JPH08245423A - Aqueous enteric coating solution - Google Patents

Abstract

PURPOSE: To provide the subject enteric coating that contains a specific succinate as the enteric polymer and use ammonia as a neutralizing agent, thus markedly reduces alkali salt residue and can give a good enteric function. CONSTITUTION: This enteric coating solution for solid drugs comprises (A) hydroxypropylmethyl cellulose acetate succinate and (B) ammonia in an amount that more than 80 mol.% of the carboxyl groups in the component (A) can be neutralized. For example, the component A is dispersed in purified water, and 28% aqueous ammonia is added, under slow stirring and the stirring is continued until the solution becomes clear, followed by addition of triethyl citrate and talc and stirring is further continued.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an aqueous enteric coating solution used for producing an enteric coating preparation. More particularly, it relates to an aqueous enteric coating solution for forming an enteric coating film of an enteric coating preparation, which imparts the property of being dissolved in intestinal fluid but not in water and gastric juice.

[0002]

Description of the Prior Art Enteric coated preparations are one of the important preparations widely used for the administration of acid-labile drugs and the protection of gastric mucosa. In order to produce an enteric coating preparation, conventionally, a method of dissolving an enteric polymer in an organic solvent and spraying the polymer to form an enteric film on the drug surface has been generally used. However, in this case, a large amount of organic solvent that is removed by drying is released into the atmosphere, so a large-scale solvent recovery device is required, and environmental protection and safety, solvent recovery cost, and the amount of solvent remaining in the drug product are required. There were many problems.

On the other hand, in recent years, in order to avoid these problems, a so-called water-based enteric coating method has been developed in which an enteric polymer is used as an aqueous latex or finely pulverized and used as an aqueous dispersion.

As the water-based enteric coating method, a method in which a copolymer of methacrylic acid of an acrylic enteric polymer and methyl acrylate is made into an aqueous emulsion by an emulsion polymerization method (Japanese Patent Publication No. 60-43334) has been known for the longest time. However, it has been pointed out as a problem in this method that the polymerization initiator or the monomer remains, or the interaction with the basic drug is strong.

Examples of the method using a cellulosic enteric polymer include the following: i) A coating solution prepared by dispersing a finely ground enteric polymer in water containing a high-boiling gelling agent such as triethyl citrate. Method (Japanese Patent Publication Showa 57-53329, 58-55125), i
i) A coating solution prepared by dissolving the enteric polymer in 83% by volume of alcohol / water solution, and then partially adding an alkali metal hydroxide or ammonia as an alkaline substance to the solution to partially neutralize it and further adding water to dilute it. (Japanese Patent Publication No. 62-53486), iii) Furthermore, after dissolving the enteric polymer in alkaline water, a coating solution is prepared by adding a carboxylic acid in an amount of 50% or more of the equivalent of the alkali. (Japanese Patent Publication No. 02-24251), and many other methods are disclosed. However, in the example of (i), since the coating liquid is sensitive to heat, gelation is likely to occur during coating and nozzle clogging is likely to occur, and advanced technology is required to form the film from the suspension. . In the example of (ii), it is still essential to use an alcohol as an organic solvent, and in the last example of (iii), in order to improve water resistance, acetic acid, monocarboxylic acids such as succinic acid, and polycarboxylic acids are used. Acid must be added.
As described above, in the conventional method, many contrivances have been made to make the film-forming property compatible with the acid resistance and the water resistance, but each has many serious defects in promoting industrialization.

[0006]

[Problems to be Solved] It is usual that the preparations obtained by the aqueous solvent method have higher water permeability than the preparations obtained by the organic solvent method, and thus they are compatible with the enteric-coated preparation test of the Japanese Pharmacopoeia test method. However, there are some cases where swelling and softening are remarkable due to permeation of the test solution. In particular, it is difficult to apply the water-based solvent method to a plain tablet containing many disintegrants or to a direct pressure tablet. This is due to the fact that a large amount of plasticizer (film forming agent) must be blended and that the emulsifier must be blended.
Due to their dissolution, some water permeability is unavoidable and has required larger coating amounts compared to organic solvent-based enteric coating methods. In order to deal with such a situation, Japanese Examined Patent Publication No. 6-27076 discloses an aqueous system using an oxycarboxylic acid type cellulose derivative as an enteric polymer and ammonia having a neutralization amount of 0.5 to 5 mol% of a carboxylic acid amount as a neutralizing agent. An enteric coating solution is disclosed. However, since this coating solution is a dispersion system in which neutralized particles have an average particle size of 100 microns or less and is dispersed in water, there is a problem in film-forming property, and further ammonia remaining in the film after film-forming It is hard to say that the amount has been sufficiently removed.

Generally, a method of neutralizing an acid-type enteric polymer with an alkali such as sodium hydroxide or ammonia to form an enteric coating is conventionally known.
However, enteric-coated preparations obtained by these methods not only cannot obtain sufficient acid resistance due to the residual alkali salt of carboxylic acid, but also have high hygroscopicity and tend to be easily dissolved in water. For this reason, in the extreme cases, it had a drawback that it was immediately dissolved in the oral cavity when taken.

[0008]

SUMMARY OF THE INVENTION With respect to the above problems, the present inventors have found that an enteric polymer contains hydroxypropylmethylcellulose acetate succinate (HPM).
Only when ammonia is used as the neutralizing agent, the residual amount of the alkali salt is remarkably reduced, and other conventional solvent methods, the emulsion method and the fine pulverization method which have already been put to practical use are not used. It has been found that an enteric preparation having a quality equal to or higher than that obtained by the water-based enteric coating method can be easily obtained. That is, the present inventors have paid attention to the amount of ammonium salt remaining in the film formed by the alkali neutralization method, and as a result of diligent studies, as a result, only when the HPMCAS was neutralized with ammonia, the coating operation and the coating were performed. By drying after the completion, it was found that deammonification easily occurs, the amount of ammonium salt in the enteric coating layer can be significantly reduced, and as a result, a good enteric function can be imparted, and the present invention has been completed.

As a matter of course, according to the method of the present invention, since the water-based solvent method is adopted, there is no risk of explosion in the organic solvent method, environmental conservation problems, and residual solvent problems in the preparation. Also, there is no problem of residual monomers in the enteric polymer obtained by the emulsion polymerization method, which is often pointed out in other water-based enteric coating methods that are currently in practical use. Therefore, according to the method of the present invention, the conventional coating equipment and techniques can be directly scaled up for industrialization, and in that case, excellent acid resistance and water resistance can be easily ensured and there is no ammonia odor at all.

The present invention is an aqueous enteric coating solution prepared by dissolving hydroxypropylmethylcellulose acetate succinate (HPMCAS) together with an amount of ammonia necessary for neutralizing about 80 mol% or more of carboxyl groups in the molecule. Regarding Further, more preferably, it is an aqueous enteric coating liquid containing no organic solvent. As another aspect, the present invention relates to a method for producing an aqueous enteric coating solution of the present invention, which comprises adding HPMCAS to an aqueous solvent and then adding aqueous ammonia to neutralize the carboxyl groups in the HPMCAS.

The enteric polymer used in the method of the present invention is hydroxypropyl methylcellulose acetate succinate (HPMCAS). Other phthalates,
It is difficult to reduce the residual ammonium salt with a methacrylic acid-based enteric polymer. The neutralizing agent is ammonia.

The water resistance and hygroscopicity of the enteric polymer depend almost on the residual amount of ammonium salt, but the amount of residual ammonium cannot be sufficiently reduced except for the combination of the above enteric polymer and the neutralizing agent. An enteric film having good water resistance and hygroscopicity cannot be obtained.

The method for producing the coating liquid and the method for coating will be specifically described below. Granular HPMCAS
(Commercial grade G type) is dispersed in water at room temperature, and then commercially available 28% ammonia water is added in an amount necessary to neutralize the carboxyl groups of HPMCAS and dissolved by stirring. At this time, the amount of ammonia added is equimolar to the carboxyl group, or 80% or more, preferably 95% to
Add 105% amount. When the amount of ammonia added is 80% or less, the dissolution of HPMCAS is insufficient and, for example, 120% or more can be added freely, but in this case, the unneutralized ammonia odor is strong and the coating finishes. The subsequent drying requires a long time, which is not advantageous. Although HPMCAS may be added to the aqueous ammonia solution to dissolve it, the former has a shorter dissolution time. Finely pulverized HPMCAS (commercial grade F type) can also be used for water dispersion coating, but when used in a complete solution system, granular HPMC can be used because of its ease of handling and dissolution time.
AS (G type) is advantageous.

As the ammonia to be used, commercially available 28% ammonia water may be used, but it may be appropriately diluted and used from the viewpoint of odor and workability. HPMCAS is currently marketed in three grades (L, M, H types) having different dissolution initiation pHs depending on the purpose of use. The L-type, M-type, and H-type dissolution initiation pHs achieved by the organic solvent method are 5.0, 6.0, and 7.0, respectively.
Is. The present invention only changes the addition amount of ammonia,
The coating liquid can be easily manufactured by any type of HPMCAS. In addition, the pH at which the obtained preparation starts to dissolve is
It was found to be in agreement with the case of the organic solvent method.
The preferable addition amount of 28% ammonia water to various commercially available HPMCAS is shown in Table 1 below, but the addition amount is extremely small.

[0015]

[Table 1] Preferred amount of ammonia water added to various grades of HPMCAS Commercial HPMCAS grade 28% Ammonia water amount HPMCAS-L 100g 9.4g HPMCAS-M 100g 6.7g HPMCAS-H 100g 4.5g

The obtained coating liquid is a pharmaceutically acceptable pigment such as titanium oxide, lake pigment, iron oxide, plasticizer such as triacetin and triethyl citrate, lubricant such as talc and magnesium stearate, silicone resin. Various additives such as defoaming agents such as and dispersants such as sodium lauryl sulfate may be added.

A normal propeller-type stirrer is sufficient as a stirrer used for dissolving HPMCAS and dispersing additives, and water used does not need to be cooled. Therefore, no special device is required for producing the liquid. do not need.

Examples of preparations to which the water-based enteric coating liquid of the present invention can be applied include tablets, granules and fine granules. The coating device is a conventional coating pan or aeration type coating for tablets. For the device, granules or fine granules, a fluidized bed coating device or a rolling fluid coating device can be used as a suitable device.
The conditions of the pump, spray gun, liquid feed line, and coating are the same as in the conventional method, and no special device is required. When the coating liquid of the present invention is used, the residual amount of ammonia in the final preparation can be controlled to about 25% by weight or less based on the completely neutralized amount by applying a known drying method (see Table 2 below).

[0019] Sugar coating and printing on the obtained tablets, polishing, antistatic of granules, improvement of fluidity, etc.
The present invention is not limited to the secondary processing of the preparation. The present invention will be specifically described below with reference to Examples and Comparative Examples, but these are for the purpose of explaining the present invention and do not limit the scope of the present invention.

[0020]

EXAMPLES Example 1 1. Preparation of enteric coating solution Disperse 100 g of HPMCAS-LG type (Shin-Etsu Chemical Co., Ltd.) in 1850 g of purified water at 25 ° C., and slowly stir with a propeller-type stirrer, 28% ammonia water (Wako Pure Chemical Industries)
9.4 g (100 mol% of the carboxyl groups of HPMCAS
Was neutralized) and stirred for 10 minutes until the solution became clear. Subsequently, triethyl citrate (Pfizer) 10
g and 30 g of talc (Fuji talc) are added for another 10
Stir for minutes.

The pH and viscosity of the obtained enteric coating solution and the amount of ammonia immediately after the solution preparation and after stirring for 5 hours were measured. The results are shown below. The amount of ammonia is shown as the amount remaining relative to the amount of ammonia initially added. Viscosity of coating liquid 30.5cp / 25 ℃ Immediately after the amount of ammonia 87.3% by weight Coating liquid pH 6.33 After 5 hours 80.0% by weight The viscosity of the enteric coating liquid is so low that it does not hinder the coating of granules. Immediately after the coating solution was prepared, the amount of ammonia was 87.3% of the initial amount added, but no ammonia odor was observed.

2. Preparation of enteric-coated preparation Aspirin is known to have a side effect of causing a gastric ulcer-like symptom when it is administered in a large amount in naked granules, for example, and it is one of the typical drugs for which an enteric-coated coating is desired to be applied. Using 400 g of extruded cylindrical granules of φ0.8 mm containing 50% of aspirin as a sample, a Wurster type fluidized bed coating machine Uniglat (Freund Industrial Co., Ltd.) was used, and the coating liquid was 25% by weight with respect to the elementary granules under the following conditions. It was applied and coated until. At this time, the coating solution was gently stirred at room temperature until the coating was completed. Blower temperature 65 ° C. Blower amount 2.5 m ³ / min Spray supply amount 5 g / min Spray pressure 2.0 kg / cm ^{2 The} obtained coating preparation was finally dried at 70 ° C. for 10 minutes.

Example 2 1. Preparation of enteric coating liquid An enteric coating liquid was prepared in the same manner as in Example 1.1 except that 100 g of HPMCAS-HG type (Shin-Etsu Chemical) was used. 2. Preparation of enteric coated preparation Aspirin cylindrical granules 4 were treated in the same manner as in Example 1.2.
00g was coated.

Comparative Example 1 Hydroxypropyl methylcellulose phthalate (HPMCP-5) was used as an enteric polymer instead of HPMCAS.
5) (Shin-Etsu Chemical) 100g, and 28% ammonia water 1
Substantially the same as Example 1, but using 2.2 g.

Comparative Example 2 As a neutralizing agent, 10% Na was used instead of 28% ammonia water.
Substantially the same as in Example 1, except that an aqueous OH solution was used. HPMCAS was added to 1794.5 g of purified water at 25 ° C.
-Disperse 100 g of L type, add 61.7 g of 10% NaOH solution while slowly stirring with a propeller stirrer,
The solution was stirred for 10 minutes until it became clear. Then, add 10 g of triethyl citrate and 30 g of talc, and add 1 more.
Stir for 0 minutes.

Disintegration test The disintegration test of each enteric-coated granule prepared above was carried out by using, as test solutions, JP No. 1 liquid, JP No. 2 liquid, 37 ° C. purified water, and each pH.
Of McKilvein buffer solution. The Japanese Pharmacopoeia No. 1 solution corresponds to artificial gastric juice and is used to evaluate acid resistance to gastric juice. The Japanese Pharmacopoeia Second Solution corresponds to artificial intestinal fluid and is used to evaluate the solubility in intestinal fluid. Purified water is used to evaluate water resistance. The McIlvain buffer solution is a phosphate buffer solution having a high ionic strength, and is used to evaluate the dissolution dependence on pH. The pH solubility dependence is a parameter for determining in which part of the intestinal tract, that is, in the upper small part, the middle part, the lower part, or the large intestine, the part is dissolved. Therefore, if the pH solubility dependence is sensitive, it means that precise drug delivery is possible. Finally, the residual amount of ammonia in the coating film of the final preparation was quantified by capillary electrophoresis and expressed as% of the initial addition amount (the amount that neutralizes 100 mol% of carboxyl groups).

[0027]

[Table 2]

In Examples 1 and 2 of the present invention, sufficient acid resistance and fast solubility, and a sharp dependency on pH as in the organic solvent method, were exhibited, and even when the test solution was water. No water permeation was observed. On the other hand, in Comparative Example 1 in which the enteric polymer was changed to HPMCP-55 and Comparative Example 2 in which the neutralizing agent was changed to NaOH, both of them disintegrated early, and particularly in Comparative Example 2, the first liquid. Dissolution was also observed in. This is apparently due to the residual amount of the neutralizing agent. Nonvolatile neutralizer NaOH
In Comparative Example 2 using, the dissolution was observed even in an acidic region, and even if ammonia as a volatile neutralizing agent was used, in the case of Comparative Example 1 in which the enteric polymer is HPMCP-55, the initial addition amount was half. Since some ammonia remains,
It dissolves rapidly even in purified water.

Example 3 HPMCAS-H type 10 was added to 900 g of purified water at 25 ° C.
0 g was dispersed, and while stirring slowly with a propeller-type stirrer, 4.5 g of 28% ammonia water was added, and the mixture was stirred for 10 minutes until the liquid became clear. Subsequently, 10 g of triethyl citrate and 30 g of talc were added, and the mixture was further stirred for 10 minutes. 15,000 simulated tablets of lactose and starch composition having a diameter of 7.0 mm and a weight of 150 mg were placed in a venting type coating machine type 48 (Freund Industrial Co., Ltd.), and the above coating solution was applied to 1
0 mg / tablet was coated.

Blower temperature 60 ° C Pan speed 20r.pm Blower amount 3.4m ³ / min Exhaust amount 3.8m ³ / min Spray supply amount 8g / min Slave pressure 2kg / cm ²

Comparative Example 3 10 g of triethyl citrate was added to 627 g of purified water at 25 ° C., and the mixture was stirred with a propeller stirrer for 10 minutes to dissolve triethyl citrate, then 30 g of talc was dispersed, and further Eudragit L30D-55. (Ream Pharma) 333
g was added and stirred for 10 minutes to prepare a coating liquid.
This solution was coated on the same simulated tablet as in Example 3 under the same conditions to the same coating amount.

Water Absorption Rate Test The enteric coated tablets obtained in Example 3 and Comparative Example 3 were tested according to the Japanese Pharmacopeia Disintegration Test Method using the first liquid and water as test liquids to permeate the enteric coated film. The water absorption rate of the test solution was tested. The% value in the table represents the weight ratio increased after the disintegration test for a predetermined time with respect to the weight before the test, which indicates the water absorption amount.

[0033]

[Table 3] Water absorption rate test result 1 hour 2 hours 3 hours Test solution Example 3 Comparative example 3 Example 3 Comparative example 3 Example 3 Comparative example 3 First solution 1.61% 2.63% 2.33% 5.28% 3.42% 7.11% Purified Water 1.97% 4.64% 2.53% 7.35% 3.91% 9.99% In Example 3 of the present invention, the permeation amount of the test solution was obviously smaller than that of Comparative Example 3, and the difference between the test solutions was also small.

Front Page Continuation (72) Inventor Nail Earl Anderson, USA 47906 West Lafayette, Indiana, Northwest Avenue 906 (72) Inventor Peter El Auren USA 46038 Manchester, Fisherman, Indiana Drive 6358 (72) Inventor Toshihiro Ogura 2-7 Aoyamadai Suita City Osaka Prefecture A4-107 (72) Inventor Toshio Fujii 1-1 1-1 Mukoyama Takarazuka City, Hyogo Prefecture

Claims (2)

[Claims] 1. An aqueous enteric coating solution obtained by dissolving hydroxypropylmethylcellulose acetate succinate (HPMCAS) together with an amount of ammonia necessary for neutralizing about 80 mol% or more of carboxyl groups in the molecule. 2. The water-based enteric coating liquid according to claim 1, which contains substantially no organic solvent.