|Title:||Sustained-release formulations of topiramate|
|Abstract:||Pharmaceutical compositions of topiramate for once-a-day oral administration are provided. The formulations comprise a sustained-release component and an optional immediate-release component, the compositions of which can be selectively adjusted, respectively, to release the active ingredient along a pre-determined release profile. Method of treating or preventing pathological disorders in mammalian subjects comprising the administration of the novel formulations disclosed herein is also provided.|
|Inventor(s):||Liang; Likan (Boyds, MD), Wang; Hua (Clarksville, MD), Bhatt; Padmanabh P. (Rockville, MD), Vieira; Michael L. (Gaithersburg, MD)|
|Assignee:||Supernus Pharmaceuticals, Inc. (Rockville, MD)|
1. A sustained release formulation of topiramate for oral administration to a mammalian subject comprising topiramate as an active ingredient that is released in a
continuous manner from the formulation along a pre-determined release profile, wherein the formulation comprises: an extended release (XR) component comprising at least one population of beads, wherein greater than or equal to 80% of the topiramate
contained therein is released in vitro in less than or equal to about 4 hours, and (ii) an immediate release (IR) component, wherein 80% of the topiramate contained therein is released in vitro in not more than 1 hour, wherein each bead population of the
XR component is coated with its own release controlling coating and characterized by its own rate of release.
2. The formulation of claim 1, wherein the immediate release component comprises a complexing agent, an enhancing agent, or both.
3. The formulation of claim 2, wherein the complexing agent is a cyclodextrin selected from a group consisting of hydroxypropyl-beta-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, alpha-cyclodextrin, and derivatives thereof.
4. The formulation of claim 2, wherein the enhancing agent is selected from a group comprising solubility enhancing agents, dissolution enhancing agents, absorption enhancing agents, penetration enhancing agents, surface active agents, stabilizers, enzyme inhibitors, p-glycoprotein inhibitors, multidrug resistance protein inhibitors and combinations thereof.
5. The formulation of claim 4, wherein the enhancing agent is selected from a group consisting of d-alpha tocopheryl polyethylene glycol succinate, glutamic acid, glycine, sorbitol, mannose, amylose, maltose, mannitol, lactose, sucrose, glucose, xylitose, dextrins, glycerolpolyethylene glycol oxystearate, polyethylene glycol-32 glyceryl palmitostearate, sodium lauryl sulfate, polyoxyethylene sorbitan rnonooleate, benzyl alcohol, sorbitan monolaurate, polyethylene-polypropylene glycol, polyethylene glycol-3350, polyvinylpyrrolidone-K25, oleic acid, glyceryl monooleate, sodium benzoate, cetyl alcohol, sucrose stearate, crospovidone, sodium starch glycolate, croscarmellose sodium, carboxymethylcellulose, starch, pregelatinized starch, hydroxypropylmethylcellulose, substituted hydroxypropylcellulose, microcrystalline cellulose sodium bicarbonate, calcium citrate, sodium docusate, menthol and combinations thereof.
6. The formulation of claim 1, wherein at least a part of the active ingredient is in a form of micronized particles.
7. The formulation of claim 6, wherein the particles have an average size of from about 2 .mu.m to about 100 .mu.m.
8. The formulation of claim 1, wherein the total amount of topiramate in the formulation is from 0.5 to 3000 mg.
9. The formulation of claim 1, wherein the beads comprise an inert carrier, topiramate, an optional enhancing agent, and a release controlling coating comprising a coating material and optionally a pore former and other excipients.
10. The formulation of claim 9, wherein the inert carrier is selected from a group consisting of cellulose spheres, silicon dioxide, starch and sugar spheres.
11. The formulation of claim 9, wherein the enhancing agent is selected from a group consisting of solubility enhancers, dissolution enhancers, permeability enhancers, stabilizers, enzyme inhibitors, p-glycoprotein inhibitors, multidrug resistance protein inhibitors and combinations thereof.
12. The formulation of claim 9, wherein the coating material is selected from a group consisting of ethylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulose acetate, cellulose acetate phthalate, polyvinyl alcohol, polyacrylates, polymethacrylates and copolymers thereof; and/or the pore former is selected from a group consisting of glucose, fructose, mannitol, mannose, galactose, sorbitol, pullulan, dextran, water-soluble hydrophilic polymers, hydroxyalkylcelluloses, carboxyalkylcelluloses, hydroxypropylmethylcellulose, cellulose ethers, acrylic resins, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyethylene oxide, carbomers, diols, polyols, polyhydric alcohols, polyalkylene glycols, polyethylene glycols, polypropylene glycols or block polymers thereof, polyglycols, poly (.alpha.-.omega.)alkylenediols; inorganic compounds selected from a group consisting of alkali metal salts and alkaline earth metal salts, and combinations thereof.
13. The formulation of claim 1, wherein the pre-determined release profile comprises a sustained rate of release after an initial immediate release.
14. The formulation of claim 1, suitable for once-a-day oral administration.
15. The formulation of claim 1, wherein the IR component is coated on top of the at least one population of beads of the XR component.
16. The formulation of claim 9, wherein the enhancing agent is contained in a layer separate from the release controlling coating.
17. The formulation of claim 1, further comprising at least one enhancing agent, wherein the enhancing agent is incorporated into the formulation in the form of a powder or of a population of beads that are optionally characterized by a controlled rate of release, and wherein the enhancing agent is separated from the active ingredient.
18. A method for the treatment or prevention of a neurological and/or psychiatric condition in a mammalian subject, comprising orally administering to the subject a therapeutically effective amount of a sustained release formulation of topiramate according to claim 1.
19. The method of claim 18, wherein the condition is selected from a group consisting of epilepsy, migraine, essential tremor, restless limb syndrome, cluster headaches, neuralgia, neuropathic pain, Tourrette's syndrome, infantile spasms, bipolar disorder, dementia, depression, psychosis, mania, anxiety, schizophrenia, obsessive-compulsive disorder, post-traumatic stress disorder, attention deficit hyperactivity disorder, impulse control disorders, border line personality disorder, addiction, autism, chronic neurodegenerative disorders, acute neurodegeneration, and amyotrophic lateral sclerosis.
20. The formulation of claim 1, which is a capsule, a tablet, a pill, a caplet, a troche, a pouch or sprinkles.
21. The formulation of claim 20, wherein the tablet is a multilayered tablet comprising at least one layer comprising the extended release component, and at least one layer comprising the immediate release component.
22. The formulation of claim 1, further comprising a pharmaceutically active ingredient in combination with topiramate.
23. The method of claim 19, wherein the condition is epilepsy.
24. The method of claim 19, wherein the condition is migraine.