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Pharmaceutical formulations comprising nitrocatechol derivatives and methods of making the same

The technology of a pharmaceutical preparation and nitrobenzene is applied in the field of pharmaceutical preparations including nitrocatechol derivatives and their preparation, and can solve the problems of sensitivity, low bulk density, lack of stability and the like

Active Publication Date: 2012-05-02
BIAL PORTELA & CA SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, it has also been found that compounds of formula I are sensitive to certain excipients which may cause decomposition of compounds of formula I and / or destabilize compositions and formulations comprising these compounds
Compounds of formula I may also exhibit low bulk density and / or poor flow properties, which may increase the difficulty of formulating and / or producing stable dosage forms comprising the active compound

Method used

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  • Pharmaceutical formulations comprising nitrocatechol derivatives and methods of making the same
  • Pharmaceutical formulations comprising nitrocatechol derivatives and methods of making the same
  • Pharmaceutical formulations comprising nitrocatechol derivatives and methods of making the same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0100] Four low-dose capsules were prepared in pilot batches by first mixing API, starch, and lactose in the amounts shown in Table 1 below (Batches A-D). The API used in these examples is 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl )-4,6-lutidine 1-oxide. Purified water was then added to each mixture, and the mixture was granulated by mixing.

[0101] The granules were then dried using a fluidized bed dryer until the granules had a loss on drying value of less than 6%. The dried granules were sieved and mixed with the remaining ingredients described in Table 1. This formulation was used to fill gelatin capsules using an InCAP HS capsule filling machine.

[0102] The bulk and tap densities of the granules and final compositions were evaluated using the methods described above. Mobility / flow rate was also evaluated by testing the flow rate through the orifice described in USP 31, Volume 1, Test , USP Regulations, 2008. Flowability can be measured a...

Embodiment 2

[0113]Four high-dose capsules were prepared on a laboratory scale by first mixing the API, starch, and lactose in the amounts shown in Table 1 below in a V-blender (batches E-H). The API used in these examples is 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl )-4,6-lutidine 1-oxide. Purified water was added to each mixture and mixed by hand. The wet mass thus obtained is then granulated in a vibrating granulator laboratory.

[0114] The granules were then dried in a box dryer until the loss on drying of the granules was below 6%. The dried granules are sieved. The granules were then mixed with the remaining ingredients described in Table 1 in a V-blender. This formulation was used to fill gelatin capsules using an InCAP HS capsule filling machine.

[0115] Each of batches E-H were evaluated as described in Example 1 above and the results are presented in Table 3 below. All batches exhibited good granule and capsule properties.

[0116] Table 1: B...

Embodiment 3

[0124] All batches of Examples 1 and 2 were subjected to accelerated studies to determine their stability. Each of the eight batches was stored for 15 days at room temperature and under stress conditions (70°C, no relative humidity control). All batches were tested for impurity content at both storage conditions and the results are presented in Tables 4 and 5. Impurity values ​​were obtained using the HPLC method with a limit of quantification of less than 0.05%.

[0125] The API used in these batches contained approximately 3% impurities (including Impurity 8) prior to formulation.

[0126] Table 4: Stability test results for batches A-D

[0127]

[0128] RT - room temperature

[0129] SC-stress condition

[0130] NP - not present (below detection limit)

[0131] Table 5: Stability test results for batches E-H

[0132]

[0133] RT - room temperature

[0134] SC-stress condition

[0135] NP - not present (below detection limit)

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Abstract

The present disclosure relates to compositions and pharmaceutical formulations comprising at least one active pharmaceutical ingredient chosen from nitrocatechol derivatives of formula I as defined herein and salts, esters, hydrates, solvates and other derivatives thereof and methods of making the same.

Description

technical field [0001] The present invention relates to compositions and pharmaceutical preparations comprising at least one active pharmaceutical ingredient selected from nitrocatechol derivatives and salts thereof. Background technique [0002] Levodopa (L-DOPA) has been used in clinical practice for decades for the symptomatic treatment of a variety of conditions, including Parkinson's disease. L-DOPA is able to cross the blood-brain barrier and then be converted to dopamine and increase dopamine levels. However, the conversion of L-DOPA to dopamine can also occur in peripheral tissues, potentially causing side effects when L-DOPA is administered. Accordingly, co-administration of peripheral amino acid decarboxylase (AADC) inhibitors such as carbidopa or benserazide, which prevent conversion to dopamine in peripheral tissues, has become standard clinical practice. [0003] This has led to an interest in developing inhibitors of the enzyme catechol-O-methyltransferase (C...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/16A61K31/00A61K9/48
CPCA61K9/4858A61K9/1623A61K31/4439A61P1/00A61P25/00A61P25/14A61P25/16A61P7/10A61P9/12A61K9/20A61K9/48A61K31/4245A61K31/4415A61K47/36A61K47/38
Inventor T·C·D·瓦斯康塞洛斯R·J·D·S·利马P·M·D·C·巴罗卡斯L·S·D·C·佩雷拉R·C·D·C·科斯塔
Owner BIAL PORTELA & CA SA
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