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Delayed release pharmaceutical composition containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol

a technology of dimethylamino-1-ethyl-2-methylpropylphenol and pharmaceutical composition, which is applied in the direction of drug compositions, biocide, microcapsules, etc., can solve the problems of undesirable concentration variation and errors in administration, and achieve good therapeutic efficacy and high repeatability of release properties

Inactive Publication Date: 2005-03-17
GRUNENTHAL GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

Accordingly, it is an object of the present invention to provide a pharmaceutical formulation which achieves slow release of 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol.
It is particularly surprising that the formulation according to the invention not only ensures long-lasting therapeutic efficacy over a relatively long period (at least 12 hours) due to the slow release of the active ingredient, but at the same time allows the active ingredient to start flowing rapidly in the plasma when the pharmaceutical composition is first administered, leading to a rapid onset of pain relief in the patient. Therefore, the pain suffered by a patient can rapidly be alleviated when the formulation according to the invention is administered without the analgesic action quickly fading again. The formulation according to the invention therefore combines properties of a formulation with immediate release of active ingredient—rapid pain relief due to adequately high concentration of active ingredient just after administration of the pharmaceutical composition—with properties of a formulation having slow release—long-lasting analgesic action due to maintenance of an adequately high level of active ingredient over a prolonged time. By taking the analgesic in the formulation according to the invention, the patient can effectively combat his pain acutely and, at the same time, treat it effectively over a prolonged period without further measures and merely by regular administration at 12 (or 24) hourly intervals.
The production of pharmaceutical formulations according to the invention is characterized by high repeatability of the release properties of the resulting compositions containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof. The release profile of pharmaceutical compositions according to the invention has proven to be stable for a storage time of at least one year under conventional storage conditions according to ICH Q1AR Stability Testing Guidelines.

Problems solved by technology

However, the need for frequent dosing easily leads to errors in administration and to undesirable variations in concentration in the plasma which are detrimental to patient compliance and the therapeutic benefit, particularly when treating chronically painful conditions.

Method used

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  • Delayed release pharmaceutical composition containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol

Examples

Experimental program
Comparison scheme
Effect test

example 1

A batch of 1,000 matrix tablets was produced as described below having with the following composition per tablet:

(−)-(1R,2R)3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol100 mghydrochlorideHydroxypropylmethyl cellulose (Metolose 90 80 mgSH 100,000 from Shinetsu,100,000 mPa · sMicrocrystalline cellulose (Avicel PH 102 from FMC)123 mgHighly dispersed silicon dioxide 4 mgMagnesium stearate 3 mgTotal amount310 mg

All components were weighed in and screened on a Quadro Comil U10 screening machine using a screen size of 0.813 mm, mixed in a container mixer (Bohle LM 40) for 15 minutes±15 seconds at a speed of 20±1 rpm and pressed on a Korsch EK0 eccentric press to tablets curved in the manner of dragees with a diameter of 10 mm, a radius of curvature of 8 mm and an average tablet weight of 310 mg. The in vitro release was determined by the Ph. Eur. Paddle Method at 75 rpm in 900 ml pH 6.8 buffer according to Ph. Eur. at 37° C. and with detection using a UV spectrometer, and is repro...

example 2

Using a process similar to that described in Example 1, 3,000 matrix tablets were produced having the following composition per tablet:

(−)-(1R,2R)3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol200 mghydrochlorideHydroxypropylmethyl cellulose (Metolose 90 SH 100,000 80 mgfrom Shinetsu, 100,000 mPa · sMicrocrystalline cellulose (Avicel PH 102 from FMC) 23 mgHighly dispersed silicon dioxide 4 mgMagnesium stearate 3 mgTotal amount310 mg

The in vitro release was determined as in Example 1.

Total amount ofactive ingredientTime (min)released [%] 00 3019 6030120461805824068360844809372099

example 3

Using a process similar to that described in Example 1, a batch of 3,000 matrix tablets were produced having the following composition per tablet:

(−)-(1R,2R)3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol100 mghydrochlorideHydroxypropylmethyl cellulose (Metolose 90 SH 100,000 from 40 mgShinetsu, 100,000 mPa · sMicrocrystalline cellulose (Avicel PH 102 from FMC)163 mgHighly dispersed silicon dioxide 4 mgMagnesium stearate 3 mgTotal amount310 mg

The in vitro release was determined as in Example 1. In addition, the release was determined under otherwise identical conditions at stirring speeds of 50 and 100 rpm.

Total amount ofTotal amount ofTotal amount ofactive ingredientactive ingredientactive ingredientTimereleased [%]released [%]released [%](min)at 50 rpmat 75 rpmat 100 rpm 0000 30202021 60353335120545153180676366240767376360898789480979597600100100100

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Abstract

A pharmaceutical formulation for delayed release of the active ingredient 3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol or a pharmaceutically acceptable salt thereof in a matrix containing between 1 and 80 wt. % of at least one pharmaceutically acceptable hydrophilic or hydrophobic polymer as a matrix forming agent and exhibiting in vivo the following release rate: 3 to 35% by weight (based on 100% by weight active ingredient) 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 0.5 hours; 5 to 50% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 1 hour; 10 to 75% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 2 hours; 15 to 82% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 3 hours; 30 to 97% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 6 hours; more than 50% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 12 hours; more than 70% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 18 hours, and more than 80% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 24 hours.

Description

BACKGROUND OF THE INVENTION The present invention relates to a slow-release pharmaceutical formulation, containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof in a matrix. 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol is known from European patent no. EP 693,475 as an analgesic pharmaceutical composition and can be administered orally. Conventional formulations for oral administration of 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol lead to rapid release of the active ingredient in the gastrointestinal tract, so its analgesic action begins rapidly. At the same time, a rapid reduction in the action is observed. Therefore, the treatment of pronounced chronic pain with 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol formerly required administration of the pharmaceutical composition at relatively short intervals, for example four to eight times daily, to ensure an adequately high concentration of active ingredient in the pa...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K47/30A61K9/20A61K9/22A61K9/50A61K31/135A61K31/136A61K31/137A61K47/38A61P25/04
CPCA61K9/2054A61K9/5047A61K31/137A61K31/136A61K31/135A61P25/00A61P25/04A61P29/00A61K9/20A61K9/0053
Inventor BARTHOLOMAEUS, JOHANNESZIEGLER, IRIS
Owner GRUNENTHAL GMBH
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