Modified release compositions 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 unit dosage of a delayed and extended release pharmaceutical composition for oral administration 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 said tramadol hydrochloride and about 2 to about 30% by weight of the core dry weight is 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 present in the coating in an amount of 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 said coating becomes permeable to the tramadol hydrochloride in the presence of an aqueous medium; and
wherein said composition provides a delayed and extended release of the tramadol hydrochloride such that
(i) 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;
(ii) 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
(iii) 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 unit dosage of claim 1 , wherein said unit dosage 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 said 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 said tramadol hydrochloride is released.
3. The unit dosage of claim 1 , wherein said unit dosage 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 said 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 said 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 said tramadol hydrochloride is released.
4. The unit dosage of claim 1 , wherein said unit dosage when administered to a 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 unit dosage of claim 1 , wherein said unit dosage 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 unit dosage of claim 1 , wherein said unit dosage exhibits a statistically significant reduction in adverse events when compared to an extended but not delayed release composition of the tramadol hydrochloride.
7. The unit dosage of claim 1 , wherein the core of said unit dosage comprises from about 100 mg to about 300 mg of the tramadol hydrochloride.
8. The unit dosage of claim 1 , wherein said pharmaceutically acceptable excipients comprising the core are selected from the group consisting of a binder, a lubricant, a filler, a glidant and combinations thereof.
9. The unit dosage of claim 8 , wherein the excipients comprise a binder that is a water-soluble polymer.
10. The unit dosage of claim 9 , wherein said water-soluble polymer is present in an amount of from about 1% to about 25% by weight of the core dry weight.
11. The unit dosage of claim 10 , wherein said water-soluble polymer is selected from the group consisting of a starch derivative gelatin, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, xanthan gum, a carbomer, caragheen and combinations thereof.
12. The unit dosage of claim 10 , wherein said water-soluble polymer is polyvinyl alcohol.
13. The unit dosage of claim 12 , wherein said polyvinyl alcohol is present at about 2% by weight of the core dry weight.
14. The unit dosage of claim 8 , wherein the excipients comprise a lubricant that is present in an amount from about 0.5% to about 10% by weight of the core dry weight.
15. The unit dosage of claim 14 , wherein said lubricant is selected from the group consisting of stearic acid, magnesium stearate, glyceryl behenate, talc, mineral oil (in PEG), sodium stearyl fumarate, a hydrogenated vegetable oil, sodium benzoate, calcium stearate and combinations thereof.
16. The unit dosage of claim 15 , wherein said lubricant is sodium stearyl fumarate.
17. The dosage of claim 16 , wherein said sodium stearyl fumarate is present at about 1% by weight of the core dry weight.
18. The unit dosage of claim 8 , wherein the excipients comprise a filler that is present in an amount from about 1% to about 25% by weight of the core dry weight.
19. The unit dosage of claim 18 , wherein said filler is selected from the group consisting of lactose monohydrate, anhydrous lactose, mannitol, sorbitol, microcrystalline cellulose, dibasic calcium, calcium sulfate, pulp cellulose, and combinations thereof.
20. The unit dosage of claim 19 , wherein said filler is microcrystalline cellulose.
21. The unit dosage of claim 8 , wherein the excipients comprise a glidant that is colloidal silicon dioxide and is present at about 1% by weight of the core dry weight.
22. The unit dosage of claim 1 , wherein said water-insoluble 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.
23. The unit dosage of claim 1 , wherein said water-insoluble film-forming polymer is a cellulose ether.
24. The unit dosage of claim 23 , wherein said cellulose ether is ethylcellulose.
25. The unit dosage of claim 1 , wherein said water-soluble polymer is selected from the group consisting of methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and combinations thereof.
26. The unit dosage of claim 1 , wherein said water-soluble polymer is polyvinylpyrrolidone.
27. The unit dosage of claim 1 , wherein said plasticizer is selected from the group consisting of an ester, an oil, a polyalkylene glycol and combinations thereof.
28. The unit dosage of claim 1 , wherein said plasticizer is an ester.
29. The unit dosage of claim 28 , wherein said ester is dibutyl sebacate.
30. The unit dosage of claim 1 , wherein said water-insoluble film-forming polymer is ethyl cellulose and is present in an amount from about 53% to about 70% of the coating dry weight, said water-soluble polymer is polyvinyl pyrrolidone and is present in an amount from about 20% to about 26% of the coating dry weight, and said plasticizer is dibutyl sebacate and is present from about 14% to about 18% by weight of the coating dry weight.
31. The unit dosage of claim 1 wherein, said coating is present at about 16% by weight of the core dry weight.
32. The unit dosage of claim 1 , in the form of a tablet.
33. The unit dosage of claim 1 , in the form of a capsule.
34. The unit dosage of claim 1 , which upon an in vivo administration releases substantially no tramadol into the plasma until at least 3 hours after administration.
35. The unit dosage of claim 1 , wherein the plurality of excipients comprises a lubricant, a binder, and a glidant.