Drug delivery systems comprising solid solutions of weakly basic drugs
Inventors
Venkatesh, Gopi • Boltri, Luigi • Colombo, Italo • Lai, Jin-Wang • Fabiani, Flavio • Mapelli, Luigi
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10864166-B2
Publication Date
2020-12-15
Expiration Date
Abstract
The present invention is directed to pharmaceutical compositions and dosage forms comprising TPR beads, wherein said TPR beads comprise a solid dispersion of at least one active pharmaceutical ingredient in at least one solubility-enhancing polymer, and a TPR coating comprising a water insoluble polymer and an enteric polymer, wherein the active pharmaceutical ingredient comprises a weakly basic active pharmaceutical ingredient having a solubility of not more than 100 μg/mL at pH 6.8.
Core Innovation
The invention relates to a pharmaceutical composition that uses timed pulsatile release beads and rapidly dispersing microgranules to achieve therapeutically effective plasma concentrations for a sustained period. The TPR beads comprise a solid dispersion of at least one active pharmaceutical ingredient in at least one solubility-enhancing polymer, where the active pharmaceutical ingredient comprises a weakly basic active pharmaceutical ingredient having a solubility of not more than 100 μg/mL at pH 6.8.
A key aspect is the use of a TPR coating comprising a water insoluble polymer and an enteric polymer. The solid dispersion is described as at least one amorphous and/or molecularly dispersed drug state within a solubility-enhancing, crystallization-inhibiting polymer, and this is related to improved dissolution behavior for weakly basic drugs with low solubility at pH 6.8.
The rapidly dispersing microgranules include particles of at least one disintegrant and a sugar alcohol and/or saccharide, with particle size constraints for the particles and an overall particle size constraint for both the TPR beads and the microgranules. Formulation variables are described as modulating release/lag time and sustaining plasma levels over an extended duration.
Claims Coverage
The coverage centers on one independent claim directed to a pharmaceutical composition combining timed pulsatile release beads with rapidly dispersing microgranules, with particle-size constraints and a requirement to provide a therapeutically effective plasma concentration for at least about 18 hours. Dependent claims refine the composition with additional quantitative constraints and selected exemplars.
Timed pulsatile release beads with solid dispersion of weakly basic drug
The TPR beads comprise a solid dispersion of at least one active pharmaceutical ingredient in at least one solubility-enhancing polymer, where the active pharmaceutical ingredient comprises a weakly basic active pharmaceutical ingredient having a solubility of not more than 100 μg/mL at pH 6.8.
TPR coating comprising water insoluble polymer and enteric polymer
The TPR beads comprise a TPR coating comprising a water insoluble polymer and an enteric polymer.
Rapidly dispersing microgranules with disintegrant and sugar alcohol/saccharide particles
The rapidly dispersing microgranules comprise particles of at least one disintegrant, and a sugar alcohol and/or saccharide.
Overall particle size constraints for TPR beads and microgranules
The average particle size of the TPR beads and rapidly dispersing microgranules is not more than 400 μg/mL.
Sustained therapeutically effective plasma concentration
The composition provides a therapeutically effective plasma concentration of the active pharmaceutical ingredient over a period of at least about 18 hours.
Enteric coating over a solid dispersion with defined coating fraction and lag time
The TPR beads comprise an enteric coating over the solid dispersion, wherein the coating makes up up to about 40% of the beads’ total weight, and wherein the beads provide a lag time of about 1–4 hours.
Water-insoluble polymer to enteric polymer ratio
The TPR coating has a water-insoluble polymer to enteric polymer ratio ranging from about 9:1 to about 1:9.
Solid dispersion deposited on an inert core
The solid dispersion of an active pharmaceutical ingredient with a solubility-enhancing polymer is deposited on an inert core.
Solubility-enhancing polymer selection
The solubility-enhancing polymer is chosen from specified polymers and cyclodextrins, including polyvinylpyrrolidone, vinyl acetate/vinyl pyrrolidone copolymers, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene oxide, polyethylene glycol, and cyclodextrins.
Lercanidipine as the active pharmaceutical ingredient
The active pharmaceutical ingredient is lercanidipine, including its pharmaceutically acceptable salts, solvates, and/or esters.
Overall, the claims define a composition combining timed pulsatile release beads and rapidly dispersing microgranules, with solid dispersion in a solubility-enhancing polymer, a TPR coating of water-insoluble and enteric polymers, particle size limits, and a functional requirement to provide therapeutically effective plasma concentrations for at least about 18 hours. Dependent claims further constrain coating ratio, coating placement and fractions, deposition on an inert core, selection of solubility-enhancing polymers from a specified list, and exemplify lercanidipine.
Stated Advantages
Provides a therapeutically effective plasma concentration of the active pharmaceutical ingredient over a period of at least about 18 hours.
Improved oral bioavailability for weakly basic drugs with low solubility at pH 6.8 is described in the context of the disclosed approach.
Documented Applications
Oral bioavailability improvement for weakly basic active pharmaceutical ingredients having low solubility at pH 6.8 (≤100 μg/mL) is described.
Example drug applications include lercanidipine HCl and nifedipine used to illustrate formulation and coating concepts.
Interested in licensing this patent?