Sustained-release formulations of topiramate

• US 8,889,191 B2
• Filed: 12/17/2010
• Issued: 11/18/2014
• 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.
• Primary Examiner(s): ZISKA, SUZANNE E
• Application Number:
  US12/926,936
• Publication Number:
  US 20110287103A1
• Time in Patent Office: 1,432 Days
• Field of Search: None
• US Class Current: 424/490
• 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 method of treatment of a neurological and/or psychiatric condition in a mammalian subject, comprising orally administering to said subject in need thereof a therapeutically effective amount of a sustained release formulation of 2,3:

4,5-Di-O-isopropylidene-beta-D-fructopyranose sulfamate (topiramate), wherein all of the topiramate is released in a continuous manner from the formulation, wherein at least 85% by weight of the total topiramate in the formulation is contained in an extended release (XR) component comprising at least two populations of beads coated with a release controlling coating and each having its own rate of release, and wherein at least one of the at least two XR populations releases 80% of the topiramate contained therein in vitro in not more than 4 hours.

2. The method of claim 1, wherein said formulation provides for a maximum steady state plasma concentration (Cmax) of topiramate which is in the range of 50% to 125% of the maximum plasma concentration produced by the same amount of topiramate administered as an immediate release formulation BID.

3. The method of claim 2, wherein said Cmax is higher than the minimal therapeutically effective concentration, but lower than the maximum plasma concentration produced by the same amount of topiramate administered as an immediate release formulation BID.

4. The method of claim 2, wherein said Cmax is in the range of 80% to 125% of the maximum plasma concentration produced by the same amount of topiramate administered as an immediate release formulation BID.

5. The method of claim 1, wherein said formulation provides for a relative steady state AUC in the range of 80% to 125%, as compared to the same amount of topiramate administered as an immediate release formulation BID.

6. The method of claim 1, wherein said formulation provides for a degree of fluctuation in the range of 25% to 90% as compared to the same amount of topiramate administered as an immediate release formulation BID.

7. The method 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.

8. The method of claim 7, wherein said inert carrier is selected from the group consisting of cellulose spheres, silicon dioxide, starch and sugar spheres.

9. The method of claim 7, wherein said pore former is selected from the 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(α

-ω

)alkylenediols;

inorganic compounds;

alkali metal salts and alkaline earth metal salts, and combinations thereof.

10. The method of claim 7, wherein said enhancer is selected from the group consisting of solubility enhancers, dissolution enhancers, permeability enhancers, stabilizing agents, complexing agents, enzyme inhibitors, p-glycoprotein inhibitors, multidrug resistance protein inhibitors and combinations thereof.

11. The method of claim 1, wherein a specific amount of each bead population is determined according to a pre-determined release profile.

12. The method of claim 1, wherein the sustained release is after an initial immediate release.

13. The method of claim 1, wherein said formulation is administered orally once a day.

14. The method of claim 1, having a reduced level of undesirable CNS side effects as compared to the same amount of topiramate administered as an immediate release formulation BID.

15. The method of claim 1, wherein the total amount of topiramate in the formulation is from 0.5 mg to 3000 mg.

16. The method of claim 1, wherein said formulation is in a dosage form of a tablet, a pill, a capsule, a caplet, a troche, a pouch, or sprinkles.

17. The formulation of claim 1, further comprising an immediate release (IR) component.

18. The method of claim 17, wherein said IR component comprises topiramate and (a) a complexing agent selected from the group consisting of hydroxypropyl-beta-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, alpha-cyclodextrin, and cyclodextrin derivative and/or (b) an enhancing agent selected from the group consisting of solubility enhancing agents, dissolution enhancing agents, absorption enhancing agents, penetration enhancing agents, surface active agents, stabilizing agents, enzyme inhibitors, p-glycoprotein inhibitors, multidrug resistance protein inhibitors and combinations thereof.

19. The method of claim 18, wherein said IR component exhibits a release profile such that 80% of the active ingredient is dissolved in not more than 30 min.

20. The method of claim 19, wherein said IR component exhibits a release profile selected from the group consisting of:

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

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

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

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

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

21. The method of claim 7, wherein said coating material is selected from the group consisting of ethylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulose acetate, cellulose acetate phthalate, polyvinyl alcohol, polyacrylates, polymethacrylates and copolymers thereof.

22. The method of claim 1, wherein the condition is selected from the 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.

23. The method of claim 22, wherein the condition is epilepsy.

24. The method of claim 22, wherein the condition is migraine.