WO2017206096A1

WO2017206096A1 - Agomelatine soft capsule preparation

Info

Publication number: WO2017206096A1
Application number: PCT/CN2016/084251
Authority: WO
Inventors: 彭俊清; 顾颂恩; 王志云
Original assignee: 浙江华海药业股份有限公司
Priority date: 2016-06-01
Filing date: 2016-06-01
Publication date: 2017-12-07
Also published as: CN109069437A

Abstract

Provided is an agomelatine soft capsule preparation, wherein the agomelatine soft capsule preparation is composed of a liquid composition and a soft capsule shell; the liquid composition is sealed inside the soft capsule shell; the liquid composition contains agomelatine, polyethylene glycol, a surfactant and a humectant; and the agomelatine is completely dissolved in the polyethylene glycol. The agomelatine soft capsule preparation not only has a good stability, but also improves the drug dissolution rate and solves the problem of poor bioavailability. In addition, due to the addition of a surfactant, only a comparatively small amount of PEG is needed for the dissolution of agomelatine per dose unit, such that the loading capacity of an agomelatine soft capsule in the present invention is comparatively small, thus improving the compliance of elderly patients or patients suffering from dysphagia.

Description

Agomelatine soft capsule preparation

Technical field

The invention belongs to the technical field of medicine, and in particular relates to a gelatin preparation of agomelatine.

Background technique

Agomelatine tablets are developed by Servier, France. The specification is 25mg. The Chinese product name is Dimension New and the English name is English.

Agomelatine tablets are mainly used for the treatment of adult depression. They were approved by the European Union in February 2009 and are the world's first melatonin receptor agonist antidepressants. The active ingredient of agomelatine tablets is agomelatine, and its molecular structure is as follows:

Agomelatine is poorly soluble in a pH 2.0 hydrochloric acid solution similar to the human body environment, a pH 4.5 acetate buffer solution, a pH 6.8 phosphate buffer solution, and water, resulting in dissolution of the formulation. Low, it brings great technical difficulties to the development of the preparation, and low dissolution leads to difficulty in absorption or decreased bioavailability; in addition, agomelatine is currently only available in oral tablets, and its oral absolute bioavailability is less than 5 %, and for elderly patients or those with dysphagia, there is also a problem of poor compliance.

Summary of the invention

The object of the present invention is to provide a gelatin preparation of agomelatine, which can improve the dissolution rate of the drug, solve the problem of poor bioavailability, and improve the compliance of elderly patients or those with difficulty in swallowing.

The agomelatine soft capsule preparation is composed of a liquid composition and a soft capsule shell, the liquid The body composition is sealed in a soft capsule shell containing agomelatine, polyethylene glycol, a surfactant and a humectant, and agomelatine is completely dissolved in the polyethylene glycol .

According to the United States Pharmacopoeia (USP), Polyethylene Glycol (PEG) is a polymer obtained by addition polymerization of ethylene oxide with water. At room temperature, polyethylene glycol of grade 200-600 is a transparent, colorless or light yellow viscous liquid. Polyethylene glycol grades above 600 are gradually becoming semi-solid, and polyethylene glycol of grade 1000 or higher is usually It is solid.

Polyethylene glycol (PEG) is widely used in various pharmaceutical dosage forms in the field of formulation, such as injections, topical preparations, oral solutions, and the like. PEG is a chemically stable, hydrophilic substance that is substantially non-irritating to the skin and is not suitable for microbial survival and is not susceptible to rancidity. The liquid PEG can be filled in a soft capsule as a solvent.

The present inventors have found that polyethylene glycol can better dissolve agomelatine, thereby contributing to an increase in drug dissolution rate and bioavailability. Polyethylene glycol having an average molecular weight of from 200 to 650, such as one or more of the types PEG200, PEG300, PEG400, and PEG600, may be selected in the present invention.

The inventors have also discovered that the addition of a surfactant to a liquid composition can effectively improve the solubility of agomelatine in polyethylene glycol, and is advantageous for reducing the volume of agomelatine soft capsules, thereby improving the patient's Compliance.

The above surfactant is generally a nonionic surfactant, and may be, for example, one or more of caprylic acid diglyceride, polyoxyethylene 40 hydrogenated castor oil, and polyoxyethylene 35 castor oil. A preferred surfactant is glyceryl caprylate.

Among them, the surfactant accounts for 1-3% by weight of the polyethylene glycol, preferably 2-3%. The use of the above surfactant can significantly increase the solubility of agomelatine in polyethylene glycol, effectively reducing the amount of PEG used, thereby reducing the loading of agomelatine soft capsules, and ultimately reducing The volume of agomelatine soft capsules plays a positive role in improving patient compliance. In one embodiment, a surfactant is typically added in an amount of from 2 to 3% by weight based on the weight of the polyethylene glycol, and only 25 mg of the drug can be dissolved by simply containing a liquid composition of 100-110 mg of polyethylene glycol.

In order to completely dissolve agomelatine in polyethylene glycol, and at the same time make the volume of the prepared agomelatine soft capsule as small as possible, the weight ratio of polyethylene glycol to agomelatine can generally be 100 to 150:25, preferably 100 to 110:25.

The soft capsule shell of the present invention may be a conventional material in the art, for example, the soft capsule shell may contain gelatin, glycerin, water, etc., and may be added with an appropriate amount of a preservative, an opacifier or a pigment.

In order to ensure that the moisture in the soft capsule shell is not lost, thereby ensuring the flexibility of the capsule shell and avoiding the loss of the capsule shell, the liquid composition of the present invention also contains a moisturizing agent. Usually, the moisturizing agent can use one of glycerin, propylene glycol and the like. Or a variety. Generally, the humectant accounts for 5-15% by weight of PEG to achieve a better moisturizing effect.

The agomelatine soft capsule preparation of the present invention can be prepared by a conventional method in the art, for example, agmelatin, PEG, a surfactant, a moisturizer, etc., and the agmelatin is completely dissolved by stirring. In PEG, a clear liquid composition is obtained in which the content of each substance can be adjusted as described above. The agomelatine soft capsule preparation is prepared by dissolving the liquid composition in a soft capsule shell at a dose of 25 mg of agomelatine per dosage unit.

The implementation of the inventive solution has at least the following advantages:

The invention provides a new gelatin preparation of agomelatine, which not only has good stability, but also improves on the one hand compared with the conventional ordinary tablet. The drug dissolution rate solves the problem of poor bioavailability. On the other hand, due to the addition of the surfactant, only a small amount of PEG is needed to dissolve the unit dose of agomelatine, thereby making the Ago of the present invention The loading of Melatin soft capsules is significantly reduced, improving the compliance of elderly patients or those with dysphagia.

detailed description

In order to make the objects, technical solutions and advantages of the present invention more comprehensible, the present invention will be described in detail below with reference to the embodiments. It is apparent that the described embodiments are only a part of the embodiments of the invention, and not all of the embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative efforts are within the scope of the present invention.

Preparation of agomelatine soft capsules:

Example 1

Weigh 25g of agomelatine, 110g of PEG400, 3.3g of polyoxyethylene 40 hydrogenated nettle The oil and 10 g of glycerol were then mixed and stirred until a clear solution. The solution was encapsulated in a soft capsule shell at a dose of 25 mg of agomelatine per dosage unit to obtain a agomelatine soft capsule preparation.

Example 2

25 g of agomelatine, 100 g of PEG 400, 2 g of polyoxyethylene 35 castor oil and 15 g of propylene glycol were weighed, and then stirred and mixed to a clear solution. The solution was encapsulated in a soft capsule shell at a dose of 25 mg of agomelatine per dosage unit to obtain a agomelatine soft capsule preparation.

Example 3

25 g of agomelatine, 100 g of PEG400, 2.5 g of caprylic acid diglyceride and 5 g of glycerin were weighed and then mixed and stirred until a clear solution. The solution was encapsulated in a soft capsule shell at a dose of 25 mg of agomelatine per dosage unit to obtain a agomelatine soft capsule preparation.

Example 4

25 g of agomelatine, 100 g of PEG400, 2 g of caprylic acid diglyceride, 0.5 g of polyoxyethylene 35 castor oil and 5 g of glycerin were weighed, and then stirred and mixed to a clear solution. The solution was encapsulated in a soft capsule shell at a dose of 25 mg of agomelatine per dosage unit to obtain a agomelatine soft capsule preparation.

Example 5

25 g of agomelatine, 110 g of PEG400, 1 g of caprylic acid diglyceride, 0.5 g of polyoxyethylene 35 castor oil and 7 g of glycerin were weighed and then mixed and stirred until a clear solution. The solution was encapsulated in a soft capsule shell at a dose of 25 mg of agomelatine per dosage unit to obtain a agomelatine soft capsule preparation.

Example 6

25 g of agomelatine, 110 g of PEG 200, 2 g of caprylic acid diglyceride, 0.5 g of polyoxyethylene 35 castor oil and 10 g of glycerin were weighed, and then stirred and mixed to a clear solution. The solution was encapsulated in a soft capsule shell at a dose of 25 mg of agomelatine per dosage unit to obtain a agomelatine soft capsule preparation.

Example 7

25 g of agomelatine, 100 g of PEG300, 1 g of caprylic acid diglyceride, 1 g of polyoxyethylene 35 castor oil and 10 g of propylene glycol were weighed, and then stirred and mixed to a clear solution. Will dissolve The solution was filled in a soft capsule shell at a dose of 25 mg of agomelatine per dosage unit to obtain a agomelatine soft capsule preparation.

Example 8

25 g of agomelatine, 100 g of PEG 600, 1 g of caprylic acid diglyceride, 2 g of polyoxyethylene 35 castor oil and 10 g of propylene glycol were weighed, and then stirred and mixed to a clear solution. The solution was encapsulated in a soft capsule shell at a dose of 25 mg of agomelatine per dosage unit to obtain a agomelatine soft capsule preparation.

Comparative example 1

25 g of agomelatine and 180 g of PEG400 were weighed, and agomelatine was dissolved in PEG400 and stirred until a clear solution. The agomelatine soft capsule preparation was prepared by dissolving the solution in a soft capsule shell at a dose of 25 mg of agomelatine per dosage unit.

Comparative example 2

25 g of agomelatine and 180 g of PEG 200 were weighed, and agomelatine was dissolved in PEG 200 and stirred until a clear solution. The agomelatine soft capsule preparation was prepared by dissolving the solution in a soft capsule shell at a dose of 25 mg of agomelatine per dosage unit.

Comparative example 3

25 g of agomelatine and 180 g of PEG 600 were weighed, and agomelatine was dissolved in PEG 600 and stirred until a clear solution. The agomelatine soft capsule preparation was prepared by dissolving the solution in a soft capsule shell at a dose of 25 mg of agomelatine per dosage unit.

Comparative example 4

25 g of agomelatine, 180 g of PEG 300 and 10 g of glycerin were weighed and then mixed and stirred until a clear solution. The solution was encapsulated in a soft capsule shell at a dose of 25 mg of agomelatine per dosage unit to obtain a agomelatine soft capsule preparation.

Dissolution determination:

According to the second method of dissolution measurement method (paddle method) prescribed in the four general rules of the Chinese Pharmacopoeia 2015, the original tablets, Examples 1-8, Comparative Example 1 and Comparative Example 4 were respectively measured under the conditions of pH=2.0 and rotation speed of 75 rpm. Preparation of agomelatine soft capsule preparation The dissolution was sampled at 15 min, 30 min, 45 min and 60 min, and the samples were examined by HPLC. The results are shown in Table 1 below.

The results in Table 1 show that the agomelatine soft capsule preparation of the present invention has a significantly faster dissolution rate than the original tablet. Further, according to Table 1, in the examples of the present invention, the lowest use of 100 mg of PEG can dissolve 25 mg of agomelatine, while the dissolution of the same weight of agomelatine in Comparative Examples 1-4 requires 180 mg of PEG. Compared with Comparative Examples 1-4, the quality of the PEG required for the unit dose drug (25 mg) of the present invention was significantly smaller, indicating that the surfactant can significantly increase the solubility of agomelatine in polyethylene glycol. Effectively reduce the amount of PEG used, thereby reducing the loading of agomelatine soft capsules, and ultimately reducing the volume of agomelatine soft capsules, which plays a positive role in improving patient compliance.

Table 1

Stability study:

The agomelatine soft capsules prepared in Examples 1-8 were placed at a temperature of 60 ° C, relatively wet A forced acceleration test was conducted under a high temperature and high humidity environment of 75% to examine the stability. The total impurity change of the fresh sample and the sample after 10 days in a high temperature and high humidity environment was compared as shown in Table 2 below. The results showed that the fresh impurities and the total impurities of the samples after being placed in a high temperature and high humidity environment for 10 days were less than 0.05%, which was less than the instrument detectable range, indicating that the agomelatine soft capsule preparation prepared by the invention has good stability.

Table 2

The above is only the preferred embodiment of the present invention, and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included in the protection of the present invention. Within the scope of.

Claims

A agomelatine soft capsule preparation, characterized in that the agomelatine soft capsule preparation is composed of a liquid composition and a soft capsule shell, and the liquid composition is sealed in the soft capsule shell, The liquid composition contains agomelatine, polyethylene glycol, a surfactant, and a humectant, and the agomelatine is completely dissolved in the polyethylene glycol.
The agomelatine soft capsule preparation according to claim 1, wherein the polyethylene glycol has an average molecular weight of from 200 to 650.
The agomelatine soft capsule preparation according to claim 1 or 2, wherein the polyethylene glycol is of one or more of PEG200, PEG300, PEG400 and PEG600.
The agomelatine soft capsule preparation according to any one of claims 1 to 3, wherein the surfactant is a nonionic surfactant, preferably comprising caprylic acid diglyceride, polyoxyethylene One or more of 40 hydrogenated castor oil and polyoxyethylene 35 castor oil.
The agomelatine soft capsule preparation according to any one of claims 1 to 4, wherein the surfactant accounts for 1-3% by weight of the polyethylene glycol.
The agomelatine soft capsule preparation according to claim 5, wherein the surfactant accounts for 2-3% by weight of the polyethylene glycol.
The agomelatine soft capsule preparation according to any one of claims 1 to 6, wherein the weight ratio of the polyethylene glycol to agomelatine is from 100 to 150:25.
The agomelatine soft capsule preparation according to claim 7, wherein the weight ratio of the polyethylene glycol to agomelatine is from 100 to 110:25.
The agomelatine soft capsule preparation according to any one of claims 1 to 8, wherein the humectant is glycerin and/or propylene glycol.
The agomelatine soft capsule preparation according to any one of claims 1 to 9, wherein the humectant accounts for 5 to 15% by weight of the polyethylene glycol.