Modified release formulations of at least one form of tramadol
View Patent ↗The present invention relates to a modified release composition of at least one form of tramadol which is a delayed and extended release composition for oral administration suitable for once daily dosing. That composition comprises a core comprising at least one form of tramadol selected from the group consisting of tramadol, racemic mixtures thereof, enantiomers thereof, pharmaceutically acceptable salts thereof, and combinations thereof in combination with a pharmaceutically acceptable excipient. That composition further comprises a modified release coating which substantially surrounds said core. The compositions of the invention provide delayed and extended release of said at least one form of tramadol such that the mean plasma concentration of the at least one form of tramadol reaches a therapeutically effective level at a time which is after at least about 3 hours after first administration.
1. A method for treating pain in a patient in need thereof, comprising, administering a composition to the patient in need thereof in an amount sufficient to treat the pain,
wherein the composition is a unit dosage of a delayed and extended release pharmaceutical composition for oral administration suitable for once daily, comprising per unit dosage:
a) an immediate release core comprising about 100 to about 400 mg of tramadol hydrochloride, wherein about 70 to about 98% by weight of the core dry weight is tramadol hydrochloride in combination with about 2 to about 30% by weight of the core dry weight of a plurality of pharmaceutically acceptable excipients, and
b) about 8 to about 30% by weight of the core dry weight of a coating completely surrounding said core, said coating comprising a water-insoluble film-forming polymer in an amount from about 20% to about 89% by weight of the coating dry weight, a water-soluble polymer present in the coating in an amount of from about 10% to about 75% of the coating dry weight, and a plasticizer present in the coating from about 1% to about 30% of the coating dry weight,
wherein, in the presence of an aqueous medium, the coating completely surrounding the core becomes permeable to the tramadol hydrochloride in the presence of the aqueous medium; and
wherein the composition provides a delayed and extended release of the tramadol hydrochloride such that the mean plasma concentration of the tramadol hydrochloride reaches a therapeutically effective level at a time which is after at least about 3 hours after first administration of said composition in the fasted state,
wherein in the fed state, the mean time to reach maximum plasma concentration of the tramadol hydrochloride after first administration of said composition is delayed by at least about one hour compared to that in the fasted state, and
wherein at steady state the composition has a fluctuation index lower than an immediate-release composition of the tramadol hydrochloride administered 3 or 4 times a day.
2. The method of claim 1 , wherein the composition provides an in vitro dissolution profile using the USP Basket Method at 75 rpm in 900 ml 0.1 N HCl at 37° C. such that after about 2 hours, from about 0% to about 22% by weight of the tramadol hydrochloride is released, after about 4 hours from about 5% to about 30% by weight of the tramadol hydrochloride is released, after about 6 hours, from about 15% to about 38% by weight of the tramadol hydrochloride is released, and after about 8 hours, more than about 40% by weight of the tramadol hydrochloride is released.
3. The method of claim 1 , wherein the composition provides an in vitro dissolution profile using the USP Basket Method at 75 rpm in 900 ml 0.1 N HCl at 37° C. such that after about 2 hours, from about 0% to about 10% by weight of the tramadol hydrochloride is released, after about 4 hours from about 12% to about 20% by weight of the of the tramadol hydrochloride is released, after about 6 hours, from about 30% to about 38% by weight of the tramadol hydrochloride is released, after about 8 hours, from about 48% to about 56% by weight of the tramadol hydrochloride is released, after about 10 hours from about 64% to about 72% by weight of the tramadol hydrochloride is released, and after about 12 hours, more than about 76% by weight of the tramadol hydrochloride is released.
4. The method of claim 1 , wherein the composition, when administered to the patient in need thereof, provides a mean time to maximum plasma concentration (T max ) of the tramadol hydrochloride ranging from about four to about fourteen hours.
5. The method of claim 1 , wherein the composition exhibits an incidence of adverse events which is less than or equal to that of an immediate-release composition of the tramadol hydrochloride.
6. The method of claim 1 , wherein the composition exhibits a statistically significant reduction in adverse events when compared to an extended but not delayed release composition of the tramadol hydrochloride.
7. The method of claim 1 , wherein, in the composition, the core comprises a lubricant, a binder, and a glidant.
8. The method of claim 7 , wherein the glidant is colloidal silicon dioxide, the lubricant is selected from the group consisting of stearic acid, magnesium stearate, glyceryl behenate, mineral oil (in PEG), talc, sodium stearyl fumarate, a hydrogenated vegetable oil, sodium benzoate, calcium stearate and combinations thereof,
the binder is selected from the group consisting of a starch derivative, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, xanthan gum, a carbomer, caragheen and combinations thereof,
the water-insoluble water-permeable film-forming polymer is selected from the group consisting of a cellulose ether, a cellulose ester, a methacrylic acid derivative, an aqueous ethylcellulose dispersion, an aqueous acrylic enteric system, a polyvinyl derivative, and combinations thereof,
the water-soluble polymer is selected from the group consisting of methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and combinations thereof, and
the plasticizer is selected from the group consisting of an ester, an oil, a polyalkylene glycol and combinations thereof.
9. The method of claim 7 , wherein the lubricant is present in an amount of from about 0.5% to about 10% by weight of the core dry weight,
the binder is present in an amount of from about 1% to about 25% by weight of the core dry weight, and
the glidant is present in an amount of about 1% by weight of the core dry weight.
10. The method of claim 9 , wherein the glidant is colloidal silicon dioxide,
the lubricant is selected from the group consisting of stearic acid, magnesium stearate, glyceryl behenate, mineral oil (in PEG), talc, sodium stearyl fumarate, a hydrogenated vegetable oil, sodium benzoate, calcium stearate and combinations thereof,
the binder is selected from the group consisting of a starch derivative, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, xanthan gum, a carbomer, caragheen and combinations thereof,
the water-insoluble water-permeable film-forming polymer is selected from the group consisting of a cellulose ether, a cellulose ester, a methacrylic acid derivative, an aqueous ethylcellulose dispersion, an aqueous acrylic enteric system, a polyvinyl derivative, and combinations thereof,
the water-soluble polymer is selected from the group consisting of methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and combinations thereof, and
the plasticizer is selected from the group consisting of an ester, an oil, a polyalkylene glycol and combinations thereof.
11. The method of claim 10 , wherein
the glidant is colloidal silicon dioxide,
the binder is polyvinyl alcohol,
the lubricant is sodium stearyl fumarate,
the water-insoluble water-permeable film-forming polymer is ethyl cellulose,
the plasticizer is dibutyl sebacate, and
the water-soluble polymer is polyvinyl pyrrolidone.