Orally Effective Methylphenidate Extended Release Powder and Aqueous Suspension Product
An oral methylphenidate powder which is reconstitutable into a final oral aqueous sustained release formulation containing at least about 50%, or at least about 80% by weight water based on the total weight of the suspension, is provided. The powder is a blend containing a combination of an uncoated methylphenidate—ion exchange resin complex, a barrier coated methylphenidate—ion exchange resin complex—matrix, and a water soluble buffering agent such that upon formed into an aqueous liquid formulation, the formulation has a pH in the range of about 3.5 to about 5, or about 4 to about 4.5. Following administration of a single dose of the oral aqueous methylphenidate suspension, a therapeutically effective amount of methylphenidate is reached in less than one hour and the composition provides a twelve-hour extended release profile.
1 . A methylphenidate aqueous oral suspension, wherein said suspension has a pH of about 4.2;
(i) an immediate release methylphenidate component;
(ii) a sustained release methylphenidate component comprising a water-insoluble, water-permeable, sustained release barrier coated methylphenidate—ion exchange resin complex—optional matrix, and
(iii) water;
wherein the aqueous oral suspension provides a pharmacokinetic profile in which d-methylphenidate has an area under the curve (AUC) 0-∞ of about 114 ng-hr/mL to about 180 ng-hr/mL following a single oral administration of the aqueous oral suspension to adult subjects under fasted conditions at a dose equivalent to 60 mg racemic methylphenidate HCl.
2 . The methylphenidate aqueous oral suspension according to claim 1 , wherein said suspension comprises at least about 80% w/w water based on the total weight of the suspension.
3 . The methylphenidate aqueous oral suspension according to claim 1 , wherein the immediate release methylphenidate component and the sustained release methylphenidate component in said suspension provides a dose equivalent to about 25 mg racemic methylphenidate HCl per 5 mL suspension.
4 . The methylphenidate aqueous oral suspension according to claim 1 , wherein the therapeutic effect of the suspension is observed and has an onset at least as early as 45-minutes and throughout an extended release profile in the subject following a single oral administration.
5 . The methylphenidate aqueous oral suspension according to claim 1 , wherein the barrier coated methylphenidate—ion exchange resin complex of the sustained release component—optional matrix comprises a matrix forming component, wherein said coating is over the methylphenidate—ion exchange resin complex—matrix.
6 . The methylphenidate aqueous oral suspension according to claim 5 , wherein the methylphenidate-ion exchange resin complex-matrix comprises a hydrophilic polymer or co-polymer matrix forming component.
7 . The methylphenidate aqueous oral suspension according to claim 6 , wherein the methylphenidate—ion exchange resin complex—matrix comprises a hydrophilic polymer in an amount of about 5 to about 20% by weight, based on the weight of the methylphenidate—ion exchange resin complex—matrix.
8 . The methylphenidate aqueous oral suspension according to claim 1 , wherein the methylphenidate in the immediate release methylphenidate component comprises about 20% w/w of the total methylphenidate in said suspension.
9 . The methylphenidate aqueous oral suspension according to claim 1 , wherein the immediate release methylphenidate component comprises an uncoated methylphenidate-ion exchange resin complex.
10 . The methylphenidate aqueous oral suspension according to claim 1 , wherein the immediate release methylphenidate component comprises a methylphenidate-ion exchange resin complex having a coating that provides immediate release.
11 . The methylphenidate aqueous oral suspension according to claim 1 , wherein in the water-insoluble, water-permeable, sustained release barrier coated methylphenidate-ion exchange resin complex of the sustained release component, the barrier coat is pH-independent and comprises a polyvinyl acetate polymer and a plasticizer.
12 . The methylphenidate aqueous oral suspension according to claim 1 , wherein in the barrier coating of the water-insoluble, water-permeable, sustained release barrier coated methylphenidate-ion exchange resin complex of the sustained release component, the barrier coat is pH-independent and comprises ethylcellulose.
13 . The methylphenidate aqueous oral suspension according to claim 1 , wherein in the water-insoluble, water-permeable, sustained release barrier coated methylphenidate-ion exchange resin complex of the sustained release component, the barrier coat is pH-independent and comprises a methyl methyacrylate polymer or co-polymer.
14 . The methylphenidate aqueous oral suspension according to claim 1 wherein the suspension further comprises a buffering agent selected from the group consisting of one or more of a pharmaceutically acceptable acid consisting of citric acid, ascorbic acid, acetic acid, tartartic acid, phosphoric acid, a pharmaceutically acceptable salt of citric acid, ascorbic acid, acetic acid, tartartic acid, phosphoric acid, and mixtures thereof.
15 . A method of treating a patient having a disorder selected from Attention Deficit Disorder (ADD), Attention Deficit Hyperactivity Disorder (ADHD), postural orthostatic tachycardia syndrome, and narcolepsy, said method comprising delivering an effective amount of a methylphenidate aqueous oral suspension according to claim 1 to the patient.
16 . The method according to claim 15 , wherein the immediate release methylphenidate component and the sustained release methylphenidate component in the suspension provides a methylphenidate dose equivalent to about 25 mg racemic methylphenidate HCl per 5 mL.
17 . The method according to claim 15 , wherein the suspension has an onset of action for methylphenidate of about 45 minutes and a continuous extended release profile of up to about 12 hours post-dosing.
18 . A methylphenidate aqueous oral suspension, wherein said methylphenidate aqueous oral suspension has a pH of about 4.2,
(i) an immediate release methylphenidate component,
(ii) a sustained release methylphenidate component comprising a water-insoluble, water-permeable, pH-independent sustained release barrier coated methylphenidate—ion exchange resin complex, and
(iii) water,
wherein said methylphenidate aqueous oral suspension provides a pharmacokinetic profile in which d-methylphenidate has an area under the curve (AUC) 0-∞ of 114 ng-hr/mL to 180 ng-hr/mL in adult subjects following a single oral dose of said methylphenidate aqueous oral suspension under fasted conditions and a reduced T max in adults fed with a high-fat meal prior to administration compared to adult subjects in a fasted state prior to said single oral dose, and
wherein following a single oral dose said methylphenidate aqueous oral suspension at a dose equivalent to 60 mg racemic methylphenidate HCl has a therapeutic effect which has an onset at least as early as 45-minutes and which is maintained for at least about 12 hours post-dosing.