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Drug delivery systems comprising weakly basic selective serotonin 5-HT3 blocking agent and organic acids

A 5-HT3, organic acid technology, applied in the direction of drug delivery, medical preparations containing active ingredients, drug combinations, etc., can solve the problem of unable to maintain plasma distribution dosing regimen and other problems

Inactive Publication Date: 2009-04-15
ADARE PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although moderately protracted drug release is possible in these published documents, these documents suffer from two disadvantages, the inability to maintain sufficient plasma distribution to achieve a once-daily dosing regimen and the preference for complete in situ formation of the salt form. situ formation) thus forming new chemical entities

Method used

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  • Drug delivery systems comprising weakly basic selective serotonin 5-HT3 blocking agent and organic acids
  • Drug delivery systems comprising weakly basic selective serotonin 5-HT3 blocking agent and organic acids
  • Drug delivery systems comprising weakly basic selective serotonin 5-HT3 blocking agent and organic acids

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Experimental program
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Effect test

Embodiment approach

[0079] According to one embodiment of the present invention, the method may include the following steps:

[0080] a. Provide organic acid containing core particles (e.g. organic acid crystals with desired size distribution or particles comprising inert particles (e.g. sugar spheres, cellulose spheres, silica spheres) layered with polymer organic acids in the binder solution);

[0081] b. Core particles containing organic acids are coated with an SR coating film consisting of a single water-insoluble polymer (e.g. EC-10 (ethylcellulose with an average viscosity of 10 cps)) or a combination of a water insoluble polymer with a water soluble polymer such as povidone or PEG 400 or an enteric polymer such as hydroxypropylmethylcellulose phthalate (eg HP-55);

[0082] c. Coat weakly basic drugs (such as ondansetron hydrochloride dihydrate) layer on the SR-coated core particles containing organic acids, and then further coat Pharmacoat 603 or Clear's protective seal coat to form IR...

Embodiment 1

[0108] A. SR-coated fumaric acid crystals

[0109] 40-80 mesh fumaric acid crystals (3750 g) were loaded into a fluid bed coater Glatt GPCG 5 equipped with a 9" bottom spray Wurster insert, column length 10" and tubing 16 mm . 250g of ethyl cellulose (Ethocel Premium, 10cps) and 166.7g of polyethylene glycol (PEG 400) (the ratio of the two is 60 / 40) were dissolved in 98 / 2 acetone / water (6528.3g), with the The resulting solution (6% solids concentration) was used to coat the above-mentioned acid crystals with a gain of up to 10% by weight. The treatment conditions are as follows: atomization air pressure is 2.0 bar; nozzle diameter is 1.00 mm; bottom distribution plate is B with No. 15 100 mesh screen; spray / shaking interval is 30s / 3s; product temperature is maintained at 35 ±1 °C; inlet air volume of 155-175 cubic feet per minute (cfm); and spray rate increased from about 8 g / min to 30 g / min.

[0110] In addition, fumaric acid crystals were coated with different ratios of e...

Embodiment 2

[0117] To evaluate the type of in vitro release profile required to achieve a once-daily plasma concentration profile, use Bozigian et al. in "Ondansetron Absorption in Adults: Effect of Dosage Form, Food, and Antacids", Journal of Pharmaceutical Sciences Vol. (1994) The reported pharmacokinetic parameters of ondansetron hydrochloride were used for modeling experiments. Using the software program WinNonlin TM Standard Version 2.1, assuming first-order elimination kinetics, will yield mean plasma concentrations in 24 healthy adult male volunteers who received a single 8 mg ondansetron hydrochloride IR tablet in the fasted state Substitute into the 1-compartment level model together with the lag time. get the following parameters:

[0118] Primary parameters: F=1.0 (assumed); V d =238.26;K a = 1.49 / hour; K e = 0.19 / hour (thus t 1 / 2 = 3.65 hours); T lag = 0.41 hours. Secondary parameters: AUC=0.17mg.hr / L; Cl=46.06L. / hour; T max = 1.98 hours; C m = 0.0248 mg / L. These p...

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Abstract

A pharmaceutical dosage form such as a capsule, a conventional or orally disintegrating tablet capable of delivering a weakly basic, nitrogen (N)-containing selective serotonin 5- HT3 blocking agent having a pKa in the range of from about 5 to 14 and a solubility of not more than about 200 [mu]g / mL at pH 6.8 into the body in a sustained-released fashion, suitable for a once-daily dosing regimen, comprises at least one organic acid, which solubilizes the weakly basic selective serotonin 5-HT3 blocking agent prior to releasing it into the hostile intestinal environment wherein the blocking agent is practically insoluble. The unit dosage form may be composed of a multitude of multicoated particulates (i.e., immediate-release beads, sustained-release beads and / or one or more timed, pulsatile- release bead populations) and is designed in such a way that the weakly basic blocking agent and the organic acid do not come into close contact during processing and / or storage thereby avoiding in-situ formation of acid addition compounds while ensuring that the acid is not depleted prior to completion of the drug release.

Description

[0001] This application claims priority to US Provisional Application 60 / 762,750, filed January 27, 2006, the contents of which are hereby incorporated by reference. technical field [0002] The present invention relates to a modified-release dosage form comprising one or more timed, pulsatile-release bead populations comprising a weak base Nitrogenous (N) selective serotonin 5-HT 3 blocking agent and one or more pharmaceutically acceptable organic acids, the weakly basic nitrogen-containing (N) selective serotonin 5-HT 3 Blockers have a pK of about 5 to 14 a and a solubility of not more than 200 μg / mL at pH 6.8. When testing dissolution by the United States Pharmacopeia (USP) dissolution methodology using a two-stage dissolution medium (first two hours in 0.1N HCl followed by testing in pH 6.8 buffer) , the dosage form of the present invention shows comparable release profiles of active substance and organic acid after a preset delay (lag-time). Another aspect of the pres...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/22
CPCA61K9/5073A61K9/2077A61K9/0056A61K9/5084A61K31/4178A61P1/08A61P1/12A61K9/50A61K9/20
Inventor 戈皮·M·文卡特施赖金旺尼霍尔·H·维亚斯
Owner ADARE PHARM INC
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