JPS5825646B2 - Coating method for solid pharmaceuticals - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for coating solid pharmaceutical products, ie pharmaceutical tablets, powders, granules or capsules.

In recent years, solid medicines that are taken have become unstable in the gastric juices, irritate the gastric mucosa and cause side effects such as vomiting, or when it is desired to have a concentrated effect on the intestines. As is well known, it is widely known that the enteric coating is applied to the skin so that it does not change in the stomach and quickly disintegrates once it reaches the intestines.

Conventionally known methods for producing enteric-coated drugs include coating drugs with copolymers of cellulose esters such as cellulose acetate phthalate, unsaturated carboxylic acids and their esters, vinyl acetate, styrene, and the like.

However, in the former case, when applied to certain drugs, such as enzyme preparations such as pancreatin, lipase, and trypsin, the enteric effect of cellulose esters deteriorates over time during drug storage. However, it has been pointed out that it does not dissolve even in pharmacopoeial artificial intestinal fluid, but rather dissolves in artificial gastric fluid.

The cause of the deterioration of the enteric effect of cellulose esters is thought to be due to the decomposition of cellulose esters by esterases or drugs having hydrolysis ability.

On the other hand, the latter method, which uses a copolymer, has problems such as the fact that the copolymer is very sticky, so solid drugs tend to stick to it during the coating operation, and there is also the problem of toxicity due to residual monomers. The film also has the disadvantage that it is easy to peel off, and it is difficult to form a beautiful film.

Based on the above-mentioned problems of the conventional technology, cellulose ethers are a new type of enteric coating that improves the poor hydrolysis resistance of conventional cellulose esters in addition to the good coating suitability peculiar to cellulose derivatives. (Japanese Patent No. 649218, JP-A-55-4333, and JP-A-55-9040)
(see issue).

These cellulose ethers are characterized in that at least a portion of the hydroxyl groups (3 per glucose unit) of cellulose are -0.
CnH2nC00H (n is an integer from 1 to 5) and a carboxyalkylcellulose derivative substituted with an ether group, which generally meet the conditions that enteric coating agents must meet, i.e., they do not dissolve in the stomach but do not dissolve in the intestines. Not only can it be dissolved, but it itself is non-toxic and stable, and it must not be altered by coating agents, etc. For example, it must not only be stable against enzymes, but also use low-toxicity organic solvents such as ethyl alcohol. It has excellent physical properties such as being soluble in

As described above, the carboxyalkylcellulose derivative of the present invention as defined above (hereinafter referred to as carboxyalkylcellulose) has excellent physical properties, but its solubility in organic solvents is generally lower than that in a single solvent. Generally, it is used after being dissolved in a mixed solvent.

However, when these carboxyalkyl cellulose derivatives are used as an organic mixed solvent solution to coat solid pharmaceuticals such as tablets, cracks may occur on the coating surface of the coated tablets unless a plasticizer is added, although it is rare. Alternatively, due to insufficient uniformity of the coating film, the medicinal efficacy may be significantly reduced during storage or in the pharmacopeia 1 solution, despite the stability of the film itself.

Therefore, the carboxyalkyl cellulose derivatives used as plasticizers include phthalate esters, polyethylene glycol, holiflopylene glycol, oils and fats such as castor oil, etc.
By adding higher alcohols such as cetyl alcohol, higher fatty acids such as stearic acid, glycerin fatty acid esters such as acetylated monoglyceride, etc., it is possible to completely prevent cracks from occurring in the formed coating film. However, the present inventors investigated to find a method of forming a uniform and highly dense coating film without adding these plasticizers whose safety has not been sufficiently confirmed in terms of toxicity. By using a single or mixed solvent containing a small amount of lower alkanol having 1 to 3 carbon atoms as a component as a solvent for dissolving the carboxyalkyl cellulose derivative,
The present inventors have discovered that a uniform and highly dense coating film can be formed without using a plasticizer, and have completed the present invention.

That is, the present inventors have found that the present carboxyalkyl cellulose derivative has excellent affinity for lower alkanols having 1 to 3 carbon atoms, and therefore, the present inventors have determined that the present carboxyalkyl cellulose derivative has excellent affinity for lower alkanols having 1 to 3 carbon atoms. After conducting various studies on the solubility of the carboxyalkylcellulose derivative and the viscosity characteristics of its solution, it was found that the carboxyalkylcellulose derivative has excellent solubility in a mixed solvent rather than in a single solvent, and that the viscosity of the solution is also reduced. We concluded that in order to obtain a dense coating film, it is important to select a solvent that not only dissolves uniformly, but also produces a solution with as low a viscosity as possible.

In other words, the solution viscosity of a polymer compound generally varies depending on the type of solvent used even if the degree of polymerization is the same, but this is due to differences in the conformation of the polymer chains in the solution. It is thought that in solvents with high viscosity, the molecular chains take a more spread out conformation, and in solvents with low viscosity, the molecular chains form a more dense conformation.

The basic gist of the present invention is to select an appropriate coating solvent for the carboxyalkyl cellulose derivative by focusing on the relationship between the conformational difference in the solution and the uniformity and density of the resulting coating film. .

To explain the present invention in more detail, the medium for preparing the coating liquid used in the present invention is a single or mixed solvent containing a lower alkanol having 1 to 3 carbon atoms as at least one component, as described above. In this case, the content of the alkanol component is preferably 40 to 100 wt%, preferably 60 to 100 wt%.

On the other hand, the solvent used in combination with the alkanol in the present invention includes solvents that are compatible with the alkanol within the above range, such as water, ketones such as acetone, aromatic hydrocarbons such as toluene and benzene, It can be selected from one or a combination of two or more of ethers such as dioxane and methyl selon rub, halogenated hydrocarbons such as methylene chloride and trichloroethane, and esters such as ethyl acetate.

However, from the viewpoint of toxicity or safety of the coating solvent, water is particularly desirable.

1 The above is the first main point of the present invention.

Next, the conformation of the present carboxyne alkylcellulose derivative in the coating solution is regulated by the medium for preparing the coating solution as described above,
In order to form a uniform and dense coating film, it is important to select the solvent composition as described above. However, when implementing the present invention, when selecting a mixed solvent system other than a single alkanol solvent, it is necessary to select the solvent composition in the coating process. Although the solvent composition may change over time, such a phenomenon is not necessarily desirable for achieving reproducible and stable coatings.

A method for minimizing such phenomena and realizing a reproducible and stable coating is to use an azeotropic mixture composition among the solvent compositions or a solvent composition that can substantially form an azeotropic mixture composition in the coating process. This can be easily achieved by setting appropriate conditions.

That is, as a solvent composition forming an azeotropic mixture composition, for example, methyl alcohol-ethyl acetate (48,6:51.4,
weight ratio), methyl alcohol-toluene (71,5:2
8.5), ethyl alcohol-toluene (69,2:3
0.8), inpropyl alcohol-toluene (76,
6:23.4), ethyl alcohol-water (96:4),
Examples include isopropyl alcohol-water (87,6:12.4).

Furthermore, a solvent composition that can substantially form an azeotropic mixture composition in a coating process is a composition that has a high content of low-boiling components in the azeotropic mixture composition, for example, in a methyl alcohol-toluene system, the methyl alcohol content is 71.5% or more. It means a mixed solvent composition consisting of.

As mentioned above, at least one component has 1 to 3 carbon atoms.
By selecting as a coating solvent an azeotropic mixture composition containing a lower alkanol or a mixed solvent that can substantially form an azeotropic mixture composition in the coating process, the gist of the present invention can be more reliably realized. .

The above is the second main point of the present invention.

That is, the gist of the present invention is an improved coating method for solid pharmaceuticals as summarized in the following two items.

(1) A carboxyalkyl cellulose derivative in which at least a portion of the hydroxyl groups (3 per glucose unit) of cellulose is substituted with 10-CnH2nCOOH (n is an integer of 1 to 5) and an ether group is used as at least one carbon atom number 1~3
1. A method for coating a solid pharmaceutical, comprising coating the solid pharmaceutical using a solution obtained by dissolving a lower alkanol in a single or mixed solvent.

(2) In paragraph (1), the solvent has an azeotropic composition or is a solvent that can substantially form an azeotropic composition in the coating process, that is, it consists of the same components as the azeotropic composition but has a lower boiling point. A method for coating a solid pharmaceutical, characterized by being a mixed solvent containing more than an azeotropic composition of components.

In addition, examples of the carboxyalkylcellulose derivatives include carboxybutylethylcellulose, -)1
carboxyethyl ethyl cellulose, carboxybutylethyl cellulose, carboxypropyl methyl cellulose, etc., and generally the degree of substitution of the carboxyl alkyl group per anhydroglucose unit is about 0.3 to 1.2, and the degree of substitution of other ether groups is about 1. An enteric coated material having a molecular weight of about 2.4 is used.

Of course, the present invention does not prohibit the use of plasticizers, etc., and examples include phthalate esters, polyethylene glycol, polypropylene glycol, chrycerin, phlopylene glycol, fats and oils such as castor oil, higher alcohols such as cetyl alcohol, and stearin. It is possible to blend higher fatty acids such as acids, glycerin fatty acid esters such as acetylated monoglycerides, silicone oil, or various surfactants.

Furthermore, coloring agents, flavoring agents, flavoring agents, etc. may be added to improve the quality of the coated pharmaceutical product.

In the present invention, there is no particular restriction on the method of preparing the coating solution, and a normal dissolution method is sufficient. However, when a mixed solvent is used, the carboxyalkylcellulose derivative is included in one component of the mixed solvent. A method in which the remaining component solvents are added after sufficiently dispersing the components is preferable in terms of increasing the dissolution rate.

Further, the solution concentration is mainly regulated by the capacity of the coating apparatus and is not regulated by the present invention, but a range of approximately 3 to 15 wt% is appropriate.

To coat solid pharmaceuticals with the solution mainly composed of carboxyalkyl cellulose derivatives obtained in this way, pan coating equipment, drum type coating equipment, or fluid coating equipment can be used. There are no restrictions on the equipment used.

Next, the present invention will be explained in more detail using Examples.
The present invention is not limited to the following examples unless the scope thereof is exceeded.

Note that parts and % in the examples mean parts by weight and % by weight unless otherwise specified.

In addition, the test methods implemented in the following examples are as follows.

(1) Artificial gastric fluid test and artificial intestinal fluid test According to the disintegration test method described in the Ninth Edition Japanese Pharmacopoeia, the test using the first liquid and the test using the second liquid.

(2) Amylase activity test Brltish Pharmacopoeia, A
This was carried out according to the method described in 126 Appendix X-C.

The evaluation was performed by setting the activity before the artificial gastric juice test as 100 and determining the activity retention rate after the test.

(3) Observation of coating film The surface condition of the coated tablet was observed in a conventional manner using a scanning electron microscope JSM-U3 model manufactured by JEOL.

Examples 1 to 3, Comparative Example 1 Uncoated tablets for coating tests were prepared under the following conditions.

Pancreatin: Lactose G (manufactured by Freund Sangyo): Carboxymethylcellulose calcium (manufactured by Daicel, trade name ECG-505) Magnesium nistearate-20
A mixture of 6.5:3.5:0.5 (weight ratio) was directly compressed into tablets each weighing 200 square meters and having a diameter of 8 mm.

Using carboxymethylethyl cellulose with a degree of carboquine methyl group substitution of 0.50 and a degree of ethoxyl group substitution of 2.10, coating solutions (■ to ■) with the formulations listed in Table 1 were prepared, and the above tablets were spray coated. Ta.

Additionally, all of these coatings were performed under almost the same conditions, with an ambient temperature of 18-22°C and a relative humidity of 35°C.
It was ~40%.

The coating device used was an automatic pan film coating device HCT type manufactured by Freund Sangyo, and 350 g of uncoated tablets were charged in each case, and a coating solution of the formulation shown in Table 1 was applied at a rate of 12 to 15 rfLl/r/u! The uncoated tablets were sprayed with a liquid amount of 10 to 12% to cover the uncoated tablets.

During this time, the coating pan is under rotation and the
Continuous drying was performed while blowing dry air at ℃.

Furthermore, after the spraying was completed, it was dried for 10 minutes using the same dry air.

The surface of the obtained coated tablets was visually observed to confirm the presence or absence of cracks, and furthermore, a disintegration test with artificial gastric fluid and artificial intestinal fluid, an amylase activity test, and an electron microscope observation of the surface of the coating film were performed. Ta.

The results are shown in Table 1.

As shown in Table 1, the method of the present invention provides a uniform dense film and almost completely retains amylase activity.
In the comparative example, only a non-uniform and porous film was obtained;
Although the appearance of the tablet does not change at all in artificial gastric juice (Pharmacopoeia No. 1 liquid), the amylase activity retention rate is extremely low at approximately 10%, indicating that it has sufficient performance as an enteric protective coating. It's hard to say.

Examples 4 to 6, Comparative Example 2 Except for preparing coating solutions (V to ■) with the formulations listed in Table 2 using carboxymethyl ethyl cellulose with a carboxymethyl group substitution degree of 0.601 and a hydroxyl group substitution degree of 2.20. All operations were performed in the same manner as in Examples 1 to 3 and Comparative Example 1 to coat pancreatin tablets with a 10 to 12% coating film.

The results are shown in Table 2.

As shown in Table 2, the method of the present invention yields a uniform dense film and almost completely retains amylase activity.
In the comparative example, only a non-uniform and porous film was obtained;
Although the appearance of the tablet does not change in artificial gastric juice (Pharmacopoeia No. 1 liquid), the amylase activity retention rate is as low as approximately 42%, and it has sufficient performance as an enteric protective coating agent. It's hard to say.

Examples 7 to 8, Comparative Example 3 Using carboxyethyl ethyl cellulose with a degree of carboxyethyl group substitution of 1.81 and a degree of ethoxyl group substitution of 0.56, coating solutions (■ to Xt) having the formulations listed in Table 3
Pancreatin tablets were coated with a 10 to 12% coating film in the same manner as in the previous example, except that the amount was adjusted.

The results are shown in Table 3. As shown in Table 3, the method of the present invention yields a uniform, dense membrane and almost completely retains amylase activity, whereas the comparative example yields only a heterogeneous and porous membrane. In gastric juice (pharmacopoeia No. 1 liquid),
Although the appearance of the tablet did not change at all, the amylase activity retention rate was as low as about 15%, and it cannot be said that it has sufficient performance as an enteric protective coating agent.

The coating films of the Examples and Comparative Examples were photographed using an electron microscope (X2000). The coating films of each Example had slight irregularities but no pores, and the uniformity of the film was extremely good. The coating film had large irregularities and pores with a diameter of 20 to 50 μm, and was porous and extremely poor in uniformity.

From the above, the superiority of the present invention is clear.

Claims (1)

[Claims] 1 At least a portion of the hydroxyl groups (3 per glucose unit) of cellulose are -0-CnH2nC00H (n is 1
an azeotropic mixture composition containing at least a portion of a lower alkanol having 1 to 3 carbon atoms, or an azeotropic mixture composition consisting of the same components as the azeotropic mixture composition but with a low boiling point. A method for coating a solid pharmaceutical, comprising coating the solid pharmaceutical using a solution obtained by dissolving components in a mixed solvent containing more components than the azeotrope composition.