Escalating dosing regimen (escalatingdosingregimen) for achieving weight reduction and treating obesity

0001<u style="single">Cross-reference to related applications</u> This application is a partial continuation of US Patent Application No. 12 / 135,953 filed June 9, 2008, the disclosure of which is incorporated by reference.

0002Background of the invention The prevalence of obesity in both children and adults is rising not only in developed countries, especially in the United States, but also in many developing countries such as China and India. Obesity affects many aspects of people's lives, from physical problems such as knee and ankle joint deterioration to emotional problems due to self-esteem and social attitudes towards heavy people. .. Medical problems resulting from obesity can be serious and often life-threatening, with diabetes, shortness of breath and other respiratory diseases such as asthma and pulmonary hypertension, biliary sac disease, dyslipidemia (eg, hypercholesterolemia or). High levels of triglyceride) and dyslipidemia hypertension, osteoarthritis and other orthopedic disorders, reflux esophagitis (chest burn), sneezing, sleep aspiration, irregular menstruation, infertility, pregnancy-related disorders , Cardiovascular disorders such as gout, coronary artery disease and other heart diseases, muscular dystrophy, and metabolic disorders such as low α-lipoproteinemia, familial complex hyperlipidemia, and syndrome X including insulin resistance syndrome X Including. In addition, obesity is associated with an increased incidence of certain cancers, especially colon cancer, rectal cancer, prostate cancer, breast cancer, uterine cancer, and cervical cancer.

0003Obesity substantially increases the risk of prevalence from hypertension, dyslipidemia, type II diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis and endometrial cancer, breast cancer, prostate cancer, and colorectal cancer To do. Heavier weight is also associated with increased all-cause mortality. Many of these problems are alleviated or ameliorated if the affected individual experiences persistent and significant weight loss. Weight loss in these individuals can also promote a significant increase in lifespan.

0004Strategies to treat obesity and related disorders include dietary restrictions, increased physical activity, pharmacological methods, and even surgery, the choice of which, at least in part, is the weight loss that individuals are trying to achieve. It depends not only on the degree of obesity, but also on the severity of obesity indicated by the subject. For example, treatments such as a low-calorie, low-fat diet and / or regular exercise are often appropriate for individuals who are slightly overweight. However, the difficulty of maintaining long-term weight loss through diet and behavior modification has led to increased interest in other treatments, especially drug therapy.

0005Traditional pharmacological interventions typically induce weight loss between 5 and 15 kilograms; withdrawal of medication often results in recurrence of weight gain. Surgical treatment is relatively successful and is intended for patients with extreme obesity and / or serious medical complications.

0006The treatment may be enhanced by controlled use of over-the-counter appetite suppressants, including caffeine, ephedrine and phenylpropanolamine (Acutrim®, and Dexatrim®). In addition, amphetamine, diethylpropion (Tenuate®), mazindol (Mazanor®, and Sanorex®), phentermine (Fastin®). ), And phenmetrazine (Ionamin®)), phenmetrazine (Preludin®), phenmetrazine (Bontrol®, Plegine®) , Adipost (registered trademark), Dital (registered trademark), Dyrexan (registered trademark), Melphiat (registered trademark), Prelu-2 (registered trademark), And Rexigen Prescription medications containing Forte®)), benzphetamine (Didrex®) and fluoxetine (Prozac®) are severely overweight and / or obese subjects or patients Often used to treat obesity.

0007While society is making significant progress in the field of medicines, there are, of course, weaknesses in the administration of any medicine. Sometimes the disadvantages, or "side effects," are so severe that it prevents certain drugs from being administered in therapeutically effective amounts. In addition, many drugs in the same therapeutic class exhibit similar side effect characteristics, which means that patients must refrain from treatment or suffer from varying degrees of side effects associated with the drug therapy of their choice. Means have to.

0008The present invention is an escalating dosing regimen for administering topiramate alone or in combination with a second therapeutic agent that directly or indirectly reduces side effects associated with one or both of the administered agents. ). Reducing "indirectly" side effects means that the second therapeutic agent allows the first drug to be administered at a lower dose without compromising the therapeutic effect, and therefore a dose-dependent unwanted effect. Means that there is no.

0009Topiramate (2,3,4,5-bis-O- (1-methylethylidene) -β-D-fructopyranose sulfamate) is an FDA for the treatment of certain seizure disorders and for the prevention of migraine. And a wide range of neurotherapeutic agents approved by regulators in many other countries. E. Faught et al. (1996) Neurology 46: 1648-90; Karim et al. (1995) Epilepsia 36 (S4): 33; SK Sachdeo et al. (1995) Epilepsia 36 (S4): 33; TA Glauser ( 1999) Epilepsia 40 (S5): S71-80; RC Sachdeo (1998) Clin. Pharmacokinet. 34: 335-346). Topiramates are diabetes (US Pat. Nos. 7,109,174 and 6,362,220), neuropathy (US Pat. No. 6,908,902), depression (US Pat. No. 6,627,653), mental illness (US Pat. No. 6,620,819), headache (US Pat. There is also evidence that it is effective in treating hypertension (US Pat. No. 6,201,010). However, in humans, there are adverse effects associated with the use of topiramate, such as cognitive decline and difficulty finding words, which can prevent many obese patients from taking the drug.

<p num="0010"> Therefore, there is great interest in developing additional methods and compositions for treating obesity and related conditions that improve the therapeutic effect of known therapeutic agents and compositions. In addition, two or more active agents are administered in combination to reduce the dose of the individual active agent administered and to reduce one or more side effects of the other active agent or agents. Combination therapy may be used. Obesity and / or related conditions, including combination therapies that result in reduced toxicity, reduced side effects and effective treatment due to the increased incidence of obesity and conditions caused by or associated with obesity. There is an urgent need for an effective method for the treatment of obesity.</p>

<p num="0011">Outline of the invention The present invention provides novel topiramate compositions and methods for achieving weight loss, treating obesity, and treating conditions resulting from or associated with overweight or obesity. The composition may contain topiramate as a single active agent, but more typically it contains topiramate in combination with at least one sympathomimetic. The term "sympathomimetic agent" is a terminology that refers to a drug or compound that mimics or alters the stimulation of the sympathetic nervous system. Representative sympathomimetics include phentermine and bupropion. Preferably, the topiramate and the sympathomimetic are contained in a single dosage form and the immediate release of the sympathomimetic and the controlled release of the topiramate, eg, sustained release, delayed release, or sustained release and delayed release. Provide both.</p><p num="0012"> In another aspect of the invention, a controlled release topiramate composition comprising an effective amount of topiramate, microcrystalline cellulose, and methyl cellulose is provided. The composition will provide a sustained release of the topiramate. For example, the composition in the form of beads or tablets may be coated with ethyl cellulose, polyvinylpyrrolidone, etc. to further provide delayed release of the topiramate. Although not always, it preferably contains a sympathomimetic and, if present, is preferably of the immediate release type.</p><p num="0013"> The present invention features an escalating dosing regimen for administering topiramate alone or in combination with a sympathomimetic agent, wherein the dosing regimen is a method of achieving weight loss, such as obesity, overweight. Or related to methods for treating conditions associated with obesity, or with alternative methods, such as treating epilepsy, or treating impaired impulse control. The method comprises administration of the above-mentioned topiramate composition, which is generally, but not necessarily, administered in a controlled release composition and / or in combination with a sympathomimetic agent. The escalating dosing regimen comprises administering to an individual an initial daily dose for a specific period of time and gradually increasing the dose at various designated points in time.</p><p num="0014"> The present invention also provides a packaged pharmaceutical formulation comprising topiramate, optionally a sympathomimetic, and instructions for administering, eg, self-administering the active agent. In general, the instructions for administration include reference to an escalating dosing regimen, where a lower daily dose of topiramate is first administered and then gradually at various designations. Includes references to increasing dosing regimens. Ideally, a titration card will be provided that specifies the recommended dose for at least 4 weeks.</p>

0015<figref num="1">FIG. 1 provides an overview of the plasma concentrations of controlled release topiramate vs. topiramate (Topamax®) of the present invention in normal obese subjects.</figref>

0016<figref num="2">Figure 2 shows the mean plasma phentermine concentration pair for subjects who received phentermine in combination with controlled-release topiramate and subjects who received phentermine in combination with immediate-release topiramate (Topamax®). Indicates the time.</figref>

0017<u style="single">Detailed description of the invention</u><u style="single">Definition and nomenclature:</u> As used herein and in the appended claims, the singular forms "a," "an," and "the" shall include multiple referents unless explicitly stated otherwise in the context. You have to be careful. So, 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, and "a dosage form" is a single dosage form. Not only does it refer to a combination of dosage forms, etc.

0018Unless otherwise defined, all technical and scientific terms used herein have meanings commonly understood by those skilled in the art to which the present invention belongs. Specific terminology that is particularly important to the description of the present invention is defined below.

0019When referring to an active agent, the applicant refers to the term "active agent" not only for the specified molecular entity, but also for salts, esters, amides, prodrugs, conjugates, active metabolites as discussed below. It is intended to include, but not limited to, pharmaceutically acceptable and pharmacologically active analogs thereof, including, but not limited to, other similar derivatives, analogs, and related compounds. Therefore, for example, references to "phentermine" or "bupropion" refer not only to phentermine and bupropion itself, but also to salts and other derivatives of phentermine and bupropion, such as phentermine hydrochloride and bupropion hydrochloride, respectively. Also includes. When an amount or dose is specified, it should be understood that the amount or dose refers to the amount or dose of the active agent itself, not salt or the like. For example, if the dose or amount of phentermine is shown to be 7.5 mg, it would correspond to 9.84 phentermine hydrochloride and not 7.5 phentermine hydrochloride.

0020As used herein, the terms "treating" and "treating" refer to reducing the severity and / or frequency of symptoms, eliminating symptoms and / or the underlying cause, and ameliorating or repairing damage. In certain embodiments, the terms "treating" and "treatment" as used herein refer to the prevention of the development of symptoms. In other aspects, the terms "treating" and "treating" as used herein refer to the prevention of the underlying cause of symptoms associated with obesity, overweight, and / or associated conditions. The phrase "administering to a subject" refers to the process of introducing the composition or dosage form of the invention into a subject (eg, a human or other mammalian subject) using a transfer method recognized in the art. ..

0021The terms "effective amount" and "therapeutically effective amount" are books that are non-toxic and effective in producing some desired therapeutic effect when administered to a subject or patient (eg, a human subject or patient). Refers to the amount of a drug, compound, drug, composition or combination of the invention.

0022The term "dosage form" means any form of a pharmaceutical composition containing an amount of active agent sufficient to achieve a therapeutic effect with a single dose. When the formulation is a tablet or capsule, the dosage form is usually one such tablet or capsule. The frequency of administration that will effectively provide the most effective results without overdose will vary depending on the properties of the particular active agent, including both pharmacological and physical properties such as hydrophilicity. Let's go.

0023The term "controlled release" refers to a drug-containing preparation or fraction thereof in which the release of the drug is not immediate, that is, the "controlled release" preparation does not result in immediate release of the drug into the absorption pool. Point to. The term is used interchangeably with "non-immediate release" as defined in "Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, PA: Mack Publishing Company, 1995)". Typically, the term "controlled release" as used herein includes continuous release, modified release and delayed release formulations.

0024The term "sustained release" (synonymous with "extended release") is used in its traditional sense to provide, but not always, a slow release of the drug over a long period of time. , Preferred, refers to a drug formulation that results in a substantially constant blood concentration of the drug over a long period of time. The term "delayed release" is also used in its conventional sense to refer to a drug formulation that provides a measurable time delay after administration to the patient and before the drug is released from the formulation into the patient's body.

0025"Pharmaceutically acceptable" means a substance that is not biologically or otherwise undesired, i.e. may be incorporated into a pharmaceutical composition administered to a patient, but neither is desired. Means a substance that does not produce a biological effect or interacts with any of the other components of the composition in which the substance is contained in a detrimental manner. When the term "pharmaceutically acceptable" is used to refer to a pharmaceutical carrier or excipient, it means that the carrier or excipient meets the required criteria for toxicity and manufacturing testing, or Inactive Ingredient Guide (Inactive Ingredient) prepared by the US Food and Drug Administration It means that it is included in Guide). As used in "pharmacologically active" (or "active") derivatives or analogs, "pharmacologically active" (or simply "active") is the same pharmacological activity as the parent compound. Refers to a derivative or analog having about the same amount. The term "pharmaceutically acceptable salt" includes acid addition salts formed of, for example, inorganic acids such as hydrochloric acid or phosphoric acid, or organic acids such as acetic acid, oxalic acid, tartaric acid, or mandelic acid. Salts formed with free carboxyl groups can also be derived from inorganic bases such as sodium, potassium, ammonium, calcium, or ferric hydroxide, and organic bases such as isopropylamine, trimethylamine, histidine, or prokine. Good.

0026As used herein, "subject," "individual," or "patient" refers to any subject in need of treatment, generally to a person receiving treatment performed in accordance with the present invention. The subject may be any vertebrate, but will typically be a mammal. If it is a mammal, the subject may be a human in many embodiments, but may be a domestic animal, a laboratory animal or a pet animal.

0027Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. In the practice or testing of the present invention, either methods and substances similar or equivalent to those described herein may be used, but preferred methods and substances are described below. All publications referred to herein are incorporated herein by disclosing and describing and referring to the methods and / or substances cited as relevant to such publications.

0028If a range of values is provided, the upper and lower limits of that range, to the tenth of the unit of the lower limit, unless explicitly stated otherwise in the context. It is understood that the respective intermediate values between the values, and any other indication or intermediate value of any of its indication range, are included within the scope of the invention. The upper and lower limits of these smaller ranges may be independently contained within the smaller range, are also included within the scope of the invention, and follow any specifically excluded boundary of the display range. .. If the scope of display includes one or both of the boundaries, then the scope of the invention also includes excluding one or both of those included boundaries.

0029Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. In the practice or testing of the present invention, either methods and substances similar or equivalent to those described herein may be used, but preferred methods and substances are described below.

0030The publications discussed herein are provided solely for their disclosure prior to the filing date of this application. Nothing in this specification is construed as recognizing that the present invention has no right to precede the publication by prior invention. In addition, the published dates provided may differ from the actual published dates, which may need to be confirmed independently.

0031Methods and formulations of the present invention: The present invention achieves weight loss and is obesity, overweight or a condition associated with obesity, diabetes (whether or not associated with obesity), and other conditions as described below. And provide novel methods and compositions for treating disorders. According to the US Center for Disease Control, the clinical definition of overweight (the term is used synonymously herein with the term "overweight") is a body between 25.0 and 29.9 kg / m. Have a body mass index (BMI); BMI is calculated by multiplying an individual's weight (kilograms) by height (meters). The CDC defines obesity as having a BMI of 30 or higher. In one embodiment, the invention provides a method of achieving weight loss and treating overweight, obesity, and conditions associated with overweight and obesity, the sympathomimetic agents phentermine and anticonvulsants. Includes administration of a combination of agents topiramate.

0032Topiramate is an anticonvulsant sulfamate compound sold in the United States under the trade name Topamax (registered trademark) (Ortho-McNeil Pharmaceuticals, Raritan, NJ, USA). Topiramate was approved for use as an antiepileptic drug in adjuvant therapy for patients with partial onset seizures or primary systemic tonic-clonic seizures, and for the prevention of migraine. See Physician's Desk Reference, 56th ed. (2002); U.S. Pat. No. 4,513,006 granted to Maryanoff et al. And U.S. Patent No. 4,513,006 granted to Almarssoo et al. See also Nos. 7,351,695.

0033"Topiramate" is commonly referred to as the chemical name 2,3,4,5-bis-O- (1-methylethylidene) -β-D-fructopyranose sulfamate and the molecular formula C.₁₂H₂₁NO₈Refers to sulfamate-substituted monosaccharides with S. The structure of the compound is represented by the formula (I).<chemistry num="1"><img id="000002" he="28" wi="55" file="JP2015166380A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry> (I) The term "topiramate" as used herein refers to not only 2,3,4,5-bis- (O)-(1-methylethylidene) -β-D-fructopyranose sulfamate, but also individually. Enantiomers, individual diastereomers, or mixtures thereof. As used herein, the term "topiramate" refers to polymorphs, solvates (including hydrates and mixed solvates, and salt hydrates), co-crystals (eg, hydrates of salts) as well as topyramate salts. , Co-crystallized with other compounds or other forms of topiramate), amorphous, and also includes anhydrous forms of compounds of formula (I). As evidenced by the fact that the compound is a sulfamic acid derivative, a useful topiramate salt in connection with the present invention is a pharmaceutically acceptable base addition salt. The salt is prepared from a base that provides a pharmaceutically acceptable cation that binds to the sulfamic acid group of the compound of formula (I). Suitable pharmaceutically acceptable cations include both organic and inorganic cations, including sodium, sodium, potassium, lithium, magnesium, calcium, aluminum, zinc, prokine, benzatin, chloroprokine, choline, diethylamine, ethylenediamine, N- Methylglucamine, venetamine, cremisol, diethylamine, piperazine, tromethamine, triethylamine, ethanolamine, triethanolamine, arginine, lysine, histidine, tributylamine, 2-amino-2-pentylpropanol, 2-amino-2-methyl-1 , 3-Propanediol, tris (hydroxymethyl) aminomethane, benzylamine, 2- (dimethylamino) ethanol, barium or bismuth counter ions, but not limited to these. Particularly preferred cations are sodium, lithium, and potassium. The other forms of topiramate referred to above may be manufactured using methods well known in the art; for example, US Pat. No. 7,351, See No. 695. The methods of the invention include dosing regimens for administration of topiramate alone or, more preferably in combination with sympathomimetics. In certain aspects, the invention provides a dosing regimen for administration of a pharmaceutical composition comprising topiramate in combination with, for example, bupropion or phentermine.

0034In one embodiment of the invention directed to an escalating dosage regimen, the dosing strategy involves daily doses of lower doses of topiramate, alone or in sympathetic nerves, for a period of time. It comprises administering to the patient in combination with a stimulant and then gradually increasing the dose at various designated time points.

0035For example, when treating a patient who is overweight or obese, and who may suffer from a condition associated with or resulting from overweight or obesity, the patient may be treated for one week, 15 mg / day to 30 mg / day, eg, Take a dose of 23 mg / day of topiramate. The patient then receives 35 mg / day to 55 mg / day, eg, 46 mg / day dose of topiramate during the second week. The patient then ingests topiramate at a dose of 60 mg / day-80 mg / day, eg 69 mg / day, during the third week, and then 85 mg-125 mg / day, eg 92 mg / day, during the fourth week. Take the final daily dose of topiramate.

0036In another example, when treating a patient for obesity and / or related conditions, the patient may receive topiramate at a dose of 15 mg / day to 30 mg / day, eg, 23 mg / day, 3.75 mg / day for one week. Take in combination with doses of phentermine. The patient then takes 35 mg / day to 55 mg / day, eg, 46 mg / day dose of topiramate, in combination with 7.5 mg / day dose of phentermine during the second week. The patient then ingests topiramate at a dose of 60 mg / day to 80 mg / day, eg, 69 mg / day, in combination with a dose of 11.25 mg / day of phentermine for the third week, followed by a second. For four weeks, take a final dose of topiramate from 85 mg to 125 mg / day, eg 92 mg / day, in combination with a 15 mg / day dose of phentermine.

0037After the fourth week of administration, further administration of topiramate alone or in combination with phentermine is continued indefinitely, or more typically, until sufficient reduction of symptoms is achieved. In certain embodiments, a final dose of 92 mg / day of topiramate is administered alone or in combination with a dose of 15 mg / day of phentermine until indefinite or a sufficient reduction in symptoms is achieved. In other embodiments, the final dose of topiramate alone or in combination with phentermine is reduced to the initial starting dose of the dosing regimen and maintained indefinitely or until a sufficient reduction in symptoms is achieved. In a weight loss dosing regimen, the dosing regimen generally depends on the severity of the individual's weight problem, the amount of weight to be lost, and the rate at which weight loss occurs for a considerable period of time, eg, about 4 weeks ~. Includes continuous, ie, continuous administration over a range of approximately 67 weeks.

0038In another embodiment of the invention, topiramate is administered continuously, i.e., generally according to the escalating dosage regimen described above. One of these methods, i.e., the escalating dosage regimen or the ongoing maintenance dosage regimen. In regimen), a pharmaceutical composition comprising an effective amount of topiramate is administered as the active agent, where the "effective amount" of topiramate is generally at least associated with obesity, overweight, and / or related disorders. An amount that results in a reduction in one pathological parameter. In the methods of the invention, eg, methods of achieving weight loss such as treatment of obesity and / or conditions associated with obesity, effective amounts of topiramate suffer from obesity, overweight, and / or related disorders. In individuals not treated with topiramate composition, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, compared to parameters such as the expected reduction in weight loss. 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%, An amount effective to achieve a reduction of at least about 85%, at least about 90%, or at least about 95%.

0039Suitable daily doses of topiramate are in the range of 10 mg to 1500 mg. For example, 10mg, 20mg, 30mg, 60mg, 90mg, 120mg, 150mg, 180mg, 210mg, 240mg, 270mg, 300mg, 330mg, 360mg, 390mg, 420mg, 450mg, 480mg, 500mg, 600mg, 800mg, 1000mg, 1200mg or 1500mg. Etc. are administered to the patient as a daily dose. In another example, patients are given daily doses such as 23 mg, 46 mg, 69 mg and 92 mg. In some embodiments, the daily dose of topiramate ranges from 10 mg to 150. In certain embodiments, the daily dose of topiramate is in the range of 10 mg to 100 mg. Each of the aforementioned "daily dosages" is generally, but not necessarily, administered as a single daily dose.

0040The patient takes a specific dose of topiramate for weeks, months, or years, such as 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 It may be taken for months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, or 5 years.

0041Aspects of the present invention provide topiramate monotherapy or combination therapy in which the topiramate preparation of the present invention is effective when administered at a low initial dose of 10-23 mg. In certain embodiments, the topiramate preparation is effective at a dose of approximately 20 mg. The novel topiramate formulations of the present invention have a lower maximum concentration (Cmax) without reducing total drug exposure as defined by the area under the concentration-time curve (AUC). In addition, the novel topiramate formulations of the present invention have a time delay of 6-8 hours after administration of the drug before the time (Tmax) at which maximum plasma concentration is achieved. As shown in Figure 1, drug exposure measured by AUC for controlled release (CR) capsule formulation is 100 mg immediate release topiramate (Topamax®), despite a 20% reduction in Cmax. It is the same as a tablet. Therefore, this product can reduce Cmax, and since the AUC is the same, it will reduce side effects without compromising the effectiveness of treatment. This reduction in Cmax is preferred because topiramate can have a sedative effect, and delaying the time to reach maximum plasma concentration until evening or night will improve drug resistance.

0042As such, the effective amount of topiramate is reduced, thereby further reducing any toxic or adverse side effects in the patient. The amount of topiramate administered to the patient is less than the amount that would cause toxicity in the patient. In certain embodiments, the amount of the compound administered to the patient is less than the amount that results in the concentration of the compound in the patient's plasma at levels equal to or greater than the toxic levels of the compound. is there. The optimum amount of the compound to be administered to the patient in the practice of the present invention will depend not only on the individual but also on the severity of the individual's symptoms.

0043Depending on the method of administration of interest, the pharmaceutical formulation may be solid, semi-solid or liquid, eg, tablets, capsules, caplets, liquids, suspensions, emulsions, suppositories, granules, small pills, beads. , Or powders, etc., preferably in a unit dosage form suitable for a single dose of the correct dose. Suitable pharmaceutical compositions and dosage forms are conventional methods well known to those skilled in the art of pharmaceutical formulations, as well as related texts and literature, such as "Remington: The Science and Practice of Pharmacy (Easton, PA: Mack Publishing Co.). , 1995) . Oral administration, and therefore oral dosage forms, are generally preferred, including tablets, capsules, caplets, solutions, suspensions and syrups, and multiple granules, beads, powders, which may or may not be encapsulated. Alternatively, small capsules may also be included. As mentioned above, preferred oral dosage forms are capsules and tablets, especially controlled release capsules and tablets.

0044As described above, it is particularly advantageous to formulate the composition of the present invention into a unit dosage form because of the convenience of administration and the uniformity of dose. As used herein, the term "unit dosage form" refers to a physically separated unit suitable as a unit dose for an individual being treated. That is, the composition is formulated into separate dosage units each containing a predetermined "unit dose" of the active agent calculated to produce the desired therapeutic effect in collaboration with the required pharmaceutical carrier. .. The specification of the unit dosage form of the present invention depends on the unique properties of the active agent being delivered. The dosage can be further determined by reference to the usual dose of the ingredient and the mode of administration. Of note, in some cases, two or more individual dosage units combine to provide a therapeutically effective amount of the active agent, eg, two tablets or capsules together are therapeutically effective. Dosages may be provided, and the unit dose in each tablet or capsule may be approximately 50% of the therapeutically effective dose.

0045Tablets may be manufactured using standard tablet processing methods and equipment. Direct compression and granulation techniques are preferred. In addition to active agents, tablets generally contain inert, pharmaceutically acceptable carrier substances such as binders, lubricants, disintegrants, fillers, stabilizers, surfactants, and colorants. contains.

0046Capsules are also preferred oral dosage forms, in which case the active agent-containing composition may be encapsulated in the form of a liquid or solid (including microparticles such as granules, beads, powders or small pills). Suitable capsules can be either hard or soft and are generally made from gelatin, starch, or cellulosic material, with gelatin capsules being preferred. The two pieces of hard gelatin capsules are preferably sealed with a gelatin band or the like. See, for example, "Remington: The Science and Practice of Pharmacy," cited earlier herein, which describes substances and methods for making encapsulated medicines.

0047The oral dosage form, whether tablet, capsule, caplet, or microparticle, may optionally be formulated to provide a controlled release of topiramate, and in a preferred embodiment, the formulation is controlled. It is a release oral dosage form. In general, the dosage form provides a long-term, sustained release, i.e., a slow release of topiramate from the dosage form to the patient's body, typically for a period ranging from about 4 to about 12 hours. It provides a substantially constant blood concentration of the agent over a range of about 6 to about 10 hours or 6 to about 8 hours. The release of the topiramate may be delayed; i.e., there may be a time lag between administration and the onset of topiramate release. Thus, for example, an individual will not experience drowsiness or other side effects of topiramate on school or work days. Therefore, preferred dosage forms include both sustained release of the topiramate, delayed release of the topiramate, or sustained and delayed release of the topiramate.

0048Generally, as those skilled in the art will understand, the sustained release dosage form is a solid, drug, either by dispersing the active agent within a matrix of slowly hydrolyzing substances such as hydrophilic polymers. It is formulated by coating the containing dosage form with the substance. Hydrophilic polymers useful for providing sustained release coatings or matrices include: cellulose polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate, and sodium carboxymethyl cellulose; preferably acrylic acid. , Acrylic acid polymers and copolymers formed from methacrylic acid, acrylic acid alkyl esters, and methacrylate alkyl esters, such as acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and / or ethyl methacrylate copolymers; and vinyl. polymers and copoly mers, such as polyvinyl pyrrolidone, e.g., povidone K30, polyvinyl acetate, and ethylene - containing vinyl acetate copolymer. Preferred sustained release polymers herein are those available from Dow Chemical as "Methocel" polymers, in particular Metocel A (with a viscosity grade of about 4,000 cps and a methoxyl content of about 27.5% to 31.5%). Includes methylcellulose ether polymers of the Methocel A group, such as Methocel A15LV (Methocel A15LV), Methocel A15C (Methocel A15C), and Methocel A4M (Methocel A4M).

0049When a sustained-release preparation is produced, tablets, granules, powders, capsules, etc. are excipients and, if necessary, binders, disintegrants, lubricants, colorants, taste modifiers, and After adding a fragrance or the like, it can be produced according to a conventional method. These additives may be those commonly used in the art and include, for example, lactose, sodium chloride, glucose, starch, microcrystalline cellulose and silicic acid as excipients, water, ethanol as binders. Propanol, monosyrup, gelatin solution, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, cellac, calcium phosphate, and polyvinylpyrrolidone, agar powder as disintegrant, sodium hydrogen carbonate, sodium lauryl sulfate, and monoglyceride stearate, purified talc as lubricant, Examples include stearate, borosand, and polyethylene glycol, β-carotene as colorants, yellow iron sesquioxide, and caramel, and saccharose and orange peel as taste modifiers. Of note, various grades of microcrystalline cellulose are preferred fillers herein, eg, Avicel PH101 (Avicel® PH101) with particle sizes of about 50 microns, 100 microns, and 190 microns, respectively. ), Avicel PH102 (Avicel® PH102), and Avicel PH200 (Avicel® PH200) (FMC). Microcrystalline cellulose having a particle size in the range of about 50 microns to 200 microns is preferred herein.

0050The dosage form may be provided with a delayed release coating and may consist of, for example, an acrylate and / or methacrylate copolymer. An example of such a polymer is a polymer available from ROHM Pharma (Germany) under the trade name "Eudragit". Eudragit series E, L, S, RL, RS, and NE copolymers are available in solubilized forms in organic solvents, in aqueous dispersions, or as dry powders. Preferred acrylate polymers are copolymers of methacrylic acid and methyl methacrylate, such as Eudragit L and Eudragit S series polymers. Other preferred Eudragit polymers are cationic, such as Eudragit E, RS, and RL series polymers. Eudragit E100 and E PO is a cationic copolymer of dimethylaminoethyl methacrylate and neutral methacrylate (eg, methyl methacrylate), while Eudragit RS and Eudragit RL polymers are similar polymers, neutral methacrylic acid esters and Consists of a small amount of trimethylammonioethyl methacrylate.

0051In certain embodiments, controlled release topiramate beads for oral administration, for example by being incorporated into orally administrable capsules or compressed into orally administrable tablets, are produced using an extruded spheroidizing process. Topiramate, 40.0% w / w; microcrystalline cellulose, eg, Avicel PH102 (Avicel® PH102), 56.5% w / w; and methyl cellulose, eg, Methocel A15LV (Methocel® A15LV), 3.5% A matrix core consisting of w / w is manufactured. The topiramate core is then coated with ethyl cellulose, 5.47% w / w and povidone K30: 2.39% w / w. Beads of a second active agent, such as a sympathomimetic, may also be produced and incorporated into the capsule, as described in detail below. For example, phentermine or bupropion beads with an immediate release drug coating on sugar spheres or a similar inert core may be utilized. The two sets of beads may then be encapsulated in one capsule.

0052The formulations of the present invention for parenteral administration include sterile aqueous and non-aqueous solutions, suspensions, and emulsions. Aqueous solutions for injection contain active agents in water-soluble form. Examples of non-aqueous 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, and liposomes. Including. Parenteral formulations may contain adjuvants such as solubilizers, preservatives, wetting agents, emulsifiers, dispersants, and stabilizers, and aqueous suspensions are suspensions such as sodium carboxymethyl cellulose, sorbitol, and dextran. It may contain a substance that increases the viscosity of the liquid. Injectable formulations are sterilized by uptake of sterile agent, filtration through a bacterial retention filter, irradiation, or heat. They can also be produced by using sterile injectable media. The active agent may be in a dry, eg, lyophilized form, which can be rehydrated with a suitable vehicle immediately prior to injection administration.

0053The active agent may be administered through the skin using a conventional transdermal drug delivery system, and the active agent is contained in a laminated structure that acts as a drug delivery device applied to the skin. In that structure, the drug composition is contained in the underlying layer, or "reservoir," of the upper backing layer. The laminated structure may contain a single reservoir or may contain multiple reservoirs. In one embodiment, the reservoir comprises a polymer matrix of pharmaceutically acceptable contact adhesives that function to attach the system to the skin during drug delivery. Alternatively, the drug-containing reservoir and the skin contact adhesive exist as separate and separate layers, which form the basis of the reservoir, in this case the polymer matrix described above, or a liquid or hydrogel reservoir. Or it may take some other form. The transdermal drug delivery system may further contain a skin permeation enhancer.

0054In addition to the above-mentioned preparations, the active agent may be formulated as a depot preparation for controlled release, preferably long-term sustained release of the active agent. These sustained release dosage forms are generally administered by implantation (eg, by subcutaneous or intramuscular or intramuscular injection).

0055The composition will generally be administered orally, parenterally, transdermally, or by implantable depot, but other methods of administration are similarly appropriate. For example, the administration may be transmucosal, eg, rectal or vaginal, preferably a suppository containing an excipient such as a suppository wax in addition to the active agent. Formulations for nasal or sublingual administration are also made with standard excipients well known in the art. The pharmaceutical composition of the present invention may be formulated for inhalation, for example, as a solution in physiological saline, as a dry powder, or as an aerosol.

0056In another embodiment, the method of the invention, ie, an escalating dosage regimen or on going maintenance dosing, comprises the administration of a combination of topiramate and a sympathomimetic agent.

0057Sympathomimetics for use in the present invention, and their general clinical uses or effects, are specified in Table 1.<tables num="1-1"><img id="000003" he="208" wi="163" file="JP2015166380A_D0001.tif" img-format="tif" img-content="drawing" /></tables><tables num="1-2"><img id="000004" he="231" wi="164" file="JP2015166380A_D0001.tif" img-format="tif" img-content="drawing" /></tables><tables num="1-3"><img id="000005" he="114" wi="164" file="JP2015166380A_D0001.tif" img-format="tif" img-content="drawing" /></tables>

0058In certain embodiments, the sympathomimetic is a phentermine or phentermine-like compound. As defined herein, a "phentermine-like compound" is a compound that is structurally associated with phentermine (eg, an analog or derivative) and maintains an appetite-suppressing activity similar to phentermine. is there. One phentermine-like compound is chlorphentermine. In yet another embodiment, the sympathomimetic is an amphetamine or amphetamine-like compound. As used herein, an "amphetamine-like compound" is a compound that is structurally associated with amphetamine (eg, an analog or derivative) and maintains the appetite-suppressing effect of amphetamine. In yet another embodiment, the sympathomimetic is a phenmetrazine or a phenmetrazine-like compound. As defined herein, "phenmetrazine-like compounds" are structurally associated with phenmetrazine (eg, analogs or derivatives) and maintain the appetite-suppressing effect of phenmetrazine. It is a compound. One phenmetrazine-like compound is phenmetrazine. Analogs and / or derivatives of the compounds of the invention can be tested for their ability to suppress appetite (eg, suppress food intake) in a subject (eg, a mammalian subject).

0059In another embodiment, the sympathomimetic is a bupropion or a bupropion-like compound. As defined herein, a "bupropion-like compound" is a compound that is structurally associated with bupropion (eg, an analog or derivative) and maintains antidepressant activity similar to that of bupropion.

0060In a typical embodiment, the sympathomimetic agent is selected from bupropion, amphetamine, methamphetamine, benzphetamine, phenylpropanolamine, phentermine, chlorfentermine, diethylpropion, phenmetrazine, and phenmetrazine (No. 1). 1 as specified in the table).

0061In one embodiment, the sympathomimetic is phentermine. It is also possible to utilize pseudoephedrine (a stereoisomer of ephedrine), methylphenidate, dexmethylphenidate, tuaminoheptane, and other sympathomimetics, including other CNS stimulants, including, for example, caffeine and bupropion. It is included within the scope of the present invention.

0062The choice of appropriate dosage for the drug used in the combination therapy of the present invention can be determined and optimized by one of ordinary skill in the art by observation of the patient, including, for example, the overall health of the patient and the response to the combination therapy. If it is determined that the patient does not show the desired therapeutic effect, or conversely, the patient experiences unwanted or adverse side effects that are very numerous or have annoying severity. If so, optimization may be needed.

0063The dosage used will vary depending on the clinical goals to be achieved, but the appropriate daily dose range for the sympathomimetic is generally in the range of 2 mg to 1500 mg. It is administered to patients continuously for a certain period of time. For example, 2mg, 4mg, 10mg, 20mg, 30mg, 60mg, 90mg, 120mg, 150mg, 180mg, 210mg, 240mg, 270mg, 300mg, 330mg, 360mg, 390mg, 420mg, 450mg, 480mg, 500mg, 600mg, 800mg, 1000mg, 1200 mg, 1500 mg, etc. are administered to the patient as a daily dose, which may be a single daily dosage. In another example, 3.75 mg, 7.5 mg, 11.75 mg, 15 mg, etc. are administered to the patient as a daily dose, which may also be a once-daily dose.

0064In one embodiment, each component of the combination (eg, (i) topiramate, and (ii) sympathomimetic drug) is at a dose below the dose typically described for each component as monotherapy. Be prescribed. The ingredients may be formulated separately or as a combination dosage. In one embodiment, each component of the combination (eg, (i) topiramate, and (ii) sympathomimetic) is prescribed at a dose greater than or equal to the dose typically described as monotherapy for each component. The ingredients may be prescribed separately or in combination.

0065In another embodiment, the prescription dose of the sympathomimetic is greater than or equal to the dose typically described for monotherapy, and topiramate is at or less than the dose typically described for monotherapy. Be prescribed. In another embodiment, the prescription dose of the sympathomimetic is at or below the dose typically described for monotherapy, and topiramate is at a dose greater than or equal to the dose typically described for monotherapy. Be prescribed.

0066In certain embodiments, when phentermine is a sympathomimetic, phentermine may be administered, for example, in a daily dose, eg, a once-daily dose in the range of 2 mg to 60 mg. In one embodiment, the phentermine is administered at a daily dose, eg, a once-daily dose in the range of 2 mg to 30 mg. In another aspect, the phentermine is administered at a daily dose, eg, a once-daily dose in the range of 2 mg to 15 mg.

0067In certain embodiments, when bupropion is a sympathomimetic, bupropion is administered once daily, eg, in a daily dose, eg, in the range of 50 mg to 400 mg, more typically in the range of 50 mg to 200 mg. It may be administered at a dose.

0068The method of administration of the pharmaceutical combinations of the present invention will depend in particular on the type of sympathomimetic used. Topiramate and the sympathomimetics may be administered together in the same composition, or simultaneously or sequentially in two separate compositions. Also, one or more sympathomimetics are therapeutic compositions (therapeutic). It may be administered to the subject or patient in the form of composition) or in combination, eg, in the form of one or more separated compositions administered simultaneously or sequentially. The dosing schedule will depend on the type of sympathomimetic drug selected. For example, a sympathomimetic may have a stimulating effect, but the extent of the stimulating effect may vary depending on the sympathomimetic selected. Sympathomimetics with a significant stimulating effect will preferably be administered earlier in the day as compared to sympathomimetics with a weaker stimulating effect. Topiramate typically has at least some sedative effect, even at low doses, but may be administered later in the day compared to administration of a compound with a weaker sedative effect.

0069In one embodiment, topiramate is administered in a controlled release form, i.e., a sustained release form and / or a delayed release form, preferably both, and phentermine is administered in an immediate release form. As such, phentermine is not only an appetite suppressant but also a stimulant, so the drug may be taken in the morning. In this embodiment, topiramate may be taken later in the day as compared to phentermine. Preferably, because topiramate has a sedative effect, the patient takes the drug shortly before or even late at night.

0070In yet another embodiment, topiramate is administered in a controlled release form, ie, sustained release and / or delayed release form, and bupropion is administered in an immediate release form. As such, bupropion is not only an appetite suppressant but also a stimulant, so the drug may be taken in the morning. In this embodiment, topiramate may be ingested later in the day as compared to bupropion. Preferably, because topiramate has a sedative effect, the patient takes the drug shortly before or even late at night.

0071As described above, the controlled release dosage form of the present invention for which combination therapy is indicated may be a capsule containing controlled release topyramate beads and immediate release phentermine beads, bupropion beads and the like. The topiramate beads may be manufactured using an extrusion spheroidization process, such as topiramate, 40.0% w / w; microcrystalline cellulose, eg, Avicel PH102 (Avicel® PH102), 56.5% w / w; and A matrix core consisting of methyl cellulose, for example Methocel A15LV (Methocel A15LV), 3.5% w / w may be prepared. The topiramate core is then coated with ethyl cellulose, 5.47% w / w and povidone K30: 2.39% w / w. Phentermine beads, such as bupropion beads, consist of an immediate release drug coating on sugar spheres or a similar inert core. The two sets of beads are then encapsulated in one capsule.

0072In certain embodiments, the phentermine beads may be provided with a controlled release drug coating on sugar spheres or other inert cores. In another aspect, the phentermine beads may be coated on controlled release topiramate beads.

0073Then, in combination therapy, preferred methods of administration include co-administration of the two active agents, either in a single composition or in two separate compositions each containing one of the active agents. The method of administration may include administration of the two active agents at different times of the day, with sympathomimetics generally administered earlier in the day and topiramate generally later in the day. May be administered. However, usually the two agents are administered simultaneously using one or more dosage forms that provide immediate release of the sympathomimetic and controlled release of the topiramate. In a typical embodiment, the sympathomimetic and the topiramate simply provide both immediate release of the sympathomimetic and sustained and / or delayed release of the topiramate, preferably sustained and delayed release. It is administered in a single dosage form. As mentioned above, the dosage form may be a coated core or encapsulated beads, or they may be tablets, eg, the tablet contains at least two separated segments. , At least one of which contains a sympathomimetic agent such as phentermine or bupropion, which is an immediate release form, and another segment within it contains a controlled release form of topiramate.

0074Indications: Particularly interesting conditions in which the usefulness of the present invention can be found include overweight, obesity and conditions often associated with and / or resulting from overweight and obesity. Topiramate compositions and combinations administered according to the dosing regimens provided herein produce significant therapeutic effects and reduced adverse effects, making these pharmaceutical compositions highly effective treatments, especially overweight. , Obesity and / or are effective in treating overweight or related conditions associated with or due to obesity itself, and / or conditions resulting from them. Therefore, suitable subjects for treatment in the treatment regimen of the combination therapies of the present invention include, but are not limited to, individuals suffering from conditions associated with obesity, including, and not limited to: Diabetes, insulin resistance, and impaired glucose tolerance; Respiratory disorders such as pulmonary hypertension, asthma, and shortness of breath; Gallbladder disease; Dyslipidemia, such as high cholesterol and high levels of triglycerides; Osteoarthritis and other orthopedic disorders; Reflux esophagitis; Sleep-related adverse conditions, including sleep apnea and snoring; Irregular menstruation, infertility, and pregnancy complications; gout; Hypertension, ie hypertension; Cardiovascular disorders such as coronary artery disease and other heart diseases; Muscular dystrophy; Stroke, especially thrombosis and deep vein thrombosis (DVT); Migraine; Metabolic disorders such as low α-lipoproteinemia, familial complex hyperlipidemia, and syndrome X, including insulin resistant syndrome; and Colon cancer, rectal cancer, kidney cancer, esophageal cancer, bile sac cancer, pancreatic cancer, prostate cancer, breast cancer, uterine cancer, ovarian cancer, endometrial cancer, and cervical cancer.

0075Heavier weight is also associated with increased all-cause mortality. Almost or all of these problems are alleviated or ameliorated by sustained and significant weight loss. With sustained and significant weight loss, lifespan is also significantly increased.

0076Diabetes is very common in obese individuals and is associated with persistent and pathologically elevated blood glucose levels. It is one of the leading causes of death in the United States and accounts for about 5% of all mortality rates. Diabetes can be divided into two major subclasses: type I, also known as juvenile diabetes, or insulin-dependent diabetes mellitus (IDDM); and adult-onset diabetes, or non-insulin-dependent diabetes mellitus (NIDDM). It is type II.

0077According to the American Diabetes Association, there are more than 1 million juvenile diabetics in the United States. Type I diabetes is a form of autoimmune disease. Autoantibodies produced by the patient completely or partially destroy insulin-producing cells in the pancreas. Therefore, juvenile diabetics must take extrinsic insulin for the rest of their lives. Without treatment, it can lead to excessive acidosis, dehydration, kidney damage, and death. Even with treatment, complications such as blindness, atherosclerosis, and impotence can occur.

0078Over 5 million people with type II (adult-onset) diabetes have been diagnosed in the United States. Type II disease usually develops in middle age; now the main causes are known to be overweight and obesity. In patients with type II diabetes, postprandial elevated blood glucose levels do not adequately stimulate pancreatic insulin production. In addition, peripheral tissues are generally resistant to the effects of insulin. The resulting high blood glucose levels (hyperglycemia) can result in extensive tissue damage. People with type II diabetes are often referred to as insulin resistance. They often have higher than normal plasma insulin levels (hyperinsulinemia) as the body seeks to overcome its insulin resistance. Hyperinsulinemia is now a causative factor in the development of hypertension, high levels of circulating low-density lipoproteins (LDLs), and lower than normal levels of beneficial high-density lipoproteins (HDLs), according to some researchers. I believe in it. Moderate insulin resistance can be compensated for by increased insulin secretion in the early stages of type II diabetes, while insulin secretion is also impaired in more advanced conditions.

0079Insulin resistance and hyperinsulinemia are also associated with two other metabolic disorders that pose significant health risks: impaired glucose tolerance and metabolic obesity. Impaired glucose tolerance is characterized by normal glucose levels before eating but a tendency for elevated levels (hyperglycemia) after eating. According to the World Health Organization, it is estimated that approximately 11% of the US population between the ages of 20 and 74 has impaired glucose tolerance. These individuals are considered to be at higher risk for diabetes and coronary artery disease.

0080Obesity can also be associated with insulin resistance. A causal link between obesity, impaired glucose tolerance, and type II diabetes has been proposed, but the physiological basis has not yet been established. Some researchers believe that impaired glucose tolerance and diabetes are clinically observed and diagnosed only later in the disease process after a person develops insulin resistance and hyperinsulinemia.

0081Insulin resistance is frequently associated with hypertension, coronary artery disease (arteriosclerosis), and lactic acidosis, as well as related medical conditions. The basic relationship between these medical conditions, and treatment methods, have not been established.

0082Hypertension is another condition that is often seen in obese individuals and occurs when blood pressure in the aorta rises chronically. Hypertension affects about 50 million people in the United States alone. It is more common as people get older, more common in African Americans, and more severe. The etiology of hypertension in most cases is unknown. It is known that the tendency to develop hypertension can be inherited. The environment also plays a very important role in hypertension. For example, hypertension can be avoided by controlling weight, maintaining physical health, eating a healthy diet, limiting alcohol intake, and avoiding drugs that can increase blood pressure. Other less common causes of hypertension include damage to the kidneys or endocrine glands. Hypertension is called a "silent killer" because it can cause death in the absence of obvious symptoms. People with untreated hypertension die or are impaired by cardiovascular complications such as stroke, heart attack, heart failure, abnormal heart rhythm, and renal failure than people with normal blood pressure. Much more likely to bear.

0083Current treatments for hypertension include medications as well as lifestyle changes (such as diet, exercise, and smoking cessation). The main types of drugs currently used to treat hypertension are adrenergic neuronal antagonists (peripheral), α-adrenergic agonists (centrally active), α-adrenergic blockers, α and Beta blockers, angiotensin II receptor blockers, angiotensin converting enzyme (ACE) inhibitors, β-adrenergic agonists, calcium channel blockers, thiazides (benzothia diazine derivatives) and related diuretics, and vasodilators ( (Acts by direct relaxation of vascular smooth muscles).

0084A particularly serious hypertensive disorder is primary pulmonary hypertension, also known as idiopathic pulmonary hypertension. This is a condition in which the blood pressure in the pulmonary arteries is abnormally high in the absence of other diseases of the heart or lungs. The cause of primary pulmonary hypertension is unknown. Pulmonary hypertension develops in response to increased resistance to blood flow. Due to the increased pumping of blood against the resistance, pulmonary arteriole stenosis occurs and the right heart becomes hypertrophied. Eventually, progressive heart failure develops. Currently, there is no known treatment for primary pulmonary hypertension. Although some success has been seen with the use of vasodilators, treatment is primarily focused on controlling symptoms. Other drugs used to treat the symptoms of primary pulmonary hypertension include diuretics and calcium channel blockers. Typically, oxygen is often needed as the disease progresses. In certain cases, the availability of donor organs remains very limited, but heart-lung transplantation may be indicated as a particular suitable candidate. Unfortunately, primary pulmonary hypertension is a progressive disease, usually resulting in congestive heart failure and respiratory failure.

0085Secondary pulmonary hypertension is a serious disorder that occurs as a complication of other conditions, such as scleroderma. Treatment is similar to that for primary pulmonary hypertension, and unfortunately the prognosis is the same.

0086Other respiratory illnesses frequently found in obese individuals include asthma and shortness of breath, both of which are often relieved by weight loss.

0087Perhaps the most worrisome of the harmful conditions and disorders associated with sleep is sleep apnea. Sleep apnea is a more common form of obstructive sleep apnea that occurs when the pharyngeal muscles relax, or central sleep that occurs when the brain does not signal the muscles that control breathing. Classified as one of sleep apnea. In addition, some people have mixed sleep apnea, which is a combination of obstructive and central sleep apnea. Sleep apnea literally means "stop breathing." It is characterized by repetitive episodes of upper airway obstruction that occur during sleep and is usually associated with decreased blood oxygen saturation. In other words, the airways are blocked at some potential sites. The upper airway can be blocked by excess tissue in the airway, large tonsils, and a large tongue, usually involving airway muscle relaxation and collapse during sleep. Another occlusion site can be the nasal cavity. At times, the structure of the jaw and airways can contribute to sleep apnea.

0088The overlapping signs and symptoms of obstructive and central sleep apnea sometimes make it more difficult to determine the type of sleep apnea. The most common signs and symptoms of obstructive and central sleep apnea include: Excessive drowsiness during the day (hypersomnia); Great snoring; Observed episodes of respiratory arrest during sleep; Sudden awakening with; arousal with dry mouth or pharyngitis; headache when waking up; and / or difficulty maintaining sleep (hypersomnia). Destructive snoring can be a more prominent feature of obstructive sleep apnea, while arousal with shortness of breath can be more common in central sleep apnea.

0089Sleep apnea is a progressive disease that can be very serious; it is a potentially life-threatening condition that requires urgent treatment. Risks of undiagnosed obstructive sleep apnea include heart attack, stroke, hypertension, heart disease, arrhythmias, and impotence. In addition, obstructive sleep apnea causes daytime sleepiness, which can lead to accidents, loss of productivity and interpersonal problems. The severity of the symptoms can be mild, moderate or severe.

0090Sleep apnea is diagnosed using a sleep test called polysomnography, but treatment depends on the severity of the disorder. Mild sleep apnea is usually treated by several behavioral changes; weight loss and sleeping sideways are often recommended. There are oral mouth devices (which help keep the airways open) that can help reduce snoring in three different ways. Some devices (1) bring the jaw forward, (2) raise the soft palate, or (3) hold the tongue (so that it does not return to the airways and block breathing).

0091Moderate to severe sleep apnea is usually treated with continuous positive airway pressure (C-PAP). C-PAP is a machine that uses a nasal mask to blow air into the nose to keep the airway open and unobstructed. For more severe apneas, there are two-layer (Bi-level (Bi-PAP)) machines. The two-layer machine differs in that it blows air at two different pressures. When a person inhales, the pressure is higher, and when exhaling, the pressure is lower.

0092Some people have facial deformities that can cause sleep apnea. It may simply be that their jaws are smaller than they should be, or they may have a smaller opening in the back of the pharynx. Some people have enlarged tonsils, a large tongue, or some other tissue that partially blocks the airways. Treatment of deviated septum can help open the nasal passages. Removal of tonsils and pharyngeal tonsils or polyps may also help. Children appear to be more likely to have tonsils and pharyngeal tonsils removed. Surgery, such as tracheal opening, uvula palatine pharyngoplasty (UPPP), laser-based uvula palatine arch plasty (LAUP), somnoplasty, and mandibular myotomy It is often needed to effectively treat sleep apnea. However, weight loss, especially in obese people, can significantly reduce sleep apnea and other sleep-related adverse conditions, such as loud snoring.

0093Relatively recently, a link between obesity and the incidence or increased incidence of migraine has been pointed out. Migraine begins with mild pain and increases in intensity in a short period of time. There are two major types of migraine. Normal migraine affects 80-85% of people who suffer from migraine, and aura classic migraine affects 15% of people who suffer from migraine. Symptoms associated with migraine are headache, psychological symptomology, such as pollakiuria, depression, fatigue, drowsiness, or restlessness; neurological symptoms, such as photophobia or voice phobia, or gastrointestinal symptoms. , For example, changes in defecation habits, or changes in food intake, or urinary symptoms, such as frequent urination, a neurological defect in the migraine population, a precursor to various defects, but usually in individuals. I am addicted to a fixed mold (stereotyped). These deficiencies are visual scotoma or visual designs, hemiplegia, and migrating. It may be paraesthesia), dysarthria, aphasia, or déjà vu. The headache is usually associated with light or sound sensitivity, photophobia or phonophobia, irritability and decreased concentration. For individuals whose migraine is caused by or exacerbated by obesity, treatment according to the methodology of the present invention may be effective.

0094Other signs to which the present invention can be immediately adapted include certain psychological signs such as epilepsy and impulse control disorders.

0095Topiramate has long been known as an antiepileptic drug. However, as shown elsewhere herein, topiramate treatment resulted in significant side effects at doses previously required or believed to be necessary for efficacy. According to the present invention, co-administration of phentermine can reduce topiramate doses, and most, if not all, significantly reduce the side effects of dose-dependent topiramate.

0096Of the psychological signs, depression is especially common. "Depression" is manifested by a combination of symptoms that, as is well known, impede the ability to work, study, sleep, eat, and enjoy activities that were once enjoyable. Depression includes major depression, especially refractory depression, bipolar depression, and degeneration associated with depression. Symptoms of depression include persistent sad, anxious, or "empty" moods, despair, pessimism, guilt, worthlessness, helplessness, and interest in or pleasure in previously enjoyable hobbies and activities, including sexual intercourse. Loss of energy, loss of energy, fatigue, "slowed down", decreased concentration, decreased memory, decreased determination, insomnia, early morning awakening, or oversleeping, appetite and / or weight loss or overeating and weight gain, death or Thoughts of suicide; including attempted suicide, insomnia, irritability, and persistent physical symptoms that do not respond to treatment, such as headache, digestive disorders, and chronic pain.

0097Other psychiatric disorders can also be treated using the compositions and methods of the invention. These disorders include impulse control disorder, panic syndrome, general anxiety disorder, all kinds of fear syndrome, mania, mania, hypomania, unipolar depression, stress disorder, PTSD, and somatic symptom. Includes disability, personality disorder, mental illness, and schizophrenia.

0098"Impulse control disorder" is characterized by harmful actions performed in response to uncontrollable impulses. An essential feature of impulse control disorder is the inability to withstand the urge, drive or temptation to perform actions that are harmful to oneself or others. Symptoms include increased pre-act tension or arousal, and experience of joy, satisfaction, or liberation during the act. You may or may not have regrets or guilt after performing the act. Intermittent explosive disorder, kleptomania, morbid gambling, burning habits, hair loss habits, impulse buying, repetitive self-injury, nonparaphilic sexual addictions, severe nail biting, compulsive skin Numerous disorders, including picking, personality disorders with impulseive features, attention deficits / hyperactivity disorders, eating disorders characterized by overeating, and substance abuse disorders such as alcohol and substance addiction. Can be considered an impulse control disorder. Binge eating disorders and bulimia nervosa are also sometimes classified as impulse control disorders.

0099Packaged pharmaceutical product: A packaged pharmaceutical formulation for carrying out the method of the present invention is also provided. The packaged formulation contains the composition of the invention in a sealed container, typically containing multiple individual dosage forms, each in a sealed housing such as a blister pack. It may also contain one or more dosage forms in a single sealed container. Optionally, dosage forms with low doses of one or both active agents may also be included for dose titration and dose escalation.

0100In certain embodiments, the packaged pharmaceutical formulation achieves weight loss, treats obesity, treats conditions associated with obesity, or treats other conditions previously described herein. Includes instructions for the patient to perform drug administration to do so. For example, the instructions describe the daily dose of topiramate to be ingested, the daily dose of phentermine or other sympathomimetics to be ingested, and / or controlled release containing topiramate and optionally a second active agent. It may include a dosing regimen for self-administration of the dosage form. The instructions may be recorded on a suitable recording medium or printed on a substrate such as paper or plastic. As such, the instructions may be present as an attachment, on the label of the package, as a container, or a component thereof (ie, accompanying packaging or subpackaging), and the like. In another embodiment, the instructions are present as electronic storage data files present on a suitable computer-readable storage medium, such as a CD-ROM or diskette. In yet another embodiment, there is no actual instruction, but a method of obtaining the instruction from a remote source, eg, an internet method, is provided. As an example, a web address may be included to direct the patient to a website where the instructions can be viewed and / or downloaded. As with the instructions themselves, this method of obtaining instructions is recorded on the appropriate substrate.

0101Some or all of the ingredients contained may be packaged in appropriate packaging to maintain sterility. In many embodiments, the component is packaged within a containment element to provide a single, manageable unit, eg, to further maintain the sterility of some or all of the component. , The containment element, eg, a box or similar structure, may or may not be an airtight container. In certain embodiments, a sealed package of controlled release dosage forms is provided in which the dosage form contains immediate release phentermine and controlled release, such as sustained and delayed release topiramate. Alternatively, separated phentermine-containing and topiramate-containing dosage forms may be included.

<p num="0102"> The following examples are provided to provide those skilled in the art with complete disclosure and description of the methods of manufacture and use of the invention, without the purpose of limiting the scope of what the inventor considers to be his invention. There is no purpose to mean that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to the numbers used (eg quantity or temperature), but some experimental error and deviation should be considered. Unless otherwise stated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric pressure.</p><p num="0103">Example 1 Controlled release topiramate beads are produced using an extruded spheroidization process with topiramate, 40.0% w / w; microcrystalline cellulose (Avicel® PH102), 56.5% w / w; and metocell A15LV. (Methocel A15LV) manufactures a matrix core consisting of 3.5% w / w. The topiramate core was then coated with ethyl cellulose, 5.47% w / w, and povidone K30, 2.39% w / w.</p><p num="0104"> The composition of the produced topiramate beads is as follows: Ingredient% w / w Topiramate 36.85 Microcrystalline cellulose, (Avicel® PH102) 52.05 Methyl cellulose (Methocel A15LV) 3.22 Ethyl cellulose 5.47 Polyvinylpyrrolidone (Povidon K30) 2.39</p><p num="0105"> Phentermine hydrochloride was coated on sugar spheres to prepare immediate release phentermine beads. The two sets of beads were then encapsulated in each of the plurality of capsules.</p><p num="0106">Example 2 In a study comparing the controlled release of topiramate of the present invention in combination with phentermine with the immediate release topiramate (Topamax®), the controlled release of topiramate of the present invention was treated against phentermine exposure. It had a 10 to 15% lower effect (Fig. 2).</p><p num="0107"> Mean and statistical comparisons of steady-state plasma phentermine PK parameters at multiple doses are summarized in Table 2.<tables num="2"><img id="000006" he="197" wi="163" file="JP2015166380A_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0108"> These data indicate the maximum and range of reduced phentermine exposure during study vs. reference treatment after multiple doses. As such, a controlled release formulation of topiramate will reduce drug interactions with phentermine and then reduce additional side effects associated with phentermine.</p>