Pharmaceutical formulation for histone deacetylase inhibitors
Inventors
Chappell, Todd W. • Johnson, Keith A.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11607399-B2
Publication Date
2023-03-21
Expiration Date
Abstract
A pharmaceutical composition, comprising a therapeutically effective amount of an active pharmaceutical ingredient (API) compound represented by the following structural formulaat least one acidifying agent; and a vehicle base comprising at least one pharmaceutically acceptable non-aqueous solvent. Values and preferred values of the variables in structural formula (I) are defined herein.
Core Innovation
The disclosure provides pharmaceutical compositions for delivering an active pharmaceutical ingredient (API) compound represented by a structural formula (I), wherein the API is associated with at least one labile covalent bond and is an inhibitor of histone deacetylase. The composition includes an acidifying agent comprising citric acid and a vehicle base comprising at least one pharmaceutically acceptable non-aqueous solvent, and the pharmaceutical composition has a measured pH of from about 3 to about 5. The non-aqueous solvent system comprises ethanol.
The compositions are described as acidified non-aqueous vehicles for an API having a labile covalent bond, for example an ester bond. Acidifying the non-aqueous vehicle provides an unexpected enhancement in room-temperature shelf life by retarding API degradation via hydrolysis/solvolysis. The disclosure further includes representative formulation components such as humectants, emollients, permeation enhancers, and a low-pH thickening gelling agent, along with antioxidant components and measured formulation pH values.
The disclosed compositions are described for cutaneous administration, including treatment methods for basal cell carcinoma and other proliferative and immune/skin disorders. The document also includes kit embodiments with multiple containers for mixing to produce the pharmaceutical composition, and describes stability and degradation product detection, along with skin absorption/penetration testing in a human skin model with quantified degradation products.
Claims Coverage
The independent claims cover cutaneous administration of a therapeutically effective topical pharmaceutical composition with a specified histone deacetylase inhibitor API, an acidifying agent comprising citric acid, and a pharmaceutically acceptable non-aqueous solvent vehicle comprising ethanol. The independent claims include quantified limitations on measured pH, API concentration, and the presence of ethanol in the non-aqueous solvent system.
Cutaneous treatment with a citric-acid acidified non-aqueous API formulation
A method of cutaneously administering a therapeutically effective amount of a pharmaceutical composition comprising an API compound represented by structural formula (I), at least one acidifying agent comprising citric acid, and a vehicle base comprising at least one pharmaceutically acceptable non-aqueous solvent, wherein the pharmaceutical composition has a measured pH of from about 3 to about 5.
Ethanol-containing non-aqueous vehicle and specified pH/API loading
The pharmaceutical composition has an API present in an amount of about 0.5 to 5.0% (w/w) and the at least one non-aqueous solvent comprises ethanol.
The inventive coverage is centered on cutaneous administration of an acidified non-aqueous formulation containing citric acid and ethanol, while restricting the measured pH to about 3 to about 5 and the API concentration to about 0.5 to 5.0% (w/w).
Stated Advantages
Unexpected enhancement of room-temperature shelf life by retarding API degradation (hydrolysis/solvolysis).
Documented Applications
Cutaneous administration for treatment of basal cell carcinoma.
Cutaneous administration for treatment of proliferative and immune/skin disorders, including cutaneous T cell lymphoma, psoriasis, acne, actinic keratosis, dermatitis, neurofibromatosis, malignant melanoma, hair loss, and skin hyperpigmentation.
Kit embodiments with multi-container mixing to produce the pharmaceutical composition for cutaneous administration.
Interested in licensing this patent?