SUSTAINED-RELEASE FORMULATIONS OF TOPIRAMATE

• US 20120321708A1
• Filed: 08/27/2012
• Published: 12/20/2012
• Est. Priority Date: 11/17/2006
• Status: Active Grant

• Current Assignee: Supernus Pharmaceuticals Incorporated
• Original Assignee: Supernus Pharmaceuticals Incorporated
• Inventors: Liang, Likan, Wang, Hua, Bhatt, Padmanabh P., Vieira, Michael L.
• Granted Patent: US 8,663,683 B2
• Time in Patent Office: Days
• US Class Current: 424/458
• CPC Class Codes: A61K 31/357 having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/6951 using cyclodextrin cyclodextrins used as simple excipients A61K47/40
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/1676 having a drug-free core with discrete complete coating layer containing drug adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61K 9/5042 Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5047 Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/16 Central respiratory analeptics
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 : Antimigraine agents
• CPC Class Codes: A61P 25/08 : Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 : for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/18 : Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 : Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 : Anxiolytics
• CPC Class Codes: A61P 25/24 : Antidepressants
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/30 : for treating abuse or dependence
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 27/06 : Antiglaucoma agents or miotics
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: B82Y 5/00 : Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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.

Claims

1. A sustained release formulation of topiramate for oral administration to a mammalian subject comprising topiramate as an active ingredient that is released from the formulation along a pre-determined release profile, wherein said formulation comprises an extended release component and an immediate release component, wherein the extended release component is contained in at least one population of beads and releases topiramate in a continuous manner and each bead population is coated with its own release controlling coating and characterized by its own rate of release.

2. The formulation of claim 1, wherein said XR component releases topiramate in vivo in a continuous manner, and 80% of the active ingredient is released in vitro in a period of time selected from not more than 24 hours, not more than 16 hours, not more than 12 hours, not more than 8 hours and not more than 4 hours.

3. The formulation of claim 1, wherein the immediate release component is an enhanced immediate release (EIR) composition comprising a complexing agent, an enhancing agent, or both.

4. The formulation of claim 3, wherein said E1R composition exhibits an in vitro release profile such that 80% of the active ingredient is dissolved in not more than 30 min.

5. The formulation of claim 4, wherein said EIR composition exhibits an in vitro release profile selected from a group consisting of:

a) a dissolution of at least 50% of the active compound in not more than 10 minutes;

b) a dissolution of at least 70% of the active compound in not more than 10 minutes;

c) a dissolution of at least 25% of the active compound in not more than 5 minutes;

d) a dissolution of at least 40% of the active compound in not more than 5 minutes; and

e) a dissolution of at least 55% of the active compound in not more than 5 minutes.

6. The formulation of claim 3, 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.

7. The formulation of claim 3, wherein said 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.

8. The formulation of claim 7, wherein said enhancing agent is selected from a group consisting of Vitamin E TPGS, glutamic acid, glycine, sorbitol, mannose, amylose, maltose, mannitol, lactose, sucrose, glucose, xylitose, dextrins, glycerolpolyethylene glycol oxystearate, PEG-32 glyceryl palmitostearate, sodium lauryl sulfate, polyoxyethylene sorbitan rnonooleate, benzyl alcohol, sorbitan monolaurate, Poloxamer 407, PEG3350, PVP K25, oleic acid, glyceryl monooleate, sodium benzoate, cetyl alcohol, sucrose stearate, crospovidone, sodium starch glycolate, croscarmellose sodium, carboxymethylcellulose, starch, pregelatinized starch, HPMC, substituted hydroxypropylcellulose, microcrystalline cellulose sodium bicarbonate, calcium citrate, sodium docusate, menthol and combinations thereof.

9. The formulation of claim 1, wherein at least a part of the active ingredient is in a form of micronized particles.

10. The formulation of claim 9, wherein said particles have an average size of from about 2 pm to about 100 pm.

11. The formulation of claim 1, wherein a specific amount of each component is determined according to the purpose of administration and the pre-determined release profile, and the total amount of topiramate in the formulation is from 0.5 to 3000 mg.

12. The formulation of claim 1, wherein said beads comprise an inert carrier, topiramate, an optional enhancer, and a release controlling coating that comprises a coating material and optionally a pore former and other excipients.

13. The formulation of claim 12, wherein said inert carrier is selected from a group consisting of cellulose spheres, silicon dioxide, starch and sugar spheres.

14. The formulation of claim 12, wherein said enhancer is selected from a group consisting of solubility enhancers, dissolution enhancers, permeability enhancers, stabilizers, complexing agents, enzyme inhibitors, p-glycoprotein inhibitors, multidrug resistance protein inhibitors and combinations thereof.

15. The formulation of claim 12, wherein said 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 said 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, Carbowaxes, Carbopol, diols, polyols, polyhydric alcohols, polyalkylene glycols, polyethylene glycols, polypropylene glycols or block polymers thereof, polyglycols, poly(a-w)alkylenediols;

inorganic compounds selected from a group consisting of alkali metal salts and alkaline earth metal salts, and combinations thereof.

16. The formulation of claim 1, wherein a specific amount of every bead population is determined according to the pre-determined release profile.

17. The formulation of claim 1, wherein said pre-determined release profile comprises a sustained rate of release after an initial immediate release.

18. The formulation of claim 1 suitable for once a day oral administration.

19. The formulation of claim 1, wherein at least one population of beads consists of extended release topiramate beads additionally comprising an immediate release component coated on top of the release controlling coating.

20. The formulation of claim 12, wherein said enhancer is contained in a layer separate from the release controlling coating.

21. The formulation of claim 1 additionally comprising at least one enhancing agent, wherein said 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 said enhancing agent is separated from the active ingredient.

22. A sustained release formulation of claim 1 comprising 3 populations of extended release topiramate-containing beads designated as XR1, XR2 and XR3, and an immediate release (IR) bead population, wherein the proportional amounts of each population in a formulation are selected according to the following Table:

23. The formulation of claim 22, wherein the immediate release bead population is composed of EIR such that the following condition is true:

for in-vitro dissolution, T_80%<

=30 min.

24. The formulation of claim 1 for use in a method for the treatment or prevention of a pathological condition in a mammalian subject, comprising orally administering to said subject a therapeutically effective amount of a sustained release formulation of topiramate, wherein topiramate is released from the formulation along the pre-determined release profile, and wherein said formulation comprises an extended release component and an immediate release component.

25. The formulation of claim 24, wherein said formulation has a reduced level of undesirable CNS side effects as compared to the same amount of topiramate administered as an immediate release formulation BID,

26. The formulation of claim 24, wherein said 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, perinatal hypoxia ischemia and related damage, glaucoma, ocular disorders, obesity,

weight loss, Type II diabetes mellitus, diabetic retinopathy, impaired oral glucose tolerance, diabetic skin lesions, diabetic neuropathy, elevated blood glucose levels,

syndrome X, elevated blood pressure, elevated lipids, bipolar disorder, dementia, depression, psychosis, mania, anxiety, schizophrenia, obsessive-compulsive disorder, post-traumatic stress disorder, ADHD, impulse control disorders, border line personality disorder, addiction, autism, asthma, autoimmune disorders, chronic neurodegenerative disorders, acute neurodegeneration, ALS, sleep apnea and sleep disorders.

27. An oral dosage form comprising a sustained release formulation of topiramate as defined in claim 1.

28. The dosage form of claim 27, which is a capsule, a tablet, a pill, a caplet, a troche, a sachet, a cachet, a pouch or sprinkles.

29. The oral dosage form of claim 28, wherein said tablet is a mutilayered tablet comprising at least one layer containing said extended release component, and at least one layer comprising said immediate release component.

30. The formulation of claim 1, further comprising an additional pharmaceutically active ingredient in combination with topiramate.