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-11090269-B1
Publication Date
2021-08-17
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 concerns controlled-release drug formulations that include an immediate release portion and a sustained release portion, with both portions comprising at least one pharmaceutically active ingredient selected from gamma-hydroxybutyrate and pharmaceutically acceptable salts of gamma-hydroxybutyrate. In the sustained release portion, a functional coating is deposited over a core, and the core comprises the gamma-hydroxybutyrate active ingredient. The functional coating includes one or more methacrylic acid-methyl methacrylate co-polymers that are from about 20% to about 50% by weight of the functional coating.
The formulations are defined by specific dissolution performance thresholds in a dissolution apparatus 2 in deionized water at 37°C with a paddle speed of 50 rpm, including that the sustained release portion releases greater than about 40% of its gamma-hydroxybutyrate by about 4 to about 6 hours, while the overall formulation releases at least about 30% by one hour and releases greater than about 90% by 8 hours. The immediate release portion comprises about 75% and about 98% by weight of the gamma-hydroxybutyrate and the amount of gamma-hydroxybutyrate in the immediate release portion is about 10% to 50% by weight of the gamma-hydroxybutyrate and salts in the formulation.
The invention also addresses unit dosage forms and solid sustained release portions where the same immediate-release/sustained-release architecture is used, including specified unit dosage gamma-hydroxybutyrate amounts and the same dissolution release bounds. In some formulations, additional performance requirements are included, such as providing a mean plasma Cmax of at least about 25 μg/ml when administered to a subject. Further in vivo exposure constraints are stated in dependent claims, including mean plasma AUCinf thresholds and bounded ranges.
Claims Coverage
The independent claims are directed to four closely related embodiments: an immediate and sustained release formulation, an immediate and solid sustained release formulation, a unit dosage form with the same split, and a formulation requiring a mean plasma Cmax threshold. The inventive features center on the methacrylic acid-methyl methacrylate functional coating, the immediate-release and sustained-release drug loading split, and the defined dissolution-release thresholds.
Immediate and sustained release formulation for gamma-hydroxybutyrate with methacrylic acid-methyl methacrylate functional coating
A formulation comprising an immediate release 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; the sustained release portion comprises a functional coating deposited over a core comprising the active ingredient, wherein 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; the sustained release portion releases greater than about 40% of its gamma-hydroxybutyrate by about 4 to about 6 hours; and the formulation releases at least about 30% by one hour and greater than about 90% by 8 hours under the stated dissolution conditions.
Immediate and solid sustained release formulation for gamma-hydroxybutyrate with methacrylic acid-methyl methacrylate coating and defined dissolution release
A formulation comprising an immediate release portion and a solid sustained release portion, with a functional coating deposited over a core comprising the active ingredient; 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; and the sustained release portion and overall formulation satisfy the stated dissolution release thresholds.
Unit dosage form with immediate and sustained release portions using methacrylic acid-methyl methacrylate functional coating
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; the sustained release portion comprises the methacrylic acid-methyl methacrylate functional coating over a core; the immediate release portion comprises about 75% and about 98% by weight of the active ingredient; the amount in the immediate release portion is about 10% to 50% by weight of the active ingredient in the unit dosage form; and the unit dosage form satisfies the stated dissolution release thresholds.
Immediate and sustained release formulation providing mean plasma Cmax for gamma-hydroxybutyrate
A formulation comprising an immediate release portion and a sustained release portion with the same functional coating and dissolution-release limitations, and further providing a mean plasma Cmax of at least about 25 μg/ml when administered to a subject.
Across the independent claims, the claim coverage centers on a combined immediate-release and sustained-release oral formulation or unit dosage form containing gamma-hydroxybutyrate or pharmaceutically acceptable salts, with a sustained-release core and methacrylic acid-methyl methacrylate co-polymers in the functional coating. The claims are further defined by the stated drug loading split and by specific in-vitro dissolution release thresholds. One independent claim also adds a mean plasma Cmax requirement of at least about 25 μg/ml.
Stated Advantages
Reduces early release/dose dumping and limits PK pulsatility and inter-patient variability.
Provides time-dependent sustained delivery over about 4 to about 12 hours.
Improves robustness in alcohol dissolution without dose dumping.
Documented Applications
Controlled-release dosage forms intended for use with gamma-hydroxybutyrate, including pharmaceutically acceptable salts and related forms, including sodium oxybate and calcium oxybate.
Formulations evaluated in clinical crossover evaluation comparing controlled-release treatments B–E vs sodium oxybate oral solution with plasma concentration-time graphs and summarized PK parameters.
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