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Publication Number
US-12161643-B2
Publication Date
2024-12-10
Expiration Date
Abstract
The disclosure relates to stable topical pharmaceutical compositions of SHR0302 (also known as ARQ-250). In certain embodiments, pharmaceutical compositions of SHR0302 having a pH of less than about 4.6 have improved stability and do not exhibit crystal formation of the API. In certain embodiments, pharmaceutical compositions of SHR0302 comprising about 20% to about 30% dimethyl sulfoxide (DMSO) have improved stability and do not exhibit crystal formation of the API. The improved formulations of SHR0302 can exhibit acceptable commercial product shelf life and do not exhibit loss of potency of the API after prolonged storage.
Core Innovation
The invention relates to stable topical pharmaceutical formulations of the JAK1 inhibitor SHR0302/ARQ-250, including the bisulfate salt, that reduce or eliminate API crystallization and preserve potency during prolonged storage. The formulations are defined as topical pharmaceutical compositions containing a pharmaceutically effective amount of SHR0302 with a pH less than 4.6.
A key aspect of the invention is controlling the pH of the topical pharmaceutical composition to improve API stability. Formulations with pH less than 4.6, including ranges of about 3.8 to about 4.6 and optionally about 3.8 to about 4.2, are reported to show improved stability and no crystal formation.
Another aspect is selecting dimethyl sulfoxide (DMSO) and, in some examples, laureth-4 to improve stability by inhibiting crystal growth. Formulations containing about 20% to about 30% w/w DMSO, including about 25% w/w DMSO and about 20% to about 27% w/w DMSO with laureth-4, are described as showing improved stability versus higher DMSO levels. The document provides topical dosage forms including cream, lotion, emulsions, microemulsions/nanoemulsions, foam, spray, and gels, together with hydrophilic and hydrophobic ointments.
The invention also documents skin penetration-related testing using IVPT. Laureth-4 is described as a skin penetration enhancer in combinations that include DMSO and other solvents, using excised human cadaver skin and LC/MS/MS measurements.
Claims Coverage
The provided independent claims define topical pharmaceutical compositions comprising SHR0302 with specific pH and/or DMSO content, and in one case include a functional stability condition tied to inhibition of crystal growth over a defined storage duration at controlled room temperature. Across the independent claims, the main inventive features are centered on pH less than 4.6, about 25% w/w DMSO, and about 20% to about 30% w/w DMSO with crystal-growth inhibition over 6 months, with optional laureth-4 and specific topical vehicles covered in dependent claims.
Acidic pH topicals for SHR0302
A topical pharmaceutical composition comprising a pharmaceutically effective amount of SHR0302, wherein the pharmaceutical composition has a pH of less than 4.6.
Topical SHR0302 with about 25% w/w DMSO
A topical pharmaceutical composition comprising a pharmaceutically effective amount of SHR0302 and about 25% w/w of dimethyl sulfoxide (DMSO).
DMSO-range topicals inhibiting crystal growth for 6 months
A topical pharmaceutical composition comprising a pharmaceutically effective amount of SHR0302 and about 20% w/w to about 30% w/w of dimethyl sulfoxide, wherein the pharmaceutical composition inhibits crystal growth at controlled room temperature for 6 months.
Overall, the independent claims cover SHR0302 topical compositions defined by an acidic pH below 4.6, and by specific DMSO concentrations (about 25% w/w, and about 20% to about 30% w/w) with an explicit crystal-growth inhibition requirement for the 20% to 30% DMSO range over 6 months.
Stated Advantages
Reduces or eliminates API crystallization.
Preserves potency during prolonged storage.
Improves stability and provides formulations with no crystal formation under the specified pH conditions.
Inhibits crystal growth at controlled room temperature for the defined storage duration.
Laureth-4 is described as a skin penetration enhancer in IVPT testing.
Documented Applications
Topical pharmaceutical compositions for inflammatory skin diseases, including atopic dermatitis, psoriasis, eczema, alopecia areata, and bisulfate salt formulations of SHR0302/ARQ-250 [as stated in the provided partial content].
IVPT-based skin penetration enhancement testing for laureth-4 in combinations including DMSO and other solvents, using excised human cadaver skin and LC/MS/MS measurements.
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