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Dosage regimen for COMT inhibitors

A technology for dosing and administration, applied in pharmaceutical formulations, pill delivery, drug combinations, etc., to solve problems such as lack of drug efficacy and doubts about the clinical efficacy of entacapone

Active Publication Date: 2010-01-20
BIAL PORTELA & CA SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thus, the clinical efficacy of entacapone is questionable - indeed, recent studies (Parashos, S.A. et al., Clin. Neuropharmacol., 27(3): 119-123, 2004) have shown of patients discontinued entacapone treatment mainly due to lack of efficacy
[0005] In addition, the relatively short in vivo half-lives of known COMT inhibitors often require a continuous treatment regimen, including multiple daily doses, which is prohibitive for many patients

Method used

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  • Dosage regimen for COMT inhibitors
  • Dosage regimen for COMT inhibitors
  • Dosage regimen for COMT inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0103] The preparation of embodiment 1-compound A

[0104] (5-[3-(2,5-dichloro-4,6-dimethyl-1-oxo-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl] -3-nitrobenzene-1,2-diol)

[0105] a) Add one portion of 1,1-carbonyldiimidazole (0.24g, 1.48mmol) to 3,4-dibenzyloxy-5-nitrobenzoic acid (0.50g, 1.318mmol) at room temperature in a stirred solution of methylformamide (5 mL). After stirring for ninety minutes, a portion of 2,5-dichloro-N'-hydroxy-4,6-dimethylnicotinamide (0.40 g, 1.71 mmol) was added. The resulting mixture was stirred at 135°C for 5 hours and then left overnight at room temperature. The reaction mixture was poured on ice-2N HCl (100 mL), then the resulting precipitate was filtered off, washed with water and dried in air. Recrystallization in isopropanol gave a pale yellow solid (0.55 g, 72%).

[0106] b) One portion of urea-hydroperoxide addition complex (0.41 g, 4.36 mmol) was added to a stirred solution of the solid obtained above (0.50 g, 0.866 mmol) in dichloromethane ...

Embodiment 2

[0108] Embodiment 2-pharmaceutical dosage form

[0109] Suitable exemplary pharmaceutical dosage forms are prepared according to the following formulations:

[0110] capsule:

[0111] Compound A 15.0%

[0112] Lactose monohydrate 43.0%

[0113] Microcrystalline Cellulose 30.0%

[0114] Polyvinylpyrrolidone 4.0%

[0115] Croscarmellose Sodium 5.0%

[0116] Talc 2.0%

[0117] Magnesium Stearate 1.0%

[0118] capsule:

[0119] Compound A 15.0%

[0120] Microcrystalline Cellulose 72.5%

[0121] Ethylcellulose 5.0%

[0122] Sodium starch glycolate 6.0%

[0123] Colloidal silicon dioxide 0.5%

[0124] Magnesium Stearate 1.0%

[0125] pill:

[0126] Compound A 20.0%

[0127] Microcrystalline Cellulose 25.0%

[0128] Calcium Phosphate, Binary Dihydrate 40.0%

[0129] Polyvinylpyrrolidone 6.0%

[0130] Croscarmellose Sodium 6.0%

[0131] Talc 2.0%

[0132] Magnesium Stearate 1.0%

Embodiment 3

[0133] Example 3 - Dosing regimen

[0134] Patients suffering from dyskinesias and treated with levodopa are treated with tablets containing 50 mg of a compound of general formula I. The results demonstrated a significant improvement in the clinical picture.

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Abstract

The invention relates to the use of an oxodiazolyl compound for the preparation of a medicament for the prevention or treatment of central and peripheral nervous system associated disorders, wherein said medicament is administered according to a dosing regimen having a dosing periodicity ranging from about twice a day to about once every other day.

Description

technical field [0001] The present invention relates to novel substituted nitrocatechols and their use in the treatment of central and peripheral nervous system disorders according to specific dosage regimens. Background technique [0002] The rationale for using COMT inhibitors as adjuncts to L-DOPA / AADC therapy is based on their ability to reduce the oxomethylation of metabolized L-DOPA to 3-O-methyl-levodopa (3-OMD). The duration of clinical improvement induced by levodopa is manifested simply by the shorter in vivo half-life of L-DOPA, in contrast to the longer half-life of 3-OMD. In addition, 3-OMD competes with L-DOPA for transport across the blood-brain barrier (BBB), which means that only very small amounts of orally administered doses of L-DOPA actually reach the site of action, the brain. Typically, within only a few years of initiating L-DOPA treatment at usual doses, the induced clinical improvement in L-DOPA declines at the end of each cycle of dosing, leading ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4439A61P25/16
CPCA61K45/06C07D413/04A61K31/4439A61K31/198A61P25/00A61P25/02A61P25/14A61P25/16A61P25/18A61P43/00A61K31/4427A61K9/20
Inventor D·A·利尔蒙斯L·E·基什P·N·L·帕尔马H·D·S·费雷拉P·M·V·A·S·D·西尔瓦
Owner BIAL PORTELA & CA SA