DE1617363B1 - Process for the production of highly active enzyme digestive preparations - Google Patents

Description

A method for producing a new application form A has now been found, which meets all intermediate and technical requirements and no more has the disadvantages of the previously known commercial products. The inventive Process for the production of highly active enzyme digestive preparations from stomach and small intestine active substances Enzymes in tablet or dragee form are characterized in that they are active in the small intestine Enzymes as dry powder with a solution of an acid-insoluble and an alkali-soluble one Plastic wet granulated, the granulate dries and this together with a gastric enzyme containing granules, possibly with the addition an antifoam and disintegrant in granular form, known per se Compressed into tablets.

To achieve a quick phase separation between the gastric and small intestine active To reach enzymes, the gastric enzymes are appropriately disintegrated like finely divided silica and methyl cellulose too. Other disintegrants are agar-agar pulvis, starch and other hydrocolloids. Of course you can use gastric juice soluble Share easily add an acid component and / or an antifoam agent. The tablets or dragees produced according to the invention disintegrate. in gastric juice within a few minutes in two phases, one of which is immediately the gastric enzymes in finely divided form and any antifoam agents present and releases acid components. The second phase contains the pancreatic enzymes in shape of small granules, which are protected against the digestive juices of the stomach. In contrast to the previously known forms of application, the pancreatic enzymes rapidly and completely released in the weakly alkaline environment of the small intestine and can develop their full enzymatic effect there. Because the individual Particles of the pancreatic enzymes through an acid-insoluble and alkali-soluble plastic varnish are glued together, they are even then removed from the digestive juices of the stomach not attacked if the granules are crushed or deformed during compression should be.

The new form of application differs from the ones mentioned above known preparations (cf.

Gs t i r n er, loc. cit.) in that there is no protective layer, but the powdery pancreatic enzymes by an acid-insoluble and an alkali-soluble one Plastic varnish are glued together; d. i.e., each one of the granules is made over its entire cross-section from a mixture of pancreatic enzymes and varnish, the components are evenly distributed.

It was not foreseeable that the pancreatic enzymes could be used without a loss of activity Glue to form granules with an acid-insoluble and alkali-soluble plastic varnish can and thereby both against the attack of gastric acid or the acidic component of the combination product protect as well as quickly and in finely divided form can release in the small intestine. The activity of pancreatic enzymes is already going lost to a considerable extent by small amounts of isopropanol or acetone. the commonly used acid-insoluble and alkali-soluble plastic varnishes, such as cellulose acetate phthalate (CAP varnish) or varnishes based on polyacrylic acid (Eudragit varnish), contain acetone or isopropanol as solvents. So one should have expected that the solvents used to dissolve the plastic paints have significant losses in activity of the sensitive pancreatic enzymes. Furthermore, one had to assume that from something like that When granules "stick together", the enzymes are only released very slowly in the small intestine. (According to Gs t i r n e r, the layer thickness of coatings is relatively critical [cf. P.534 3rd paragraph; when G s t i r n he mentions that a coating should not be too thick is allowed, granules completely bonded to the acid-insoluble lacquer must a priori be considered unusable.) Surprisingly, it was found that the Inactivation of the Pancreatic enzymes by the said organic solvents almost is completely reversible and practical if carefully but completely removed can be completely canceled. In addition, it was unexpectedly found that the granules dissolve very quickly and also the pancreatic enzymes in the release desired finely divided form.

For easier processing of the plastic lacquers, the addition of plasticizers such as diethyl phthalate or polyglycols, which are not Have an influence on the activity of the pancreatic enzymes. The careful but complete Removal of the activity-reducing solvents from the plastic paints either by drying in a vacuum drying cabinet or in an even simpler way Way by displacing the activity-reducing solvents by a likewise highly volatile but harmless solvent. Trichioethylene has proven itself here particularly proven.

The new enzyme digestive preparations produced according to the invention have proven themselves brilliantly in clinical trials and have the following advantages compared to the previous commercial products: 1. The individual active ingredient components are released rapidly with full activity at the point where they take effect should come.

2. The enzymes sensitive are during storage and during the gastric passage protected against destruction.

3. By protecting the sensitive enzymes that pass through the stomach and in that the active ingredients quickly develop to their full potential at the site of their action come, with significantly lower amounts of the valuable enzymes, higher effects can be achieved can be achieved, whereby the therapy can be made much cheaper.

4. The process according to the invention for the production of the new preparations is technically very simple and can be compared with those used in pharmaceuticals at no high cost Industry usual practices and existing machinery can be easily carried out.

The following examples are the preparation and composition of the enzyme digestive preparations according to the invention are described: Example 1 30 kg pancreas dry powder are with 6.64 kg of a varnish based on polyacrylic acid (Eudragit varnish L with approx 13% dry matter) moistened and mixed well. The resulting granules are dried at 40 ° C. 2 kg of dimethylpolysiloxane and 2 kg of polyethylene glycol 20,000 are dissolved in 31 trichlorethylene, distributed evenly over the granules and dried again at 400 ° C.

3.81 kg of milk sugar and 3.81 kg of starch are made with 10% starch paste granulated and, after drying, mixed with 1.3 kg of Aspergillus peptidase.

9 kg of finely divided silica (Aerosil) and 2 kg of methyl cellulose are mixed well, moistened with a little water, granulated and dried at 60 ° C.

The three granules are mixed and made into tablet or dragee cores compressed. The mixture enough to produce about 100,000 Cores of the following composition: pancreatic enzymes. 300.0 mg aspergillus peptidase ... .... 13.0mg dimethylpolysiloxane ........... 20.0mg polyacrylic acid varnish (Eudragit-L) 9.0 mg milk sugar. ... 38.1 mg starch .................... 38.1 mg polyethylene glycol 20 000 .. .... 20.0 mg methyl cellulose ............ 20.0 mg coll. Silicic acid (Aerosil) . . .. 90.0 mg total weight .... . . If desired, the tablets are 548.2 mg coated with a protective varnish, the tablet cores are coated in the usual way with a Sugar layer provided.

Example 2 30 kg of dry pancreas powder weighs 6.64 kg evenly Eudragit-L varnish (13% dry content) soaked, mixed and dried at 40 ° C. The granules obtained in this way are mixed with 2 kg of dimethylpolysiloxane in 1.5 l of trichlorethylene treated and dried at 400 C.

9.8 kg of citric acid are granulated with alcohol and heated to 40 ° C dried. 8.5 kg of Aerosil and 3.5 kg of methyl cellulose are mixed with water granulated and dried at 60 ° C. The three granules and 1.3 kg of Aspergillus peptidase are mixed and pressed into tablet or dragee cores. The approach is enough for the production of around 100,000 tablet cores with the following composition: pancreatic enzymes *. . .... . . . . . 300 mg Aspergillus peptidase ....... ... 13 mg dimethylpolysiloxane .. 20 mg citric acid DAB 98 mg methyl cellulose ................. 35 mg polyacrylic acid varnish (Eudragit L) .. 9 mg Aerosil. . ..... ...... 85mg total weight .... 560 mg Die If desired, tablets are coated with a protective varnish, the tablet cores are coated in the usual way.

Example 3 30 kg of dry pancreas powder are mixed evenly with 15 kg of a varnish soaked in the following composition: parts of cellulose acetate phthalate, 3 parts of diethyl phthalate dissolved in 42.5 parts of ethyl acetate and 42.5 parts of isopropyl alcohol. The granules obtained in this way are dried at 40 ° C. with 2 kg of dimethylpolysiloxane treated in 1.51 trichlorethylene and dried again at 400.degree.

9.8 kg of citric acid are granulated with alcohol and dried at 40 ° C. 8.5 kg of Aerosil and 3.5 kg of methyl cellulose are mixed and granulated with water and dried at 600 C. The three granules and 1.3 kg of Aspergillus peptidase mixed and pressed into tablet or dragee cores. The kernels have practical the same composition as that prepared according to Example 2, but contain instead of 9 mg of Eudragit varnish, 18 mg of cellulose acetate phthalate and 4.5 mg of diethyl phthalate per unit.

From the following comparative experiments with coated tablets according to the example 1, with the commercial products Nutrizym (A), Combizym comp. (B), Pancreatan (C), Festal (D) is the superiority of the novel enzyme digestive preparations produced according to the invention from: I. Disintegration time (measured in the ERWEKA disintegration tester) disintegration time in art.

Water duodenal juice (min.) (Min.) Trial preparation ......... 15 10 Commercial preparation A ........ 120 120 Commercial preparation B. . . . . . . 120 90 commercial preparation C. . . . ... . 150 240 commercial preparation D. . . . . . . . 90 90 II. Provision the lipase activity after a preincubation at pH 3 coated tablets according to Example 1 as well as the coated commercial preparations A-D are 30 minutes at pH 3 and Pre-incubated at 30 ° C. Then after 30 and 60 minutes at pH 8.5 and 300C the released lipase activity measured (triglyceride cleavage; 12.5 g olive oil per 500ml) and compared with the amount of lipase originally contained in the dragee (determined by grinding the coated tablets).

Triglyceride cleavage based on an ester bond preparation according to included 30 minutes 60 minutes L E. lipase%% per coated tablet test preparation ... 14.4 47.5 3000 commercial preparation A .. 12, 4 20.7 5320 commercial ice cream preparation R .. 5.5 23.4 4320 commercial preparation C .. 11.8 22.2 4420 commercial preparation D .. 2.8 8.3 2790 Aus The above values clearly show that the preparation produced according to the invention significantly higher enzyme activities despite the lower use of active pancreatic powder releases. In the case of the comparator preparations, either the acidic preincubation, which inactivates part of the lipase, or by the very slow and incomplete Release a much lower enzyme activity to take effect.

III. Clinical testing in pancreatectomized or severely pancreatic insufficiency patients (the assessment is based in particular on the weight of the stool and the excretion of trypsin, chymotrypsin and fat in the stool) Pat dude No gender diagnosis dosage assessment 1 27 years old, # total pancreatectomy 12 coated tablets over the very good therapy Day distributed success 2 48 years, # total pancreatectomy 12 dragées over the gut Day distributed 3 51 years, # subtotal pancreatectomy 12 coated tablets over the very good Day distributed 4 36 years, # chron. calcified pancreatitis 3 x 4 dragees good 5 43 years, # op. Pancreatic cyst after acute 3 x 3 coated tablets very good Pancreatitis 6 26 y., Oß excretor. Pancreatic Insufficiency 3 x6 Dragees very good after resection of the paper 7 59 years, # chron. calcified pancreatitis 3/4/3 coated tablets 5/5/5 very good 8 22.J., #excretor. Pancreatic insufficiency 3/4/3 coated tablets are good with accompanying pancreatitis 9 # chron. recurrent. Pancreatitis 3 x 5 coated tablets well 10 # primary-chron. Pancreatitis 3 x 3 coated tablets very well As can be seen from the above values, patients with total pancreatectomy can be completely compensated for with just 12 coated tablets of the new preparation a day. By comparison, in such severe cases up to 20 g of commercially available preparations (25 to 40 dragees) must be administered (cf. Ritter, "Die chronic pancreatitis, current diagnostics and therapy", German Medical Journal, 18 [1967], p. 484).

Claims (1)

Claim: Process for the production of highly active enzyme digestive preparations composed of enzymes active in the stomach and small intestine in tablet or dragee form, characterized that small intestine-active enzymes as dry powder with a solution of an acid-insoluble and alkali-soluble plastic wet granulated, the granulate dries and this together with a granulate containing gastric enzyme, optionally under Addition of an antifoam agent and disintegrant in granular form, in a manner known per se Compressed into tablets. The present invention relates to a method of production highly active enzyme digestive preparations made from enzymes active in the stomach and small intestine in Tablet or dragee form, which has good stability and a low disintegration time exhibit. Have combination products with gastric and small intestinal enzymes has become of great importance for the treatment of digestive disorders. Such preparations can additionally contain a component which replaces gastric acid or stimulates its natural secretion. For fighting from flatulence, such preparations can also be treated with antifoam agents such as dimethylpolysiloxane, combine. Combination preparations of this kind meet the medical requirements then ideally do justice if the individual components work in an analogous manner as in the physiological digestive process in the gastrointestinal tract in the right place come to full effect at the right time. So the stomach-active enzyme component, the acid component and the antifoam act as quickly as possible in the stomach unfold, the enzyme fraction active in the small intestine should only after leaving the stomach, but then as quickly and completely effective as possible, and the antifoam should be active during the entire intestinal passage if possible. Since some of the enzymes are very sensitive, we are involved in the manufacture Such complex combination preparations are associated with considerable pharmaceutical problems. The major digestive supplements on the market include, for example the pancreatic enzyme complex with proteases, amylases and lipases, their activity can only develop in the pH range of the small intestine. Be during the gastric passage these pancreatic enzymes as proteins themselves are attacked by the digestive juice of the stomach and inactivated by gastric acid due to the pH instability. With the commercial preparations partial protection of the enzymes active in the small intestine has been achieved in that they are compressed very hard in tablet or dragee form. During the gastric passage These preparations only partially disintegrate and are therefore only superficial attacked. In common disintegration test devices for tablets or coated tablets (according to USP XVII or Erweka disintegrability tester) is therefore measured in the most important im Commercially available digestive preparations disintegrate times between 1 and 3 hours. A major disadvantage of all these commercial products is that only the part of the hard-compressed tablet or dragee cores is really used released in the correct part of the digestive tract. the Enzyme activities active in the small intestine are converted from the hard-compressed tablet or tablet cores partially released too early and thereby inactivated and partially in the small intestine, but only released there very slowly. Another disadvantage These preparations consist in the fact that the enzymes that are active in the small intestine cannot be left without may compress further together with the acid component, otherwise already with the sensitive enzymes, such as lipases, are destroyed during storage. With some For this reason, commercial preparations include the enzymes and the acid component in three dimensions separated from each other in different layers of so-called "multilayer tablets" contain. The manufacture of multilayer tablets is very expensive and requires complicated special machines. Multi-layer tablets still do not work either Protection for the pancreatic enzymes against the digestive juices of the stomach. A very good one, but very expensive and technically complex The solution to the problem is the individual components of a digestive preparation to granulate separately and to sugar-coat these granules, whereby the acid-sensitive and covers components that are only needed in the small intestine with acid-resistant protective layers (cf. in particular G s t i rn e r, raw materials and methods of drug preparation, Stuttgart 1960, pp. 529 and 530; also Bamann, The Method of Ferment Research, 1941, p. 2937; and B ü c h i, Galenisches Praktikum, 1959, p. 760). The beads obtained in this way cannot be made into tablets or coated tablets be compressed, as they burst when compressed and thus their protective effect lose. It is therefore necessary to correctly identify the different types of beads Mix ratio and fill in gelatine capsules. Compared to the usual method, a compressed file with or without To produce a coating (coated tablet or tablet), this process is very laborious, time-consuming and expensive: apart from the technical effort involved in granulation, Coating and filling in gelatine capsules are proportionate to the weight the active ingredients require considerable amounts of auxiliary substances. Since in push-in capsules the Pellets can only be poured loosely, one needs compared to one Compress a lot more space, and because the individual capsule is not arbitrary can make it big without making swallowing much more difficult for the patient add only relatively small amounts of active ingredient per dosage unit.