Novel topiramate compositions and an escalating dosing strategy for treating obesity and related disorders   

The prevalence of obesity in both children and adults is on the rise in first world countries, especially in the United States, as well as in many developing countries such as China and India. Many aspects of a person\'s life are affected by obesity, from physical problems such as knee and ankle joint deterioration, to emotional problems resulting from self-esteem issues and society\'s attitude towards heavy people. The medical problems caused by obesity can be serious and often life-threatening and include diabetes, shortness of breath and other respiratory problems, gallbladder disease, hypertension, dyslipidemia (for example, high cholesterol or high levels of triglycerides), cancer, osteoarthritis, other orthopedic problems, reflux esophagitis (heartburn), snoring, sleep apnea, menstrual irregularities, infertility, gout, problems associated with pregnancy, heart trouble, muscular dystrophy and metabolic disorders, including hypoalphalipoproteinemia, familial combined hyperlipidemia, insulin resistant syndrome X or multiple metabolic disorder, coronary artery disease, and dyslipidemic hypertension. In addition, obesity has been associated with an increased incidence of certain cancers, notably cancers of the colon, rectum, prostate, breast, uterus, and cervix.

Moreover, obesity substantially increases the risk of morbidity from hypertension, dyslipidemia, type 2 diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis and endometrial, breast, prostate, and colon cancers. Higher body weights are also associated with increases in all-cause mortality. Most or all of these problems are relieved or improved by permanent significant weight loss as well as a significant increase in longevity.

The currently available strategies for treating obesity and/or related disorders include dietary restriction, increased physical activity, pharmacological and surgical approaches which vary depending, at least in part, on the degree of weight loss one is attempting to achieve as well as on the severity of obesity exhibited by the subject. For example, treatments such as low-fat diet and/or regular exercise are often adequate in cases where a subject is only mildly overweight. The difficulty in maintaining long-term weight loss through diet and behavior modification has led to an increasing interest in other avenues for treatment, particularly pharmacotherapy.

Present pharmacological interventions typically induce a weight loss of between five and fifteen kilograms; if the medication is discontinued, renewed weight gain ensues. Surgical treatments are comparatively successful and are reserved for patients with extreme obesity and/or with serious medical complications.

The above treatments, i.e., diet, exercise, surgery, and pharmaceutical treatments, can be enhanced by controlled use of over-the-counter appetite suppressants including caffeine, ephedrine and phenylpropanolamine (Acutrim®, Dexatrim®). Moreover, prescription medications including amphetamine, diethylpropion (Tenuate®), mazindol (Mazanor®, Sanorex®), phentermine (Fastin®, Ionamin®), phenmetrazine (Preludin®), phendimetrazine (Bontrol®, Plegine®, Adipost®, Dital®, Dyrexan®, Melfiat®, Prelu-2®, Rexigen Forte®), benzphetamine (Didrexg®) and fluoxetine (Prozac®) are often used in the treatment of seriously overweight and/or obese subjects or patients.

Accordingly, while society has seen tremendous advances in the field of pharmaceuticals, there are, of course, drawbacks to the administration of any given pharmaceutical agent. Sometimes, the disadvantages, characterized as “side effects,” are so severe as to preclude administration of a particular agent at a therapeutically effective dose. For example, these drugs may be effective only in a subset of patients and their long term use is limited by side effects, some of which are severe. In such a case, drug therapy is discontinued, and other pharmaceutical agents may be tried. Many agents in the same therapeutic class, however, display similar side effect profiles, meaning that patients either have to forego therapy or suffer from unpleasant side effects associated with a particular medication.

The present invention is directed to an escalating dosing strategy for administering topiramate alone or in combination with a second therapeutic agent which directly or indirectly reduces the side effects associated with one or both of the agents administered. By “indirectly” reducing side effects is meant that a first pharmaceutical agent allows the second agent to be administered at a lower dose without compromising therapeutic efficacy, thus resulting dose-dependent unwanted effects.

Topiramate (2,3,4,5-Bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate) is a broad-spectrum neurotherapeutic agent approved by the FDA and more than 75 countries around the world for selected seizure disorders (E. Faught et al. (1996) Neurology 46:1684-90.; Karim et al. (1995) Epilepsia 36 (S4):33; S. K. Sachdeo et al. (1995) Epilepsia 36(S4):33; T. A. Glauser (1999) Epilepsia 40 (S5):S71-80; R. C. Sachdeo (1998) Clin. Pharmacokinet. 34:335-346). There has also been evidence that topiramate is effective in the treatment of diabetes (U.S. Pat. Nos. 7,109,174 and 6,362,220), neurological disorders (U.S. Pat. No. 6,908,902), depression (U.S. Pat. No. 6,627,653), psychosis (U.S. Pat. No. 6,620,819), headaches (U.S. Pat. No.6,319,903) and hypertension (U.S. Pat. No.6,201,010). However there have been adverse effects associated with the use of topiramate in humans, such as diarrhea and anal leakage, which can discourage many obese patients from taking this drug.

As such, there is interest in the development of additional methods and compositions for treating obesity and related conditions in which the therapeutic efficacy of known compositions are improved. In addition, combination treatment may be employed to decrease the doses of the individual components in the resulting combinations while still preventing unwanted or harmful side effects of the individual components. Thus, there is an urgent need to discover suitable methods for the treatment of obesity and/or a related condition, including combination treatments that result in reduction of toxicity, decreased side effects and effective treatment.

SUMMARY

The present invention provides novel topiramate compositions and methods for treating obesity and related conditions, including conditions associated with and/or caused by obesity per se.

The present invention also features a pharmaceutical composition that includes, e.g., topiramate alone or in combination with a sympathomimetic agent. The term “sympathomimetic agent” is a term of art and refers to agents or compounds which mimic or alter stimulation of the sympathetic nervous system. In certain aspects, the combination compositions include topiramate with two or more sympathomimetic agents.

The present invention also features a pharmaceutical composition that includes topiramate in combination with phentermine for treating obesity or a related condition.

The present invention also features a pharmaceutical composition that includes topiramate in combination with bupropion for treating obesity or a related condition.

The present invention also features a novel escalating dosing strategy for administering topiramate alone or in combination with a sympathomimetic agent.

In certain embodiments, the present invention features a controlled release composition for treating obesity or a related condition.

In certain embodiments, the present invention is used for treating diabetes.

In certain aspects, the present invention comprises an effective amount of topiramate, microcrystalline cellulose and methocellulose.

In certain aspects of the invention, the topiramate, the microcrystalline cellulose, and the methocellulose are present in a matrix core of a bead.

In certain aspects of the invention, the matrix core is coated with ethyl cellulose.

In certain aspects of the invention, the matrix core is further coated with polyvinyl pyrrolidone.

In certain aspects of the invention, the bead is encapsulated into a capsule.

In certain aspects of the invention, the capsule further comprises a sympathomimetic agent.

In certain aspects of the invention, the sympathomimetic agent is phentermine.

In certain aspects of the invention, the phentermine is coated onto a sugar sphere.

In certain aspects of the invention, the phentermine is coated onto the topiramate controlled release beads.

In certain aspects of the invention, the phentermine is an immediate release form.

In certain aspects of the invention, the phentermine is a controlled release form.

In certain aspects of the invention, the topiramate reduces phentermine exposure and reduces side effects associated with phentermine.

In certain aspects of the invention, the sympathomimetic agent is bupropion.

In certain aspects of the invention, the bupropion is coated onto a sugar sphere.

In certain aspects of the invention, the bupropion is coated onto the topiramate controlled released beads.

In certain aspects of the invention, the bupropion is an immediate release form.

In certain aspects of the invention, the bupropion is a controlled release form.

In certain aspects of the invention, the topiramate reduces bupropion exposure and reduces side effects associated with bupropion.

In certain embodiments, the present invention features a method for treating an individual for obesity or a related condition, the method comprising administering an effective amount of topiramate according to an escalating dosage strategy, wherein the topiramate is in a controlled-release form.

In certain aspects of the invention, the dosing strategy includes administering an initial daily dosage of topiramate to the individual for a specific period of time and incrementally increasing the dosage at various designated time points.

In certain aspects of the invention, the method includes administering the topiramate at a dosage ranging from 20-150 mg/day.

In certain aspects of the invention, the method includes administering an initial dosage of 23 mg/day of topiramate.

In certain aspects of the invention, the method further includes administering an effective amount of a sympathomimetic agent.

In certain aspects of the invention, the sympathomimetic agent is phentermine.

In certain aspects of the invention, the sympathomimetic agent is bupropion.

In certain aspects of the invention, the sympathomimetic agent is in immediate release form.

In certain embodiments, the present invention features a method for treating obesity or a related condition in an individual by administering a non-toxic, effective amount of topiramate according to an escalating dosage strategy.

In certain aspects of the invention, the method includes administering an initial dose of 23 mg/day of topiramate in a first one-week administration.

In certain aspects of the invention, the method further includes administering a dosage of 46 mg/day of topiramate for a second one-week administration.

In certain aspects of the invention, the method further includes administering a dosage of 69 mg/day of topiramate for a third one week administration.

In certain aspects of the invention, the method further includes administering a dosage of 92 mg/day of topiramate for a fourth one week administration.

In certain aspects of the invention, the method further includes administering 3.75 mg/day of phentermine in the first one week administration.

In certain aspects of the invention, the method further includes administering a 7.5 mg/day of phentermine in the second one week administration.

In certain aspects of the invention, the method further includes administering a dosage of 11.25 mg/day of phentermine in the third one week administration.

In certain aspects of the invention, the method further includes administering a 15.0 mg/day of phentermine in the fourth one week administration.

In certain embodiments, the present invention features a kit comprising topiramate and instructions providing a dosing strategy for administering topiramate to an individual for treating obesity or a related condition.

In certain aspects of the invention, the kit includes a dosing strategy which includes administering a lower daily dosage of topiramate for a specific period of time and then incrementally increasing the dosage at various designated time points.

In certain aspects of the invention, the kit includes a sympathomimetic agent and instructions providing a dosing strategy for administering the sympathomimetic agent in combination with the topiramate.

In certain aspects of the invention, the kit also includes the topiramate and sympathomimetic agent in a titration card, wherein the card provides dosages for four weeks.

In certain aspects of the invention, the dosages in the titration card increase each week.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides a summary of the plasma concentration of controlled release topiramate according to the present invention versus topiramate (Topomax®) in normal obese subjects.

FIG. 2 depicts the mean plasma phentermine concentrations versus time for subjects administered phentermine in combination with controlled release topiramate and phentermine in combination with immediate release topiramate (Topomax®).

It must be noted that, as used in this specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, “an active agent” refers not only to a single active agent but also to a combination of two or more different active agents, “a dosage form” refers to a combination of dosage forms as well as to a single dosage form, and the like. Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which the invention pertains. Although any methods and materials similar or equivalent to those described herein may be useful in the practice or testing of the present invention, preferred methods and materials are described below. Specific terminology of particular importance to the description of the present invention is defined below.

When referring to an active agent, applicants intend the term “active agent” to encompass not only the specified molecular entity but also its pharmaceutically acceptable, pharmacologically active analogs, including, but not limited to, salts, esters, amides, prodrugs, conjugates, active metabolites, and other such derivatives, analogs, and related compounds.

The terms “treating” and “treatment” as used herein refer to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, and improvement or remediation of damage. In certain aspects, the term “treating” and “treatment” as used herein refer to the prevention of the occurrence of symptoms. In other aspects, the term “treating” and “treatment” as used herein refer to the prevention of the underlying cause of symptoms associated with obesity and/or a related condition.

By the terms “effective amount” and “therapeutically effective amount” of an agent, compound, drug, composition or combination of the invention which is nontoxic and effective for producing some desired therapeutic effect upon administration to a subject or patient (e.g., a human subject or patient).

The term “dosage form” denotes any form of a pharmaceutical composition that contains an amount of active agent sufficient to achieve a therapeutic effect with a single administration. When the formulation is a tablet or capsule, the dosage form is usually one such tablet or capsule. The frequency of administration that will provide the most effective results in an efficient manner without overdosing will vary with the characteristics of the particular active agent, including both its pharmacological characteristics and its physical characteristics, such as hydrophilicity.

The term “controlled release” refers to a drug-containing formulation or fraction thereof in which release of the drug is not immediate, i.e., with a “controlled release” formulation, administration does not result in immediate release of the drug into an absorption pool. The term is used interchangeably with “nonimmediate release” as defined in Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995). In general, the term “controlled release” as used herein includes sustained release, modified release and delayed release formulations.

The term “sustained release” (synonymous with “extended release”) is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of a drug over an extended time period. The term “delayed release” is also used in its conventional sense, to refer to a drug formulation which, following administration to a patient provides a measurable time delay before drug is released from the formulation into the patient\'s body.

By “pharmaceutically acceptable” is meant a material that is not biologically or otherwise undesirable, i.e., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. When the term “pharmaceutically acceptable” is used to refer to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration. “Pharmacologically active” (or simply “active”) as in a “pharmacologically active” derivative or analog, refers to a derivative or analog having the same type of pharmacological activity as the parent compound and approximately equivalent in degree. The term “pharmaceutically acceptable salts” include acid addition salts which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.

As used herein, “subject” or “individual” or “patient” refers to any subject for whom or which therapy is desired, and generally refers to the recipient of the therapy to be practiced according to the invention. The subject can be any vertebrate, but will typically be a mammal. If a mammal, the subject will in many embodiments be a human, but may also be a domestic livestock, laboratory subject or pet animal.

Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

DETAILED DESCRIPTION

The present invention provides novel topiramate compositions and methods of treating obesity and conditions associated with and/or caused by obesity per se. The present invention also features a pharmaceutical composition that includes, e.g., topiramate alone or in combination with a sympathomimetic agent. In certain aspects, the sympathomimetic agent is phentermine or bupropion. The present invention, in certain aspects, is directed to an escalating dosing strategy for administering topiramate alone or in combination with one or more sympathomimetic agents.

Topiramate is an anticonvulsant sulfamate compound (Topamax®), which is also referred to in the art as 2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate.

In certain aspects, the pharmaceutical compositions of the subject invention include an effective amount of topiramate as the active agent. In some embodiments, an “effective amount” of topiramate is an amount that results in a reduction of at least one pathological parameter associated with obesity and/or a related disorder. Thus, e.g., in some embodiments, an effective amount of topiramate is an amount that is effective to achieve a reduction of at least about 10%, at least about 15%, at least about 20%, or at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95%, compared to the expected reduction in the parameter in an individual suffering from obesity and/or a related disorder and not treated with the topiramate compositions.

A suitable dose range for topiramate is one which ranges from 10-1500 mg in a single daily dosage which is administered to a patient over a specific period of time. For example, 10 mg, 20 mg, 30 mg, 60 mg, 90 mg, 120 mg, 150 mg, 180 mg, 210 mg, 240 mg, 270 mg, 300 mg, 330 mg, 360 mg, 390 mg, 420 mg, 450 mg, 480 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, 1500 mg or the like is administered to a patient as a single daily dosage. In another example, 23 mg, 46 mg, 69 mg and 92 mg or the like is administered to a patient as a single daily dosage. In some embodiments, the single dosing range of the present invention is from 10-150 mg of topiramate. In certain embodiments, the single dosing range of the present invention is from 10-100 mg of topiramate.

Further, the patient may receive a specific dosage of topiramate over a period of weeks, months, or years. For example, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, 5 years and the like.

Aspects of the invention provide a topiramate monotherapy or combination therapy in which the subject topiramate formulation is effective when administered at a initial dose as low as 10-23 mg. In certain aspects, the topiramate formulation is effective at a dose of approximately 20 mg. The novel topiramate formulations of the present invention have a lower maximum concentration (Cmax) without decreasing total drug exposure defined by the area under the concentration-time curve (AUC). Further, the novel topiramate formulations of the present invention have a delay in time after administration of a drug when the maximum plasma concentration is reached (Tmax) by six to eight hours. As depicted in FIG. 1, drug exposure as measured by AUC for the control release (CR) formulation capsule is the same as the 100 mg of immediate release topiramate (Topamax®) tablet despite a 20% reduction in the Cmax. Therefore, this formulation is capable of reducing the Cmax which would reduce side effects without compromising the efficacy of the treatment, since the AUC is the same. This reduction in Cmax is preferred as topiramate can be sedating and a delay in the time to reach maximum plasma concentration to the late afternoon or evening time would improve the tolerability of the drug.

As such, the effective amount of topiramate is decreased, thereby further reducing any toxicity or harmful side effects in the patient. The amount of topiramate administered to the patient is less than an amount that would cause toxicity in the patient. In certain embodiments, the amount of the compound that is administered to the patient is less than the amount that causes a concentration of the compound in the patient\'s plasma to equal or exceed the toxic level of the compound. The optimal amount of the compound that should be administered to the patient in the practice of the present invention will depend on the individual as well as the severity of the individual\'s symptoms.

Depending on the intended mode of administration, the pharmaceutical formulation may be a solid, semi-solid or liquid, such as, for example, a tablet, a capsule, a caplet, a liquid, a suspension, an emulsion, a suppository, granules, pellets, beads, a powder, or the like, preferably in unit dosage form suitable for single administration of a precise dosage. Suitable pharmaceutical compositions and dosage forms may be prepared using conventional methods known to those in the field of pharmaceutical formulation and described in the pertinent texts and literature, e.g., in Remington. The Science and Practice of Pharmacy (Easton, Pa.: Mack Publishing Co., 1995). For those compounds that are orally active, oral dosage forms are generally preferred, and include tablets, capsules, caplets, solutions, suspensions and syrups, and may also comprise a plurality of granules, beads, powders, or pellets that may or may not be encapsulated. Preferred oral dosage forms are tablets and capsules.

As noted above, it is especially advantageous to formulate compositions of the invention in unit dosage form for ease of administration and uniformity of dosage. The term “unit dosage forms” as used herein refers to physically discrete units suited as unitary dosages for the individuals to be treated. That is, the compositions are formulated into discrete dosage units each containing a predetermined, “unit dosage” quantity of an active agent calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications of unit dosage forms of the invention are dependent on the unique characteristics of the active agent to be delivered. Dosages can further be determined by reference to the usual dose and manner of administration of the ingredients. It should be noted that, in some cases, two or more individual dosage units in combination provide a therapeutically effective amount of the active agent, e.g., two tablets or capsules taken together may provide a therapeutically effective dosage of topiramate, such that the unit dosage in each tablet or capsule is approximately 50% of the therapeutically effective amount.

Tablets may be manufactured using standard tablet processing procedures and equipment. Direct compression and granulation techniques are preferred. In addition to the active agent, tablets will generally contain inactive, pharmaceutically acceptable carrier materials such as binders, lubricants, disintegrants, fillers, stabilizers, surfactants, coloring agents, and the like.

Capsules are also preferred oral dosage forms for those pharmaceutical active agents that are orally active, in which case the active agent-containing composition may be encapsulated in the form of a liquid or solid (including particulates such as granules, beads, powders or pellets). Suitable capsules may be either hard or soft, and are generally made of gelatin, starch, or a cellulosic material, with gelatin capsules preferred. Two-piece hard gelatin capsules are preferably sealed, such as with gelatin bands or the like. See, for example, Remington: The Science and Practice of Pharmacy, cited earlier herein, which describes materials and methods for preparing encapsulated pharmaceuticals.

Oral dosage forms, whether tablets, capsules, caplets, or particulates, may, if desired, be formulated so as to provide for controlled release of topiramate, and in a preferred embodiment, the present formulations are controlled release oral dosage forms. Generally, the dosage forms provide for sustained release, i.e., gradual, release of topiramate, from the dosage form to the patient\'s body over an extended time period, typically providing for a substantially constant blood level of the agent over a time period in the range of about 4 to about 12 hours, typically in the range of about 6 to about 10 hours or 6 to about 8 hours.

Generally, as will be appreciated by those of ordinary skill in the art, sustained release dosage forms are formulated by dispersing the active agent within a matrix of a gradually hydrolyzable material such as a hydrophilic polymer, or by coating a solid, drug-containing dosage form with such a material. Hydrophilic polymers useful for providing a sustained release coating or matrix include, by way of example: cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose e.g., Methocel™ A15LV, ethyl cellulose, cellulose acetate, and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, acrylic acid alkyl esters, methacrylic acid alkyl esters, and the like, e.g. copolymers of acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate; and vinyl polymers and copolymers such as polyvinyl pyrrolidone e.g., Povidone K30, polyvinyl acetate, and ethylene-vinyl acetate copolymer.

When sustained release preparations are prepared, tablets, granules, powder, capsules, and the like can be produced according to a conventional method after adding excipient, and as necessary, binder, disintegrating agent, lubricant, coloring agent, taste-modifying agent, flavoring agent, and the like. These additives may be ones generally used in the field, and for example, lactose, sodium chloride, glucose, starch, microcrystalline cellulose, e.g., Avicel®, and silicic acid as the excipient, water, ethanol, propanol, simple syrup, gelatin solution, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, shellac, calcium phosphate, and polyvinylpyrrolidone as the binder, agar powder, sodium hydrogencarbonate, sodium lauryl sulfate, and stearic acid monoglyceride as the disintegrating agent, purified talc, stearic acid salt, borax, and polyethylene glycol as the lubricant, β-carotene, yellow iron sesquioxide, and caramel as the coloring agent, and saccharose and orange peel as the taste-modifying agent can be listed as examples.

Additional sustained release dosage forms of the present invention may be composed of the acrylate and methacrylate copolymers available under the trade name “Eudragit” from Rohm Pharma (Germany). The Eudragit series E, L, S, RL, RS, and NE copolymers are available as solubilized in organic solvent, in an aqueous dispersion, or as a dry powder. Preferred acrylate polymers are copolymers of methacrylic acid and methyl methacrylate, such as the Eudragit L and Eudragit S series polymers. Particularly preferred such copolymers are Eudragit L-30D-55 and Eudragit L-100-55 (the latter copolymer is a spray-dried form of Eudragit L-30D-55 that can be reconstituted with water). The molecular weight of the Eudragit L-30D-55 and Eudragit L-100-55 copolymer is approximately 135,000 Da, with a ratio of free carboxyl groups to ester groups of approximately 1:1. The copolymer is generally insoluble in aqueous fluids having a pH below 5.5. Another particularly suitable methacrylic acid-methyl methacrylate copolymer is Eudragit S-100, which differs from Eudragit L-30D-55 in that the ratio of free carboxyl groups to ester groups is approximately 1:2. Eudragit S-100 is insoluble at pH below 5.5, but unlike Eudragit L-30D-55, is poorly soluble in aqueous fluids having a pH in the range of 5.5 to 7.0. This copolymer is soluble at pH 7.0 and above. Eudragit L-100 may also be used, which has a pH-dependent solubility profile between that of Eudragit L-30D-55 and Eudragit S-100, insofar as it is insoluble at a pH below 6.0. It will be appreciated by those skilled in the art that Eudragit L-30D-55, L-100-55, L-100, and S-100 can be replaced with other acceptable polymers having similar pH-dependent solubility characteristics. Other preferred Eudragit polymers are cationic, such as the Eudragit E, RS, and RL series polymers. Eudragit E100 and E PO are cationic copolymers of dimethylaminoethyl methacrylate and neutral methacrylates (e.g., methyl methacrylate), while Eudragit RS and Eudragit RL polymers are analogous polymers, composed of neutral methacrylic acid esters and a small proportion of trimethylammonioethyl methacrylate.

In a specific embodiment, controlled release topiramate beads are made using an extrusion spheronization process to produce a matrix core comprised of topiramate: 40.0% w/w; microcrystalline cellulose, Avicel® PH102: 56.5% w/w; and Methocel™ A15 LV: 3.5% w/w. The topiramate cores are then coated with ethyl cellulose: 5.47% w/w and Povidone K30: 2.39% w/w.

Preparations according to this invention for parenteral administration include sterile aqueous and nonaqueous solutions, suspensions, and emulsions. Injectable aqueous solutions contain the active agent in water-soluble form. Examples of nonaqueous solvents or vehicles include fatty oils, such as olive oil and corn oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, low molecular weight alcohols such as propylene glycol, synthetic hydrophilic polymers such as polyethylene glycol, liposomes, and the like. Parenteral formulations may also contain adjuvants such as solubilizers, preservatives, wetting agents, emulsifiers, dispersants, and stabilizers, and aqueous suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, and dextran. Injectable formulations are rendered sterile by incorporation of a sterilizing agent, filtration through a bacteria-retaining filter, irradiation, or heat. They can also be manufactured using a sterile injectable medium. The active agent may also be in dried, e.g., lyophilized, form that may be rehydrated with a suitable vehicle immediately prior to administration via injection.

The active agent may also be administered through the skin using conventional transdermal drug delivery systems, wherein the active agent is contained within a laminated structure that serves as a drug delivery device to be affixed to the skin. In such a structure, the drug composition is contained in a layer, or “reservoir,” underlying an upper backing layer. The laminated structure may contain a single reservoir, or it may contain multiple reservoirs. In one embodiment, the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery. Alternatively, the drug-containing reservoir and skin contact adhesive are present as separate and distinct layers, with the adhesive underlying the reservoir which, in this case, may be either a polymeric matrix as described above, or it may be a liquid or hydrogel reservoir, or may take some other form. Transdermal drug delivery systems may in addition contain a skin permeation enhancer.

In addition to the formulations described previously, the active agent may be formulated as a depot preparation for controlled release of the active agent, preferably sustained release over an extended time period. These sustained release dosage forms are generally administered by implantation (e.g., subcutaneously or intramuscularly or by intramuscular injection).

Although the present compositions will generally be administered orally, parenterally, transdermally, or via an implanted depot, other modes of administration are suitable as well. For example, administration may be transmucosal, e.g., rectal or vaginal, preferably using a suppository that contains, in addition to the active agent, excipients such as a suppository wax. Transmucosal administration also encompasses transurethral administration, as described, for example, in U.S. Pat. Nos. 5,242,391, 5,474,535, and 5,773,020 to Place et al. Formulations for nasal or sublingual administration are also prepared with standard excipients well known in the art. The pharmaceutical compositions of the invention may also be formulated for inhalation, e.g., as a solution in saline, as a dry powder, or as an aerosol.

In some embodiments, a subject method of treating obesity and/or a related disorder comprises administering topiramate in an individual and a sympathomimetic agent. In certain aspects, the subject methods may comprise administering topiramate with two or more sympathomimetic agents.

Sympathomimetic agents for use in the present invention and their general clinical uses or effects are set forth in Table I.

TABLE I Sympathomimetic Agents and Clinical Uses Thereof Ring α Receptor β Receptor CNS, Agent name substituent(s) Rα Rβ Rγ A N P V B C 0 Bupropion 3-Cl ═O CH3 C(CH3)3 Phenylethylamine H H H Epinephrine 3-OH, 4-OH OH H CH3 A, P, V B, C Norepinephrine 3-OH, 4-OH OH H H P Epinine 3-OH, 4-OH H H CH3 Dopamine 3-OH, 4-OH H H H P Dobutamine 3-OH, 4-OH H H 1* C Nordefrin 3-OH, 4-OH OH CH3 H V Ethylnorepinephrine 3-OH, 4-OH OH CH2CH3 H B Isoproterenol 3-OH, 4-OH OH H

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