Controlled- or delayed-release forms of topiramate

Details Controlled- or delayed-release forms of topiramate Controlled- or delayed-release forms of topiramate

2002-11-18

2004-03-02

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S454000, C514S459000, C514S517000, C424S457000, C424S468000, C424S499000

Reexamination Certificate

active

06699840

ABSTRACT:

1. FIELD OF INVENTION
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.
2. BACKGROUND OF THE INVENTION
2.1. TOPIRAMATE
Topiramate is a sulfamate-substituted monosaccharide, which is chemically named 2,3:4,5-Di-O-isopropylidene-&bgr;-D-fructopyranose sulfamate. The molecular formula of topiramate is C
12
H
21
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).
Topiramate is sold in the United States under the trade name TOPAMAX® (Ortho-McNeil Pharmaceutical, Inc., Raritan, N.J., 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. Pat. 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 antimanic, 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. However, the time it takes for topiramate to reach peak plasma levels (i.e., about two hours) may be too slow for its effective use in the treatment of some conditions, such as neuropathic pain. Moreover, 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.
2.2. EPILEPSY, SEIZURES, AND TREMORS
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 L R,
Clinician Reviews,
10(3): 79 (2000). A variety of seizure types can occur, from partial seizures to generalized seizures.
There are three classifications of partial seizures: simple, complex, and secondarily generalized. A patient with a simple partial seizure (also called Jacksonian 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. With 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. Finally, 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 I E.
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 nonconvulsive, 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. These brief seizures tend to occur in groups, and can occur 50 to 100 times in a day. See, Leppik I E.
Contemporary Diagnosis and Management of the Patient With Epilepsy.
4
th
Ed., Newtown, Pa.: Handbooks in Health Care Co (1999). Atypical absence seizures, begin and end less abruptly the typical absence seizures, but last longer and result in more pronounced changes in 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 I E.
Contemporary Diagnosis and Management of the Patient With Epilepsy.
4
th
Ed., Newtown, Pa.: Handbooks in Health Care Co (1999).
Generalized tonic-clonic seizures (also called “grand mal”) are the ones most commonly identified with epilepsy and are the most dramatic. They can occur at any age but are rare in very young infants. See Morton et al., “Diagnosis and treatment of epilepsy in children and adolescents”,
Drugs.
51:399-414 (1996). They start with a sudden-onset tonic phase, typically lasting less than a minute, and all of the skeletal muscles contract at once, causing the patient to fall stiffly. In addition, the patient's diaphragm and chest muscles will contract, forcing out air in an sigh or “epileptic cry.” During the clonic phase, the patient may clench the jaws, biting the inside of the cheek or side of the tongue with the molars, and consciousness may not return for 10 to 15 minutes. The patient will often be left feeling confusion, fatigue, and headache, which can last several hours to several days. See, Leppik I E.
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, Leppik I E.
Contenmporary Diagnosis and Management of the Patient With Epilepsy.
4
th
Ed., Newtown, Pa.: Handbooks in Health Care Co (1999).
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. 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. Often, patients suffering from Lennox-Gastaut syndrome will have varying degrees of psychomotor

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