Inhibition of crystal growth of roflumilast
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Publication Number
US-12257242-B2
Publication Date
2025-03-25
Expiration Date
Abstract
Roflumilast crystals have been shown to increase in size during storage. The size of the roflumilast crystals can affect the bioavailability and efficacy of a pharmaceutical composition. The growth of roflumilast crystals can be inhibited during storage by including hexylene glycol in the composition. The resulting composition has improved bioavailability and efficacy and can be used to inhibit phosphodiesterase 4 in a patient in need of such treatment.
Core Innovation
The invention relates to topical pharmaceutical compositions that include roflumilast, hexylene glycol, and water. The hexylene glycol is provided in an amount sufficient to inhibit crystal growth of roflumilast in the composition for at least six weeks of storage at 15°C-26°C, and the composition is described in the form of a cream or foam.
The compositions are also described as inhibiting growth of precipitated roflumilast particles and inhibiting a change in particle size distribution during storage at 15°C-26°C. The disclosure addresses temperature excursions, including freeze-thaw cycling, while maintaining stability of roflumilast crystals and particle size.
In addition, the disclosure includes redissolution behavior in which any precipitated roflumilast returns to a dissolved state when the formulation returns to 15°C-26°C after exposure to a temperature below 15°C. The document further describes solvent-based topical compositions and indicates that changes in particle size distribution are relevant to bioavailability/efficacy.
Claims Coverage
The document includes two independent claims. Both independent claims center on hexylene glycol-containing topical pharmaceutical compositions with roflumilast, with one independent claim focused on inhibiting crystal growth during storage and the other independent claim additionally requiring redissolution after cold exposure.
Hexylene glycol crystal growth inhibition in roflumilast topical cream or foam
A topical pharmaceutical composition comprising roflumilast, hexylene glycol, and water, wherein the hexylene glycol is in an amount sufficient to inhibit crystal growth of roflumilast in the composition for at least six weeks of storage at 15°C-26°C, wherein the composition is in the form of a cream or foam.
Redissolution of precipitated roflumilast after cold exposure
A topical pharmaceutical composition comprising roflumilast, hexylene glycol, water, and one or more pharmaceutically acceptable excipients, wherein the hexylene glycol is in an amount sufficient to inhibit crystal growth of the roflumilast, and wherein any precipitated roflumilast returns to a dissolved state when the formulation returns to 15°C-26°C following exposure to a temperature below 15°C.
Across the independent claims, the inventive concept is the use of hexylene glycol in roflumilast topical compositions to inhibit crystal growth during storage, with the second independent claim further requiring that any precipitated roflumilast redissolves when the formulation returns to 15°C-26°C after exposure to below 15°C.
Stated Advantages
Inhibits crystal growth of roflumilast for at least six weeks during storage at 15°C-26°C.
Inhibits growth of precipitated roflumilast particles and inhibits a change in particle size distribution during storage at 15°C-26°C.
Maintains behavior where any precipitated roflumilast returns to a dissolved state when the formulation returns to 15°C-26°C following exposure to a temperature below 15°C.
Bioavailability/efficacy impact is addressed as being related to changes in particle size distribution.
Documented Applications
Topical pharmaceutical compositions for delivery in cream or foam form containing roflumilast and hexylene glycol to inhibit roflumilast crystal growth and particle size changes during storage at 15°C-26°C.
Use in solvent-based topical formulations, including cases involving precipitation during temperature excursions such as freeze-thaw cycling, where stability and redissolution after returning to 15°C-26°C are described.
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