DE19907764A1 - Preparation of acid-resistant pancreatin granulates - Google Patents

Abstract

Preparation of acid-resistant pancreatin granulates comprises high-speed spraying of pancreatin powder with a coating solution at low temperatures. Preparation of coated pancreatin granulates that are resistant to gastrointestinal fluid comprises high-speed spraying of pancreatin powder with a coating solution at low temperatures. Pancreatin tablets are prepared by mixing and tableting 5-80 % (based on the total weight of the tablet) of the granulate with conventional pharmaceutical additives.

Description

The invention relates to a method for producing enteric-coated pancreatin granules, which are used in acidic pH values and when tableting is stable.

Pancreatin is a mammalian pancreatic like cattle and pigs with isolated digestive enzyme Amylase, protease and lipase activities. It is known that cystic fibrosis, pancreatitis, the pancreoprive syndrome and similar diseases with pancreatin can be treated. That from the pancreas Formed pancreatic enzymes are in the duodenum released, its pH value almost neutral or slightly alkaline is. Under these pH conditions, the Pan released kreasenzyme active, and the digestion of food by the Enzymes usually happen in the upper part of the small intestine. Becomes however, the pancreatin in treating the patient Pancreatin disorder is administered externally, the enzymes through the digestive conditions in the stomach, especially the Presence of stomach acid and pepsin, irreversibly inactive made. Under the acidic conditions, the enzymes 10 to  40% of their normal activity. The acid affects pH especially the lipase activity. Therefore, have to be taken orally Enzymes administered before gastric acid inactivation protected so that they can pass through the stomach remain unchanged into the duodenum.

The best way to protect the enzymes is by opening bring an enteric coating. Around two methods can be used. The first, well known method involves mixing the Pancreatins with a suitable additive, tableting the resulting mixture and applying one enteric coating on the thus obtained Tablets. The pancreatin is rather combined with other ver digestive enzymes, because used as a single active ingredient. As those under the additional ver duration enzymes that work in the stomach are coated, which is why they do not gain enough benefits in the stomach unfold. The other method is in the US patents Nos. 5,260,074 and 5,302,400. It is that Pancreatin with a suitable additive, binder and to mix organic solvents, the mixture too granulate, the granules too spherical particles too compact animals to dry the spherical particles and onto the dried particles an enteric coating to apply. In particular, the pancreatin with the suitable binders, stabilizers and degradants and the mixed suitable organic solvents which in U.S. Patent No. 4,079,125, subsequently resulting mixture granulated. The granules thus obtained is formed into balls by Marumerizer compacting be coated. Alternatively, the pancreatin powder comes with mixed with a lubricant and the resulting mixture Roll compacting, concave or convex compacting too curved platelets compacted. The platelets thus obtained are ground, sieved and without organic solvents coated. This method is not advantageous because the  Enzyme activity from the solution used in the granulation medium and the heat generated during compacting is reduced. The process is also inefficient because of it includes many levels. If the enteric coated Granules are tabletted, it must be against the tablettie pressure and be very fine. Since the Converting tableting pressure into heat, you can stomach that Form juice-resistant coated granules without it becomes crumbly. By the methods of the prior art however, can not very fine and uniform granules and therefore no granules are produced, the gastric juice consistently coated, stable under acidic conditions and for Tableting is suitable.

That is why, although pancreatin is beneficial when used as a complex preparation, d. H. in the form of tablets in which gastrointestinal compartments by mere Ta tableting or protective coating up to the stomach there is still a need for the development of gastric juice resistant coated granules that are resistant to the tablet pressure is stable when used alone. Of an improved coating process for the protection is provided to the intestine, which in the stomach unchanged activity of pancreatin, the rapid Dissolution of the enteric coated granules in the Intestine and the stability of the coated granules the tabletting pressure is ensured.

A feature of the invention is that it is a method for the production of enteric coated granules which provides spraying the pancreatin powder with a coating solution at high speed while the pancreatin powder floats at a low temperature, whereby coated fine pancreatic granules is obtained, and if necessary, spray the resultant again fine granules with another coating solution, the is different from or equal to the first coating solution,  at high speed, while using the fine granules low temperature floats, with the coated pan forms creatine granules.

Another feature of the invention is that it is a Provides processes for the production of pancreatin tablets, which is spraying the pancreatin powder with a Coating solution at high speed while the Low temperature pancreatin powder floats, with coated fine pancreatic granules is obtained, expl if necessary, spraying the resulting fine again Granules with another coating solution, the ver is different from or equal to the first coating solution, at high speed, taking coated pancreatin Granules forms, mixing 5 to 80% of the resulting coated granules, based on the total weight of the Ta bletten, with a pharmaceutically acceptable additive and Tableting the mixture obtained.

The coating base according to the invention comprises corn protein extract, sodium alginate, alginic acid, methacrylic acid-ethyl meth acrylate copolymer, shellac, carbopol (carbomer, carboxy vi nylpolymer), hydroxypropyl methyl cellulose phthalate, hydroxypro pylmethyl cellulose acetate succinate, hydroxypropyl methyl acetate succinate carboxymethyl cellulose, cellulose acetate phthalate, Hydroxypropyl cellulose, ethyl cellulose, methyl cellulose, Polyvinyl acetate phthalate, soybean protein, wheat protein, Chitin, chitic acid, agar, carrageenan, pectin, guar flour, Locust bean gum, xanthan gum, gellan gum, gum arabic and medium chain fatty acid with 6 to 12 carbon atoms. These can be used individually or as a mixture of two or several of them are used. The coating base can be in proportions of 1 to 250 wt .-% and preferably of 50 up to 180 wt .-%, based on the total weight of the used Pancreatins.  

The Weichma used for the coating according to the invention cher includes polyethylene glycol, glycerin fatty acid esters, Sorbi tan fatty acid ester, propylene glycol, glycerin, triethyl citrate, Triacetin, cetyl alcohol and stearyl alcohol. these can used individually or as a mixture of two or more thereof become. The plasticizer can be used in proportions of 1 to 50% by weight. and preferably from 5 to 30 wt .-%, based on the total Ge importance of the pancreatin used.

Are the coating base and the plasticizer in other ratios than this, is delayed the degradation of the coated grain or the coating is in the Gastric juice unstable. As a result, either the pan works creatine not fast or its activity decreases.

The solvent for the coating solution according to the invention includes water, alcohol, acetone, acetonitrile, methylene chloride, Ether, hexane, chloroform, 1,4-dioxane, tetrahydrofuran, Dimethyl sulfoxide, ethyl acetate, methyl acetate or a mixture from that.

Many fluidized bed apparatuses or similar devices are used. For the invention the SFC-MINI fluid bed apparatus (Freund Co., Japan) used. The temperature of the incoming air is 35 up to 70 ° C. The temperature of the granules must be during the total process at least 25 ° C to aggregate and prevent the grains from crumbling. It is before increases the temperature of the grains during the process to 25 to 60 ° C because the enzyme activity at temperatures of over 60 ° C.

The following examples illustrate the combination according to the invention composition and the inventive method for the manufac treatment of enteric coated pancreatic granules.

Examples

example 1

(A) Preparation of the first coated fine granules

While the pancreatin powder in the fluidized bed apparatus (SFC-MINI) floated, it was loaded with the above first coating solution sprays. The product in the fluidized bed was heated to a tem temperature set from 25 to 60 ° C.

(B) Preparation of the second coated granulate

During the first coated fine granules in the vortex layer floated, it became with the second coating above sprayed solution, the Eudragit® L 30D and a plasticizer held. The granules in the fluidized bed left the temp temperature range from 25 to 60 ° C not. As a second coating The basis of the choice can be used with Kollicoat MAE 30 DP become.  

Example 2

The first and second coated granules were opened prepared in the same manner as described in Example 1, wherein however, the above components were used.

Example 3

The first and second coated granules were opened prepared in the same manner as described in Example 1, wherein  however, the above components were used. Be the first Coating base can optionally be used HPC.

Example 4

The first and second coated granules were opened prepared in the same manner as described in Example 1, wherein however, the above components were used.

Example 5

The pancreatin was prepared in the same manner as in Example 1 wrote one-layer coated, but the aforementioned Components were used.

Example 6

The pancreatin was prepared in the same manner as in Example 1 wrote one-layer coated, but the aforementioned Components were used. If necessary, instead of le of this coating base Kollicoat 30 DP is used become. By taking the single-layer coated granulate under An increase in spray speed can be produced Reduction of enzyme activity by the coating solution be prevented.

Experimental example 1

The particle size distribution of that in Examples 1 up to 8 coated granules produced. The he Results are shown in Table 1 below.

Table 1

Particle size distribution (%) of the coated pan creatine granules

Table 1 shows that particles of 30 to 40 mesh make up at least 80% of the coated granules. The he Results show that the coating produced according to the invention granules is uniform.

Experimental example 2

Of the pancreatin prepared in Examples 1 to 6 The lipase, amylase and protease activity became granular using the pan described in the European Pharmacopoeia creatine experiment measured. The activities were aligned with those of the compared raw pancreatins as a control. The results are summarized in Table 2 below.

Table 2

Table 2 shows that the enzyme activity of the in the Examples 1 to 6 produced coated pancreatins almost is the same as the raw pancreatin used as a control, that was free of coating base and plasticizer. The Results show that the enzyme activity of pancreatin in Coating had not decreased.

Experimental example 3

Of those coated in Examples 1-6 Granules became two granules depending on the particle size selected and compressed to obtain tablets. With the A dissolution test was carried out to obtain tablets the influence of tableting pressure on coated granules to determine with different particle size. As an additive microcrystalline cellulose was used, and the proportion of coated granules on a tablet was 50% by weight. Each 800 ml of artificially produced gastric juice with one pH values of 2.0 and 3.0 were measured in an apparatus 1 for the Dissolution test stirred at 100 rpm for 60 minutes. she were in an artificially produced intestinal fluid (Phos phate buffer, pH 6.0) and placed in an apparatus 2 stirred for 30 minutes for the dissolution test at 100 rpm. Samples taken in an appropriate amount were checked for their lipase activity examined. The results are as follows Table 3 listed.

Table 3

The results of Table 3 show that the gastric juice resistant coated pancreatin granules depending on the Particle size of the grains in acidic conditions appropriate protection.

The coating of the gastric juice-resistant according to the invention coated pancreatin granules was through the tablettie pressure is not broken. The acid resistance test showed that the enzyme activity increases with increasing size of the coated grains decreased. That means that since smaller coated grains are more capable of tableting converting pressure into heat or absorbing their coating is not broken.

Experimental example 4

The coated pancreatin granules were made using microcrystalline cellulose compressed as an additive. With the dissolution test was carried out on the tablet obtained, to the influence of the additive on the tablet examine. Coated pancreatin granules of 30 to 40 mesh in proportions of 25 wt%, 50 wt%, 75 wt% and 90 wt .-%, based on the tablet used. The Absolute Amounts of coated pancreatin granules in the tablets were the same. The results are shown in Table 4 below listed.  

Table 4

The results of Table 4 show that when the additive is used in too small amounts in the tablets, it does not serve as a buffer against the tableting pressure and the loading layering can be easily broken.

Claims (11)

1. Process for the preparation of enteric be layered pancreatin granules, which are the spraying of Pancreatin powder with a coating solution at high Speed while the pancreatin powder at lower Temperature hovers, with the coated pancreatingra nulate is obtained. 2. The method of claim 1, wherein the resulting coated Pancreatin granules with another coating solution, which are different from or equal to the first coating solution is sprayed again at high speed, while the granules are floating at a low temperature. 3. The method of claim 1 or 2, wherein the coating basis is selected from a group consisting of Corn protein extract, sodium alginate, alginic acid, methacrylic acid-ethyl methacrylate copolymer, shellac, Carbopol, Hy hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, hydroxypropyl methylacetate succinate Carboxymethyl cellulose, cellulose acetate phthalate, hydroxy propyl cellulose, ethyl cellulose, methyl cellulose, poly vinyl acetate phthalate, soybean protein, wheat protein, Chitin, chitic acid, agar, carrageenan, pectin, guar flour, Locust bean gum, xanthan gum, gellan gum, gum arabic and medium chain fatty acid with 6 to 12 carbons atoms exist. 4. The method of claim 1 or 2, wherein the plasticizer from selected from a group consisting of polyethylene glycol, Glycerin fatty acid esters, sorbitan fatty acid esters, propylene glycol, glycerin, triethyl citrate, triacetin, cetyl alcohol and stearyl alcohol and a mixture thereof.   5. The method of claim 1 or 2, wherein the plasticizer in Proportions from 1 to 50%, based on the total weight of the used pancreatins. 6. The method of claim 1 or 2, wherein the pancreatin in Proportions from 1 to 95%, based on the total weight of the Korn, is used. 7. The method of claim 1 or 2, wherein the coating basis in proportions of 1 to 250%, based on the Total weight of the pancreatin used. 8. The method of claim 1 or 2, wherein the solvent is selected from a group consisting of water, alcohol, Acetone, acetonitrile, methylene chloride, ether, hexane, Chloroform, 1,4-dioxane, tetrahydrofuran, dimethyl sulfoxide, There is ethyl acetate, methyl acetate and mixtures thereof. 9. The method of claim 1 or 2, wherein the entire process is carried out at a temperature of 20 to 70 ° C. 10. The method of claim 1 or 2, wherein a fluidized bed layer or a CF granulator is used. 11. Process for the preparation of pancreatin tablets, which the mixing of 5 to 80%, based on the total Ge weight of the tablet, enteric coated Gra nulates according to claim 1 or 2 with a pharmaceutical compatible additive and tableting the obtained Mixture includes.