Stabilized modified release vitamin d formulation and method of administering same
AssigneeOpko IP Holdings II, Inc.
InventorsJay A. White, Samir P. Tabash, Sammy A. Agudoawu, Joel Z. Melnick
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Abstract
A stabilized formulation for controlled release of a vitamin D compound is disclosed. The formulation comprises one or both of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 and a cellulosic compound. The stabilized formulations exhibit a stable dissolution profile following exposure to storage conditions and demonstrate improved pharmacokinetic parameters compared to unstabilized formulations.
Claims42
A controlled release formulation of a vitamin D compound comprising one or both of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3, the formulation comprising a matrix that releasably binds and controllably releases the vitamin D compound, the matrix comprising a cellulose derivative.
A stabilized formulation for controlled release of a vitamin D compound in the gastrointestinal tract of a subject which ingests the formulation, the formulation comprising a mixture of:
- one or both of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3;
- and an effective amount of a stabilizing agent, which is optionally a cellulosic compound, to maintain a difference of less than 30% between the amount of vitamin D compound released at any given time point after four hours during in vitro dissolution after two months exposure to storage conditions of 25° C. and 60% relative humidity and the amount released at the same dissolution time point during in vitro dissolution conducted prior to exposing the formulation to the storage conditions.
A stabilized formulation for controlled release of a vitamin D compound, said formulation comprising a mixture of:
- one or both of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3;
- a wax matrix;
- and
- a stabilizing agent, which is optionally a cellulosic compound.
A stabilized formulation for controlled release of a vitamin D compound, said formulation comprising a mixture of:
- one or both of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3;
- a wax matrix;
- and
- an effective amount of a stabilizing agent, optionally a cellulosic compound, to maintain a difference of less than 30% between the amount of vitamin D compound released at any given time point after four hours during in vitro dissolution testing after exposure for two months to storage conditions of 25° C. and 60% relative humidity and the amount released at the same dissolution time point during in vitro dissolution conducted prior to exposing the formulation to the storage conditions.
A stabilized formulation for controlled release of a vitamin D compound in the gastrointestinal tract of a subject which ingests the formulation, said formulation comprising a mixture of:
- an active-loaded wax matrix comprising one or both of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3;
- and
- a cellulosic stabilizing agent;
- wherein the formulation releases an amount of 25-hydroxyvitamin D during in vitro dissolution after two months exposure to storage of 25° C. and 60% relative humidity that varies at any given dissolution time point compared to the amount released at the same dissolution time point during in vitro dissolution conducted prior to exposing the formulation to the storage conditions by 30% or less in the absence of the cellulosic stabilizing agent.
In a formulation for controlled release of a vitamin D compound in the gastrointestinal tract of a subject which ingests the formulation, the improvement comprising admixing a cellulosic stabilizing agent into the formulation.
In a formulation for controlled release of a vitamin D compound in the gastrointestinal tract of a subject which ingests the formulation, the improvement comprising an effective amount of a cellulosic compound admixed in the formulation to maintain a change of less than 30% in the amount of 25-hydroxyvitamin D released during in vitro dissolution after exposure to storage conditions of at least one month at 25° C. and 60% relative humidity at any given dissolution time point after four hours compared to the amount released at the same dissolution time point during in vitro dissolution conducted prior to exposing the formulation to the storage conditions.
A stabilized sustained release oral dosage form comprising a vitamin D compound characterized by an in vitro dissolution profile providing release of vitamin D compound of
- less than 30% at 100 to 140 minutes;
- greater than 45% at 5 to 7 hours;
- and
- greater than 80% at 11 to 13 hours.
A stabilized sustained release oral dosage form comprising a vitamin D compound characterized by an in vitro dissolution profile providing release of vitamin D compound of
- about 20% to about 40% at 2 hours;
- at least 35% at 6 hours;
- and
- at least 70% at 12 hours.
A stabilized sustained release dosage form comprising a vitamin D compound characterized by a tmax following administration of the dosage form to a human patient, of at least 4 hours.
A stabilized sustained release dosage form comprising a 25-hydroxyvitamin D compound, the dosage form characterized by providing a baseline-adjusted Cmax per microgram of 25-hydroxyvitamin D in a range of about 0.0133 ng/mL to about 0.04 ng/mL when administered to an adult human.
A method of administering a stabilized sustained release dosage form comprising a 25-hydroxyvitamin D compound to a human patient, comprising administering an effective amount of the dosage form to the patient to provide a baseline-adjusted Cmax of at least about 0.2 ng/mL and less than 110 ng/mL.
A method of administering a stabilized sustained release dosage form comprising a 25-hydroxyvitamin D compound to a human patient, comprising administering an effective amount of the dosage form to the patient to provide a baseline-adjusted AUC0-inf of at least 52 ng*h/mL and less than 34500 ng*h/mL.
Dependencies are inferred from the claim text.