WO2003070738A2 - Topiramate salts and compositions comprising and methods of making and using the same - Google Patents
Topiramate salts and compositions comprising and methods of making and using the sameInfo
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- WO2003070738A2 WO2003070738A2 PCT/US2003/004357 US0304357W WO03070738A2 WO 2003070738 A2 WO2003070738 A2 WO 2003070738A2 US 0304357 W US0304357 W US 0304357W WO 03070738 A2 WO03070738 A2 WO 03070738A2
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- topiramate
- disorder
- crystal
- pharmaceutically acceptable
- sodium
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Definitions
- This invention relates to compounds, pharmaceutical compositions, and methods for the treatment or prevention of seizures, epilepsy, tremors, affective disorders, obesity, neuropathic pain, and migraines.
- Topiramate is a sulfamate-substituted monosaccharide, which is chemically named 2,3:4,5-Di-0-isopropylidene-
- the molecular formula of topiramate is C ⁇ 2 H ⁇ NO 8 S, and its chemical structure is represented by formula I:
- Topiramate is a white crystalline powder with a solubility in water of 9.8 mg/mL, and it is freely soluble in acetone, chloroform, dimethylsulfoxide, and ethanol. See, Physician 's Desk Reference, 56 th ed., pp. 2590-2595 (2002).
- TOPAMAX ® Ortho- McNeil Pharmaceutical, Inc., Raritan, NJ, U.S.A.
- TOPAMAX ® has been approved for use as an antiepileptic agent as an adjuvant therapy for patients with partial onset seizures, or primary generalized tonic-clonic seizures. See generally, Physician 's Desk Reference, 56 th ed., 2590-2595 (2002); see also, U.S. Patent No. 4,513,006.
- Adverse effects associated with the administration of topiramate include, but are not limited to, somnolence, dizziness, ataxia, speech disorders and related speech problems, psychomotor slowing, abnormal vision, difficulty with memory, paresthesia, diplopia, renal calculi (kidney stones), hepatic failure, pancreatitis, renal tubular acidosis, acute myopia and secondary angle closure glaucoma. Physician's Desk Reference, 56 th ed., pp. 2590-2595 (2002).
- Topiramate has been investigated for use as anti-obesity agent, a blood pressure lowering agent, and a mood stabilizer, including use as an anti anic, antidepressant, and for the treatment of post-traumatic stress disorder, migraines, cluster headaches, and neuropathic pain. See, e.g., U.S. Pat Nos. 6,191,117; 6,201,010; 5,753,693; 5,998,380; 6,319,903; 5;935,933; and 5,760,007.
- the time it takes for topiramate to reach peak plasma levels i.e., about two hours
- the compound's relatively low aqueous solubility makes it difficult to provide in a controlled release dosage form, which may be necessary for the effective treatment of conditions such as obesity, and which may allow a reduction in adverse effects associated with peak plasma levels of the drug. Therefore, new highly soluble and bioavailable forms of topiramate are needed in order to increase the safety and effectiveness of the compound.
- Epilepsy is a chronic disorder or condition characterized by recurring motor, sensory, or behavioral or psychic alterations or malfunctions that can include unconsciousness or convulsive movements. See Valente LR, Clinician Reviews, 10(3): 79 (2000). A variety of seizure types can occur, from partial seizures to generalized seizures.
- a patient with a simple partial seizure may experience jerking or shaking in one area of the body, which may progress to other areas.
- a simple partial seizure may also manifest >with somatosensory, visual, auditory, olfactory, autonomic (sweating, pupillary dilation, epigastric rising), or psychic symptoms.
- complex partial seizures the patient's consciousness may be impaired, either immediately, or gradually over time after simple partial onset. Patients experiencing a complex partial seizure will often exhibit a blank stare followed by automatism, which may include lip smacking, chewing, picking at clothing, or purposeless walking.
- Secondarily generalized seizures can evolve directly from simple partial or complex partial seizures, or progress from simple partial to complex partial to generalized. See, Leppik IE. Contemporary Diagnosis and Management of the Patient With Epilepsy. 4 th Ed., Newtown, PA: Handbooks in Health Care Co (1999).
- Generalized seizures can be convulsive or no convu ive, but always involve a loss of consciousness. Absence seizures (formerly called "petit mal") may be typical or atypical, and are strongly linked to genetic predisposition. Typical absence seizures may be precipitated by photic stimulation or hyperventilation. The symptoms include a blank stare, eye blinking, and in some instances automatisms, and the patient may experience increased or decreased tone.
- Myoclonic seizures manifest with quick, involuntary muscle jerks lasting a few seconds. These muscle jerks or movements may be isolated to one body part or involve the entire body. Myoclonic seizures may accompany other generalized seizures and are common to specific epilepsy syndromes. Tonic seizures are generally associated with other epileptic syndromes, and typically last less than a minute. Tonic seizures involve violent spasm or stiffening, and in many instances, the lower extremities are extended and the upper extremities are flexed. In addition, the patient may turn the head or eyes to one side. Clonic seizures, most common in neonates and children, also exhibit repetitive muscular jerks but at a slower rate, and while clonic seizures can last as long as several minutes, brief episodes are more common. See, Leppik IE. Contemporary Diagnosis and Management of the Patient With Epilepsy. 4 th Ed., Newtown, PA: Handbooks in Health Care Co (1999).
- Atonic seizures result in a sudden loss of postural tone, causing the patient to fall. In a few seconds, the patient will regain full consciousness. Atonic seizures are commonly associated with other seizure types and are common in Lennox-Gastaut syndrome. See,
- Other epileptic conditions include juvenile myoclonic epilepsy and Lennox-Gastaut syndrome.
- Juvenile myoclonic epilepsy often begins during the teenage years, and is a generalized, idiopathic epileptic syndrome, often exhibiting three seizure types: myoclonic, absence, and generalized tonic-clonic.
- myoclonic, absence, and generalized tonic-clonic Many patients will manifest clumsiness or jitters, which are exacerbated by stress.
- Lennox-Gastaut syndrome may be symptomatic (brain lesion identified) or cryptogenic (brain lesion assumed), and the generalized syndrome may include atypical absence, tonic, atonic, and tonic-clonic seizures.
- patients suffering from Lennox-Gastaut syndrome will have varying degrees of psychomotor retardation.
- anticonvulsants drugs available that are used to treat epilepsy or epileptic conditions, and they are commonly referred to as anticonvulsants or antiepileptics.
- These drugs include older anticonvulsants, such as phenobarbital, primidone, and phenytoin, and more recent anticonvulsants, such as carbamazepine; valproic acid; felbamate; gabapentin; lamotrigine; tiagabine; topiramate; levetiracetam, and oxacarbazepine.
- the newer anticonvulsants are approved as adjunctive therapy for use in conjunction with other anticonvulsants, although some of these have been approved or demonstrated efficacy as a monotherapy. See U.S. Patent No. 6,309,406.
- Common tremors including essential, familial, and senile tremors, are relatively common in people over forty, but can also result from or be made worse by stimulants (e.g., caffeine) or during periods of stress or anxiety.
- stimulants e.g., caffeine
- tremors may be localized in the upper extremities, such as the hands, but can also include movements or nodding of the head, with both often occurring as a patient ages.
- the lips, tongue, jaw, and larynx may be involved in tremors, and they can sometimes result in a noticeable quiver in the voice of the patient.
- beta-blockers e.g., propanolol
- sedatives such as benzodiazepines and barbituates
- some patients may "self- medicate” using alcohol due to its sedative properties.
- Obesity is one of the most prevalent medical disorders afflicting humans today, affecting more than 30% of the population. Obesity can result in a number of other medical conditions or complications, including hypertension, cardiovascular disease, diabetes mellitus, insulin resistance, sleep apnea, cholecystitis, osteoarthritis, and cancer.
- Body mass index, or BMI is common used to measure obesity, and is calculated by dividing the patient's weight in kilograms divided by their height in meters squared. The severity or degree of obesity is then determined by comparing a patient's BMI with standard deviations above the BMI means for males and females.
- Neuropathic pain describes pain that is associated with damage or permanent alteration of the peripheral or central nervous system.
- Neuropathic pain includes, but is not limited to, neuralgia, trigeminal neurologia, diabetic neuropathy and other forms of nerve damage, allodynia, paraesthesia, hyperaesthesia, phantom pain, phantom limb pain, hyperalgesia, and tinnitus.
- Clinical manifestations of neuropathic pain include a sensation of burning or electric shock, feelings of bodily distortion, allodynia and hyperalgesia.
- the term allodynia describes the phenomenon of the perception of stimuli which are not painful per se, such as contact or heat cold, as pain. See Rogers and Valley, Clin Podiatr Med Surg., 11(1): 73-83 (January 1994).
- Manic-depressive illnesses such as manic-depressive bipolar disorder
- manic-depressive bipolar disorder are progressive psychiatric disorders of unknown etiology, although there are some hypotheses that recurrences of manic-depressive illness arise by electrophysiologic kindling.
- topiramate may be useful in treating manic-depressive illnesses, as it has been shown to be effective in blocking kindled seizures in rats. See U.S. Patent No. 5,753,693; and Wauquier et al, Epilepsy Res., 24:73-77 (1996).
- Migraine is a neurological disorder that is characterized by recurrent attacks of headache, with pain most often occurring on one side of the head, accompanied by various combinations of symptoms such as nausea, vomiting, and sensitivity to light and sound.
- the migraine can occur at any time of day or night, but occurs most frequently on arising in the morning. Routine activity or slight head movement typically makes the pain worse. These episodes can last from several hours to several days and are often disabling.
- the pain may migrate from one part of the head to another, and may radiate down the neck into the shoulder.
- Scalp tenderness occurs in the majority of patients during or after an attack.
- Migraine with aura, or classic migraine refers to a severe, throbbing headache that is often preceded by visual, motor, or sensory symptoms, called an "aura.”
- Migraines can also occur without an aura, which is called common migraine.
- Migraine is familial and often hereditary, and is most common in women, particularly young adult women. Common characteristics of migraine include: moderate to severe headache lasting from four to 72 hours; pain that is often, but not always, located on one side of the head and throbbing; pain is aggravated by moving or physical activity; pain is often accompanied with nausea, vomiting, sensitivity to light, sound, and odors. Following a migraine attack, many patients will feel tired, washed out, irritable, or listless or have impaired concentration.
- drugs that are currently available for prophylactic treatment of migraine, including propanolol, amitriptyline, valproate, verapamil, phenelzine, and methysergid, as well as aspirin-like drugs, including aspirin, naproxen, ibuprofen, mefenamic acid, flufenamic acid, and tolfenamic acid.
- these drugs must be taken daily, and some are associated with severe adverse effects or the high dosage amounts required for effectiveness make them undesirable.
- the estimated probability of success with any one of these prophylactic antimigraine drugs is about 60 to 75%. See, Harrison's Principles of Internal Medicine, eds.
- Cluster headache also called “migrainous neuralgia”
- erythroprosopalgia Raeder's syndrome
- spenopalatine neuralgia ciliary neuralgia
- vidian neuralgia histamine cephalalgia
- cluster headaches There are several types of cluster headaches, including: the episodic type, which is the most common, is characterized by one to three short-lived attacks of periorbital pain per day over a 4 to 8 week period, followed by a pain-free interval; the chronic form, also called chronic migrainous neuralgia, which may begin without previous occurrence of episodic type cluster headache, or several years after an episodic pattern, and is characterized by the absence of sustained periods of remission. See A. Kudrow, "The pathogenesis of a cluster headache", Curr. Opin. Neurol., 7:278-282 (1994).
- the pain associated with a cluster headache starts quickly, without warning, and is often excruciating in intensity, and is deep, nonfluctuating, and explosive in quality; only occasionally is it pulsatile. Pain usually begins in, around, or above the eye or the temple, although occasionally the face, neck, ear, or hemicranium may be affected. It is always unilateral, and generally affects the same side in subsequent bouts. Periodicity is a characteristic feature in most cluster headache patients, with attacks lasting from ten minutes to several hours, often repeating in very close intervals, and many also experience additional attacks that occur randomly throughout the day.
- a transitory, partial Homer's syndrome (pupillary miosis and lid ptosis) occurs in two-thirds of patients when they are examined during attacks, and is highly characteristic of the cluster headache syndrome and, after repeated occurrences, may become a permanent feature.
- Cluster headache more often afflicts men than women, and most patients begin experiencing headache between the ages of 20 and 50 years, though cluster headaches can start to occur as early as the first decade and as late as the eighth decade.
- This invention encompasses salts of topiramate, and polymorphs, solvates, hydrates, dehydrates, co-crystals, anhydrous, and amorphous forms thereof.
- the invention further encompasses pharmaceutical compositions and dosage forms comprising pharmaceutically acceptable salts of topiramate, and polymorphs, solvates, hydrates, dehydrates, co-crystals, anhydrous, and amorphous forms thereof.
- Specific salts encompassed by the invention include, but are not limited to, topiramate sodium, topiramate lithium, and topiramate potassium.
- Specific co-crystals encompassed by the invention include, but are not limited to, co-crystals or complexes of caffeine.
- Certain pharmaceutical compositions and dosage forms of the invention also comprise at least one additional anticonvulsant or antiepileptic agent.
- the invention further provides methods of treating and preventing conditions in a patient that include, but are not limited to, seizures, convulsions, epileptic conditions, tremors, cerebral function disorders, obesity, neuropathic pain, affective disorders, migraines, and cluster headaches.
- Methods of the invention comprise administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a pharmaceutically acceptable salt of topiramate, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, and amorphous form thereof.
- the topiramate salt is ( topiramate sodium, topiramate lithium, topiramate potassium, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof.
- Specific co-crystals of topiramate salts are co-crystals or complexes of caffeine.
- Additional methods of the invention comprise adjunctively administering to a patient a therapeutically or prophylactically effective amount of a pharmaceutically acceptable salt of topiramate, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, and amorphous form thereof, and at least one additional anticonvulsant or antiepileptic agent.
- the term "patient” includes mammals, and preferably humans.
- topiramate refers to 2,3:4,5-Di-O-isopropylidene- ⁇ -D- fructopyranose sulfamate, and isomers thereof.
- salt encompasses salts that are pharmaceutically acceptable, as well as those that are not. Salts that are not pharmaceutically acceptable are preferably not administered to patients, but may be used to provide, for example, intermediate or bulk forms of drugs.
- the terms "pharmaceutically acceptable salt” or “pharmaceutically acceptable base addition salt” refers to a salt prepared with various pharmaceutically acceptable bases.
- Bases that can be used to prepare pharmaceutically acceptable salts are those that form non-toxic base addition salts, i.e., salts containing pharmacologically acceptable cations, such as, but not limited to, sodium, potassium, lithium, magnesium, calcium, aluminum, zinc, procaine, benzathine, chloroprocaine, choline, diethylamine, ethylenediamine, N-methylglucamine, benethamine, clemizole, dietheylamine, piperazine, tromethamine, triethylamine, ethanolamine, triethanolamine, arginine, lysine, histidine, tributylamine, 2-amino-2-pentylpropanol, 2-amino-2-methyl-l,3-propanediol, tris(hydroxymethyl)aminomethane,
- the term "adjunctively administering” refers to the administration of one or more compounds or active ingredients in addition to a pharmaceutically acceptable salt of topiramate, or polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof, either simultaneously with the same or at intervals prior to, during, or following administration of the pharmaceutically acceptable salt of topiramate to achieve the desired therapeutic or prophylactic effect.
- seizures includes but is not limited to, partial seizures, including without limitation: simple partial seizures, complex partial seizures, and secondarily generalized seizures; generalized seizures, including without limitation absence seizures (also called “petit mal”) typical absence seizures, atypical absence seizures, myoclonic seizures, tonic seizures, clonic seizures, generalized tonic-clonic seizures (also called “grand mal”), and atonic seizures; and seizures associated with juvenile myoclonic epilepsy and Lennox-Gastaut syndrome.
- absence seizures also called “petit mal”
- myoclonic seizures tonic seizures
- clonic seizures generalized tonic-clonic seizures (also called “grand mal"), and atonic seizures
- seizures associated with juvenile myoclonic epilepsy and Lennox-Gastaut syndrome includes but is not limited to, partial seizures, including without limitation: simple partial seizures, complex partial seizures, and secondarily generalized seizures; generalized seizures, including without limitation absence seizures (also called “petit mal”) typical absence seizures, atypical absence seizures, myoclonic seizures, tonic seizures, clonic
- Cerebral function disorder includes, but is not limited to, disorders involving intellectual deficits such as senile dementia, Alzheimer's type dementia, memory loss, amnesia/amnesic syndrome, disturbances of consciousness, coma, lowering of attention, speech disorders, Parkinson's disease, autistic disorder, autism, hyperkinetic syndrome, and schizophrenia. Also within the meaning of the term are disorders caused by cerebrovascular diseases (including, but not limited to, cerebral infarction, cerebral bleeding, cerebral arteriosclerosis, cerebral venous thrombosis, head injuries, and the like) where symptoms include disturbance of consciousness, senile dementia, coma, lowering of attention, and speech disorders.
- cerebrovascular diseases including, but not limited to, cerebral infarction, cerebral bleeding, cerebral arteriosclerosis, cerebral venous thrombosis, head injuries, and the like
- the term "method of treating Parkinson's disease” means relief from the symptoms of Parkinson's disease, which include, but are not limited to, a slowly increasing disability in purposeful movement, tremors, bradykinesia, ticks, rigidity, and posture disturbance.
- tremors refers to familial, essential and senile tremors.
- a method for treating obesity or weight gain means reduction of weight, relief from being overweight, relief from gaining weight, or relief from obesity, all of which are usually due to extensive consumption of food.
- neurodegeneration pain includes, but is not limited to, neuralgia, trigeminal neurologia, diabetic neuropathy and other forms of nerve damage, allodynia, paraesthesia, hyperaesthesia, phantom pain, phantom limb pain, hyperalgesia, and tinnitus.
- the term "affective disorder” includes, but is not limited to, manic conditions (e.g., acute mania), manic rapid cycling, bipolar mood disorders or conditions (e.g., manic-depressive bipolar disorder), mood stabilization, post-traumatic stress disorder, depression, anxiety disorders, attention deficit disorder, attention deficit disorder with hyperactivity, compulsive or obsessive-compulsive disorder, narcolepsy, premenstrual syndrome, chronic fatigue syndrome, seasonal affective disorder, substance abuse or addiction, nicotine addiction or craving, and obesity or weight gain.
- manic conditions e.g., acute mania
- manic rapid cycling e.g., bipolar mood disorders or conditions (e.g., manic-depressive bipolar disorder), mood stabilization, post-traumatic stress disorder, depression, anxiety disorders, attention deficit disorder, attention deficit disorder with hyperactivity, compulsive or obsessive-compulsive disorder, narcolepsy, premenstrual syndrome, chronic fatigue syndrome, seasonal affective disorder, substance abuse or addiction, nicotine
- AD attention deficit disorder
- ADH attention deficit disorder with hyperactivity
- AD/HD attention deficit/hyperactivity disorder
- depression includes a disease or condition characterized by changes in mood, feelings of intense sadness, despair, mental slowing, loss of concentration, pessimistic worry, agitation, and self-deprecation.
- Physical symptoms of depression that may be reduced or alleviated by the methods of the invention include, but are not limited to, insomnia, anorexia, weight loss, decreased energy and libido, and abnormal hormonal circadian rhythms.
- cluster headache includes, but is not limited to, migrainous neuralgia, chronic migrainous neuralgia, erythroprosopalgia, Raeder's syndrome, spenopalatine neuralgia, ciliary neuralgia, vidian neuralgia, histamine cephalalgia, episodic cluster headache, and chronic cluster headache.
- FIGS. 1-3 relate to analysis of topiramate sodium trihydrate synthesized in Example 1. Specifically, FIG. 1 shows the powder X-ray diffraction pattern of the compound, FIG. 2 shows the differential scanning calorimetric (DSC) analysis for the compound, and FIG. 3 shows the thermogravimetric analysis (TGA) of the compound.
- FIG. 4 relates to analysis of topiramate sodium trihydrate synthesized in Example 2 using Raman spectroscopy, and the Raman spectrum for the compound is shown.
- FIG. 5 shows the powder X-ray diffraction pattern of the compound synthesized in Example 2.
- FIG. 6 shows the aqueous solubility of topirimate sodium trihydrate as compared to that of topiramate.
- FIG. 7 shows the dissolution curves in 0.01 N HC1 of (1) topiramate crystals, (2) topiramate sodium trihydrate, and (3) topiramate sodium trihydrate dry mixed with 1.1 equivalents of tartaric acid.
- FIGS. 8 and 9 relate to analysis of topiramate sodium trihydrate synthesized in Example 3. Specifically, FIG. 8 shows the thermogravimetric analysis (TGA) of the compound, and FIG. 9 shows an powder X-ray diffraction pattern of the compound.
- TGA thermogravimetric analysis
- FIG. 10 shows the pharmacokinetics in rats after 30 mg/kg oral doses of topiramate crystal form as compared to topiramate sodium trihydrate and topiramate sodium trihydrate with added tartaric acid.
- FIGS. 11 and 12 relate to analysis of topiramate lithium. Specifically, FIG. 11 shows the thermogravimetric analysis (TGA) of the compound, and FIG. 12 shows the differential scanning calorimetric (DSC) analysis for the compound.
- TGA thermogravimetric analysis
- DSC differential scanning calorimetric
- FIG. 13 shows the thermogravimetric analysis (TGA) of topiramate potassium.
- This invention relates to salts of topiramate and polymorphs, solvates, hydrates, dehydrates, co-crystals, anhydrous and amorphous forms thereof, pharmaceutical compositions and dosage forms comprising pharmaceutically acceptable salts of topiramate and polymorphs, solvates, hydrates, dehydrates, co-crystals, anhydrous and amorphous forms thereof, and their use to treat or prevent a variety of diseases, conditions, or disorders in a patient, and humans in particular.
- One embodiment of the invention encompasses a base-addition salt of topiramate, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous forms thereof.
- the base-addition salt of topiramate is a pharmaceutically acceptable salt, and more preferably, the base-addition salt is topiramate sodium, topiramate lithium, or topiramate potassium, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof.
- Another embodiment of the invention encompasses a form of topiramate that has an aqueous solubility at 25°C of greater than about 10, 20, 50, 100, 250, 500, 750, 1000, 1100, or 1250 mg/ml.
- Another embodiment of the invention encompasses pharmaceutically acceptable salts of topiramate, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof.
- the pharmaceutically acceptable salt of topiramate is topiramate sodium, topiramate lithium, topiramate potassium, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof. More preferably, the pharmaceutically acceptable salt of topiramate is topiramate sodium, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof.
- compositions and dosage forms comprising a therapeutically or prophylactically effective amount of a pharmaceutically acceptable salt of topiramate, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof.
- the pharmaceutically acceptable salt of topiramate is topiramate sodium, topiramate lithium, topiramate potassium, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof, and more preferably, the pharmaceutically acceptable salt of topiramate is topiramate sodium, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof.
- the pharmaceutical compositions and dosage forms can contain one or more pharmaceutically acceptable excipients or a carrier.
- the pharmaceutically acceptable salt of topiramate is topiramate sodium
- the dosage form is a tablet.
- the topiramate sodium is topiramate sodium trihydrate, or a polymorph thereof.
- the pharmaceutically acceptable salt of topiramate is in a dosage form that is a controlled-release or extended release dosage form.
- the controlled-release dosage form of the invention is an oral osmotic pump tablet.
- the pharmaceutically acceptable salt of topiramate in said dosage forms is topiramate sodium, topiramate lithium, or topiramate potassium.
- a further embodiment of the invention encompasses a method of treating or preventing seizures or convulsions in a patient which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a pharmaceutically acceptable salt of topiramate, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof.
- the pharmaceutically acceptable salt of topiramate is topiramate sodium, topiramate lithium, topiramate potassium, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof, and more preferably, the pharmaceutically acceptable salt of topiramate is topiramate sodium, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof.
- Another embodiment of the invention encompasses a method of treating or preventing an epileptic condition in a patient which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a pharmaceutically acceptable salt of topiramate, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof.
- the pharmaceuticalfy acceptable salt of topiramate is topiramate sodium, topiramate lithium, topiramate potassium, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof, and more preferably, the pharmaceutically acceptable salt of topiramate is topiramate sodium, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof.
- the pharmaceutically acceptable salt of topiramate is adjunctively administered with another anticonvulsant or antiepileptic, i.e., the pharmaceutically acceptable salt of topiramate and additional anticonvulsant or antiepileptic are administered as a combination, concurrently but separately, or sequentially by any suitable route (e.g., orally, parenterally, transdermally, or mucosally).
- Additional anticonvulsants or antiepileptics include, but are not limited to, carbamazepine, phenytoin, ethotiagabine, valproic acid, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, and oxcarbazepine.
- Another embodiment of the invention encompasses a method for treating or preventing tremors in a patient which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a pharmaceutically acceptable salt of topiramate, or a pharmaceutically acceptable polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof.
- Yet another embodiment of the invention encompasses a method of treating or preventing a cerebral function disorder which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a pharmaceutically acceptable salt of to, or a pharmaceutically acceptable polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof.
- a further embodiment of the invention encompasses a method for treating obesity or weight gain in a patient which comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of topiramate, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof.
- the pharmaceutically acceptable salt of topiramate is topiramate sodium, topiramate lithium, topiramate potassium, or a polymorph, solvate, hydrate, dehydrate, co- crystal, anhydrous, or amorphous form thereof, and more preferably, topiramate sodium, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof.
- Another embodiment of the invention encompasses a method for treating or preventing neuropathic pain in a patient which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a pharmaceutically acceptable salt of topiramate, or a pharmaceutically acceptable polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof.
- the pharmaceutically acceptable salt of topiramate is topiramate sodium, topiramate lithium, topiramate potassium, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof, and more preferably, topiramate sodium, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof.
- a further embodiment of the invention encompasses a method of treating or preventing an affective disorder in a patient which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a pharmaceutically acceptable salt of topiramate, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof.
- a pharmaceutically acceptable salt of topiramate is topiramate sodium, topiramate lithium, and topiramate potassium, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amo ⁇ hous form thereof.
- Another embodiment of the invention comprises a method of eliciting smoking cessation in a patient which comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of topiramate, or a polymo ⁇ h, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amo ⁇ hous form thereof.
- Yet another embodiment of the invention encompasses a method of treating migraine in a human patient which comprises administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutically acceptable salt of topiramate, or a pharmaceutically acceptable polymo ⁇ h, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amo ⁇ hous form thereof.
- Another aspect of this embodiment comprises a method of reducing the frequency or severity of migraine in a human patient which comprises administering to the patient in need thereof an effective amount of a pharmaceutically acceptable salt of topiramate, or a pharmaceutically acceptable polymo ⁇ h, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amo ⁇ hous form thereof.
- the pharmaceutically acceptable salt of topiramate is topiramate sodium, topiramate lithium, topiramate potassium, or a polymo ⁇ h, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amo ⁇ hous form thereof, and more preferably, the pharmaceutically acceptable salt of topiramate is topiramate sodium, or a polymo ⁇ h, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amo ⁇ hous form thereof.
- a further embodiment of the invention encompasses a method for treating or preventing cluster headache in a patient which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a pharmaceutically acceptable salt of topiramate, or a polymo ⁇ h, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amo ⁇ hous form thereof.
- the pharmaceutically acceptable salt of topiramate is topiramate sodium, topiramate lithium, topiramate potassium, or a polymo ⁇ h, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amo ⁇ hous form thereof.
- Another method encompassed by the invention comprises adjunctively administering the pharmaceutically acceptable salt of topiramate, or a polymo ⁇ h, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amo ⁇ hous form thereof, with caffeine, wherein the pharmaceutically acceptable salt of topiramate and caffeine are administered as a combination, concurrently but separately, or sequentially by any suitable route (e.g., orally, parenterally, transdermally, or mucosally).
- caffeine and a pharmaceutically acceptable salt of topiramate, or a polymo ⁇ h, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amo ⁇ hous form thereof are administered in combination.
- the pharmaceutically acceptable salt of topiramate is topiramate sodium, topiramate lithium, or topiramate potassium, or a polymo ⁇ h, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amo ⁇ hous form thereof. More preferably, the pharmaceutically acceptable salt of topiramate is topiramate sodium, or a polymo ⁇ h, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amo ⁇ hous form thereof.
- inventions comprise a co-crystal or complex of caffeine and topiramate, pharmaceutical compositions and dosage forms comprising a therapeutically or prophylactically effective amount of a co-crystal or complex of topiramate, and methods of treating and preventing conditions in a patient , including without limitation migraine, cluster headache, neuropathic pain, affective disorders, obesity, seizures, convulsions, epileptic conditions, tremors, and cerebral function disorders, comprising administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a co-crystal or complex of caffeine and topiramate.
- Topiramate can be made using various methods known to those skilled in the art. For example, methods for the chemical synthesis of topiramate are described in U.S. Patent No. 4,513,006, which is inco ⁇ orated by reference herein in its entirety. Other methods well known in the art for preparing topiramate may also be used, including, for example, those disclosed in U.S. Patent Nos. 6,319,903, 5,387,700; 5,258,402, 5,384,327, 5,242,942, 4,792,569, 2,554,816 and 2,980,679, all of which are inco ⁇ orated herein by reference in their entireties.
- the present invention involves the unexpected discovery that the sulfamate (- OSO 2 NH 2 ) group of topiramate is slightly acidic and thus may be a handle for generation of salts, co-crystals, and complexes with the basic compounds such as, but not limited to, caffeine, N-methyl pyrrolidine, nicotine, nicotinamide, and ethers such as PEGs (examples include but are not limited to PEG 200 and PEG 300).
- Salts are often associated with improved chemical stability and increased solubility of drugs leading to better delivery of drug to the body, by reducing unwanted degradation product exposure and increasing levels of drug in the body. Salt forms of drugs therefore constitute a useful set of options for development of drug formulations.
- compositions of topiramate can be prepared by treating topiramate with appropriate bases, such as organic or inorganic bases.
- Bases that can be used to prepare pharmaceutically acceptable salts of topiramate are those that form non-toxic base addition salts, i.e., salts containing pharmacologically acceptable cations, including, but not limited to, sodium, potassium, lithium, magnesium, calcium, aluminum, zinc, procaine, benzathine, chloroprocaine, choline, diethylamine, ethylenediamine, N-methylglucamine, benethamine, clemizole, diethylamine, piperazine, tromethamine, triethylamine, ethanolamine, triethanolamine, arginine, lysine, histidine, tributylamine, 2-amino-2- pentylpropanol, 2-amino-2-methyl-l ,3-propanediol, tris(hydroxymethyl)aminomethane, benz
- Crystallization of pharmaceutically acceptable salts of topiramate can be accomplished by several means, as would be apparent to one skilled in the art. For instance, saturation of an aqueous solution of the salt can be increased by cooling, and the cooling curve can be a determinant of the particle properties (e.g., size, habit) that result from a crystallization process. Alternatively, addition of an anti-solvent (or non-solvent), such as an alcohol or other water miscible solvent, can be used to increase saturation of the salt form in the medium and hence effect nucleation and growth of crystals.
- an anti-solvent or non-solvent
- an alcohol or other water miscible solvent can be used to increase saturation of the salt form in the medium and hence effect nucleation and growth of crystals.
- anti-solvents examples include, but are not limited to, iso-propanol, THF, and ethanol. Preferably, ethanol would be used, due to its azeotrope with water, anti-solvent quality with many salt forms, and pharmaceutical acceptance.
- Co-crystals and complexes of topiramate and other compounds can be prepared using conventional crystallization techniques, e.g., from solutions comprising topiramate and the other compounds. Crystallization from melts of topiramate and other compounds may also be used to prepare co-crystals or complexes of topiramate.
- a co-crystal or complex of topiramate and caffeine can be prepared by melting and recrystallizing caffeine, allowing such to cool, then contacting topiramate melt with the recrystallized caffeine, and allowing this to cool.
- caffeine is melted and recrystallized between a glass slide and glass cover slip on a hot-stage microscope (such as a Mettler-Toledo FP950tstage mounted on a Zeiss Axioplan II polarized light microscope). The hot-stage is allowed to cool to about 30°C.
- Topiramate is then placed on a glass slide in contact with the edge of the glass cover slip. The solid topiramate is melted and the melt is allowed to come into contact with the recrystallized caffeine.
- the temperature of the hotstage is lowered (e.g., to about 70°C) and held there overnight. During that time the melted topiramate recrystallizes and a cocrystalline phase crystallizes between the caffeine and topiramate regions. The slide can then be heated to determined the melting point of the caffeine -.topiramate co-crystal.
- compositions and dosage forms thereof, of the invention possess potent activity as antiepileptics, anticonvulsants, anti-obesity agents, and mood stabilizers.
- the pharmaceutically acceptable salts of topiramate, or polymo ⁇ hs, solvates, hydrates, dehydrates, co-crystals, anhydrous, or amo ⁇ hous forms thereof, and pharmaceutical compositions and dosage forms thereof, of the invention can be used to treat or prevent a variety of diseases and conditions including, but not limited to, seizures, epileptic conditions, tremors, obesity, cerebral function disorders, neuropathic pain, affective disorders, migraine, and cluster headaches.
- a prophylactic or therapeutic dose of each active ingredient in the acute or chronic management of a disease or disorder will vary with the disease or disorder itself, the specific active ingredients, and the route of administration.
- the dose, dose frequency, or both, may also vary according to age, body weight, response, and the past medical history of the patient. Suitable dosing regimens can be readily selected by the skilled artisan with due consideration of such factors by following, for example, dosages and dose regimens reported in the literature and recommended in the Physician 's Desk Reference ® f
- the magnitude of a prophylactic or therapeutic dose of the pharmaceutically acceptable salt of topiramate used in an embodiment of the invention will be that which is safe and effective (e.g., has received regulatory approval).
- the pharmaceutically acceptable salt of topiramate e.g., topiramate sodium, topiramate lithium, or topiramate potassium
- the pharmaceutically acceptable salt of topiramate is administered as needed in an amount of from about 10 mg to about 1500 mg, preferably in an amount of from about 25 mg to about 1000 mg, more preferably in an amount from about 50 mg to about 75 mg, and most preferably in an amount of from about 100 mg to about 500 mg.
- topiramate sodium, topiramate lithium, or topiramate potassium is administered as needed in an amount of from about 10 mg to about 1500 mg, preferably in an amount of from about 25 mg to about 1000 mg, more preferably in an amount from about 50 mg to about 75 mg, and most preferably in an amount of from about 100 mg to about 500 mg.
- the ratio of molecular mass of topiramate sodium trihydrate to free form topiramate is 1.224, and thus a dose of about 122 mg of topiramate sodium trihydrate is equivalent to about 100 mg dose of topiramate.
- the dosage amounts and frequencies provided above are encompassed by the terms "therapeutically effective,” “prophylactically effective,” and “therapeutically or prophylactically effective” as used herein.
- a particular route of administration employed for a particular active ingredient will depend on the active ingredient itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream) and the disease or disorder to be treated or prevented.
- topical administration is typically preferred for treating or preventing local diseases or disorders of the skin
- oral or parenteral administration is typically preferred for systemic diseases or disorders, or diseases or disorders within the body of the patient.
- oral or parenteral administration may be preferred for the treatment or prevention of acute diseases or disorders
- transdermal or subcutaneous routes of administration may typically be employed for treatment or prevention of a chronic disease or disorder.
- compositions and dosage forms of the invention comprise a pharmaceutically acceptable salt of topiramate, or a pharmaceutically acceptable polymo ⁇ h, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amo ⁇ hous form thereof.
- Specific salts of topiramate include, but are not limited to, topiramate sodium, topiramate lithium, and topiramate potassium.
- Specific co-crystals of topiramate include, but are not limited to, co- crystals of caffeine.
- Pharmaceutical compositions and unit dosage forms of the invention typically also comprise one or more pharmaceutically acceptable excipients or diluents.
- Pharmaceutical unit dosage forms of this invention are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., intramuscular, subcutaneous, intravenous, intraarterial, or bolus injection), topical, or transdermal administration to a patient.
- mucosal e.g., nasal, sublingual, vaginal, buccal, or rectal
- parenteral e.g., intramuscular, subcutaneous, intravenous, intraarterial, or bolus injection
- topical e.g., topical, or transdermal administration to a patient.
- dosage forms include, but are not limited to: tablets; caplets; capsules, such as hard gelatin capsules and soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in- water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline or amo ⁇ hous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.
- suspensions e.g.
- compositions, shape, and type of dosage forms of the invention will typically vary depending on their use.
- a dosage form used in the acute treatment of a disease or disorder may contain larger amounts of the active ingredient than a dosage form used in the chronic treatment of the same disease or disorder.
- a parenteral dosage form may contain smaller amounts of the active ingredient than an oral dosage form used to treat the same disease or disorder.
- Suitable excipients are well known to those skilled in the art of pharmacy or pharmaceutics, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for inco ⁇ oration into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a patient. For example, oral dosage forms such as tablets or capsules may contain excipients not suited for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form. For example, the decomposition of some active ingredients can be accelerated by some excipients such as lactose, or when exposed to water. Active ingredients that comprise primary or secondary amines are particularly susceptible to such accelerated decomposition.
- compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose.
- Such compounds which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
- pharmaceutical compositions or dosage forms of the invention may contain one or more solubility modulators, such as sodium chloride, sodium sulfate, sodium or potassium phosphate or organic acids.
- a specific solubility modulator is tartaric acid.
- dosage forms of the invention comprise a pharmaceutically acceptable salt of topiramate, or a pharmaceutically acceptable polymo ⁇ h, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amo ⁇ hous form thereof, in an amount of from about 10 mg to about 1000 mg, preferably in an amount of from about 25 mg to about 750 mg, and more preferably in an amount of from 50 mg to 500 mg. 4.2.1. ORAL DOSAGE FORMS
- compositions of the invention that are suitable for oral administration can be presented as discrete dosage forms, such as, but not limited to, tablets (including without limitation scored or coated tablets), pills, caplets, capsules, chewable tablets, powder packets, cachets, troches, wafers, aerosol sprays, or liquids, such as but not limited to, syrups, elixirs, solutions or suspensions in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil emulsion.
- Such compositions contain a predetermined amount of the pharmaceutically acceptable salt of topiramate, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington 's Pharmaceutical Sciences, 18 th ed., Mack Publishing, Easton, PA (1990).
- Typical oral dosage forms of the invention are prepared by combining the pharmaceutically acceptable salt of topiramate in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques.
- Excipients can take a wide variety of forms depending on the form of the composition desired for administration.
- excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
- excipients suitable for use in solid oral dosage forms include, but are not limited to, starches, sugars, microcrystalline cellulose, kaolin, diluents, granulating agents, lubricants, binders, and disintegrating agents.
- tablets and capsules represent the most advantageous solid oral dosage unit forms, in which case solid pharmaceutical excipients are used. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. These dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredient(s) with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
- a tablet can be prepared by compression or molding.
- Compressed tablets can be prepared by compressing in a suitable machine the active ingredient(s) in a free-flowing form, such as a powder or granules, optionally mixed with one or more excipients.
- Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
- excipients that can be used in oral dosage forms of the invention include, but are not limited to, binders, fillers, disintegrants, and lubricants.
- Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, com starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.
- Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, and AVICEL-PH- 105 (available from FMC Co ⁇ oration, American Viscose Division, Avicel Sales, Marcus Hook, PA, U.S.A.), and mixtures thereof.
- An exemplary suitable binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581.
- Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103TM and Starch 1500 LM.
- fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
- the binder or filler in pharmaceutical compositions of the invention is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
- Disintegrants are used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may swell, crack, or disintegrate in storage, while those that contain too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) should be used to form solid oral dosage forms of the invention. The amount of disintegrant used varies based upon the type of formulation and mode of administration, and is readily discernible to those of ordinary skill in the art. Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, preferably from about 1 to about 5 weight percent of disintegrant.
- Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, clays, other algins, other celluloses, gums, and mixtures thereof.
- Lubricants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.
- Additional lubricants include, for example, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Piano, TX), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are inco ⁇ orated.
- AEROSIL 200 a syloid silica gel
- a coagulated aerosol of synthetic silica marketed by Degussa Co. of Piano, TX
- CAB-O-SIL a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA
- lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are inco ⁇ orated.
- lactose-free pharmaceutical compositions and dosage forms wherein such compositions preferably contain little, if any, lactose or other mono- or di-saccharides.
- lactose-free means that the amount of lactose present, if any, is insufficient to substantially increase the degradation rate of an active ingredient.
- Lactose-free compositions of the invention can comprise excipients which are well known in the art and are listed in the USP (XXI)/NF (XVI), which is inco ⁇ orated herein by reference.
- lactose-free compositions comprise a pharmaceutically acceptable salt of topiramate (e.g., topiramate sodium), a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts.
- Preferred lactose-free dosage forms comprise a pharmaceutically acceptable salt of topiramate, microcrystalline cellulose, pre- gelatinized starch, and magnesium stearate.
- This invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds.
- water e.g., 5%
- water and heat accelerate the decomposition of some compounds.
- the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.
- Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
- Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine are preferably anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
- anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are preferably packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials) with or without desiccants, blister packs, and strip packs.
- compositions of topiramate can be administered by controlled- or delayed-release means.
- Controlled-release pharmaceutical products have a common goal of improving drag therapy over that achieved by their non-controlled release counte ⁇ arts.
- the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
- Controlled-release formulations include: 1) extended activity of the drug; 2) reduced dosage frequency; 3) increased patient compliance; 4) usage of less total drug; 5) reduction in local or systemic side effects; 6) minimization of drug accumulation; 7) reduction in blood level fluctuations; 8) improvement in efficacy of treatment; 9) reduction of potentiation or loss of drug activity; and 10) improvement in speed of control of diseases or conditions.
- Kim Chemg-ju, Controlled Release Dosage Form Design, 2 (Technomic Publishing, Lancaster, PA: 2000).
- Conventional dosage forms generally provide rapid or immediate drug release from the formulation. Depending on the pharmacology and pharmacokinetics of the drug, use of conventional dosage forms can lead to wide fluctuations in the concentrations of the drug in a patient's blood and other tissues.
- controlled-release formulations can be used to control a drug's onset of action, duration of action, plasma levels within the therapeutic window, and peak blood levels.
- controlled- or extended- release dosage forms or formulations can be used to ensure that the maximum effectiveness of a drug is achieved while minimizing potential adverse effects and safety concerns, which can occur both from under dosing a drug (i.e., going below the minimum therapeutic levels) as well as exceeding the toxicity level for the drug.
- Controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release other amounts of drag to maintain this level of therapeutic or prophylactic effect over an extended period of time.
- the drug In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.
- Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, ionic strength, osmotic pressure, temperature, enzymes, water, and other physiological conditions or compounds.
- a variety of known controlled- or extended-release dosage forms, formulations, and devices can be adapted for use with the topiramate salts and compositions of the invention. Examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,733,566; and 6,365,185 Bl; each of which is inco ⁇ orated herein by reference.
- dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems (such as OROS ® (Alza Co ⁇ oration, Mountain View, CA USA)), multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profile in varying proportions.
- ion exchange materials can be used to prepare immobilized, adsorbed salt forms of topiramate and thus effect controlled delivery of the drug. Examples of specific anion exchangers include, but are not limited to, Duolite ® A568 and Duolite ® AP143 (Rohm&Haas, Spring House, PA USA).
- One embodiment of the invention encompasses a unit dosage form which comprises a pharmaceutically acceptable salt of topiramate (e.g., a sodium, potassium, or lithium salt), or a polymo ⁇ h, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amo ⁇ hous form thereof, and one or more pharmaceutically acceptable excipients or diluents, wherein the pharmaceutical composition or dosage form is formulated for controlled-release.
- Specific dosage forms utilize an osmotic drag delivery system.
- OROS ® Alza Co ⁇ oration, Mountain View, CA USA.
- This technology can readily be adapted for the delivery of compounds and compositions of the invention.
- Various aspects of the technology are disclosed in U.S. Patent Nos. 6,375,978 Bl; 6,368,626 Bl; 6,342,249 Bl; 6,333,050 B2; 6,287,295 Bl; 6,283,953 Bl; 6,270,787 Bl; 6,245,357 Bl; and 6,132,420; each of which is inco ⁇ orated herein by reference.
- Additional OROS ® systems that can be used for the controlled oral delivery of compounds and compositions of the invention include OROS -CT and L-OROS . Id. ; see also, Delivery Times, vol. II, issue II (Alza Co ⁇ oration).
- Conventional OROS ® oral dosage forms are made by compressing a drug powder
- a specific dosage form of the invention comprises: a wall defining a cavity, the wall having an exit orifice formed or formable therein and at least a portion of the wall being semipermeable; an expandable layer located within the cavity remote from the exit orifice and in fluid communication with the semipermeable portion of the wall; a dry or substantially dry state drag layer located within the cavity adjacent the exit orifice and in direct or indirect contacting relationship with the expandable layer; and a flow-promoting layer inte ⁇ osed between the inner surface of the wall and at least the external surface of the drag layer located within the cavity, wherein the drag layer comprises a salt of topiramate, or a polymo ⁇ h, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amo ⁇ hous form thereof.
- Another specific dosage form of the invention comprises: a wall defining a cavity, the wall having an exit orifice formed or formable therein and at least a portion of the wall being semipermeable; an expandable layer located within the cavity remote from the exit orifice and in fluid communication with the semipermeable portion of the wall; a drag layer located within the cavity adjacent the exit orifice and in direct or indirect contacting relationship with the expandable layer; the drug layer comprising a liquid, active agent formulation absorbed in porous particles, the porous particles being adapted to resist compaction forces sufficient to form a compacted drug layer without significant exudation of the liquid, active agent formulation, the dosage form optionally having a placebo layer between the exit orifice and the drug layer, wherein the active agent formulation comprises a salt of topiramate, or a polymo ⁇ h, solvate, hydrate, dehydrate, co-crystal, anhydrous, or
- Parenteral dosage forms can be administered to patients by various routes, including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Since administration of parenteral dosage forms typically bypasses the patient's natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
- controlled-release parenteral dosage forms can be prepared for administration of a patient, including, but not limited to, administration DUROS ® -type dosage forms, and dose-dumping.
- Suitable vehicles that can be used to provide parenteral dosage forms of the invention are well known to those skilled in the art.
- Examples include, without limitation: sterile water; Water for Injection USP; saline solution; glucose solution; aqueous vehicles such as but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and propylene glycol; and non-aqueous vehicles such as, but not limited to, com oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
- aqueous vehicles such as but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
- water-miscible vehicles such as, but not limited to, e
- Topical dosage forms of the invention include, but are not limited to, creams, lotions, ointments, gels, shampoos, sprays, aerosols, solutions, emulsions, and other forms know to one of skill in the art. See, e.g., Remington 's Pharmaceutical Sciences, 18 ed., Mack Publishing, Easton, PA (1990); and Introduction to Pharmaceutical Dosage Forms, 4 ed., Lea & Febiger, Philadelphia, PA (1985).
- viscous to semi-solid or solid forms comprising a carrier or one or more excipients compatible with topical application and having a dynamic viscosity preferably greater than water are typically employed.
- Suitable formulations include, without limitation, solutions, suspensions, emulsions, creams, ointments, powders, liniments, salves, and the like, which are, if desired, sterilized or mixed with auxiliary agents (e.g., preservatives, stabilizers, wetting agents, buffers, or salts) for influencing various properties, such as, for example, osmotic pressure.
- auxiliary agents e.g., preservatives, stabilizers, wetting agents, buffers, or salts
- suitable topical dosage forms include sprayable aerosol preparations wherein the active ingredient, preferably in combination with a solid or liquid inert carrier, is packaged in a mixture with a pressurized volatile (e.g., a gaseous propellant, such as freon), or in a squeeze bottle.
- a pressurized volatile e.g., a gaseous propellant, such as freon
- Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, e.g., Remington's Pharmaceutical Sciences, 18 th Ed., Mack Publishing, Easton, PA (1990).
- Transdermal and mucosal dosage forms of the invention include, but are not limited to, ophthalmic solutions, patches, sprays, aerosols, creams, lotions, suppositories, ointments, gels, solutions, emulsions, suspensions, or other forms known to one of skill in the art. See, e.g., Remington 's Pharmaceutical Sciences, 18 th Ed., Mack Publishing, Easton, PA (1990); and Introduction to Pharmaceutical Dosage Forms, 4 th Ed., Lea & Febiger, Philadelphia, PA (1985).
- Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes, as oral gels, or as buccal patches.
- Additional transdermal dosage forms include "reservoir type” or "matrix type” patches, which can be applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredient.
- transdermal dosage forms and methods of administration that can be used to administer the active ingredient(s) of the invention include, but are not limited to, those disclosed in U.S. Patent Nos.: 4,624,665; 4,655,767; 4,687,481; 4,797,284; 4,810,499 4,834,978; 4,877,618; 4,880,633; 4,917,895; 4,927,687; 4,956,171; 5,035,894; 5,091,186 5,163,899; 5,232,702; 5,234,690; 5,273,755; 5,273,756; 5,308,625; 5,356,632; 5,358,715 5,372,579; 5,421,816; 5,466;465; 5,494,680; 5,505,958; 5,554,381; 5,560,922; 5,585,111 5,656,285; 5,667,798; 5,698,217; 5,741,511; 5,747,783; 5,770
- Suitable excipients e.g., carriers and diluents
- other materials that can be used to provide transdermal and mucosal dosage forms encompassed by this invention are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue or organ to which a given pharmaceutical composition or dosage form will be applied.
- typical excipients include, but are not limited to water, acetone, ethanol, ethylene glycol, propylene glycol, butane- 1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof, to form dosage forms that are non-toxic and pharmaceutically acceptable.
- additional components may be used prior to, in conjunction with, or subsequent to treatment with pharmaceutically acceptable salts of topiramate of the invention.
- penetration enhancers can be used to assist in delivering the active ingredients to or across the tissue.
- Suitable penetration enhancers include, but are not limited to: acetone; various alcohols such as ethanol, oleyl, an tetrahydrofiiryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water-soluble or insoluble sugar esters such as TWEEN 80 (polysorbate 80) and SPAN 60 (sorbitan monostearate).
- the pH of a pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied may also be adjusted to improve delivery of the active ingredient(s).
- the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery.
- Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of the active ingredient(s) so as to improve delivery.
- stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery-enhancing or penetration-enhancing agent.
- Different hydrates, dehydrates, co-crystals, solvates, polymo ⁇ hs, anhydrous, or amo ⁇ hous forms of the pharmaceutically acceptable salt of topiramate can be used to further adjust the properties of the resulting composition.
- active ingredients of the invention are preferably not administered to a patient at the same time or by the same route of administration.
- This invention therefore encompasses kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a patient.
- a typical kit of the invention comprises a unit dosage form of a pharmaceutically acceptable salt of topiramate and a unit dosage form of a second pharmacologically active compound, such as caffeine, anticonvulsants, or antiepileptics.
- the pharmaceutically acceptable salt of topiramate is topiramate sodium, topiramate lithium, or topiramate potassium, or a polymo ⁇ h, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amo ⁇ hous form thereof.
- the pharmaceutically acceptable salt of topiramate is topiramate sodium, or a polymo ⁇ h, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amo ⁇ hous form thereof.
- a kit may further comprise a device that can be used to administer the active ingredient. Examples of such devices include, but are not limited to, syringes, drip bags, patches, and inhalers.
- Kits of the invention can further comprise pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients.
- the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration.
- Examples of pharmaceutically acceptable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and propylene glycol; and non-aqueous vehicles such as, but not limited to, com oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
- Water for Injection USP Water for Injection USP
- aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
- water-miscible vehicles
- topiramate (Cheminor Drags Ltd., India, Batch No. TPOOUOO) was suspended in 10 mL of distilled water in a scintillation vial. 1.4 mL of 1 N NaOH (VWR, West Chester, PA) was added to dissolve the drug with heating. A TEFLON-coated magnetic stirbar and hotplate-stirrer were used to bring the compound into solution, after which the warm solution was filtered through a #1 filter paper (Whatman) into a clean beaker containing a dry TEFLON-coated stirbar. The beaker was then heated with stirring to reduce the volume of the solution to the point of super saturation.
- VWR West Chester, PA
- the beaker was stored at room temperature, lightly capped to allow for slow evaporation. After 3 days, small block-like crystals were observed by optical microscopy at 100-fold magnification. On the fourth day, two large crystals were seen which had the approximate dimensions of 0.5 cm x 0.5 cm x 0.2 cm. The resulting product was a clear colorless birefringent crystalline substance.
- the crystals are square plates with angled sides. The crystals lose waters of hydration above 50°C, decomposes above ⁇ 150°C. Alternatively, storage under low humidity conditions (close to zero percent, controlled by the presence of phosphorous pentoxide) removes the water of hydration from the crystals even at room temperature.
- Thermal microscopy indicates more than one polymo ⁇ h, or hydration state, exists.
- a small crystallite was cleaved from a large crystal of topiramate sodium trihydrate prepared in this example. The crystal extinguished on the polarizing microscope when the crystal edges were aligned with the polarizer and analyzer. Conoscopy showed that the crystals were biaxial.
- the crystallite was loaded into a glass crucible and covered with the crucible's glass cover, and then placed into a FP900 Hotstage microscope (Mettler Toledo). The sample was heated from 30°C to 180°C at 10°C/minute, in 5°C increments.
- a powder X-ray diffraction pattern for the salt sample prepared in this example was performed using a D/Max Rapid diffractometer (Rigaku/MSC, The Woodlands, TX, U.S.A.), which uses as its control software RINT Rapid Control Software, Rigaku Rapid XRD, version 1.0.0 ( ® 1999 Rigaku Co.).
- RINT Rapid Control Software Rigaku Rapid XRD, version 1.0.0 ( ® 1999 Rigaku Co.).
- the analysis software used were RINT Rapid display software, version 1.18 (Rigaku/MSC), and JADE XRD Pattern Processing, versions 5.0 and 6.0 ( ® 1995-2002, Materials Data, Inc.).
- the acquisition parameters were as follows: source wasCu/K ⁇ 1.5406A; x-y stage was manual; collimator size was 0.3mm; capillary (Charles Supper Company, Natick, MA, U.S.A.) was 0.3 mm; reflection mode was used; the power to the X-ray tube was 46 kV; the current to the X-ray tube was 40 mA; the omega-axis was oscillating in a range of 0-5 degrees at a speed of 1 degree/minute; the phi-axis was spinning at an angle of 360 degrees at a speed of 2 degrees/second; 0.3 mm collimator; the collection time was 60 minutes; the temperature was room temperature; and the heater was not used.
- the sample was presented to the X-ray source in a quartz capillary.
- the analysis parameters were as follows: the integration 2-theta range was
- the PXRD pattern for the resulting compound is shown in FIG. 1. In the diffractogram of FIG. 1 , the background has not been removed.
- DSC analysis of the salt sample prepared in this example was performed using a Q1000 Differential Scanning Calorimeter (TA Instruments, New Castle, DE, U.S.A.), which uses Advantage for QW-Series, version 1.0.0.78, Thermal Advantage Release 2.0 ( ® 2001 TA Instruments- Water LLC).
- the analysis software used was Universal Analysis 2000 for Windows 95/95/2000/NT, version 3.1E;Build 3.1.0.40 ( ® 2001 TA Instruments- Water LLC).
- the purge gas used was dry nitrogen
- the reference material was an empty aluminum pan that was crimped
- the sample purge was 50 mL/minute.
- DSC analysis of the sample was performed by placing 3.230 mg of sample in an aluminum pan with a crimped pan closure. The starting temperature was 20°C with a heating rate of 10°C/minute, and the ending temperature was 200°C. The resulting DSC analysis is shown in FIG. 2. TGA analysis of the salt sample prepared in this example was performed using a
- Thermogravimetric Analyzer (TA Instruments, New Castle, DE, U.S.A.), which uses Advantage for QW-Series, version 1.0.0.78, Thermal Advantage Release 2.0 ( ⁇ 2001 TA Instruments- Water LLC).
- the analysis software used was Universal Analysis 2000 for Windows 95/95/2000/NT, version 3.1E;Build 3.1.0.40 ( ® 2001 TA Instruments- Water LLC).
- the purge gas used was dry nitrogen, the balance purge was 40 mL/minute N 2 , and the sample purge was 60 mL/minute N 2 .
- TGA of the sample from this example was obtained by weighing 4.159 mg of sample in a platinum pan and placing it in the analyzer. The starting temperature was 20°C with a heating rate of 10°C/minute, and the ending temperature was 300°C. The resulting TGA analysis is shown in FIG. 3.
- Raman spectroscopy of a sample from this example was performed using a Nicolet Almega Dispersive Raman Spectrometer/Microscope, controlled by Omnic software v. 5.2a. Spectra ranges were 3250 to 105 cm "1 , using 10 ⁇ m pinhole aperture, and ten consecutive 2- second exposures. The resulting spectra were displayed using Omnic software v. 5.2a.
- a powder X-ray diffraction pattern for the salt sample prepared in this example was performed using a the same methods and equipment described in this example.
- the PXRD pattern for the resulting compound is shown in FIG. 5.
- the solubility of the topiramate sodium trihydrate prepared in this example in water, ethanol, methanol, and THF was estimated by determining the minimum amount of solvent necessary to dissolve a known amount of the compound. In general, a predetermined amount of the compound was placed in a small glass vial, and then solvent was added drop-wise at room temperature until no visible solid remained in the vial. The specific details of each experiment are set forth in Table 2 below:
- FIG. 6 provides results of a comparison between the aqueous solubility of topirimate sodium trihydrate with that of topiramate.
- the sodium salt was found to be over 100 times more soluble at 1.3 g/mL vs. the literature value of 9.8 mg/mL.
- a set of dissolution curves were obtained in 0.01 N HC1 (representative of a modestly acidic stomach), and these are shown in FIG. 7.
- Three preparations were tested: (1) topiramate crystal form (Reddy Cheminor), (2) topiramate sodium salt trihydrate and (3) topiramate sodium salt trihydrate dry mixed with 1.1 equivalents of tartaric acid. Dissolution was found to be rapid with all forms, and was essentially complete in 5 minutes.
- sample (2) showed increased solubility at the equilibrium condition, with an associated pH of 9.5.
- the nominal concentration of drug in each case was about 110 mM (37 mg/mL free acid concentration) and hence (1) and (3) remained as suspensions while (2) was not saturated at the end of the experiment.
- the solution was filtered through a #4 filter paper and transferred into a clean vial with a TEFLON-coated stir bar.
- the solution was concentrated by evaporation until solid formed.
- the mixture was dried further by blowing air over the vial.
- the dried solid was dissolved in 5 mL of 2% water (v/v) in ethanol.
- the solution was concentrated and cooled in a refrigerator at 4 °C overnight. Fine white crystals formed and were filtered, dried, and weighed (0.85 g, 88%).
- TGA of a sample from this example was observed by weighing 3.0630 mg of sample in a platinum pan and placing it in the analyzer. The starting temperature was 20°C with a heating rate of 10°C/minute, and the ending temperature was 190°C. The resulting TGA analysis is shown in FIG. 8. Mass losses of 13% and 39% at 41 °C and 174°C, respectively, were observed by TGA.
- a sample of the compound prepared in this example was examined by PXRD using a collection time of 10 minutes.
- the PXRD pattern for the resulting compound is shown in FIG. 9.
- a PXRD pattern for topiramate sodium trihydrate includes the identifying features listed below in Table 3 : TABLE 3 Topiramate Sodium Trihydrate
- EXAMPLE 4 IN VIVO CHARACTERISTICS OF TOPIRAMATE SODIUM TRIHYDRATE The bioavailability of topiramate provided by (1) TOPAMAX ® was compared to that of topiramate provided by (2) topiramate sodium trihydrate and a (3) combination of topiramate sodium trihydrate dry mixed with 1.1 equivalents of tartaric acid using male Sprague-Dawley rats dosed with oral gavage of size 9 gelatin capsules (To ⁇ ac, Fairfield, NJ). The capsules contained an amount of solid powder sufficient to provide a dose equivalent to 30 mg/kg (mpk) of free topiramate (corrected for any counterion, hydrate and tartaric acid constituent). Plasma samples were analyzed by LC/MS/MS using a method based on a human plasma assay of topiramate. Tests were conducted by MDS Pharma Services (Montreal, Canada).
- the in vivo data yielded by these tests are shown in FIG. 10.
- the crystalline salt in (2) has a very fast onset time, with the peak of plasma concentration being observed at the first time point of 0.5 h.
- the data for (2) are comparable to an oral solution of TOPAMAX ® .
- the comparison between (1) and (3) illustrates the possibility of modulating the rate of abso ⁇ tion of the sodium salt by changing formulation in the solid oral dosage form.
- TGA thermogravimetric analysis
- DSC differential scanning calorimetry
- TGA of a sample from this example was observed by weighing 6.4900 mg of sample in a platinum pan and placing it in the analyzer and running in dynamic mode.
- the starting temperature was room temperature with a heating rate of 50°C/minute, and the ending temperature was 400°C.
- the resulting TGA analysis is shown in FIG. 13. Cumulative mass losses of 2.1%, 2.8% and 2.7% at 85, 132 and 172°C, respectively, were observed by TGA relative to the starting mass in the pan.
Abstract
Description
Claims
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
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JP2003569645A JP2005524645A (en) | 2002-02-15 | 2003-02-14 | Topiramate salts, compositions comprising them, and methods for their production and use |
MXPA04007968A MXPA04007968A (en) | 2002-02-15 | 2003-02-14 | Topiramate salts and compositions comprising and methods of making and using the same. |
EP03742731A EP1485388A2 (en) | 2002-02-15 | 2003-02-14 | Topiramate salts and compositions comprising and methods of making and using the same |
AU2003211021A AU2003211021A1 (en) | 2002-02-15 | 2003-02-14 | Topiramate salts and compositions comprising and methods of making and using the same |
BR0307919-8A BR0307919A (en) | 2002-02-15 | 2003-02-14 | Topiramate salts and compositions comprising them and methods for their manufacture and use |
KR10-2004-7012709A KR20050002826A (en) | 2002-02-15 | 2003-02-14 | Topiramate salts and compositions comprising and methods of making and using the same |
CA002476422A CA2476422A1 (en) | 2002-02-15 | 2003-02-14 | Topiramate salts and compositions comprising and methods of making and using the same |
IL16354903A IL163549A0 (en) | 2002-02-15 | 2003-02-14 | Topiramate salts and compositions comprising and methods of making and using the same |
NO20043819A NO20043819L (en) | 2002-02-15 | 2004-09-13 | Topiramate salts and preparations comprising these as well as the method and preparation for their use |
HR20040847A HRP20040847A2 (en) | 2002-02-15 | 2004-09-15 | Topiramate salts and compositions comprising and methods of making and using the same |
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Families Citing this family (85)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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US20070059356A1 (en) * | 2002-05-31 | 2007-03-15 | Almarsson Oern | Pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen |
US7939102B2 (en) * | 2002-06-07 | 2011-05-10 | Torrent Pharmaceuticals Ltd. | Controlled release formulation of lamotrigine |
US20040115262A1 (en) * | 2002-07-29 | 2004-06-17 | Frank Jao | Formulations and dosage forms for controlled delivery of topiramate |
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MY147767A (en) * | 2004-06-16 | 2013-01-31 | Janssen Pharmaceutica Nv | Novel sulfamate and sulfamide derivatives useful for the treatment of epilepsy and related disorders |
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EP1765379A4 (en) * | 2004-06-17 | 2009-05-27 | Transform Pharmaceuticals Inc | Pharmaceutical co-crystal compositions and related methods of use |
WO2006007323A2 (en) * | 2004-06-28 | 2006-01-19 | Alza Corporation | Dosage forms for low solubility and/or low dissolution rate free acid pharmaceutical agents |
WO2006009403A1 (en) * | 2004-07-22 | 2006-01-26 | Amorepacific Corporation | Sustained-release preparations containing topiramate and the producing method thereof |
US20060047001A1 (en) * | 2004-08-24 | 2006-03-02 | Parker Michael H | Novel benzo-fused heteroaryl sulfamide derivatives useful as anticonvulsant agents |
EP1827580A1 (en) * | 2004-10-21 | 2007-09-05 | Advanced Neuromodulation Systems, Inc. | New stimulation design for neuromodulation |
US7638291B2 (en) * | 2004-10-25 | 2009-12-29 | Seradyn, Inc. | Immunoassays for topiramate |
US8779175B2 (en) * | 2004-10-25 | 2014-07-15 | Synthonics, Inc. | Coordination complexes, pharmaceutical solutions comprising coordination complexes, and methods of treating patients |
US20060088886A1 (en) * | 2004-10-25 | 2006-04-27 | Anlong Ouyang | Topiramate analogs |
US20110117070A1 (en) * | 2005-04-19 | 2011-05-19 | Aurora Sheena K | Compositions and methods for treating headache |
US20060233892A1 (en) * | 2005-04-19 | 2006-10-19 | Curt Hendrix | Topiramate compositions for treatment of headache |
US8283478B2 (en) * | 2005-05-20 | 2012-10-09 | Janssen Pharmaceutica Nv | Process for preparation of sulfamide derivatives |
JP2008542237A (en) * | 2005-05-25 | 2008-11-27 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Topiramate pediatric formulation |
US20070043120A1 (en) * | 2005-08-18 | 2007-02-22 | Bettina Beyreuther | Therapeutic combination for painful medical conditions |
WO2007038524A2 (en) * | 2005-09-28 | 2007-04-05 | Ssci, Inc. | Cocrystallization methods |
US20070155827A1 (en) * | 2005-12-19 | 2007-07-05 | Smith-Swintosky Virginia L | Use of benzo-fused heterocycle sulfamide derivatives for the treatment of depression |
US8492431B2 (en) * | 2005-12-19 | 2013-07-23 | Janssen Pharmaceutica, N.V. | Use of benzo-fused heterocycle sulfamide derivatives for the treatment of obesity |
US8691867B2 (en) * | 2005-12-19 | 2014-04-08 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocycle sulfamide derivatives for the treatment of substance abuse and addiction |
US8937096B2 (en) * | 2005-12-19 | 2015-01-20 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocyle sulfamide derivatives for the treatment of mania and bipolar disorder |
US8497298B2 (en) * | 2005-12-19 | 2013-07-30 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocycle sulfamide derivatives for lowering lipids and lowering blood glucose levels |
US20070155823A1 (en) * | 2005-12-19 | 2007-07-05 | Smith-Swintosky Virginia L | Use of benzo-fused heterocycle sulfamide derivatives as neuroprotective agents |
US8716231B2 (en) * | 2005-12-19 | 2014-05-06 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocycle sulfamide derivatives for the treatment of pain |
US20090176882A1 (en) | 2008-12-09 | 2009-07-09 | Depomed, Inc. | Gastric retentive gabapentin dosage forms and methods for using same |
US20070191474A1 (en) * | 2006-02-15 | 2007-08-16 | Smith-Swintosky Virginia L | Use of benzo-fused heterocyle sulfamide derivatives for the treatment of migraine |
EA200870556A1 (en) * | 2006-05-19 | 2009-06-30 | Янссен Фармацевтика Н.В. | COMBINED THERAPY IN THE TREATMENT OF EPILEPSY AND RELATED DISORDERS |
BRPI0713594A2 (en) | 2006-06-15 | 2012-10-30 | Sanol Arznei Schwarz Gmbh | pharmaceutical composition with synergistic anticonsulsive effect |
WO2008027557A2 (en) * | 2006-08-31 | 2008-03-06 | Spherics, Inc. | Topiramate compositions and methods of enhancing its bioavailability |
US20090239942A1 (en) * | 2006-09-15 | 2009-09-24 | Cloyd James C | Topiramate Compositions and Methods of Making and Using the Same |
PT2061458E (en) * | 2006-09-15 | 2015-03-11 | Univ Minnesota | Topiramate compositions and methods for their use |
CN101547922B (en) | 2006-10-04 | 2012-06-20 | 辉瑞产品公司 | Pyrido[4,3-d]pyrimidin-4(3h)-one derivatives as calcium receptor antagonists |
US8298576B2 (en) | 2006-11-17 | 2012-10-30 | Supernus Pharmaceuticals, Inc. | Sustained-release formulations of topiramate |
WO2008070670A2 (en) * | 2006-12-04 | 2008-06-12 | Supernus Pharmaceuticals, Inc. | Enhanced immediate release formulations of topiramate |
CN100432087C (en) * | 2007-04-26 | 2008-11-12 | 杭州盛美医药科技开发有限公司 | Preparation method of topiramate |
US7751907B2 (en) | 2007-05-24 | 2010-07-06 | Smiths Medical Asd, Inc. | Expert system for insulin pump therapy |
ATE526969T1 (en) * | 2007-07-17 | 2011-10-15 | Meddev Inc | TREATMENT OF DEPRESSION AND DEPRESSIVE MOODS |
US8986253B2 (en) | 2008-01-25 | 2015-03-24 | Tandem Diabetes Care, Inc. | Two chamber pumps and related methods |
US20110251468A1 (en) * | 2010-04-07 | 2011-10-13 | Ivan Osorio | Responsiveness testing of a patient having brain state changes |
US20090247617A1 (en) * | 2008-03-26 | 2009-10-01 | Abdel-Magid Ahmed F | Process for the preparation of benzo-fused heteroaryl sulfamates |
US20090247616A1 (en) * | 2008-03-26 | 2009-10-01 | Smith-Swintosky Virginia L | Use of benzo-fused heterocyle sulfamide derivatives for the treatment of anxiety |
WO2009120390A2 (en) * | 2008-03-27 | 2009-10-01 | Seton Hall University | Cyclopropanated carbohydrates |
US20090304789A1 (en) * | 2008-06-09 | 2009-12-10 | Thomas Najarian | Novel topiramate compositions and an escalating dosing strategy for treating obesity and related disorders |
US8580298B2 (en) | 2008-06-09 | 2013-11-12 | Vivus, Inc. | Low dose topiramate/phentermine composition and methods of use thereof |
PE20110060A1 (en) | 2008-06-23 | 2011-01-31 | Janssen Pharmaceutica Nv | CRYSTALLINE FORM OF (2S) - (-) - N- (6-CHLORO-2,3-DIHYDRO-BENZO [1,4] DIOXIN-2-ILMETHYL) -SULFAMIDE |
US8815939B2 (en) * | 2008-07-22 | 2014-08-26 | Janssen Pharmaceutica Nv | Substituted sulfamide derivatives |
US8408421B2 (en) | 2008-09-16 | 2013-04-02 | Tandem Diabetes Care, Inc. | Flow regulating stopcocks and related methods |
US8650937B2 (en) | 2008-09-19 | 2014-02-18 | Tandem Diabetes Care, Inc. | Solute concentration measurement device and related methods |
KR20110074611A (en) * | 2008-10-21 | 2011-06-30 | 노보더믹스 인터내셔널 리미티드 | Composition for treatment of epithelial tissue |
CA2769030C (en) | 2009-07-30 | 2016-05-10 | Tandem Diabetes Care, Inc. | Infusion pump system with disposable cartridge having pressure venting and pressure feedback |
US9180242B2 (en) | 2012-05-17 | 2015-11-10 | Tandem Diabetes Care, Inc. | Methods and devices for multiple fluid transfer |
US9555186B2 (en) | 2012-06-05 | 2017-01-31 | Tandem Diabetes Care, Inc. | Infusion pump system with disposable cartridge having pressure venting and pressure feedback |
US9173998B2 (en) | 2013-03-14 | 2015-11-03 | Tandem Diabetes Care, Inc. | System and method for detecting occlusions in an infusion pump |
WO2014167439A1 (en) | 2013-03-26 | 2014-10-16 | Wockhardt Limited | Modified release pharmaceutical compositions of topiramate or salts thereof |
GB201311984D0 (en) * | 2013-07-04 | 2013-08-21 | Univ Cardiff | Methods and compounds for preventing or treating osteoarthritis |
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US10278948B1 (en) | 2015-09-03 | 2019-05-07 | Tian Xia | Method for transnasal delivery of anticonvulsant and therapeutic treatments |
EP3423103A1 (en) | 2016-03-01 | 2019-01-09 | Ascendis Pharma Bone Diseases A/S | Pth prodrugs |
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JP7085535B2 (en) | 2016-09-29 | 2022-06-16 | アセンディス ファーマ ボーン ディジージズ エー/エス | PTH compounds with a small peak-to-trough ratio |
EP3883546A1 (en) | 2018-11-21 | 2021-09-29 | Rosemont Pharmaceuticals Ltd | Oral topiramate suspension formulations with extended shelf stability and enhanced bioavailability |
MA55726A (en) * | 2019-04-18 | 2022-02-23 | Prevep Llc | THERAPEUTIC COMBINATIONS, LIQUID PHARMACEUTICAL COMPOSITIONS, KITS FOR THEIR PREPARATION AND METHODS OF USE |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000050020A2 (en) * | 1999-02-24 | 2000-08-31 | University Of Cincinnati | Use of sulfamate derivatives for treating impulse control disorders |
WO2000072841A1 (en) * | 1999-05-28 | 2000-12-07 | Jeffrey Berlant | Compounds and methods for the treatment of post traumatic stress disorder |
WO2003006467A1 (en) * | 2001-07-09 | 2003-01-23 | Ortho-Mcneil Pharmaceutical, Inc. | Novel anticonvulsant derivative salts |
Family Cites Families (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4513006A (en) | 1983-09-26 | 1985-04-23 | Mcneil Lab., Inc. | Anticonvulsant sulfamate derivatives |
US5242942A (en) | 1992-04-28 | 1993-09-07 | Mcneilab, Inc. | Anticonvulsant fructopyranose cyclic sulfites and sulfates |
US5384327A (en) | 1992-12-22 | 1995-01-24 | Mcneilab, Inc. | Anticonvulsant sorbopyranose sulfamates |
US5498629A (en) * | 1993-12-23 | 1996-03-12 | Ortho Pharmaceutical Corporation | Anticonvulsant pseudofructopyranose sulfamates |
DE69505251T2 (en) * | 1994-05-18 | 1999-03-04 | Zeneca Ltd | DISAZO CONNECTION |
US5998380A (en) | 1995-10-13 | 1999-12-07 | New England Medical Center Hospitals, Inc. | Treatment of migraine |
US5952187A (en) * | 1995-12-01 | 1999-09-14 | Oxis International, Inc. | Topiramate immunoassay |
US5753693A (en) | 1996-06-28 | 1998-05-19 | Ortho Pharmaceutical Corporation | Anticonvulsant derivatives useful in treating manic-depressive bipolar disorder |
NZ333586A (en) | 1996-06-28 | 2000-05-26 | Ortho Mcneil Pharm Inc | Anticonvulsant sulfamate derivatives, preferably topiramate, useful in treating obesity |
EP0826633B1 (en) | 1996-08-30 | 2002-03-13 | Showa Denko Kabushiki Kaisha | Particles, aqueous dispersion and film of titanium oxide, and preparation thereof |
US5760007A (en) | 1997-07-16 | 1998-06-02 | Ortho Pharmaceutical Corporation | Anticonvulsant derivatives useful in treating neuropathic pain |
US5935933A (en) | 1997-07-16 | 1999-08-10 | Ortho-Mcneil Pharmaceutical, Inc. | Anticonvulsant derivatives useful in treating neuropathic pain |
US6541520B1 (en) | 1998-08-05 | 2003-04-01 | Brookhaven Science Associates | Treatment of addiction and addiction-related behavior |
US6890951B2 (en) | 1998-08-05 | 2005-05-10 | Brookhaven Science Associates Llc | Treatment of addiction and addiction-related behavior |
AU1238500A (en) * | 1998-11-02 | 2000-05-22 | Alza Corporation | Controlled delivery of active agents |
US6342249B1 (en) * | 1998-12-23 | 2002-01-29 | Alza Corporation | Controlled release liquid active agent formulation dosage forms |
CA2359541C (en) | 1999-01-19 | 2005-06-21 | Ortho-Mcneil Pharmaceutical, Inc. | Anticonvulsant derivatives useful in treating cluster headaches |
NZ514812A (en) | 1999-04-08 | 2005-01-28 | Ortho Mcneil Pharm Inc | Anticonvulsant derivatives useful in lowering blood pressure |
US6488962B1 (en) * | 2000-06-20 | 2002-12-03 | Depomed, Inc. | Tablet shapes to enhance gastric retention of swellable controlled-release oral dosage forms |
US6191117B1 (en) | 2000-07-10 | 2001-02-20 | Walter E. Kozachuk | Methods of producing weight loss and treatment of obesity |
US6455666B1 (en) * | 2000-10-11 | 2002-09-24 | Daicel Chemical Industries, Ltd. | Polyesters and production process thereof |
US20030072802A1 (en) | 2001-10-11 | 2003-04-17 | R.T. Alamo Ventures, Inc. | Sustained release topiramate |
US6559293B1 (en) | 2002-02-15 | 2003-05-06 | Transform Pharmaceuticals, Inc. | Topiramate sodium trihydrate |
-
2002
- 2002-09-03 US US10/232,589 patent/US6559293B1/en not_active Expired - Lifetime
- 2002-11-18 US US10/295,995 patent/US6699840B2/en not_active Expired - Lifetime
-
2003
- 2003-02-14 CN CNA038085305A patent/CN1646538A/en active Pending
- 2003-02-14 BR BR0307919-8A patent/BR0307919A/en not_active Application Discontinuation
- 2003-02-14 WO PCT/US2003/004357 patent/WO2003070738A2/en not_active Application Discontinuation
- 2003-02-14 IL IL16354903A patent/IL163549A0/en unknown
- 2003-02-14 AU AU2003211021A patent/AU2003211021A1/en not_active Abandoned
- 2003-02-14 JP JP2003569645A patent/JP2005524645A/en active Pending
- 2003-02-14 MX MXPA04007968A patent/MXPA04007968A/en not_active Application Discontinuation
- 2003-02-14 CA CA002476422A patent/CA2476422A1/en not_active Abandoned
- 2003-02-14 EP EP03742731A patent/EP1485388A2/en not_active Withdrawn
- 2003-02-14 KR KR10-2004-7012709A patent/KR20050002826A/en not_active Application Discontinuation
- 2003-08-08 US US10/637,829 patent/US20040053853A1/en not_active Abandoned
- 2003-11-19 US US10/716,976 patent/US7351695B2/en not_active Expired - Lifetime
-
2004
- 2004-09-13 NO NO20043819A patent/NO20043819L/en not_active Application Discontinuation
- 2004-09-15 HR HR20040847A patent/HRP20040847A2/en not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000050020A2 (en) * | 1999-02-24 | 2000-08-31 | University Of Cincinnati | Use of sulfamate derivatives for treating impulse control disorders |
WO2000072841A1 (en) * | 1999-05-28 | 2000-12-07 | Jeffrey Berlant | Compounds and methods for the treatment of post traumatic stress disorder |
WO2003006467A1 (en) * | 2001-07-09 | 2003-01-23 | Ortho-Mcneil Pharmaceutical, Inc. | Novel anticonvulsant derivative salts |
Non-Patent Citations (1)
Title |
---|
ROSENFELD W E: "TOPIRAMATE: A REVIEW OF PRECLINICAL, PHARMACOKINETIC, AND CLINICAL DATA" CLINICAL THERAPEUTICS, EXCERPTA MEDICA, PRINCETON, NJ, US, vol. 19, no. 6, 1997, pages 1294-1308, XP000921219 ISSN: 0149-2918 * |
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US8362062B2 (en) | 2002-02-15 | 2013-01-29 | Mcneil-Ppc, Inc. | Pharmaceutical compositions with improved dissolution |
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US10633344B2 (en) | 2002-03-01 | 2020-04-28 | University Of South Florida | Multiple-component solid phases containing at least one active pharmaceutical ingredient |
US8183290B2 (en) | 2002-12-30 | 2012-05-22 | Mcneil-Ppc, Inc. | Pharmaceutically acceptable propylene glycol solvate of naproxen |
WO2004063210A1 (en) * | 2003-01-03 | 2004-07-29 | Ortho-Mcneil Pharmaceutical Inc. | Novel anticonvulsant derivative salts |
WO2005016306A3 (en) * | 2003-08-06 | 2005-08-25 | Alza Corp | Uniform delivery of topiramate over prolonged period of time with enhanced dispersion formulation |
WO2005016306A2 (en) * | 2003-08-06 | 2005-02-24 | Alza Corporation | Uniform delivery of topiramate over prolonged period of time with enhanced dispersion formulation |
WO2005020957A3 (en) * | 2003-08-22 | 2005-09-22 | Alza Corp | Stepwise delivery of topiramate over prolonged period of time |
WO2005020957A2 (en) * | 2003-08-22 | 2005-03-10 | Alza Corporation | Stepwise delivery of topiramate over prolonged period of time |
JP2008503533A (en) * | 2004-06-24 | 2008-02-07 | シュバルツ ファルマ アクチェンゲゼルシャフト | A new use of peptide compounds to treat essential tremor and other tremor syndromes. |
US9457008B2 (en) | 2012-03-23 | 2016-10-04 | Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China | Joint product comprising synephrine and topiramate |
US9421188B2 (en) | 2012-03-23 | 2016-08-23 | Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China | Combination product comprising phentermine and topiramate, and preparation method thereof |
US8889190B2 (en) | 2013-03-13 | 2014-11-18 | Upsher-Smith Laboratories, Inc. | Extended-release topiramate capsules |
US8652527B1 (en) | 2013-03-13 | 2014-02-18 | Upsher-Smith Laboratories, Inc | Extended-release topiramate capsules |
US10363224B2 (en) | 2013-03-13 | 2019-07-30 | Upsher-Smith Laboratories, Llc | Extended-release topiramate capsules |
US9101545B2 (en) | 2013-03-15 | 2015-08-11 | Upsher-Smith Laboratories, Inc. | Extended-release topiramate capsules |
US9555005B2 (en) | 2013-03-15 | 2017-01-31 | Upsher-Smith Laboratories, Inc. | Extended-release topiramate capsules |
US10172878B2 (en) | 2013-03-15 | 2019-01-08 | Upsher-Smith Laboratories, Llc | Extended-release topiramate capsules |
CN103304483A (en) * | 2013-05-23 | 2013-09-18 | 江汉大学 | N-3-arylamine-5-cyclopropane spirohydantoin and preparation method and application thereof |
US11633374B2 (en) | 2019-12-10 | 2023-04-25 | Tulex Pharmaceuticals Inc. | Compositions and methods for treating epilepsy, seizures and other conditions |
US11826343B2 (en) | 2019-12-10 | 2023-11-28 | Tulex Pharmaceuticals Inc. | Compositions and methods for treating epilepsy, seizures and other conditions |
US11911362B2 (en) | 2019-12-10 | 2024-02-27 | Tulex Pharmaceuticals Inc. | Compositions and methods for treating epilepsy, seizures and other conditions |
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US20050169982A1 (en) | 2005-08-04 |
JP2005524645A (en) | 2005-08-18 |
MXPA04007968A (en) | 2005-10-18 |
EP1485388A2 (en) | 2004-12-15 |
KR20050002826A (en) | 2005-01-10 |
AU2003211021A1 (en) | 2003-09-09 |
IL163549A0 (en) | 2005-12-18 |
CA2476422A1 (en) | 2003-08-28 |
US20040053853A1 (en) | 2004-03-18 |
HRP20040847A2 (en) | 2005-06-30 |
US7351695B2 (en) | 2008-04-01 |
BR0307919A (en) | 2004-12-21 |
US6699840B2 (en) | 2004-03-02 |
CN1646538A (en) | 2005-07-27 |
US6559293B1 (en) | 2003-05-06 |
WO2003070738A3 (en) | 2003-09-25 |
NO20043819L (en) | 2004-09-13 |
US20030166581A1 (en) | 2003-09-04 |
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