CN116710067A

CN116710067A - Compositions and methods for deep skin drug delivery

Info

Publication number: CN116710067A
Application number: CN202180085066.3A
Authority: CN
Inventors: D·W·奥斯本; B·N·托菲戈
Original assignee: Alcutis Biotherapy Co ltd
Current assignee: Alcutis Biotherapy Co ltd
Priority date: 2020-11-17
Filing date: 2021-11-16
Publication date: 2023-09-05
Also published as: CN116723832A

Abstract

Pharmaceutical compositions for topical administration to a pilosebaceous unit and methods of administration thereof. As described herein, the inventors of the present application have surprisingly found that a pharmaceutical composition comprising small particles of an active pharmaceutical ingredient and a silicone, such as simethicone or cyclomethicone, can be administered to the pilosebaceous unit. The pharmaceutical composition may comprise SHR0302 or spirolactone as active pharmaceutical ingredient.

Description

Compositions and methods for deep skin drug delivery

Cross reference to related applications

The present application claims priority from U.S. provisional patent application Ser. No. 63/114,887, filed 11/17/2020, and U.S. provisional patent application Ser. No. 63/221,349, filed 7/2021, the disclosures of which are incorporated herein by reference in their entireties.

Technical Field

The subject matter described herein relates generally to pharmaceutical compositions and methods of administration for the topical administration of drugs to the pilosebaceous unit. As described herein, the inventors of the present application have surprisingly found that a pharmaceutical composition comprising small particles of an active pharmaceutical ingredient and a silicone, such as dimethicone or cyclomethicone, can be targeted to the pilosebaceous unit. In a preferred embodiment, the pharmaceutical composition comprises SHR0302 or spirolactone as active pharmaceutical ingredient.

Background

Transdermal topical delivery of drugs has a number of advantages over other routes of administration. Transdermal local delivery can be used to continue drug delivery to the systemic circulation and to avoid first pass metabolism. In contrast, oral drug delivery has a pronounced hepatic first pass effect, which can lead to premature metabolism of the drug. Transdermal topical delivery also has the advantage over intravenous administration, which must be a sterile product and can lead to increased patient non-compliance due to pain. Transdermal delivery, on the other hand, may be non-sterile, non-invasive and self-administered.

Traditional drug delivery systems have focused on the transdermal drug delivery route (Andrea c.lauer et al Transfollicular Drug Delivery, pharmaceutical Research 12:2 (1995)). The skin is mainly composed of four layers: (a) stratum corneum (inactive epidermis), (b) active epidermis, (c) dermis and (d) subcutaneous tissue. The skin also contains appendages in the form of terminal hairs, which can extend beyond 3mm below the skin surface and into subcutaneous adipose tissue, and vellus hairs, which are fine, unnoticeable body hairs that extend less than 1mm and into the dermis layer. The structure known as the pilosebaceous unit comprises the hair follicle, hair shaft and sebaceous glands, which secrete lubricious oil substances into the hair follicle. While the stratum corneum is traditionally thought to be the primary route of drug permeation, it is also the primary barrier to percutaneous absorption. In the past, researchers have suspected the importance of the pilosebaceous unit in drug delivery.

However, recent studies have been made on the potential role of the pilo-sebaceous unit and on the alternative mechanism of transdermal delivery of drugs (Amit Verma et al Transfollicular drug delivery: current perspectives, research and Reports in Transdermal Drug Delivery (2016, 4, 20)). Mammalian hair follicles are a complex, dynamic structure in which unique biochemical and immunological reactions occur. While the pilosebaceous unit may be an acceptable target for drug delivery, there are challenges in delivering drugs to the pilosebaceous unit. One of the challenges associated with delivering drugs to the pilosebaceous unit is the need to bypass the stratum corneum, which is about 10-20 μm deep, and the upper capillary plexus, which is about 80 μm deep.

There is a need for pharmaceutical compositions that penetrate deeper into the dermis layer, about 1000 μm to 2000 μm deep, to reach the pilosebaceous unit. There remains an unmet need for new pharmaceutical compositions and methods for administration via the pilosebaceous unit.

Summary of The Invention

The present application relates to pharmaceutical compositions and methods of administration for topical administration to a pilosebaceous unit. The inventors of the present application have surprisingly found that a pharmaceutical composition comprising small particles of an active pharmaceutical ingredient and a silicone, such as dimethicone or cyclomethicone, can be delivered to the pilo-sebaceous unit resulting in deeper penetration to the dermis layer and improved efficacy. In a preferred embodiment, the pharmaceutical composition comprises SHR0302 or spirolactone as active pharmaceutical ingredient.

In certain embodiments of the present application, pharmaceutical compositions are 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 (primary particle size distribution) characterized by: the D90 value is less than about 20 μm. In certain embodiments, the active pharmaceutical ingredient has a primary particle size distribution characterized by: the D90 value is 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 application is capable of delivering an active pharmaceutical ingredient to the pilosebaceous unit. In certain embodiments, the active pharmaceutical ingredient is capable of achieving dermal penetration of at least 1mm in the individual.

In certain embodiments of the application, pharmaceutical compositions are provided comprising a therapeutically effective amount of SHR0302, or a pharmaceutically acceptable salt thereof. SHR0302 may have a primary particle size distribution characterized as follows: the D90 value is 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 as follows: the D50 value is 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 as follows: the D10 value is less than about 1 μm, less than about 0.5 μm, or more preferably less than about 0.25 μm.

The pharmaceutical composition further comprises a silicone selected from the group consisting of dimethicone, cyclomethicone, and combinations thereof. In certain embodiments of the application, the pharmaceutical composition comprises SHR0302 suspended in at least one of dimethicone and cyclomethicone.

In certain embodiments, the pharmaceutical composition may comprise from about 0.10% w/w to about 5% w/w SHR0302, or a salt thereof. In a preferred embodiment, the pharmaceutical composition may comprise from about 0.1% w/w to about 3% w/w of SHR0302 or a salt thereof.

In certain embodiments of the application, a method of treating alopecia areata in an individual in need thereof is provided. The method comprises topically administering to the subject a pharmaceutical composition of SHR0302 as described herein. In the method of the application SHR0302 or a salt thereof may be delivered to the pilosebaceous unit. In the methods described herein, administration of the pharmaceutical composition may result in dermal penetration of SHR0302 in an individual by at least about 1mm, preferably to a hair bulb depth of the individual's terminal hair of about 2-3 mm.

In certain embodiments of the application, pharmaceutical compositions are provided comprising a therapeutically effective amount of spirolactone, or a pharmaceutically acceptable salt thereof. Spirolactones can have a primary particle size distribution characterized as follows: the D90 value is less than about 6 μm, less than about 1 μm, or more preferably less than about 0.25 μm. The spirolactone may further have a primary particle size distribution characterized by: the D50 value is less than about 2.7 μm, less than about 0.75 μm, or more preferably less than about 0.15 μm. The spirolactone may further have a primary particle size distribution characterized by: the D10 value is less than about 1.2 μm, less than about 0.50 μm, or more preferably less than about 0.10 μm.

The pharmaceutical composition further comprises a silicone selected from the group consisting of dimethicone and cyclomethicone. In certain embodiments of the application, the pharmaceutical composition of spirolactone is an oil-in-water emulsion.

Additionally, the pharmaceutical composition may comprise from about 0.10% w/w to about 7.5% w/w spirolactone or a salt thereof. In certain embodiments, the pharmaceutical composition may comprise about 0.5% w/w to about 5% w/w spirolactone or a salt thereof.

In certain embodiments of the application, a method of treating acne in an individual in need thereof is provided. In certain embodiments, the individual is a male human or a female human. In a preferred embodiment, the subject is a female human. The method comprises topically administering to the subject a pharmaceutical composition of spirolactone described herein. In the methods of the application, the spirolactone, or salt thereof, can be delivered to the pilosebaceous unit. In the methods described herein, administration of the pharmaceutical composition may result in dermal penetration of the spironolactone in the subject by at least 1mm, preferably at a depth of about 2 or 3mm in the subject.

Brief Description of Drawings

The accompanying drawings, which are incorporated herein and form a part of the disclosure, help illustrate different embodiments of the present application and, together with the description, further serve to describe the application so as to enable a person skilled in the relevant art to make and use the embodiments disclosed herein.

Fig. 1 shows the particle size distribution diagram of SHR0302 in an exemplary pharmaceutical composition.

FIG. 2 shows the depth profile of Fourier transform ion cyclotron resonance-high resolution-matrix assisted laser Desorption ionization Mass Spectrometry (FTICR-HR-MALDI) for a 0.3% SHR0302 partial 30% DMSO cream for the first donor (donor A).

FIG. 3 shows the depth profile of FTICR-HR-MALDI for a local suspension of 3% SHR0302 in dimethicone for the first donor (donor A).

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

FIG. 5 shows the depth profile of FTICR-HR-MALDI for a 3% SHR0302 partial suspension of a second donor (donor B) in dimethicone.

Figure 6 shows the particle size distribution of 5.0% of nanomilled spirolactone in a suspension in water containing 0.05% dioctyl sodium sulfosuccinate (DOSS) and 1% hydroxypropyl cellulose.

FIG. 7 is a photomicrograph taken of a 5% spirolactone suspension in cyclomethicone after milling and storage for two weeks, the spirolactone forming a suspension with a D90 of less than about 5 μm by roller milling.

FIG. 8 shows two exemplary formulations (formulation 1 and formulation 2 described in example 4) and a comparative gel formulation (also described in example 4) in a single administration of 5.0 μl/chamber (10 mg/cm) ² Skin tissue) for 24 hours, the cumulative amount of spirolactone present in the receiving solution (receptor solution).

Figure 9 shows the amounts of spironolactone (ng) in the epidermis and dermis 24 hours after administration of two exemplary formulations (formulation 1 and formulation 2 described in example 4) and a comparative gel formulation (also described in example 4).

Detailed Description

Before the present application is explained in detail below, it is to be understood that the application is not limited to the particular methodology, protocols and reagents described herein as such may vary. It is also to 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 present application which will be limited only by the appended claims. Unless defined otherwise, 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 application belongs.

All publications, patents, and patent applications cited herein are incorporated by reference in their entirety unless otherwise indicated. When the same terms are defined in publications, patents, or patent applications, and the present application incorporated by reference herein, the definitions in the present application represent controlling definitions. For publications, patents, or patent applications cited for the purpose of describing particular types of compounds, chemistries, etc., the portions thereof that are relevant to the compounds, chemistries, etc. are those portions of this document that are incorporated by reference herein.

It should be noted that, as used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an active ingredient" includes a single ingredient and two or more different ingredients, and reference to "a sulfate" includes a single sulfate and two or more different sulfates.

The term "about" when used in conjunction with a numerical value is intended to encompass a range of values having a lower limit of 5% below the indicated value and an upper limit of 5% above the indicated value.

The term "effective" refers to an amount of a compound, agent, substance, formulation, or composition that is sufficient to result in a decrease in the severity of a symptom of a disease, an increase in the frequency and duration of an asymptomatic period of a disease, or to prevent damage or disability due to affliction of a disease. The amounts may be used alone or in combination with other compounds, agents or substances, in a single dose or multiple dose regimen. It will be within the ability of those skilled in the art to determine the effective amount based on factors such as the size of the individual, the severity of the individual's symptoms, and the particular composition or route of administration selected.

By "pharmaceutically acceptable" is meant generally safe for administration to humans or animals. Preferably, the pharmaceutically acceptable component is an ingredient approved by a regulatory agency of the federal or a state government or recorded in the U.S. pharmacopeia published by the U.S. pharmacopeia convention company located in rocville, maryland or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

The "pharmaceutical composition" of the application may be in the form of a composition in which the different active ingredients and diluents and/or carriers are mixed with each other, or may be in the form of a combined preparation in which the active ingredients are present in partially or completely different forms. An example of such a combination or combination formulation is a kit of parts.

The term "individual" or "patient" as used herein most preferably refers to a human. The term "individual" or "patient" may include any mammal that may benefit from the compounds described herein.

"therapeutic amount" or "therapeutically effective amount" refers to an amount of a therapeutic agent sufficient to achieve the intended purpose. The effective amount of a given therapeutic agent may vary depending upon factors such as the nature of the active agent, the route of administration, the size of the individual receiving the therapeutic agent, and the purpose of administration. The effective amount of each individual case can be determined empirically by the skilled artisan according to established methods in the art.

For administration of a drug or composition, the term "topical" refers to the application of the drug or composition to an epithelial surface in vitro, including the skin or cornea. For such administration, administration within a body opening, such as at the oral cavity, vagina or rectum, where the mucosal epidermis does not contain pilosebaceous units is not considered topical administration.

As used herein, "treatment" or "treatment" of a disease or disorder refers to achieving one or more of the following effects: (a) reducing the severity and/or duration of the condition; (b) Limiting or preventing the development of symptoms characteristic of the disease being treated; (c) inhibiting exacerbation of the characteristic symptoms of the disease being treated; (d) Limiting or preventing disease recurrence in patients previously suffering from the disease; (e) Limiting or preventing recurrence of symptoms in patients who previously had symptoms of the disease.

The abbreviation "w/w" stands for the relative concentration of the components in the composition as "weight ratio" (i.e., percent refers to percent by total weight), rather than on a volume or other basis.

The present application relates to pharmaceutical compositions for topical administration of a drug to a pilosebaceous unit and methods of administration thereof. The inventors of the present application have surprisingly found that a pharmaceutical composition comprising small particles of an active pharmaceutical ingredient in silicone, such as simethicone or cyclomethicone, can target the pilo-sebaceous unit, resulting in deeper penetration into the dermis layer and improved efficacy. In a preferred embodiment, the pharmaceutical composition comprises SHR0302 or spirolactone as active pharmaceutical ingredient.

In certain embodiments of the present application, there is provided a pharmaceutical composition comprising a therapeutically effective amount of an active pharmaceutical ingredient and a silicone selected from the group consisting of simethicone, 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 comprises any one 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%, 1.7%, 1.8%, 1.9%, 2.0%, 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.

In the pharmaceutical composition of the present application, the active pharmaceutical ingredient is present in the form of small particles. The particle size of the drug may be measured using laser diffraction methods. Laser diffraction is accepted by standards and guidelines including ISO and ASTM, and is widely used to determine particle size distribution. In making the measurement, the sample is passed through a laser beam, causing the laser to scatter at a series of angles. A detector placed at a fixed angle measures the intensity of the light scattered at that location. A mathematical model is then applied to obtain the particle size distribution. The particle size values described herein are determined by liquid or wet dispersion methods.

In granulometry, median is defined as the number above which half of the population lies and below which half lies. The median value of the particle size distribution is referred to as D50. D50 is the value dividing the distribution into half above the diameter and half below it. The distribution width can also be characterized by referencing one, two, or three values on the x-axis, typically some combination of D10, D50, and D90. D50 is the median value, which is defined as the diameter below which half of the population is below that value. Similarly, 90% of the distribution is below D90 and 10% of the population is below D10.

In certain embodiments, the active pharmaceutical ingredient has a primary particle size distribution characterized by: the D90 value is less than about 20 μm, less than about 15 μm, 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 distribution characterized by: the D90 values are from about 0.001 μm, 0.01 μm or 0.1 μm to about 5 μm, 10 μm, 15 μm and 20 μm. The active pharmaceutical ingredient may further have a primary particle size distribution characterized by: the D50 value is 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 distribution characterized by: the D50 value is from 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: the D10 value is 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 distribution characterized by: the D10 value is from 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.

In certain embodiments, the pharmaceutical compositions of the present application are capable of delivering an active pharmaceutical ingredient to the pilosebaceous unit. In certain embodiments, the active pharmaceutical ingredient is capable of achieving dermal penetration of at least 1mm in the individual.

In certain embodiments of the application, the pharmaceutical composition comprises the JAK1 inhibitor (3 ar,5s,6 as) -N- (3-methoxy-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. In this context, the terms SHR0302 and ARQ-250 may be substituted for each other. The structural formula of SHR0302 is:

SHR0302 is a potent small molecule inhibitor of JAK1, which has been demonstrated to be more selective for JAK1 than JAK2, and thus has the potential to treat inflammatory diseases without causing hematopoietic adverse reactions associated with JAK2 inhibition, such as anemia, thrombocytopenia and neutropenia. SHR0302 is disclosed in U.S. patent No. 9,527,851, which is incorporated herein by reference.

In certain embodiments of the application, the pharmaceutical composition comprises the aldosterone agonist 17-hydroxy-7α -mercapto-3-oxo-17α -pregna-4-ene-21-carboxylic acid γ -lactone acetate, also known as spirolactone. The structure of spirolactone is:

spironolactone is a drug that acts on mineralocorticoid receptor levels by competitively inhibiting aldosterone binding. The steroid compounds are useful for blocking aldosterone dependent sodium transport in the distal tubular of the kidney, thereby reducing edema and treating primary hypertension and primary aldosteronism. Oral administration of spironolactone is equally effective in treating female 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); charny et al, spironolactone for the treatment of acne in women, a retrospective study of 110patients,Int.J.Womens Dermatol.3 (2): 111-115 (2017). Spironolactone is a commercial drug with the trade nameAnd->Spirolactones are disclosed in U.S. patent No. 3,013,012, which is incorporated herein by reference.

In the present application, the pharmaceutical composition is administered topically. The pharmaceutical composition may comprise SHR0302 or spirolactone in free base or pharmaceutically acceptable salt form. Suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17 th edition, mack Publishing Company (1985), which is incorporated herein by reference.

In certain embodiments, the pharmaceutical composition comprises SHR0302, which has a primary particle size distribution characterized as follows: the D90 value is less than about 20 μm, less than about 15 μm, less than about 10 μm, or more preferably less than about 5 μm. In certain embodiments, SHR0302 has a primary particle size distribution characterized as follows: the D90 values are from about 0.01 μm, 0.1 μm or 1.0 μm to about 5.0 μm, 10.0 μm, 15.0 μm and 20.0 μm.

SHR0302 may further have a primary particle size distribution characterized as follows: the D50 value is 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, SHR0302 has a primary particle size distribution characterized as follows: the D50 value is from 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.

SHR0302 may further have a primary particle size distribution characterized as follows: the D10 value is 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, SHR0302 has a primary particle size distribution characterized as follows: the D10 value is from 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.

In certain embodiments, the pharmaceutical composition comprising spirolactone has a primary particle size distribution characterized by: the D90 value is less than about 6 μm, less than about 5 μm, less than about 2 μm, less than about 1 μm, less than about 0.5 μm, less than about 0.25 μm, or more preferably less than about 0.2 μm. In certain embodiments, the spirolactone has a primary particle size distribution characterized by: the D90 values are from 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 and 6 μm.

The spirolactone may further have a primary particle size distribution characterized by: the D50 value is less than about 2.7 μm, less than about 2.0 μm, less than about 1.0 μm, less than about 0.75 μm, less than about 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 spirolactone has a primary particle size distribution characterized by: the D50 values are from 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 and 2.7 μm.

The spirolactone may further have a primary particle size distribution characterized by: the D10 value is less than about 1.2 μm, less than about 1.0 μm, 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 spirolactone has a primary particle size distribution characterized by: the D10 values are from 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 and 1.2 μm.

The pharmaceutical composition of the present application further comprises a silicone selected from the group consisting of dimethicone, cyclomethicone, or combinations thereof. Dimethicone, also known as Polydimethylsiloxane (PDMS), is a polymeric organosilicon compound. Cyclomethicone is a group of methicones which, unlike dimethicone, are cyclic organosilicon compounds. In certain embodiments, the pharmaceutical composition comprises a combination of silicones, including dimethicone and cyclomethicone. For example, the pharmaceutical composition comprises simethicone-cyclosimethicone-simethicone/vinyl simethicone. Additional methylsilicone compatible adjuvants such as cyclopentadimethicone (cyclomethicone), dimethiconol and phenyldimethicone may be added to the dimethicone and/or cyclomethicone to adjust aesthetics or viscosity. Silicones such as simethicone and cyclomethicone have a polarity similar to sebum, allowing for targeted hair follicle delivery of the pharmaceutical composition.

In certain embodiments, the pharmaceutical composition is a suspension in which the active ingredient (e.g., SHR0302 or spirolactone) is suspended in a silicone (e.g., simethicone or cyclomethicone). In certain embodiments, the pharmaceutical composition may be formulated as an emulsion. For example, the pharmaceutical composition may be formulated in one of the following forms:

oil-in-water emulsion: the product may be an emulsion comprising a hydrophobic component in a discrete phase and a continuous aqueous phase comprising water and optionally one or more polar hydrophilic excipients, as well as solvents, co-solvents, salts, surfactants, emulsifiers and other ingredients. These emulsions may contain polymers that help stabilize the water solubility and water swellability of the emulsion.

Water-in-oil emulsion: the composition may be an emulsion comprising a hydrophobic component of a continuous phase and an aqueous phase comprising water and optionally one or more polar hydrophilic carriers, as well as salts and other ingredients. These emulsions may contain oil-soluble and oil-swellable polymers and one or more emulsifiers to help stabilize the emulsion.

Microemulsion: microemulsions are clear, thermodynamically stable, isotropic liquid systems that contain oil, water, and surfactants, and often contain cosurfactants. Microemulsions may be water-continuous, oil-continuous or bicontinuous mixtures. These formulations may also optionally contain up to 60% by weight of water. In some compositions, higher levels may be suitable.

Nanoemulsion: nanoemulsions are isotropic dispersions comprising water, oil and an emulsifier. The system may be an oil system dispersed in an aqueous system, or an aqueous system dispersed in an oil system to form nano-sized droplets or an oil phase. Nanoemulsions generally have a higher loading capacity for lipophilic active ingredients than microemulsions. Hydrophobic and hydrophilic active ingredients may also be formulated in nanoemulsions. Nanoemulsions may be prepared by any suitable method known in the art, including high pressure homogenization, microfluidization, and phase transition temperatures.

In certain embodiments, the pharmaceutical composition consists essentially of an active ingredient and a silicone selected from dimethicone, cyclomethicone, or a combination thereof. Alternatively, the pharmaceutical compositions may be formulated using other ingredients, including those conventionally known in cosmetic and pharmaceutical topical products.

Administration and dosage

The application includes methods of treating disorders of hair loss, such as hair loss, androgenic alopecia, hair rarefaction, and telogen effluvium. The method may comprise treating a condition of hair loss in a patient in need thereof by administering to the patient a composition of SHR0302 or spironolactone as described herein.

In a preferred embodiment, the application includes a method of treating Alopecia Areata (AA). AA is one of the most common autoimmune diseases, resulting in hair loss due to immune privilege failure and subsequent autoimmune destruction of the hair follicle. AA is a skin disease that leads to hair loss from the scalp and other areas. Prior to the present application, topical administration of JAK inhibitors did not show reproducible clinical effects. Without being bound by theory, the reason that JAK inhibitors were unable to treat AA prior to the present application is believed to be that there was insufficient drug delivered to the pilosebaceous unit, more specifically to the hair bulb. The inventors of the present application have surprisingly found that the pharmaceutical compositions described herein are capable of penetrating at least about 1mm, at least about 2mm and at least about 3mm into the hair follicle of an AA patient.

In certain embodiments, the application provides a method of treating AA in a patient in need thereof, comprising topically administering to the patient a therapeutically effective amount of a SHR0302 pharmaceutical composition as described herein. In certain embodiments, the active ingredient SHR0302 may be administered in a therapeutically effective amount. In certain embodiments, the amount of SHR0302 ranges 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, the topical formulation comprises any one of the following SHR0302 weight 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%, 1.7%, 1.8%, 1.9%, 2.0%, 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.

The application also provides methods of treating acne in a patient in need thereof. Acne is a disease of the pilo-sebaceous units located in the face, chest and back. Acne may be one selected from the group consisting of: acne, acne vulgaris, inflammatory acne, non-inflammatory acne, fulminant acne, nodular papulopustular acne, conflagration acne, rosacea, artificial acne, adult acne, persistent recurrent acne after puberty, and acne associated with other diseases. In certain embodiments, the patient is a human male or female patient. In a preferred embodiment, the patient is a human female. In addition, the patient may be: (a) experiencing acne that occurs with the menstrual cycle; (b) Even without clinical or laboratory signs of hyperandrogenic symptoms, with adult acne or persistent recurrent acne after puberty; (c) Oral contraceptives and exhibit moderate to severe acne, especially with clinical hormonal characteristics; or (d) does not respond to conventional treatment and is not a candidate for oral isotretinoin treatment.

In certain embodiments, the application provides a method of treating acne in a patient in need thereof, comprising topically administering to the patient a therapeutically effective amount of a spirolactone pharmaceutical composition described herein. In certain embodiments, the active ingredient spironolactone can be administered in a therapeutically effective amount. In certain embodiments, the amount of spirolactone ranges 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, with exemplary ranges 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, the topical formulation comprises any one of the following spironolactones in weight percent: 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%, 1.7%, 1.8%, 1.9%, 2.0%, 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.

In certain embodiments, the pharmaceutical composition may be administered topically according to a dosing regimen, such as at regular intervals. For example, the topical pharmaceutical composition may 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 may be administered in accordance with a prescribed period of time. For example, the topical pharmaceutical composition may be administered for a period of about two weeks to at least about six months, or until a macroscopic improvement of the skin condition or disease occurs. The time period of an exemplary treatment regimen includes: two weeks, one month, six weeks, two months, three months, four months, five months, six months, seven months, eight months, nine months or one year. In preferred embodiments, the topical pharmaceutical composition is administered twice or three times daily for at least 3 months, 4 months, 5 months or 6 months.

The following examples illustrate, without limitation, certain embodiments of the application.

Examples

While various embodiments have been described above, it should be understood that they have been presented by way of example only, and not limitation. Thus, the breadth and scope of the present application should not be limited by any of the above-described exemplary embodiments. Moreover, unless indicated otherwise or clearly contradicted by context, the present application encompasses any combination of the above elements in all possible variations thereof.

Comparative example 1

Comparative example 1 was prepared as a 0.3% SHR0302 topical cream having the composition shown in table 1.

TABLE 1 composition of SHR0302 cream

Composition of the components	SHR0302 0.3% cream
		SHR0302	0.30％w/w
Dimethyl sulfoxide (DMSO)	30.0％w/w
		Propylene glycol	15％w/w
Polyethylene glycol 200	15％w/w
		Cyclomethicone	7.0％w/w
ST-elastomer 10	2.0％w/w
		Dimethicone	1.0％w/w
Pemulen TR 1	0.8％w/w
		Carbopol 974P	1.5％w/w
EDTA	0.05％w/w
		BHT	0.05％w/w
Benzyl alcohol	2.0％w/w
		D-limonene	0.1％w/w
Triethanolamine (25% solution to adjust pH)	Proper amount is added to pH 5.5
		Pure water	Proper amount is added to 100%
Totals to	100％

Example 1

A pharmaceutical composition comprising 3% SHR0302 suspended in simethicone was prepared. The SHR0302 used in the composition has a particle size distribution as shown in figure 1.SHR0302 has a primary particle size distribution characterized as follows: a D10 value of less than about 0.25 μm; a D50 value of less than about 0.7 μm; the D90 value is less than about 5 μm. The pharmaceutical composition is a transparent solution because the particles are too small to scatter visible light. The particle size distribution profile of SHR0302 was determined using Malvern Metasizer Model 3000 (using Hydro MV dispersion units). The sample preparation procedure was performed as follows: 10-20mg of SCP treated ARQ-250 to 30ml vials were weighed, 20ml ethyl acetate was added and the suspension was sonicated with a 40% power ultrasound probe in a 5℃water bath, transferring the suspension samples to a Malvern Hydro MV dispersion unit to obtain a 5-15% shading value. The parameters of the instrument are: (i) refractive index of the particles: 1.5; (ii) dispersant refractive index: 1.395; (iii) absorbance index: 0.01; (iv) measuring duration: 10 seconds; (v) number of measurements: 3, a step of; (vi) stirring speed: 3500rpm; (vii) ultrasound: and closing.

Example 2

The penetration ability of comparative example 1 and example 1 into human cadaver scalp skin was assessed. Two different human cadaveric scalp skins (donor a and B) were immobilized in a special stretching chamber. One dose (7.5 μl) of comparative example 1 or example 1 was applied to the scalp skin sample for 6 hours. All formulation residues were washed off the skin. 8mm biopsy samples were drilled from the dermal side of the skin and flash frozen in liquid nitrogen. A series of 10 μm frozen sections were taken, with every other section being hematoxylin and eosin stained (H & E) and adjacent sections being reserved for fourier transform ion cyclotron resonance-high resolution-matrix assisted laser desorption ionization mass spectrometry (FTICR-HR-MALDI). The FTICR-HR-MALDI was analyzed using a Bruker 7T FTICR-HR-MALDI MS system.

FIGS. 2 and 4 show FTICR-HR-MALDI depth maps of 0.3% SHR0302 topical 30% DMSO creams for donor A and donor B, respectively. As shown in FIG. 2, in donor A, comparative example 1 achieved a maximum dermal penetration of less than 160 μm. As shown in FIG. 4, in donor B, comparative example 1 achieved a maximum dermal penetration of less than 500 μm. This result is consistent with the ability of the pharmaceutical composition to deliver drug across the stratum corneum and indicates that the drug is not penetrating below the upper capillary plexus.

Figures 3 and 5 show the depth maps of FTICR-HR-MALDI for a 3% SHR0302 partial suspension of donor a and donor B in simethicone, respectively. As shown in fig. 3 and 5, example 1 achieved a maximum dermal penetration of greater than 1mm. These results surprisingly show that the pharmaceutical composition is capable of delivering a drug to hair bulb.

Example 3

After storage of a 50mg/ml aqueous suspension of 5.0% spironolactone (containing 0.5% dioctyl sodium sulfosuccinate and 1% hydroxypropyl cellulose) at 5 ℃ and ambient light for two weeks, nano-milling was successfully completed to provide stable submicron particles of the drug particle suspension. The particle size distribution of spirolactone is shown in figure 6. The spirolactone volume-based profile was determined using Horiba laser scattering particle size distribution analyzer model LA-950. The cycle, agitation and ultrasound are turned off and the instrument is set to a manual repeat mode.

A stable oil-in-water emulsion of 0.3% spirolactone was prepared, the composition of which is shown in Table 2.

TABLE 2 composition of oil-in-water emulsion of spironolactone

Composition of the components	Spironolactone oil-in-water emulsion
		Spirolactones	0.30％w/w
Cyclomethicone	10.0％w/w
		P-hydroxybenzoic acid methyl ester	0.10％w/w
Propyl p-hydroxybenzoate	0.01％w/w
		Sepineo P600	4.0％w/w
Pure water	Proper amount is added to 100%
		Totals to	100％

Example 4

A suspension of 5.0% -5.5% spirolactone in water, which contains 0.05% -0.055% dioctyl sodium sulfosuccinate and 1.0-1.1% hydroxypropyl cellulose, was nanomilled to a particle size distribution as shown in figure 6. The composition of the final suspension is shown in formulation 1 of table 3. A suspension of 5% spirolactone in cyclomethicone was roll milled to form a suspension with D90 less than about 5 μm as shown in fig. 7 (photomicrographs taken after two weeks of milling and storage are completed). The composition of the final suspension is shown in formulation 2 of table 3. The comparative gel formulations described in the literature were prepared and listed as comparative gels in Table 3 (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.).

TABLE 3 composition of two deep dermal drug delivery formulations and comparative gels from literature

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An in vitro skin penetration test (IVPT) was used to determine the rate of penetration of different formulations through ex vivo human skin. Human cadaveric skin (caucasian females, age 48 years, abdomen skinning, average thickness 580 μm, and spanish males, age 50 years, abdomen skinning, average thickness 910 μm) was obtained from two donors. The harvested skin was received from the American tissue bank in a frozen state and stored at-20℃until use. Skin was loaded into a vertical Franz chamber with 0.503cm ² (diameter 8 mm) diffusion area and the receiving chamber was filled with 3.0ml of 4% aqueous BSA containing 0.01% gentamicin sulphate at a controlled temperature of 32 ℃. Using an external piston pipette, 5 microliters of each formulation (10 mg/cm ² Skin). The received solutions were analyzed using a validated LC-MS/MS (Kinetex C18,5 μm,2.1x50mm column, shimadzu LC20ADXR pump, AB Sciex API 4000 turbine spray detector). The cumulative amount of spirolactone measured in the receiving solution is the average of four replicates of the IVPT measurement.

To determine the level of spirolactone retained in the epidermis and dermis 24 hours after skin administration, any unabsorbed and impermeable spirolactone was cleared from the skin surface. This is achieved by the following method: the tissue surface was rubbed 3 times with 1 XPBS-soaked Q-tip, followed by two tape peels. Epidermis (including stratum corneum) was peeled from dermis and soaked in 4.0ml DMSO/Acetonitrile (ACN) (50/50 v/v) mixture using an orbital shaker overnight at room temperature. The remaining dermis was cut into small pieces and extracted overnight at room temperature using an orbital shaker using 4.0ml DMSO/ACN mixture. Extracts of dermis and epidermis were analyzed using validated LC-MS/MS (Kinetex C18,5 μm,2.1x50mm column, shimadzu LC20ADXR pump, AB Sciex API 4000 turbine spray detector).

FIG. 8 illustrates the results of a single 5.0. Mu.l/chamber (10 mg/cm ² Skin tissue), formulation 1, formulation 2, and comparative gel, the cumulative amount of spirolactone present in the receiving solution 24 hours after gel. In fig. 8, the numerical value of each plotted point is the average of four individual resected human skin pieces. Figure 9 illustrates the amount of spironolactone (ng) in dermis and epidermis 24 hours after administration of formulation 1, formulation 2 and comparative gel. As shown in fig. 8, the comparative gel containing 5% dissolved spirolactone delivered more spirolactone through the ex vivo human skin than either an aqueous suspension of 5% spirolactone or a cyclomethicone suspension of 5% spirolactone. However, as shown in fig. 9, the deposition of spirolactone in both suspensions was significantly more on the epidermis (at the funnel site of the pilosebaceous unit). High levels of API in epidermis and dermis indicate that spironolactone targets the pilo-sebaceous unit and has significantly more hair follicle deposition from aqueous suspensions (D90 < 0.5 μm, formulation 1) and cyclomethicone suspensions (D90 < 5.0 μm, formulation 2).

The foregoing description has been provided for the purposes of illustration and description. The description is not intended to limit the application to the precise form disclosed. Those skilled in the art will appreciate that modifications and substitutions may be made to the basic inventive description.

Claims

1. A pharmaceutical composition comprising:

a therapeutically effective amount of SHR0302 or a pharmaceutically acceptable salt thereof, wherein the primary particle size distribution of SHR0302 is characterised by a D90 value of less than about 20 μm; and

silicone selected from dimethicone and cyclomethicone.

2. The pharmaceutical composition according to claim 1, wherein the composition is a suspension.

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

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

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

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

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

8. A method of treating alopecia areata in an individual in need thereof, the method comprising:

topically administering to an individual a pharmaceutical composition comprising: (a) A therapeutically effective amount of SHR0302 or a pharmaceutically acceptable salt thereof, wherein the primary particle size distribution of SHR0302 is characterised by a D90 value of less than about 20 μm; and (b) a silicone selected from the group consisting of dimethicone and cyclomethicone.

9. The method according to claim 8, wherein said SHR0302 is delivered to a pilosebaceous unit.

10. The method according to claim 8, wherein the SHR0302 achieves dermal penetration of at least 1mm in an individual.

11. The method according to claim 8, wherein the pharmaceutical composition is a suspension.

12. The method according to claim 8, wherein the composition comprises about 0.10% w/w to about 5% w/w SHR0302 or salts thereof.

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

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

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

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

17. A pharmaceutical composition comprising:

a therapeutically effective amount of an active pharmaceutical ingredient, wherein the primary particle size distribution of the active pharmaceutical ingredient is characterized by a D90 value of less than about 20 μm; and

a silicone selected from the group consisting of dimethicone and cyclomethicone.

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

19. The pharmaceutical composition according to 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. The pharmaceutical composition according to 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. The pharmaceutical composition according to claim 17, wherein the active pharmaceutical ingredient is delivered to the pilosebaceous unit.

22. The pharmaceutical composition according to claim 17, wherein the active pharmaceutical ingredient is capable of achieving dermal penetration of at least 1mm in an individual.