Controlled release dosage forms for high dose, water soluble and hygroscopic drug substances
Inventors
Allphin, Clark • Pfeiffer, James
Assignees
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Publication Number
US-11207270-B2
Publication Date
2021-12-28
Expiration Date
Abstract
Controlled release dosage forms are described herein. The controlled release formulations described herein provide prolonged delivery of high dose drugs that are highly water soluble and highly hygroscopic. In specific embodiments, controlled release dosage forms for delivery of a drug selected from GHB and pharmaceutically acceptable salts, hydrates, tautomers, solvates and complexes of GHB. The controlled release dosage forms described herein may incorporate both controlled release and immediate release formulations in a single unit dosage form.
Core Innovation
The invention provides a unit dosage form comprising an immediate release portion and a sustained release portion for gamma-hydroxybutyrate and pharmaceutically acceptable salts of gamma-hydroxybutyrate. The sustained release portion comprises a functional coating deposited over a core, where the functional coating comprises one or more methacrylic acid-methyl methacrylate co-polymers from about 20% to about 50% by weight of the functional coating.
The immediate release portion is configured to provide an initial release fraction that is a defined portion of the total gamma-hydroxybutyrate content in the unit dosage form. The functional coating and core are designed to control dissolution behavior and thereby sustain release over time, with the sustained release portion releasing greater than about 40% of its gamma-hydroxybutyrate by about 4 to about 6 hours and the overall unit dosage form releasing at least about 30% of its gamma-hydroxybutyrate by one hour.
The unit dosage form is also characterized by a single-dose plasma exposure criterion, providing plasma gamma-hydroxybutyrate concentration of at least 10 μg/mL over at least about 6 hours. In additional embodiments, the invention relates to formulations for high-dose, water-soluble and hygroscopic drugs including sodium oxybate, together with other gamma-hydroxybutyrate forms such as salts, hydrates, tautomers, solvates, and complexes.
Coated unit dosage forms are used, including moisture-barrier and cosmetic coatings, to manage hygroscopicity for sodium oxybate. The invention further includes integrated immediate-release and sustained-release designs to provide rapid onset followed by prolonged therapeutic levels, with defined release and in vivo plasma timing targets.
Claims Coverage
The document contains two independent claims. Both focus on immediate-release plus sustained-release unit dosage forms or formulations for gamma-hydroxybutyrate and pharmaceutically acceptable salts, with defined functional coating composition and time-dependent dissolution and in vivo plasma performance criteria.
Immediate-release and sustained-release unit dosage form for gamma-hydroxybutyrate
A unit dosage form comprising an immediate release portion and a sustained release portion, each portion comprising at least one pharmaceutically active ingredient selected from gamma-hydroxybutyrate and pharmaceutically acceptable salts of gamma-hydroxybutyrate.
Methacrylic acid-methyl methacrylate copolymer functional coating for sustained release
The sustained release portion comprises a functional coating deposited over a core, where the functional coating comprises one or more methacrylic acid-methyl methacrylate co-polymers that are from about 20% to about 50% by weight of the functional coating.
Sustained release dissolution target at about 4 to about 6 hours
The sustained release portion releases greater than about 40% of its gamma-hydroxybutyrate by about 4 to about 6 hours when tested in a dissolution apparatus 2 in deionized water at a temperature of 37°C and a paddle speed of 50 rpm.
Defined immediate-release fraction and total dose amount
The immediate release portion comprises between about 75% and about 98% by weight of at least one pharmaceutically active ingredient selected from gamma-hydroxybutyrate and pharmaceutically acceptable salts of gamma-hydroxybutyrate, where the amount in the immediate release portion is about 10% to about 50% by weight of the gamma-hydroxybutyrate and pharmaceutically acceptable salts of gamma-hydroxybutyrate in the unit dosage form; and the unit dosage form comprises about 4.5 g to about 9 g of the gamma-hydroxybutyrate and pharmaceutically acceptable salts of gamma-hydroxybutyrate.
Early dissolution and minimum plasma exposure criteria
The unit dosage form releases at least about 30% of its gamma-hydroxybutyrate by one hour when tested in a dissolution apparatus 2 in deionized water at a temperature of 37°C and a paddle speed of 50 rpm; and administration of a single dose of the unit dosage form provides plasma gamma-hydroxybutyrate concentration of at least 10 μg/mL over a period of at least about 6 hours.
Immediate-release and sustained-release formulation with sustained-release dissolution target
A formulation comprising an immediate release portion and a sustained release portion, each portion comprising at least one pharmaceutically active ingredient selected from gamma-hydroxybutyrate and pharmaceutically acceptable salts of gamma-hydroxybutyrate, where the sustained release portion comprises a functional coating and a core deposited over the core and the functional coating comprises one or more methacrylic acid-methyl methacrylate co-polymers from about 20% to about 50% by weight of the functional coating; and the sustained release portion releases greater than about 40% of its gamma-hydroxybutyrate by about 4 to about 6 hours when tested in a dissolution apparatus 2 in deionized water at a temperature of 37°C and a paddle speed of 50 rpm.
Defined immediate-release fraction, early dissolution, and late dissolution targets
The immediate release portion comprises between about 75% and about 98% by weight of at least one pharmaceutically active ingredient selected from gamma-hydroxybutyrate and pharmaceutically acceptable salts of gamma-hydroxybutyrate, where the amount in the immediate release portion is about 10% to about 50% by weight of the gamma-hydroxybutyrate and pharmaceutically acceptable salts of gamma-hydroxybutyrate in the formulation; the formulation releases at least about 30% of its gamma-hydroxybutyrate by one hour; and the formulation releases greater than about 90% of its gamma-hydroxybutyrate by 8 hours, each tested in a dissolution apparatus 2 in deionized water at a temperature of 37°C and a paddle speed of 50 rpm.
Mean plasma Tmax timing window
The formulation provides a mean plasma Tmax of gamma-hydroxybutyrate between 0.5 hours and 5.0 hours when administered to a subject.
Overall, claim coverage centers on an immediate-release plus sustained-release oral dosage form or formulation for gamma-hydroxybutyrate or pharmaceutically acceptable salts, with a sustained-release functional coating using methacrylic acid-methyl methacrylate co-polymers from about 20% to about 50% by weight, time-dependent in vitro dissolution performance, and specified in vivo exposure metrics.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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