DOSAGE FORM FOR NICOTINE REPLACEMENT THERAPY
A novel dosage form for intra-oral delivery of nicotine for use in nicotine replacement therapy; a process for preparation of said dosage form and intermediate compositions therefor; and methods for treatment.
1 . A tablet for intra-oral delivery of nicotine to a subject in need thereof which comprises:
(a) an orally disintegrating portion comprising a sensory marker/signal and a disintegration promoting excipient, and
(b) a troche/lozenge portion comprising a nicotine active agent, a buffer system, and a hydrophilic matrix.
2 . A tablet according to claim 1 wherein the sensory marker/signal comprises an organoleptic stimulus.
3 . A tablet according to claim 2 wherein the organoleptic stimulus comprises a flavor, and optionally a sweetener.
4 . A tablet according to claim 3 wherein the flavor is mint.
5 . A tablet according to claim 1 wherein the disintegration promoting excipient of (a) comprises a disintegration promoting excipient premix comprising mannitol, xylitol, dibasic calcium phosphate anhydrous, crospovidone, and microcrystalline cellulose.
6 . A tablet according to claim 1 wherein the buffer system of (b) comprises sodium carbonate anhydrous and sodium bicarbonate in relative amounts by weight of about 10:1 to about 7:1; and the hydrophilic matrix comprises Hypromellose and xanthan gum in relative amounts by weight of about 0.75:1 to about 3:1.
7 . A tablet according to claim 6 wherein (b) additionally comprises a lubricant which is magnesium stearate in an amount of at least about 2 wt. % but no more than 3 wt. %,
8 . A tablet according to claim 1 wherein (a) is capable of disintegrating in the oral cavity in about 60 seconds or less.
9 . A tablet according to claim 1 wherein (b) disintegrates or dissolves in the oral cavity over a period of from about 5 to about 20 minutes.
10 . A tablet according to claim 1 wherein the nicotine active agent of (b) comprises Nicotine Polacrilex.
11 . A tablet according to claim 6 wherein the Nicotine Polacrilex is present in an amount equivalent to 2 mg of nicotine.
12 . A tablet according to claim 6 wherein the Nicotine Polacrilex is present in an amount equivalent to 4 mg of nicotine.
13 . A tablet according to claim 1 comprising the nicotine active agent in an amount of 2 mg or 4 mg (calculated as nicotinee), wherein said tablet is bioequivalent to the corresponding 2 mg or 4 mg Reference Product, and bioequivalence is established by at least one pharmacokinetic parameter that is selected from (i) a confidence interval for mean AUC (0-t) between about 80% and about 125%; (ii) a confidence interval for mean AUC (0-infin) between about 80% and about 125%; (iii) a confidence interval for mean C max between about 80% and about 125%; (iv) a confidence interval for mean T max between about 80% and about 125%; and (v) combinations of any of (i)-(iv).
14 . A tablet according to claim 1 comprising the nicotine active agent in an amount of 2 mg or 4 mg (calculated as nicotine base), wherein said tablet is bioequivalent to the corresponding 2 mg or 4 mg Reference Product, and bioequivalence is established by at least one pharmacokinetic parameter that is selected from (i) a confidence interval for mean AUC (0-t) between about 70% and about 143%; (ii) a confidence interval for mean AUC (0-infin) , between about 70% and about 143%; (iii) a confidence interval for mean C max between about 70% and about 143%; (iv) a confidence interval for mean T max between about 70% and about 143%; and (v) combinations of any of (i)-(iv).
15 . A tablet according to claim 13 wherein bioequivalence is established by pharmacokinetic parameters (i), (ii) and (iii).
16 . A tablet according to claim 14 wherein bioequivalence is established by pharmacokinetic parameters (i), (ii) and (iii).
17 . A method for reducing withdrawal symptoms associated with smoking or use of a tobacco containing material; and/or for obtaining a reduction of the urge or craving to smoke or use tobacco containing material; and/or for providing a sense of smoking satisfaction without smoking, comprising the steps of replacing at least partly the tobacco containing material with a tablet of the invention, administering the tablet into the oral cavity of the subject and allowing the nicotine of the tablet to be released in the saliva in the oral cavity and absorbed by the subject into the systemic circulation of the subject.
18 . A direct compression process for preparing a tablet according to claim 1 comprising:
(i) separately blending and optionally sieving the ingredients comprising each of (a) and (b), in the absence of granulation;
(ii) optionally pre-compressing each of (a) and (b); and
(iii) compressing (a) and (b) together to form the tablet.