DE4332985A1 - Pharmaceutical composition for the treatment of exocrine pancreas dysfunction - Google Patents

Abstract

The present invention relates to a pharmaceutical composition which is characterised by a combination of a) an enzyme mixture comprising at least one protease, one lipase and one amylase, with b) at least one buffer substance. The pharmaceutical composition is suitable for the treatment of dysfunction of the excretory pancreas (DEP). This disorder comprises disturbance of the function of the exocrine pancreas, the disturbance occurring in rhythmic intervals of about 24 hours. This pancreatic dysfunction has been detected in other syndromes such as dyspepsia, Crohn's disease, colitis, hypotension, gastritis, duodenitis and ulcers.

Description

The present invention relates to a pharmaceutical composition containing a Combination of an enzyme mixture of at least one Pro tease, an amylase and a lipase with at least one Buffer substance contains. The drug is especially for Treatment of dysfunction of excretory (exocrine) Pancreas suitable.

Indigestion is widespread in the population (occurring in 30-40% of the world population). Numerous Ver Condition disorders are the result of enteral infections, such as for example by coliform bacteria or different virus types. Furthermore, indigestion can be caused by a Insufficiency of the pancreas are caused. At the pancreas Insufficiency, the exocrine function is permanently disturbed. ur The cause of this disorder is for the most part true apparently genetically determined damage of the excretory Pancreatic tissue. A total pancreatic insufficiency ever plays but only at a very small percentage of over Ver the causative role of patients suffering from for the appearance of the complaints.

The present invention is based on the finding that Ver Dysfunction often not caused by a persistent pancreas insufficiency are conditional, but that for these disorders a rhythmic dysfunction of the exocrine pancreas ver is responsible. This rhythmic disorder of pancreatic radio tion is hereafter called dysfunction of the exocrine pancreas or abbreviated as "DEP".

Dysfunction of the exocrine pancreas is the disorder not only in that the exocrine performance is qualitative and disturbed quantitatively in the different components is, but in addition, that they are with phases normal function alternates. For this purpose wear next to the open  visibly genetic determination nor vegetative neural Influences in different qualitative and quantitative Extent and age at. For these reasons occur alternating pathological and normal stool findings. So you can not always get the DEP at the first chair bottom search (3 individual samples), but it must gege if necessary, be repeated once or twice. From the same Reasons are also the clinical complaints not continuous but at irregular intervals (therefore These are only occasionally occurring from time to time Psyche attributed), provided sub-functions and normal Function phases are ever off at regular intervals change - why the DEP most likely by a sinusoid of exocrine pancreatic function performance can (abscissa: time, ordinate: exocrine pancreatic function).

If the intersection of abscissa and ordinate, so the Null the missing exocrine pancreatic function, d. H. the should represent total exocrine pancreatic insufficiency, so For example, the DEP sine curve is approximately in the positive ordinate area that the valleys of the curve in about 12-hour intervals in each case close to the abscissa.

Consequently, the DEP is therefore not always straight off the lab to prove chemically, she can most likely with an im 24-hour rhythm oscillating sinusoid become.

From this circumstance results the rhythmic dysfunction In comparison, the more difficult diagnosis of this disease to pancreatic insufficiency, as alternating at dysfunction pathological and normal findings of the stool, depending on the momentary Functional performance of the pancreas, occur. From the same Reasons are also the clinical complaints not continuous but are interdependent at irregular intervals speed of the respective functional state of the pancreas. Furthermore, DEP is a genetic condition  Pancreatic disorder, which is hereditary and already in newborns and to observe the parents and siblings of the patients is.

The present invention is the technical problem a new drug for the treatment of the first once described dysfunction of the exocrine pancreas deliver.

This problem is solved by a drug that is caused by the combination a) of an enzyme mixture comprising at least a protease, at least one lipase and at least one Amylase, labeled b) at least one buffer substance is.

Suitable enzymes are preferably digestive enzymes, as they are naturally produced by the pancreas. These include proteases, such as trypsin and chymotrypsin, as well Aminopolypeptidase, Dipeptidase, Prolinase, Carboxylpolypepti dase, protaminase and elastase.

Preferably, at least one lipase is used, as in Pancreas occurs. These include phospholipase, licithinase A and B, phosphatase and cholinesterase. As a preferred enzyme Mixture finds the commercially available pancreatin, which an extract of porcine pancreas and / or bovine pancreas and amylase, trypsin, lipase, ribonuclease and Contains protease, application. In addition, gastric lipase ver be used.

As carbohydrate-cleaving enzymes of the pancreas come amylase and maltase.

It is also important that, at the same time as the Enzyme is administered a buffer substance, which serves the disturbed buffer environment occurring in the intestine during DEP, to the buffer condition present in a healthy person  to adjust. With the DEP it comes to diminished Hydrogen carbonate release of the pancreas, with the result that the pH of intestinal contents in DEP patients in the acidic environment is shifted, since the gastric acid, which from the digestive porridge be towed, can not be neutralized accordingly can. The administration of an alkaline buffer substance with The enzymes enable the adjustment of the pH in the intestinal lumen in DEP patients to the normal, physiological value, namely to pH 7 to 8.

The drug to be administered does not necessarily have the enzymes and contain the buffer substance in a tablet, but the both components can also be separated, i. H. in two ver various forms of administration as a combined preparation (in for example in the form of two different tablets) are sufficient, provided the administration of the two components Almost simultaneously, so that both components their Effect in the intestine can develop simultaneously.

Preferably, the enzyme mixture may also be a dry extract from Aspergillus orycae as commercially available believe it. This extract contains protease, lipase, cellulase and amylase activity.

The buffer substance, which ensures that after administration range of the drug in the intestine that of a healthy Pancreas generated physiological buffer conditions can be made from any physiological ver suitable buffer substance can be selected. Preferably come for this the salts of acetate, citrate, lactate, titrate, Bicarbonate, monohydrogen phosphate and dihydrogen phosphate into consideration. Hydrogen carbonate is particularly suitable because these Buffer substance also from the healthy pancreas to pH adjustment is secreted into the intestinal lumen. In particular is the sodium salt of bicarbonate for the pH adjustment in the intestine suitable.  

A further preferred embodiment contains in addition to the enzymes and the buffer substance magnesium, which the Activity of the enzymes in the intestine is able to increase and in DEP often not or only insufficiently secreted by pancreas and in the metabolism of 300 biochemical reactions performs catalytic reactions.

The medicament according to the invention can by conventional Her be obtained with the active ingredients, the customary auxiliaries and carriers are added.

The medicament according to the invention is particularly suitable for Treatment of dysfunction of the excretory pancreas, such as they already briefly described above and in the following he closer is purified.

Fig. 1 shows schematically the position of the pressure points in the abdomen space for the diagnosis of appendicitis after "Nc Burney" and the DEP after "summer".

The DEP is a recurrent, acute one every day Disease per se, which is the clinical manifestation picture of a chronic illness. For diagnosis The following investigations totaled 1300 Patients performed.

1. blood tests

A. The blood cell lowering rate according to Westergren always within the normal range. It is only increased if a be sliding intestinal infection is present. The average BKS n.W. was 3/6 in DEP patients without intestinal infection, in DEP patients with concomitant intestinal infection average 12/25, significant deviations from these There were no sectional values.  

B. The following serum parameters were determined: trypsin, Bile acids, pancreatic amylase, parotisamylase, lipase, lactate dehydrogenase, LAP, sodium, potassium, calcium, secretin, Secretin evocation, gastrin, serum electrophoresis, fetal electro phoresis, total protein in the serum, urea, uric acid, creatine nin, all pancreatic tumor markers, pancreoauryl test, cholesterol, HDL and LDL cholesterol, triglycerides, SGOT, SGPT, gamma GT, Erytrocytes, hemoglobin, HBE, middle corpuscular Erytroy volume, hematocrit, blood cell lowering rate according to Westergren, leukocytes, segmented lymphocytes, mono cyten and eosinophils as well as partial immunoelectrophoresis. The pancreolauryl test, determined only in serum, was in 3.33% of cases positive, pancreatic amylase was in 1.67% Cases increased, serum lipase in less than 1%, and only in two cases serum trypsin was elevated. At 9.12% of Patients had increased bile acids and in 6% were Trypsin levels decreased. The varied blood samples were for the detection of other gastroenterological diseases intended or to exclude metabolic disorders, which cause similar clinical complaints as the DEP. Porphyrinuria had been checked in individual cases, This study was once positive, as in Case 1 of the case play in detail.

C. The pancreatic tumor markers were elevated in 2% of cases however, no pancreatic carcinoma could be detected.

2. Stool examinations

• A. Stool examination for use
• B. Chymotrypsin Examination
• C. Microscopic examination for pathogenic germs
• D. Cultural examination for pathogenic bacteria aerobic, Campylobacter, Jersinia, Salmonella, Shigella and examination of the intestinal flora

ad A: In all 1300 patients, the stool examination on Exploitation performed. 38% showed already at the first under positive findings. The results occur in changing Diversity on - Dysfunction! Partially is at all nine Samples only one parameter z. B. muscle fibers positive, partial are two parameters in one or two, sometimes in three samples positive. In the rarest cases, all three were Parameters positive in all three samples. Of the o.g. 38% were positive in 26.27% patients once in 19.26 % of cases were positive three times, in 7.41% of cases was twice a positive value, in 4.44% of the cases were three times two values positive and 0.77% were in the first sub three times three values positive, ie nine positive ones Single results right away. The last ten cases mentioned are the patients suffering from Crohn's disease (0.77%).

On average, the parameter "fat" was in all samples on most positive (68%), followed by muscle fibers (56%), and strength (50%).

ad. B chymotrypsin
Here, 34% of cases of initial examination were positive and 66% of cases of initial examination were negative. When repeated and nutritive load then show in the second, third or fourth examination, all stool samples reduced chymotrypsin concentrations. After three samples were examined for each utilization test, the combination of the two parameters (utilization and chymotrypsin) provided significantly better accuracy. This is 54% of the first stool examination.

ad C.u.D. Accompanying intestinal infection: See the frequency in% (see Table I). Overall, 86% of the 1300 patients suffered in addition to an infectious colitis. Of these, 67.8% suffered from  Patients with a colitis caused by fungi of all kinds 39% Candida colitids (germ count <10³ / ml).

Statistics: The clinical symptoms and complaints of DEP at 1300 patients by percentage frequency of their individual come out (see Table 2).

On average, each of the DEP patients suffered from 16 of the 34 Symptoms at the same time.

To 1: The DEP pressure pain:
The DEP pressure pain can only be triggered in the middle abdomen by the author for the first time, this is two transverse fingers on the left paraumbilical (see Fig. 1). The severity of pressure pain is independent of the clinical symptoms. After enzyme substitution the DEP pressure pain is no longer triggerable. If the patient forgets to take his pills, the DEP pressure pain becomes positive again.

Furthermore, the medicament of the invention is suitable for Be Treatment of dyspeptic complaints, their occurrence Consequence of the dysfunction of the exocrine pancreas is.

Furthermore, the medicament according to the invention is suitable for Treatment of Crohn's disease. This disease depends just if causal with the dysfunction of the exocrine pancreas together, whereby in Crohn's disease the dysfunction mainly on the ileum.

Finally, the drug is used to treat more DEP sequelae, such as colitis, for lifting hypotonic blood pressure values, gastritis and duodenitis as well as for the treatment of Ulcers suitable.

Epithelial lesions are absent in DEP patients  of the pancreatic buffer and disturbance of the vitamin synthesis records. Here, the vitamin A special attention, as this is known as the "mucosa protective factor", and thus for the regeneration of the intestinal mucosa of all Ulcerations associated colitis forms urgently needed (See Eco-System Darm III, Seiffert J., Springer-Verlag, Heidelberg 1991, p. 250). Instead of reducing the stomach acid As taught in the prior art, it is according to the important for the first time, the disturbed buffer environment in the duodenum in DEP patients normalize by administering buffer substances.

In summary, as a result of the investigations 1300 patients notice that in all patients with dyspeptic symptoms a pancreatic enzyme deficiency - as a result the DEP - and a 100% cure rate by admin rich of the drug according to the invention can be achieved could.

The medicament according to the invention is preferably administered orally passes, in particular in the form of stomach-resistant tablets (Dragees), which release their active ingredients only in the duodenum put.

The following examples serve to explain the Er making.

Patient 1

In the eleven-year-old male patient was "hemorrhagic The child had been diagnosed from birth daily bloody stools up to 5 times a day. In this Patients were able to trigger the typical DEP pressure pain become. Otherwise, the clinical examination was unceasing due.  

laboratory findings

• 1. chair on exploitation: in the first sample three times negative (ie nine negative findings);
• 2. Chymotrypsin in the stool: already in the first examination two out of three samples are positive, d. H. pathological he niedrigt. In addition, further findings were collected: Porpho bilinogen in the urine pathologically increased to 6.7 ng / l (Reference: 0.0-2.0), urinary porphyrin normal.
• 3. Cultural Stool Examination: Missing intestinal flora in Dys Bacteria, enterocolitis by Candida albicans. The second Stool examination, which was carried out two months later was then showed, among other things, even the sub search for exploitation positively, d. H. Strength positive and Chymotrypsin in the chair twice pathologically decreased.

The patient received 104,000 units per day as therapy Lipase, 88,000 units of amylase and 6400 units of protease in Combined with buffer between 1320 and 2640 mg / day administered, wherein the administered buffer of 25 wt .-% Potassium sodium tartrate, 25% by weight sodium citrate and 50% by weight Sodium bicarbonate composed.

Just 4 days after the start of treatment, the normalized Condition of the patient, however, the complaints are set back within a day when the enzymes and the buffers were discontinued.

Patient 2

The 30-year-old patient had an "essential dyspepsia" been diagnosed. Also in this patient was the DEP pressure pain can be triggered.  

The laboratory findings showed:

• 1. Chair on utilization: Three muscle fibers each positive, Strength positive and neutral fat positive, so nine positive Individual results already in the first examination.
• 2. Chymotrypsin in the stool in the first sample to 1.8 U / g he low (normal 3.0 to 60.0) and in the second sample the same study to 2.7 U / g. In a Further investigation found the value to be only 0.5 U / g decreased.

Serum examination: All values except trypsin were in the normal range, this was at only 1 ng / ml at one reference range of 140 ng / ml.

The patient received 480000 units of lipase per day, 43200 Units of amylase and 12,000 units of protease in combination with a buffer, dosed as in patient 1 and together was set.

Also in this patient, the symptoms disappeared inside Half a few days after the start of treatment.

Patient 3

In the 43-year-old patient, "chronic duodenitis et Ulcera duodeni "has been diagnosed, he has suffered since his Childhood dyspeptic symptoms.

The laboratory findings showed the following:

• 1. Chair examination on utilization positive - here only at the third investigation, d. H. in the seventh, eighth and Ninth sample, then starch, muscle fibers and  Neutral fat positive.
• 2. All three chymotrypsin fractions were at the first Examination negative.
• 3. There was an accompanying enterocolitis due to Candida albicans ago.
• 4. The serum values were with the exception of iron deficiency and and a pathologically decreased immunoelectrophoresis inconspicuous, especially the pancreas values.

The patient was given 672,000 units of lipase, 528,000 units amylase and 36,000 units of protease per day in Kombina tion with buffer - as stated above - treated.

From regular intake of the buffer enzyme combination was the patient is completely symptom free regardless of the type, Quantity and temperature of food and drinks supplied.

In the event that an additional administration of magnesium is indicated, a daily dosage may be preferred 180 to 360 mg take place.

The DEP accompanying intestinal infections with the following frequency in% in 1300 patients Candida albicans | 39% Gram-positive cocci 10% Penicillium 7.5% mold 3.3% Mucor 2.5% Microsporon canis 2.5% Geotrichum candidum 2.5%   Candida pseudotropicalis 2.5% dysbacteria 2.5% Saccharomyces 1.6% Candida parapsilosis 1.6% E-Coli 1.6% Torulopsis inconspicua 1.6% Torulopsis glabrata 1.6% Rodothorula rubra 0.8% Torulopsis mares 0.8% Torulopsis candida 0.8% Yersinia enterocolitica 0.8% Proteus mirabilis 0.8% Salmonella enteridis 0.8% Candida species 0.8% Campylobacter 0.8%

The helicobacter pylori was not determined (from the blood).

Table 2 Clinical symptoms and complaints of DEP at n = 1300

Patients by percentage frequency of their single incidence shown.

1. 82.16% DEP - Pressure pain in the abdomen
2. 80.28% flatulence incl. Pp upset the body
3. 48.00% low back pain, especially in the lumbar region
4. 42.50% hypotension
5. 38.03% fat intolerance
6. 36.03% sparkling wine intolerance
7. 35,45% acidic wine intolerance
8. 31.10% pp peeping, rumbling, gargling
9. 29.46% heartburn
10. 28.76% constipation
11. 25,00% fatigue, lack of energy, general performance kink
12. 23.36% flank pain and / or fibers u. Grains in the chair
13. 22,30% changing chair color, light chair
14. 18.78% stomach pain, gastritis and / or calf cramps
15. 14.79% of ulcers vd; gallstones
16. 13.15% retrosternal pain
17. 8.22% "non-cardiac-chest-pain"
18. 7.75% pulpy chair
19. 6,81% intolerance to nuts
20. 4.34% intolerance to sweets
21. 4.23% intolerance to fruit juice fruit
22. 3.99% itching on the anus
23. 3.52% foul odor of the stool
24. 3.29% intolerance to coffee, carbonated. beverages
25. 3.05% incompatibility with onion
26. 2.93% dysbacteria
27. 2.82% greasiness of the stool
28. 2,70% night sweats
29. 2.58% belching, belching
30. 2.46% no weight gain with arbitrarily high calorie intake
31. 2.35% bad breath
32. 2.30% Anorexia
33. 2.16% headache
34. 0.35% white chair

Claims (15)

1. A pharmaceutical composition, characterized by the combination of a) an enzyme mixture comprising at least one protease, a lipase and an amylase, with b) at least one physiologically acceptable buffer substance. 2. Medicament according to claim 1, characterized in that the enzyme mixture comprises an extract of Aspergillus orycae. 3. Medicament according to claim 1 or 2, characterized marked characterized in that the enzyme mixture comprises pancreatin. 4. Medicament according to one of claims 1 to 3, characterized characterized in that the buffer substance is alkaline and the buffer conditions generated by a healthy pancreas Intestine sets. 5. Medicament according to claim 4, characterized in that the buffer substance is selected from salts of acetate, Citrate, lactate, titrate, bicarbonate, monohydrogenphosphate and dihydrogen phosphate. 6. Medicament according to claim 5, characterized in that the buffer substance comprises bicarbonate. 7. Medicament according to claim 6, characterized in that the buffer substance comprises sodium bicarbonate. 8. Medicament according to one of claims 1 to 7, characterized characterized in that it further contains magnesium. 9. Use of the medicament according to one of claims 1 to 8 for the treatment of dysfunction of the excretory pancreas (DEP).   10. Use of the medicament according to one of claims 1 to 8 for the treatment of dyspepsia. 11. Use of the medicament according to one of claims 1 to 8 for the treatment of Crohn's disease. 12. Use of the medicament according to one of claims 1 to 8 for the treatment of any form of colitis. 13. Use of the medicament according to one of claims 1 to 8 for the treatment of hypotension blood pressure. 14. Use of the medicament according to one of claims 1 to 8 for the treatment of gastritis and duodenitis. 15. Use of the medicament according to one of claims 1 to 8 for the treatment of ulcers.