November 17, 2020, and U.S. Provisional Application No. 63 / 221,349, filed July 13, 2021, the disclosures of which are incorporated by reference in their entirety into this specification.

[0002] FIELD OF THEINVENTION

[0002] The subject matter disclosed herein generally relates to pharmaceutical compositions for topical administration of drugs to the pilosebaceous unit and methods for administering the same. As disclosed herein, the inventors of the present invention have made a surprising discovery that pharmaceutical compositions comprising small particles of active pharmaceutical ingredient and silicone, such as dimethicone or cyclomethicone, can be targeted to the pilosebaceous unit. In a preferred embodiment, the pharmaceutical composition comprises SHR0302 or spironolactone as the active pharmaceutical ingredient. [Background technology]

[0003]

[0003] Transdermal and topical delivery of drugs have various advantages compared to other routes of administration. Transdermal and topical delivery can be used to continuously deliver drugs into the systemic circulation and avoid first-pass metabolism. In contrast, for oral drug delivery, there is a significant first-pass effect of the liver that can cause premature metabolism of the drug. Transdermal and topical delivery also have advantages over intravenous administration, which requires sterile products and can be painful, thereby increasing non-compliance by patients. On the other hand, transdermal delivery is not sterile, non-invasive, and can be self-administered.

[0004]

[0004] Traditional drug delivery systems have focused on administration via the transepidermal delivery route. Andrea C. Lauer et al., Transfollicular Drug Delivery, Pharmaceutical Research 12:2 (1995). Skin is composed of four main layers: (a) the stratum corneum (non-viable epidermis), (b) the viable epidermis, (c) the dermis, and (d) the subcutaneous tissue. Skin also contains appendages in the form of terminal hairs, which can extend more than 3 mm below the skin surface into the subcutaneous adipose tissue, and vellus hairs, which are thin and often unnoticed hairs that extend less than 1 mm into the dermis. The hair follicles, hair shafts, and sebaceous glands that secrete lubricating substances into the hair follicles comprise what is known as the pilosebaceous unit. Although the stratum corneum has traditionally been viewed as the primary route for the penetration of drugs, it is also the main barrier to transdermal absorption. In the past, researchers have questioned the importance of the pilosebaceous unit in drug delivery.

[0005]

[0005] More recently, however, the potential role of the pilosebaceous unit and alternative mechanisms for transdermal drug delivery have been investigated. Amit Verma et al., Transfollicular drug delivery: current perspectives, Research and Reports in Transdermal Drug Delivery (April 20, 2016). Mammalian hair follicles are complex and dynamic structures in which unique biochemical and immunological reactions occur. Although the pilosebaceous unit may be an acceptable target for drug delivery, several challenges exist for drug delivery to the pilosebaceous unit. One of the challenges for drug delivery to the pilosebaceous unit is the need to bypass the stratum corneum, which extends to a depth of approximately 10-20 μm, and the upper capillary network, which extends to a depth of approximately 80 μm. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Andrea C. Lauer et al., Transfollicular Drug Delivery, Pharmaceutical Research 12:2 (1995) [Non-Patent Document 2] Amit Verma et al., Transfollicular drug delivery: current perspectives, Research and Reports in Transdermal Drug Delivery (April 20, 2016) Summary of the Invention

[0007]

[0006] Currently, there is a need for pharmaceutical compositions that can penetrate deeper into the dermis, approximately 1,000 μm to 2,000 μm to the pilosebaceous unit. There is an unmet need for new pharmaceutical compositions and methods of administering drugs via the pilosebaceous unit.

[0008] The present invention relates to a pharmaceutical composition for topical administration of drugs to the pilosebaceous unit and a method for administering the pharmaceutical composition. The inventors of the present invention have made a surprising discovery that a pharmaceutical composition comprising small particles of active pharmaceutical ingredient and silicone, such as dimethicone or cyclomethicone, can be delivered to the pilosebaceous unit, resulting in deeper penetration into the dermis and improved efficacy. In a preferred embodiment, the pharmaceutical composition comprises SHR0302 or spironolactone as the active pharmaceutical ingredient.

[0009] In certain embodiments of the present invention, a pharmaceutical composition is provided comprising a therapeutically effective amount of an active pharmaceutical ingredient and a silicone selected from the group consisting of dimethicone, cyclomethicone, and combinations thereof. The active pharmaceutical ingredient has a primary particle size distribution characterized by a D90 value of less than about 20 μm. In certain embodiments, the pharmaceutical ingredient has a primary particle size distribution characterized by a D90 value of less than about 10 μm or more preferably less than about 5 μm. In certain embodiments, the composition comprises about 0.10% w / w to about 7.5% w / w of the active pharmaceutical ingredient. The pharmaceutical composition of the present invention may be capable of delivering the active pharmaceutical ingredient to the pilosebaceous unit. In certain embodiments, the active pharmaceutical ingredient is capable of achieving at least 1 mm of skin penetration in a subject.

[0010]

[0009] In a particular embodiment of the present invention, a pharmaceutical composition is provided comprising a therapeutically effective amount of SHR0302 or a pharma- ceutically acceptable salt thereof. SHR0302 may have a primary particle size distribution characterized by a D90 value of less than about 20 μm, less than about 10 μm, or more preferably less than about 5 μm. SHR0302 may further have a primary particle size distribution characterized by a D50 value of less than about 5 μm, less than about 1 μm, or more preferably less than about 0.7 μm. SHR0302 may further have a primary particle size distribution characterized by a D10 value of less than about 1 μm, less than about 0.5 μm, or more preferably less than about 0.25 μm.

[0011]

[0010] The pharmaceutical composition comprises dimethicone, cyclomethicone and combinations thereof. In certain embodiments of the present invention, the pharmaceutical composition comprises SHR0302 suspended in at least one of dimethicone and cyclomethicone.

[0012] In certain embodiments, the pharmaceutical composition comprises from about 0.10% w / w to about 5% w / w The pharmaceutical composition may contain about 0.1% w / w to about 3% w / w of SHR0302 or a salt thereof.

[0013] In certain embodiments of the present invention, there is provided a method for treating alopecia areata in a subject in need thereof. Methods of treating hair loss are provided. The methods include topically administering to a subject a pharmaceutical composition of SHR0302 as described herein. In the methods of the present invention, SHR0302 or a salt thereof can be delivered to the pilosebaceous unit. In the methods disclosed herein, administration of the pharmaceutical composition can result in transdermal penetration of SHR0302 to a depth of at least about 1 mm in the subject, preferably about 2-3 mm in the subject, of the hair bulb for terminal hair.

[0014]

[0013] In a particular embodiment of the present invention, a pharmaceutical composition is provided that comprises a therapeutically effective amount of spironolactone or its pharma- ceutically acceptable salt.Spironolactone can have a primary particle size distribution characterized by a D90 value of less than about 6 μm, less than about 1 μm, or more preferably less than about 0.25 μm.Spironolactone can further have a primary particle size distribution characterized by a D50 value of less than about 2.7 μm, less than about 0.75 μm, or more preferably less than about 0.15 μm.Spironolactone can further have a primary particle size distribution characterized by a D10 value of less than about 1.2 μm, less than about 0.50 μm, or more preferably less than about 0.10 μm.

[0015]

[0014] The pharmaceutical composition comprises a compound selected from the group consisting of dimethicone and cyclomethicone. It further comprises a silicone.In certain embodiments of the invention, the pharmaceutical composition of spironolactone is an oil-in-water emulsion.

[0016]

[0015] In addition, the pharmaceutical composition contains from about 0.10% w / w to about 7.5% w / w of spironol. The lactone or salt thereof may be included. In certain embodiments, the pharmaceutical composition may include from about 0.5% w / w to about 5% w / w of spironolactone or a salt thereof.

[0017] In certain embodiments of the present invention, a method for treating acne in a subject in need thereof is provided. A method is provided for treating schizophrenia. In certain embodiments, the subject is a human male or female. In a preferred embodiment, the subject is a female human. The method comprises topically administering to the subject a pharmaceutical composition of spironolactone as described herein. In the method of the present invention, spironolactone or its salt can be delivered to the pilosebaceous unit. In the method disclosed herein, administration of the pharmaceutical composition can result in skin penetration of spironolactone of at least 1 mm in the subject, preferably about 2 or 3 mm in the subject.

[0018] BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The accompanying drawings, which are incorporated in this specification and form a part of this disclosure, illustrate the invention in a simplified form. These help explain the various embodiments and, together with the description, further serve to describe the invention so that one skilled in the relevant art can make and use the embodiments disclosed herein. [Brief description of the drawings]

[0019] [Figure 1] FIG. 1 shows a particle size distribution plot of SHR0302 in an exemplary pharmaceutical composition. [Diagram 2] FIG. 2 shows the Fourier transform ion cyclotron resonance-high resolution-matrix assisted laser desorption / ionization mass spectrometry (FTICR-HR-MALDI) depth profile of 0.3% SHR0302 topical 30% DMSO cream for the first donor (Donor A). [Diagram 3]

[0020] FIG. 3 shows the FTICR-HR-MALDI depth profile of a 3% SHR0302 topical suspension in dimethicone for the first donor (Donor A). [Figure 4]

[0021] FIG. 4 shows the FTICR-HR-MALDI depth profile of 0.3% SHR0302 topical 30% DMSO cream for a second donor (Donor B). [Diagram 5]

[0022] FIG. 5 shows the FTICR-HR-MALDI depth profile of a 3% SHR0302 topical suspension in dimethicone for a second donor (Donor B). [Figure 6]

[0023] FIG. 6 shows the particle size distribution of spironolactone in a suspension of 5.0% nano-milled spironolactone in water with 0.05% dioctyl sulfosuccinate (DOSS) and 1.0% hydroxylpropylcellulose. [Figure 7]

[0024] FIG. 7 is a photomicrograph taken after two weeks of storage past the completion of milling of a 5% spironolactone suspension in cyclomethicone that had been roller milled to form a suspension having a D90 of about less than 5 μm. [Figure 8]

[0025] FIG. 8 shows the cumulative amount of spironolactone appearing in the receptor solution over 24 hours following a single 5.0 μl dose per cell (10 mg per cm2 of skin tissue) for two exemplary formulations (Formulation 1 and Formulation 2 described in Example 4) and a comparative gel formulation (also described in Example 4). [Figure 9]

[0026] FIG. 9 shows the amount of spironolactone (ng) in the epidermis and dermis after 24 hours for two exemplary formulations (Formulation 1 and Formulation 2 described in Example 4) and a comparative gel formulation (also described in Example 4). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020]

[0027] 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 specific methodologies, protocols, and reagents, as these may vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the invention, which will be limited only by 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.

[0021]

[0028] All publications, patents and patent applications cited herein are hereby incorporated by reference in their entirety. Unless otherwise stated, the term is incorporated herein by reference in its entirety. Where the same term is defined in a publication, patent or patent application incorporated herein by reference and in this disclosure, 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.

[0022]

[0029] 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, "an active ingredient" includes a single ingredient as well as two or more different ingredients, and "a sulfate" includes a single sulfate as well as two or more different sulfates.

[0023]

[0030] 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.

[0024]

[0031] The term "efficacious" refers to a reduction in the severity of disease symptoms, a period free of disease symptoms, or the like. It refers to an amount of a compound, drug, substance, combination or composition sufficient to cause an increase in the frequency and duration of symptoms during treatment or to prevent a defect or disorder due to the affliction of a disease. The amount can be alone or in combination with other compounds, drugs or substances, as a single dose or according to a multiple dose regimen. One skilled in the art will be able to determine such amounts based on factors such as the size of the subject, the severity of the subject's symptoms and the particular composition or route of administration selected.

[0025]

[0032] "Pharmaceutical acceptable" means a substance that is generally safe for administration to humans or animals. Preferably, a pharma- ceutical acceptable component is one approved by a federal or state regulatory agency or 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.

[0026]

[0033] 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.

[0027]

[0034] As used herein, the term "subject" or "patient" most preferably refers to a The term "subject" or "patient" can include any mammal that can benefit from the compounds described herein.

[0028]

[0035] 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.

[0029]

[0036] The term "topical" in reference to administration of a drug or composition refers to administration to the skin or cornea. It refers to the application of such a drug or composition to epithelial surfaces outside the body, including the epithelium of the skin. With respect to this application, application inside body orifices where the mucosal surface does not contain pilosebaceous units, such as the mouth, vagina or rectum, is not considered a topical application.

[0030]

[0037] 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).

[0031]

[0038] 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).

[0032]

[0039] The present invention relates to a pharmaceutical composition and method for the topical administration of a drug to the pilosebaceous unit. The present inventors have made the surprising discovery that pharmaceutical compositions comprising small particles of active pharmaceutical ingredients in silicones such as dimethicone or cyclomethicone can be targeted to the pilosebaceous unit, resulting in deeper penetration into the dermis and improved efficacy.In a preferred embodiment, the pharmaceutical composition comprises SHR0302 or spironolactone as the active pharmaceutical ingredient.

[0033]

[0040] In certain embodiments of the present invention, a therapeutically effective amount of the active pharmaceutical ingredient and dimethy A pharmaceutical composition is provided comprising a silicone selected from the group consisting of cyclomethicone, cyclomethicone, and combinations thereof. In certain embodiments, the amount of active pharmaceutical ingredient may range from about 0.01% w / w to about 10% w / w, or from about 0.01% w / w to about 5% w / w, or from about 0.1% w / w to about 3% w / w. Exemplary ranges are from about 0.01% w / w to about 10% w / w, or from about 0.01% w / w to about 7.5% w / w, or from about 0.01% w / w to about 5% w / w, or from about 0.1% w / w to about 3% w / w, or from about 1.0% w / w to about 3% w / w, or from about 0.3% w / w to about 3.0% w / w. For example, the pharmaceutical composition may contain any of the following w / w percentages of active pharmaceutical ingredient: 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 7%, 1.8%, 1.9%, 1.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, etc.

[0034]

[0041] In the pharmaceutical composition of the present invention, the active ingredient is present as small particles. The particle size of an object can be evaluated using laser diffraction. Laser diffraction is recognized by standards and guidance bodies including ISO and ASTM and is widely used to determine particle size distribution. In performing the evaluation, a sample is passed through a laser beam, which results in laser light scattered at a range of angles. A detector placed at a certain angle measures the intensity of the scattered light at that position. A mathematical model is then applied to generate a particle size distribution. The particle size values ​​reported herein were determined by using a liquid or wet dispersion method.

[0035]

[0042] In particle size determination, the median is the point above which half of the population lies and half It is defined as the value that lies below this point. In terms of particle size distribution, the median is called the D50. The D50 is the size that separates the distribution into upper and lower halves above this diameter. The distribution width can also be characterized by listing one, two or three values ​​on the X-axis, typically some combination of D10, D50 and D90. The median, D50, is defined above as the diameter below which half of the population lies. Similarly, 90 percent of the distribution lies below D90 and 10 percent of the population lies below D10.

[0036]

[0043] In certain embodiments, the active pharmaceutical ingredient has a particle size of less than about 20 μm, less than about 15 μm, The primary particle size distribution is characterized by a D90 value of less than about 10 μm or more preferably less than about 5 μm. In certain embodiments, the active pharmaceutical ingredient has a primary particle size characterized by a D90 value of about 0.001 μm, 0.01 μm or 0.1 μm to about 5 μm, 10 μm, 15 μm and 20. The active pharmaceutical ingredient may further have a primary particle size distribution characterized by a D50 value of less than about 5 μm, less than about 2 μm, less than about 1 μm, less than about 0.8 μm, or more preferably less than about 0.7 μm. In certain embodiments, the active pharmaceutical ingredient has a primary particle size characterized by a D50 value of about 0.001 μm, 0.01 μm or 0.1 μm to about 0.7 μm, 0.80 μm, 1.0 μm, 2.0 μm or 5.0 μm. The active pharmaceutical ingredient may further have a primary particle size distribution characterized by a D10 value of less than about 1 μm, less than about 0.5 μm, less than about 0.4 μm, or more preferably less than about 0.25 μm. In certain embodiments, the active pharmaceutical ingredient has a primary particle size characterized by a D10 value of about 0.0001 μm, 0.001 μm, or 0.01 μm to about 0.25 μm, 0.4 μm, 0.5 μm, or 1.0 μm.

[0037]

[0044] In certain embodiments, the pharmaceutical compositions of the present invention administer the active pharmaceutical ingredient to the pilosebaceous unit. In certain embodiments, the active pharmaceutical ingredient is capable of achieving skin penetration of at least 1 mm in a subject.

[0038]

[0045] In certain embodiments of the present invention, the pharmaceutical composition comprises SHR0302 or ARQ The JAK1 inhibitors include (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 SHR0302-250. The terms SHR0302 and ARQ-250 are used interchangeably herein. The structure of SHR0302 is as follows:

[0039] [ka]

[0040] .

[0041]

[0046] SHR0302 has high selectivity for JAK1 over JAK2. SHR0302 is a potent small molecule inhibitor of JAK1 that has been shown to be active in treating inflammatory diseases and therefore 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. SHR0302 is disclosed in U.S. Patent No. 9,527,851, which is incorporated herein by reference.

[0042]

[0047] In a particular embodiment of the present invention, the pharmaceutical composition comprises spironolactone, also known as The structure of spironolactone is:

[0043] [ka]

[0044]

[0048] Spironolactone acts by competitively inhibiting the binding of aldosterone. It is a drug that acts at the mineralocorticoid receptor level. This steroid compound is used to reduce edema and to treat essential hypertension and primary hyperaldosteronism. It has been used to block aldosterone-dependent sodium transport in the distal tubules of the kidney. Orally administered spironolactone is also effective in treating women with acne. EM Attwa et al., Efficacy and safety of topical spironolactone 5% gel versus placebo in the treatment of acne vulgaris, J. Dermatol. Venerol. 39:89-94 (2019); JW Charny et al., Spironolactone for the treatment of acne in women, a retrospective study of 110 patients, Int. J. Womens Dermatol. 3(2): 111-115 (2017). Spironolactone is commercially available under the trade names ALDACTONE® and CAROSPIR®. Spironolactone is disclosed in U.S. Pat. No. 3,013,012, which is incorporated herein by reference.

[0045]

[0049] In the present invention, the pharmaceutical composition is administered locally. 0302 or spironolactone may be included as a free base or as a pharma- ceutically acceptable salt. Suitable pharma-ceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company (1985), which is incorporated herein by reference.

[0046]

[0050] In certain embodiments, the pharmaceutical composition has a diameter of less than about 20 μm, less than about 15 μm, less than about The present invention includes SHR0302 having a primary particle size distribution characterized by a D90 value of less than 10 μm, or more preferably less than about 5 μm. In certain embodiments, SHR0302 has a primary particle size distribution characterized by a D90 value of about 0.01 μm, 0.1 μm, or 1.0 μm to about 5.0 μm, 10.0 μm, 15.0 μm, or 20.0 μm.

[0047]

[0051] SHR0302 is further characterized by a diameter of less than about 5 μm, less than about 2 μm, less than about 1 μm, It may have a primary particle size distribution characterized by a D50 value of less than 0.8 or more preferably less than about 0.7 μm. In certain embodiments, SHR0302 has a primary particle size characterized by a D50 value of about 0.001 μm, 0.01 μm, or 0.1 μm to about 0.7 μm, 0.8 μm, 1.0 μm, 2.0 μm, or 5.0 μm.

[0048]

[0052] SHR0302 further comprises less than about 1 μm, less than about 0.5 μm, less than about 0.4 μm The primary particle size distribution may be characterized by a D10 value of less than about 0.0001 μm, or more preferably less than about 0.25 μm. In certain embodiments, SHR0302 has a primary particle size distribution characterized by a D10 value of about 0.0001 μm, 0.001 μm, or 0.01 μm to about 0.25 μm, 0.4 μm, 0.5 μm, or 1.0 μm.

[0049]

[0053] In certain embodiments, the pharmaceutical composition has a particle size of less than about 6 μm, less than about 5 μm, less than about 2 μm, In certain embodiments, the spironolactone has a primary particle size distribution characterized by a D90 value of about 0.001 μm, 0.01 μm, or 0.1 μm to about 0.2 μm, 0.25 μm, 0.5 μm, 1 μm, 2 μm, 5 μm, or 6 μm.

[0050]

[0054] Spironolactone is further classified as less than about 2.7 μm, less than about 2.0 μm, and less than about 1. The spironolactone may have a primary particle size distribution characterized by a D50 value of less than 0 μm, less than about 0.75 μm, 0.5 μm, less than about 0.25 μm, less than about 0.2 μm, or more preferably less than about 0.15 μm. In certain embodiments, the spironolactone has a primary particle size characterized by a D50 value of about 0.001 μm, 0.01 μm, or 0.1 μm to about 0.15 μm, 0.2 μm, 0.25 μm, 0.5 μm, 0.75 μm, 1.0 μm, 2.0 μm, or 2.7 μm.

[0051]

[0055] Spironolactone may further be used in combination with a spheroid having a diameter of less than about 1.2 μm, less than about 1.0 μm, less than about 0.5 μm, or less than about 1.0 μm. The primary particle size distribution may be characterized by a D10 value of less than about 0.5 μm, less than about 0.25 μm, less than about 0.15 μm, less than about 0.10 μm, or more preferably less than about 0.08 μm. In certain embodiments, the spironolactone has a primary particle size characterized by a D10 value of about 0.0001 μm, 0.001 μm, or 0.01 μm to about 0.10 μm, 0.15 μm, 0.25 μm, 0.5 μm, 1.0 μm, or 1.2 μm.

[0052]

[0056] The pharmaceutical composition of the present invention comprises dimethicone, cyclomethicone or a combination thereof. The silicone further comprises a silicone selected from the group consisting of a combination of. Dimethicone, also known as polydimethylsiloxane (PDMS), is a polymerizable organosilicon compound. Cyclomethicone is a group of methylsiloxanes, which, unlike dimethicone, is a cyclic organosilicon compound. In certain embodiments, the pharmaceutical composition can comprise a combination of silicones, including dimethicone and cyclomethicone. For example, the pharmaceutical composition can comprise dimethicone-cyclomethicone-dimethicone / vinyl dimethicone. Additional methylsiloxane compatible excipients, such as cyclopentasiloxane, dimethiconol and phenyl trimethicone, can be added to dimethicone and / or cyclomethicone to adjust aesthetics or viscosity. Silicones, such as dimethicone or cyclomethicone, have a polarity similar to sebum, allowing the pharmaceutical composition to target hair follicle delivery.

[0053]

[0057] In certain embodiments, the pharmaceutical composition is a suspension, in which the active ingredient (e.g. For example, SHR0302 or spironolactone) is suspended in a silicone (for example, dimethicone or cyclomethicone). In certain embodiments, the pharmaceutical composition can be formulated as an emulsion. For example, the pharmaceutical composition can be formulated in one of the following forms:

[0058] 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.

[0054]

[0059] Water-in-oil emulsion: The composition has 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.

[0055]

[0060] 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]

[0061] Nanoemulsions: These are isotropic dispersions containing water, oil, and an emulsifier. Nanoemulsions are systems that can be oil-based systems dispersed in an aqueous system forming nanometer-sized droplets or an oily phase, or aqueous systems dispersed in an oily system. 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]

[0062] In certain embodiments, the pharmaceutical composition comprises an active ingredient and dimethicone, cyclomethicone, The pharmaceutical composition may consist essentially of a silicone selected from the group consisting of ticone, methacrylate, methacrylate crosslinker ...

[0058]

[0063] Administration and Dosage

[0064] The present invention relates to a method for treating hair loss disorders, such as alopecia, androgenetic alopecia, hypotrichosis, and the like. The method includes a method of treating hair loss conditions, such as telogen effluvium (TEF) and telogen effluvium (Telogen effluvium), in a patient in need thereof by administering to the patient a composition of SHR0302 or spironolactone as described herein.

[0059]

[0065] In a preferred embodiment, the present invention includes a method of treating alopecia areata (AA). AA is one of the most prevalent autoimmune diseases, resulting in hair loss due to the breakdown of immune privilege of hair follicles and subsequent autoimmune destruction. AA is a skin disease that causes hair loss on the scalp and elsewhere. Prior to the present invention, topical administration of JAK inhibitors has not shown reproducible clinical efficacy. Without being bound by theory, it is believed that the failure of JAK inhibitors to treat AA prior to the present invention as claimed is due to insufficient drug delivery to the pilosebaceous unit, more specifically to the hair bulb. The inventors of the present invention have made the surprising discovery that the pharmaceutical compositions disclosed herein can penetrate at least about 1 mm, at least about 2 mm, and at least about 3 mm into hair follicles in AA patients.

[0060]

[0066] In certain embodiments, the present invention provides a therapeutically effective amount of a SHR0 described herein. 302 provides a method for treating AA in a patient in need thereof, comprising topically applying the pharmaceutical composition to the patient. In certain embodiments, the active ingredient, SHR0302, may be administered in a therapeutically effective amount. In certain embodiments, the amount of SHR0302 may range from about 0.01% w / w to about 7.5% w / w, or from about 0.01% w / w to about 5% w / w, or from about 0.1% w / w to about 3% w / w. Exemplary ranges are from about 0.01% w / w to about 5% w / w, or from about 0.01% w / w to about 3% w / w, or from about 0.1% w / w to about 3% w / w, or from about 0.3% w / w to about 3.0% w / w. For example, topical formulations may contain any of the following w / w percentages of SHR0302: 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 7%, 1.8%, 1.9%, 1.0%, 2.1%, and 2.2%. 2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6% , 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, etc.

[0061]

[0067] The present invention further provides a method of treating acne in a patient in need thereof. The present invention provides a method for treating acne. Acne is a disorder of the pilosebaceous unit located on face, chest and back. Acne can be one selected from the group consisting of acne, acne vulgaris, inflammatory acne, non-inflammatory acne, flash acne, nodular papulopustular acne, confluent acne, acne rosacea, rosacea, exfoliative acne, adult onset acne, persistent recurrent acne after teenage years and acne associated with other disorders. In certain embodiments, the patient is a human male or female patient. In a preferred embodiment, the patient is a human female. In addition, patients: (a) experience acne flares that cycle with menstruation; (b) suffer from adult-onset acne or persistent recurrent acne beyond the teenage years, even in the absence of clinical or laboratory signs of hyperandrogenism; (c) use oral contraceptives and exhibit moderate to severe acne, especially with a clinically hormonal pattern; or (d) have not responded to conventional therapy and are not candidates for oral isotretinoin therapy.

[0062]

[0068] In certain embodiments, the present invention provides a therapeutically effective amount of a spironolactone compound described herein. A method for treating acne in a patient in need thereof is provided, comprising topically applying a lactone pharmaceutical composition to the patient. In certain embodiments, the active ingredient, spironolactone, may be administered in a therapeutically effective amount. In certain embodiments, the amount of spironolactone may range from about 0.01% w / w to about 10% w / w, or from about 0.01% w / w to about 7.5% w / w, or from about 0.01% w / w to about 5% w / w, or from about 0.1% w / w to about 3% w / w. Exemplary ranges are from about 0.1% w / w to about 10% w / w, or from about 0.1% w / w to about 7.5% w / w, or from about 0.1% w / w to about 5% w / w, or from about 0.1% w / w to about 3% w / w, or from about 1.0% w / w to about 5% w / w, or from about 0.3% w / w to about 5.0% w / w. For example, topical formulations may contain spironolactone in any of the following w / w percentages: 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 7%, 1.8%, 1.9%, 1.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%. , 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, 5.1%, 5.2%, 5.3%, 5.4%, 5. 5%, 5.6%, 5.7%, 5.8%, 5.9%, 6.0%, 6.1%, 6.2%, 6.3%, 6.4%, 6.5%, 6.6%, 6.7%, 6.8%, 6.9%, 7.0%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5%, etc.

[0063]

[0069] In certain embodiments, the pharmaceutical composition is administered in a regimen, such as at regular intervals. The topical pharmaceutical composition is administered topically as a treatment regimen. For example, the topical pharmaceutical composition can be administered once a day, twice a day, three times a day, once a week, twice a week, three times a week, or four times a week. The pharmaceutical composition can be administered for a predetermined period of time. For example, the topical pharmaceutical composition can be administered for a period of about 2 weeks to at least about 6 months, or until an improvement in the skin condition or disease is visually observed. Exemplary periods for treatment regimens include 2 weeks, 1 month, 6 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, or 1 year. In a preferred embodiment, the topical pharmaceutical composition is administered two or three times daily for a period of at least 3 months, 4 months, 5 months, or 6 months.

[0064]

[0070] The following examples illustrate certain aspects of the invention without limiting them. EXAMPLES

[0065]

[0071] While various embodiments have been described above, they have been presented by way of example only. It should be understood that these are not limiting. Thus, the breadth and scope of the present disclosure should in no way be limited by any of the above-described exemplary aspects. 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.

[0066]

[0072] Comparative Example 1

[0073] Comparative Example 1 is a 0.3% SHR0302 topical cream having the composition shown in Table 1. It was prepared as a ream.

[0067] [Table 1]

[0068]

[0074] Example 1

[0075] A pharmaceutical composition was prepared containing 3% SHR0302 suspended in dimethicone. The SHR0302 used in the composition had a particle size distribution as shown in Figure 1. The primary particle size distribution of SHR0302 is characterized by a D10 value of less than about 0.25 μm; a D50 value of less than about 0.7 μm; and a D90 value of less than about 5 μm. The pharmaceutical composition was a clear solution as the particles were too small to scatter visible light. To determine the particle size distribution profile of SHR0302, a Malvern Metasizer Model 3000 using a Hydro MV dispersion unit was used. The sample preparation procedure followed was as follows: weigh 10-20 mg of SCP-treated ARQ-250 into a 30 mL vial, add 20 mL of ethyl acetate, sonicate the suspension with an ultrasonic probe at 40% power in a 5°C water bath for 2 minutes, and transfer the sample suspension to a Malvern Hydro MV dispersion unit to obtain 5-15% obscuration. The parameters of the instrument were: (i) refractive index of the particles: 1.5; (ii) refractive index of the dispersant: 1.395; (iii) absorption index: 0.01; (iv) measurement duration: 10 s; (v) number of measurements: 3; (vi) stirring speed: 3500 rpm. (vii) Ultrasound: Off.

[0069]

[0076] Example 2

[0077] The ability of Comparative Example 1 and Example 1 to penetrate human cadaver scalp skin was evaluated. Two different human cadaveric scalp skins (Donors A and B) were mounted on special tension cells. A dose (7.5 μL) of either Comparative Example 1 or Example 1 was applied to the scalp skin specimens for 6 hours. All formulation residues were washed off the skin. 8 mm punch biopsies were taken from the dermal side of the skin and flash frozen in liquid nitrogen. Serial 10 μm frozen sections were taken, every other section was prepared for hematoxylin and eosin (H&E) staining, and adjacent sections were retained for analysis using Fourier transform ion cyclotron resonance-high resolution-matrix-assisted laser desorption / ionization mass spectrometry (FTICR-HR-MALDI). FTICR-HR-MALDI analysis was performed using a Bruker 7T FTICR-HR-MALDI MS system.

[0070]

[0078] Figures 2 and 4 show the 0.3% SH for donor A and donor B, respectively. 1 shows the FTICR-HR-MALDI depth profile of R0302 topical 30% DMSO cream. As shown in FIG. 2, Comparative Example 1 achieved maximum dermal penetration of less than 160 μm in Donor A. As shown in FIG. 4, Comparative Example 1 achieved maximum dermal penetration of less than 500 μm in Donor B. The results are consistent with a pharmaceutical composition capable of delivering drug across the stratum corneum, indicating that the drug has not penetrated below the upper capillary network.

[0071]

[0079] Figures 3 and 5 show the 3% SH in dimethicone for Donor A and Donor B. 3 and 5 show the FTICR-HR-MALDI depth profiles of R0302 topical suspension, respectively. As shown in FIG. 3 and FIG. 5, Example 1 achieved maximum skin penetration of more than 1 mm. The results surprisingly show that the pharmaceutical composition is capable of delivering drugs to the hair bulb.

[0072]

[0080] Example 3

[0081] 0.5% dioctyl sodium sulfosuccinate and 1% hydroxypropyl A 50 mg / mL aqueous suspension of 5% spironolactone containing pyrocellulose was successfully nanomilled to provide stable submicron particles of drug particle suspension after 2 weeks storage at 5° C. and ambient light. The spironolactone had a particle size distribution as shown in FIG. 6. A Horiba laser scattering particle size distribution analyzer model LA-950 was used to determine the volume-based distribution profile of spironolactone. Circulation, stirring, and ultrasound were all turned off and the instrument was set to manual repeat mode.

[0073]

[0082] A stable 0.3% spironolactone oil-in-water emulsion having the composition shown in Table 2 was prepared. A solution was prepared:

[0083]

[0074] [Table 2]

[0075]

[0084] Example 4

[0085] 0.05%-0.055% dioctyl sodium sulfosuccinate and 1. A 5.0%-5.5% spironolactone suspension in water containing 0-1.1% hydroxylpropylcellulose was nanomilled to achieve the particle size distribution shown in Figure 6. The composition of the finished suspension is listed in Table 3 as Formulation 1. A 5% spironolactone suspension in cyclomethicone was roller milled to form a suspension with a D90 of approximately less than 5 μm, as shown in Figure 7 (micrograph taken after 2 weeks of storage past the completion of milling). The composition of this finished suspension is listed in Table 3 as Formulation 2. Comparative gel formulations described in the literature were prepared and are listed in Table 3 as comparative gels. (Attwa EM, Ibrahim AM, Abd El-Halim MF, Mahmoud HM, Efficacy and safety of topical spironolactone 5% gel versus placebo in the treatment of acne vulgaris, Egypt J Dermatol Venerol (2019); 39:89-94.)

[0086]

[0076] [Table 3]

[0077]

[0087] Different formulations were excised using in vitro skin permeation testing (IVPT) We determined how rapidly human skin could be traversed. Human cadaveric skin was procured from two donors (Caucasian female, age = 48 years, abdominal skin harvest resulting in an average thickness of 580 μm; and Hispanic male, age = 50 years, abdominal skin harvest resulting in an average thickness of 910 μm). Harvested skin was received frozen from a US tissue bank and stored at -20°C until use. Skin was cut into sections measuring 0.503 cm. 2The IVPT samples were loaded onto a vertical Franz cell with a diffusion area of ​​1.5 mm (8 mm diameter) and a receptor chamber filled with 3.0 ml of 4% BSA in water containing 0.01% gentamicin sulfate thermostated at 32°C. Five microliters of each formulation was administered to each Franz cell using a positive displacement pipette (10 mg per square centimeter of skin). The receptor solutions were analyzed using a validated LC-MS / MS (Kinetex C18, 5 μm, 2.1×50 mm column, Shimadzu LC20ADXR pump and AB Sciex API 4000 Turbo Spray detector). The cumulative amount of spironolactone assayed in the receptor solution is the average of four replicate IVPT measurements.

[0078]

[0088] Spironolactone retention in the epidermis and dermis 24 hours after cutaneous administration. To determine the levels of spironolactone, all unabsorbed and unpenetrated spironolactone was washed from the skin surface. This was accomplished by wiping the tissue surface three times with a Q-tip wetted with 1xPBS, followed by two tape strips. The epidermis (including the stratum corneum) was peeled from the dermis and immersed in 4.0 ml of DMSO / acetonitrile (ACN) (50 / 50 v / v) mixture overnight at room temperature on an orbital shaker. The remaining dermal layer was cut into small pieces and extracted overnight at room temperature with 4.0 ml of DMSO / ACN mixture on an orbital shaker. The dermis and Extracts of the skin and epidermis were analyzed using a validated LC-MS / MS (Kinetex C18, 5 μm, 2.1 × 50 mm column, Shimadzu LC20ADXR pump and AB Sciex API 4000 Turbo Spray detector).

[0079]

[0089] FIG. 8 shows that the 5.0% lysate per cell was stained for Formulation 1, Formulation 2, and the comparative gel. μl (1 cm of skin tissue 2FIG. 8 illustrates the cumulative amount of spironolactone appearing in the receptor solution over 24 hours after a single dose of 10 mg per 1000 μg of spironolactone. In FIG. 8, each plotted value is the average of four separate pieces of excised human skin. FIG. 9 illustrates the amount of spironolactone (ng) in the epidermis and dermis after 24 hours for Formulation 1, Formulation 2, and the comparative gel. As seen in FIG. 8, the comparative gel with 5% dissolved spironolactone delivered more spironolactone across the excised human skin than either the 5% spironolactone water suspension or the 5% spironolactone cyclomethicone suspension. However, significantly greater deposition of spironolactone into the epidermis (location of the infundibulum of the pilosebaceous unit) is seen in FIG. 9 for both suspensions. High levels of API in the epidermis and dermis indicate that spironolactone targets the pilosebaceous unit and has significantly greater follicular deposition from the aqueous suspension (D90<0.5 μm, formulation 1) and the cyclomethicone suspension (D90<5.0 μm, formulation 2).

[0080]

[0090] 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, as those skilled in the art will recognize that modifications and substitutions to the basic invention description can be made. This specification includes the disclosure of the following inventions. [Item 1] A pharmaceutical composition comprising the following: a therapeutically effective amount of SHR0302 or a pharma- ceutically acceptable salt thereof, wherein the primary particle size distribution of the SHR0302 is characterized by a D90 value of less than about 20 μm; and Silicones selected from the group consisting of dimethicone and cyclomethicone 23. A pharmaceutical composition comprising: [Item 2] The pharmaceutical composition according to item 1, wherein the composition is a suspension. [Item 3] The pharmaceutical composition according to item 1, wherein the composition comprises about 0.10% w / w to about 5% w / w of SHR0302 or a salt thereof. [Item 4] The pharmaceutical composition according to item 1, wherein the primary particle size distribution of SHR0302 is characterized by a D90 value of less than about 10 μm. [Item 5] The pharmaceutical composition according to item 1, wherein the primary particle size distribution of SHR0302 is characterized by a D90 value of less than about 5 μm. [Item 6] The pharmaceutical composition according to item 1, wherein the primary particle size distribution of SHR0302 is characterized by a D50 value of less than about 1.0 μm. [Item 7] The pharmaceutical composition according to item 1, wherein the primary particle size distribution of SHR0302 is characterized by a D10 value of less than about 0.50 μm. [Item 8] A method for treating alopecia areata in a subject in need thereof, comprising: administering to the subject: (a) a therapeutically effective amount of SHR0302, or a pharma- ceutically acceptable salt thereof, wherein a primary particle size distribution of the SHR0302 is characterized by a D90 value of less than about 20 μm; and (b) a silicone selected from the group consisting of dimethicone and cyclomethicone. topically administering a pharmaceutical composition comprising The method includes: [Item 9] The method according to item 8, wherein the SHR0302 is delivered to the pilosebaceous unit. [Item 10] The method according to item 8, wherein the SHR0302 achieves skin penetration of at least 1 mm in the subject. [Item 11] The method according to item 8, wherein the pharmaceutical composition is a suspension. [Item 12] The method according to Item 8, wherein the composition comprises about 0.10% w / w to about 5% w / w of SHR0302 or a salt thereof. [Item 13] The method according to item 8, wherein the primary particle size distribution of the SHR0302 is characterized by a D90 value of less than about 10 μm. [Item 14] The method according to item 8, wherein the primary particle size distribution of the SHR0302 is characterized by a D90 value of less than about 5 μm. [Item 15] The method according to item 8, wherein the primary particle size distribution of the SHR0302 is characterized by a D50 value of less than about 1.0 μm. [Item 16] The method according to item 8, wherein the primary particle size distribution of the SHR0302 is characterized by a D10 value of less than about 0.50 μm. [Item 17] A pharmaceutical composition comprising the following: a therapeutically effective amount of an active pharmaceutical ingredient, the active pharmaceutical ingredient having a primary particle size distribution characterized by a D90 value of less than about 20 μm; and Silicones selected from the group consisting of dimethicone and cyclomethicone 23. A pharmaceutical composition comprising: [Item 18] The pharmaceutical composition according to Item 17, wherein the composition comprises about 0.10% w / w to about 5% w / w of an active pharmaceutical ingredient. [Item 19] The pharmaceutical composition according to item 17, wherein the primary particle size distribution of the active pharmaceutical ingredient is characterized by a D90 value of less than about 10 μm. [Item 20] The pharmaceutical composition according to item 17, wherein the primary particle size distribution of the active pharmaceutical ingredient is characterized by a D90 value of less than about 5 μm. [Item 21] The pharmaceutical composition according to item 17, wherein the active pharmaceutical ingredient is delivered to the pilosebaceous unit. [Item 22] The pharmaceutical composition according to item 17, wherein the active pharmaceutical ingredient is capable of achieving skin penetration of at least 1 mm in the subject.

Claims

1. 1. A pharmaceutical composition comprising: a therapeutically effective amount of SHR0302 or a pharma- ceutically acceptable salt thereof, wherein the primary particle size distribution of the SHR0302 is characterized by a D90 value of less than about 20 μm; and Silicones selected from the group consisting of dimethicone and cyclomethicone 23. A pharmaceutical composition comprising:

2. 10. The pharmaceutical composition of claim 1, wherein the composition is a suspension.

3. 2. The pharmaceutical composition of claim 1, wherein the composition comprises about 0.10% w / w to about 5% w / w of SHR0302 or a salt thereof.

4. 2. The pharmaceutical composition of claim 1, wherein the primary particle size distribution of the SHR0302 is characterized by a D90 value of less than about 10 μm.

5. 2. The pharmaceutical composition of claim 1, wherein the primary particle size distribution of the SHR0302 is characterized by a D90 value of less than about 5 μm.

6. 2. The pharmaceutical composition of claim 1, wherein the primary particle size distribution of SHR0302 is characterized by a D50 value of less than about 1.0 μm.

7. 2. The pharmaceutical composition of claim 1, wherein the primary particle size distribution of the SHR0302 is characterized by a D10 value of less than about 0.50 μm.

8. 1. A method of treating alopecia areata in a subject in need thereof, comprising: administering to the subject: (a) a therapeutically effective amount of SHR0302, or a pharma- ceutically acceptable salt thereof, wherein a primary particle size distribution of the SHR0302 is characterized by a D90 value of less than about 20 μm; and (b) a silicone selected from the group consisting of dimethicone and cyclomethicone. topically administering a pharmaceutical composition comprising The method includes:

9. 9. The method of claim 8, wherein the SHR0302 is delivered to the pilosebaceous unit.

10. 9. The method of claim 8, wherein said SHR0302 achieves at least 1 mm of skin penetration in said subject.

11. 9. The method of claim 8, wherein the pharmaceutical composition is a suspension.

12. 9. The method of claim 8, wherein the composition comprises about 0.10% w / w to about 5% w / w of SHR0302 or a salt thereof.

13. 9. The method of claim 8, wherein the primary particle size distribution of the SHR0302 is characterized by a D90 value of less than about 10 μm.

14. 9. The method of claim 8, wherein the primary particle size distribution of the SHR0302 is characterized by a D90 value of less than about 5 μm.

15. 9. The method of claim 8, wherein the primary particle size distribution of the SHR0302 is characterized by a D50 value of less than about 1.0 μm.

16. 9. The method of claim 8, wherein the primary particle size distribution of the SHR0302 is characterized by a D10 value of less than about 0.50 μm.

17. 1. A pharmaceutical composition comprising: a therapeutically effective amount of an active pharmaceutical ingredient, the active pharmaceutical ingredient having a primary particle size distribution characterized by a D90 value of less than about 20 μm; and Silicones selected from the group consisting of dimethicone and cyclomethicone 23. A pharmaceutical composition comprising:

18. 18. The pharmaceutical composition of claim 17, wherein the composition comprises from about 0.10% w / w to about 5% w / w of the active pharmaceutical ingredient.

19. 20. The pharmaceutical composition of claim 17, wherein the primary particle size distribution of the active pharmaceutical ingredient is characterized by a D90 value of less than about 10 μm.

20. 18. The pharmaceutical composition of claim 17, wherein the primary particle size distribution of the active pharmaceutical ingredient is characterized by a D90 value of less than about 5 μm.

21. 20. The pharmaceutical composition of claim 17, wherein the active pharmaceutical ingredient is delivered to the pilosebaceous unit.

22. 18. The pharmaceutical composition of claim 17, wherein the active pharmaceutical ingredient is capable of achieving a skin penetration of at least 1 mm in the subject.

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