Modified release ibuprofen dosage form
Inventors
Hite, Michael • Federici, Cathy • Brunelle, Alan • Turner, Stephen
Assignees
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Publication Number
US-9028869-B2
Publication Date
2015-05-12
Expiration Date
Abstract
The present invention is a solid dosage form for oral administration of ibuprofen comprising a modified release formulation of ibuprofen which provides an immediate burst effect and thereafter a sustained release of sufficient ibuprofen to maintain blood levels at least 6.4 μg/ml over an extended period of at least 8 hours following administering of a single dose.
Core Innovation
The invention describes a modified release formulation of ibuprofen in a solid dosage form that provides immediate and sustained drug release. The formulation uses a hydrophilic polymer matrix in which ibuprofen is uniformly dispersed. The solid dosage form releases at least 20% of the ibuprofen within 2 hours following oral administration or exposure to an agitated aqueous medium of a single dosage unit.
After the initial release, the formulation releases ibuprofen at a relatively constant rate such that the relationship between percentage of ibuprofen released and elapsed time is substantially linear over a period of at least 8 hours. The formulation further requires that at least 70% of the ibuprofen is released over a period of not more than 14 hours following such administration or exposure. The hydrophilic polymer comprises a first hydroxypropyl methylcellulose (HPMC) having a viscosity of about 100 cps and a second HPMC having a viscosity between about 200 cps to about 50,000 cps or, in a narrower embodiment, about 4,000 cps.
The composition includes a dissolution additive dispersed in the hydrophilic polymer in an amount in the range of 10% to 35% by weight of the ibuprofen. The dissolution additive comprises an alkali metal salt, an amino acid having a neutral to alkaline side chain, croscarmellose sodium, or combinations thereof. The formulation also includes an inert formulation additive dispersed in the hydrophilic polymer in an amount in the range of 15% to 75% by weight of the ibuprofen.
In specific embodiments, the dissolution additives include glycine and croscarmellose sodium, and the inert formulation additives include silica, stearic acid, and two silicified microcrystalline cellulose materials having different average particle sizes. The described example formulations are evaluated using in vitro dissolution and in vivo pharmacokinetic comparisons, including comparison against immediate-release Motrin® IB and BRUFEN RETARD, where the described criteria relate to achieving the immediate burst and substantially linear constant-rate release behavior.
Claims Coverage
The partial content includes two independent claims. Across these independent claims, the inventive subject matter centers on a specific ibuprofen modified-release monolithic tablet composition with a hydrophilic polymer matrix using first and second HPMC viscosity grades, defined dissolution and inert formulation additive types and amounts, and defined release performance thresholds and kinetics over time.
Hydrophilic polymer matrix with first and second HPMC viscosity grades
A modified release formulation of ibuprofen comprising a hydrophilic polymer, wherein said hydrophilic polymer comprises a first hydroxypropyl methylcellulose (HPMC) having a viscosity of about 100 cps and a second HPMC having a viscosity between about 200 cps to about 50,000 cps (or, in the narrower embodiment, a second HPMC having a viscosity of about 4,000 cps).
Uniformly dispersed ibuprofen with defined dosing range
300 to 800 mg of ibuprofen in solid dosage form uniformly dispersed in said polymer.
Dissolution additive in 10% to 35% by weight of ibuprofen
A dissolution additive dispersed in said hydrophilic polymer in an amount in the range of 10% to 35% by weight of the ibuprofen, said dissolution additive comprising an alkali metal salt, an amino acid having a neutral to alkaline side chain, croscarmellose sodium, or a combination thereof (or, in the narrower embodiment, comprising glycine and croscarmellose sodium).
Inert formulation additive in 15% to 75% by weight of ibuprofen
An inert formulation additive dispersed in said hydrophilic polymer in an amount in the range of 15% to 75% by weight of the ibuprofen.
Monolithic tablet release criteria: burst within 2 hours, constant-rate linear profile, and ≥70% by 14 hours
The formulation is in a solid dosage form comprising a monolithic tablet and releases at least 20% of the ibuprofen within 2 hours following oral administration or exposure to an agitated aqueous medium of a single dosage unit, then thereafter releases ibuprofen at a relatively constant rate in a substantially linear relationship between percentage of ibuprofen released and elapsed time over a period of at least 8 hours, and wherein at least 70% of the ibuprofen is released over a period of not more than 14 hours following such administration or exposure.
Defined silicified microcrystalline cellulose particle sizes and specified inert components
In the narrower embodiment, the inert formulation additives comprise silica, stearic acid, a first silicified microcrystalline cellulose having an average particle size of about 60 microns, and a second silicified microcrystalline cellulose having an average particle size of about 110 microns, and wherein said first and second silicified microcrystalline celluloses are each present in an amount in the range of 15% to 35% by weight of the ibuprofen.
The independent claims collectively require a modified-release ibuprofen monolithic tablet with an HPMC hydrophilic polymer matrix using first and second HPMC viscosity grades, specified dissolution and inert additive compositions and weight percentages, and a release profile defined by an initial ≥20% within 2 hours, a substantially linear constant-rate release over at least 8 hours, and ≥70% release within no more than 14 hours.
Stated Advantages
Provides an immediate burst effect by releasing at least 20% of the ibuprofen within 2 hours following oral administration or exposure to an agitated aqueous medium.
Provides sustained release at a relatively constant rate with a substantially linear relationship between percentage of ibuprofen released and elapsed time over at least 8 hours.
Achieves at least 70% ibuprofen release within no more than 14 hours following administration or exposure.
Documented Applications
Oral administration or exposure to an agitated aqueous medium of a single dosage unit as the release-performance testing contexts.
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