CA2513064C - Nanoparticulate topiramate formulations - Google Patents

Nanoparticulate topiramate formulations Download PDF

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CA2513064C
CA2513064C CA002513064A CA2513064A CA2513064C CA 2513064 C CA2513064 C CA 2513064C CA 002513064 A CA002513064 A CA 002513064A CA 2513064 A CA2513064 A CA 2513064A CA 2513064 C CA2513064 C CA 2513064C
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less
chloride
topiramate
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ammonium
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CA2513064A1 (en
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Evan Gustow
Tuula Ryde
Eugene R. Cooper
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Elan Pharma International Ltd
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • AHUMAN NECESSITIES
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    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/06Antimigraine agents
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    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/08Antiepileptics; Anticonvulsants
    • AHUMAN NECESSITIES
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    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/18Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • AHUMAN NECESSITIES
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    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/22Anxiolytics
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    • A61P25/24Antidepressants
    • AHUMAN NECESSITIES
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    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/30Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32Alcohol-abuse
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/30Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34Tobacco-abuse
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/30Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36Opioid-abuse
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention is directed to nanoparticulate compositions comprising topiramate. The topiramate particles of the composition have an effective average particle size of less than about 2 microns.

Description

NANOPARTICULATE TOPIRAMATE FORIVNLATIONS
CP OSS-F'~.EFEI'r.EI`-TCE TO RELAJED Al:"P'I_,ICATIOL15 [0001] The present in trention claims benefit of U.S. F"ro,,,isic,nal .~,-pf+li(~a.tion No.
60/444,377, filed on January 31, '2003; U.S. Provisional ~:.pplication No.
60/477,789., filed on June 12, 2003; and U.S. Provisional Application No. 60/511,318, filed on October 16, 2003.

FIELD OF THE 1I1"OrEI1TIOIr [0002] The present invention relates to a nanoparticulate composition comprising topiramate and at least one surface stabilizer that is preferably adsorbed to or associated with the surface of the drug. The nanoparticulate topiramate particles have an effective average particle size of less than about 2000 nm.

BACKGROUND OF THE INVENTION
A. Backaround Reearding Nanoparticulate Compositions [0003] Nanoparticulate compositions, first described in U.S. Patent No.
5,145,684 ("the `684 patent"), are particles consisting of a poorly soluble therapeutic or diagnostic agent having adsorbed onto or associated with the surface thereof a non-crosslinked surface stabilizer. The `684 patent does not describe nanoparticulate compositions of topiramate.
[0004] Methods of making nanoparticulate compositions are described, for example, in U.S. Patent Nos. 5,518,187 and 5,862,999, both for "Method of Grinding Pharmaceutical Substances;" U.S. Patent No. 5,718,388, for "Continuous Method of Grinding Pharmaceutical Substances;" and U.S. Patent No. 5,510,11S for "Process of Preparing Therapeutic Compositions Containing Nanoparticles."
[0005] Nanoparticula.te compositions are also described, for example, in U.S.
Patent Nos. 5,298,262 for "Use of Ionic Cloud Point Modifiers to Prevent Particle Aggzegation During Sterilization;" 5,302,401 for 6LMfethod to Reduce Particle Size Growth During Lyophilization;" 5,318,767 for "X-Ray Contrast Compositions Useful in I

Medical Imaging;" 5,326,552 for "Novel Formulation For Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weiglit Non-ionic Surfactants;"
5,328,404 -For "Method of X-Ray Imaging LTsing lodinated Aromatic. Propanedioates;"
5,336; 507 for `TTsr of C'harged Phi)spholipids to F".Fdu~~rz~ Na.n.opa.rtic,=le ~,_ggreg~.tic~n,'" 5.3,1'-,5~~4 for " Formulations Comprising Olin 10-0 to Prevent Particle Aggregation and Increase Stability;" 5,346,702 for "Use of Non-Ionic Cloud Point Modifiers to I,4inimize Nanoparticulate Aggregation During Sterilization;" 5,349,957 for "Preparation and Ivlagnetic Properties of Very Small I<Zagnetic-Dextran Particles;" 5;352,459 for "Use of Purified Surface Modifiers to Prevent Particle Aggregation During Sterilization;"
5,399,363 and 5,494,683, both for "Surface Modified Anticancer Nanoparticles;"
5,401,492 for "Water Insoluble Non-Magnetic Manganese Particles as Magnetic Resonance Enhancement Agents;" 5,429,824 for "Use of Tyloxapol as a Nanoparticulate Stabilizer;" 5,447,710 for "Method for Making Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants;" 5,451,393 for "X-Ray Contrast Compositions Useful in Medical Imaging;" 5,466,440 for "Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents in Combination with Pharmaceutically Acceptable Clays;" 5,470,583 for "Method of Preparing Nanoparticle Compositions Containing Charged Phospholipids to Reduce Aggregation;"
5,472,683 for "Nanoparticulate Diagnostic Mixed Carbamic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;" 5,500,204 for "Nanoparticulate Diagnostic Dimers as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;"
5,518,738 for "Nanoparticulate NSAID Formulations;" 5,521,21S for "Nanoparticulate lododipamide Derivatives for Use as X-Ray Contrast Agents;" 5,525,328 for "Nanoparticulate Diagnostic Diatrizoxy Ester'-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;" 5,543,133 for "Process of Preparing X-Ray Contrast Compositions Containing Nanoparticles;" 5,552,160 for "Surface Modified NSAID
Nanoparticles;" 5,560,931 for "bFormulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty.PLcids;" 5,565,18,8 for "Polyall~-ylene Block Copolymers as Surface Modifiers for Nanoparticles;" 5,569,44S for "Sulfa.ted Non-ionic Block Copolymer Surfactant as Stabilizer C'oatings for Nanoparticle Composition.,;49 5,571,536 for "Formulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatt3r Acids;" 5,573,749 for "Nanoparticula.te Diagnostic Mixed Carboxylic ~nydridEs as X-Ray Contrast Agents for Blood Pool and L}mpriatic. System Ima.ging;õ
5,573,750 for "Diagnostic hnaghng ati-f".ay Contrast Agents,,''5,5 73, 7~:~3 for "F.edispersible Nanopa.rticula.te Film I14atrices With Protective Overcoats;" 5,580,579 for "Site-specific Adhesion Within the GI Tract Using Nanoparticles Stabilized by High Molecular Weight, Linear Poly(ethylene Oxide,) Pol}nners;" 5,585.108 for "Formulations of Oral Gastrointestinal Therapeutic Agents in Combination with Pharmaceutically Acceptable Clays;" 5,587,143 for "Butylene Oxide-Ethylene Oxide Block Copolymers Surfactants as Stabilizer Coatings for Nanoparticulate Compositions;" 5,591,456 for "1l+Tilled Naproxen with Hydroxypropyl Cellulose as Dispersion Stabilizer;" 5,593,657 for "Novel Barium Salt Formulations Stabilized by Non-ionic and Anionic Stabilizers;" 5,622,938 for"Sugar Based Surfactant for Nanocrystals;" 5,628,981 for "Improved Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents and Oral Gastrointestinal Therapeutic Agents;" 5,643,552 for "Nanoparticulate Diagnostic Mixed Carbonic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;" 5,718,388 for "Continuous Method of Grinding Pharmaceutical Substances;" 5,718,919 for "Nanoparticles Containing the R(-)Enantiomer of Ibuprofen;" 5,747,001 for "Aerosols Containing Beclomethasone Nanoparticle Dispersions;" 5,834,025 for "Reduction of Intravenously Administered Nanoparticulate Formulation Induced Adverse Physiological Reactions;" 6,045,829 "Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers;" 6,068,858 for "Methods of Making Nanocrystalline Formulations of Human Imrnunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers;" 6,153,225 for "Injectable Formulations of Nanoparticulate Naproxen;" 6,165,506 for "New Solid Dose Form of Nanoparticulate Naproxen;" 6,221,400 for "Methods of Treating Mammals Using Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors;" 6,264,92~~' for "Yebulized Aerosols Containing Nanoparticle Dispersions;"
6,267,989 for "Methods for Preventing Crystal Growth and Particle Aggregation in Nanoparticle Compositions;" 6,270,806 for "Use of PEG-Derivatized Lipids as Surface WO 2004/078162 PCT/US2004/002,548 Stabilizers for Nanoparticulate Compositions;" 6,316,029 for "Rapidly Disintegrating Solid Oral Dosage Forn1," 6,375,956 for "SOlid Dose Nanoparticulate Compositions Comprising a S;aaergistic Cornbination of a Pn1_;meric Surfac.e Stabilizer and Dioctyl Sodium SLilfo"11Cxinate'" 6,420.,S 14 fbr "Blo0.dl1es1`dC
n:inop,3rtIcuta.t~:orn~ ~~~~Itior_~s _ ~
ha.ving cationic surface sta.L-ilizer..;" 6.;431,475 fo_r'`Small Sca1=
I.1i11;" 66432.351 for "Methods for Targeting Druc, Delivery to the Upper andi'or Lower Gastrointestinal Tract,"
n 552,285 for Vkpparatus for Sanitary Wet I,.%Iilling," 6,592,903 for "Nanoparticulate Dispersions Comprising a Synergistic Combination of a Fol~,Tneric Surface Stabilizer and Dioctyl Sodium Sulfosuccina.te," and 6,656,504 for "Nanoparticulate Compositions Comprising: Amorphous Cyclosporine and Methods of IAaking and Using Such `Composirions".

[0006] In addition, U.S. Patent Application No. 20020012675 Al, published on January 31, 2002,-for "Controlled Release Nanoparticulate Compositions," and WO
02/098565 for "System and Method for Milliuig Materials," describe nanoparticulate active agent compositions. None of these references describe nanoparticulate compositions of topiramate.
[0007] Amorphous small particle compositions are described, for example, in U.S.
Patent Nos. 4,783,4S4 for "Particulate Composition and Use Thereof as Antimicrobial Agent;" 4,826,689 for "Method for Making Uniformly Sized Particles from Water-Insoluble Organic Compounds;" 4,997,454 for "Method for Making Uniformly-Sized Particles From Insoluble Compounds;" 5,741,522 for "Ultrasmall, Non-aggregated Porous Particles of Uniform Size for Entrapping Gas Bubbles Within and Methods;" and 5,776,496, for "Ultrasmall Porous Particles for Eiihancing Ultrasound Back Scatter."

B. Background Rellarding Topiramate .[0008] Topiramate is a sulfamate-substituted monosaccharide designated chemic.a.ll_y as 2,3:4,5-Di-0-isopropylidene-F3-D-uctopyranosF. sulfa.mate, having the rnolFcular formula C12 HG1 NT~'J8S, a molecular weight of 339.36, and the follo~ving structural fonnula:

Q \;CM,,OSC,NH2 QW"', 0 f HsC CH3 H3C CHa.

[0009] Topiramate has a solubility in water of 9.8 mg/mL. It is most soluble in alkaline solutions containing sodiuni hydroxide or sodium phosphate and having a pH of 9 to 10. Topiramate is freely soluble in acetone, chloroform, dimethylsulfoxide, and ethanol. See Playsicians' Desk Refererace, 57th Edition, pp. 2501 (2003).
Topiramate is a white crystalline powder with a bitter.taste.

[00010] Topiramate is an anticonvulsant intended for use as an antiepileptic drug.
It is considered a broad spectrum anti-epileptic drug (AED) because it works to prevent both partial onset and generalized seizures. Epilepsy is a chronic condition characterized by recurrent, unprovoked seizures, or electrical disturbances in the brain that can alter a patient's consciousness, movement, or behaviors. Seizures are characterized as either partial or generalized, depending on where they originate in the brain.
Epilepsy affects an estimated 2.3 million Americans and each year approximately 181,000 people in the United States are newly diagnosed with the condition. See http ://www.phazmaceutic alonline. com.

[00011] Topiramate is chemically unrelated to any other anticonvulsant or mood regulating medication. Topiramat ; has potentially five mechanisms of action.
They include the blockage of sodium charuzels (similar to many of the traditional epileptics), enhancement of CTA.BA-a receptors (an inhibitory neurotransmitter), inhibitory effect on glutamate receptors, inhibition of L-type high-voltage calcium ion channels, and a diamosz tyPe effect. The relatively importance of these mechanisms in the functioning of topiramate is not clearly kno,~jm but it does not appear that any other single AED shares thFse five properties.

[000121 `pecifi::all,r; topira_mate eutliances a chemical sub.E.-.tancr that ii,liibits electrical activity in the brain, -A%hile blocking other substances triat in lrease acti=rit-i-.
Thus, topiramate appears to help balance electrical activity in the brain to reduce the frequenc.y of seizures. Electropriysio logical and bioc.hemic.a.l studies of the cffects of topiramate on cultured neurons have revealed tkiree properties that may contributc to topiramatc's antiepileptic efficacy. First, action potentials elicited repetitively by a sustained depolarization of the neurons are blocked bytopiramate in a time-dependent.
manner, suggestive of a state-dependent sodium channel blocking action.
Second, topiramate increases the frequency at which y-aminobutyrate (GABA) activates GABAA
receptors, and enhances the ability of GABA to induce. a flux of chloride ions irito neurons, suggesting that topiramate potentiates the activity of this inhibitory neurotransmitter; Third, topiramate antagonizes the ability of kainae to activate the kainate/AIVIl'A (oc amino-3-hydroxy-5-methylisoxazole-4-propionic acid, non-NMDA), subtype of excitatory amino acid (glutamate) receptor, but has no apparent effect on the activity of N-methyl-D-aspartate (NNIDA) at the NMDA receptor subtype.

[00013] Patients newly diagnosed with epilepsy are routinely prescribed multiple medications to treat their seizures. The results of a recent study demonstrate that topiramate has a significant effeet on controlling seizures in newly diagnosed epilepsy patients, even when used as a stand-alone therapy.
See "New Study Shows TOPAMAX6 Used Alone Helps Many Newly-Diagnosed Epilepsy Patients Achieve Seizure Control.".

Currently, topiramate is approved around the world as adjunctive (add-on) treatment for a variety of seizure types. In addition, more than 30 countries also have approved its use as stand-alone (monotrierapy) treatment for epilepsy. In the United States, an application for this Lise was filed ~Trith the Food and Drug Administration in October 2002. If approved, topiramate will be the first AED indicated for initial monotherapy treatment for both partial and generalized tonic-clonic seizures in children and adults. Id.

[00014] T'opirama.tc seems to be effective in some people ;t,Tith bipolar mood' disorders that have not responded to Iitl~.um and/or other mood-stabili ers.
Sonie people r,,ho have not been able to tolerate any antidep_ressant because of svvitches to ma.nia or increased speed or intensity of cycling, or because of the development of mixed states, have been able to tolerate therapeutic doses of anti-depressants when tgdng topiramate.
The weight loss that accompanies topiramate therapy in some instances is useful for those individuals who have gained weight while taking other mood stabilizing drugs.
Tn some studies 20-50% of people taking topiramate lost weight.
[00015] Topiramate is also used for indications other than epilepsy. Among the most common uses of topiramate is the prevention of migraines. Less commonly than some of the other AEDs, topiramate is used for neuropathic pain relief. In some groups of patients, diabetics for example, the potential of weight loss is desirable and may therefore be a major reason for trying this medication for the treatment of diabetic neuropathic pain.
Topiramate has also been shown in open label trials to be useful for treating essential type tremor. In addition, topiramate has been shown in multiple small trials to be effective in cluster headache. Finally, topiramate is also used by psychiatrists. A recent article in Lancet demonstrated a substantial benefit for using this medication to help alcoholics to quit drinking. See Johnson et al., "Oral topiramate for treatment of alcohol dependence:
a randomized controlled trial," Lancet, 361(9370):1666-7 (May 17, 2003).

[00016] Topiramate is commercially available as TOPAMAX (Ortho-McNeil Pharmaceutical, Raritan, NJ). TOPAMAX is available in tablet of various sizes as well as a sprinkle form which can be used in those who cannot swallow. It is typically dosed twice daily. TOPAMA.X (topiramate) is available as 25 mg, 100 mg, and 200 mg round tablets for oral administration. The tablets contain the following inactive ingredients:
lactose monohydrate, pregelatinized starch, microcrystalline cellulose, sodium starch glycolate, mapesium stearate, purified water, carnauba wax, h}Fdrox-vpropy l methylcellulose, titanium dioxide, polyethylene glycol, synthetic iron oxide (100 and 200 mg tablets), and polysorbate 80. Physiciaras' Desk Refereiace, 57`fi Edition, pp. 2501 (2003)..
[00017] TOPAI,LtA-'~' is indicated in the United States as adjt,nctive therapy for adults and children aged 2-1it-) vvi.th partial-onset seizure:, primary genera.lized tonic-cl_oiZc seizures, and in patients 2 years of age and older ~vith sekiL?res associated with Lenno-X-Gastaut syndrome.

[00018] P'eak- plasma concentrations of TOFA.IVI-,`~"occur at approxiniately 2 hours following a 400 mg oral dose. The relative bioavailabilit-;r of TOPAAIAX
from the tablet formulation is about 80% compared to a solution. The bioavailability of TOPANIAX is not affected by food. Fhysiciaris' Desk Refer=ertce at 2502.

[00019] The pharmacokinetics of TOPAMAX are linear with dose proportional increases in plasma concentration over the dose range studied (200 to 800 mg/day): The mean plasma elimination half-life is 21 hours after single or multiple doses.
Steady state is reached in about 4 days in patients with normal renal function. Id.
[00020] TOPAMAX is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Overall, oral plasma clearance is approximately 20 to 30 mL/min in humans following oral administration. Id.

[00021]. The recommended total daily dose of TOPAMA.X as adjunctive therapy is 400 mg/day in two divided doses. In studies of adults with partial onset seizures, a daily dose of 200 mg/day has inconsistent effects and is less effective than 400 mg/day. It is recommended that therapy be initiated at 25-50 mg/day followed by titration to an effective dose in increments of 25-50 mg/week. Id.
[00022] In clinical trials of TOPAMAX used as adjunctive therapy for partial-onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome, the most common side effects observed in children included excessive dro-~vsiness, loss of appetite, fatigue, nervousness, difficulty with concennstion/attention, vfeight loss, ag,-ressive reaction and memory difficulties. In adults, the most common side effects were sleepiness, dizziness, poor coordination, speech difficulties, slowed thinking (psychomotor sloviiny), blurred or double vision, memory difficulties and changes in sensation. However, these effects were generally temporary. Fdtysiciat2s' Dcsk IiGi`Lren.ce at 2502-03.
[00023] TOF~1.~~ITA)a"''lacks many of the more serious side effPcts seen with the older ~~Ds including a lack of knovrn problcnzs with bone maxrovr and an er tremely small incidence tif liver abnormalitiEs apparently confined to patients -avith prior liver abnonnalities. The drug does have a fairly comm.on side effect of kidney stones (between 1-2%). It is also one of only two AEDs that have a statistically proven propensity to lose weight (Felbamate is the other). . Other side effects include a change in taste, particularly with carbonated drinks, tingling in the eXtremities, and at times interference with mental function. 'The last side effect is highly dependent upon the rate of dose administration and is relatively uncommon among patients started at a low dose and advanced slowly.
Dosing rates must be individualized based upon the patient and the other medications they are currently prescribed.:
[00024] The following adverse events are related to topiramate in 5% or more of patients: ataxia, impaired concentration, confusion, dizziness, fatigue, paraesthesia, somnolence and abnormal thinking. Topiramate may also cause agitation and emotional lability (which may manifest as abnormal behavior) and depression. Less common adverse effects include amnesia, anorexia, aphasia, diplopia, nausea, nystagmus, speech disorder, alteration of the sense of taste, abnomial vision, and weight loss.
Topiramate increases the risk of nephrolithiasis (formation of kidney stones).

[00025] There is a need in the art for topiramate fomlulations which can decrease frequency of dosing, improve clinical efficacy, and potentially reduce side effects. The present invention satisfies these needs.

SUMMARY OF THE INV"NTION

[00026] The present invention relates to nanoparticulate compositions comprising topiramate. The compositions comprise topiramate and at least one surface stabilizer preferably a.dsorbed on or associated with the surface of thc: topiramate particles. The nanoparticulate topiramate particles have an effective average particle size of less than about 2 microns.
[00027] Another aspect of the invention is directed to pharmaceutical compositions comprising a nanoparticulate topiramate composition of the invention. The phs.nnaceutical compositions preferably comprise topiramate, at least one surface stabilizer, and at least one l:~harrn.a~~eutic~all,r acceptable carrier, as ~.~,rel1 as, a.i1 -e desir~~~d e<_cipients.

[00028] The present invention is also directed to topiramate compositions vfith improved pharmacokinetic profiles over traditional forms of topiramate. In particular, the nanoparticulate topiramate formulations of the invention may produce the same therapeutic effect with lo-wer and/or fewer doses. Such lower doses are preferred as they may decrease or eliminate adverse effects of the drug. Tn addition, such lower doses decrease the cost of the dosage form and may increase patient compliance.

[00029], In yet another embodiment,. the invention is directed to bioadhesive nanoparticulate topiramate formulations. Such compositions, when orally administered, adhere to the gut increasing the time for absorption, and thereby increasing the effectiveness of the dosage form.
[00030] Other advantages of the nanoparticulate topiramate compositions of the invention are described herein.
[00031] The invention further discloses a method of making a nanoparticulate topiramate composition. Such a method comprises contacting topiramate and at least one surface stabilizer for a time and under conditions sufficient to provide a nanoparticulate topiramate compositien., The one or more surface stabilizers can be contacted with topiramate either before, preferably during, or after size reduction of the topiramate.

[00032] The present invention is also directed to methods of treatment using the nanoparticulate topiramate compositions of the invention for conditions such as, but not limited to, seizures, mood disorders, post traumatic stress syndrome (PTSD), Bipolar Disorder, mania (all forms, such as acute mania, severe treatment-refractory mania, bipolar mania, etc.), depression, personality disorders, bipolar mood instability, schiwophrenia, f+sychosis, bipolar spectrum disorders, rapid-cycling bipolar d-isorders, etc.
The nanoparticulate topiramate compositions of the invention are also useful for treating patients with mood disorders or bipolar mood disorders that have not been adequately controlled by otller medications, such as lithium, lamotrigine, gabapentin, and/or other mood-stabilizers.
[00033] In other embodinients of the invention, the nanoparticulate topiramate compositions are useful in treating or preventing, for e,_ample, inigraines, neuropathic pain relief, essential type tremor, cluster headache, and addictive behaviors, stich as alcoholism, nicotine addiction, drug addiction, and food addiction.

[00034] Finally, the nanoparticulate topiramate compositions of the invention are useful for achieving weight loss, particularly when diet and exercise fail to result in a patient's ideal body weight.

[00Q35] Both the foregoing general doscription and the following brief description of the drawings and detailed descr iption are exemplary and explanatory and are intended to provide further explanation of the invention as claimed. Other objects,. .
advantages, and novel features will be readily apparent to those skilled in the art from the following detailed description of the invention.

BRIEF DESCRIPTION OF THE FIGURES
[00036] FIGLTRE 1: Graphically shows the average concentration (ng/mL) of topiramate following oral administration to four male dogs of a nanoparticulate topiramate dispersion as compared to a conventional composition of topiramate, TOPAMAXS, over a 25 hour time period; and [00037] FIGLTRE 2: Graphically shows the average concentration (ng/mL) of topiramate following oral administration to four male dogs of a nanoparticulate topiramate dispersion as compared to a conventional composition of topiramate, TOPAMA.X , over a 1 hour time period.

DETAILED DESCRIPTION OF THE INVENTION
[0003S] The present invention is directed to nanoparticulate compositions coinprising topiramate. The compositions comprise topiramate 2nd at least nne surface stabilizer that is preferably adsorbed on or associated with the surface of the drug. The nanoparticulate topiramate particles have an effective average particle size of less than about 2 microns.

[00039] As taught in the '654 patent, not every combination of surface stabilizer and active agent will resz,lt in a stable nranoparticuls,te composition. _Tt v~ss surpricingly discovered that stable nanoparticulate topiramate forrnulations can be made.

[00040] The current fomlulations of topiramate suffer from the following problems: (1) the poor solubility of the drug results in a relatively low bioa:b ailabilitj ;
(2) dosing must be repeated several times. each day; and (3) a wide variety of side effects are associated with the current dosage forms of the drug.

[00041] The present invention overcomes problems encountered with the prior art topiramate formulations. Specifically, the nanoparticulate topiramate formulations of the invention may offer the following advantages: (1) faster onset of action; (2) a potential decrease in the frequency of dosing; (3) smaller doses of topiramate required to obtain the same pharmacological effect as compared to conventional microcrystalline forms of topiramate; (4) low viscosity liquid nanoparticulate topiramate dosage forms can be made;
(5) for liquid nanoparticulate topiramate compositions having a low viscosity -better subject compliance due to the perception of a lighter formulation which is easier to consume and digest; (6) for liquid nanoparticulate topiramate compositions having a low viscosity - ease of dispensing because one can use a cup or a syringe; (7) increased bioavailability; (8) substantially similar pharmacokinetic profiles of the nanoparticulate topiramate compositions when administered in the fed versus the fasted state;

(9) bioequivalency of the nanoparticulate topiramate compositions when administered in the fed versus the fasted state; (10) the nanoparticulate topiramate compositions may have improved pharmacokinetic profiles as compared to traditional forms of topiramate, such as improved Tn,a,, Cma,,, and AUC profiles; (11) the topiramate composition can be formulated in a dried form which readily redisperses; (12) excellent redispersibility of the nanoparticulate topiramate particles present in the compositions of the invention follo~,ving administration; (13) the nanoparticulate topiramate compositions preferably exhibit an increased rate of dissolution as compared to conventional microcrystalline forms of topirarnate; (14) a bioadhesive topiramate formul,ation can coat the gut, or the desired site of application, and be retained for a period of time, thereby increasing the efficacy of the drug as well as eliminating or decreasing the frequency of dosing; (15) the nanoparticulate topzramate compositions can be used in conjunction other active agents; (161) the nanoparticulate topiramate coinposit.ioiis can be steril_e filtered; (17) the nanoparticulate topiramate compositions may erhibit improved performance characteristics for oral, intravenous, subcutaneous, or intramuscular injection, such as higher dose loading and smaller tablet or liquid dose volumes; (18) the nanoparticulate topiramate com.positions, are suitable for parenteral administration; and (19) the nanoparticulate topiramate compositions do not require organic solvents or pH
extremes.

[00042] ' The present invention is described herein using, several definitions, as sdt forth below and throughout the application.

[00043] As used herein, "about" will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used..
If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, "about" will mean up to plus or minus 10% of the particular term.

[00044] "Pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[00045] "Pharmaceutically acceptable salts" as used herein refers to derivatives wherein the parent compound is modified by making acid or base salts thereof.
Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quatemary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such cenventional non-ta:-dc salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearir., lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, niethanesulfonic9 ethane distilfonic, oxalic, isethionic, and the like.

[00046] As used herein v,t ith reference to stable drvg particles, "stable"
includes, but is not limited to, one or more of the follo~nring parameters: (1) that the topiramate particles do not appreciably flocculate or agglomerate due to interparticle attractive forces, or otherwise significantly increase in particle size over time; (2) that the physical structure of the topiramate, particles is not altered over time, such as by comrersion from an amorphous phase to crystalline phase; (3) that the topiramate particles are chemically stable; and/or (4) where the topiramate has not been subject to a heating step at or above the melting point of the topiramate in the preparation of the nanoparticles of the invention.

[00047]. "Conventional active'agents or drugs" refers to non-nanoparticulate compositions of active agents or solubilized active agents or drugs. Non-nanoparticulate active agents have an effective average particle size of greater than about 2 microns, meaning that at least 50% of the active agent particles have a size greater than about 2 microns. (Nanoparticulate active agents as defined herein have an effective average particle size of less than about 2 microns.) [00048] "Therapeutically effective amount" as used herein with respect to a drug dosage, shall mean that dosage that provides the specific pharmacological response for which the drug is administered in a significant number of subjects in need of such treatment. It is emphasized that `therapeutically effective amount,' administered to a particular subject in a particular instance will not always be effective in treating the diseases described herein, even though such dosage is deemed a "therapeutically effective amount" by those skilled in the art. It is to be fiirther understood that drug dosages are, in particular instances, measured as oral dosages, or with reference to drug levels as measured in blood.

A. Preferred Characteristics of the Nanoparticulate Topiramate Compositions of the Invention 1. F,,ust On set ol' ~ ct'.i:V;At,' [00049] The use of conventional formulations of topiramate is not ideal due to delayed onset of action. In contrast, the nanoparticulate topirarnate compositions of the invention exhibit faster therapeutic effects.
[00050] Topiramate is commercially available as TOPAM-A-X-O (Ortho-McNeil Pha.rmaceuticaI, Raritan, N.T). TOPAMAX`- R) (topiramate) is available as 25 mg, 100 mg, and 200 mg round tablets for oral administration. See Physicians 'Desk Refei=eF1ce, 5 7t"
Edition, pp. 2501 (2003). Peak plasma concentrations of TOPAMA.XL occur at approximately 2 hours following a 400 mg oral dose. See Physiczans' DeskReferen.ce at 2502.
[00051] When the nanoparticulate topiramate compositions of the invention are formulated into an oral dosage form (e.g., the dosage form of TOPAMAX ), peak plasma concentration of the nanoparticulate topiranlate can be obtained in less than about 2 hours (Tma,). In other embodiments of the invention, peak plasma concentration of the nanoparticulate topiramate can be obtained in less than about 110 min., less than about 100 min., less than about 90 min., less than about 80 min. less than about 70 min., less than about 60 min., less than about 50 min., less than about 40 min., less than about 30 min., less than about 25 min., less than about 20 min., less than about 15 min., less than about 10 min., less than about 5 min., or less than about 3 min.

2. Frequency of Dosing and Dosage Quantity [00052] The recommended total daily dose of TOPAIVIAX's as adjunctive therapy is 400 mg/day in two divided doses. In studies of adults with partial onset seizures, a daily dose of 200 mg/day has inconsistent effects and is less effective than 400 mg/day. See PhYsicians' Deslc Reference, 57 th Edition, pp. 2502 (2003).
[00053] Dosages of topiramate for treating conditions other than epilepsy tend to be less.

[00054] In contrast, the topiramate compositions of the invention may be administered less frequently and at lower doses in dosage forms such as liquid dispersions, povvders, sprays, solid re-dispersable dosage forms, ointm:nts, creams, etc.
Exemplary types of formulations us,eful in the faresent invention incl-_,de,but are not limited to, liquid dispersions, gvls, aerosols (pulmonar-y and nasal), ointments, creams, solid dose forms, etc. of nanoparticulate topiramate. Lower dosages can be used because the small particle size of the topiramate particles ensure greater absorption, and in the case of bioadhesive nanoparticulate, topiramate compositions, the topirarilate is retained at the desired site of application for a longer period of time as compared to conventional topiramate dosage forrns.

[00055] In one embodiment of the invention, the therapeutically effective amount of the nanoparticulate topiramate compositions is 1/6, 1/5, '/4, 1/3d, or'/2 of the tlierapeutically effective amount of a conventional non-nanoparticulate topiramate composition.

3. Low Viscosity [00056] A liquid dosage form of a conventional microcrystalline or non-nanoparticulate topiramate composition would be expected to be a relatively large volume, highly viscous substance which would not be well accepted by patient populations. Moreover, viscous solutions can be problematic in parenteral administration because these solutions require a slow syringe push and can stick to tubing.
In addition, conventional formulations of poorly water-soluble active agents, such as topiramate, tend to be unsafe for intravenous administration techniques, which are used primarily in conjunction with highly water-soluble substances.

[00057] Liquid dosage forms of the nanoparticulate topiramate compositions of the invention provide significant advantages over a liquid dosage form of a conventional topiramate microcrystalline compound. The low viscosity and silky texture of liquid dosage forms, of the nanoparticu!late topiramate compositions of the invention result in advantages in both preparation and use. These advantages include, for example:
(1) better subject compliance due to the perception of a lighter forrrmula.tion which is easier to consume and digest; (2) ease of dispensing because one can use a cup or a syringe;

(3) potential for formulating a higher concentration of topiramate resulting in a smaller dosage volume and thus less volume for the subject to consume; and (4) easier overall form2ila.tion ctncean>a.

[0005 S] Liquid topiramate dosage forms which are easier to consume are especially important when considering juvenile patients, terminally ill patients, and elderly patients. Viscous or gritty formulations, and those that require a relatively large dosage volume, are not well tolerated by these patient populations. Liquid oral dosage forms can be particularly preferably for patient populations who have difficulty consuming tablets, such as infants and the elderly.

[00059] The viscosities of liquid dosage forms of nanoparticulate topiramate according to the invention are preferably less than about 1/200, less than about 1/175, less than about 1/150, lessthan about 1/125, less than about 1/100, less than about 1/75, less than about 1/50, or less than about 1/25 of a liquid oral dosage form of a conventional, non-nanoparticulate topiramate composition, at about the same concentration per ml of topiramate.

[00060] Typically the viscosity of liquid nanoparticulate topiramate dosage forms of the invention, at a shear rate of 0.1 (1/s), is from about 2000 mPa s to about 1 mPa s, from about 1900 mPa-s to about 1 mPa-s, from about 1800 mPa-s to about 1 mPa=s, from about 1700 mPa-s to about 1 mPa-s, from about 1600 mPa-s to about 1 mPa-s, from about 1500 mPa-s to about 1 mPa-s, from about 1400 mPa-s to about 1 mFa-s, from about 1300 mPa-s to about 1 mPa-s, from about 1200 mPa-s to about 1 mPa-s, from about 1100 mPa-s to about 1 mPa-s, from about 1000 mPa-s to about 1 mPa-s, from about 900 mPa-s to about 1 mPa-s, from about 800 mPa-s to about 1 mPa=s, from about 700 mPa-s to about 1 mPa-s, from about 600 mPa-s to about 1 mPa-s, from about 500 mPa-s to about 1 mPa-s, from about 400 mPa-s to about 1 mFa-s, from about 300 mPa-s to about 1 mPa-s, from about 200 mPa-s to about 1 mFa-s, from about 175 mPa-s to about 1 mFa=s, from about 150 mPa-s to about 1 mFa-.--,, from about 125 mPa-s to about 1 rrLPa-v, from about 100 mPa-s to about 1 mFa=s, from about 75 mFa-s to about 1 mFa-s, from about 50 mpa-s to about 1 rrPa-s, rorn about 25 rnPa-s to about 1 mF'a-s, from about 15 mPa-s to about 1 mPa-s, from about 10 mPa-s to about.1 mPa-s, or from about 5 nTa-s to about I
mPa-s.
Such a viscosity is much more attractive for subject consuniption and may lead to better overall subject compliance.

[00061] Viscosity is concentration and temperature dependent. Typically, a higher concentration results in a higher Y isc~,sit5, e.vhile a higher temperature results in a lower viscosity. Viscosity as defined above refers to measurements taken at about 20 C.
(The viscosity of vrater at 20"C is I mPa s.) The invention encompasses equivalent viscosities measured at different temperstures, [00062] Another important aspect of the invention is that the nanoparticulate topiramate compositions of the invention are not turbid. "Turbid," as used herein refers to the property of particulate matter that can be seen with the naked eye or that which can be felt as `.`gritty." The nanoparticulate topiramate compositions of the invention can be poured out of or extracted from a container as easily as water, whereas a liquid dosage form of a non-nanoparticulate or solubilized topiramate is expected to exhibit notably more "sluggish" characteristics.

[00063] The liquid formulations of this invention can be fozmulated for dosages in any volume but preferably equivalent or smaller volumes than a liquid dosage form of a conventional non-nanoparticulate topiramate composition.

4. Increased Bioavailability [00064] The nanoparticulate topiramate compositions of the invention may preferably exhibit increased bioavailability and require smaller doses as compared to prior conventional topiramate compositions administered at the same dose.

[00065] Any drug, including topiramate, can have adverse side effects. Thus, lower doses of topiramate which can achieve the same or better therapeutic effects as those observed with larger doses of conventional topiramate compositions are desired.
Such losver doses may be realized with the nanoparticulate topiramate compositions of the invention becaa,ise the nanoparticulate topiramate compositions may elthibit greater bioavailability as compared to conventional non-nanoparticulate topiramate formulations, 1~

which means that smaller dose of topiramate are likely required to obtain the desired therapeutic effect.
[00066] Thr relative bioa.vailabilit-y of TOP~:.T~QLXL from the tablet formulation z: about 80%compa.red tcR a. solution. Sce F"11_ysicaaia.s' DoslcRFJct=erZce.
at -2501-1 [00067] When the nanop articula.te topiramate compositions of the invention are formulated into an oral dosage forrn the dosage form of TOPAl\/1A.X(7), the relative bioavaila.bility of the nanoparticulate topiramate composition compared to a solution is preferably greater than about 80%. In other embodiments of the invention, the relative bioavailability of the nanoparticulate topiramate composition as compared to a solution can preferably be greater than about 85%, greater than about 90%, or greater than about 95%:

5. The Pharmacokinetic Profiles, of the Nanoparticulate Topiramate Compositions of the Invention are Preferably not Substantially Affected by the Fed or Fasted State of the Subject Ingesting the Compositions [00068] The invention encompasses nanoparticulate topiramate compositions wherein preferably the pharmacol:inetic profile of the topiramate is not substantially affected by the fed or fasted state of a subject ingesting the composition.
This means that there is no substantial difference in the quantity of topiramate absorbed or the rate of topiramate absorption when the nanoparticulate topiramate compositions are administered in the fed versus the fasted state. Thus, the nanoparticulate topiramate compositions of the invention substantially eliminate the effect of food on the pharmacokinetics of topiranlate.
[00069] The difference in absorption of the nanoparticulate topiramate composition of the invention, when administered in the fed versus the fasted state, is preferably less than about 100 '0, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than a.bout 35%, less than about 30%, less than about 25%, less than about 20%, less, than about 15%, less than about 10%, less than about 5%, or less than about 3%.
This is an especially importa.nt feature in tTeating patients with difficulty in maintaining a fed state.

[00070] In addition, preferably the difference in the rate of absorption (i.e., Tmax) of the nanoparticulate topirama.te compositions of the invention, when administered in the fed versus the fasted state, is less than about 100%, less than about 90%, less than about 801'/'0*, less than about 70%, less than about 60Q1~, less thai1 about 50%, less than about 40%, less than aboi.it 30110, less than about 20%, less than about 15 %0, less than about 10%, less than about 5%, less than about 3 %, or essentially no difference.

[00071] Benefits of a dosage form which substantially eliminates the effcct of food include an increase i:n subject convenience, thereby increasing subject compliance, as the subject does not need to ensure that they are taking a dose either with or without food. 6. Redispersibility Profiles of the Nanoparticulate Topiramate Compositions of the Invention [00072] An additional feature of the nanoparticulate topiranlate compositions of the invention is that the compositions redisperse such that the effective average particle size of the redispersed topiramate particles is less than about 2 microns.
This is significant, as if upon administration the nanoparticulate topiramate particles present in the compositions of the invention did not redisperse to a substantially nanoparticulate particle size, then the dosage form may lose the benefits afforded by formulating topiramate into a nanoparticulate particle size.

[00073] This is because nanoparticulate topiramate compositions benefit from the small particle size of topiramate; if the nanoparticulate topiramate particles do not redisperse into the small particle sizes upon administration, then "clumps" or agglomerated topiramate particles are formed. With the formation of such agglomerated particles, the bioavailability of the dosage form may fall.

[00074] Moreover, the nanoparticulate topiramate compositions of the invention e:dhibit dramatic redispersion of the nanoparticulate topiramate particles upon administration to a mammal, such as a hLUnan or animal, as demanstrated by reconstitution in a biorele,,-ant aqueous media. Such biorelevant aqtieous media can be any aqueous media that e~_hibit the desired ionic strength and pH, ti=,jhich form the basis for the biorelevance of the media. The desired pH and ionic strength are thosP
that are representative of physiological conditions found in the human body. Such biorelevant aqueous media can be, for example, aqueous electrolyte solutions or aqueous solutions of any salt, acid, or base, or a combination thereof, which exhibit the desired pH and ionic strength.
[00075] Eiorele:EVant pH i: well knovm i2 the art. For e.~an7ple, in the stomach, the pH ran;es from slightly less than -2 (but t-;Tically greater than 1) up to 4 or 5, In the small intestine the pH can range from 4 to 6, and in the colon it can range from 6 to S.
Biorelevant ionic strength is also well 1modFm in the art. Fasted state gastric fluid has an ionic strength of about 0.1M while fasted state intestinal fluid has an ionic strength of about 0.14. See e.1u., Lindahl et al., "Characterization of Fluids from the Stomach and Proximal J.ejunum in Men and d'oTomen," PIrczrna. Fces., 14 (4): 497-502 (1997).

[00076] It is believed that the pH and ionic strength of the test solution is more critical thaiz the specific chemical content: Accordingly,.appropriate pH and ionic strength values can be obtained through numerous combinations of~strong acids, strong bases, salts, single or multiple conjugate acid-base pairs (i.e., weak acids and corresponding salts of that acid), monoprotic and polyprotic electrolytes, etc.

[00077] Representative electrolyte solutions can be, but are not limited to, HCl solutions, ranging in concentration from about 0.001 to about 0.1 M, and NaCl solutions, ranging in concentration from about 0.001 to about 0.1 M, and mixtures thereof. For example, electrolyte solutions can be, but are not limited to, about 0.1 M HCl or less, about 0.01 M HCl or less, about 0.00 1 M HCl or less, about 0.1 M NaCl or less, about 0.01 M NaCl or less, about 0.001 M NaCl or less, and mixtures thereof. Of these electrolyte solutions, 0.01 M HCl and/or 0.1 M NaCI, are most representative of fasted human physiological conditions, owing to the pH and ionic strength conditions of the proximal gastrointestinal tract.
[00078] Electrolyte concentrations of 0.001 M HCI, 0.01 M HCI, and 0.1 M HCl correspond to pH 3, pH 2, and pH 1, respectively. Thus, a 0.01 M HCl solution simulates typical acidic conditions found in the stomach. A solution of 0.1 M NaCI
provides a reasonable approyimation of the ionic strength conditions found throug..out the body, including the gastrointestinal fluids, although concentrations higher than 0.1 NI may be employed to simulate fed conditions within the human GI tract.

[00079] Exemplary solutions of salts, acids, bases or combinations thereof, which exhibitthe desired pH and ionic strength, include but are not limited to phosphoric acid/phosphate salts + sodivzn, potassium and calcium salts of cl-doridF, acetic acid/acetate salts + sodium, potassiurn and calcium sa.lts of chlori~~le, carbonic acidlbicarbonate ~alts +
sodivm, potassium and ca.lci_tun salts of chloride, and citric acid/citrate salts + sodium, potassium and calcium salts of chloride.
[00080] In other embodiments of the invention, the redispersed topirarnate particles of the invention (redispersed in an aqueous, biorelevant, or any other suitable media) have an effective averaVe particle size of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than.about 800 nm;
less than about '700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm,. less than about 100 nm, less than about 75 nm, or less than about 50 nm, as measured by light-scattering methods, microscopy, or other appropriate methods.

[00081] By "an effective average particle size of less than about 2000 nm" it is meant that at least 50% of the topiramate particles have a particle size of less than the effective average, by weight, i.e., less than about 2000 nm, 1900 nm, 1800 nm, etc., when measured by the above-noted techniques. Preferably, at least about 70%, about 90%, about 95%, or about 99% of the topiramate particles have a particle size of less than the effective average, i.e., less than about 2000 nm, 1900 nm, 1800 nm, 1700 nm, etc.

[00082] Redispersibility can be tested using any suitable means known in the art.
See e.g., the example sections of U.S. Patent No. 6,375,986 for "Solid Dose Nanoparticulate Compositions Comprising a Synergistic Combination of a Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate."

7. Elomlhe'; a-ve 1 Tinola,-trtlciil-ite Top1r~,)mate Con2pocltaons [0010] Bioadhesive nanoparticulate topiramate compositions of the invention comprise at least one cationic surface stabilizer, which ar: described in more detail below.

Bioadhesive formulations of topiramate exhibit exceptional bioadhesion to biological surfaces, such as mucous.

[0011 ] In the case of bioadhesi e nanoparticulate topiramate compositions, the tcnn "bioadhesic,n'" is us_rl tc- describe the adhe"lon bEt,;veen th~
nanoparticulate topirarnate compositions and a biological s=ubstrate I i. c.
ga~=tr.ointestinal mucin, lung tissue,. nasal mucosa, cic.). LCee e.g., U.S. Patent No. 6,428,S14 for "Bioadhesive Nanoparticulate Compositions Having Cationic Surface Stabilizers ".

[00122] The bioadhesive topiramate compositions of the invention are useful in any situation in ivhich it is desirable to -apply the compositions to. a biological surface. The bioadhesive topiramate compositions preferably coat the targeted surface in a continuous and uniform film which is invisible to the naked human eye.

[0013] A bioadhesive nanoparticulate topiraniate composition slows the transit of the composition, and some topiramate particles would also most likely adhere to tissue other than the= mucous cells and therefore give a prolonged exposure to topiramate, thereby increasing absorption and the bioavailability of the administered dosage.

8. Pharmacokinetic Profiles of the Nanoparticnlate Topiramate Compositions of the Invention [0014] The present invention also provides compositions of nanoparticulate topiramate having a desirable pharmacokinetic profile when administered to mammalian subject. The nanoparticulate topiramate compositions of the invention preferably have a more preferred pharmacokinetic profile as compared to conventional currently marketed forms of topiramate, e.g., TOPAMAII .
[0015] The desirable pharmacokinetic profile, as used herein, is the pharmacokinetic profile measured after the initial dose of topirama.te. The compositions can be formulated in any way as described below.

[001 E] ;:.n improved or more prEferrrd ph.a.?macol:inetic profile according to the invc:ntion can have several different t},pes of attributes. For example, the improved pK
profile of the nanopartic'ulatE topLramatF compositions of the invFnt.ion may produce tho same pK profile as a conventional topiramate formulation (i.e., TOPAIvIAX(&), but at a lower dose. Such an improved pK profile may also correspond to a topiramate composition which requires less frequent dosing as compared to a conventional topiramate formulation, such as once a day dosing. An improved pK profile may show faster onset of activity and/or greater quantitti" of drug aba~.~rbed. (i. E., greater bioavailability). The improved pK profile of the nanoparticulate topiramate compositions of the invention may permit more effective or faster titration of the patient to therapeutic doses, etc. Combinations of these examples of improved pK profiles may also be efllibited by the nanoparticulate topiramate compositions of the invention.
[0017] An improved or more preferred pharmacol:inetic profile according to the invention may also exhibit improved Tmax, Cma,;, and/or AUC profiles.

[0018] In one embodiment of the invention, preferably, the Tma,, of an administered dose of a nanop articulate. topiramate composition is less than that of a conventional non-nanoparticulate topiramate composition, administered at the same dosage. In another embodiment of the invention, preferably the Cmax of a nanoparticulate topiramate composition is greater than the C,,,a, of a conventional non-nanoparticulate topiramate composition, administered at the same dosage. Finally, in yet another embodiment of the invnetion, preferably the AUC of a nanoparticulate topiramate composition is greater than the AUC of a conventional non-nanoparticulate topiramate composition, administered at the same dosage.

[0019] A preferred nanoparticulate topiramate composition of the invention may exhibit, in comparative pharmacokinetic testing with a conventional non-nainoparticulate formulation of topiramate, such as TOPAMAX9, a T,r,, which is less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, or less than about 10% of the Tn,3, exhibited by the conventional non-nanoparticulate formulation of topiramate.

[0020] A preferred nanoparticulate topiramate composition of the invention may e, hibit, in comparative pharmacolR:inetic testing with a conventional non-nanoparticulate formulation of topiramate, such as TOPAMA:.~'(i:?, a C,na, which is greater than about 5%, greater than about 109'0, greater than about 15%, greater than about. 20%, greater than about 30%, greater than about 40%, greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, greater than about 90%, gr'eater than about 100%, greater than about 110%, greater than about 120%, `reater than about 130%, greater than about 140`io, or greater than about 1_50"'ia than the Cm,,_ e_tihibitei by the conventional non-nanoparticula.te formulation of topi-ramate, [0021] A preferred nanoparticulate topiramate composition of the invention may exhibit, in comparative pharmacolcinetic testing with a conventional non-nanoparticzilate formulation of topiramate, such as TQPA.N4A--K , an AUC which is greater than about 5greater than about 10%, greater than about 150,'0, greater than about 20%, greater than about 30%, greater than about 40%, greater than about 50%, greater than about'60 '0, greater than about 70%, greater than about 80%, greater than about 90%, greater than about 100%, greater than about 110%, greater than about 120%, greater than about 130%, greater than about 140%, or greater than about 150% than the AUC exhibited by the conventional non-nanoparticulate formulation of topiramate.

[0022], Any formulation giving the desired pharmacokinetic profile is suitable for administration according to the present methods. Exemplary types of formulations giving such profiles are liquid dispersions and solid dose forms of nanoparticulate topiramate. If the liquid dispersion media is one in which the nanoparticulate topiramate has very low solubility, the nanopartioulate topiramate particles are present as suspended particles. The smaller the topiramate particles, the higher the probability that the formulation will exhibit the desired pharmacokinetic profile.

9. Combination Pharmacokinetic Prof.rle Compositions [0023] In yet another embodiment of the invention, a first nanoparticulate topiramate composition providing a desired pharmacokinetic profile is co-administered, sequentially administered, or combined with at least one other topiramate composition that generates a desired different pharmacokinetic prnfile. Aelore than trvo topiramate compositions can be co-administered, sequentially adrnuv.stered, or combined.
jArhile the first topiramate composition has a nanoparticulate particle size, the additional one or more topiramate compositions can be nanoparticulate, solubilized, or have a conventional microparticulate particle size.
[0024] For er ample, a first topiramate compositi_on cm have a nanor~articulate particle size, conferring a short T,,,,, and typically a hsgher Cm..,.. Thi:;
first topirarilate composition can be combined, co-a.~ininistered,or sequentiallyr administercd with a second composition comprising: (1) topiramate having a larger (but still nanoparticulate as defined herein) particle size, and therefore e1liibiting slower absorption, a longer T,,,ax., and typicall}J a lower C,,,a,; or (2) a m.icroparticulate or solubilized topiramate composition, exhibiting a longer Tn,a;v, and typically a lower Cmax.
[0025] The second, third, fourth, etc .; topiramate conzpositions can differ from the first, and from each other, for example: (1) in the effective average particle sizes of topiramate; or (2) in the dosage of topiramate. Such a combination composition can reduce the dose frequency required.
[0026] If the second topiramate composition has a nanoparticulate particle size, then preferably the topiramate particles of the second composition have at least one surface stabilizer associated with the surface of the drug particles. The one or more surface stabilizers can be the same as or different from the surface stabilizer(s) present in the first topiramate composition.
[0027] Preferably where co-administration of a "fast-acting" formulation and a "longer-lasting" formulation is desired, the two formulations are combined within a single composition, for example a dual-release composition.

10. Combination Active Agent Compositions [0028] The invention encompasses the nanoparticulate topiramate compositions of the invention formulated or co-administered with one or more non-topiramate active agents, which are either conventional (solubilized or microparticulate) or nanoparticulate.
Methods of using such combination compositions are also encompassed by the invention.
The non-topiramate active agents can be present in a cr-ystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, or a mixture thereof.

[0029] The compound to be administered in combination with a nanoparticulate topiramate composition of the invention can be formulated separately from the nanoparticulate topiramate composition or co-formulated with the nanoparticula.te topiramate composition. VJhere a na.nopa_rLic=ulate topiramate c .oznpc,sition is co-formulated dvith a second active agent, the second acti-,=e agent can be formula.ted in any suitable manner, such as immediate-release, rapid-onset, sustained-release, or dual-release form.
[0030] If the non-topirainate active agent has a nanoparticulate particle size i.e., a particle size of less than about 2 microns, then preferably it v ill have one or more surface stabilizers associated with the surface of the active agent. In addition, if the active agent has a nanoparticulate particle size, then it is preferably poorly soluble and dispersible in at least one liquid dispersion media: By "poorly soluble" it is meant that the active agent has a solubility in a liquid dispersion media of less than about 30 mg/mL, less than about 20 mg/mL, less than about 10 mg/mL, or less than about I mg/rnL. Useful liquid dispersion medias include, but are not limited to, water, aqueous salt solutions, safflower oil, and solvents such as ethanol, t-butanol, hexane, and glycol.
[0031 ] Such non-topiramate active agents can be, for example, a therapeutic agent. A therapeutic agent can be a pharmaceutical agent, including biologics.
The active agent can be selected from a variety of lmown classes of drugs, including, for example, amino acids, proteins, peptides, nucleotides, anti-obesity drugs, central nervous system stimulants, carotenoids, corticosteroids, elastase inhibitors, anti-fungals, oncology therapies, anti-emetics, analgesics, cardiovascular agents, anti-inflammatory agents, such as NSAIDs and COX-2 inhibitors, anthelmintics, anti-arrhythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anadolytics, sedatives (hypnotics and neuroleptics), ast-ringents, alpha-adrenergic receptor blocking agents, beta-adrenoceptor blocking agents, blood prodlicts and substittites, cardiac inotropic agents, contrast media, corticosteroids, cough suppressants (expectorants and mucolytics), diapostic a.gents, diapostic imaging agrnts, diuretics, dopaminergics (antiparkinsonian agents), haemostatics, immunological agents, lipid regulating agents, muscle xelaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaccuticals, sF ~ L~~rrnones (including steraids), anti-a1lerQic acents, stimulants and a.noretics, s;mipathomirneti~~s., thyroid ag_nts,, vasodilators, and xanthines.

[0032]. A description of these classes of active agents and a listing of species within each class can be found in 1\4artindalF's Thc .E'xtra Plzk7rInacopc%Giw, 31s` Edition (The Pharmaceutical Press, London, 1 ?96), The active agents are commercially available and/or can be prepared by teclvziques known in the art.

[0033] Exemplary nutraceuticals and dietary supplements are disclosed, for example, in Roberts et al., Nittraceu.ticals: The Complete Encvclopedia of Si~pplements, Herbs, Vitainins, and Healirtg Foods (American Nutraceutical Association, 2001), which is specifically incorporated by reference. Dietary supplements and nutraceuticals are also disclosed in Physicians' Desk Reference for Nutritional Stspplements, 1st Ed.
(2001) and The Plzysicians ' Desk Ref erence for Herbal Medicines, 1 st Ed. (2001), both of which are also incorporated by reference. A nutraceutical or dietary supplement, also knoum as a phytochemical or functional food, is generally any one of a class of dietary supplements, vitamins, minerals, herbs, or healing foods that have medical or pharmaceutical effects on the body.

[0034] Exemplary nutraceuticals or dietary supplements include, but are not limited to, lutein, folic acid, fatty acids (e.g., DHA and ARA), fruit and veDetable extracts, vitamin and mineral supplements, phosphatidylserine, lipoic acid, melatonin, glucosamine/chondroitin, Aloe Vera, Guggul, glutamine, amino acids (e.g., arginine, iso-leucine, leucine, lysine, methionine, phenylanine, threonine, tryptophan, and valine), green tea, lycopene, whole foods, food additives, herbs, phytonutrients, antioxidants, flavonoid constituents of fruits, evening primrose oil, flax seeds, fish and marine animal oils, and probiotics. rTutraceuticals and diEtarl supplGnlents also include bio-en~ineered foods genetically engineered to have a desired property, also 1.-noivn as "pharmafnods."
11. Sterile Filtered Nanoparticulate Topiramate Compositions .[0035] The nanoparticulate topiramate compositions of the invention can be sterile filtered. This obviates the need for heat sterilization, evhich can harm. or degade topirarnate, as ivell as, result iii crystal gra~vth and particle aggre-,ation.

[0036] Sterile filtration can be difficult because of the required small particle size of the composition. Filtration is an effective method for sterilizing, homogeneous solutions when the membrane filter pore size is less than or equal to about 0.2 microns (200 nm) because a 0.2 micron filter is sufficient to remove essentially all bacteria.
Sterile filtration is normally not used to sterilize conventional suspensions of micron-sized topiran7ate because the topiramate particles are too large to pass through the membrane pores.

[0037] A sterile nanoparticulate topiramate dosage form is particularly useful in treating immunocompromised patients, infants or juvenile patients, and the elderly, as these patient groups are the most susceptible to infection caused by a non-sterile liquid dosaae form.

[0038] Because the nanoparticulate topiramate compositions of the invention can be sterile filtered, and because the compositions can have a very small topiramate effective average particle size, the compositions are suitable for parenteral administration.
12. Miscellaneous Benefits of the Nanoparticulate Topiramate Compositions of the Invention [0100] The nanoparticulate topiramate conipositions preferably exhibit an increased rate of dissolution as compared to conventional microcrystalline or non-nanoparticulate forms of topiramate. In addition, the nanoparticulate topiramate compositions preferably exhibit improved performance characteristics for oral, intravenous, subcutaneous, or intramuscular injection, such as higher dose loading and smaller tablet or liquid dose volumes. ~4oreover, the nanoparticulate topiramate compositions of the invention do not require organic solvents or pH extxemes.

B. Topiramate Compositions [Q101] The invention provides compositions comprising nanoparticulate topiramate particles and at least one surface stabilizer. The surface stabilizers are preferably associated vrith the curface of the topiraniate particles.
Surfae:~:~ stabili:,~ers useful herein do not chernic:a.ll,r reac=t ~Ath the topiramate particles or itsell: Preferabl;r, individual molecules of the surface stabilizer are essentially free of intermolecular cross-linkages. The compositions can comprise two or more surface stabilizers.

[0102] The present invention also includes nanoparticulate topirarnate compositions together with one or more non-toxic physiologically acceptable carriers, adjuvants, or vehicles;.collcctively referred to as carriers. The compositions can be formulated for parenteral injection (e.g., intravenous, intramuscular, or subcutaneous), oral administration (in solid, liquid, or aerosol (i. e.; pulmonary) form), vaginal, nasal, rectal, ocular, local (powders, creams, ointments or drops), buccal, intracistemal, intraperitoneal, topical administration, and the like.

1. Topiramate Particles [0103] As used in this invention, "topiramate" means the sulfamate-substituted monosaccharide designated chemically as 2,3:4,5-Di-O-isopropylidene-Q-D-fructopyranose sulfamate, having the molecular formula C12 H,1 NO&S, a molecular weight of 339.36, and the following structural formula:

0 `CH2OSO2NH2 O
H3C *CHS
O

Derivatives of topiramate are also encompassed by the term "topiramate."
[0104] Topiramate has a solubilit=,f in water of 9.8 mg/mL. It is most soluble in alka.line solutions conta.ining sodium hydro,--ide or sodium phosphate and having a pH of 9 to 10. Topiramate is freely soluble in acetone, chloroform, dimethylsulfoxide, and ethanol. See Physicians' Desk Reference, 57`h Edition, pp. 2501 (2003).
Topiramate is a evhite crystalline powder with a bitter taste.
[0105] The topiramate can be in a cr-istalline phase, an arnorphous phase, a semi-./stalline phase, a sern1-amorpl_lous phase, or a nzirtu_res thereo cr-[0106] Topiranla.te is an anticon~,rulsant intended for use as an antie-pileptic d.rug.
The drug is useful in treating conditions such as, but not limited to, seizures, mood disorders, post traumatic strvss syndrome (PTSD), Bipolar Disorder, mania (all forms, such as acute mania, severe treatment-refractcIry mania, bipolar mania, etc.), depression, personality disorders, bipolar mood instability, schizophrenia, psychosis, bipolar spectrum disorders, rapid-cycling, bipolar disorders, etc. The nanoparticulate topiramate compositions of the invention are also useful for treating patients with mood disorders that have not been.adequately controlled by other medications, such as lamotrigine and gabapentin, and for treating patients with bipolar mood disorders that have not responded to lithium and/or other mood-stabilizers.

2. Surface Stabilizers [0107] The choice of a surface stabilizer for topiramate is non-trivial and required extensive experimentation to realize a desirable formulation. Accordingly, the present invention is directed to the surprising discovery that topiramate nanoparticulate compositions can be made.

[0108] Combinations of more than one surface stabilizer can be used in the invention. Useful surface stabilizers which can be employed in the invention include, but are not limited to, known organic and inorganic pharmaceutical excipients.
Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants. Surface stabilizers include nonionic, cationic, zwitterionic, and ionic surfactants.

[0109] Representative examples of other useful surface stabilizers include hydro7~~propyl methy_cellulose, hydrohypropylcel_ulose, pol~otinylp=,2Tolidone, sodium lauryl sulfate, dioctylsulfosuccinate, gelatin, casein, lecithin (phosphatides), dextran, gum acacia, cholesterol, tTagacanth, stearic acid, benA,allconium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.,-., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbita.n fatty acid esters the commercially available Tvveens'r' such as e.g., Tween 2(:-c' and Ttve,n ("IC'1 wpecialty Chemicals)); polyethylene glycols (r.. -., Carbowx--s 3550'"' and 934`~"
(!Tnion Carbide)), polyoxyethylene stearates, colloidal silicon dioxide, phosphates, carboxymethylcellulose calcium, carbohymethylcelh2lose sodium, methylcellulose, hydroxyethylcellulose, hydroxypxopylmethylcellulose phthalate, noncrystalline cellulose, magnesiuin aluminium silicate, triethanolamine, polyr7inyl ,alcohol (PVA), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also k-nown as tyloxapol, superione, and triton), poloxamers (e.g., Pluronics F6S0" and F10SO; which are block copolymers of ethylene oxide and propylene oxide); poloxamines (e.g., Tetronic 9W", also known as Poloxamine 908which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF
Wyandotte Corporation, Parsippany, N.J.)); Tetronic 1508 (T-1508) (BASF Wyandotte Corporation), Tritons X-2000, which is an alkyl aryl polyether sulfonate (Rohm and Haas); Crodestas F-110 , which is a mixture of sucrose stearate and sucrose distearate (Croda Inc.); p-isononylphenoxypoly-(glycidol), also known as Olin-lOG or Surfactant 10-G (Olin Chemicals, Stamford, CT); Crodestas SL-40(-R) (Croda, Inc.); and SA9OHCO, which is C18H37CH,) (CON(CH3)-CH2(CHOH)4(CH21 OH)2 (Eastman Kodak Co.);
decanoyl-N-methylglucamide; n-decyl (3-D-glucopyranoside; n-decyl [,~-D-maltopyranoside; n-dodecyl P-D-glucopyranoside; n-dodecyl P-D-maltoside;
heptanoyl-N-methylglucamide; n-heptyl-o-D-glucopyranoside; n-heptyl [i-D-thioglucoside;
n-hexyl P-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl (3-D-glucopyranoside;
octanoyl-N-methylglucamide; n-octyl-(3-D-glucopyranoside; octyl (3-D-thioglucopyranoside; PEG-derivatized phospholipid, PEG- derivatized cholesterol, PEG-deriljatized cholesterol derivative, PEG- derivatized vitamin A, PEG-derivatized vitamin E, lysoz3,Tne, random copolymers of vinyl pyrrolidone and vinyl acetate, and the like.
[0110] Depending upon the desired method of administration, bioadhesive formulations of nanoparticulate topiramate can be prepared by selecting one or more cationic surface stabilizers that impart bioadhesive properties to the resultant composition.
Useful cationic surface stabilizers are described below.
[0111] Examples of useful cationic surface st.abilizers include, bu.t are not limited nates, phospholipids, and to, poljmners, biopol,rmers, polysaccharides, cellulosicz~, algi nonpol,rmeric compounds, stich as z,,Fritterionic stabilizers, poly-n-meth;`lpyridinium, anthryul pyridinium chloride, cationic phospholipids, chitosaii, polylysine, polyvinylimidazole; polybrene, pol}n.nethyhnethacryla.te trimethylammoniumbromide bromide (F1 IIeITIlADr), he xyldesyltrimethylammonium bronude (HDTvLAB), polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, 1,2 Dipalmitoyl-sn-Glycero-3-Phosphoethanolamine-N-[Amino(Polyethylene Glycol)2000]
(sodium salt) (also known as DPPE-PEG(2000)-Ainine Na) (Avanti Polar Lipids, Alabaster, Al); Poly(2-methacryloxyethyl trimethylammonium biomide) (Polysciences, Inc., Warrington, PA) (also known as S1001), poloxamines such as Tetronic 9050; also known as Poloxamine 908 , which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF
Wyandotte Corporation, Parsippany, N.J.), lysozyme, long-chain polymers such as alginic.
acid, carrageenan (FMC Corp.), and POLYOX (Dow, Midland, MI).

[0112] Other useful cationic stabilizers include, but are not limited to, cationic lipids, sulfonium, phosphonium, and quarternary ammonium compounds, such as stearyltrimethylammonium chloride, benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride or bromide, coconut methyl dihydroxyethyl ammonium chloride or bromide, decyl triethyl ammonium cl-doride, decyl dimethyl hydroxyethyl ammonium chloride or bromide, C12_15dimethyl hydroxyethyl ammonium chloride or bromide, coconut dimethyl hydroxyethyl ammonium chloride or bromide, myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl anunonium chloride or bromide, lauryl dimethyl (ethenoxy)4 ammonium chloride or bromide, N-alkyl (C12-is)dimethylbenz.yl ammonium chloride, N-alkyl (Cla-1s)dimethyl-benzyl ammonium chloride, N-tetra.decylidmeth,,{lbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C12_14) dimethyl 1-napthylmethyl ammonium chloride, trimethylammonium halide, alk-yl-trimethylanunonium salts and dialk-yl-dimethylammonium salts, lauryl trimethyl ainmonium chloride, ethoxylated alkyamidoalkyldialkylammonium salt and/or an ethoxylated trialkyl ammonium salt, dialkylberizene dialk-ylamn-ionium chloride, N-didecyldimethyl arrinionium chloride, N-tetradecyldimetriyltienzyl s:r-ru.nonium., chloride monohydrate, N-allcyl(C12_14) dimethyl 1-naphthylmethyl amriionium chloride and dodecyldimethylben%yl ammonium chloride, dialk-yl ben-7enealkyl ammonium chloride, lauryl trimethyl arnmonium chloride, alkylben--yl methyl annnonium chloride, a.ll,:yl berzyl dimethyl anun.oni.um bromide, C12, C15, C17 trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium chloride, poly-diallyldimethylamn-ionium chloridr (DA.DMA C), diniethyl amnaonium chlorides, alk-yldimethylaxnmonium halogenides, tricetyl methyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride (ALIQUAT
336TM), POLYQUAT lOT.,M, tetrabutylammonium bromide,.benzyl trimethylammonium bromide, choline esters (such as choline esters of fatty acids), benzalkonium chloride, stearalkonium chloride compounds (such as stearyltrimonium chloride and Di-stearyldimonium chloride), cetyl pyridinium bromide or chloride, halide salts of quatemized polyoayethylalkylamines, MIRAPOLTM and ALKAQUATTM (Alkaril Chemical Company), alkyl pyridinium salts; amiries, such as alkylamines, dialkylamines, alkanolamines, polyethylenepolyamines, N,N-dialkylaminoalkyl acrylates, and vinyl pyridine, amine salts, such as lauryl amine acetate, stearyl amine acetate, alkylpyridinium salt, and alkylimidazolium salt, and amine oxides; imide azolinium salts;
protonated quaternary acrylamides; methylated quaternary polymers, such as poly[diallyl dimethylammonium chloride] and poly-[N-methyl vinyl pyridinium chloride]; and cationic guar.
[0113] Such exemplary cationic surface stabilizers and other useful cationic surface stabilizers are described in J. Cross and E. Singer, CUtiotaic Saiifactarats:
Analytical and Biological Eval2.ratiorz (Marcel Dekker, 1994); P. and D.
Rubingh (Editor), ccqioilic,S2erfacterzts: F"Izi~si.ccrl C110111isi7y (IvIarcel Del~:.er, 1991); and J. F:ichmond, Cationic LCwfactarr.ts: G1rganic Ch.cnaistq, (R+Iarcel Dekker, 1 q90).

[0114] Nonpolymeric cationic surface stabilizers are any nonpolymeric conzpound, such as benzalkonium chloride, a carbonium compound, a phosphonium compound, an oxonium compound, a haloiium compound, a cationic organometallic compouaid, a quarternary phosphorous c.onnl:aound, ap;"ridiniurii connpozund, an anilinium cornpound, an a.mmoniur.a compojjnd, a hydro:,-ylaman.onium compound, a 1?rimai3r ammonium compound, a secondary ammonium compound, a tertiary ammonium compound, and quarternary anunc+nium compounds of the formula NR1RzRzI'\4.(+).
For compounds of the formula NR1R2R~R4~+7:

(i) none of RI-R4 are CH3;
(ii) one of RI-R4 is CHI;
(iii) three of RI-R4 are CH3i (iv) all of RI-R4 are CH3i (v) two of RI-R4 are CH3, one of RI-R4 is C6H5CH" and one of RI-R4 is an alk-yl chain of seven carbon atoms or less;

(vi) two of Rl.-R4 are CH3, one of Rl-R4 is C6HSCH2, and one of RI-R4 is an alkyl chain of nineteen carbon atoms or more;

(vii) two of Rl-R4 are CH3 and one of RI-R4 is the group C6H5(CH2),,, where n>1;

(viii) two of RI-R4 are CH3, one of RI-R4 is C6H5CH2, and one of RI-R4 comprises at least one heteroatom;

(ix) two of RI-R4 are CH3, one of RI-R4 is CbHSCHZ, and one of RI-R4 comprises at least one halogen;

(x) two of RI-R4 are CH3, one of RI-R4 is C6H5CH2, and one of Rl-R4 comprises at least one cyclic fragment;

(xi) two of RI-R4 are CH3 and one of R1-R4 is a phenyl ring; or (xii) two of Rl-R4 are CH3 and two of RI-R4 are purely aliphatic fragments.
[0115] Such compounds include, but are not limited to, behenalkonium chloride, benzethoniuan chloride, ,et_Ap;rridinium chloride, behentrimonium chl_oridP, lauralkonium chloride, cetalkonium chloride, cetrimonium bromide, cetrimnium chloride, cethylamine hydrofluoride, chlorallylmethenamine chloride (Qua.ternium-15), distearyldimonium chloride (Quaternium-5), dodecyl dimethyl ethylbenzyl ammonium chloride(Quatemium-14), Quatemium-22, Quaternium-26, Quaternium-18 hectorite, dimcthylaminoethylrhloride hydrochloridF, cysteine hydrochloride, diethanolammonium PC.~E. (10)oleryl ether phosphatEõ diethanolamuroniLUn P(--)E (3 )oleyrl cther phosphat:e, tallow alkonium chloride, dimethyl dioctadec-; la.rninoniurnbentonite., stearalkonium chloride, domiphen bromide, denatonium bernwate, myristalkoniuan chloride, laurtrim.onium chloride, ethylenediamine dihydrochloride, guanidine hyd_rochloride, pyridoxine HCI, iofetamine hydrocl-iloride, meglumine. hydrochloride, methylber,zethonium chloride, myrtrimonium bromide, oleyltrimonium chloride, polyquaternium-l, procainehydrochloride, cocobetaine, stearalkonium bentonite, stearalkoniumhectonite, stearyl trihydroxyethyl propylenediamine diliydrofluoride, tallowtrimonium chloride, and hexadecyltrimethyl ammonium bromide..

[0116] Most of these surface stabilizers are known phamlaceutical excipients and are described in detail in the Handbook of Plzar=rraaceut.ical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain (The Pharniaceutical Press, 2000).

[0117] Most of these surface stabilizers are known pharmaceutical excipients and are described in detail in the Handbook of Pharrnaceutical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain (The Pharmaceutical Press, 2000).
[0118] The surface stabilizers are commercially available and/or can be prepared by techniques knoAm in the art.

3. Pharmaceutical Excipients [0119] Pharmaceutical compositions according to the invention may also comprise one or more binding agents, filling agents, lubricating agents, suspending agents, sweeteners, flavoring agents, presercratives, buffers, wetting agents, disintegrants, effervescGnt agFnts, and othEr e~:.cipients. Such e.~cipients arE l:novm in the art.
[0120] Examples of fillinG agents are lactose monohydrate, lactose anhydrous, and various starches; :xa,_mples of bindirtg a.genr.s areva.rious celluloses and cross-link-ed polyvinylpyrrolidone, microcrystalline cellulose, such as Avicel`~' PH101 and Avicel~

PH102, microcrystalline cellulose, and silicified microcrystalline cellulose (ProSolv SMCCT111). [0121] Suitable lubricants, including agents that act on the floe~rability of the powder to be compressed, are collc)idal silicon dio.;.ide, such as Aeros&"200, talc, stearic a.cid, magnesium stearate, calcium stearate, and silica gel.
[0122] Examples of sweeteners are any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acsulfame.
Examples of flavoring agents are Nlagnasweet`R (trademark of NIAFCO), bubble gum flavor, and fruit flavors, and the like.
[0123] Examples of preservatives are potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or quartern.ary compound's such as benzalkonium chloride.
[0124] Suitable diluents include pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and/or mixtures of any of the foregoing. Examples of diluents include microcrystalline cellulose, such as Avicel PH101 and Avicel PH102; lactose such as lactose monohydrate, lactose anhydrous, and Pharmatose DCL21; dibasic calcium phosphate such as Emcompress ;
mannitol; starch; sorbitol; sucrose; and glucose.
[0125] Suitable disintegrants include lightly crosslinked polyvinyl pyrrolidone, corn starch, potato starch, maize starch, and modified starches, croscarmellose sodium, cross-povidone, sodium starch glycolate, and mixtures thereof.
[0126] Examples of effervescent agents are effervescent couples such as an organic acid and a carbonate or bicarbonate. Suitable organic acids include, for exaniple, citric, tartaric, malic, fumaric, adipic, succinic, and alginic acids and anhydrides and acid salts. Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, mapesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate.
Alternati-vely, only the sodium bicarbonate component of the effervescent couple may be present.

4. Nanoparticulate Topiramate Particle Size [0127] As used herein, particle size is determined on the basis of the weight a-.ferage particle size as nze:asured by conventional paz-ticle sizc rneasuring techniques well kno<<vn to those skilled iri the art. Such techniques include, for e,~ample, sedimentation field flow fractionation, photon correlation spectroscopy, light scattering, and disk centrifugation.
[0123] The compositions of the invention comp_rise topiramate nanoparticles which have an effective average particle size of less than about 2000 nm (i.e., 2 microns), less than about 1900 nm,. less than less than about 1800 nm, less than about 1700 nm,less than about 1600 nm, less than about 1500 nm, less than about 1400-nm, less than about 1300 nm, less than about.1200 nm, less than about 1100 nm, less than about 1000 nm;
less,than about 900 nm, less than about 800 nm, less than about 700 mn, less than about.
600 nm, less thanabout 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than.about 200 mn, less than about 150 nm, less than about 140 nm, less than about 130 nm, less than about 120 mn, less than about 110 nm, less than about 100 nm, less than about 90 nm, less than about 80 nm, less than about 70 nni, less than about 60 nm, or less than about 50 nm, when measured by the above-noted techniques.

[0129] If the nanoparticulate topiramate composition additionally comprises one or more non-topiramate nanoparticulate active agents, then such active agents have an effective average particle size of less than about 2000 nm (i.e., 2 microns).
In. other embodiments of the invention, the nanoparticulate non-topiramate active agents can have an effective average particle size of less than about 1900 nm, less than about 1800 nm, less than about 1700 mn, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 mn, less than about 1200 nm, less than about 1100 nm, less than about 1000 mn, less than about 900 mn, less than about 800 nm, less than a.bout 700 nm, less than about 600 mn, less than about 500 mn, less than about 400 mn, less than about 300 nm, less than about 250 mn, less than about 200 nm, less than about 150 nrri, less than a.botit 100 nm, less than about 75 nm, or less than about 50 nm, as measured by the above-noted techniques.

[0130] By "an effective average particle size of less than about 2000 n.m" it is meant that at least 50% of the nanoparticulate topiramate particles or nanoparticulate non-topiramate active agent particles have a weight average particle size of less than about 2000 nm, vuhen rneasured b;F the above-noted technique<. In other enibodiments of the invention, at least about: 70 ,0, at least about 90L%, at least about 95~,0, or at least about 99% of the nanoparticulate topiramate particles or nanoparticulate non-topiramate active agent particles have a particle size of less than the effective average, by weight, i.e., less than about 2000 nm, less than about 1900 mn, less than less than about 1800 nm, less than about 1700 nm, etc.
[O131] If the nanoparticulate topiramate composition is combined with a conventional or microparticulate topiramate composition or non-topiramate.
active agent composition, then such a composition is either solubilized or has an effective average particle size of greater than about 2 microns. By "an effective average particle size of greater than about 2 microns" it is meant that at least 50% of the conventional topiramate or conventional non-topiramate active agent particles have a particle size of greater than, about 2 microns, by weight, when measured by the above-noted techniques. In other embodiments of the invention, at least about 70%, about 90%, about 95%, or about 99%, by weight, of the conventional topiramate or conventional non-topiranlate active agent particles have a particle size greater than about 2 microns.

[0132] In the present invention, the value for D50 of a nanoparticulate topiranlate composition is the particle size below which 50% of the t'opiramate particles fall, by weight. Similarly, D90 is the particle size below which 90% of the topiramate particles fall, by weight.

5. Concentration of Nanoparticulate Topiramate and Surface Stabilizers [0133] The relative amounts of topiramate and one or more surface stabilizers can vary vAdely. The optimal amount of the individual components can depend, for example, upon the hydrophilic lipophilic balance (HLB), melting point, a_nd the surface tension of vvater solutions of the stabilizer, etc.
[0134] The concentration of topira-rn.ate can vary from about 99.5 ~,('l to about 0.001%, from about 95% to about 0.1%, or from about 90% to about 0.5%, by weight, based on the total combined dry weight of the topiramate and at least one surface stabilizer, not including other excipients.
[0135] The concentration of the at least one surface stabilizer can vary from about 0.5% to about 199.9990i`0, from about 5.0'1`41 to about 99.91"/C., -or from about 10 ii, tca about 99.5by weight, based on the total corn.bined dry j.F,Teight of the topiramate and at least one surface stabilizer, not including other excipients.

C. IJethodc of 1,4a.Hng P~,TanQ,aarticulate Topiramate FQrrnaxlatbonc [0136].
The nanoparticulate topiramate compositions can be made using, for example, milling, homogenization, or precipitation techniques. Exemplary methods of malcing nanoparticulate compositions are described in the'684 patent. Methods of making nanoparticulate compositions are also described in U.S. Patent No.
5,518,187 for "Method of Grinding Pharmaceutical Substances;" U.S. Patent No. 5,718,388 for "Continuous Method of Grinding Pharmaceutical Substances;" U.S. Patent No.
5,862,999 for "Method of Grinding Pharmaceutical Substances;" U.S. Patent No. 5,665,331 for "Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents with Crystal Growth Modifiers;" U.S. Patent No. 5,662,883 for "Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents with Crystal Growth Modifiers;" U.S. Patent No.
5,560,932 for "Microprecipitation of Nanoparticulate Pharmaceutical Agents;" U.S. Patent No.
5,543,133 for "Process of Preparing X-Ray Contrast Compositions Containing Nanoparticles;" U.S. Patent No. 5,534,270 for "Method of Preparing Stable Drug Nanoparticles;" U.S. Patent No. 5,510,118 for "Process of Preparing Therapeutic Compositions Containing Nanoparticles;" and U.S. Patent No. 5,470,583 for "Method of Preparing Nanoparticle Compositions Containing Charged Phospholipids to Reduce Aggregation," all of which are specifically incorporated by reference.

[0137] Following milling, homogenization, precipitation, etc., the resultant nanoparticulate topiramate compositions can be utilized in solid or liquid dosage formulationso such as controlled release formulations, solid dose fast melt formulations, aerosol formulations, nasal_ formulations, lyophilized formulations, tablets, capstiiles, solid lozenge, powders, creams, ointments, etc.

1. Milling to Obtain Nanoparticulate Topiramate Dispersions .[0138] Milling topiramate to obtain a nanoparticulate dispersion conlprises dispersing topiramate particles in a liquid dispersion media iri vbrhic=h topiramate is poorly soluble, follo~,ved by applying mechanical means in the presence of grinding media to reduce the particle size of topiramate to the desired effective a,=erage particle size. The dispersion media can be, for example, water, safflower oil, ethanol, t-butanol, glycerin, polyethylene glycol (PEG), hexane, or glycol.
[0139] The topiramate particles can re reduced in size in the presence of at least one surface stabilizer. Alternatively, the topiramate particles can be contacted with one or more surface stabilizers after attrition. Other compounds, such as a diluent, can be added to the topiramate/surface stabilizer composition during the size reduction process.

Dispersions can be manufactured continuously or in a batch mode.

2. Precipitation to Obtain Nanoparticulate Topiramate Compositions [0140] Another method of forming the desired nanoparticulate topiramate composition is by microprecipitation. This is a method of preparing stable dispersions of poorly soluble active agents in the presence of one or more surface stabilizers and one or more colloid stability enhancing surface active agents free of any trace toxic solvents or solubilized heavy metal impurities. Such a.method comprises, for example: (1) dissolving topiramate in a suitable solvent; (2) adding the formulation from step (1) to a solution comprising at least one surface stabilizer; and (3) precipitating the formulation from step (2) using an appropriate non-solvent. The method can be followed by removal of any formed salt, if present, by dialysis or diafiltration and concentration of the dispersion by conventional means.

3. Homogenization to Obtain Topiramate Nanoparticulate Compositions [0141] Exemplary homogenization methods of preparing active agent nanoparticulate compositions are described in U.S. Patent No. 5,510,118, for "Process of Preparing Therapeutic Compositions Containing Nanoparticles."

[01422] Sa.ich a method comprises dispersing topiramate particles in a 1_iquid dispersion media in which topiramate is poorly soluble, followed by subjecting the dispersion to homogenization to reduce the particle size of the topiramate to the desired effective average particle size. The dispersion media can be, for example, water;
safflo~ver oil, ethanol, t-butanol, glycerin, polyethylene glycol (PEG), heJ~,ane, or glycol.

[0143] The topiramate particles can lae reduced in size in the presence of at least one surface stabilizer. Alternatively, the topiramate particles can be cnntacted i3rith one or more surface stabilizers either before or after attrition. Other compounds, such as a diluent, can be added to the topiramate/surface stabilizer composition either before, during, or after the size reduction process. Dispersions can be manufactured continuously or in a batch mode.

D. Methods of Using Nanoparticulate Topiramate Formulations [0144] The method of the invention comprises administering to a subject an effective amount of a composition comprising nanoparticulate topiramate. The topiramate compositions of the present invention can be administered to a subject via any conventional means including, but not limited to, orally, rectally, ocularly, parenterally (e.g., intravenous, intramuscular, or subcutaneous), intracistemally, pulmonary, intravaginally, intraperitoneally, locally (e.g., powders, ointments or drops), or as a buccal or nasal spray. As used herein, the term "subject" is used to mean an animal, preferably a mammal, including a human or non-human. The terms patient and subject may be used interchangeably.

[0145] Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles including water, ethanol, polyols (propyleneglycol, polyethylene-glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0146] The nanoparticulate compositions may also contain adjuvants such as preserving, wetting, emulsifjing, and dispensing agents. Prevention of the growth of microorganisms can be ensured by various antibacterial and antifiungal agents, such as parabens,, chlorobutanol, phenol_, :orbic acid, and the like. It may also be desirable to include isotonic agents, such as, sugars, sodium chloride, and the like.
Prolonged absorption of the injectabl_e pharmaceutical form can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin.

[0147] Solid dosage forms for oral administration include, but are not limited to, powder aerosols, capsules, tablets, pills, powders, and granules. In suc.h solid dosage forms, the active agent is adniixed with at least one of the following: (a) one or more inert excipients (or carriers), such as sodium citrate or dicalcium phosphate;
(b), fillers or extenders,, such as starches, lactose, sucrose, glucose,, mannitol, and silicie acid; (c) binders, such as carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone,, sucrose, and acacia; (d) humectants, such as glycerol; (e) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (f) solution retarders, such as paraffin; (g) absorption accelerators, such as quaternary arnmonium compounds; (h) wetting agents, such as cetyl alcohol and glycerol monostearate; (i) adsorbents, such as kaolin and bentonite; and (j) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. For capsules, tablets, and pills, the dosage forms may also comprise buffering agents.

[0148] Liquid dosage forms for oral administration include pharmaceutically acceptable aerosols, emulsions, solutions, suspensions, syrups, and elixirs.
In addition to the active agent, the liquid dosage forms may comprise inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers. Exemplary emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benF,yl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, fatt3r acid esters of sorbitan, or mixtuxes of these stibstaalc=es, and the like.

[0149] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfiuning agents.

[0150] One of ordi.nary s1;;L will appreuiate that effective arnounts of topiramate can be dete_rmi_ned empirically and can be eriiployed in pure form or, where such fomis exist, in pharnlaceutically acceptable salt, ester, or prodrug form. Actual dosage levels of topiramate in the nanoparticulate compositions of the invention may be varied to obtain an amount of topiramate that is effective to obtain a desired therapeutic response for a particular composition and method of administration. The selected dosage level therefore depends upon the desired therapeutic effect, the route of adn-iinistration, the potency of the administered topiramate, the desired duration of treatment, and other factors.

[0151] Dosage unit compositions may contain such amounts of such submultiples thereof as may be used to make up the daily dose. It will be understood, however,: that the specific dose level for any particular patient will depend upon a variety of factors: the type and degree of the cellular or physiological response to be achieved;
activity of the specific agent or composition employed; the specific agents or composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the agent; the duration of the treatment;
drugs used in combination or coincidental with the specific agent; and like factors well known in the medical arts.

1. Uses in Treating Epilepsy and Related Disorders [0152] Depending on the mode of administration, the nanoparticulate topiramate compositions of the invention are useful in treating, for example, seizures, mood disorders, post traumatic stress syndrome (PTSD), Bipolar Disorder, mania (all fonns, such as acute mania, severe treatment-refractory mania, bipolar mania, etc.), depression, personality disorders, bipolar mood instability, schizophrenia, psychosis, bipolar spectram disorders, rapid-cycling bipolar disorders, etc. The nanoparticulate topiramate compositions of the invention are also useful for treating patients tivith mood disorders that have not bee.n adequat ;1;- controlled by other medications, such as lainotrigine and gabapentin, and for treating patients with bipolar mood disorders that have not responded to lithium and/or other mood-stabilizers.

`. I~~,~~, ir_ 'T~=~ a~:in.~

[0153] In other embodiments of the invention, the nanoparticiflate topiramate compositions are useful in treating or preventing, for example, migraines, neuropathic pain relief, essential type tremor, cluster headache.

[0154] 66Neuropatluc pain" is pain being caused to the peripheral nerve fibers themselves. Descriptions of neuropathic pain by patients typically include s-lo_rds such as burning, shooting; stabbing, or electric like and not aching or crushing. The 'distribution of pain will be along the course of a particular peripheral nerve or a group of nerves of similar length. For neuropathic pain, nonnarcotic pain relievers are generally not helpful.

[0155] "Migraines" and "cluster headaches" are types of headaches.
Neurologists diagnose headaches according to the International Headache Society (I.H.S.) Classification System. This system recognizes four primary headache types. The phrase, "primary headache type" means that the headache is not caused by some other disease process. These headache types are migraine, tension, cluster and chronic paroxysmal hemicrania, and miscellaneous. Of these, cluster is by far the most severe headache. The headache intensity is severe enough to make some patients contemplate suicide.
These headaches are called cluster because the patient will experience a "cluster"
or series of headaches for some period of time and they will then disappear for several months before they recur.

3. Uses in Treating Addictive Behaviors, Including Obesity [0156] In addition to being useful in treating epilepsy and related conditions, new research demonstrates that topiraniate is useful in treating a range of conditions potentially associated ~vith addictive behaviors, such as obesity, smoking, alcohol dependence, and drug addiction.

a. Treatment of Obesity .[0157] Soon after the epilepsy drug topiramate hit the market in 1996, doctors noticed something une-2~pected: patients using the anti-seizure rn.edication suddenly began losing ~4,reight -- _rapidly.~.~'ti,e R. Stein, "Epilipsy Drd,igs l,Za.,j Curb Obesity," Tasla. Fos!, p. A03 (Oct. 7, 2003). Recent studies designed specifically to test topiramate as a~veight-loss aid have found that it helps people, especially those prone to binge eating, to lose --and keep off -- sisuificant a_mounts of v,jeight.
[0158] Topiramate has helped obese people lose as much as 10 percent of their body weight. See Bray et al., "A 6-Month rtandomized, Placebo-Controlled, Dose-Ranging Trial of Topiramate for 'Weigh.t Loss in Obesity," Obesi.ty Research, 11:722-733 (2003).
[0159] One unusual trend observed during the topiramate obesity studies was a consistent decline in weight over the entire study period, enabling people to keep, the weight off. No currently approved obesity drug exhibits this property.

[0160] Moreover, the proportion of patients who responded to treatment by losing more than 5% of their body weight was high -- 80% to 88% for one study. The proportion of patients who lost 10% or more of their body weight was also high -- 59% to 64% for the same study. In addition, researchers observed benefits in low-density lipoprotein (LDL) levels, and high-density lipoprotein (HIDL), as well as in the LDL-to-1-IDL ratio with topiramate.
[0161] Obesity has proven to be difficult to target, perhaps because of the complexity of factors governing weight control. Even the most common form of obesity, diet-induced obesity, has a complex pathophysiology for which fundamental protein targets are both poorly understood and involved in multiple metabolic and physiologic pathways such that modifying their activity is fraught with adverse effects.
The most notorious obesity treatment was a combination known as fen-phen, which was recalled from the market in 1997 after it was associated with heart valve damage, adverse cardiovascular effects, and other serious ailments in an unacceptably high proportion of recipients. Many other anti-obesity agents have failed in clinical trials.
Nothing currently in the clinical. trial pipeline to treat obesity appears to be able to overcome these and other limitations.

[0162] IMoreo=,fer, v.rhilc topiramate has been shtT7,m to be usefl!1 in treating or_sit~,.. tht_re is a con~~.~rn tLiat the ad~,re_rse event profile for th:;
dnig v;ill make vridespread use of topir3rr_a.te for treating obesiry unlikFl;. The ad rr_-rsi,: effect profile in mid-to-late stage clinical trials in obesity included memory problems, fatigue, sleepiiiess, difficulty in concentration. and tingling in the finCers and toes. i;s a result of this adverse effect profilE, Jormson R; Johnson d-ccided to discontinuE clinical trials for topirarnate for trea.ting obesity. See L. Henderson et al., "Ja'LJ willi not Pursue Topamax for Obesity,"
TTech..News (February S, 2002).

[0163] Specifically, a Johnson & Johnson sponsored study recently reported that topiramate, used in combination with an intensive behavioural intervention, seems to be safe and effective for weight reduction in newly diagnosed obese, type 2 diabetics who are:
following a controlled diet. The study comprised 541 randomized patients who were given 60 weeks treatment with topiramate 96 mg/d or 192 mg/d, or placebo, following a six-week placebo run-in period. However, while positive results were observed, the study was terminated prematurely to develop an improved formulation with the potential for enhanced tolerability in this population. Thus, no patient completed the 52-week maintenance phase. During the study, 19% of patients withdrew because of side effects.
The most common treatment-related adverse events were related to the central nervous system and included paraesthesia, fatigue, hypoesthesia, injury, and abnormal vision. The most common adverse events resulting in withdrawal were paraesthesia in 5% of patients, depression in 3%, and difficulty with memory in 3%. See J. Stein, "International Diabetes Federation (IDF): Topirarnate Shows Potential for Weight Loss Obese Diabetics"
(Aug.
?6, 2003);

(summarizing study results reported on August 25'h at the Eighteenth International_ Diabetes Federation (IDF) Congress, entitled "Safety and Efficacy of topiramatE in the treatment of tvpe 2 diabetic obese subjects: a randomised, double blind, placebo controlled trial").

[0164] Nanoparticulate topiramate compositions according to the invention can overcome these and other disadvantages with prior art topiraniate compositions, because of the improved formulation characteristics as well as enhancFd bioava.ilability of the novel topiramate compo.-ition5.

b. '':'a-eatment oGJAohol Pepencl nee [0165] In May of 2003, the results of a study designed to determine the effectiveness in treating alcohol dependence were reported at the 2003 Am-iual NIeeting of the American Psycliiatric Association. The results showed that patients taking oral topiramate Yvere 6 times more likely to be continuously alcohol-free for at least one month during the three-montli trial. Over the same period, those taking the placebo were four times more likely to drink heavily for an entire month during the trial.. Not only was self-reported driilking reduced, but a strictly objective lab test measure for evidence of recent alcohol use (plasma GGT) showed the benefit of topiraznate. See Johnson et al., "Oral topiramate for treatment of alcohol dependence: a randomized controlled trial," Lancet, 361(9370):1666-7 (May 17, 2003).

[0166] The study comprised 150 subjects in a 12-week, placebo-controlled, randomized study. All subjects met Diagnostic and Statistical Manual IV
criteria for alcohol dependence by scoring 8 or higher on the alcohol use disorders identification test.
In the 90 days prior to the study, women reported drinking a mean of at least 21 standard drinks per week, and men reported consuming at least 35 standard drinks per week. A
"standard drink" is 12 oz of beer, 5 oz of wine, or 1.5 oz of SO-proof liquor.
See Johnson et al. Topiramate was given to 75 subjects at ?5 mg/day, titrated upwards at mg/week to either 300 mg/day or maximum tolerated dose. The remaining 75 patients received escalating placebo tablets. Average daily dose of topiramate at end point was 120 mg/day. See Johnson et al.

The researchers reported that topiramate significantly reduced the amount and severity of drinking. See Johnson et al. Moreover, alcohol-dependent patients frequently have liver disease, one indicator of which is a rise in the plasma level of the enzyme gamma glutamyl transferase (GGT). Notably, topiramate was superior to placebo at significantly reducing the plasma GGT levels during the trial. Further, topiramate was shown to be effective treatment for all types of alcohol-dependent patients.

Topiramate is from a different class of drug than those previously used in the treatment of alcoholism. Thus, topi_ramate can brisr_g benefits to patiFnt.s for whom ot.her druas are not successfitl.

Nearly 14 rnillion A` rnericans - 1 in every 13 adults - abuse alcohol or are alcoholic, according to the National Institutes ofHea.lth National Institute on Alcohol Abuse and Alcoholism (NIALPIu4). Several rnillion more adults en,a`e in risky drinking that could lead to alcohol problems. This behavior includes binge drinking and heaTrY
drinking on a regular basis. In addition, 5= 0-o of men and women in the United States Teport drinking problems in close relatives. Alcohol-related problems cost society about $185 billion per year, the NTAAA. estimates.

.[0167],While topiramate may be useful in treating, alcohol dependence, side effects associated with the drug may decrease the utility of the drug.
Nanoparticulate topiramate compositions according to the invention can overcome these and other disadvantages with prior art topiramate compositions.

c. Treatment of Nicotine Addiction [0168] In late 2001, the U.S. Department of Energy's Brookhaven National Laboratory reported that topiramate could be a cure for nicotine addiction.
See "Therapeutic Drug, Blocks Nicotine's 'Effects on Brain Chemistry" (Nov. 8, 2001).

[0169] Nicotine is believed to tri gger dependence by reacting with a brain chemical called dopamine, which is associated with pleasure and reward. The Brookhaven National Laboratory (`BNL") study experimented on neurochemical activity in rats. The researchers found that topiramate targets two different neurotransmitter pathways that reduce the excitatory input into the dopamine system, and raise the activity of a brain chemical that inhibits dopamine. Topiramate was also found to increase serotonin, which has been found by previous studies to help reduce the iricidence of smol:inal.

[0170] In the study, scientists injected one group of rats with topiramate while another group received control injections of saline. The scientists then gave both groups an acute dose of nicotine and meastired dopamine, norepinephrine, and serotonin levels in their bra.lns. ~1lmals gl~,ren topiranla.te bu.t no nicotzne ~~'ere also -tttd2ed to see if topiramate alone had any effect on the neLirotransrnitters. The scientists also tested the effect of topiranlate on dopamine in animals that had been pret_reated with nicotine fior 14 days prior to the experiment, to serve as a model for humans addic=ted to the drug.
[0171 ] As expected, animals that received saline and then nicotine showed signific.ant increases in all three brain chemicals. Rats that had been previously "addicted" to nicotine shovded even gxeater elevations in brain dopamine than those that received just the acute dose - similar to what you'd expect to see in a smoker who has a cigarette after a period of not smoking.

(0172] Pretreatment with topiramate, however, co7rapletEly blocked nicotine-triggered increases in norepinephrine and dopamine - and even modulated the dopamine response in the "addicted" animals. Since the brain's dopamine and norepinephrine systems are closely linked, the ability of topiramate to, reduce increases in both neurotransmitters suggests that this drug has potential for treating nicotine abuse.

[0173] The researchers concluded that the ability of topiramate to increase serotonin activity, while at the same time control dopamine, might make it an effective treatment for nicotine addiction.
[0174] While topiramate may be useful in treating nicotine addiction, side effects associated with the drug may decrease the utility of the drug. Nanoparticulate topiramate compositions according to the invention can overcome these and other disadvantages with prior art topiramate compositions.

4. Treatment of Drug Addiction and Addictive Behaviors Generally [0175] The scientific resa.ilts related to obesity treatment, alcohol dependence, and nicotine addiction have led scientists to explore what could be a new approach for other addictive behaviors. Topiramate appears to help some people control obsessive behw7iors, including eating, alcohol abuse, and smoking. It is theorized that topirainate works by tamping down uncontrolled electrical firings of nerve cells that lead to compulsive eating, drinking or smoking in the same way that blocking uncontrolled electrical fixing in the brain prevents scizures.
[0176] Similar addictions are observed v.rith drugs, such as for examf-le cocaine, heroin, oxycontin, etc. Along with apparEntly reducing uncontrolled electrical firings in the brain, topiramate seems to affect chemical signals involved in pleasure --serotonin and dopamine.
[0177] Thus, topiramate is likely also useful in treating drug addiction, as well. as other undesirable addictive behaviors.
[017S] While topiramate maybe.useful'in treating drug addiction as well as other addictive behaviors, side 'effects associated with the drug may decrease the utility of the drug. Nanoparticulate topiramate conlpositions according to the invention can overcome these and other disadvantages with prior art, topiramate compositions.

[0179] The following examples are given to illustrate the present invention.
It should be understood, however, that the invention is not to be limited to the specific conditions or details described in these examples.

Example 1 [0180] The purpose of this exaniple was to screen several surface stabilizers to detezmine their suitability for preparing a nanoparticulate dispersion of topiramate.
[0181] Aqueous mixtures of 5% (w/w) topiramate and 1.25% (w/w) surface stabilizer, with and without 0.05% docusate sodium (DOSS) (USP), were milled under higli energy milling conditions in a NanoM111Tk' (Elan Drug Delivery, Inc.) (seeG.g., WO
00/72973 for "Small-Scale Mill and Method Thereof'), utilizing 500 m polymeric attrition media (Dow Chemical Co.) for 45 minutes. The surface stabilizers screened were hydroxypropylcellulose (HPC-SL) (USP), Hypromellose (USP), polyvinylpyrrolidone (PVP) C-30 (USP), Plasdone S630 (ISP) (USP), which is a random , cop~.~l}mer of vinyl acetate and vinyl pyrrolidone, and lysozyme, as shown in the follo~F,=ing ta.ble, [01 fi::] Folio3.ving rn.ilizng, the relative homogeneity of the dispersions vras determined based on comparative light microscopy utili.:ing a Letca oil immersion photo microscopy system (Leica DN4RR; Wetzlar,Germany). The results are shown in Table 1.
TABLE I
Re.ult:~ of Surface ;tabilter Screening Composition Hornogeneity of Resulting Dis .ersiQu 5% (w/w) topiramate Very Good 1.25% (w/w) HPC-SL
5% (w/w) topiramate Good 1.25% (w/w) HPC-SL
0'.05% DOSS
5% (w/w) topiramate Excellent 1.25% (w/w) Hypromellose 5% (w/w) topiramate Excellent 1.25% (w/w) Hypromeilose 0.05% DOSS
5%. (w/w) topiramate Poor 1.25% w/w) PVP
5% (w/w) topiramate Very good 1.25% (w/w) PVP
0.05% DOSS
5% (w/w) topiramate Very good 1.25% (w/w) Plasdone 5% (w/w) topiramate Very good 1.25% (w/w) PlasdoneL' 0.05 1o DOSS
5% (w/w) topiramate Good 1.25% (w/w) lysozyme [013] It was concluded that hST+romellose was the lead candidate for scale-up, based on the results of a comparative lig t microscopy test.

Example 2 [01 S4] The purpose of this elample was to prepare a nanoparticulate dispersion of topiramate.

[01 85] PLZ aqueous mis-ture of 15"a topiraniate, 3111a Hypromellose 1ISF, and 0.05? ~~ DCS~S UCF" ~T~Fas 1ni11ed ublderh.gh energy rs-i_llinb conditions in a DYNQ -T.Zill T,:DL (Willy A. Bachofen AG, Maschinenfabrilc, Basel, Switzerland) equipped with a 150 cc batch chamber and utilizing 500 m pol}meric attrition media ( 'Dow Chemical Co.) for 4 hours, Particle size analysis was performed with a Horiba LA-910 particle size analyzer (Trvine, CA). The mean particle size of the milled topiramate dispersion was 110 nm.

[0186] Following particle size reduction, the mean particle size (nm) of the topiramate dispersion was measured at 5 C, 25 C, and at 40 C at various time intervals, as sliown below in Table 2.

Mean Particle Size nm - Following illing of a To iramate Dispersion Time 5 C 25 C 40 C
4 hours 110 1 day 158 154 166 days 172 167 157 8 days 190 171 201 29 days 175145 235 54 days 529 [0187] The results demonstrate the stability of the nanoparticulate dispersion of topiramate over an extended time period.

Example 3 [0188] The purpose of this example was to deternline the i~i vivo pharma.coll:inetics ofnan~.~l-aarticulate topiramate compositions.

De-~~ S-tusly Protocol [01 89] Eight male Beagle dogs were not fasted and had food available prior to dosing. Each dog received the follo,.,ling tv..,o formulations:

Forrntalation # 1: Liquid Ditpersiran of l~ Tao:.oparticulate Topiramate [0190] 12 1- of topiramate (Elan Pharmaceuticals, Inc.) was added to a solution containing 2.4 g hypromellose USP (HPMC) (Shinetzu), 40 mg docusate sodium USP
(DOSS) (Cytec), and 80 g water q.s. WFI (Water for Injection, Abbott Laboratories).
[0191] This mixture was then milled for 160 min. in a DYNO-Mill KDL.(Willy A. Bachofen AG, Maschinenfabrik, Basel, Switzerland) with PolyMillTM-500 polymeric media (Dow Chemical Co.).

[0192] The final mean (volume average)'particle size of the nanoparticulate topiramate dispersion was 183 nm, as measured on a Horiba LA-910 particle size analyzer (Horiba Instruments, Irvine, CA). Sufficient diluent (DI water) was supplied and added to a 150 mg/g concentrate of the nanoparticulate topiramate dispersion to achieve a final concentration of 50 mg/g.

Formulation # 2: Tablet of Conventional Microparticulate Topiramate [0193] TOPAMAX R Tablets (Ortho-McNeil Pharmaceutical, Inc.), 25 mg.
[0194] In Phase I, four dogs received a single oral gavage dose of 25 mg of the nanoparticulate topiramate composition (Topiramate Formulation #1) (0.5 g of a mg/g), followed by an approximately 10 mL tap water flush of the gavage tube.
In addition, four different dogs were given a. 25 mg Topamax~5~ tablet dose (Topira.tnate Formulation #2).

[0195] In Phase 2, after a one week washout period, the four do~s which received the oral gavage dose of Topiramate Formulation #1 in Phase 1 received a 25 mg Topama,-, R tablet dose (Topiramate Formulation #2). The foux dogs ,~~rhich received the Topamax(1 tablet dose (Topirainate Formulation #2) in F"hase I received a single oral gavage dose of the nanoparticulate topiramate composition (Ttpiramate Fornlulation #1)s followed by an approximately 10 mL tap water flush of the gavage dose.
[0196] Blood samples (approx-imately 1 mL) were drav.rn at specified time points into pre-cooled tubes containing sodiuin heparin. The samples were placed on wet ice/ice block following collection. Plasma was separated and stored frozen at approximately -70 C. The protocols of Phase I.and II are sumrnarized in Table 3, below.

Phase Compound #males Dose # Dose Matrix route articles (mg) collected 1 Nanoparticulate 4 PO NA 25 Blooda Topiramate Dispersion 2 To amax 4 Tablet 1 25 Blooda [0197] The summary of the results of the pharmacokinetic tests are shown below in Table 4 and in Figures 1 and 2, and the raw data is shown in Table 5.
Figure 1 graphically shows the average concentration (ng/mL) of Formulation #1 and #2 over a 25 hour time period, and Figure 2 graphically shows the average concentration (ng/mL) of Formulation #1 and #2 over a 1 hour time period.

C,,,ar (ng/mL) (hours) AUC n hr/ml) Formulation 1 1688.78 0.687 12008.273 To amaxg 1878.2 1.531 13592.199 TABLE S
Treatment Dog Cmax Tmax AUClast AUCINF(observed) (nc/mL) (hours) (ng hr/nil) (ng hr/mi) Nanoparticulate A. 1732.98 0.50 12830.37 13406.21 Topiramate Disp:raion B 1495.43 0.33 9122.03 9546.03 C 2008.57 0.1-5 13538.65 14082.49 D 1963.74 0.75 14008.02 14637.54 E 1785.52 0.75 11624,62 12085.61 F 768.81 2.00 7864.06 8563.12 G 1646.89 0.75 13148.19 13678.43 H 2108.30 0.17 13930,25 14459.54 Treatment Dog Cmax Tmai AUClast AUCUTI+(observed) TOFA2v1AX8t A 1912.81 1.00 14349.04 14906.04 Tablet B 1797.61 1.00 14521.30 15183.95 C 2130.23 0.50. 13967.65 14505.60 D 2410,57 1.00 12266.89 12714.00 E 2007.58 '150 15053.38 15819.91 F 821.26 - 6.00 10403.61 11405.12 G 2018.93 0.50 12268.48 12619.10 H 1926.61 0.75 15907.25 16566.29 [0198] Tm,,, for the nanoparticulate topiramate composition was less than half that of the conventional microcrystalline topiramate composition. Therefore, the nanoparticulate topiramate composition exhibited an onset of activity which is about twice that of the conventional non-nanoparticulate topiramate composition.

[0199] While the Cma,, and AUC were slightly less than that observed for the conventional microcrystalline topiramate composition, it is possible that nanoparticulate topiramate compositions having, for example, different concentrations of active agent and/or surface stabilizer, different surface stabilizers, or formulated into a different dosage form, would exhibit preferably Cma, and/or AUC profiles as compared to a conventional non-nanoparticulate topiramate composition.

[0200] It vTill be apparent to those si_;illed in the art that various modifications and varia.tions can bF inade in the methods and compositions of the present invention evithout departing from the spirit or scope of the invention. Thus, it is intended that the present invention cover the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents.

Claims (92)

1. A nanoparticulate topiramate composition comprising:
(a) particles of topiramate or a salt thereof, wherein the topiramate particles have an effective average particle size of less than 2 microns;
and (b) at least one surface stabilizer.
2. The composition of claim 1, wherein the effective average particle size of the nanoparticulate topiramate particles is selected from the group consisting of less than 1900 nm, less than 1800 nm, less than 1700 nm, less than 1600 nm, less than 1500 nm, less than 1400 nm, less than 1300 nm, less than 1200 nm, less than 1100 nm, less than 1000 nm, less than 900 nm, less than 800 nm, less than 700 nm, less than 600 nm, less than 500 nm, less than 400 nm, less than 300 nm, less than 250 nm, less than 200 nm, less than 150 nm, less than 140 nm, less than 130 nm, less than 120 nm, less than 110 nm, less than 100 nm, less than 90 nm, less than 80 nm, less than 70 nm, less than 60 nm, and less than 50 nm.
3. The composition of claim 2, wherein at least about 70%, at least about 90%, at least about 95%, or at least about 99% of the topiramate particles have a particle size less than the effective average particle size.
4. The composition of claim 1, wherein the topiramate is selected from the group consisting of a crystalline phase, an amorphous phase, and a semi-crystalline phase.
5. The composition of claim 1, wherein the composition is formulated for administration selected from the group consisting of oral, pulmonary, rectal, opthalmic, colonic, parenteral, intracistemal, intravaginal, intraperitoneal, local, buccal, nasal, and topical administration.
6. The composition of claim 1, wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers, or a combination thereof.
7. The composition of claim 1, wherein the topiramate is present in an amount selected from the group consisting of from about 99.5% to about 0.001%, from about 95% to about 0.1%, and from about 90% to about 0.5%, by weight, based on the total combined dry weight of the topiramate and at least one surface stabilizer, not including other excipients.
8. The composition of claim 1, wherein the at least one surface stabilizer is present in an amount selected from the group consisting of from about 0.5% to about 99.999%, from about 5.0% to about 99.9%, and from about 10% to about 99.5%, by weight, based on the total combined dry weight of the topiramate and at least one surface stabilizer, not including other excipients.
9. The composition of claim 1, comprising at least two surface stabilizers.
10. The composition of claim 1, wherein the surface stabilizer is selected from the group consisting of an anionic surface stabilizer, a cationic surface stabilizer, a zwitterionic surface stabilizer, and an ionic surface stabilizer.
11. The composition of claim 10, wherein the at least one surface stabilizer is selected from the group consisting of cetyl pyridinium chloride, gelatin, casein, phosphatides, dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oils, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, hydroxypropyl celluloses, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde, poloxamers; poloxamines, a charged phospholipid, dioctylsulfosuccinate, dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate, alkyl aryl polyether sulfonates, mixtures of sucrose stearate and sucrose distearate, p-isononylphenoxypoly-(glycidol), decanoyl-N-methylglucamide; n-decyl .beta.-D-glucopyranoside; n-decyl .beta.-D-maltopyranoside; n-dodecyl .beta.-D-glucopyranoside; n-dodecyl .beta.-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-.beta.-D-glucopyranoside; n-heptyl-.beta.-D-thioglucoside; n-hexyl .beta.-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl .beta.-D-glucopyranoside;
octanoyl-N-methylglucamide; n-octyl-.beta.-D-glucopyranoside; octyl .beta.-D-thioglucopyranoside; lysozyme, PEG-derivatized phospholipid, PEG-derivatized cholesterols, PEG-derivatized vitamin A, PEG-derivatized vitamin E, and random copolymers of vinyl acetate and vinyl pyrrolidone.
12. The composition of claim 10, wherein the at least one cationic surface stabilizer is selected from the group consisting of a polymer, a biopolymer, a polysaccharide, a cellulosic, an alginate, a nonpolymeric compound, a phospholipid, zwitterionic stabilizers, poly-n-methylpyridinium, anthryul pyridinium chloride, chitosan, polylysine, polyvinylimidazole, polybrene, polymethylmethacrylate trimethylammoniumbromide bromide (PMMTMABr), hexyldesyltrimethylammonium bromide (HDMAB), polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, 1,2 Dipalmitoyl-sn-Glycero-3-Phosphoethanolamine-N-[Amino(Polyethylene Glycol)2000] (sodium salt), Poly(2-methacryloxyethyl trimethylammonium bromide), poloxamines, lysozyme, alginic acid, carrageenan, POLYOX, cationic lipids, sulfonium, phosphonium, quarternary ammonium compounds, stearyltrimethylammonium chloride, benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride, coconut trimethyl ammonium bromide, coconut methyl dihydroxyethyl ammonium chloride, coconut methyl dihydroxyethyl ammonium bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium bromide, C12-15dimethyl hydroxyethyl ammonium chloride, C12-15dimethyl hydroxyethyl ammonium bromide, coconut dimethyl hydroxyethyl ammonium chloride, coconut dimethyl hydroxyethyl ammonium bromide, myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl (ethenoxy)4 ammonium chloride, lauryl dimethyl (ethenoxy)4 ammonium bromide, N-alkyl (C12-18)dimethylbenzyl ammonium chloride, N-alkyl (C14-18)dimethyl-benzyl ammonium chloride, N-tetradecyldimethylbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C12-14) dimethyl 1-napthylmethyl ammonium chloride, trimethylammonium halide, alkyl-trimethylammonium salts, dialkyl-dimethylammonium salts, lauryl trimethyl ammonium chloride, ethoxylated alkyamidoalkyldialkylammonium salt, an ethoxylated trialkyl ammonium salt, dialkylbenzene dialkylammonium chloride, N-didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl ammonium, chloride monohydrate, N-alkyl(C12-14) dimethyl 1-naphthylmethyl ammonium chloride, dodecyldimethylbenzyl ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C12, C15, C17 trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium chloride, poly-diallyldimethylammonium chloride, dimethyl ammonium chlorides, alkyldimethylammonium halogenides, tricetyl methyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride, polyquaternium 10, tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters, benzalkonium chloride, stearalkonium chloride compounds, cetyl pyridinium bromide, cetyl pyridinium chloride, halide salts of quaternized polyoxyethylalkylamines, quaternized ammonium salt polymers, alkyl pyridinium salts, amines, protonated quaternary acrylamides, methylated quaternary polymers, and cationic guar.
13. The composition of claim 12, wherein the amine is selected from the group consisting of alkylamines, dialkylamines, alkanolamines, polyethylenepolyamines, N,N-dialkylaminoalkyl acrylates, vinyl pyridine, amine salts, lauryl amine acetate, stearyl amine acetate, alkylpyridinium salt, alkylimidazolium salt, amine oxides, and, imide azolinium salts.
14. The composition of claim 10, wherein the cationic surface stabilizer is a nonpolymeric compound selected from the group consisting of benzalkonium chloride, a carbonium compound, a phosphonium compound, an oxonium compound, a halonium compound, a cationic organometallic compound, a quarternary phosphorous compound, a pyridinium compound, an anilinium compound, an ammonium compound, a hydroxylammonium compound, a primary ammonium compound, a secondary ammonium compound, a tertiary ammonium compound, behenalkonium chloride, benzethonium chloride, cetylpyridinium chloride, behentrimonium chloride, lauralkonium chloride, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cethylamine hydrofluoride, chlorallylmethenamine chloride (Quaternium-15), distearyidimonium chloride (Quaternium-5), dodecyl dimethyl ethylbenzyl ammonium chloride(Quaternium-14), Quaternium-22, Quaternium-26, Quaternium-18 hectorite, dimethylaminoethylchloride hydrochloride, cysteine hydrochloride, diethanolammonium POE (10) oletyl ether phosphate, diethanolammonium POE (3)oleyl ether phosphate, tallow alkonium chloride, dimethyl dioctadecylammoniumbentonite, stearalkonium chloride, domiphen bromide, denatonium benzoate, myristalkonium chloride, laurtrimonium chloride, ethylenediamine dihydrochloride, guanidine hydrochloride, pyridoxine HCI, iofetamine hydrochloride, megiumine hydrochloride, methylbenzethonium chloride, myrtrimonium bromide, oleyltrimonium chloride, polyquaternium-1, procainehydrochloride, cocobetaine, stearalkonium bentonite, stearalkoniumhectonite, stearyl trihydroxyethyl propylenediamine dihydrofluoride, tallowtrimonium chloride, and hexadecyltrimethyl ammonium bromide.
15. The composition according to any one of claims 10, 12, 13, or 14, wherein the composition is bioadhesive.
16. The composition of claim 1, comprising hypromellose, docusate sodium, or a combination thereof as surface stabilizers.
17. The composition of claim 1, further comprising a topiramate composition having an effective average particle size of greater than 2 microns.
18. The composition of claim 1, further comprising at least one additional nanoparticulate topiramate composition having an effective average particle size of less than 2 microns, wherein said additional nanoparticulate topiramate composition has an effective average particle size which is different than the effective average particle size of the nanoparticulate topiramate composition of claim 1.
19. The composition of claim 1, additionally comprising at least one non-topiramate active agent.
20. The composition of claim 19, wherein said active agent is selected from the group consisting of amino acids, proteins, peptides, nucleotides, anti-obesity drugs, nutraceuticals, dietary supplements, central nervous symptom stimulants, carotenoids, corticosteroids, elastase inhibitors, anti-fungals, alkylxanthine, oncology therapies, anti-emetics, analgesics, opioids, antipyretics, cardiovascular agents, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobactenal agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytics, sedatives, astringents, alpha-adrenergic receptor blocking agents, beta-adrenoceptor blocking agents, blood products, blood substitutes, cardiac inotropic agents, contrast media, corticosteroids, cough suppressants, diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics, haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones, anti-allergic agents, stimulants, anoretics, sympathomimetics, thyroid agents, vasodilators, vasomodulator, xanthines, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic analgesics, monoamine uptake inhibitors, adenosine regulating agents, cannabinoids, Substance P antagonists, neurokinin-1 receptor antagonists, and sodium channel blockers.
21. The composition of claim 20, wherein said nutraceutical is selected from the group consisting of lutein, folic acid, fatty acids, fruit extracts, vegetable extracts, vitamin supplements, mineral supplements, phosphatidylserine, lipoic acid, melatonin, glucosamine/chondroitin, Aloe Vera, Guggul, glutamine, amino acids, green tea, lycopene, whole foods, food additives, herbs, phytonutrients, antioxidants, flavonoid constituents of fruits, evening primrose oil, flax seeds, fish oils, marine animal oils, and probiotics.
22. The composition of any one of claims 19, 20, or 21, wherein at least one non-topiramate active agent has an effective average particle size of less than 2 microns.
23. The composition of any one of claims 19, 20, or 21, wherein at least one non-topiramate active agent has an effective average particle size of greater than 2 microns.
24. The composition of claim 1 formulated into a liquid dosage form, wherein the dosage form has a viscosity of less than 2000 mPa s at a shear rate of 0.1 (I/s).
25. The composition of claim 24 having a viscosity at a shear rate of 0.1 (I/s) selected from the group consisting of from about 2000 mPa-s to about 1 mPa s, from about 1900 mPa-s to about 1 mPa-s, from about 1800 mPa-s to about 1 mPa-s, from about 1700 mPa s to about 1 mPa s, from about 1600 mPa s to about 1 mPa's, from about 1500 mPa's to about 1 mPa-s, from about 1400 mPa s to about 1 mPa's, from about 1300 mPa s to about 1 mPa-s, from about 1200 mPa-s to about 1 mPa-s, from about 1100 mPa-s to about 1 mPas, from about 1000 mPa's to about 1 mPa-s, from about 900 mPa-s to about 1 mPa's, from about 800 mPa-s to about 1 mPa-s, from about 700 mPa*s to about 1 mPa's, from about 600 mPa*s to about 1 mPa-s, from about 500 mPa.cndot.s to about 1 mPa.cndot.s, from about 400 mPa.cndot.s to about 1 mPa.cndot.s, from about 300 mPa.cndot.s to about 1 mPa.cndot.s, from about 200 mPa.cndot.s to about 1 mPa.cndot.s, from about 175 mPa.cndot.s to about 1 mPa.cndot.s, from about 150 mPa.cndot.s to about 1 mPa.cndot.s, from about 125 mPa.cndot.s to about 1 mPa.cndot.s, from about 100 mPa.cndot.s to about 1 mPa.cndot.s, from about 75 mPa.cndot.s to about 1 mPa.cndot.s, from about 50 mPa.cndot.s to about 1 mPa.cndot.s, from about 25 mPa.cndot.s to about 1 mPa.cndot.s, from about 15 mPa.cndot.s to about 1 mPa.cndot.s, from about 10 mPa.cndot.s to about 1 mPa.cndot.s, and from about 5 mPa.cndot.s to about 1 mPa.cndot.s.
26. The composition of claim 1 formulated into a liquid dosage form, wherein the viscosity of the dosage form is selected from the group consisting of less than 1/200, less than 1/100, less than 1/50, less than 1/25, and less than 1/10 of the viscosity of a liquid dosage form of a conventional non-nanoparticulate topiramate composition, at the same concentration per ml of topiramate.
27. The composition of claim 1 formulated into a liquid dosage form, wherein the viscosity of the dosage form is selected from the group consisting of less than 5%, less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, less than 50%, less than 55%, less than 60%, less than 65%, less than 70%, less than 75%, less than 80%, less than 85%, and less than 90% of the viscosity of a liquid dosage form of a conventional non-nanoparticulate topiramate composition at the same concentration per ml of topiramate.
28. The composition of claim 1 formulated into a liquid dosage form, wherein the amount of topiramate per ml is equal to or greater than the amount of topiramate per ml of a liquid dosage form of a conventional non-nanoparticulate topiramate composition.
29. The composition of claim 1, wherein upon administration the composition redisperses such that the topiramate particles have an effective average particle size selected from the group consisting of less than 2 microns, less than 1900 nm, less than 1800 nm, less than 1700 nm, less than 1600 nm, less than 1500 nm, less than 1400 nm, less than 1300 nm, less than 1200 nm, less than 1100 nm, less than 1000 nm, less than 900 nm, less than 800 nm, less than 700 nm, less than 600 nm, less than 500 nm, less than 400 nm, less than 300 nm, less than 250 nm, less than 200 nm, less than 150 nm, less than 100 nm, less than 75 nm, and less than 50 nm.
30. The composition of claim 1, wherein the composition redisperses in a biorelevant media such that the topiramate particles have an effective average particle size selected from the group consisting of less than 2 microns, less than 1900 nm, less than 1800 nm, less than 1700 nm, less than 1600 nm, less than 1500 nm, less than 1400 nm, less than 1300 nm, less than 1200 nm, less than 1100 nm, less than 1000 nm, less than 900 nm, less than 800 nm, less than 700 nm, less than 600 nm, less than 500 nm, less than 400 nm, less than 300 nm, less than 250 nm, less than 200 nm, less than 150 nm, less than 100 nm, less than 75 nm, and less than 50 nm.
31. The composition of claim 1, wherein the composition does not produce significantly different absorption levels when administered under fed as compared to fasted conditions.
32. The composition of claim 1, wherein upon administration the T max is less than that of a conventional non-nanoparticulate topiramate composition, administered at the same dosage.
33. The composition of claim 32, wherein in comparative pharmacokinetic testing with a conventional non-nanoparticulate topiramate composition, administered at the same dosage, the nanoparticulate composition exhibits a T max selected from the group consisting of less than 100%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 15%, and less than 10% of the T max exhibited by the non-nanoparticulate topiramate composition.
34. The composition of claim 1, wherein following administration the composition has a T max selected from the group consisting of less than 2 hours, less than 110 min., less than 100 min., less than 90 min., less than 80 min. less than 70 min., less than 60 min., less than 50 mm., less than 40 min., less than 30 min., less than 25 min., less than 20 min., less than 15 min., less than 10 min., less than 5 min., and less than 3 min.
35. The composition of claim 1, wherein upon administration the C max of the composition is greater than the C max of a conventional non-nanoparticulate topiramate composition, administered at the same dosage.
36. The composition of claim 35, wherein in comparative pharmacokinetic testing with a conventional non-nanoparticulate topiramate composition, administered at the same dosage, the nanoparticulate composition exhibits a C max selected from the group consisting of greater than 5%, greater than 10%, greater than 15%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, greater than 60%, greater than 70%, greater than 80%, greater than 90%, greater than 100%, greater than 110%, greater than 120%, greater than 130%, greater than 140%, and greater than 150% than the C.
exhibited by the non-nanoparticulate topiramate composition.
37. The composition of claim 1, wherein the therapeutically effective amount of topiramate is selected from the group consisting of 1/6, 1/5, 1/3rd and 1/2 of the therapeutically effective amount of a conventional non-nanoparticulate topiramate composition.
38. The nanoparticulate topiramate composition of claim 1 formulated into a dosage form for oral administration, wherein the relative bioavailability of the nanoparticulate topiramate composition compared to a solution is selected from the group consisting of greater than 80%, greater than 85%, greater than 90%, and greater than 95%.
39. A method of making a nanoparticulate topiramate composition comprising contacting topiramate particles with at least one surface stabilizer for a time and under conditions sufficient to provide a nanoparticulate topiramate composition having an effective average particle size of less than 2 microns.
40. The method of claim 39, wherein said contacting comprises grinding.
41. The method of claim 40, wherein said grinding comprises wet grinding.
42. The method of claim 39, wherein said contacting comprises homogenizing.
43. The method of claim 39, wherein said contacting comprises:
(a) dissolving the topiramate particles in a solvent;
(b) adding the resulting topiramate solution to a solution comprising at least one surface stabilizer; and (c) precipitating the solubilized topiramate and at least one surface by the addition thereto of a non-solvent.
44. The method of claim 39, wherein the effective average particle size of the nanoparticulate topiramate particles is selected from the group consisting of less than 1900 nm, less than 1800 nm, less than 1700 nm, less than 1600 nm, less than 1500 nm, less than 1400 nm, less than 1300 nm, less than 1200 nm, less than 1100 nm, less than 1000 nm, less than 900 nm, less than 800 nm, less than 700 nm, less than 600 nm, less than 500 nm, less than 400 nm, less than 300 nm, less than 250 nm, less than 200 nm, less than 150 nm, less than 140 nm, less than 130 nm, less than 120 nm, less than 110 nm, less than 100 nm, less than 90 nm, less than 80 nm, less than 70 nm, less than 60 nm, and less than 50 nm.
45. The method of claim 44, wherein at least 70%, at least 90%, at least 95%, or at least 99% of the topiramate particles have a particle size less than the effective average particle size.
46. The method of claim 43, wherein the topiramate is selected from the group consisting of a crystalline phase, an amorphous phase, and a semi-crystalline phase.
47. The method of claim 39, wherein the composition is formulated for administration selected from the group consisting of oral, pulmonary, rectal, opthalmic, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, local, buccal, nasal, and topical administration.
48. The method of claim 39, wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers, or a combination thereof.
49. The method of claim 39, wherein the topiramate is present in an amount selected from the group consisting of from about 99.5% to about 0.001%, from about 95% to about 0.1%, and from about 90% to about 0.5%, by weight, based on the total combined dry weight of the topiramate and at least one surface stabilizer, not including other excipients.
50. The method of claim 39, wherein the at least one surface stabilizer is present in an amount selected from the group consisting of from about 0.5%
to about 99.999%, from about 5.0% to about 99.9%, and from about 10% to about 99.5%, by weight, based on the total combined dry weight of the topiramate and at least one surface stabilizer, not including other excipients.
51. The method of claim 39, comprising at least two surface stabilizers.
52. The method of claim 39, wherein the surface stabilizer is selected from the group consisting of an anionic surface stabilizer, a cationic surface stabilizer, a zwitterionic surface stabilizer, and an ionic surface stabilizer.
53. The method of claim 52, wherein the at least one surface stabilizer is selected from the group consisting of cetyl pyridinium chloride, gelatin, casein, phosphatides, dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oils, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, hydroxypropyl celluloses, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde, poloxamers; poloxamines, a charged phospholipid, dioctylsulfosuccinate, dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate, alkyl aryl polyether sulfonates, mixtures of sucrose stearate and sucrose distearate, p-isononylphenoxypoly-(glycidol), decanoyl-N-methylglucamide; n-decyl .beta.-D-glucopyranoside; n-decyl .beta.-D-maltopyranoside; n-dodecyl .beta.-D-glucopyranoside; n-dodecyl .beta.-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-.beta.-D-glucopyranoside; n-heptyl .beta.-D-thioglucoside; n-hexyl .beta.-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl .beta.-D-glucopyranoside;
octanoyl-N-methylglucamide; n-octyl-.beta.-D-glucopyranoside; octyl .beta.-D-thioglucopyranoside; lysozyme, PEG-derivatized phospholipid, PEG-derivatized cholesterols, PEG-derivatized vitamin A, PEG-derivatized vitamin E, and random copolymers of vinyl acetate and vinyl pyrrolidone.
54. The method of claim 52, wherein the at least one cationic surface stabilizer is selected from the group consisting of a polymer, a biopolymer, a polysaccharide, a cellulosic, an alginate, a nonpolymeric compound, a phospholipid, zwitterionic stabilizers, poly-n-methylpyridinium, anthryul pyridinium chloride, chitosan, polylysine, polyvinylimidazole, polybrene, polymethylmethacrylate trimethylammoniumbromide bromide (PMMTMABr), hexyldesyltrimethylammonium bromide (HDMAB), polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, 1,2 Dipalmitoyl-sn-Glycero-3-Phosphoethanolamine-N-[Amino(Polyethylene Glycol)2000] (sodium salt), Poly(2-methacryloxyethyl trimethylammonium bromide), poloxamines, lysozyme, alginic acid, carrageenan, POLYOX, cationic lipids, sulfonium, phosphonium, quarternary ammonium compounds, stearyltrimethylammonium chloride, benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride, coconut trimethyl ammonium bromide, coconut methyl dihydroxyethyl ammonium chloride, coconut methyl dihydroxyethyl ammonium bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium bromide, C12-15dimethyl hydroxyethyl ammonium chloride, C12-15dimethyl . hydroxyethyl ammonium bromide, coconut dimethyl hydroxyethyl ammonium chloride, coconut dimethyl hydroxyethyl ammonium bromide, myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl (ethenoxy)4 ammonium chloride, lauryl dimethyl (ethenoxy)4 ammonium bromide, N-alkyl (C12-18)dimethylbenzyl ammonium chloride, N-alkyl (C14-18)dimethyl-benzyl ammonium chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C12-14) dimethyl 1-napthylmethyl ammonium chloride, trimethylammonium halide, alkyl-trimethylammonium salts, dialkyl-dimethylammonium salts, lauryl trimethyl ammonium chloride, ethoxylated alkyamidoalkyldialkylammonium salt, an ethoxylated trialkyl ammonium salt, dialkylbenzene dialkylammonium chloride, N-didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl ammonium, chloride monohydrate, N-alkyl(C12-14) dimethyl 1-naphthylmethyl ammonium chloride, dodecyldimethylbenzyl ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C12, C15, C17 trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium chloride, poly-diallyldimethylammonium chloride, dimethyl ammonium chlorides, alkyldimethylammonium halogenides, tricetyl methyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride, polyquaternium 10, tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters, benzalkonium chloride, stearalkonium chloride compounds, cetyl pyridinium bromide, cetyl pyridinium chloride, halide salts of quaternized polyoxyethylalkylamines, quaternized ammonium salt polymers, alkyl pyridinium salts, amines, protonated quaternary acrylamides, methylated quaternary polymers, and cationic guar.
55. The method of claim 54, wherein the amine is selected from the group consisting of alkylamines, dialkylamines, alkanolamines, polyethylenepolyamines, N,N-dialkylaminoalkyl acrylates, vinyl pyridine, amine salts, lauryl amine acetate, stearyl amine acetate, alkylpyridinium salt, alkylimidazolium salt, amine oxides, and, imide azolinium salts.
56. The method of claim 52, wherein the cationic surface stabilizer is a nonpolymeric compound selected from the group consisting of benzalkonium chloride, a carbonium compound, a phosphonium compound, an oxonium compound, a halonium compound, a cationic organometallic compound, a quarternary phosphorous compound, a pyridinium compound, an anilinium compound, an ammonium compound, a hydroxylammonium compound, a primary ammonium compound, a secondary ammonium compound, a tertiary ammonium compound, behenalkonium chloride, benzethonium chloride, cetylpyridinium chloride, behentrimonium chloride, lauralkonium chloride, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cethylamine hydrofluoride, chlorallylmethenamine chloride (Quaternium-15), distearyldimonium chloride (Quaternium-5), dodecyl dimethyl ethylbenzyl ammonium chloride(Quaternium-14), Quaternium-22, Quaternium-26, Quaternium-18 hectorite, dimethylaminoethylchloride hydrochloride, cysteine hydrochloride, diethanolammonium POE (10) oletyl ether phosphate, diethanolammonium POE (3)oleyl ether phosphate, tallow alkonium chloride, dimethyl dioctadecylammoniumbentonite, stearalkonium chloride, domiphen bromide, denatonium benzoate, myristalkonium chloride, laurtrimonium chloride, ethylenediamine dihydrochloride, guanidine hydrochloride, pyridoxine HCI, iofetamine hydrochloride, megiumine hydrochloride, methylbenzethonium chloride, myrtrimonium bromide, oleyltrimonium chloride, polyquaternium-1, procainehydrochloride, cocobetaine, stearalkonium bentonite, stearalkoniumhectonite, stearyl trihydroxyethyl propylenediamine dihydrofluoride, tallowtrimonium chloride, and hexadecyltrimethyl ammonium bromide.
57. The method according to any one of claims 52, 54, 55 or 56, wherein the composition is bioadhesive.
58. The method of claim 39, comprising hypromellose, docusate sodium, or a combination thereof as surface stabilizers.
59. The method of claim 39, wherein after preparation of the nanoparticulate topiramate composition, a second topiramate composition having an effective average particle size of greater than 2 microns is combined with the nanoparticulate topiramate composition.
60. The method of claim 39, wherein either prior or subsequent to preparation of the nanoparticulate topiramate composition, at least one non-topiramate active agent is added to the nanoparticulate topiramate composition.
61. The method of claim 60, wherein said non-topiramate active agent is selected from the group consisting of amino acids proteins, peptides, nucleotides, anti-obesity drugs, nutraceuticals, dietary supplements, carotenoids, central nervous system stimulants, corticosteroids, elastase inhibitors, anti-fungals, alkylxanthine, oncology therapies, anti-emetics, analgesics, opioids, antipyretics, cardiovascular agents, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytics, sedatives, astringents, alpha-adrenergic receptor blocking agents, beta-adrenoceptor blocking agents, blood products, blood substitutes, cardiac inotropic agents, contrast media, corticosteroids, cough suppressants, diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics, haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones, anti-allergic agents, stimulants, anoretics, sympathomimetics, thyroid agents, vasodilators, vasomodulator, xanthines, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic analgesics, monoamine uptake inhibitors, adenosine regulating agents, cannabinoids, Substance P antagonists, neurokinin-1 receptor antagonists, and sodium channel blockers.
62. The method of claim 61, wherein said nutraceutical is selected from the group consisting of lutein, folic acid, fatty acids, fruit extracts, vegetable extracts, vitamin supplements, mineral supplements, phosphatidylserine, lipoic acid, melatonin, glucosamine/chondroitin, Aloe Vera, Guggul, glutamine, amino acids, green tea, lycopene, whole foods, food additives, herbs, phytonutrients, antioxidants, flavonoid constituents of fruits, evening primrose oil, flax seeds, fish oils, marine animal oils, and probiotics.
63. The method of any one of claims 60, 61, or 62, wherein at least one non-topiramate active agent has an effective average particle size of less than 2 microns.
64. The method of any one of claims 60, 61, or 62, wherein at least one non-topiramate active agent has an effective average particle size of greater than 2 microns.
65. Use of an effective amount of a nanoparticulate topiramate formulation composition comprising topiramate particles and at least one surface stabilizer, wherein the topiramate particles have an effective average particle size of less than 2 microns to treat a subject in need.
66. The use of claim 65, wherein the subject has a condition selected from the group consisting of seizures, mood disorders, post traumatic stress syndrome (PTSD), Bipolar Disorder, mania, depression, personality disorders, bipolar mood instability, schizophrenia, psychosis, bipolar spectrum disorders, and rapid-cycling bipolar disorders.
67. The use of claim 65, wherein the subject has a mood disorder or a bipolar mood disorder which has not been adequately controlled by other medications.
68. The use of claim 65, wherein the subject is being treated for obesity.
69. The use of claim 65, wherein the subject is being treated for alcohol dependence.
70. The use of claim 65, wherein the subject is being treated for nicotine addiction.
71. The use of claim 65, wherein the subject is being treated for drug addiction.
72. The use of claim 65, wherein the subject is being treated for an undesirable addictive behavior.
73. The use of claim 65, wherein the subject is being treated for migraines.
74. The use of claim 65, wherein the subject is being treated for neuropathic pain relief.
75. The use of claim 65, wherein the subject is being treated for essential type tremor.
76. The use of claim 65, wherein the subject is being treated for cluster headaches.
77. The use of claim 65, wherein said subject is a human.
78. The use of claim 65, wherein the effective average particle size of the nanoparticulate topiramate particles is selected from the group consisting of less than 1900 nm, less than 1800 nm, less than 1700 nm, less than 1600 nm, less than 1500 nm, less than 1400 nm, less than 1300 nm, less than 1200 nm, less than 1100 nm, less than 1000 nm, less than 900 nm, less than 800 nm, less than 700 nm, less than 600 nm, less than 500 nm, less than 400 nm, less than 300 nm, less than 250 nm, less than 200 nm, less than 150 nm, less than 140 nm, less than 130 nm, less than 120 nm, less than 110 nm, less than 100 nm, less than 90 nm, less than 80 nm, less than 70 nm, less than 60 nm, and less than 50 nm.
79. The use of claim 65, wherein at least 70%, at least 90%, at least 95%, or at least 99% of the topiramate particles have a particle size less than the effective average particle size.
80. The use of claim 65, wherein the topiramate is selected from the group consisting of a crystalline phase, an amorphous phase, and a semi-crystalline phase.
81. The use of claim 65, wherein the composition is formulated for administration selected from the group consisting of oral, pulmonary, rectal, opthalmic, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, local, buccal, nasal, and topical administration.
82. The use of claim 65, wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers, or a combination thereof.
83. The use of claim 65, wherein the topiramate is present in an amount selected from the group consisting of from about 99.5% to about 0.001%, from about 95% to about 0.1%, and from about 90% to about 0.5%, by weight, based on the total combined dry weight of the topiramate and at least one surface stabilizer, not including other excipients.
84. The use of claim 65, wherein the at least one surface stabilizer is present in an amount selected from the group consisting of from about 0.5%
to about 99.999%, from about 5.0% to about 99.9%, and from about 10% to about 99.5%, by weight, based on the total combined dry weight of the topiramate and at least one surface stabilizer, not including other excipients.
85. The use of claim 65, comprising at least two surface stabilizers.
86. The use of claim 65, wherein the surface stabilizer is selected from the group consisting of an anionic surface stabilizer, a cationic surface stabilizer, a zwitterionic surface stabilizer, and an ionic surface stabilizer.
87. The use of claim 86, wherein the at least one surface stabilizer is selected from the group consisting of cetyl pyridinium chloride, gelatin, casein, phosphatides, dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oils, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, hydroxypropyl celluloses, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde, poloxamers; poloxamines, a charged phospholipid, dioctylsulfosuccinate, dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate, alkyl aryl polyether sulfonates, mixtures of sucrose stearate and sucrose distearate, p-isononylphenoxypoly-(glycidol), decanoyl-N-methylglucamide; n-decyl .beta.-D-glucopyranoside; n-decyl .beta.-D-maltopyranoside; n-dodecyl .beta.-D-glucopyranoside; n-dodecyl .beta.-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-.beta.-D-glucopyranoside; n-heptyl .beta.-D-thioglucoside; n-hexyl .beta.-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl .beta.-D-glucopyranoside;
octanoyl-N-methylglucamide; n-octyl-.beta.-D-glucopyranoside; octyl .beta.-D-thioglucopyranoside; lysozyme, PEG-derivatized phospholipid, PEG-derivatized cholesterols, PEG-derivatized vitamin A, PEG-derivatized vitamin E, and random copolymers of vinyl acetate and vinyl pyrrolidone.
88. The use of claim 86, wherein the at least one cationic surface stabilizer is selected from the group consisting of a polymer, a biopolymer, a polysaccharide, a cellulosic, an alginate, a nonpolymeric compound, a phospholipid, zwitterionic stabilizers, poly-n-methylpyridinium, anthryul pyridinium chloride, chitosan, polylysine, polyvinylimidazole, polybrene, polymethylmethacrylate trimethylammoniumbromide bromide (PMMTMABr), hexyldesyltrimethylammonium bromide (HDMAB), polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, 1,2 Dipalmitoyl-sn-Glycero-3-Phosphoethanolamine-N-[Amino(Polyethylene Glycol)2000] (sodium salt), Poly(2-methacryloxyethyl trimethylammonium bromide), poloxamines, lysozyme, alginic acid, carrageenan, POLYOX, cationic lipids, sulfonium, phosphonium, quarternary ammonium compounds, stearyltrimethylammonium chloride, benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride, coconut trimethyl ammonium bromide, coconut methyl dihydroxyethyl ammonium chloride, coconut methyl dihydroxyethyl ammonium bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium bromide, C12-15dimethyl hydroxyethyl ammonium chloride, C12-15dimethyl hydroxyethyl ammonium bromide, coconut dimethyl hydroxyethyl ammonium chloride, coconut dimethyl hydroxyethyl ammonium bromide, myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl (ethenoxy)4 ammonium chloride, lauryl dimethyl (ethenoxy)4 ammonium bromide, N-alkyl (C12-18)dimethylbenzyl ammonium chloride, N-alkyl (C14-18)dimethyl-benzyl ammonium chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C12-14) dimethyl 1-napthylmethyl ammonium chloride, trimethylammonium halide, alkyl-trimethylammonium salts, dialkyl-dimethylammonium salts, lauryl trimethyl ammonium chloride, ethoxylated alkyamidoalkyldialkylammonium salt, an ethoxylated trialkyl ammonium salt, dialkylbenzene dialkylammonium chloride, N-didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl ammonium, chloride monohydrate, N-alkyl(C12-14) dimethyl 1-naphthylmethyl ammonium chloride, dodecyldimethylbenzyl ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C12, C15, C17 trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium chloride, poly-diallyldimethylammonium chloride, dimethyl ammonium chlorides, alkyldimethylammonium halogenides, tricetyl methyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride, polyquaternium 10, tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters, benzalkonium chloride, stearalkonium chloride compounds, cetyl pyridinium bromide, cetyl pyridinium chloride, halide salts of quaternized polyoxyethylalkylamines, quaternized ammonium salt, alkyl pyridinium salts, amines, protonated quaternary acrylamides, methylated quaternary polymers, and cationic guar.
89. The use of claim 88, wherein the amine is selected from the group consisting of alkylamines, dialkylamines, alkanolamines, polyethylenepolyamines, N,N-dialkylaminoalkyl acrylates, vinyl pyridine, amine salts, lauryl amine acetate, stearyl amine acetate, alkylpyridinium salt, alkylimidazolium salt, amine oxides, and, imide azolinium salts.
90. The use of claim 86, wherein the cationic surface stabilizer is a nonpolymeric compound selected from the group consisting of benzalkonium chloride, a carbonium compound, a phosphonium compound, an oxonium compound, a halonium compound, a cationic organometallic compound, a quarternary phosphorous compound, a pyridinium compound, an anilinium compound, an ammonium compound, a hydroxylammonium compound, a primary ammonium compound, a secondary ammonium compound, a tertiary ammonium compound, behenalkonium chloride, benzethonium chloride, cetylpyridinium chloride, behentrimonium chloride, lauralkonium chloride, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cethylamine hydrofluoride, chlorallylmethenamine chloride (Quaternium-15), distearyldimonium chloride (Quaternium-5), dodecyl dimethyl ethylbenzyl ammonium chloride(Quaternium-14), Quaternium-22, Quaternium-26, Quaternium-18 hectonte, dimethylaminoethylchloride hydrochloride, cysteine hydrochloride, diethanolammonium POE (10) oletyl ether phosphate, diethanolammonium POE (3)oleyl ether phosphate, tallow alkonium chloride, dimethyl dioctadecylammoniumbentonite, stearalkonium chloride, domiphen bromide, denatonium benzoate, myristalkonium chloride, laurtrimonium chloride, ethylenediamine dihydrochloride, guanidine hydrochloride, pyridoxine HCI, iofetamine hydrochloride, meglumine hydrochloride, methylbenzethonium chloride, myrtrimonium bromide, oleyltrimonium chloride, polyquaternium-1, procainehydrochloride, cocobetaine, stearalkonium bentonite, stearalkoniumhectonite, stearyl trihydroxyethyl propylenediamine dihydrofluoride, tallowtrimonium chloride, and hexadecyltrimethyl ammonium bromide.
91. The use according to any one of claims 86, 88, 89, or 90, wherein the composition is bioadhesive.
92. The use of claim 65, comprising hypromellose, docusate sodium, or a combination thereof as surface stabilizers.
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Families Citing this family (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080102121A1 (en) * 1998-11-02 2008-05-01 Elan Pharma International Limited Compositions comprising nanoparticulate meloxicam and controlled release hydrocodone
US7763663B2 (en) * 2001-12-19 2010-07-27 University Of Massachusetts Polysaccharide-containing block copolymer particles and uses thereof
ATE464880T1 (en) 2002-02-04 2010-05-15 Elan Pharma Int Ltd MEDICINAL NANOPARTICLES WITH LYSOZYME SURFACE STABILIZER
US20060088886A1 (en) * 2004-10-25 2006-04-27 Anlong Ouyang Topiramate analogs
US7638291B2 (en) 2004-10-25 2009-12-29 Seradyn, Inc. Immunoassays for topiramate
JP2008535924A (en) 2005-04-12 2008-09-04 エラン ファーマ インターナショナル リミテッド Nanoparticulate quinazoline derivative formulation
EP1954253A4 (en) 2005-06-08 2011-07-27 Elan Pharma Int Ltd Nanoparticulate and controlled release compositions comprising cefditoren
CN101384247B (en) 2005-07-18 2013-05-22 麻萨诸塞州洛厄尔大学 Compositions and methods for making and using nanoemulsions
KR20080033383A (en) * 2005-08-12 2008-04-16 아스트라제네카 아베 Process
WO2007035348A2 (en) 2005-09-15 2007-03-29 Elan Pharma International, Limited Nanoparticulate aripiprazole formulations
DE202005016250U1 (en) * 2005-10-17 2006-01-26 Helm Ag Topiramate and pharmaceutical formulations thereof
HUE054852T2 (en) 2005-12-01 2021-10-28 Univ Massachusetts Lowell Botulinum nanoemulsions
US9486408B2 (en) 2005-12-01 2016-11-08 University Of Massachusetts Lowell Botulinum nanoemulsions
US20070281011A1 (en) 2006-05-30 2007-12-06 Elan Pharma International Ltd. Nanoparticulate posaconazole formulations
BRPI0714173A2 (en) * 2006-07-12 2012-12-25 Elan Pharma Int Ltd stable nanoparticulate composition, methods for preparing the composition, for preventing and / or treating disease conditions, symptoms, syndromes and conditions of the central nervous system, for improving or maintaining bioavailability of modafinil, and for treating neurologically based disorder, pharmaceutical composition, and dosage form
WO2008027557A2 (en) 2006-08-31 2008-03-06 Spherics, Inc. Topiramate compositions and methods of enhancing its bioavailability
AU2007319141B2 (en) 2006-11-17 2013-01-10 Supernus Pharmaceuticals Inc. Sustained-release formulations of topiramate
KR101518077B1 (en) 2006-12-01 2015-05-28 안테리오스, 인코퍼레이티드 Peptide nanoparticles and uses therefor
KR20090106493A (en) 2006-12-01 2009-10-09 안테리오스, 인코퍼레이티드 Micellar nanoparticles comprising botulinum toxin
EP2363113B1 (en) * 2006-12-04 2017-08-02 Supernus Pharmaceuticals, Inc. Enhanced immediate release formulations of topiramate
WO2008095221A1 (en) * 2007-02-07 2008-08-14 Gosforth Centre (Holdings) Pty Ltd Treatment of adhd
TW200848039A (en) * 2007-02-09 2008-12-16 Astrazeneca Ab Pharmaceutical compositions
WO2008097165A1 (en) * 2007-02-09 2008-08-14 Astrazeneca Ab Process for preparation of a stable dispersion of solid amorphous submicron particles in an aqueous medium
JP5424571B2 (en) * 2007-04-12 2014-02-26 協和発酵キリン株式会社 Topiramate-containing solid preparation
WO2008151022A2 (en) 2007-05-31 2008-12-11 Anterios, Inc. Nucleic acid nanoparticles and uses therefor
WO2009036368A2 (en) 2007-09-14 2009-03-19 Nitto Denko Corporation Drug carriers
AU2009279372A1 (en) * 2008-08-06 2010-02-11 Gosforth Centre (Holdings) Pty Ltd Compositions and methods for treating psychiatric disorders
US20100055187A1 (en) * 2008-08-28 2010-03-04 Dong June Ahn Nanovitamin synthesis
US20100055246A1 (en) * 2008-08-28 2010-03-04 Dong June Ahn Nutrition delivery capsules for functional foods
EP2344183B1 (en) * 2008-10-10 2015-02-25 Alvine Pharmaceuticals, Inc. Dosage forms that facilitate rapid activation of zymogen
EP2177215A1 (en) 2008-10-17 2010-04-21 Laboratorios Del. Dr. Esteve, S.A. Co-crystals of tramadol and NSAIDs
WO2010087447A1 (en) * 2009-01-30 2010-08-05 明治製菓株式会社 Finely pulverized pharmaceutical composition
WO2010138539A2 (en) 2009-05-27 2010-12-02 Elan Pharma International Ltd. Reduction of flake-like aggregation in nanoparticulate active agent compositions
WO2011146583A2 (en) 2010-05-19 2011-11-24 Elan Pharma International Limited Nanoparticulate cinacalcet formulations
WO2013074526A2 (en) 2011-11-15 2013-05-23 Byocoat Enterprises, Inc. Antimicrobial compositions and methods of use thereof
US8652527B1 (en) 2013-03-13 2014-02-18 Upsher-Smith Laboratories, Inc Extended-release topiramate capsules
US9101545B2 (en) 2013-03-15 2015-08-11 Upsher-Smith Laboratories, Inc. Extended-release topiramate capsules
US10278948B1 (en) 2015-09-03 2019-05-07 Tian Xia Method for transnasal delivery of anticonvulsant and therapeutic treatments
MX2019005833A (en) 2016-11-21 2019-10-30 Eirion Therapeutics Inc Transdermal delivery of large agents.
US20220016074A1 (en) 2018-11-21 2022-01-20 Rosemont Pharmaceuticals Limited Oral topiramate suspension formulations with extended shelf stability and enhanced bioavailability
CN114748670B (en) * 2022-04-11 2023-04-21 武汉诺薇生物科技有限公司 Nonwoven hemostatic gauze and preparation method and application thereof

Family Cites Families (70)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4826689A (en) 1984-05-21 1989-05-02 University Of Rochester Method for making uniformly sized particles from water-insoluble organic compounds
US4783484A (en) 1984-10-05 1988-11-08 University Of Rochester Particulate composition and use thereof as antimicrobial agent
US5399363A (en) 1991-01-25 1995-03-21 Eastman Kodak Company Surface modified anticancer nanoparticles
US5145684A (en) 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles
US5552160A (en) 1991-01-25 1996-09-03 Nanosystems L.L.C. Surface modified NSAID nanoparticles
AU642066B2 (en) 1991-01-25 1993-10-07 Nanosystems L.L.C. X-ray contrast compositions useful in medical imaging
CA2112905A1 (en) 1991-07-05 1993-01-21 Michael R. Violante Ultrasmall non-aggregated porous particles entrapping gas-bubbles
AU660852B2 (en) 1992-11-25 1995-07-06 Elan Pharma International Limited Method of grinding pharmaceutical substances
US5349957A (en) 1992-12-02 1994-09-27 Sterling Winthrop Inc. Preparation and magnetic properties of very small magnetite-dextran particles
US5346702A (en) 1992-12-04 1994-09-13 Sterling Winthrop Inc. Use of non-ionic cloud point modifiers to minimize nanoparticle aggregation during sterilization
US5298262A (en) 1992-12-04 1994-03-29 Sterling Winthrop Inc. Use of ionic cloud point modifiers to prevent particle aggregation during sterilization
US5302401A (en) 1992-12-09 1994-04-12 Sterling Winthrop Inc. Method to reduce particle size growth during lyophilization
US5340564A (en) 1992-12-10 1994-08-23 Sterling Winthrop Inc. Formulations comprising olin 10-G to prevent particle aggregation and increase stability
US5336507A (en) 1992-12-11 1994-08-09 Sterling Winthrop Inc. Use of charged phospholipids to reduce nanoparticle aggregation
US5429824A (en) 1992-12-15 1995-07-04 Eastman Kodak Company Use of tyloxapole as a nanoparticle stabilizer and dispersant
US5352459A (en) 1992-12-16 1994-10-04 Sterling Winthrop Inc. Use of purified surface modifiers to prevent particle aggregation during sterilization
US5326552A (en) 1992-12-17 1994-07-05 Sterling Winthrop Inc. Formulations for nanoparticulate x-ray blood pool contrast agents using high molecular weight nonionic surfactants
US5401492A (en) 1992-12-17 1995-03-28 Sterling Winthrop, Inc. Water insoluble non-magnetic manganese particles as magnetic resonance contract enhancement agents
US5264610A (en) 1993-03-29 1993-11-23 Sterling Winthrop Inc. Iodinated aromatic propanedioates
US5718388A (en) 1994-05-25 1998-02-17 Eastman Kodak Continuous method of grinding pharmaceutical substances
TW384224B (en) 1994-05-25 2000-03-11 Nano Sys Llc Method of preparing submicron particles of a therapeutic or diagnostic agent
US5525328A (en) 1994-06-24 1996-06-11 Nanosystems L.L.C. Nanoparticulate diagnostic diatrizoxy ester X-ray contrast agents for blood pool and lymphatic system imaging
US5587143A (en) 1994-06-28 1996-12-24 Nanosystems L.L.C. Butylene oxide-ethylene oxide block copolymer surfactants as stabilizer coatings for nanoparticle compositions
US5466440A (en) 1994-12-30 1995-11-14 Eastman Kodak Company Formulations of oral gastrointestinal diagnostic X-ray contrast agents in combination with pharmaceutically acceptable clays
US5585108A (en) 1994-12-30 1996-12-17 Nanosystems L.L.C. Formulations of oral gastrointestinal therapeutic agents in combination with pharmaceutically acceptable clays
US5628981A (en) 1994-12-30 1997-05-13 Nano Systems L.L.C. Formulations of oral gastrointestinal diagnostic x-ray contrast agents and oral gastrointestinal therapeutic agents
US5560932A (en) 1995-01-10 1996-10-01 Nano Systems L.L.C. Microprecipitation of nanoparticulate pharmaceutical agents
US5665331A (en) 1995-01-10 1997-09-09 Nanosystems L.L.C. Co-microprecipitation of nanoparticulate pharmaceutical agents with crystal growth modifiers
US5662883A (en) 1995-01-10 1997-09-02 Nanosystems L.L.C. Microprecipitation of micro-nanoparticulate pharmaceutical agents
US5569448A (en) 1995-01-24 1996-10-29 Nano Systems L.L.C. Sulfated nonionic block copolymer surfactants as stabilizer coatings for nanoparticle compositions
US5571536A (en) 1995-02-06 1996-11-05 Nano Systems L.L.C. Formulations of compounds as nanoparticulate dispersions in digestible oils or fatty acids
US5560931A (en) 1995-02-14 1996-10-01 Nawosystems L.L.C. Formulations of compounds as nanoparticulate dispersions in digestible oils or fatty acids
US5622938A (en) 1995-02-09 1997-04-22 Nano Systems L.L.C. Sugar base surfactant for nanocrystals
US5518738A (en) 1995-02-09 1996-05-21 Nanosystem L.L.C. Nanoparticulate nsaid compositions
US5534270A (en) 1995-02-09 1996-07-09 Nanosystems Llc Method of preparing stable drug nanoparticles
US5593657A (en) 1995-02-09 1997-01-14 Nanosystems L.L.C. Barium salt formulations stabilized by non-ionic and anionic stabilizers
US5500204A (en) 1995-02-10 1996-03-19 Eastman Kodak Company Nanoparticulate diagnostic dimers as x-ray contrast agents for blood pool and lymphatic system imaging
US5591456A (en) 1995-02-10 1997-01-07 Nanosystems L.L.C. Milled naproxen with hydroxypropyl cellulose as a dispersion stabilizer
US5573783A (en) 1995-02-13 1996-11-12 Nano Systems L.L.C. Redispersible nanoparticulate film matrices with protective overcoats
US5510118A (en) 1995-02-14 1996-04-23 Nanosystems Llc Process for preparing therapeutic compositions containing nanoparticles
US5543133A (en) 1995-02-14 1996-08-06 Nanosystems L.L.C. Process of preparing x-ray contrast compositions containing nanoparticles
US5580579A (en) 1995-02-15 1996-12-03 Nano Systems L.L.C. Site-specific adhesion within the GI tract using nanoparticles stabilized by high molecular weight, linear poly (ethylene oxide) polymers
US5565188A (en) 1995-02-24 1996-10-15 Nanosystems L.L.C. Polyalkylene block copolymers as surface modifiers for nanoparticles
US5747001A (en) 1995-02-24 1998-05-05 Nanosystems, L.L.C. Aerosols containing beclomethazone nanoparticle dispersions
US5718919A (en) 1995-02-24 1998-02-17 Nanosystems L.L.C. Nanoparticles containing the R(-)enantiomer of ibuprofen
AU4990696A (en) 1995-02-24 1996-09-11 Nanosystems L.L.C. Aerosols containing nanoparticle dispersions
US5643552A (en) 1995-03-09 1997-07-01 Nanosystems L.L.C. Nanoparticulate diagnostic mixed carbonic anhydrides as x-ray contrast agents for blood pool and lymphatic system imaging
US5573749A (en) 1995-03-09 1996-11-12 Nano Systems L.L.C. Nanoparticulate diagnostic mixed carboxylic anhydrides as X-ray contrast agents for blood pool and lymphatic system imaging
US5472683A (en) 1995-03-09 1995-12-05 Eastman Kodak Company Nanoparticulate diagnostic mixed carbamic anhydrides as X-ray contrast agents for blood pool and lymphatic system imaging
US5521218A (en) 1995-05-15 1996-05-28 Nanosystems L.L.C. Nanoparticulate iodipamide derivatives for use as x-ray contrast agents
US5573750A (en) 1995-05-22 1996-11-12 Nanosystems L.L.C. Diagnostic imaging x-ray contrast agents
US5834025A (en) 1995-09-29 1998-11-10 Nanosystems L.L.C. Reduction of intravenously administered nanoparticulate-formulation-induced adverse physiological reactions
US6045829A (en) 1997-02-13 2000-04-04 Elan Pharma International Limited Nanocrystalline formulations of human immunodeficiency virus (HIV) protease inhibitors using cellulosic surface stabilizers
WO1998035666A1 (en) * 1997-02-13 1998-08-20 Nanosystems Llc Formulations of nanoparticle naproxen tablets
GB9710699D0 (en) * 1997-05-24 1997-07-16 Danbiosyst Uk Gastro-retentive controlled release system
UA65607C2 (en) * 1998-03-04 2004-04-15 Орто-Макнейл Фармацевтикал, Інк. Pharmaceutical composition (variants) and process for its preparation
US6153225A (en) 1998-08-13 2000-11-28 Elan Pharma International Limited Injectable formulations of nanoparticulate naproxen
US6165506A (en) 1998-09-04 2000-12-26 Elan Pharma International Ltd. Solid dose form of nanoparticulate naproxen
US8293277B2 (en) 1998-10-01 2012-10-23 Alkermes Pharma Ireland Limited Controlled-release nanoparticulate compositions
US6428814B1 (en) 1999-10-08 2002-08-06 Elan Pharma International Ltd. Bioadhesive nanoparticulate compositions having cationic surface stabilizers
US6375986B1 (en) 2000-09-21 2002-04-23 Elan Pharma International Ltd. Solid dose nanoparticulate compositions comprising a synergistic combination of a polymeric surface stabilizer and dioctyl sodium sulfosuccinate
US6270806B1 (en) 1999-03-03 2001-08-07 Elan Pharma International Limited Use of peg-derivatized lipids as surface stabilizers for nanoparticulate compositions
US6267989B1 (en) 1999-03-08 2001-07-31 Klan Pharma International Ltd. Methods for preventing crystal growth and particle aggregation in nanoparticulate compositions
WO2000072973A1 (en) 1999-06-01 2000-12-07 Elan Pharma International Ltd. Small-scale mill and method thereof
US6656504B1 (en) 1999-09-09 2003-12-02 Elan Pharma International Ltd. Nanoparticulate compositions comprising amorphous cyclosporine and methods of making and using such compositions
US20040026546A1 (en) 2000-04-26 2004-02-12 Czekai David A Apparatus for sanitary wet milling
US6316029B1 (en) 2000-05-18 2001-11-13 Flak Pharma International, Ltd. Rapidly disintegrating solid oral dosage form
DK1392441T3 (en) 2001-06-05 2010-01-25 Elan Pharma Int Ltd System and method for milling materials
JP4776229B2 (en) * 2002-07-16 2011-09-21 エラン ファーマ インターナショナル,リミティド Stable nanoparticulate active substance liquid dosage composition
US20050244503A1 (en) 2003-05-19 2005-11-03 Rabinow Barrett E Small-particle pharmaceutical formulations of antiseizure and antidementia agents and immunosuppressive agents

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US20040258758A1 (en) 2004-12-23
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