Reduction of opioid blood fluctuations
Inventors
Herry, Catherine • Boyer, Maryline • Vauzelle-Kervroedan, Francoise • Oury, Pascal
Assignees
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Publication Number
US-10111869-B2
Publication Date
2018-10-30
Expiration Date
Abstract
The present invention relates to the use of a sustained release matrix containing at least one opioid for producing a solid oral formulation in table form suitable for reducing blood concentration fluctuations of said opioid.
Core Innovation
The invention relates to a method of treatment of severe pain using an oral repeated twice-a-day administration of a sustained-release matrix-type tablet that releases at least one opioid or one of its pharmaceutically acceptable salts. The method maintains, in vivo, a steady-state opioid plasma concentration with reduced fluctuation, and the dosing is spaced apart by 8 to 14 hours. In the disclosed example, the steady-state opioid plasma concentration is maintained at above 60% of Cssmax for at least 10 hours.
The sustained-release matrix-type tablet includes a compression matrix comprising granules of the opioid or pharmaceutically acceptable salt and hydroxypropylmethylcellulose (HPMC), together with a mixture of microcrystalline cellulose and polyvinyl acetate/polyvinyl pyrrolidone (80:20), precipitated silica, and magnesium stearate. The tablet further includes a sub-coating consisting of a mixture of HPMC, simethicone, micronized talc, and precipitated silica. A coating is also provided consisting of an aqueous dispersion of ethylcellulose, dibutyl sebacate, talc, and precipitated silica.
The disclosed approach targets reduced opioid plasma concentration fluctuation, including limitation of the fluctuation parameters such that the reduced-fluctuation duration is maintained for an extended period in relation to Cssmax. The patent text links this pharmacokinetic behavior to reduced peaks and troughs and to reduced resurgent pain or breakthrough pain patterns, as well as fewer side effects such as nausea, drowsiness, and cognitive effects.
Claims Coverage
The disclosed claims include one independent claim, directed to a twice-a-day oral method of treating severe pain using a specific sustained-release matrix-type tablet, with pharmacokinetic performance defined by reduced fluctuation above 60% of Cssmax for at least 10 hours. The independent claim is further refined by dependent claims adding quantitative thresholds and narrowing opioid selection and specific clinical outcomes.
Twice-a-day oral sustained-release matrix-type opioid tablet for severe pain with reduced Cssmax fluctuation
Administering orally to a patient in need thereof in a repeated manner twice-a-day a sustained-release matrix-type tablet releasing at least one opioid or one of its pharmaceutically acceptable salts, wherein each administration is spaced apart by 8 to 14 hours, and wherein the method maintains the steady-state opioid plasma concentration obtained in vivo with a reduced fluctuation at above 60% of the Cssmax value for at least 10 hours.
Compression matrix with opioid granules and HPMC plus specific excipient mixture
The matrix-type tablet comprising a compression matrix consisting of granules of one opioid or one of its pharmaceutically acceptable salts and hydroxypropylmethylcellulose (HPMC); a mixture of microcrystalline cellulose and polyvinyl acetate/polyvinyl pyrrolidone (80:20); precipitated silica; and magnesium stearate.
Sub-coating composition for the matrix-type tablet
The matrix-type tablet comprising a sub-coating consisting of a mixture of hydroxypropylmethylcellulose (HPMC), simethicone, micronized talc, and precipitated silica.
Coating composition for the matrix-type tablet using ethylcellulose dispersion
The matrix-type tablet comprising a coating consisting of an aqueous dispersion of ethylcellulose, dibutyl sebacate, talc, and precipitated silica.
Overall claim coverage centers on a twice-a-day oral method for severe pain using a sustained-release matrix-type tablet having specified compression matrix, sub-coating, and coating compositions, combined with dosing spaced 8 to 14 hours and pharmacokinetic performance defined as reduced fluctuation with steady-state concentrations above 60% of Cssmax for at least 10 hours.
Stated Advantages
Reduced opioid plasma concentration fluctuation through reduced peaks and troughs, with steady-state opioid plasma concentration above 60% of Cssmax for at least 10 hours.
Reduced resurgent pain or breakthrough pain patterns associated with reduced concentration variability.
Fewer side effects including reduced nausea, reduced drowsiness, and reduced cognitive effects.
Documented Applications
Treatment of severe pain in a patient in need thereof using repeated twice-a-day oral administration of a sustained-release matrix-type tablet releasing an opioid or pharmaceutically acceptable salt.
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