Orally effective methylphenidate extended release powder and aqueous suspension product
View Patent ↗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 extended release oral suspension, wherein said suspension has a single mean average plasma concentration peak and a therapeutically effective plasma profile for about 12 hours for d-methylphenidate, and
has a pharmacokinetic profile in which the single mean plasma concentration peak for d-methylphenidate has an area under the curve (AUC) 0-∞ of about 114 ng-hr/mL to about 180 ng-hr/mL, C max of about 11 ng/mL to about 17 ng/mL, T max of about 4 hours to about 5.25 hours and T 1/2 of about 5 hours to about 7 hours following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults.
2. The methylphenidate aqueous extended release oral suspension according to claim 1 , which maintains at least about 95% of its initial potency over a period of at least about 4 months at room temperature.
3. The methylphenidate aqueous extended release oral suspension according to claim 1 , wherein the pharmacokinetic profile of d-methylphenidate has an AUC 0-∞ of about 143.65 ng-hr/mL, C max of about 13.61 ng/mL, T max of about 5 hours and T 1/2 of about 5.65 hours following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults.
4. The methylphenidate aqueous extended release oral suspension according to claim 1 , which comprises an immediate release methylphenidate component and a sustained release methylphenidate component, wherein said sustained release methylphenidate component comprises a water-insoluble, water-permeable, pH-independent, barrier coated methylphenidate—ion exchange resin complex.
5. The methylphenidate aqueous extended release oral suspension according to claim 4 , wherein the barrier coating is selected from the group consisting of (a) a cured water-permeable, high tensile strength, water insoluble, pH-independent barrier coating comprising a polyvinylacetate polymer and a plasticizer, (b) a barrier coating comprising an solvent-based ethylcellulose; and (c) a pH-independent acrylate based barrier coating comprising a methyl methyacrylate polymer or co-polymer.
6. The methylphenidate aqueous extended release oral suspension according to claim 5 , wherein the barrier coating (a) comprises from about 70 to about 90% of polyvinylacetate, about 2.5 to about 15% of a plasticizer, and a stabilizer.
7. The methylphenidate aqueous extended release oral suspension according to claim 6 , wherein the barrier coating further comprises from about 5 to about 10% of the stabilizer and from about 0.1 to about 1% surfactant.
8. The methylphenidate aqueous extended release oral suspension according to claim 5 , wherein the plasticizer is triacetin.
9. The methylphenidate aqueous extended release oral suspension according to claim 7 , wherein the surfactant is sodium lauryl sulfate or HO(C 2 H 4 O) 86 (C 3 H 6 O) 27 (C 2 H 4 O) 87 H.
10. The methylphenidate aqueous extended release oral suspension according to claim 5 , wherein the methylphenidate—ion exchange resin complex is in a matrix formed by granulating said complex with at least one hydrophilic or hydrophobic polymeric matrix forming component.
11. The methylphenidate aqueous extended release oral suspension according to claim 10 , wherein the coated 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.
12. The methylphenidate aqueous extended release oral suspension according to claim 11 , wherein the hydrophilic polymer is polyvinylpyrrolidone.
13. The methylphenidate aqueous extended release oral suspension according to claim 4 , wherein the immediate release methylphenidate component is an uncoated methylphenidate—ion exchange resin complex, optionally in combination with a hydrophilic or hydrophobic polymeric matrix forming component.
14. The methylphenidate aqueous extended release oral suspension according to claim 1 , wherein said methylphenidate is selected from the group consisting of racemic methylphenidate and dexmethylphenidate.
15. The methylphenidate aqueous extended release oral suspension according to claim 10 , further comprising 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, and/or a pharmaceutically acceptable salt of citric acid, ascorbic acid, acetic acid, tartartic acid, phosphoric acid, and/or mixtures thereof.
16. A method of treating a patent having a disorder selected from Attention Deficit Disorder, Attention Deficit Hyperactivity Disorder, postural orthostatic tachycardia syndrome, and narcolepsy, said method comprising delivering an effective amount of a methylphenidate aqueous suspension according to claim 1 to the patient.
17. A methylphenidate aqueous extended release oral suspension comprising an immediate release methylphenidate component and a sustained release methylphenidate component,
wherein said suspension has a pH of 3.5 to 5,
wherein said sustained release methylphenidate component comprises a water-insoluble, water-permeable, pH-independent, barrier coated methylphenidate—ion exchange resin complex—matrix, and
wherein said suspension has a pharmacokinetic profile in which the d-methylphenidate has an area under the curve (AUC) 0-∞ , of about 114 ng-hr/mL to about 180 ng-hr/mL and a C max of about 11 ng/mL to about 17 ng/mL following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults.
18. The methylphenidate aqueous extended release oral suspension according to claim 17 , wherein the pH is about 4.2.
19. The methylphenidate aqueous extended release oral suspension according to claim 18 , wherein the suspension comprises at least about 80% of water based on the total weight of the suspension.
20. The methylphenidate aqueous extended release oral suspension according to claim 19 , which has less than about 5% loss in potency over a period of about 1 month of storage at room temperature.
21. The methylphenidate aqueous extended release oral suspension according to claim 19 , which has less than about 1% of threo-α-phenyl-2-piperidineacetic acid hydrochloride impurity after a period of about 1 month of storage at room temperature.
22. The methylphenidate aqueous extended release oral suspension according to claim 19 , which has less than about 5% loss in potency over a period of about 4 months of storage at room temperature.
23. The methylphenidate aqueous extended release oral suspension according to claim 19 , which has less than about 1% of threo-α-phenyl-2-piperidineacetic acid hydrochloride impurity after a period of about 4 months of storage at room temperature.
24. The methylphenidate aqueous extended release oral suspension according to claim 17 , wherein the T max is about 4 hours to about 5.25 hours following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults.
25. The methylphenidate aqueous extended release oral suspension according to claim 17 , wherein said suspension provides a therapeutically effective plasma profile for methylphenidate for about 12 hours following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults.
26. The methylphenidate aqueous extended release oral suspension according to claim 17 , wherein said suspension provides a single mean average plasma concentration peak for methylphenidate following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults.
27. The methylphenidate aqueous extended release oral suspension according to claim 17 , wherein said suspension provides a therapeutically effective amount of methylphenidate within 45 minutes after administration following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults.
28. The methylphenidate aqueous extended release oral suspension according to claim 17 , wherein following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults said suspension provides a reduced T max in subjects fed with a high-fat meal prior to administration compared to subjects in a fasted state prior to administration.
29. The methylphenidate aqueous extended release oral suspension according to claim 28 , wherein following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults said suspension provides a T max reduced by about 60 minutes in subjects fed with a high-fat meal prior to administration compared to subjects in a fasted state prior to administration.
30. The methylphenidate aqueous extended release oral suspension according to claim 17 , wherein following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults said suspension provides a C max increased by about 28% in subjects fed with a high-fat meal prior to administration compared to subjects in a fasted state prior to administration.
31. The methylphenidate aqueous extended release oral suspension according to claim 17 , wherein following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults said suspension provides an area under the curve (AUC) 0-∞ increased by about 19% in subjects fed with a high-fat meal prior to administration compared to subjects in a fasted state prior to administration.
32. The methylphenidate aqueous extended release oral suspension according to claim 17 , wherein varrier coating is cured and comprises from about 70 to about 90% of polyvinylacetate, from about 2.5 to about 15% of a plasticizer, and a stabilizer.
33. The methylphenidate aqueous extended release oral suspension according to claim 17 , wherein the barrier coating comprises ethylcellulose.
34. The methylphenidate aqueous extended release oral suspension according to claim 17 , wherein the barrier coating comprises a methyl methyacrylate polymer or co-polymer.
35. The methylphenidate aqueous extended release oral suspension according to claim 17 , further comprising 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, and/or a pharmaceutically acceptable salt of citric acid, ascorbic acid, acetic acid, tartartic acid, phosphoric acid and/or mixtures thereof.
36. The methylphenidate aqueous extended release oral suspension according to claim 17 , wherein the suspension comprises at least about 60% of water based on the total weight of the suspension.
37. The methylphenidate aqueous extended release oral suspension according to claim 17 , wherein the suspension comprises at least about 70% of water based on the total weight of the suspension.
38. The methylphenidate aqueous extended release oral suspension according to claim 17 , wherein a liquid component of the aqueous suspension is from about 80% to about 100% of water.
39. The methylphenidate aqueous extended release oral suspension according to claim 17 , wherein the AUC for d-methylphenidate at about three hours following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults under fasted conditions is about 20 ng-mL/hr.
40. The methylphenidate extended release oral suspension according to claim 1 , wherein the AUC for d-methylphenidate at about three hours following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults under fasted conditions is about 20 ng-hr/mL.
41. A methylphenidate aqueous extended release oral suspension comprising an immediate release methylphenidate component and a sustained release methylphenidate component,
wherein said suspension has a pH of about 4.2,
wherein said sustained release methylphenidate component comprises a water-insoluble, water-permeable, pH-independent, barrier coated methylphenidate—ion exchange resin complex,
wherein said suspension comprises at least about 80% of water based on the total weight of the suspension,
wherein said suspension has less than about 1% of threo-α-phenyl-2-piperidineacetic acid hydrochloride impurity after a period of about 1 month of storage at room temperature, and
wherein following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl said suspension has a pharmacokinetic profile in which the d-methylphenidate has
an area under the curve (AUC) 0-∞ of about 114 ng-hr/mL to about 180 ng-hr/mL in adults under fasted conditions,
a C max of about 11 ng/mL to about 17 ng/mL in adults 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 administration.
42. The methylphenidate aqueous extended release oral suspension according to claim 41 wherein following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl said suspension has a pharmacokinetic profile in which the d-methylphenidate has a T max reduced by about 60 minutes in adults fed with a high-fat meal prior to administration compared to adult subjects in a fasted state prior to administration.
43. The methylphenidate aqueous extended release oral suspension according to claim 41 , whether the methylphenidate—ion exchange resin complex is in a matrix with a water-insoluble polymer or co-polymer or a water-soluble polymer or co-polymer, wherein the barrier coating is over the methylphenidate—ion exchange resin complex—matrix.