KR19990072826A - A process for producing enteric-coated pancreatin granules - Google Patents

Abstract

The present invention relates to a method for preparing pancreatin enteric coated granules which are stable to tableting pressure and have excellent intestinal enzyme activity by first coating at low temperature using pancreatin as a seed and then performing second coating as necessary. will be.

Description

Method for manufacturing pancreatin enteric coated granules {A PROCESS FOR PRODUCING ENTERIC-COATED PANCREATIN GRANULES}

The present invention relates to a method for preparing fine enteric pancreatin coated granules which is stable at acidic pH, has excellent tabletting properties, and is stable at tableting.

Pancreatin is a digestive enzyme with amylase, protease, and lipase activity isolated from the pancreas of mammals such as cattle and swine, and is known as a therapeutic agent for cystic fibrosis, pancreatitis and pancreatic digestive enzyme deficiency. The pancreatic enzyme produced by the pancreas is secreted into the duodenum, where the pH is neutral to weakly alkaline. Secreted pancreatic enzymes are activated only under these pH conditions and digestion in the upper intestine can proceed normally. Pancreatin, which is ingested from the outside due to pancreatic insufficiency, must pass through the stomach, which is irreversibly inactivated by gastric acid and pepsin. Under acidic conditions, they usually exhibit low activity of 10-40%, of which lipases are particularly affected. Therefore, orally administered enzymes need a suitable protective film to prevent inactivation in the stomach.

Enteric coating is essential as an optimal protective film, and enteric coating applied to pancreatine preparation is divided into two types. The first is a technique that is widely used in the domestic market, a mixture of tablets and tablets with appropriate excipients and then enteric coating. Pancreatin is used as a multi-digestive enzyme rather than a single component, this type of formulation has an unreasonable aspect that the pharmacological action is not fully exhibited by enteric coating from the top to the component that should express the drug.

The second is a method of enteric coating (US Pat. Nos. 5,302,400 and 5,260,074) by compressing and drying granules obtained by mixing and assembling pancreatin with an appropriate excipient, binder and organic solvent, into spherical particles. The technique described in U.S. Patent No. 4,079,125 is made by mixing pancreatin with a suitable binder, stabilizer, disintegrant, and organic solvent, assembling, forming beads by marumerizer compaction, and enteric coating or creatine powder. And coating, roller compact, concave compact, convex compact, etc. are pressed into spherical plates, and then crushed and sieved to enteric coating without using organic solvents. This technique has been pointed out the problem of deactivation of the enzyme due to the use of solvent during the assembly process or the heat generated during the compression process and the inefficiency due to the multi-step process in the production. When the enteric-coated granules are applied to tablets in order to be stable to tableting pressure, the particles of the coated granules must be fine because the tablets must be fine to disperse the tableting pressure so that the enteric coating is formed without being brittle. However, the conventional method is insufficient to expect stable coating granules because the granules are not fine or non-uniform.

Therefore, there is a need for the invention of enteric coating granules which are advantageous and excellent in spontaneousness and stable to tableting pressure when pancreatin is partitioned into gastric and enteric portions only by uncoated or gastric coating. Accordingly, the present inventors have found a micro enteric coating method that is rapidly disintegrated in the intestine and stable to compression pressure based on the development of various polymers and natural product extraction raw materials as a coating base, and the enzyme is not inactivated in the gastric environment.

The present invention is characterized in that the coating solution is sprayed at high speed while the pancreatin is suspended at low temperature, and the fine coating granules formed as necessary are suspended at low temperature and re-sprayed with the same or different coating liquid as the primary coating solution at high speed to produce granules. Provided is a method for producing pancreatin enteric coated granules.

The coating bases used for the primary and secondary coatings in the method of the present invention include corn protein extracts and artificially processed analogous substances, sodium alginate, alginic acid, methacrylic acid-ethyl acrylate, shellacs, and carbopols (carbo) Mer ^(R) , carboxyvinyl polymer), hydroxypropyl methyl cellulose phthalates, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl acetate succinate, carboxymethyl cellulose, cellulose acetate phthalate, hydroxypropyl cellulose, Ethyl cellulose, methyl cellulose, polyvinylacetate phthalate, soy protein or wheat protein or artificially processed analogues, chitin or chitin acid or artificially processed analogs, agar, carrageenan, pectin ), Guar gum, Locus gum st bean gum, Xanthan gum, Gellan gum, Arabic gum, heavy chain fatty acids having 6 to 12 carbon atoms, etc. may be used alone or in combination of two or more.

The amount of the base used to prepare the coating liquid for each layer is 1 to 250% by weight, preferably 50 to 180% by weight, based on the amount of pancreatin used.

The plasticizer used in the coating of the present invention is polyethylene glycol, glycerin fatty acid esters, sorbitan fatty acid esters, propylene glycol, glycerin, triethyl citrate, triacetin, cetyl alcohol, stearyl alcohol, or the like, or a mixture thereof. The amount of plasticizer is 1 to 50% by weight, preferably 5 to 30% by weight based on the amount of pancreatin.

When the coating base and the plasticizer are out of the used range, the disintegration of the coating granules is delayed, so that rapid drug expression cannot be expected or a stable coating film cannot be obtained from gastric juice, thereby preventing enzymatic activity.

Solvents used in the coating include water, alcohols, acetone, acetonitrile, methylene chloride, ether, hexane, chloroform, 1,4-dioxane, tetrahydrofuran, dimethylsulfoxide, ethyl acetate, methyl acetate or these It contains a mixture of.

The device used for coating is a so-called "fluid bed assembly" (Fluid bed), or a similar device in the present invention used a fluid bed granulator SFC-MINI (Freund Co. Japan), but similar devices can be prepared for the formulation Do.

The manufacturing conditions of the device is that the temperature of the inlet air is in the range of 35 to 70 ℃ and the temperature of the granules in the step-by-step equipment should be at least 25 ℃ to prevent moisture absorption and aggregation of the granules.

However, all processes preferably maintain the temperature of the granules in the apparatus in the range of 25 ° C to 60 ° C. This is because at higher temperatures, the activity of the enzyme in the process may be reduced.

The following examples specifically illustrate the composition for enteric coating of pancreatin according to the present invention and a manufacturing process thereof.

Example 1

1st Coating Seed: Coating Liquid: 2nd Coating Seed: Coating Liquid: Pancreatin HPMC 2208 Water Polyethylene Glycol 6000 Primary Fine Coating Granule Eudragit ^(R) L 30D (Water Dispersion Type) Water Propylene Glycol 300 g 15 g 300 ml 2 g 300 g 1,320 ml (400 g as a solid) 500 ml 40 g

(a) Preparation of Primary Fine Coated Granules

The pancreatin powder was coated while spraying the coating liquid while floating in a fluidized bed granulator (SFC-MINI). The temperature of PRODUCT in the apparatus of the fluidized bed granulator was kept within the range of 25 ° C to 60 ° C.

(b) Preparation of Secondary Coating Granules

The fine coating granules of (a) were suspended in a fluidized bed granulator and coated by spraying the coating solution composed of Eudragit ^(R) L 30D and a plasticizer. The operating conditions of the fluidized bed granulator were within the above ranges and the temperature of the granules in the apparatus of the fluidized bed granulator was kept within the range of 25 ° C to 60 ° C. The secondary coating base may be optionally coated with Kollicoat MAE 30 DP.

Example 2

1st Coating Seed: Coating Liquid: 2nd Coating Seed: Coating Liquid: Pancreatin Alginate Sodium Water Glycerin Primary Microcoated Granules Zein-DP ^(R) (Corn Succulent Extract) Shellac 80% Ethanol Propylene Glycerin 300g3g300ml3g300g150g30g1,200ml6g12g

Prepared by primary coating and secondary coating using the above components in the same manner as described in Example 1.

Example 3

1st Coating Seed: Coating Liquid: 2nd Coating Seed: Coating Liquid: Pancreatin HPMC 2910 Water Glycerin Primary Coating Granule HPMCP 80% Ethanol Glycerin Fatty Acid Ester 300 g 10 g 200 ml 2 g 300 g 400 g 4000 ml 30 g

Prepared by primary coating and secondary coating using the above components in the same manner as described in Example 1. The primary coating base may be optionally coated with HPC.

Example 4

1st Coating Seed: Coating Liquid: 2nd Coating Seed: Coating Liquid: Pancreatin HPC Water Glycerin Primary Fine Coating Granule Polyvinylacetate Phthalate Water Propylene Glycol 300 g 10 g 200 ml 4 g 300 g 450 g 4000 ml 10 g

Prepared by primary coating and secondary coating using the above components in the same manner as described in Example 1.

Example 5

Seed: Coating Liquid: Pancreatin HPMCP 80% Ethanol Glycerin Fatty Acid Ester 300g400g4,000ml30g

The monolayer coating was carried out using the above components in the same manner as described in Example 1.

Example 6

Seed: Coating Liquid: Pancreatin Eudragit ^(R) L 30D Water Citric Acid Triethyl 300 g 1,485 ml (450 g as a solid) 300 ml 30 g

The monolayer coating was carried out using the above components in the same manner as described in Example 1. The coating base may be coated by changing to Kollicoat MAE 30 DP in some cases. In the case of monolayer coating, increasing the initial spray rate to form particles early can prevent the lowering of the titer caused by the coating liquid.

Laboratory Example 1

The particle distribution of the coated granules of Examples 1 to 8 was measured and the results are shown in Table 1 below.

Particle Size Distribution of Pancreatin Coated Granules (%) Mesh size (mm) 20 (0.84) 30 (0.59) 40 (0.42) 50 (0.297) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 7.49.59.311.74.89.0 50.547.645.844.152.254.7 38.634.437.340.038.630.5 3.58.57.64.24.45.8

As a result of Table 1, it was possible to obtain homogeneous coating granules in which the coating granules were distributed more than 80% in 30 to 40 mesh.

Laboratory Example 2

The creatine coated granules of Examples 1 to 6 were compared with the results of the pancreatin raw material by measuring lipase activity, amylase activity, and protease activity according to the European Pharmacopoeia Pancreatin Assay. The results are as shown in Table 2 below. .

Quantitative Results of Pancreatin Coated Granular Medium Creatine Content (%) Enzyme Activity (U / mg) Lipase activity Amylase activity Protease activity Raw material 73.1 80.5 6.1 Example 1 38.4 28.3 31.5 2.4 Example 2 59.1 43.3 47.0 3.6 Example 3 39.5 28.9 32.0 2.4 Example 4 37.7 27.4 30.9 2.3 Example 5 41.1 30.3 33.8 2.6 Example 6 38.5 28.2 31.3 2.3

In Table 2, the enzyme titers of Examples 1 to 6 almost corresponded to the titers (theoretical values) of pancreatin except for the coating base and the plasticizer. Therefore, the inventors have found that the enzymatic activity of pancreatin does not decrease during the coating process.

Laboratory Example 3

In order to examine the effect of tableting pressure according to the mesh size of the enteric-coated granules, the tablets obtained by directly hitting two kinds of coated granules of Examples 1 to 6 by size were eluted. At this time, microcrystalline cellulose was used as an excipient and the amount of enteric coated granules was 50% in the total tablets. Using Elution Test Device 1, the solution was stirred at 800 rpm for 60 minutes in 800 ml of artificial gastric juice at pH 2.0 and pH 3.0. Transfer it to artificial intestinal fluid (pH 6.0 phosphate buffer) and stir at 100 rpm for 30 minutes with Elution Test Apparatus 2, and then take the appropriate amount of this eluate to test lipase activity. The results are as described in Table 3 below.

Dissolution Test Results of Pancreatin When using a gastric juice of pH 2.0 When using artificial gastric juice of pH 3.0 Lipase Activity (U / mg) Tolerance (%) Lipase Activity (U / mg) Tolerance (%) Example 1 20-30 mesh 23.8 84.1 26.1 92.2 30-40 mesh 24.7 87.3 27.4 96.8 Example 2 20-30 mesh 15.0 34.6 18.5 42.7 30-40 mesh 18.0 41.6 19.1 44.1 Example 3 20-30 mesh 24.1 83.4 26.5 91.7 30-40 mesh 25.0 86.5 27.5 95.2 Example 4 20-30 mesh 23.2 84.7 24.5 89.4 30-40 mesh 24.5 89.4 26.2 95.6 Example 5 20-30 mesh 24.9 82.2 27.2 89.8 30-40 mesh 26.5 87.5 28.7 94.7 Example 6 20-30 mesh 22.8 80.9 25.1 89.0 30-40 mesh 24.8 87.9 26.8 95.0

As a result of Table 3, it can be seen that enteric-coated granules of pancreatin can serve as a protective film sufficiently under acidic conditions and are affected by the size of the coated granules.

Enteric coating granules of pancreatin of the present invention hardly cracked the coating layer due to tableting pressure. In the acid resistance test, the coating granules with large particles showed a lower titer than the coating granules with small particles. It is expected that the smaller the coating particles, the more the dispersion or absorption of tableting pressure prevents the coating layer from cracking.

Laboratory Example 4

In order to find out the effect of excipients (breaking of coated granules) when pancreatin enteric granules were directly struck, microcrystalline cellulose was used as excipients and then dissolution test was performed. The particle size of the pancreatin enteric granules used was 30-40 mesh, and the amount of tablets was 25%, 50%, 75% and 90%, respectively. The absolute amount of the pancreatin enteric granules was the same.

Dissolution Test Results of Pancreatin When using a gastric juice of pH 2.0 When using artificial gastric juice of pH 3.0 Content of Pancreatin Coating Granules (%) Lipase Activity (U / mg) Tolerance (%) Lipase Activity (U / mg) Tolerance (%) Example 1 25 26.1 92.2 27.9 98.6 50 24.7 87.3 27.4 96.8 75 21.2 74.9 24.4 86.2 90 18.3 64.7 21.0 74.2 Example 2 25 20.4 47.1 21.3 49.2 50 18.0 41.6 19.1 44.1 75 14.2 32.8 16.7 38.6 90 10.5 24.2 13.5 31.2 Example 3 25 26.8 92.7 28.2 97.6 50 25.0 86.5 27.5 95.2 75 22.7 78.5 25.1 86.9 90 19.4 67.1 21.0 72.7 Example 4 25 26.0 94.9 27.0 98.5 50 24.5 89.4 26.2 95.6 75 21.7 79.2 23.9 87.2 90 19.2 70.1 20.7 75.5 Example 5 25 28.6 94.4 29.3 96.7 50 26.5 87.5 28.7 94.7 75 23.2 76.6 26.4 87.1 90 20.0 66.0 23.1 76.2 Example 6 25 26.9 95.4 27.9 98.9 50 24.8 87.9 26.8 95.0 75 21.5 76.2 24.0 85.1 90 18.7 66.3 21.2 75.2

As a result of Table 4, the inventors were able to confirm that the coating layer is broken when the pancreatin enteric granules are directly struck with the excipient, when the ratio of the excipient is too small to act as a buffer for tableting pressure.

In view of the above experimental results, the pancreatin enteric-coated granules prepared according to the present invention have excellent stability against tableting pressure due to the fine particles, and the pancreatin intestinal activity of the tablets prepared according to the present invention is almost compared with the raw material itself. At comparable levels the invention will be very useful industrially.

Claims (11)

Method for producing a pancreatin enteric coated granules characterized in that the coating blasts are formed by spraying the pancreatin with a coating liquid at high speed while floating under low temperature. The method of claim 1, further comprising re-spraying the resulting coating granules with a coating solution that is the same as or different from the primary coating solution at high speed while floating under low temperature. The coating base according to claim 1, wherein the coating base is corn protein extract, sodium alginate, alginic acid, methacrylic acid-ethyl acrylate copolymer, shellac, carbopol, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, hydroxy Roxypropylmethyl acetate succinate, carboxymethyl cellulose, cellulose acetate phthalate, hydroxypropyl cellulose, ethyl cellulose, methyl cellulose, polyvinylacetate phthalate, soy protein, wheat protein, chitin, chitin acid, agar, carrageenan, Pectin, guar gum, low-cursor gum, xanthan gum, gellan gum, gum arabic, heavy chain fatty acids having 6 to 12 carbon atoms and mixtures thereof. The method of claim 1, wherein the plasticizer in the coating liquid is selected from the group consisting of polyethylene glycol, glycerin fatty acid ester, propylene glycol, sorbitan fatty acid esters, glycerin, triethyl citrate, triacetin, cetyl alcohol, stearyl alcohol and mixtures thereof How to be. The method of claim 1, wherein the amount of plasticizer is 1-50% by weight of the amount of pancreatin used. The method according to claim 1, wherein the content of pancreatin is 1 to 95% by weight of the granules. The method according to claim 1, wherein the content of the coating base is 1 to 250% by weight of the amount of pancreatin used. The method of claim 1, wherein the solvent in the coating liquid is water, alcohol, acetone, acetonitrile, methylene chloride, ether, hexane, chloroform, 1,4-dioxane, tetrahydrofuran, dimethyl sulfoxide, ethyl acetate, methyl Acetate and mixtures thereof. The method according to any one of claims 1 to 7, wherein all operations are carried out in the range of 20 ° C to 70 ° C. The method of claim 1 wherein the apparatus used uses a fluid bed coater or CF-Granulater. A method for preparing a tablet containing pancreatin coated granules according to claim 1, wherein the pancreatin coated granules are mixed with a pharmaceutically acceptable excipient in an amount of 5 to 80% of the total weight of the tablet and the mixture is compressed.