JPH0314813B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing a stable internal liquid preparation of dimethylpolysiloxane. More specifically, the present invention relates to a method for producing a stable dimethylpolysiloxane liquid preparation for internal use, which is characterized by adding a surfactant, a thickener, and an antioxidant to dimethylpolysiloxane. Dimethylpolysiloxane, which is the active ingredient of the internal solution in the present invention, has the formula: A polymer of organosilicon compounds represented by (n in the formula is 80 to 360) with a temperature of 100 to
It is a water-insoluble oily substance with a viscosity of 1000 centistorkes. This dimethylpolysiloxane has an outstanding antifungal or mucus removing effect,
It is a useful drug that is widely used in clinical practice. For example, it is extremely effective against abdominal bloating and flatulence, which frequently occur in gastrointestinal diseases and cause mental distress to patients.
It is used as an ameliorating agent for these symptoms.
In addition, in recent years, gastric X-ray fluoroscopy, gastroendoscopy, etc. have become important and widely used in the diagnosis of gastric diseases; however, if there is mucus in the stomach, the image becomes unclear, making it difficult to interpret the image. It interferes with internal vision,
In order to increase the reliability of these tests, it is important to remove the obstructive gastric mucus, which reduces the certainty of diagnosis. Since dimethylpolysiloxane exhibits an extremely excellent removal effect, it is frequently used as an indispensable pretreatment for these tests. Pharmaceuticals used clinically are required to be in various dosage forms such as tablets, powders, and liquids depending on their purpose, subject, and method of administration. When used as a therapeutic agent, it is necessary to have immediate effect and to reach the entire gastric region, and for this purpose, it is most preferable to use it in the form of a liquid preparation. Therefore, in this field, there has been a desire for the development of a dimethylpolysiloxane internal solution that is stable, easy to handle, and exhibits sufficient effects. Generally speaking, it is a well-known fact that when a water-insoluble or poorly water-soluble oily substance is dissolved, emulsified, or suspended to form a solution, it can be produced by using a surfactant, and this has been done for many substances including dimethylpolysiloxane. There is. however,
Liquid preparations made by emulsifying dimethylpolysiloxane with only a surfactant have poor emulsion heat resistance, and the emulsified state is unstable, and the emulsified state tends to deteriorate even when heated during sterilization. Furthermore, the particles of the oily component are large and emulsification is uneven, and the viscosity of the liquid preparation is low, making it impossible for dimethylpolysiloxane to be distributed evenly throughout the stomach, making it impossible to obtain effective effects. There was a problem. The inventors of the present invention have conducted intensive research to solve these problems, and have found that by adding a certain kind of thickener, the heat resistance of the emulsion is dramatically improved, and even when heated during sterilization. It was previously reported that the emulsification state hardly changes, the particles of the oily component are fine and the emulsification is uniform, and a liquid preparation with a suitable viscosity can be obtained. Page, 1979). However, even with the above-mentioned liquid preparations, there were still some problems to be solved, and the results were not necessarily satisfactory. In other words, if this liquid is stored for an extremely long time,
Or, if stored at relatively high temperatures, the decomposition of the surfactants, etc. contained may cause off-odors, and
There was a problem that the particle size of the oily component increased, and as a result, effective action could not be achieved depending on storage conditions and periods. Therefore, the present inventors conducted further research in order to produce an internal solution of dimethylpolysiloxane that is stable even during long-term storage and can always exert a constant effect. The present inventors have now completed the present invention by discovering that the addition of the compound dramatically increases the stability, produces almost no off-odor even during long-term storage, maintains a good emulsification state, and provides a constant level of action. The present invention is based on such knowledge. Antioxidants that can be used in the method of the present invention include dibutylhydroxytoluene, guaiac butter, dl-α-tocopherol, etc.; Dibutylhydroxytoluene shows the most excellent effect in terms of the degree of coloring and the like. The preferred range of use of these antioxidants is 0.001 to 2.0 parts by weight per 100 parts by weight of the surfactant. The surfactants used in the method of the present invention include polyoxyethylene sorbitan fatty acid esters, such as polyoxyethylene sorbitan monooleate (hereinafter referred to as polysorbate 80), sorbitan fatty acid esters, such as sorbitan monooleate, and glycerin fatty acid esters, such as glycerin. Examples include monooleate. These surfactants may be used alone or in combination, but the HLB value is preferably from 7 to 12, most preferably from 8.5 to 10.5. Specifically, a mixture of polysorbate 80 and sorbitan monooleate in a mixing ratio of 2:3 to 3:2 is most preferred. The preferred range of use of these surfactants is 20 to 80 parts by weight per 100 parts by weight of dimethylpolysiloxane, particularly 30 to 60 parts by weight, and the content in the solution is 0.6 to 1.2 percent (by weight). /capacity) is most preferable. The thickener used in the method of the present invention is sodium carboxymethylcellulose (hereinafter referred to as
CMC sodium), tragacanth powder, or a mixture of these with methyl cellulose, hydroxypropyl cellulose, etc. can be mentioned, but CMC sodium is most preferred. The amount of these thickeners used depends on the type of thickener used, viscosity, mixing ratio, target viscosity of the liquid, etc., but for example, when using CMC sodium, it is necessary to use 100 parts by weight of dimethylpolysiloxane. 20〜
A range of 100 parts by weight is preferred. In the production of internal liquid preparations by the method of the present invention,
Furthermore, sweeteners, fragrances, preservatives, solubilizing agents, suspending agents, etc. can be added as appropriate. These additives are determined according to the methods used in normal pharmaceutical manufacturing, including their types, amounts used, and
You can choose the addition method. To suitably carry out the method of the present invention, 20 to 100 parts by weight of
Add CMC sodium to an appropriate amount of water, and then add a mixture of 15 to 30 parts by weight of polysorbate 80 and 15 to 30 parts by weight of sorbitan monooleate to 100 parts by weight of dimethylpolysiloxane, surfactant 100.
Add 0.001 to 2.0 parts by weight of an ethanol solution of dibutylhydroxytoluene and dimethylpolysiloxane, stir well to emulsify, and sterilize by a conventional method to obtain a liquid preparation for internal use. The dimethylpolysiloxane liquid preparation for internal use obtained by the method of the present invention has a good emulsification state, the particles of the oily component are fine and uniform, and the liquid preparation has excellent dispersibility of the components, and has a viscosity suitable for distribution in the stomach. It is a liquid agent with Furthermore, the liquid preparation of the present invention is a liquid preparation with high heat resistance that hardly changes its emulsified state even when heated, and is an extremely stable liquid preparation for internal use that does not exhibit component separation or generation of off-odor even during long-term storage. Due to its good component dispersibility and suitable viscosity, the dimethylpolysiloxane internal liquid preparation obtained by the method of the present invention can be uniformly distributed throughout the stomach, exhibiting a remarkable de-boosting effect and removing mucus. It is an extremely useful internal solution that exhibits a constant effect even during long-term storage due to its excellent stability. Examples will be shown below to explain the manufacturing method of the present invention in more detail. Note that the following examples are illustrative of typical embodiments and are not intended to limit the method of the present invention. Example 1 (Formulation) Dimethylpolysiloxane 2.0g Polysorbate 80 0.3g Sorbitan monooleate 0.3g CMC sodium 0.8g Dibutylhydroxytoluene 10mg Ethanol 1.5g Purified water Appropriate total amount 100ml (Production method) 0.8g CMC sodium in an appropriate amount of purified water and then add 0.3 g of polysorbate 80 and 0.3
A mixed solution of 10 g of sorbitan monooleate,
A solution of mg of dibutylhydroxytoluene dissolved in 1.5 g of ethanol and 2.0 g of dimethylpolysiloxane were added in sequence, and purified water was added to bring the total volume to 100 ml. Stir well to emulsify and sterilize using the usual method. It is used as a liquid for internal use. Example 2 (Formulation) Dimethylpolysiloxane 2.0g Polysorbate 80 0.3g Sorbitan monooleate 0.3g CMC sodium 0.8g Guaiac butter 10mg Ethanol 1.5g Purified water Appropriate amount 100ml (Production method) According to the above recipe, in the same manner as Example 1 It is used as a liquid for internal use. Example 3 (Formulation) Dimethylpolysiloxane 2.0g Polysorbate 80 0.3g Sorbitan monooleate 0.3g CMC sodium 0.8g dl-α-tocopherol 10mg Ethanol 1.5g Purified water Appropriate total amount 100ml (Production method) Same as Example 1 according to the above recipe Prepare a liquid preparation for internal use by the following method. Example 4 (Formulation) Dimethylpolysiloxane 2.0g Polysorbate 80 0.3g Sorbitan monooleate 0.3g CMC sodium 0.8g Dibutylhydroxytoluene 1.0mg Ethanol 1.5g Purified water Appropriate amount total volume 100ml (Production method) Same as Example 1 according to the above recipe Depending on the method, it can be made into a liquid preparation for internal use. Example 5 (Formulation) Dimethylpolysiloxane 2.0g Polysorbate 80 0.3g Sorbitan monooleate 0.3g CMC sodium 0.8g Dibutylhydroxytoluene 0.1mg Ethanol 1.5g Purified water Appropriate amount total volume 100ml (Production method) Same as Example 1 according to the above recipe. Depending on the method, it can be made into a liquid preparation for internal use. Example 6 (Formulation) Dimethylpolysiloxane 2.0g Polysorbate 80 0.6g Sorbitan monooleate 0.6g CMC sodium 1.6g Dibutylhydroxytoluene 10mg Ethanol 1.5g Purified water Appropriate amount 100ml (Production method) Same method as Example 1 according to the above recipe It is made into a liquid preparation for internal use. Example 7 (Formulation) Dimethylpolysiloxane 2.0g Polysorbate 80 0.6g Sorbitan monooleate 0.6g CMC sodium 1.6g Dibutylhydroxytoluene 1.0mg Ethanol 1.5g Purified water Appropriate amount total volume 100ml (Production method) Same as Example 1 according to the above recipe. Depending on the method, it can be made into a liquid preparation for internal use. Example 8 (Formulation) Dimethylpolysiloxane 2.0g Polysorbate 80 0.6g Sorbitan monooleate 0.6g CMC sodium 1.6g Dibutylhydroxytoluene 0.1mg Ethanol 1.5g Purified water Appropriate amount total volume 100ml (Production method) Same as Example 1 according to the above recipe Depending on the method, it can be made into a liquid preparation for internal use. Reference example 1 Emulsion droplet average particle size and viscosity measurement Prescription A Dimethylpolysiloxane 2.0g Polysorbate 80 0.5g Sorbitan monooleate 0.5g CMC sodium 1.5g Dibutylhydroxytoluene 10mg Ethanol 1.5g Purified water Appropriate amount Total volume 100ml Prescription B Dimethylpolysiloxane 2.0g Polysorbate 80 0.5g Sorbitan monooleate 0.5g Ethanol 1.5g Purified water Appropriate amount Total volume 100ml According to the above recipe A, an emulsion with a total volume of about 600ml was prepared in the same manner as in Example 1. did. Furthermore, an emulsion with a total volume of about 600 ml was prepared in the same manner according to formulation B, which does not contain CMC sodium as a thickener and dibutylhydroxytoluene as an antioxidant.
This was used as a comparative example. Immediately after the emulsion was prepared, it was sampled, dropped onto a slide glass, and the particle size of the dimethylpolysiloxane droplets in a certain area was measured using an optical microscope (25x magnification) to determine the average particle size. Further, the viscosity of each emulsion was measured using a rotational viscometer in a constant temperature bath at 20±0.1°C. The results were as shown in Table 1 below.

[Table] As is clear from the above results, the emulsion of the present invention (test example) has a smaller average particle diameter and a better emulsification state than the emulsion in which dimethylpolysiloxane is emulsified with only a surfactant (comparative example). It is. Reference Example 2 Emulsion Heat Resistance Test Similarly to Reference Example 1, according to formulations A and B,
Emulsion of the present invention (test example) and comparative emulsion (comparative example)
The particle size of the dimethylpolysiloxane droplet fine particles of each emulsion was measured in the same manner as in Reference Example 1 after being left for 60 minutes at room temperature and 20 minutes in an autoclave at 121°C. The heat resistance of each emulsion was compared based on changes in the average particle size and particle distribution of dimethylpolysiloxane droplet fine particles of each emulsion under heating conditions. The results were as shown in Tables 2 and 3 below.

【table】

[Table] As is clear from the results, the emulsion of the present invention (test example) has a smaller average particle diameter and a smaller proportion of fine particles than the comparative emulsion (comparative example) in which dimethylpolysiloxane is emulsified with only a surfactant. It is an emulsion with an extremely good emulsification state, with a high emulsion, a narrow particle distribution, and a uniform particle size. Furthermore, the emulsion exhibits little increase in grain size due to heating and is excellent in terms of heat resistance.

Claims (1)

[Claims] 1. characterized by adding a surfactant, a thickener, and an antioxidant to dimethylpolysiloxane,
A method for producing a stable dimethylpolysiloxane liquid for internal use. 2. The manufacturing method according to claim 1, wherein the thickener is carboxymethyl cellulose sodium. 3. The manufacturing method according to claim 1, wherein the antioxidant is dibutylhydroxytoluene.