Methods and compositions for delivering mycophenolic acid active agents to non-human mammals
Inventors
KLOTSMAN, Michael • Shivanand, Padmaja • Anderson, Wayne H. • Sathyan, Gayatri
Assignees
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Publication Number
US-11633378-B2
Publication Date
2023-04-25
Expiration Date
Abstract
The present disclosure provides methods and compositions for modified delivery of mycophenolic acid active agents, including sodium mycophenolate, in veterinary subjects. Presently disclosed methods and compositions are useful, for example, to treat autoimmune diseases, blood disorders associated with IMPDH activity, and immune rejection related to transplant or graft procedures.
Core Innovation
The disclosure provides a method for delivering a sodium mycophenolate composition to a dog by oral administration to the lower gastrointestinal tract. The method uses a plurality of modified-release compositions in a layered dosage form including a core, a sodium mycophenolate layer disposed over at least a portion of the core, a seal coat disposed over the sodium mycophenolate layer, a modified-release layer disposed over the seal coat layer, and a protective layer disposed over the modified-release layer.
The modified-release layer and protective layer are characterized by specified polymer types and compositional ranges. In described embodiments, ethyl cellulose is included in the modified-release layer at from about 15 wt % to about 35 wt % of the composition, the protective layer comprises a methacrylate-based polymer at from about 8 wt % to about 15 wt % of the composition, and the protective layer does not dissolve at a pH below 6.0.
The disclosure addresses improved pharmacokinetics and drug:metabolite ratios for sodium mycophenolate delivered to veterinary subjects. The described evaluation includes reduced MPA Cmax, sustained MPA exposure after T_max, and altered exposure to MPA metabolites, including MPAG and AcMPAG, using specified MPA:metabolite ratio ranges to characterize the pharmacokinetic and drug:metabolite outcomes.
Claims Coverage
The provided independent claim set includes one independent claim. It specifies a layered modified-release oral dosage form and a timed release schedule for sodium mycophenolate delivered to a dog’s lower gastrointestinal tract, with four inventive features centered on the layered structure, polymer selection, compositional ranges, protective behavior at pH below 6.0, and the defined release schedule.
Lower GI oral delivery with layered modified-release sodium mycophenolate composition
A method for delivering a sodium mycophenolate composition to a dog by delivering a plurality of modified-release compositions to a lower gastrointestinal tract of the dog via oral administration, where the modified-release compositions comprise a core with a diameter from about 0.5 mm to about 3 mm; a sodium mycophenolate layer disposed over at least a portion of the core; a seal coat disposed over the sodium mycophenolate layer; a modified-release layer disposed over the seal coat layer; and a protective layer disposed over the modified-release layer.
Ethyl cellulose modified-release layer and methacrylate protective layer not dissolving below pH 6.0
The method where the modified-release layer comprises ethyl cellulose from about 15 wt % to about 35 wt % of the composition; the protective layer comprises a methacrylate-based polymer from about 8 wt % to about 15 wt % of the composition and does not dissolve at a pH below 6.0; and the sodium mycophenolate is from about 20 wt % to about 90 wt % of the composition.
Timed release schedule for sodium mycophenolate after administration
The method where the sodium mycophenolate is released in the dog according to a schedule of hours following administration with corresponding percentages of sodium mycophenolate released.
Across the independent claim, the inventive focus is an oral, lower GI delivery method using layered modified-release sodium mycophenolate compositions with specified core dimensions, polymer-defined modified-release and protective layers, specified compositional ranges, and a defined time-based sodium mycophenolate release schedule.
Stated Advantages
Improved pharmacokinetics and drug:metabolite ratios for sodium mycophenolate delivered to the lower gastrointestinal tract.
Reduced MPA Cmax and sustained MPA exposure following T_max.
Increased MPA AUC versus an immediate-release reference formulation.
Elevated MPA:metabolite ratios (MPA:MPAG and/or MPA:AcMPAG).
Documented Applications
A veterinary method for delivering sodium mycophenolate to a dog via oral administration to the lower gastrointestinal tract, including embodiments associated with autoimmune disease or disorder, blood disorders associated with IMPDH activity, and/or dogs having, being about to have, or recently having a transplant or graft procedure.
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