WO2015100252A1 - Deuterated felbamate, compositions containing the same, and methods of use thereof - Google Patents

Abstract

Felbamate deuterated at the 2 position, compositions containing the same, and methods of making and using thereof are described herein. Substitution of the hydrogen at the 2 position with deuterium should prevent or reduce formation of the toxic metabolite atropaldehyde (ATPAL), which is the cause of felbamate toxicity. The deuterated felbamate can be administered enterally (e.g., orally) or parenterally (e.g., by injection) to treat a variety of neurological diseases or disorders. Suitable daily dosages of the active agent are 100-2000 mg, preferably 200-1000 mg, more preferably 400-600 mg.

Description

DEUTERATED FELBAMATE, COMPOSITIONS CONTAINING THE SAME, AND METHODS OF USE THEREOF

FIELD OF THE INVENTION

This invention is in the field of felbamate derivatives that resist metabolism to atropaldehyde (ATPAL), particularly felbamate-dl , compositions containing the same, and methods of use thereof.

BACKGROUND OF THE INVENTION

Felbamate is a strychnine-insensitive glycine receptor (SIGR) antagonist used to treat a variety of seizure disorders. It was approved for the treatment of epilepsy, including Lennox-Gastaut syndrome, in August 1993. Because of its mechanism of action, it has tested extensively in animal models of stroke, head injury and cardiac arrest and found to markedly reduce post-traumatic neurological damage.

In August 1994, felbamate was "Black Boxed" after aplastic anemia was observed in 33 patients and hepatic failure was observed in 18 patients. It is believed that the liver failure and aplastic anemia is caused by the formation of a reactive aldehyde intermediate, (atropaldehyde or 2-phenylpropenol or ATPAL). Formation of ATPAL from its unstable immediate precursor, 3-carbamoyl-2- phenylpropionaldedhyde (CBMA) requires the loss of the hydrogen atom at position 2 in the propane chain of felbamate. It has been postulated that substitution of this hydrogen with another atom or group may prevent the formation of ATPAL.

For example, the corresponding fluoro derivative has been investigated.

Parker et. ah, Chem Res Toxicol. , 18(12): 1842-8 , (2005) describe the synthesis and evaluation of 2-fluoro-2-phenyl-l ,3-propanediol dicarbamate (F-FBM). The metabolism by human liver postmitochondrial suspensions (S9) in vitro of selected FBM and postulated F-FBM metabolites leading to formation of CBMA or 3- carbamoyl-2-fluoro-2-phenyl-propionaldehyde (F-CBMA) was assessed. All S9 incubations included GSH as a trapping agent for any reactive metabolites formed. The results indicated that, in phosphate buffer, pH 7.4, at 37°C, the half-life for 4- hydroxy-5-phenyltetrahydro-l,3-oxazin-2-one (CCMF) was 2.8 and 3.6 h, respectively, in the presence or absence of GSH compared to 4-hydroxy-5-fluoro-5~ phenyl-tetrahydro-l,3-oxazin-2-one (F-CCMF) which lost only 2.5% or 4.9% over 24 h under the same conditions. When incubated with S9 in the presence of the cofactor, NAD+, 2-phenyl- 1,3 -propanediol monocarbamate (MCF) was oxidized to CCMF which was further oxidized to 3-carbamoyl-2-phenylpropionic acid (CPPA). 2- Fluoro-2-phenyl- 1,3 -propanediol monocarbamate (F-MCF) under similar conditions was stable, and no metabolites were observed. When CCMF was incubated with S9 in the presence of NAD+ cofactor, oxidation to CPPA and reduction to MCF were observed. In addition, a new atropic acid GSH adduct (ATPA-GSH) was identified by mass spectrometry. When F-CCMF was incubated under the same conditions as CCMF, both reduced and oxidized metabolites, F-MCF and 3-carbamoyl-2-fluoro-2- phenylpropionic acid (F-CPPA), respectively, were formed but at significantly lower rates, and no GSH conjugates were identified. However, fluoro felbamate is a new chemical entity whose in vivo toxicology profile is unknown. This molecule requires extensive clinical studies before approval.

There exists a need for felbamate derivatives that are closely related structurally to felbamate, the toxicology of which is well understood.

Therefore, it is an object of the invention to provide felbamate derivatives which are closely related to felbamate and methods of making and using thereof.

SUMMARY OF THE INVENTION

Felbamate deuterated at the 2-position, compositions containing the same, and methods of making and using thereof are described herein. Substitution of the hydrogen at the 2-position with deuterium should prevent or reduce formation of the toxic metabolite atropaldehyde (ATPAL), which is the cause of felbamate toxicity.

The deuterated felbamate can be administered enterally (e.g., orally) or parenterally (e.g., by injection) to treat a variety of neurological diseases or disorders, such as epilepsy, preventing/r educing seizures, stroke, traumatic brain injury, brain tumor resection, brain tumor irradiation, bipolar disorder, trigeminal neuralgia, attention-deficit hyperactivity disorder (ADHD), schizophrenia, phantom limb syndrome, complex regional pain syndrome, paroxysmal extreme pain disorder, neuromyotonia, intermittent explosive disorder, and post-traumatic stress disorder. Suitable daily dosages of the active agent are 100-2000 mg, preferably 200-1000 mg, more preferably 400-600 mg. However, the appropriate dosage can be determined by the attending physician based on a variety of factors including age and weight of the patient and diseases or disorder to be treated.

In some embodiments, the deuterated felbamate is administered in

combination with glutathione. Glutathione scavenges any ATPAL that forms due to residual felbamate by complexing ATPAL and rendering it non-toxic. Glutathione can be administered at a dose of from about 100 mg to about 3000 mg/day, preferably from about 1 g to about 3 mg, more preferably from about 1 g to about 1.5 g. In some embodiments, glutathione is routinely administered at doses of 600mg (i.v. 2X day) for a total daily dosage of l,200mg. The glutathione can be administered

simultaneously with the deuterated felbamate for example, in the same dosage form or different dosage forms or can be administered sequentially, for example, before or after felbamate administration, in the same of different dosage forms.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a schematic showing felbamate metabolism in vivo.

Figure 2 is the chemical structure of mono-deuterated felbamate deuterated at the 2-position, also referred to as felbamate-dl .

DETAILED DESCRIPTION OF THE INVENTION

I. Definitions

"Microparticle", as used herein, refers to any shaped particle with at least one dimension, such as the diameter, in the range of 10

nanometers to 1 ,000 microns. The term "microspheres" or

"microcapsules" is art-recognized, and includes substantially spherical solid or semi-solid structures having a size ranging from about one or greater up to about 1000 microns. The term "microparticles" is also art- recognized, and includes microspheres and microcapsules, as well as structures that may not be readily placed into either of the above two categories, all with dimensions on average of less than about 1000 microns. A microparticle may be spherical or nonspherical and may have any regular or irregular shape. If the structures are less than about one micron in diameter, then the corresponding art-recognized terms

"nanosphere," "nanocapsule," and "nanoparticle" may be utilized. The term "diameter" is art-recognized and is used herein to refer to either of the physical diameter or the hydrodynamic diameter. The diameter of emulsion typically refers to the hydrodynamic diameter. The diameter of the capsules, both in spherical or non- spherical shape, may refer to the physical diameter in the hydrated state. The diameter of the particles and colloids which are encapsulated inside the capsules refers to the physical diameter in the hydrated state. As used herein, the diameter of a non-spherical particle or a non-spherical capsule may refer to the largest linear distance between two points on the surface of the particle. When referring to multiple particles or capsules, the diameter of the particles or the capsules typically refers to the average diameter of the p rticles or the capsules. Di meter of particles or colloids can be measured using a variety of techniques, including but not limited to the optical or electron microscopy, as well as dynamic light scattering.

"Neuroprotective", as used herein refers to any agent that reduces brain cell damage subsequent to primary neuronal cell death.

"Anticonvulsant", as used herein, refers to any agent that reduces the severity of a seizure.

"Intravenously injectable", as used herein, refers to any formulation that is capable of being injected into the circulatory system of a mammal.

"Diluent", as used herein refers to an agent that when introduced reduces the concentration of another agent.

"Slurry", as used herein, refers to any viscous suspension.

"Neuronal", as used herein, refers to pertaining to the brain.

"Primary neuronal injury" refers to cell injury or death directly resulting from a pathophysiology.

"Secondary neuronal cell death" refers to cells that die subsequent to a primary neuronal injury.

"Non- solvent" refers to any poor solvent for an agent which is incapable of dissolving more than 1 milligram of the agent in 1 milliliter of the non- solvent.

"Effective diameter" refers to the diameter of a circle with equivalent area to that of the particulate shape. "Supersaturated" refers to solutions that contain a greater quantity of a solute at a given temperature than they would without an additional processing step, such as heating.

As generally used herein "pharmaceutically acceptable" 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, organs, and/or bodily fluids of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.

II. Compounds

In some embodiments, the compound is felbamate-Dl, wherein the felbamate is deuterated at the 2-position. The chemical structure of this compound is shown below:

In other embodiments, the compound is a felbamate derivative or analog deuterated at the two position. Exemplary derivatives include, but are not limited to, carbamate derivatives, such as those described in Kwon et al, Medicinal Chemistry Research, Volume 19, Issue 5, pp. 498-513 (2010).

Felbamate (marketed under the brand name Felbatol by MedPointe) is an anticonvulsant drug used in the treatment of epile sy. It is used to treat partial seizures (with and without generalization) in adults and partial and generalized seizures associated with Lennox-Gastaut syndrome in children. However, an increased risk of potentially fatal aplastic anemia and/or liver failure, due to repeated administration over an extended period of time, has limited its usage to severe refractory epilepsy. Felbamate is an inhibitor of CYP2C19, an isoenzyme of the cytochrome P450 system involved in the metabolism of several commonly used medications. Felbamate interacts with several other anti-epileptic drugs (AEDs), including phenytoin, valproate, and carbamazepine; dosage adjustments may be necessary to avoid adverse effects. Concomitant administration of felbamate and carbamazepine decreases blood levels of both drugs, while increasing the level of carbamazepine- 10, 11 -epoxide, the active metabolite of carbamazepine.

The agent can be used as the free acid or free base or as a pharmaceutically acceptable salt. "Pharmaceutically acceptable salt", as used herein, refer to derivatives of the compounds defined by Formula I, II, and III wherein the parent compound is modified by making acid or base salts thereof. Example of

pharmaceutically acceptable salts include but are not limited to mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, tolunesulfonic, naphthalene sulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic salts.

The pharmaceutically acceptable salts of the compounds can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non- aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, p. 704; and

"Handbook of Pharmaceutical Salts: Properties, Selection, and Use," P. Heinrich Stahl and Camille G. Wermuth, Eds., Wiley- VCH, Weinheim, 2002.

The compounds described herein may have one or more chiral centers and thus exist as one or more stereoisomers. Such stereoisomers can exist as a single enantiomer, a mixture of diastereomers or a racemic mixture. As used herein, the term "stereoisomers" refers to compounds made up of the same atoms having the same bond order but having different three-dimensional arrangements of atoms which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term "enantiomers" refers to two stereoisomers which are non-superimposable mirror images of one another. As used herein, the term "optical isomer" is equivalent to the term "enantiomer". As used herein the term "diastereomer" refers to two stereoisomers which are not mirror images but also not superimposable. The terms "racemate", "racemic mixture" or "racemic modification" refer to a mixture of equal parts of enantiomers. The term "chiral center" refers to a carbon atom to which four different groups are attached. Choice of the appropriate chiral column, eluent, and conditions necessary to effect separation of the pair of enantiomers is well known to one of ordinary skill in the art using standard techniques (see e.g. Jacques, J. et al, "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc. 1981).

Suitable dosages of the active agent are 100-2000 mg, preferably 200-1000 mg, more preferably 400-600 mg. However, the appropriate dosage can be determined by the attending physician based on a variety of factors including age and weight of the patient and diseases or disorder to be treated.

The formulations can contain one or more additional active agents that are appropriate to be administered with neuroprotective agents.

III. Pharmaceutical compositions

The deuterated compounds described herein can combined with one or more pharmaceutically acceptable carriers to prepare a pharmaceutical composition. The compounds can be formulated for any route of administration. However, in some embodiments, the compounds are administered enterally (e.g., orally) or parenterally (e.g., by injection or implantation).

A. Parenteral Formulations

The compounds described herein can be formulated for parenteral

administration. "Parenteral administration", as used herein, means administration by any method other than through the digestive tract or non-invasive topical or regional routes. For example, parenteral administration may include administration to a patient intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intrapro statically, intrapleurally, intratracheally, intravitreally, intratumorally, intramuscularly, subcutaneously, subconjunctivally, intravesicularly, intrapericardially, intraumbilically, by injection, and by infusion.

Parenteral formulations can be prepared as aqueous compositions using techniques is known in the art. Typically, such compositions can be prepared as injectable formulations, for example, solutions or suspensions; solid forms suitable for using to prepare solutions or suspensions upon the addition of a reconstitution medium prior to injection; emulsions, such as water-in-oil (w/o) emulsions, oil-in- water (o/w) emulsions, and microemulsions thereof, liposomes, or emulsomes.

The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, one or more polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), oils, such as vegetable oils (e.g., peanut oil, corn oil, sesame oil, etc.), and combinations thereof. The 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 dispersion and/or by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride.

Solutions and dispersions of the active compounds as the free acid or base or pharmacologically acceptable salts thereof can be prepared in water or another solvent or dispersing medium suitably mixed with one or more pharmaceutically acceptable excipients including, but not limited to, surfactants, dispersants, emulsifiers, pH modifying agents, viscosity modifying agents, and combination thereof.

Suitable surfactants may be anionic, cationic, amphoteric or nonionic surface active agents. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions. Examples of anionic surfactants include sodium, potassium, ammonium of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfo succinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4- oleate, sorbitan acylate, sucrose acylate, PEG- 150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenylether, PEG- 1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401, stearoyl monoisopropanolamide, and polyoxyethylene

hydrogenated tallow amide. Examples of amphoteric surfactants include sodium N- dodecyl-.beta.-alanine, sodium N-lauryl-.beta.-iminodipropionate,

myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.

The formulation can contain a preservative to prevent the growth of microorganisms. Suitable preservatives include, but are not limited to, parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. The formulation may also contain an antioxidant to prevent degradation of the active agent(s).

The formulation is typically buffered to a pH of 3-8 for parenteral

administration upon reconstitution. Suitable buffers include, but are not limited to, phosphate buffers, acetate buffers, and citrate buffers.

Water soluble polymers are often used in formulations for parenteral administration. Suitable water-soluble polymers include, but are not limited to, polyvinylpyrrolidone, dextran, carboxymethylcellulose, and polyethylene glycol.

Sterile injectable solutions can be prepared by incorporating the active compounds in the required amount in the appropriate solvent or dispersion medium with one or more of the excipients listed above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. The powders can be prepared in such a manner that the particles are porous in nature, which can increase dissolution of the particles. Methods for making porous particles are well known in the art. 1. Concentrated suspensions

In one embodiment, the formulation is the form of a concentrated suspension or slurry. The suspension can prepared immediately prior to use, For example, as discussed below, microparticles can be prepared by adding a heated aqueous solution of the deuterated felbamate) to an excess of lower temperate sterile water or aqueous solution, such as an aqueous surfactant solution. The resulting microparticles are suspended in an aqueous medium, which can be administered immediately to the patient.

In other embodiments, the microparticles are prepared, isolated, and dried and stored under appropriate conditions. The microparticles can be reconstituted in an appropriate pharmaceutically acceptable carrier prior to administration.

The suspending medium can optionally contain dissolved deuterated felbamate).

The microparticles have an effective particle size from about 100 nm to about 5 microns, preferably from about 50 nm to about 3 microns, more preferably from about 10 nm to about 2 microns. In particular embodiments, the particle size distribution is at least 80% of the particles by volume have the particle size ranges above.

In some embodiments, the isolated microparticles contain one or more surfactants incorporated into, onto, and/or dispersed throughout the drug particles. In some embodiments, the surfactant is a solid at ambient temperature so that the microparticles are in the form of a powder. In other embodiments, the surfactant is a liquid at ambient temperature so that the microparticles form a slurry after isolation from the solvent.

A variety of surfactants can be used to prepare the microparticles and/or suspensions thereof. Surfactants can be classified as anionic, cationic, amphoteric, and nonionic surfactants and include phospholipids.

Examples of suitable anionic surfactants include, but are not limited to, sodium, potassium, and ammonium salts of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2~ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate, and sodium deoxycholate.

Examples of suitable cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine,

Examples of suitable nonio ic surfactants include, but are not limited to, ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates

(TWEENS®), polyoxyethylene octylphenylether, PEG- 1000 cetyl ether,

polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, POLOXAMER® 401, stearoyl monoisopropanolamide, and polyoxyethylene hydro genated tallow amide.

Examples of amphoteric surfactants include, but are not limited to, sodium N- dodecyl-β -alanine, sodium N-lauryl~p~iminodipropionate, myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.

Suitable phospholipids include, but are not limited to, phosphatide acids, phosphatidyl cholines with both saturated and unsaturated lipids, phosphatidyl ethanolamines, phosphatidylglycerols, phosphatidylserines, phosphatidylinositols, lysophosphatidyl derivatives, cardiolipin, and β-acyl-y-alkyl phospholipids.

Examples of phosphatidylcholines include such as dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine (DMPC), dipentadecanoylphosphatidylcholine dilauroylphosphatidylcholine, dipalmitoylphosphatidylcholine (DPPC),

distearoylphosphatidylcholine (DSPC), diarachidoylphosphatidylcholine (DAPC), dibehenoylphosphatidylcholme (DBPC), ditricosanoyl-phosphatidylcholine (DTPC), dilignoceroyiphatidylcholine (DLPC); and phosphatidylethanolamines such as dioleoylphosphatidylethanolamine or 1 -hexadecyl-2-palmitoylglycerophospho- ethanolamine. Synthetic phospholipids with asymmetric acyl chains (e.g., with one acyl chain of 6 carbons and another acyl chain of 12 carbons) may also be used.

Examples of phosphatidylethanol-amines include, but are not limited to, dicaprylpho sphatidylethano lamine, dioctanoylpho sphatidy 1-ethanolamine, dilauroylphosphatidylethanolamine, dimyristoylphosphatidyl-ethanolamine (DMPE), dipalmitoylphosphatidylethanolamine (DPPE),

dipalmitoleoylphosphatidylethanolamine, distearoylphosphatidylethanolamine (DSPE), dioleoylphosphatidylethanolamine, and dilineoylphosphatidylethanol-amine.

Examples of phosphatidylglycerols include, but are not limited to,

dicaprylphosphatidylglycerol, dioctanoylpho sphati dylgly cerol,

dilauroylphosphatidylglycerol, dimyristoylphosphatidylgly cerol (DMPG),

dipalmitoylphosphatidylglycerol (DPPG), dipalmitoleoylphosphatidylglycerol, distearoylphosphatidylglycerol (DSPG), dioleoylphosphatidylglycerol, and dilineoylphosphatidylglycerol .

In a preferred embodiment, the surfactant is a polysorbate. In one

embodiment, the surfactant has an HLB of at least 15, preferably greater than 15. In other embodiments, the surfactant has an HLB of at least 15, preferably greater than 15 and is a non-ionic surfactant. In one embodiment, the surfactant is a polysorbate. In a preferred embodiment, the surfactant is polysorbate 20.

The suspension can contain one or more pharmaceutically acceptable excipients including, but not limited to, pH modifying agents, dispersing agents, tonicity modifying agents, plasticizers, crystallization inhibitors, wetting agents, bulk filling agents, bioavailability enhancers, and combinations thereof.

2. Concentrated solutions

In other embodiments, the formulation is in the form of a concentrated solution. In some embodiments, the drug is dissolved at high concentrations of at least about 1% by weight, 5% by weight, 10% by weight, 15% by weight, or 20% by weight in a solvent suitable for parenteral administration. In particular embodiments, the deuterated felbamate is dissolved in a polyethylene glycol, such as PEG 300, PEG 400, PEG 600, glycerin, propylene glycol, sorbitol, ethylene glycol, or a surfactant, such as polysorbate 20. The resulting supersaturated solution is stable (e.g., no precipitation) for at least one hour, two hours, three hours, four hours, six hours, eight hours, 12 hours, 24 hours, 30 hours, 36 hours, or 48 hours. Prior to administration, the concentrated solution can be diluted in one or more solvents suitable for parenteral administration, such as water, antimicrobial agents, ethanol, propylene glycol, and combinations thereof. The solution can contain one or more pharmaceutically acceptable excipients including, but not limited to, pH modifying agents, tonicity modifying agents, plasticizers, crystallization inhibitors, wetting agents, bulk filling agents,

bioavailability enhancers, and combinations thereof. The diluting solvent may contain one or more surfactants, such as those described above,

3. Controlled release formulations

The parenteral formulations described herein can be formulated for controlled release including immediate release, delayed release, extended release, pulsatile release, and combinations thereof.

i. Nano- and microparticles

For parenteral administration, the one or more compounds, and optional one or more additional active agents, can be incorporated into microparticles, nanoparticles, or combinations thereof that provide controlled release of the compounds and/or one or more additional active agents. In embodiments wherein the formulations contains two or more drugs, the drugs can be formulated for the same type of controlled release (e.g., delayed, extended, immediate, or pulsatile) or the drugs can be independently formulated for different types of release (e.g., immediate and delayed, immediate and extended, delayed and extended, delayed and pulsatile, etc.).

For example, the compounds and/or one or more additional active agents can be incorporated into polymeric microparticles which provide controlled release of the drug(s). Release of the drug(s) is controlled by diffusion of the drug(s) out of the microparticles and/or degradation of the polymeric particles by hydrolysis and/or enzymatic degradation. Suitable polymers include ethylcellulose and other natural or synthetic cellulose derivatives.

Polymers which are slowly soluble and form a gel in an aqueous environment, such as hydroxypropyl methylcellulose or polyethylene oxide may also be suitable as materials for drug containing microparticles. Other polymers include, but are not limited to, polyanhydrides, poly(ester anhydrides), polyhydroxy acids, such as polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), poly-3- hydroxybutyrate (PHB) and copolymers thereof, poly-4-hydroxybutyrate (P4FEB) and copolymers thereof, polycaprolactone and copolymers thereof, and combinations thereof. Alternatively, the drug(s) can be incorporated into microparticles prepared from materials which are insoluble in aqueous solution or slowly soluble in aqueous solution, but are capable of degrading within the GI tract by means including enzymatic degradation, surfactant action of bile acids, and/or mechanical erosion. As used herein, the term "slowly soluble in water" refers to materials that are not dissolved in water within a period of 30 minutes. Preferred examples include fats, fatty substances, waxes, wax-like substances and mixtures thereof. Suitable fats and fatty substances include fatty alcohols (such as lauryl, myristyl stearyl, cetyl or cetosteaiyl alcohol), fatty acids and derivatives, including but not limited to fatty acid esters, fatty acid glycerides (mono-, di- and tri-glycerides), and hydrogenated fats. Specific examples include, but are not limited to hydrogenated vegetable oil, hydrogenated cottonseed oil, hydrogenated castor oil, hydrogenated oils available under the trade name Sterotex®, stearic acid, cocoa butter, and stearyl alcohol.

Suitable waxes and wax-like materials include natural or synthetic waxes,

hydrocarbons, and normal waxes. Specific examples of waxes include beeswax, glycowax, castor wax, carnauba wax, paraffins and candelilla wax. As used herein, a wax-like material is defined as any material which is normally solid at room temperature and has a melting point of from about 30 to 300°C.

In some cases, it may be desirable to alter the rate of water penetration into the microparticles. To this end, rate-controlling (wicking) agents may be formulated along with the fats or waxes listed above. Examples of rate-controlling materials include certain starch derivatives (e.g., waxy maltodextrin and drum dried corn starch), cellulose derivatives (e.g., hydroxypropylrnethyl-cellulose,

hydroxypropylcellulose, methylcellulose, and carboxymethyl-cellulose), alginic acid, lactose and talc. Additionally, a pharmaceutically acceptable surfactant (for example, lecithin) may be added to facilitate the degradation of such microparticles.

Proteins which are water insoluble, such as zein, can also be used as materials for the formation of drug containing microparticles. Additionally, proteins, polysaccharides and combinations thereof which are water soluble can be formulated with drug into microparticles and subsequently cross-linked to form an insoluble network. For example, cyclodextrins can be complexed with individual drug molecules and subsequently cross-linked. Encapsulation or incorporation of drug into carrier materials to produce drug containing microparticles can be achieved through known pharmaceutical formulation techniques. In the case of formulation in fats, waxes or wax-like materials, the carrier material is typically heated above its melting temperature and the drug is added to form a mixture comprising drug particles suspended in the carrier material, drug dissolved in the carrier material, or a mixture thereof. Microparticles can be subsequently formulated through several methods including, but not limited to, the processes of congealing, extrusion, spray chilling or aqueous dispersion. In a preferred process, wax is heated above its melting temperature, drug is added, and the molten wax-drug mixture is congealed under constant stirring as the mixture cools. Alternatively, the molten wax-drug mixture can be extruded and spheronized to form pellets or beads. These processes are known in the art.

For some carrier materials it may be desirable to use a solvent evaporation technique to produce drug containing microparticles. In this case drug and carrier material are co-dissolved in a mutual solvent and microparticles can subsequently be produced by several techniques including, but not limited to, forming an emulsion in water or other appropriate media, spray drying or by evaporating off the solvent from the bulk solution and milling the resulting material.

In some embodiments, drug in a particulate form is homogeneously dispersed in a water-insoluble or slowly water soluble material. To minimize the size of the drug particles within the composition, the drug powder itself may be milled to generate fine particles prior to formulation. The process of jet milling, known in the pharmaceutical art, can be used for this purpose. In some embodiments drug in a particulate form is homogeneously dispersed in a wax or wax like substance by heating the wax or wax like substance above its melting point and adding the drug particles while stirring the mixture. In this case a pharmaceutically acceptable surfactant may be added to the mixture to facilitate the dispersion of the drug particles.

The particles can also be coated with one or more modified release coatings. Solid esters of fatty acids, which are hydrolyzed by lipases, can be spray coated onto microparticles or drug particles. Zein is an example of a naturally water-insoluble protein. It can be coated onto drug containing microparticles or drug particles by spray coating or by wet granulation techniques. In addition to naturally water- insoluble materials, some substrates of digestive enzymes can be treated with cross- linking procedures, resulting in the formation of non-soluble networks. Many methods of cross-linking proteins, initiated by both chemical and physical means, have been reported. One of the most common methods to obtain cross-linking is the use of chemical cross-linking agents. Examples of chemical cross-linking agents include aldehydes (gluteraldehyde and formaldehyde), epoxy compounds, carbodiimides, and genipin. hi addition to these cross-linking agents, oxidized and native sugars have been used to cross-link gelatin. Cross-linking can also be accomplished using enzymatic means; for example, transglutaminase has been approved as a GRAS substance for cross-linking seafood products. Finally, cross- linking can be initiated by physical means such as thermal treatment, UV irradiation and gamma irradiation.

To produce a coating layer of cross-linked protein surrounding drug containing microparticles or drug particles, a water soluble protem can be spray coated onto the microparticles and subsequently cross-linked by the one of the methods described above. Alternatively, drug containing microparticles can be microencapsulated within protein, by coacervation-phase separation (for example, by the addition of salts) and subsequently cross-linked. Some suitable proteins for this purpose include gelatin, albumin, casein, and gluten.

Polysaccharides can also be cross-linked to form a water-insoluble network. For many polysaccharides, this can be accomplished by reaction with calcium salts or multivalent cations which cross-link the main polymer chains. Pectin, alginate, dextran, amylose and guar gum are subject to cross-linking in the presence of multivalent cations. Complexes between oppositely charged polysaccharides can also be formed; pectin and chitosan, for example, can be complexed via electrostatic interactions.

In certain embodiments, it may be desirable to provide continuous delivery of one or more compounds to a patient in need thereof. For intravenous or intraarterial routes, this can be accomplished using drip systems, such as by intravenous administration. For topical applications, repeated application can be done or a patch can be used to provide continuous administration of the compounds over an extended period of time.

2. Injectable/Implantable Solid Implants

The compounds described herein can be incorporated into injectable/implantable solid or semi-solid implants, such as polymeric implants. In one embodiment, the compounds are incorporated into a polymer that is a liquid or paste at room temperature, but upon contact with aqueous medium, such as physiological fluids, exhibits an increase in viscosity to form a semi-solid or solid material. Exemplary polymers include, but are not limited to, hydroxyalkanoic acid polyesters derived from the copolymerization of at least one unsaturated hydroxy fatty acid copolymerized with hydroxyalkanoic acids. The polymer can be melted, mixed with the active substance and cast or injection molded into a device. Such melt fabrication require polymers having a melting point that is below the temperature at which the substance to be delivered and polymer degrade or become reactive. The device can also be prepared by solvent casting where the polymer is dissolved in a solvent and the drag dissolved or dispersed in the polymer solution and the solvent is then evaporated. Solvent processes require that the polymer be soluble in organic solvents. Another method is compression molding of a mixed powder of the polymer and the drug or polymer particles loaded with the active agent.

Alternatively, the compounds can be incorporated into a polymer matrix and molded, compressed, or extruded into a device that is a solid at room temperature. For example, the compounds can be incorporated into a biodegradable polymer, such as polyanhydrides, polyhydroalkanoic acids (PHAs), PL A, PGA, PLGA, polycaprolactone, polyesters, polyamides, polyorthoesters, polyphosphazenes, proteins and polysaccharides such as collagen, hyaluronic acid, albumin and gelatin, and combinations thereof and compressed into solid device, such as disks, or extruded into a device, such as rods.

The release of the one or more compounds from the implant can be varied by selection of the polymer, the molecular weight of the polymer, and/ir modification of the polymer to increase degradation, such as the formation of pores and/or incorporation of hydrolyzable linkages. Methods for modifying the properties of biodegradable polymers to vary the release profile of the compounds from the implant are well known in the art. B. Enteral Formulations

Suitable oral dosage forms include tablets, capsules, solutions, suspensions, syrups, and lozenges. Tablets can be made using compression or molding techniques well known in the art. Gelatin or non-gelatin capsules can prepared as hard or soft capsule shells, which can encapsulate liquid, solid, and semi-solid fill materials, using techniques well known in the art.

Formulations may be prepared using a pharmaceutically acceptable carrier. As generally used herein "carrier" includes, but is not limited to, diluents,

preservatives, binders, lubricants, disintegrators, swelling agents, fillers, stabilizers, and combinations thereof.

Carrier also includes all components of the coating composition which may include plasticizers, pigments, colorants, stabilizing agents, and glidants. Delayed release dosage formulations may be prepared as described in standard references. These references provide information on carriers, materials, equipment and process for preparing tablets and capsules and delayed release dosage forms of tablets, capsules, and granules.

Examples of suitable coating materials include, but are not limited to, cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers, and methacrylic resins that are commercially available under the trade name EUDRAGIT® (Roth Pharma, Westerstadt, Germany), zein, shellac, and polysaccharides.

Additionally, the coating material may contain conventional carriers such as plasticizers, pigments, colorants, glidants, stabilization agents, pore formers and surfactants.

Optional pharmaceutically acceptable excipients include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants, stabilizers, and surfactants. Diluents, also referred to as "fillers," are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets or formation of beads and granules. Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powdered sugar,

Binders are used to impart cohesive qualities to a solid dosage formulation, and thus ensure that a tablet or bead or granule remains intact after the formation of the dosage forms. Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, cellulose, including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid/polymethacrylic acid and polyvinylpyrrolidone.

Lubricants are used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil.

Disintegrants are used to facilitate dosage form disintegration or "breakup" after administration, and generally include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, alginine, gums or cross linked polymers, such as cross-linked PVP (Polyplasdone® XL from GAF Chemical Corp).

Stabilizers are used to inhibit or retard drug decomposition reactions which include, by way of example, oxidative reactions. Suitable stabilizers include, but are not limited to, antioxidants, butylated hydroxytoluene (BHT); ascorbic acid, its salts and esters; Vitamin E, tocopherol and its salts; sulfites such as sodium metabisulphite; cysteine and its derivatives; citric acid; propyl gallate, and butylated hydroxyanisole (BHA).

i. Controlled Release Formulations

Oral dosage forms, such as capsules, tablets, solutions, and suspensions, can for formulated for controlled release. For example, the one or more compounds and optional one or more additional active agents can be formulated into nanoparticles, microparticles, and combinations thereof, and encapsulated in a soft or hard gelatin or non-gelatin capsule or dispersed in a dispersing medium to form an oral suspension or syrup. The particles can be formed of the drug and a controlled release polymer or matrix. Alternatively, the drug particles can be coated with one or more controlled release coatings prior to incorporation in to the finished dosage form.

In another embodiment, the one or more compounds and optional one or more additional active agents are dispersed in a matrix material, which gels or emulsifies upon contact with an aqueous medium, such as physiological fluids. In the case of gels, the matrix swells entrapping the active agents, which are released slowly over time by diffusion and/or degradation of the matrix material. Such matrices can be formulated as tablets or as fill materials for hard and soft capsules.

In still another embodiment, the one or more compounds, and optional one or more additional active agents are formulated into a sold oral dosage form, such as a tablet or capsule, and the solid dosage form is coated with one or more controlled release coatings, such as a delayed release coatings or extended release coatings. The coating or coatings may also contain the compounds and/or additional active agents.

Extended release dosage forms

The extended release formulations are generally prepared as diffusion or osmotic systems, which are known in the art. A diffusion system typically consists of two types of devices, a reservoir and a matrix, and is well known and described in the art. The matrix devices are generally prepared by compressing the drug with a slowly dissolving polymer carrier into a tablet form. The three major types of materials used in the preparation of matrix devices are insoluble plastics, hydrophilic polymers, and fatty compounds. Plastic matrices include, but are not limited to, methyl acrylate- methyl methacrylate, polyvinyl chloride, and polyethylene. Hydrophilic polymers include, but are not limited to, cellulosic polymers such as methyl and ethyl cellulose, hydroxyalkylcelluloses such as hydroxypropyl-cellulose,

hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and Carbopol® 934, polyethylene oxides and mixtures thereof. Fatty compounds include, but are not limited to, various waxes such as carnauba wax and glyceryl tristearate and wax-type substances including hydrogenated castor oil or hydrogenated vegetable oil, or mixtures thereof.

In certain preferred embodiments, the plastic material is a pharmaceutically acceptable acrylic polymer, including but not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer ■ poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.

In certain preferred embodiments, the acrylic polymer is comprised of one or more ammonio methacrylate copolymers. Ammonio methacrylate copolymers are well known in the art, and are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.

In one preferred embodiment, the acrylic polymer is an acrylic resin lacquer such as that which is commercially available from Rohm Pharma under the tradename Eudragit®. In further preferred embodiments, the acrylic polymer comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the tradenames Eudragit® RL30D and Eudragit ® RS30D, respectively.

Eudragit® RL30D and Eudragit® RS30D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1:20 in Eudragit® RL30D and 1:40 in Eudragit® RS30D. The mean molecular weight is about 150,000. Edragit® S-100 and Eudragit® L-100 are also preferred. The code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents. Eudragit® RL/RS mixtures are insoluble in water and in digestive fluids. However, multiparticulate systems formed to include the same are swellable and permeable in aqueous solutions and digestive fluids.

The polymers described above such as Eudragit® RL RS may be mixed together in any desired ratio in order to ultimately obtain a sustained-release formulation having a desirable dissolution profile. Desirable sustained-release multiparticulate systems may be obtained, for instance, from 100% Eudragit® RL, 50% Eudragit® RL and 50% Eudragit® RS, and 10% Eudragit® RL and 90% Eudragit® RS. One skilled in the art will recognize that other acrylic polymers may also be used, such as, for example, Eudragit® L.

Alternatively, extended release formulations can be prepared using osmotic systems or by applying a semi-permeable coating to the dosage form. In the latter case, the desired drug release profile can be achieved by combining low permeable and high permeable coating materials in suitable proportion.

The devices with different drug release mechanisms described above can be combined in a final dosage form comprising single or multiple units. Examples of multiple units include, but are not limited to, multilayer tablets and capsules containing tablets, beads, or granules. An immediate release portion can be added to the extended release system by means of either applying an immediate release layer on top of the extended release core using a coating or compression process or in a multiple unit system such as a capsule containing extended and immediate release beads.

Extended release tablets containing hydrophilic polymers are prepared by techniques commonly known in the art such as direct compression, wet granulation, or dry granulation. Their formulations usually incorporate polymers, diluents, binders, and lubricants as well as the active pharmaceutical ingredient. The usual diluents include inert powdered substances such as starches, powdered cellulose, especially crystalline and microcrystallme cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders include substances such as starch, gelatin and sugars such as lactose, fructose, and glucose. Natural and synthetic gums, including acacia, alginates, methylcellulose, and polyvinylpyrrolidone can also be used. Polyethylene glycol, hydrophilic polymers, ethylcellulose and waxes can also serve as binders. A lubricant is necessary in a tablet formulation to prevent the tablet and punches from sticking in the die. The lubricant is chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.

Extended release tablets containing wax materials are generally prepared using methods known in the art such as a direct blend method, a congealing method, and an aqueous dispersion method. In the congealing method, the drug is mixed with a wax material and either spray- congealed or congealed and screened and processed.

Delayed release dosage forms

Delayed release formulations can be created by coating a solid dosage form with a polymer film, which is insoluble in the acidic environment of the stomach, and soluble in the neutral environment of the small intestine.

The delayed release dosage units can be prepared, for example, by coating a drug or a drug-containing composition with a selected coating material. The drug- containing composition may be, e.g., a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core" dosage form, or a plurality of drug- containing beads, particles or granules, for incorporation into either a tablet or capsule. Preferred coating materials include bioerodible, gradually hydrolyzable, gradually water-soluble, and/or enzymatically degradable polymers, and may be conventional "enteric" _.polymers. Enteric polymers, as will be appreciated by those skilled in the art, become soluble in the higher pH environment of the lower gastrointestinal tract or slowly erode as the dosage form passes through the gastrointestinal tract, while enzymatically degradable polymers are degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly in the colon. Suitable coating materials for effecting delayed release include, but are not limited to, cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate and carboxymethylcellulose sodium; acrylic acid polymers and

copolymers, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate, and other methacrylic resins that are commercially available under the tradename Eudragit® (Rohm Pharma; Westerstadt, Germany), including Eudragit® L30D-55 and LI 00-55 (soluble at pH 5.5 and above), Eudragit® L-100 (soluble at pH 6.0 and above), Eudragit® S (soluble at pH 7.0 and above, as a result of a higher degree of esterification), and

Eudragits® NE, RL and RS (water-insoluble polymers having different degrees of permeability and expandability); vinyl polymers and copolymers such as polyvinyl pyrrolidone, vinyl acetate, vinylacetate phthalate, vinylacetate crotonic acid copolymer, and ethylene- vinyl acetate copolymer; enzymatically degradable polymers such as azo polymers, pectin, chitosan, amylose and guar gum; zein and shellac. Combinations of different coating materials may also be used. Multi-layer coatings using different polymers may also be applied.

The preferred coating weights for particular coating materials may be readily determined by those skilled in the art by evaluating individual release profiles for tablets, beads and granules prepared with different quantities of various coating materials. It is the combination of materials, method and form of application that produce the desired release characteristics, which one can determine only from the clinical studies.

The coating composition may include conventional additives, such as plasticizers, pigments, colorants, stabilizing agents, glidants, etc. A plasticizer is normally present to reduce the fragility of the coating, and will generally represent about 10 wt. % to 50 wt. % relative to the dry weight of the polymer. Examples of typical plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethyl acetyl citrate, castor oil and acetylated monoglycerides. A stabilizing agent is preferably used to stabilize particles in the dispersion. Typical stabilizing agents are nonionic emulsifiers such as sorbitan esters, polysorbates and polyvinylpyrrolidone. Glidants are recommended to reduce sticking effects during film formation and drying, and will generally represent approximately 25 wt. % to 100 wt. % of the polymer weight in the coating solution. One effective glidant is talc. Other glidants such as magnesium stearate and glycerol monostearates may also be used. Pigments such as titanium dioxide may also be used. Small quantities of an anti-foaming agent, such as a silicone (e.g., simethicone), may also be added to the coating composition.

III. Methods of making

A. Concentrated microparticles suspensions

In some embodiments, the deuterated felbamate is dissolved in a suitable solvent or solvent mixture. In some embodiments, the solvent or solvent mixture is water or an aqueous solvent. In other embodiments, the solvent or solvent mixture is an organic solvent. Suitable organic and aqueous solvent include, but are not limited to, dimethyl sulfoxide, heated water, glycerin and mixtures thereof.

The deuterated felbamate solution is then introduced into an excess of a non- solvent for the drug, which is miscible with the solvent. Suitable non-solvents include, but not limited to water, an aqueous solution of a surfactant (see the surfactants described above), and an aqueous surfactant (see the surfactants described above) solution containing dissolved neuroprotective agent. In some embodiments, the aqueous receiving solution is stirred. When the solvent mixes with the non- solvent, the mixture presents unfavorable solubility conditions for the drug causing it to leave solution creating a particulate suspension.

In particular embodiments, the resultant particle size distribution is at least eighty volume percent ranging from 10 nanometers to 5 microns, preferably ranging from 100 nanometers to five microns in effective diameter, more preferably ranging from 50 nanometers to three microns in effective diameter, and most preferably ranging from 10 nanometers to two microns in effective diameter.

In embodiments employing an organic solvent, the particle suspension can be stirred, in the presence of absence of heating and or vacuum, until a sufficient quantity of the organic solvent has evaporated to effect particle formation.

In particular embodiments, the non-solvent contains a surfactant. In some embodiments, the surfactant has a hydrophilic lipophilic balance (HLB) at least about fifteen. In more particular embodiments, the surfactant has an HLB of greater than 15. Suitable surfactants include, but are not limited to, polysorbate 20. The concentration of surfactant during particle formation is generally greater than 0.05 weight per volume percent, more preferably greater than 0.1 weight per volume percent, and most preferably greater than 0.4 weight per volume percent. However, the concentration can be lower or greater than these values dependent on the solvent, non-solvent, and surfactant that are used.

In some embodiments, deuterated felbamate is suspended in an aqueous surfactant solution. The aqueous felbamate suspension is then heated to at least approximately 50°, preferably to at least approximately 60°, and more preferably to at least approximately 70° until the felbamate dissolves. The heated felbamate solution is then allowed to cool in the presence or absence of an external cooling element and in the presence or absence of stirring. As the temperature decreases, the felbamate precipitates from solution to form microparticles. In preferred embodiments, the resultant felbamate particle size distribution is at least eighty volume percent ranging from 10 nanometers to 5 microns, preferably between 100 nanometers and five microns in effective diameter, more preferably between 50 nanometers and three microns in effective diameter, and most preferably between 10 nanometers and two microns in effective diameter. In particular embodiments, the particle size

distribution is at least 80% of the particles by volume have the particle size ranges above.

In embodiments in which the particle size is unstable, the resultant felbamate suspension can be rapidly frozen by any one or a combination of the following including, but not limited to, electronic refrigeration, introduction onto dry ice, and introduction into liquid nitrogen. The frozen suspension can be lyophilized to produce a felbamate microparticle slurry in the remaining surfactant, provided the surfactant is liquid in ambient conditions. In some embodiments, the surfactant is a solid in ambient conditions thereby creating a dry powder after lyophilization.

In preferred embodiments, the concentration of surfactant in solution prior to drying is reduced such that when the resultant suspension is lyophilized, it produces a dry powder. The resultant slurry or dry powder can be resuspended to create a concentrated felbamate microparticle suspension for parenteral administration or stored as a two part suspension for parenteral administration after resuspension.

1. One part suspensions

In embodiments that produce dilute suspensions of the deuterated felbamate, concentration of the suspension can be achieved by any or a combination of the following including, but not limited to, centrifugation, decanting, and resuspension in a lesser volume; drying by means of lyophilization, spray drying, air drying, or other means, followed by resuspension in a lesser volume; and reduction in the volume of the suspension media using a spin column. In preferred embodiments, the resultant suspension concentration is approximately or greater than five weight percent, more preferably approximately or greater than ten weight per volume percent, and most preferably approximately or greater than twenty weight per volume percent. In some preferred embodiments, the suspending media is one or a combination of the following including, but not limited to, water for injection, sterile phosphate buffered saline, a sterile aqueous surfactant solution, and a sterile aqueous antimicrobial solution.

2. Two part suspensions

In embodiments producing a microparticle slurry or dry powder, the resultant slurry or dry powder formulation can be stored separately from its suspending media until administration. In some embodiments the slurry or dry powder can be stored separately from the resuspension media in separate containers. In preferred

embodiments the slurry or dry powder is stored dry within one compartment of a two- compartment syringe. The resuspension media is stored in a separate compartment within the syringe. Prior to administration, the slurry or powder is resuspended in the resuspension media for administration as a single suspension.

B. Concentrated solutions

In some embodiments, the deuterated felbamate is dissolved at high concentrations, e.g. greater than about one weight percent, preferably greater than about five weight percent, and more preferably greater than about ten weight percent, in a solvent suitable for parenteral administration (e.g., injection).

In a specific embodiment, the agent is added above its solubility limit in one or more solvents. The agent is typically added to the one or more solvents at room temperature (e.g., 25°C) or close to room temperature. Suitable solvents include, but are not limited to, polyethylene glycol 300, polyethylene glycol 400, and polyethylene glycol 600. The solution of the agent is then heated, for example to temperature of at least about 50°C, preferably at least 60°C, and more preferably at least about 70°C until it dissolves and is then cooled, for example room temperature, while remaining in solution. In this embodiment, the resultant supersaturated solution remains in solution at room temperature for at least one hour at a concentration of at least 5%, preferably at least 10%, more preferably at least 15%, most preferably 20% weight per volume.

In another embodiment, the agent is dissolved in glycerin heated to above approximately 100°C and then cooled to ambient storage temperatures to form a supersaturated solution. Since felbamate has a solubility in water of less than one milligram per milliliter, the ability to create a stable supersaturated solution of felbamate in an intravenously acceptable solvent is unexpected.

In some embodiments, felbamate is dissolved in heated polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, propylene glycol, sorbitol, ethylene glycol, or polysorbate 20 in concentrations greater than would enter solution in water at 25°C.

In some embodiments, prior to injection, the solution of the agent can be diluted with another injectable solvent including, but not limited to, water, one or more antimicrobial agents, ethanol, and propylene glycol, and combinations thereof. IV. Methods of using

The formulations described herein can be used to treat a variety of

neurological diseases/disorders and/or neurological injury or trauma. Exemplary diseases or disorders include, but are not limited to, epilepsy, preventing/reducing seizures, stroke, traumatic brain injury, brain tumor resection, brain tumor irradiation, bipolar disorder, trigeminal neuralgia, attention-deficit hyperactivity disorder (ADHD), schizophrenia, phantom limb syndrome, complex regional pain syndrome, paroxysmal extreme pain disorder, neuromyotonia, intermittent explosive disorder, and post-traumatic stress disorder.

In certain embodiments, the formulations described herein are used to treat/prevent seizures and/or other neurological damage, such as stroke, traumatic brain injury, and/or brain tumor re section/irradiation, where rapid delivery of the active agent is required to prevent further damage arising from neuronal injury. For example, the formulations described herein can be used to prevent seizures and/or reduce the length and/or severity of seizures.

Felbamate has been used to treat or prevent neurological diseases and/or injury. However, long-term felbamate administration can result in aplastic anemic, a sometime fatal side effect. The risk of aplastic anemia associated with felbamate has been reported as between 1 :3,600 and 1 : 5,000, of which 30% of the cases are fatal. Aplastic anemia has not been shown to develop after a single administration of felbamate.

This toxicity is due to the metabolism of felbamate to 2-phenylpropenal

(ATPAL). Replacement of the hydrogen at the 2-position with deuterium should prevent or inhibit the metabolism of felbamate. However, to the extent that such metabolism occurs with deuterated felbamate, the suspensions and solutions described above can be administered parenterally as a single administration or a short course of treatment which is less than 48 hours in duration, preferably less than 8 hours, more preferably less than 6 hours. These formulations provide rapid delivery of the active agent to prevent further damage resulting from neurological injury or damage.

Alternatively, the deuterated felbamate can be co-administered with glutathione. Glutathione forms a complex with ATPAL rendering it non-toxic. The glutathione can be administered simultaneously with the deuterated felbamate, for example, in the same dosage form or in different dosage forms or can be administered sequentially either before or after administration of the deuterated felbamate. The glutathione can also be formulated for controlled release as described above.

Glutathione is administered in an amount effective to complex ATPAL rendering it non-toxic. In some embodiments, the daily dose of glutathione is from about 100 mg to about 3000 mg/day, preferably from about 1 g to about 3 mg, more preferably from about 1 g to about 1.5 g.

The formulations are administered to provide an effective amount of the active agent. For example, suitable amount of the suspensions and/or solutions are administered to provide a dose of the active agent ranging from 100-2000 mg, preferably 200-1000 mg, more preferably 400-600 mg. However, the appropriate dosage can be determined by the attending physician based on a variety of factors including age and weight of the patient and diseases or disorder to be treated.

Concentrated solutions and suspensions of deuterated felbamate can be prepared using the procedures described in International Patent Publication No. WO 2013/025442 to Perosphere, Inc., which is incorporated herein by reference,

Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art to which the disclosed invention belongs. Publications cited herein and the materials for which they are cited are specifically incorporated by reference.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

A com ound of the formula:

2. Microparticles comprising the compound of claim 1, the microparticles having a surface modifier adsorbed on the surface thereof, wherein the surface modifier is present in an amount of 0.1 to 90% by weight of the total weight of the surface modifier and the compound of claim 1, wherein the microparticles have an effective particle size of less than about 100 microns.

3. The microparticles of claim 2, wherein the effective particle size is from about 10 nanometers to about 5 microns, preferably from about 100 nanometers to about 5 microns, more preferably from about 50 nanometers to about 3 microns, most preferably from about 10 nanometers to about 2 microns.

4. The microparticles of claim 2 or 3, wherein the particles are rounded, ellipsoidal, or spherical.

5. The microparticles of any one of claims 2-4, wherein the surface modifier is a surfactant.

6. The microparticles of claim 5, wherein the surfactant is a solid at ambient temperature and the particles are in the form of a dry powder.

7. The microparticles of claim 5, wherein the surfactant is a liquid at ambient temperature and the particles are in the form of a slurry.

8. The microparticles of any one of claims 5-7, wherein the surfactant has an hydrophilic lipophilic balance (HLB) value of at least about 15.

9. The microparticles of claim 8, wherein the surfactant is non-ionic.

10. The microparticles of claim 9, wherein the surfactant is polysorbate 20.

11. A pharmaceutical composition comprising the compound of claim 1 or the microparticles of any one of claims 2-10 and one or more pharmaceutically acceptable carriers,

12. The composition of claim 11 , further comprising glutathione.

13. The composition of claim 12, wherein the glutathione is present in an amount providing a total daily dose of about 300 mg to about 3 g, preferably about 1 g to about 1.5 g.

14. A pharmaceutical composition comprising a concentrated solution of the compound of claim 1 or a concentrated suspension of the microparticles of any one of claims 2-10 in a pharmaceutically acceptable carrier suitable for parenteral administration.

15. The composition of claim 14, wherein the concentration of the compound in the concentrated solution is at least about 1% weight by volume, at least 5% weight by volume, preferably at least 10% weight by volume, more preferably at least about 15% weight by volume, most preferably at least about 20% by weight by volume.

16. The composition of claim 14 or 15, wherein the solvent for the solution is a polyethylene glycol.

17. The composition of claim 16, wherein the polyethylene glycol is PEG 300, 400, or 600.

18. The composition of claim 14 or 15, wherein the solvent for the solution is ethylene glycol or propylene glycol.

19. The composition of claim 14 or 15, wherein the solvent for the solution is propylene glycol.

20. The composition of claim 14 or 15, wherein the solvent for the solution is mixture of any combination of at least two solvents selected from polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, and glycerin.

21. The composition of claim 14, wherein the concentration of the particles in the suspension is at least 5% weight by volume, preferably at least 10% weight by volume, more preferably at least 15% weight by volume, more preferably at least 20% weight by volume.

22. The composition of claim 14, wherein the carrier for the suspension is water.

23. The composition of claim 14, wherein the carrier for the suspension is an aqueous solution of a surface modifier agent.

24. The composition of claim 14, wherein the surface modifier agent is a surfactant.

25. The composition of any one of claims 11-24, wherein the dose of the compound is from 100-2000mg, preferably 100-1000 mg, more preferably from 400- 600 mg.

26. A method for treating a neurological disease, injury, or trauma in a patient in need thereof, comprising administering to the patient an effective amount of the compound of claim 1.

27. The method of claim 26, further comprising co -administering glutathione.

28. A method for treating a neurological disease, injury, or trauma in a patient in need thereof, comprising administering to the patient an effective amount of the microparticles of any one of claims 2-10.

29. The method of claim 28, further comprising co-administering glutathione.

30. A method for treating a neurological disease, injury, or trauma in a patient in need thereof, comprising administering to the patient an effective amount of the composition of any one of claims 11-25.

31. The method of claim 30, wherein the neurological disease is epilepsy.

32. The method of any one of claims 26-31, wherein the total daily dose of deuterated felbamate is from about 100 to about 2000 mg, preferably from about 200 to about 1000 mg, more preferably from about 400 to about 600 mg.