JPS59157032A - Preparation of water-based enteric coating liquid - Google Patents

Abstract

PURPOSE:To prepare the titled coating liquid easily and economically, by dispersing a water-based gel of a carboxyalkyl cellulose ester derivative in water or in an aqueous solution of an alcohol. CONSTITUTION:The objective water-based enteric coating liquid having a solid concentration of >=10wt% and an extremely excellent film-forming property represented by the minimum film-forming temperature of <=40 deg.C, in some cases <=25 deg.C, can be prepared by dispersing (A) a water-based gel of a carboxyalkylcellulose ether derivative of formula (Gul is anhydrous glucose unit skeleton of a cellulose of formula C6H7O2; n is 1-5; R is methoxy, ethoxy or OH) and having a water-content of 30-70wt%, preferably 40-60wt% (wet-basis) in (B) water or an aqueous solution of an alcohol containing <=20wt% of a 1-3C lower alcohol. Addition of a small amount of alcohol is extremely effective to improve the film-forming property, eliminate the foams of the dispersion, or prevent the proliferation of bacterial cells during the storage of the dispersion.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing an aqueous enteric coating liquid. Conventionally, as a method for manufacturing enteric coating liquids, a method has generally been adopted in which a polymeric substance that does not dissolve in water or gastric juice but dissolves in intestinal fluid is dissolved in an organic solvent, and if necessary, a plasticizer, a coloring agent, etc. are added thereto. There is.

However, this method requires a large amount of organic solvent to produce the coating liquid, and recovery of the organic solvent is difficult, which is economically disadvantageous. Additionally, there have been problems with the safety of workers during manufacturing and formulation due to the use of large amounts of organic solvents, the risk of ignition, and the safety of users due to residual solvent in the drug.

From this point of view, the need for a water-based enteric coating solution has recently been recognized, and various methods have been proposed. However, enteric coating agents are generally polymeric compounds with carboxyl groups, and their characteristic is that they only become solubilized in water by forming a salt with water on the alkaline side, so they cannot simply be made into an aqueous solution. The reality is that it is not possible.

There have been no proposals for a method for producing an aqueous enteric coating liquid using such a polymeric substance having a carboxyl group.

For example, the method described in JP-A No. 51-7116, that is, the method of converting the polymer compound into a water-soluble salt form, coating it with a solid drug in the form of an aqueous solution, and then treating it with an acid to return it to the acid form again; The method described in No. 98120, that is, the method of coating a solid drug using suspendimine obtained by dispersing hydroxyglopyl methyl cellulose notalate powder with an average particle size of 100 μm or less in water containing triacetin at a temperature of 25° C. or less , a method using an aqueous emulsion obtained by emulsion polymerization of a methyl methacrylate/methacrylic acid copolymer, a method using an ammonia aqueous solution as a solvent, etc. have been reported in various documents.

However, the method described in JP-A-5i-7116 is unsuitable for coating drugs that are unstable to acids, and the liquid resistance is insufficient because it is difficult to completely convert the coating layer into an acid form. It has disadvantages such as:

The method described in JP-A No. 55-98120 has two drawbacks: 2. It is necessary to grind the coating substrate into particles of 100 μm or less prior to dispersion; 1. It is time-consuming to prepare the coating solution; 1. Dispersion stability and film-forming properties are poor. There are problems such as being sufficient. Since the aqueous emulsion system relies on the emulsion polymerization method of acrylic monomers, it poses a safety problem when applied to pharmaceuticals due to concerns about residual emulsifier 2M initiators, monomers, etc. In the method using aqueous ammonia as a solvent, after coating with ammonia, which is used to solubilize the enteric coating agent.

7 Achem, Lord, 18. (1980), etc., and in short, although each method has achieved its purpose to some extent in terms of making it water-based, there are various problems in practical use.

In order to improve the recent problems, JP-A-56-L68925
In other words, after dissolving a water-inbathable polyanionic polymer in water as a basic substance, or after dissolving a water-soluble base salt of the polyanionic polymer in water, Can neutralize basic substances! ! A hydrosil or gel of the polyanionic polymer is prepared by adding a 112 substance to the aqueous solution and neutralizing it. The submerged hydrosil or gel is diluted and washed with a large amount of water to remove the generated neutralized salt, and then subjected to coating, or the hydrosil or gel generated by freeze-drying/freezing or neutralization is stirred. A method has been proposed in which the hydrosil or gel is dehydrated by 71% and the solid-liquid separation is performed by heating above 30°C, followed by washing with a large amount of water and drying, and redispersing the resulting powder in water. .

However, such a method is not necessarily suitable for practical use. In other words, in order to make a practical aqueous coating solution, it is essential to make the particle size of the hydrosol or gel obtained in the neutralization step as small as possible, and to do so, it is essential to reduce the solid matter during the manufacturing process. In fact, in the examples described in JP-A-56-63925, etc., the solid content concentration of the hydrosol or gel during neutralization is approximately 0.95. ~2,
The density is as low as 8x, which is a major disadvantage in practical use.

In addition, if the neutralized salt in the hydrosol or gel of Chuo Old Samurai is not sufficiently desalted, the dispersion stability will be poor, and the obtained film will be prone to cracking and enteric properties will be incomplete, so after neutralization, Sufficient desalination is required □For this purpose, it is necessary to wash with a large amount of water, but by washing with water and desalting as described above)・Conversely, desalination increases the dispersion stability of the idrosol or gel. This makes subsequent concentration of the hydrosol or gel difficult, which not only makes it difficult to obtain a hydrosol or gel with a high solid content concentration, but also causes a large decrease in yield.

Therefore, in this method, when an attempt is made to improve dispersion stability and film-forming properties, there is a contradictory relationship in that the yield decreases, that is, the cost increases, which is a big problem in practice.

In addition, it is difficult to obtain a hydrosol or gel with a high solid content concentration because the hydrosol or gel obtained by this method is economically difficult to obtain. Therefore, it is difficult to obtain a hydrosol or gel with a high solid content concentration. The solid content concentration during adjustment inevitably decreases, which is one of the fatal drawbacks of coating using a high-temperature medium such as water. For example, the solid content concentration of the coating liquid formulation in the embodiment described in the above-mentioned Gikai No. 56-63925 is about 8.5 to 4.9% by weight, which is an extremely low concentration for a coating liquid.

On the other hand, a method has also been proposed in which the hydrosol or gel obtained by this method is freeze-dried or heated to a dehydration solidification temperature, and the resulting powder is redistributed into water after solid-liquid separation and drying. . However, the former method also requires a large K load.

The latter method is based on the fact that secondary agglomeration of particles tends to occur after the heating dewatering process, especially during the drying process, and that the water use capacity of the particles decreases compared to before drying, so it is not stable when redispersed in water. It has the disadvantage that it is difficult to form a clear dispersion and its film-forming properties are also reduced.

In order to solve the problems of the prior art, the present inventors have conducted intensive studies on an economical and good method for producing an aqueous enteric coating liquid. Merely reducing the particle size of the dry powder is insufficient.

We have come to the conclusion that the affinity of the base particles to the dispersion medium in an aqueous dispersion system is an extremely important factor, and have completed the present invention.

That is, the present invention has a general formula (in the formula, Gul is C1!H7
Anhydroglucose unit skeleton of glucose 02, n is 1
A carboxyalkyl cellulose ether derivative aqueous gel having a wet basis moisture content of 80 to 70 weight, preferably 40 to 60 weight, expressed as an integer of 5 to 5, where 几 represents a methoxyl group, ethoxyl group, or hydroxyl group, is prepared using water or carbon. Number of atoms: 1
By dispersing in an alcohol water bath solution having a lower alcohol content of 20% by weight or less, it is possible to economically and extremely easily reduce the solid content to 10% by weight or less at 25°C depending on the conditions.
The main objective is to produce an aqueous enteric coating liquid having extremely good film-forming properties as described below.

The enteric coated base material disclosed in the present invention is a former Rt.
The carboxyalkyl cellulose ether derivative represented by the formula I& includes, for example, carboxymethyl methyl cellulose, carboxymethyl ethyl cellulose, carboxyethylethyl cellulose, carboxypropylethyl cellulose, etc. There are no particular restrictions on the method for preparing the gel, and conventionally known methods are sufficient; however, from the viewpoint of economy and redispersibility, a gel with a wet basis water content of 30 to 70 weight, preferably 40 to 60 weight, is used. shall be. That is, if the water content is higher than this, the redispersibility decreases, and if the water content is lower than this, it is difficult to obtain economically, and the result is poor practicality.

There are no particular regulations regarding the method for preparing the aqueous gel of the carboxyalkyl cellulose derivative, and conventionally known methods may be employed. Japanese Patent Application Laid-open No. 55-108, which was first proposed by the inventors.
The method described in No. 401 can be adopted. That is, the carboxyalkylcellulose ether derivative is precipitated by dissolving the carboxyalkylcellulose derivative in an aqueous solution of a lower alcohol having 1 to 8 carbon atoms and removing the lower alcohol by distillation or the like, followed by washing with water and separating the post-liquid. The desired aqueous gel can be easily obtained. For such a method, the above-mentioned Japanese Patent Application Laid-Open No. 56-68925
Unlike the method described in the above issue, no salt is generated during the production process, so there is no need to worry about salt-related problems, and the solid content concentration during gel production can be kept above the 1O weight factor, making it economical. It is advantageous.

Of course, methods other than the above 1, such as the above-mentioned Japanese Patent Application Laid-Open No. 56-6892
After dissolving the carboxyalkyl cellulose ether derivative in water containing a basic substance by the method described in No. 5, etc.,
Alternatively, a hydrogel of the carboxyalkyl cellulose ether derivative is prepared by dissolving the water-soluble salt of the carboxyalkyl cellulose ether derivative in water and then neutralizing the basic substance, and then solidified by heating above the dehydration assimilation temperature. The desired aqueous gel can also be obtained by liquid separation and subsequent washing with water.

In this case, 1. In the present invention, it is necessary to particularly reduce the particle size of the hydrogel obtained during neutralization, so the solid content concentration of the hydrogel in the manufacturing process is set to a high concentration of 5 weight coefficient or more. It is needless to point out that this makes it possible and economically advantageous.

The following method for dispersing a carboxyalkyl cellulose derivative is an aqueous gel of a carboxyalkyl cellulose ether derivative with a wet basis water ratio of 30 to 70 weight ratio, preferably ii: 40 to 60 weight ratio. The desired purpose can be easily achieved by adding the aqueous gel under stirring into water or an aqueous alcohol solution containing 20% by weight or less of a lower alcohol having 1 to 8 carbon atoms, which has been adjusted to have a coating liquid composition with a predetermined solid content concentration. An aqueous enteric coating solution can be prepared.

The addition of a small amount of alcohol to water, which is the dispersion medium, is not particularly necessary if the purpose is simply to improve the dispersion effect; Alternatively, it is extremely effective when an effect such as preventing the proliferation of living bacteria during storage of a dispersed system is expected. Therefore, for this purpose, a predetermined amount of a lower alcohol having 1 to 8 carbon atoms is added to the aqueous gel serving as the dispersoid, and then the lower alcohol aqueous gel is added to the pure water when formulating the dividing solution.
It can also be dispersed, and this does not contradict the gist of the present invention.

In order to carry out the present invention more effectively, the liquid is cooled to a temperature of 80°C or less (preferably 25°C or less) and water or
8 in an alcohol water bath having an alcohol content of 20% by weight or less, or by thoroughly mixing the hydrogel with a kneader or the like while cooling the hydrogel to 80°C or lower (preferably 25°C or lower). All you have to do is disperse the paste. That is, dispersing or kneading while cooling K to 100/J1
Even if the aqueous gel has a particle size above 6, it can be easily reduced to a particle size of several tens of micrometers to several micrometers. I plan.

2. In the present invention, the use of various emulsifiers in combination in order to improve dispersion stability is not prohibited, but since the carboxyalkyl cellulose ether derivative itself has a moderate self-emulsifying effect, its combination is particularly recommended. F for mandatory! ,do not have. Although the use of emulsifiers is generally effective in improving dispersion stability, it has the inevitable drawback of reducing the liquid resistance of the resulting film. Therefore, since the method of the present invention does not require the use of an emulsifier, the film's resistance to -
It is also effective for the purpose of improving liquid properties.

(9) In the present invention, hydroxyglobil methylcellulose, hydroxyglobil cellulose.

Water-soluble film forming aid such as polyvinyl alcohol.

Polyethylene glycol, ethylene glycol.

It is optional to add conventionally known plasticizers such as propylene glycol, glycerin, dibutyl phthalate, diacetin, triacetin, g) serine fatty acid esters, and colorants such as food pigments during or after dispersing the aqueous gel. This does not contradict the spirit of the present invention in any way.

Next, the present invention will be further explained with reference to Examples.

The present invention is not limited to the following examples.

CMEC used in Examples and Comparative Examples is an abbreviation for carboxylmethylethyl cellulose, and CEEC is an abbreviation for cellulose ethyl ethyl cellulose.

Example I CMEC ■ Manufactured by Kojin Dicarboxylmethyl group substitution degree = 0.
4. Degree of ethoxyl group substitution -2.1. Viscosity (ethyl alcohol/water = 8/2, 5% by weight, 25°C) = 11CI))
200g of 0.8N sodium hydroxide 598g, water 80g
The mixture was added to the solution of 81g and stirred at room temperature to dissolve. After dissolution, insoluble matter was filtered, and while stirring the p solution, 0.8N sulfuric acid was gradually added to adjust the pH to 8, followed by heating to 80'C and stirring for 10 minutes.

Thereafter, the solid content was removed by filtration while hot and washed with warm water until the p liquid became neutral. After washing, one sample was dried at 105° C. for 2 hours to determine the moisture content. Collection H5
5 ot, Miyamizu rate 66.7% (purity 18B?, yield 91.
Section 5). The particle size of this 0MEC aqueous gel is approximately 31μ.

Water 2281e was cooled to below 20°C, and the plasticizer triacetin 10, Or was added while stirring vigorously with a homomixer, and then the obtained 0ME was stirred at below 20°C.
The evaluation of C aqueous gel 10 (1 (water content 6) is recorded in Table 1.

Example 2 In the dispersion of the aqueous gel in Example 1, water 208.5
Cool to below 20°C and add 14.5 g of ethyl alcohol while vigorously stirring with a homomixer.

A dispersion was obtained in the same manner as in Example 1 except that 10.07% of triacetin was added. Example 8 In the dispersion of the aqueous gel in Example 1, water a22.6% was added.
7F was cooled to 20"C or below, and while stirring vigorously with a homomixer, a plasticizer (manufactured by Eastman Kodak) was added to 10.0% of the plasticizer, and a film-forming aid, hydroxypropyl cellulose (hereinafter abbreviated as HPC), was added to 0.00% of the plasticizer. .38f added,
A dispersion liquid was obtained in the same manner as in Example 1 in other respects.

Example 4 In the dispersion of the aqueous gel in Example 1, water 228? A dispersion was obtained in the same manner except that water 1129 was used instead.

Example 5 CMEC (same quality as Example 1) was placed in a 100f, i-pul flask and completely dissolved at 70°C.

After dissolution, insoluble matter was filtered using Visine 9AF cloth.

Put this into a Mitsuro flask with a stirrer, condenser and thermometer 2, add 600 ml of water while stirring,
I-butyl alcohol was collected by simple distillation under normal pressure until the internal temperature of the flask reached 98°C, and c ME C was precipitated.
Filtered. No. 12 was sampled and dried and roasted at 105°C for 2 hours to determine the moisture content. Yield 259g, moisture content 68
, 2% (purity 95°82, yield 95.3%). This 0M
The particle size of the EC aqueous gel is approximately 48μ.

Cool 218 g of water to below 20°C and add 14.57 g of ethyl alcohol while vigorously stirring with a homomixer.

CMEC water C) obtained in this example above while adding triacetin lOf and then stirring at 20''C or less.

Weight: 9,0.55' (moisture content: 68.2%, purity: 88.
8t) was gradually added. Thereafter, the mixture was vigorously stirred for 1 hour at a temperature below 20°C. The evaluation of the obtained dispersion liquid is listed in Table 1.

Example 6 In Example 5, methyl alcohol 6889. CME C aqueous gel was obtained in the same manner except that water 1722 was used. Collection 1:19f
l, moisture content 50.9% (purity 96.2?, yield 96.2
%). The particle size of this 0MEC aqueous gel is 89μ.

Cool 255.2 r of water to 20°C or below, add 102t of triacetin while stirring vigorously with a homomixer, and then add 0MEC obtained in this example while stirring at 20°C or below.
Aqueous gel 67.82 (water content 50°9%, purity 83.8
F) was gradually added. Thereafter, the mixture was vigorously stirred at 20° C. or lower for 1 hour. The evaluation of the obtained dispersion liquid is listed in Table 1.

Example ? In Example 1, CMEC was replaced with C1, ;EC (■ Kojin dicarboxylethyl group fi conversion degree = 0.40).

Degree of ethoxyl group substitution=2.0. [4?

Moisture content 59.4% (purity 190.87. Yield 95.4%)
) was obtained as a CEEC aqueous gel with a particle size of approximately 85μ.

Water 2414 was cooled to 20° C. or below, and 10 r of triacetin was added while vigorously stirring with a homomixer.

Thereafter, the CEEC aqueous glue obtained in this example 82. , Of (hydration rate 59.4%, purity 88,82
) was added gradually. Thereafter, the mixture was slowly stirred for 1 hour at a temperature below 20°C. The evaluation of the Samurai dispersion liquid is listed in Table 1.

Comparative Example I CMEC (same quality as Example 1) 400F was added to a solution made by adding water to 0°5N sodium hydroxide]-728- to make about 40 tons, and silicone oil (manufactured by Shin-Etsu Chemical Co., Ltd.) was added as an antifoaming agent. KM-72) 0.8 r, 2. ',”,,
8 m/! F 4 Q minutes were added dropwise to form a hydrosol. This was concentrated by centrifugation using a centrifuge, pure water was added to the precipitated portion, stirred and diluted, and the dispersion was centrifuged. The sedimented part was taken out. This washing operation was repeated eight more times to obtain a concentrated hydrogel/sol of about 24,009 g. Solid content concentration 5% by weight, yield 80%.

To 1194 f of water was added 6 rl of tri'acetin, and while stirring vigorously with a homomixer, 120 (1 (CMEC 5% by weight)) of concentrated hydrogel/sol 120 (1 (CMEC 5% by weight)) prepared by Samurai was gradually added to obtain a dispersion. The evaluation of this product is shown in Table 1. description.

Comparative Example 2 A hydrosol obtained in the same manner as in Comparative Example 1 was heated at 80°C for 10 minutes while stirring with a homomixer, then filtered while hot and washed with warm water. The end point of cleaning was determined by checking for chloride ions with silver nitrate.

CMEC powder 6 obtained while vigorously stirring with a mixer
02 was gradually added to ' to form a dispersion. The evaluation of this product is listed in Table 1.

Comparative Example 3 The powder obtained in Comparative Example 2 was pulverized to about 8 μm. The other conditions were the same, and the dispersion was prepared (8% O Comparative Example 4) The solid content obtained in Comparative Example 2 was dried at 60°C (normal pressure) to obtain CM E'C powder 860 y (water content 18%).
Obtained. Yield 73.8%.

Add 6 parts of triacetin to 2,821 parts of water and mix vigorously with a homomixer to make 78 g of CME C powder (
Water ratio: 18%, pure molecular weight: 1ef) was gradually added. Table 1 shows the evaluation of the dispersion thus obtained.

From the results shown in Table 1, the method according to the present invention has a higher water content than the conventional method (5 comparative examples), but the yield is much better. The solid content concentration during dispersion is also higher than the conventional concentration of 1°Ze-φ weight coefficient or higher.

The obtained dispersion (colloidal liquid) has a viscosity and MFT.

It received good evaluations in both the enteric-coated test and the second particle size test. Therefore, it was found that the method of the present invention is excellent in both yield and evaluation as a method for producing an aqueous enteric coating agent.

[Margin below]

Test method/Viscosity = B type viscometer used, 25°C, 60 rotations/MF'
T: Emulsion minimum film formation temperature measuring device/enteric test: (1) Preparation of tablets: Bankreatin dilactose G (manufactured by Freund Sangyo ■) dicarboxyl methylcellulose calcium (manufactured by Daicel, product name: HCG-50 5 ) A mixture of magnesium nistearate ~ 20: 76.5: 3.5: 0.5 (grain ratio) was directly compressed into tablets of 200 mm each and 8 mm in diameter◇ (2) Coating; Add the above dispersion (colloid) to the tablet
The coating conditions were almost the same: temperature 18-22°C, relative humidity 85-40%.

Spray L at a flow rate of 12-15 me/m1n, 60°C
It was dried.

7-8% coach-in cut into plain tablets A coating film was coated on the plain tablet.

(3) Test: Changes were observed in a test using the first fluid (artificial gastric fluid) according to the disintegration test method described in the 10th revised Japanese Pharmacopoeia (87 °C x 2 hours), and then in the second fluid (artificial intestinal fluid). The time for disintegration was measured by immersion at 87°C.

・Patent applicant for the use of particle size dual transmission particle size distribution analyzer
Kojin Co., Ltd.

Claims (1)

Scope of Claims: General formula (where Gul is a cellulose anhydroglucose unit skeleton of C6f-170°, ■ is an integer of 1 to 5, and R is a methoxyl group, an ethoxyl group, or a hydroxyl group represented by 9); Standard government water rate 80-70 weight ratio, preferably 4.0-60
Heavy fis carboxyl alkyl cellulose ether derivative aqueous gel with water or. 1. A method for producing an aqueous enteric coating liquid, which comprises dispersing it in an aqueous alcohol solution containing a lower alcohol having 1 to 8 carbon atoms and having a weight ratio of 20 or less.