JPS6023125B2 - Method for modifying cellulose ether film - Google Patents

Description

[Detailed description of the invention] The present invention relates to a method for modifying a cellulose ether film.

More specifically, the present invention relates to a method for modifying a cellulose ether film whose main purpose is to plasticize the film and improve its green permeability. In recent years, cellulose ethers have been widely used as various coating agents for various purposes. Carboxyalkylcellulose derivatives substituted with ether groups (hereinafter referred to as carboxyalkylcellulose) are newly proposed as enteric coating agents that have excellent chemical stability and coating suitability unique to cellulose ethers. .

The present carboxyalkyl cellulose derivative generally meets the following conditions as an enteric coating agent:
In other words, it does not dissolve in the stomach but quickly dissolves in the sun, and it is also non-toxic and stable, and does not deteriorate even when coated with drugs, etc. For example, it is not only stable against enzymes, but also has a low It has excellent physical properties not found in conventional cellulose ester type enteric coating agents, such as being soluble in toxic organic solvents such as ethyl alcohol. Although the present carboxyalkyl cellulose derivative has such excellent physical properties, it was found that the uniformity of the film obtained by coating solid pharmaceuticals such as tablets is significantly affected by the coating conditions, particularly the coating solvent, and the present invention was developed. They previously proposed a method using a single or mixed solvent containing a lower alkanol having 1 to 3 carbon atoms as the coating solvent as a method for obtaining a uniform and highly dense coating film (Hakama et al. Gansho 55-55429
).

That is, when coating solid pharmaceuticals such as tablets with the carboxyalkyl cellulose derivatives using conventionally known solvents, cracks may occur on the coating surface of the coated tablets or the coating film may be insufficiently uniform. Despite the stability of the membrane itself, there were cases in which the medicinal efficacy decreased considerably during storage or in the first pharmacopoeial liquid; however, by selecting the coating solvent mentioned above, such drawbacks can be greatly improved. It is something.

Although the basic problem of obtaining a uniform and highly dense coating film is solved by this method, the present inventors completed the present invention as a result of intensive studies to further ensure the solution of the problem. I ended up doing it. In other words, the present carboxyalkyl cellulose derivative has a relatively high moisture permeability characteristic of cellulose derivatives, and the currently widely used cellulose ester type enteric coating agent has internal plasticizing properties such as cellulose acetate phthalate. In contrast, the carboxyalkylcellulose in this case is designed to have a chemical structure that does not contain phthalate groups, which have a plasticizing effect, in consideration of safety issues, so the internal plasticizing effect is due to phthalate groups. This is expected to be lower than that of cellulose esters, and the flexibility of the obtained film may be poor, leading to problems in impact strength.

Therefore, among the physical properties of the present carboxyalkyl cellulose conductive film, it is of great significance to improve the above two essential problems, namely, bubble permeability and plasticity.

As a method for improving the green transparency of cellulose ethers, for example, cellulose ethers described in Japanese Patent Publication No. 44-26679, which contain shellac and organic poppy-element compounds that are liquid at room temperature as main components, are dissolved in an organic solvent. A method of improving the moisture permeability of a film using shellac as a main additive is known, such as a method of forming a film from a solution.

Although the shellac film has abrasion resistance and high moisture permeability, shellac is thermosetting and polycondensation occurs within and between molecules when heated, reducing solubility and storage. It is widely known that it is important to apply heat inside the container, and that care must be taken when handling it, especially in the summer.

Therefore, when shellac is added for the purpose of improving transparency of coated tablets, etc., it must be said that serious problems remain, such as the presence of factors that tend to impair the disintegration properties of coated tablets. Another problem is that the shellac film has poor plasticity and low mechanical strength.

The present inventors, taking into consideration the problems in the physical properties of the cellulose ether film and the problems in its modification technology, have conducted intensive studies on methods to improve the physical properties as described above. It was found that the purpose could be sufficiently achieved by adding it, and the present invention was completed.

That is, the gist of the present invention relates to a method for improving the moisture permeability and plasticity of a cellulose ether film based on the following two points.

'11 At least a portion of the three hydroxyl groups per anhydroglucose unit of cellulose is -○-CNH2nCOOH(
n is an integer of 1 to 5) and a carboxyalkyl cellulose derivative substituted with an ether group. quality method.

■ [In Section 11, coating or casting a solution obtained by dissolving the carboxyalkyl cellulose derivative and glycerin fatty acid ester in a single or mixed solvent containing a lower alkanol having 1 to 3 carbon atoms as at least one component is described. Characteristic method for modifying cellulose ether film.

To explain the method of the present invention in more detail, the cellulose ether referred to in the present invention means that at least a portion of the three hydroxyl groups per anhydroglucose unit of cellulose is -○-CnH2
A carboxyalkyl cellulose conductor substituted with nCOOH (n is an integer of 1 to 5) and an ether group, such as carboxymethylethylcellulose, carboxymethylethylcellulose, carboxybutylethylcellulose, carboxypropylmethylcellulose, etc. Generally, the degree of substitution of carboxyalkyl groups per anhydroglucose unit of cellulose is about 0.3 to 1.2,
It is preferable that the degree of substitution of other ether groups is about 1 to 2.4, and it is enteric-coated.

Next, regarding additives, which are the first point of the present invention, it is important to select glycerin fatty acid esters as mentioned above, and there are no particular regulations for glycerin fatty acid esters, such as monoglycerides such as monobutyrin, diacetin, etc. Any compound with relatively low volatility that is compatible with the present carboxyalkyl cellulose conductor can be selected, such as diglycerides such as, and triglycerides such as triacetin and tributyrin, but preferably has a molecular weight of about several hundred. Liquid or waxy solid substances are chosen, especially triglycerides. By adding such substances, the glass transition point, elastic modulus, etc. of the carboxyalkyl cellulose derivative film are lowered, and as a result, the flexibility of the film is increased, and for example, the impact resistance strength required for the coating layer of solid pharmaceuticals is increased. becomes possible.
The amount added varies depending on the type of glycerin fatty acid esters added and the cellulose derivatives serving as the base, but in order to achieve the second objective of the present invention, which is to improve the moisture permeation resistance of the film. It is preferable to add 1 to 3 t% of the carboxyalkylcellulose derivative based on the amount of the carboxyalkylcellulose derivative.If the amount is more than this, the resulting film will form a viscous film, and the carboxyalkylcellulose derivative has a film-forming ability. As a result, the film becomes porous, making it difficult to achieve the object of the present invention. The glycerin fatty acid esters used in the present invention are listed as food additives (chemically synthesized products) in the Japan Food Additives Official Standards. By the way, cellulose esters such as cellulose acetate phthalate and/or (methyl methacrylate) copolymers are widely used as additives for modifying enteric coatings made of polyacrylic acid esters. Known phthalate esters such as dimethyl phthalate, diethyl phthalate, and dibutyl phthalate are also effective to some extent in modifying the enteric coating made of cellulose ethers used in the present invention, and their use is not prohibited. Considering the influence of free phthalic acid from such phthalate esters on safety, etc., it is not necessarily recommended.

Next is a method of mixing the glycerin fatty acid esters with the carboxyalkyl cellulose derivative of the present invention. In order to maximize the effect of the glycerin fatty acid esters, it is necessary to mix the carboxyalkyl cellulose derivative as a base material and the modifying material. It is advantageous to coat or cast a solution obtained by dissolving both the glycerin fatty acid ester and the fatty acid ester in a solvent. It is preferable to use it as a solution obtained by dissolving it in one or a mixed solvent. That is, the glycerol fatty acid esters and the present carpoxyalkyl cellulose derivatives have a particularly high affinity for the lower alkanols, and not only have excellent solubility in single or mixed solvents containing the lower alkanols, but also have excellent solubility in single or mixed solvents containing the lower alkanols. The solution viscosity is also relatively low, allowing the molecular chains of the carboxyalkyl cellulose derivative in the solution to form a more dense conformation, and the low viscosity makes the solution highly suitable for coating. Therefore, by coating or casting such a solution, the film obtained is more dense and has good uniformity.
The effect of the added glycerin fatty acid esters can be maximized, and the object of the present invention can be fully achieved.

The above is the second main point of the present invention. In this case, the content of the Alu/L component is 40 to 10% by skin t%, preferably 60 to 10%.
It is desirable that it be 10 skin t%. On the other hand, in the present invention, solvents that are compatible with the alkanol in the above range include water, ketones such as acetone, aromatic hydrocarbons such as toluene and benzene, dioxane, It can be selected from one or a combination of two or more of ethers such as methyl cellosolve, halogenated hydrocarbons such as methylene chloride and trichloroethane, and esters such as ethyl acetate. Of course, in the present invention, other plasticizers, binders, antistatic agents, colorants, flavoring agents,
It does not prohibit the addition of flavoring agents, etc. Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to the following Examples unless the gist thereof is exceeded.

Note that parts and percentages in the examples are parts by weight, unless otherwise specified.
% by weight and the test method carried out in the following examples is as follows. m Film moisture permeability JIS
- Measured according to the transparent green cup method described in Z 0208 and Z 1521.

(2) Young's modulus and stress retention rate of film The Young's modulus was calculated using a Tensilon UTM4-10 (manufactured by Toyo Bolduin Co., Ltd.) according to the method described in JIS-K-6911.

Further, the value obtained by dividing the area surrounded by the SS curve by the cross-sectional area of the sample was defined as the stress retention rate. [3} Storage modulus of film (S
The temperature dependence at 100 Hz was measured according to a conventional method using a viscoelastic spectrometer-45 paper type (manufactured by Iwamoto Seisakusho Co., Ltd.).

Examples 1-4, Comparative Examples 1-2 Degree of substitution of carboxymethyl group is 0.

50, a solution (
1 to town) were adjusted.

Transfer this solution onto the mercury surface in a glass petri dish, and add 20q
A film was formed by casting under conditions of 0.6 bulb H%, and then vacuum-dried at room temperature for 8 hours. Using the obtained dry films (thickness: approximately 100 mm), moisture permeability, stress retention, and Young's modulus were measured using the methods described above. For the results, the value when no glycerin fatty acid ester was added was set as 1. The relative values are summarized in Table 1. The storage modulus of the film is shown in FIG. 1 for Example 3 and Comparative Example 1 as representative examples.

As is clear from Table 1, by carrying out the present invention, a uniform transparent film with a lower Young's modulus and a higher stress retention rate, that is, a film with rich plasticity and excellent mechanical strength, can be produced compared to the case without the addition of glycerin fatty acid ester. It is possible to easily obtain a film with excellent penetration resistance.

On the other hand, as shown in Comparative Example 2, even if glycerol fatty acid esters are added, no effect can be observed if the addition amount or solvent composition specified in the present invention is not met.

According to comparative experiments, phthalic acid ester also exhibits some effects, but the effects are smaller than those of the present invention, and also include the problems described above.

FIG. 1 shows the storage modulus of the films obtained in Example 3 and Comparative Example 1, and by adding 1 t% of triacetin to carboxymethylethyl cellulose, the modulus of elasticity was significantly lowered. Furthermore, it is clear that the main dispersion temperature castle (the part indicated by the arrow in Fig. 1, which generally corresponds to the glass transition temperature) also shifts to the lower temperature side, and the glycerol fatty acid ester used in the present invention This shows a similar remarkable plasticizing effect.

Table 1 Solution formulation and film physical properties Note 1. CMEC carboxymethylethylcellulose is shown.

Note 2. Mbvacet is Eastman kadac
kCo. This is the trade name of acetylated monoglycerite sold by. Note 3. The amount of each glycerin fatty acid ester added is the wt amount for CM8CK.

[Brief explanation of drawings]

FIG. 1 shows the temperature change in the storage modulus of the carboxymethylethyl cellulose films obtained in Example 8 and Comparative Example 1, measured using a viscoelastic spectrometer.

Claims (1)

[Scope of Claims] 1 At least a portion of the three hydroxyl groups per anhydroglucose unit of cellulose is -O-CnH_2nCOOH(n
is an integer of 1 to 5) and an ether group), and a method for modifying a cellulose ether film, which comprises adding a glycerin fatty acid ester to the cellulose derivative when forming the film. 2. Coating or casting a solution obtained by dissolving the carboxyalkyl cellulose derivative and glycerin fatty acid ester in a single or mixed solvent containing a lower alkanol having 1 to 3 carbon atoms as at least one component in claim 1. A method for modifying a cellulose ether film, characterized by: