JPH058175B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing carboxymethylethylcellulose having low viscosity and high film properties (easily forming a tough film, and the formed film sufficiently withstanding mechanical stimulation; the same applies hereinafter). . More specifically, the present invention relates to a method for producing low-viscosity, high-film carboxymethylethylcellulose by reacting hypohalous acid with high-viscosity, high-film carboxymethylethylcellulose. Carboxymethylethyl cellulose (hereinafter referred to as
It is abbreviated as CMEC. ) is known to be effective as an enteric film-forming agent for drugs having dosage forms such as tablets and granules. Generally, the following properties 1 to 5 are required as an enteric film-forming agent for drugs. 1. In gastric juice, not subject to change and resisting for the required time. 2. Dissolve or disintegrate rapidly in intestinal fluids. 3. Easily forms a tough film, and the formed film has sufficient resistance to mechanical stimulation. 4. The film must not exhibit semipermeability. 5. Both the film and its decomposition products are non-toxic. Among these, from the point of view of film formation in 3.
The following 3,1 to 3,3 are required. 3.1 The film formed from the solution by dissolving it in a solvent must have water resistance, moisture resistance, and moisture resistance. 3,2 The film is stable against oxidation, heat, light, etc.
No change over time. 3.3 The coating operation is easy and a sufficiently good film can be obtained. CMEC is one of the excellent enteric film-forming agents in terms of these properties, but in general,
CMEC with high film properties has a high viscosity, which makes coating operations difficult, and when used as is, it is difficult to obtain a sufficiently good film. In order to overcome these difficulties, high viscosity
CMEC is depolymerized with hydrogen peroxide to create a low viscosity
Attempts have been made to produce CMEC. However, by depolymerizing CMEC, which has a high viscosity and high film property, with hydrogen peroxide, it becomes possible to obtain a low viscosity and high film property.
When trying to produce CMEC, it is not always easy to set the reaction conditions for the depolymerization reaction to obtain the desired high-film, low-viscosity product; Products with high film properties are not easily obtained, and products with low viscosity as desired cannot be easily obtained under reaction conditions that allow the desired products with high film properties to be obtained. In other words, when trying to depolymerize high-viscosity CMEC using hydrogen peroxide, hydrogen peroxide is relatively unstable in alkaline conditions, so it cannot be effectively depolymerized in a homogeneous solution reaction in an alkaline aqueous solution. In order to uniformly dissolve high viscosity CMEC and perform a homogeneous solution reaction, it is necessary to uniformly dissolve high viscosity CMEC in the aqueous solution using an organic solvent, lower alkanol having 1 to 4 carbon atoms, and then react. At the same time, it becomes necessary to recover or treat such an organic solvent after the reaction. In addition, when hydrogen peroxide is used in a suspension reaction in an aqueous solvent, it is possible to obtain the desired low viscosity and high film CMEC.
has not been obtained. That is, the desired low-viscosity product obtained by such a suspension reaction has poor film strength, and under the reaction conditions for obtaining the desired film strength, almost no reduction in viscosity due to the reaction is observed. In view of the above drawbacks, the present inventors have conducted extensive research and have found that when high viscosity CMEC is depolymerized with hypohalous acid, not only all of the above drawbacks are eliminated, but also the enteric coating agent required for the depolymerization of high viscosity CMEC with hypohalous acid is The present inventors have discovered that it is possible to produce a low-viscosity, high-film-forming CMEC that retains all of its properties without deterioration, and has completed the present invention. That is, the present invention is a method for producing low-viscosity, high-film carboxymethylethyl cellulose suitable for use as a drug film-forming agent, which is characterized by depolymerizing high-viscosity, high-film carboxymethylethyl cellulose with hypohalous acid. . In general, CMEC can be obtained by ethylating carboxymethyl cellulose (hereinafter abbreviated as CMC) using a method known per se. It is preferable to manufacture the film by the method because it can easily produce a film with the desired high film properties. Unlike hydrogen peroxide, hypohalous acid is relatively stable in alkaline conditions, so when performing the depolymerization reaction of high viscosity CMEC,
It is particularly preferable to uniformly dissolve this in an alkaline aqueous solution such as caustic alkali and allow the reaction to occur, since the reaction can be carried out uniformly in the aqueous solution. It is preferable that the high viscosity CMEC used for the depolymerization reaction has high film properties. This type of high film
Even if CMEC is used, when depolymerizing in an aqueous solvent using hydrogen peroxide, the desired low viscosity product (solvent:
80w/w% EtOH/H ₂ O, temperature: 25℃, concentration:
Under reaction conditions that yield a viscosity of about 10 cps at 5 w/w%, it is impossible to obtain the desired film strength. However, according to the present invention, by depolymerizing such highly filmy CMEC in an aqueous solution using hypohalous acid,
It is possible to produce the desired CMEC with low viscosity and high film properties. In order to cause the depolymerization reaction of the present invention to proceed in a homogeneous solution, it is sufficient to dissolve CMEC in an alkaline aqueous solution such as caustic alkali and cause the depolymerization reaction, and if necessary, heat the CMEC.
After dissolving, a reaction may be carried out using a hypohalite salt such as sodium hypochlorite or potassium hypobromite. The reaction usually proceeds by heat treatment, and the reaction temperature, reaction time, and amount of reagents used are
Although it depends on the viscosity of the CMEC used, for example, when depolymerizing with sodium hypochlorite in a caustic soda aqueous solution, CMEC with a viscosity of about 10 to 20 cps is used.
In order to obtain this, a reaction time of about 0.5 to 2 hours, a reaction temperature of about 50 to 80°C, and about 0.05 to 3.0 ml of sodium hypochlorite per glucose unit of CMEC are usually required. After the reaction is completed, the desired low-viscosity, high-film CMEC can be easily obtained by a method known per se, such as acidification and crystallization. The CMEC obtained in this way not only has a low viscosity and high film properties, but also has a low viscosity obtained by depolymerizing with hydrogen peroxide.
It has superior whiteness in the solid state compared to CMEC, and no decrease in transparency or degree of substitution was observed in the solution state, maintaining all the properties required as an enteric coating agent without loss. has been done. Examples are shown below. The viscosity measurement conditions described in the examples are: solvent (80W/W%EtOH/H ₂ O);
Viscometer (BM type viscometer), temperature (25°C), concentration (5W/W%). Or, the film strength is △
It increases in the order of ＜○＜◎. Example 1 Viscosity obtained by ethylating CMC with a degree of carboxymethyl group substitution of 0.36 using diethyl sulfuric acid according to the description in JP-A-55-90501.
CMEC of 186 cps (degree of carboxymethyl group substitution 0.36,
Degree of ethyl group substitution 2.01) 34g, water 500ml, 50% NaOH
Mix and dissolve 20g of aqueous solution, 12% NaOC aqueous solution
Add 37.5g and react at 80°C for 2 hours. After the reaction is completed, the reaction solution is added to a mixed solution of 18 g of concentrated sulfuric acid and 35 ml of water to perform acid precipitation, followed by removal, washing with water, and drying to obtain a highly film-like CMEC with a viscosity of 10.5 cps (degree of carboxymethyl group substitution 0.36). , degree of ethyl group substitution 2.02)
Gain 31g. Film strength: Good (◎) Example 2 CMEC with a viscosity of 840 cps (degree of carboxymethyl group substitution 0.41, ethyl group Degree of substitution 1.97) 6.8Kg, water
120, mix and dissolve 1.2Kg of 50% NaOH aqueous solution,
Add 7.5 kg of 12% NaOC aqueous solution and react at 80°C for 2 hours. After the reaction is complete, the reaction solution is diluted with concentrated sulfuric acid.
Acid precipitation with a mixture of 1.3Kg and 50% water is carried out, removed, washed with water, and dried to obtain 6.1Kg of CMEC (degree of carboxymethyl group substitution: 0.41, degree of ethyl group substitution: 1.97) with a viscosity of 11.5 cps. Film strength: Good (◎) Example 3 CMEC with a viscosity of 32 cps (degree of carboxymethyl group substitution 0.36, degree of ethyl group substitution 2.06) 34 g, water 500 ml, 50
Mix and dissolve 20g of %NaOH aqueous solution, 12%NaOC
Add 12.4 g of aqueous solution and react at 70-75°C for 2 hours. After the reaction is completed, the reaction solution is added to a mixture of 18 g of concentrated sulfuric acid and 35 ml of water to perform acid precipitation, followed by removal, washing with water, and drying to obtain a highly film-like CMEC with a viscosity of 11.5 cps (degree of carboxymethyl group substitution 0.36). , degree of ethyl group substitution
2.05) Get 30g. Film strength: Good (◎) Comparative Example 34 g of CMEC, the same as that used in Example 3, was mixed with 300 ml of water and treated by the following three methods. Heat and stir at 90°C for 2 hours. Add 10 g of 35% H ₂ O ₂ aqueous solution and react with stirring at 90° C. for 2 hours. Add 10 g of 35% H ₂ O ₂ aqueous solution and react with stirring at 70° C. for 2 hours. After the reaction, each product is obtained by removing, washing with water, and drying. The results are shown in Table 1.

[Table] As shown in the above results, when H ₂ O ₂ is added, when the reaction temperature is high (90°C), only the film strength deteriorates, but the viscosity does not decrease much, and when the reaction temperature is low (70°C), the film strength deteriorates. It can be seen that although the film strength is maintained, there is almost no decrease in viscosity. Experimental examples Various types obtained in Examples 1 to 3 and comparative examples
Using CMEC, we conducted a film strength test of the CMEC film and a disintegration test of tablets coated with CMEC.・Film strength test Dissolve the specified CMEC in ethanol to a concentration of 10 W/W%, pour 25 g of this solution into a vat (250 x 100 mm) pre-lined with a polyethylene sheet, and then dry. CMEC
A membrane (thickness: 0.1±0.002 mm) was obtained. The film strength of this CMEC film was measured according to the Japanese Industrial Standards ``Tensile test method for plastic films and sheets''.
(JIS K 7127). In addition, the test piece is a No. 1 type test piece (200 x 10 mm).
The test was conducted at test speed A (1±0.5 mm per minute). The results obtained are shown in Table 1.・Disintegration test of CMEC-coated tablets (CMEC coating on tablets) (1) Tablets used Contains 80 parts by weight of lactose, 19 parts by weight of corn starch, and 1 part by weight of magnesium stearate, diameter
A tablet of 9.05 mm and 4.9 mm in height (weight 253 mg) was used. (2) Coating liquid A solution having a composition of 80W/W% ethanol aqueous solution: CMEC: triacetin = 91.2:8.0:0.8 (weight ratio) was used as a coating liquid. (3) Coating machine (manufactured by Nakanishi Seisakusho) usage conditions Pan capacity: 0.75 liters. Pan rotation speed: 62-64rpm. Drying air temperature: 45-55℃. Spray gun: F type (nozzle diameter: 1.0φ). (4) Coating amount 3% (indicates that the weight of the tablet increases by 3% due to coating). (Disintegration test of CMEC-coated tablets) A disintegration test was conducted on the CMEC-coated tablets obtained by the above method according to "Disintegration test method (6) Enteric-coated preparations" of the Japanese Pharmacopoeia. The results are also shown in Table 1.

【table】

[Table] * Shows the time until no tablet residue is observed.
As is clear from the results in Table 1, it can be seen that by treating CMEC according to the method of the present invention, the viscosity can be lowered without impairing the film strength. Further, from the results shown in Table 1, it can be seen that CMEC obtained by the method of the present invention has the above-mentioned properties and is therefore highly useful as an enteric coating agent. That is, the tablets coated with CMEC obtained by processing according to the method of the present invention are different from those obtained by processing according to the conventional method.
It can also be seen that compared to tablets coated with CMEC, the tablets have an excellent effect in that they do not disintegrate in the acidic first liquid, but quickly disintegrate in the alkaline second liquid.

Claims (1)

[Claims] 1. Depolymerize carboxymethylethyl cellulose with high viscosity and high film properties (easily forms a tough film, and the formed film has sufficient resistance to mechanical stimulation. The same applies hereinafter) with hypohalous acid. A method for producing low-viscosity, highly film-forming carboxymethylethyl cellulose suitable for use as a drug film-forming agent.