JPH03504718A - Preparations with antibody activity and broad spectrum of action - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Preparations with antibody activity and broad spectrum of action The present invention provides preparations with high antibody activity and broad spectrum of action. immunoglobulin-preparation, which has not been immunized according to known methods. Obtained from mammalian colostrum. Furthermore, the present invention provides a method comprising or comprising this preparation. agents and their use in bacterial- or toxin-induced diseases, especially AIDS or other immunodeficiencies. Condition-related diarrhea, traveller's diarrhea and toxin-causing infantile diarrhea, stomach- and intestines- Used in the treatment of ulcers and chronic and acute Yersinia infections and in the eradication of protozoa. related to things.

Immunoglobulins - a group of highly effective and at the same time sensitive proteins - are particularly For the prevention or treatment of bacterial or viral diseases and optionally in the form of special compositions. used against certain toxins. These can be applied to humans by relatively expensive methods. It can be obtained from blood plasma or, in a somewhat simpler way, from mammalian milk or colostrum. Wear.

A group of immunoglobulins obtained from human plasma, e.g. Contains proteins that are effective in preventing and treating various infectious diseases.

Known immunoglobulin-containing preparations obtained from milk or colostrum are It has a slightly lower purity compared to preparations obtained from sea urchin. These are mainly veterinary medicine Used in the field to treat infectious diseases.

Many methods for obtaining immunoglobulins from milk or colostrum are known in the art.

For example, U.S. Pat. No. 4,526,715 describes various chromatographs from milk. A method is described for producing immunoglobulin through a separation step using biochemistry.

U.S. Pat. The present invention relates to a method for producing a preparation.

In US Pat. No. 4,265,925 and US Pat. No. 1,573,995, whey A method for producing a protein concentrate from In this case, this protein Mostly denatured due to heat treatment.

Finally, German Patent Application No. 2813284 and the European patent In Publication No. 0046909 and European Patent Publication No. 0064103 , a colostrum preparation method is described. In this case, the immunoglobulin-containing product is Obtained as an inflammatory agent.

When producing a pharmacologically effective immunoglobulin-containing preparation according to the above method , starting from the milk or colostrum of a hyperimmunized mammal, especially a cow. Therefore this In order to obtain antibacterial or antiviral efficiency against specific pathogens, First, a bacterial strain or one or more of its antigens that induces an antibody or a group of specific antibodies is introduced. Inject.

The effectiveness of the preparations thus obtained depends on the type and number of strains administered. Ru.

preparations obtained from milk that have specific antibody activity (e.g. against bacterial antigens) To produce the product, mammals are first immunized with a specific antigen. That special milk have high antibody titers against specific antigens. Milk is used as a carrier medium in this case. use

The present invention provides highly purified immunoglobulin preparations with high antibody activity for medical and It is also used in veterinary medicine to prepare specific antibody titers without prior hyperimmunization. The challenge is to produce according to a simple and economical method that can be used Ru.

According to the present invention, this problem is solved by collecting the colostrum of non-immunized mammals, especially cows, in a known manner. This can be resolved by handling it in accordance with the law. At that time, for the total protein content >80% immunoglobulin, as well as fat (<0.4%) and lactose (<0.1%) A highly pure preparation containing immunoglobulins is obtained, with a small proportion of . this The preparation is based on ``Pentag'', traditionally known as the most effective human immunoglobulin-drug. It has higher antibody activity than "Robin" 1).This is due to its extremely low anti-complement activity. The preparation according to the invention can be used for oral administration in humans as well as for intravenous administration in veterinary medicine. suitable for giving.

Special table Hei 3-504718 (3) According to the invention, it is preferred to use colostrum from the first 10 hours after delivery, even if For example, the preparation obtained after the purification and separation procedures normally used for milk processing is It can be produced in storage stable form as a liquid or as a powder.

For this purpose, for example, cow colostrum from the first 10 hours after calving is diluted with distilled water. Dilute with a ratio of 1:3.

The fat is separated from this solution after pasteurization and the casein is then precipitated, e.g. Separate by filtration.

The whey thus obtained is concentrated to the desired content. For product stabilization For this purpose, sterile filtration can be carried out, resulting in a sterile solution of the preparation.

Further stabilization can also be achieved by spray drying. The product is obtained in powder form. So It is surprising that the temperature required for spray drying (inlet temperature of about 145°C to 180°C) ℃, exit temperature approximately 65-70℃), no denaturation of the protein takes place, therefore the spray Under these conditions of desiccation extreme aggregate formation and concomitant increase in the anti-complement activity of the protein does not occur, which is inherently known and expected for such temperatures. there were. Therefore, when using this stabilization method, a high immunity of >80% remains unchanged. The product with anti-inflammatory globulin content has a constant low anti-complement activity and an intact organism. Obtained with chemical activity.

Additionally, the precipitation reaction is carried out using octane before and after carrying out the stabilization step according to one of the above methods. It can be carried out with acids. At that time, the immunoglobulin content should be increased to 90% or more. The increase in layer size is achieved without adversely affecting anti-complement activity.

Preparations containing immunoglobulins with high anti-complement activity can be used in other, likewise known methods. Therefore, it can be prepared from colostrum from the first 10 hours after calving. For example, The method according to DE 34 32 718 can be used. Furthermore Colostrum from non-immunized cows is first acidified and then filtered through coarse filtration to remove casein). Dilute with saline solution. The suspension obtained in this way is tial), then concentrated, then neutralized. Stabilizes concentrated whey During sterilization or spray drying, optionally also for increasing the purity of the preparation. Octanoic acid precipitation can be carried out.

Globulin-U's 'Kan' Rising 110 kg of excessively frozen bovine colostrum from the first 10 hours after birth was incubated at 5-10°C. Thaw and dilute with distilled water at a ratio of 1:3. The milk is then pasteurized and then fattened. Separate the fat. That fl? 270 kg of skim milk is obtained. This is INH Acidified with Cl, the precipitated casein is separated off via a filter cloth. child The supernatant liquid (186 kg) obtained as above was ultrafiltered, and at this time, 38 kg of concentrated A condensate is obtained.

The concentrate is sterile-filtered or spray-dried in the usual manner for stabilization. spray drying Drying is carried out at an inlet temperature of 175°C and an outlet temperature of 65°C. At this time, 83% purity A dry powder containing immunoglobulins was obtained, which weighed 3.8 kg of immunoglobulins. This corresponds to the total yield of

The antibody activity of this preparation before spray drying was quenched after spray drying and also by sterile filtration. corresponds to a standardized preparation.

five lords Thaw bovine colostrum 131 that was taken during the first 5 hours after birth and was excessively frozen. . The pH value is 6.27.

Adjust this to 4.8 by acidifying with 700 dl NHCl.

The resulting suspension was heated to 40°C for 30 min and then stored at 4°C overnight. The suspension was filtered through a gauze filter made of polyamide gauze to separate coarse particles. pump into a storage container where it is diluted to a total volume of 2i using 0.9% saline solution. Interpret.

A first tangential filtration of the resulting suspension was then carried out with an average pore size of 0.4μ, 3 Through a hollow fiber cartridge with a surface area of I12 and a fiber diameter of 1.2 mm Use of 101 0.9% salt by diafiltration This is carried out at an overpressure of 0.2 to 0.6 bar.

Even while the first coarse filtration is proceeding, the resulting diafiltrate is transferred to the second coarse filtration. 3 hollow fiber cartridges with 00OOD separation range and 1.4m” surface area supply under the use of equipment consisting of a In this device, the first coarse filtration diafiltration The solution was concentrated and then diafiltered using 100120.9% saline solution and finally Concentrate to a total volume of 251. The filtrate containing low molecular weight components is removed.

The resulting immune solution had a protein content of 6% (determined by the biuret reaction). and sterile filter by known methods.

Madarushi Bovine colostrum concentrate 257! is prepared according to Example 2.

A portion of the 10% immunoglobulin solution was heated to an inlet temperature of 145°C and 65°C. Subject to spray drying at an outlet temperature of .

1270 g of whitish immunoglobulin powder is obtained.

Antibody activity and anti-complement activity were measured before spray drying and after sterile filtration prepared according to Example 2. Corresponds to a preparation.

Nuki↓ The immunoglobulin solution prepared according to Example 1 was added to pH 4, Octanoic acid (2.5%) is added for 5 hours at temperatures of 8 and 23°C. Then filter the precipitate It is removed by filtration and the supernatant is dialyzed against 0.9% NaCl-fit solution.

The immunoglobulin content of the preparation thus obtained is >90%. anti Complement activity corresponds to low titers of intravenous compatible human IgG preparations.

Group i From the immunoglobulin powder prepared according to Example 1 (spray-dried), 5% A sterile filtered solution 200i with protein content is produced. A solution like this (5g powder, stirred in H,O at a total of 100-) has the following composition ( An experimental error margin of ±10% must be taken into account for all protein values. (No): Total protein 4.2 g/100m, including IgG 3. O g/10100NIT O, 35g/10100dI O,σ 6 g/1001R1 pH-value 4,6 Lactalbumin 1.0% CAP This solution is pl with 2.5% octanoic acid. '14, 8 and T = 5 hours of culture at 23°C. Separate the precipitate by centrifugation and diafilter the supernatant. Anti-complement activity was observed at the same concentration (5 %) of the amaranth gG-preparation.

Immunoglobulin preparations obtained according to the described or similar methods are Has higher antitoxin activity than Bulin Toyō Ino Ao's head teacher Hemolysis-inhibition of neutralization of hemolytic bacterial toxins in supernatants containing toxins of various bacteria. (HHT).

Five ■ Staphylococcus aureus smith a ureus Sm1th) 3 overnight cultures in brain heart infusion nutrient broth. , 10.000 x g for 10 minutes and sterile filter the supernatant. hemolyze The sterile supernatant of this culture, containing the toxin, is used for the hemolysis-inhibition test. .

A 5% solution of the immunoglobulin preparation prepared according to Example 2 was tested for toxin neutralization. and find out. For this, 0.1-10 μl of washed human red blood cells are added. Stuffy Rokofukas 900 to 990 with aureus toxin, IJ j! Nacl (0.9%) at 37°C for 30 minutes. At this time, 10-100 μl of each Add epiglobulin solution (5%). 5% free, available on the market as a comparative preparation. An epizootic globulin-preparation (pentaglobin) is used. The results are shown in Figure 1.

At this time, absorbance at 542 nm is used as a measure of hemolysis or its inhibition. do.

■１ As described and proposed in Example 6, but in this case Gram-negative bacteria-Ps, The toxin-containing supernatant of A. aeruginosa is used in tests for toxin neutralization. melt Blood was diluted l:10 in NaCl (0.9%) as in Example 6 or 8. Measure between 0 and 100 μl of 5% immunoglobulin solution.

anus For the tests described below, the toxin-containing supernatant of Staphylococcus aureus Use liquid. Toxin neutralization was carried out using a preparation prepared according to example 1 (by spray drying). (5% solution).

For comparison in HTT, pentaglobin is used at the same concentration.

Hemolysis was performed with O to 100 μl immunoglobulin solution (5%, 1:10 in NaCl). dilution).

The results from the tests of Examples 6-8 are shown in Figures 1-3.

Figure 1 shows the hemolysis of Staphylococcus aureus Smith 3 bacteria according to Example 6. Neutralization of the toxin by immunoglobulin from bovine colostrum prepared according to Example 2. and by pentaglobin for comparison.

FIG. 2 shows Pseudomonas aeruginosa according to Example 7. Neutralization of the bacterial toxin of S. aeruginosa in bovines prepared according to Example 2. Shown by immunoglobulin from colostrum.

Figure 3 shows the neutralization of Staphylococcus aureus bacterial toxin according to Example 8. Bovine colostrum produced according to No. 1 - with immunoglobulin and as a comparison with penta Indicated by globin.

As is clear from Figures 1-3, the immunoglobulin preparation obtained from bovine colostrum is more toxic than pentaglobin obtained from human plasma, which is comparable in composition. resulting in more effective inhibition of primary hemolysis.

Table I summarizes the results of the tests according to Examples 6-8.

Table 1 Example　　　　　　　at 50% hemolysis　　m-1 knee at 80% hemolysis　--1 skin-one 6 PG (comparison) $50μJ 93μ1RG (book) *Umbrella 10. uj! 5o11t17 RG (book) 1Bμ/ 35μ18 PG (comparison) 42μm 80111- ノ10JIL 10μl 40μl*P(:, Pentaglobi hmm Immunoglobulin Examples 6 and 8 from Umbrella RG bovine colostrum showed 50% hemolysis (toxin neutralization). ), almost three times as much known pentaglobin as for the preparation according to the invention. evidence that the process is necessary. Double the amount of penta to obtain 80% toxin neutralization. Must use globin.

As is clear from Example 7, the immunoglobulin according to the invention was obtained at a very low concentration (4 0 μ7 already has almost 100% toxin neutralization against toxins from Gram-negative bacteria. bring about

Pentag 100% hemolysis in the concentration range considered (M high 100μ 105% solution) As for Robin, it cannot be achieved. Immunoglobulin made from colostrum The preparation does not have 100% purity (80-90%) contrary to pentaglobin. The therapeutic index derived from the above results regarding antitoxicity according to the present invention is It is at least twice as antitoxic as globin.

Furthermore, as is clear from Table 1 and Figure 3, the method chosen for the production of the product This is done according to known methods in dairy industry and with special lubrication, which does not affect the activity in any way. It can be obtained by processing (eg tangential filtration).

The products according to the invention can be administered intravenously in the field of veterinary medicine and It can be administered orally to patients. This is different, as shown in Examples 9 to 11 below. It has constant toxicity and can be stored in liquid and solid form.

鮮JJjiangJLi艷 Kamibi Hero Five mice each were treated with a 5% immunoglobulin solution (Examples 6-8) tested as described above. ) was administered intraperitoneally (0.1 m/animal), and the animals were kept for up to 3 hours after administration. Observe and maintain until 5 days after administration.

Results: No animal death, no emergency reaction, no reaction until 3 hours after administration, no change.

Throwing Nlk = 0.29 μm kg (mouse body M near 7 g).

Five editions Five mice each were injected with 0.5w 15% solution, pH 4.6, by gavage. Administer orally, observe until 3 hours after administration, and maintain until 5 days after administration.

Results: No animal death, no emergency reaction, no reaction up to 5 hours, no change.

Dosage: 1.47μmkg; (mouse weight = 17g) 5U Three mice each were injected with IO+dlO% suspension, p) 14.6, via the esophageal tube. Administer orally.

Results: No symptoms were observed immediately up to 1 hour, 3 hours later and 5 hours later. 5th day After that, all the animals remained unchanged.

Dosage: 1. (The dose of ldlo% solution (0.1 g/animal) was 5.0 g/k g or equivalent to a dose of 350 g/70 kg (mouse weight - 20 g).

The immunoglobulin according to the present invention obtained from colostrum can be produced in an extremely simple and economical manner. It has unexpectedly high antitoxic activity against various bacterial toxins. Ru. It has excellent compatibility (no abnormal toxicity) and high purity (>90%). It can be stored in liquid form and in stabilized form as a powder.

Susumu Surprisingly, the preparation according to the invention is effective against the sequelae of old C. infections or other immunodeficiency conditions. According to the present invention, we have found that it is excellently suited for the treatment of acute diarrhea. If given with a preparation that A significant decrease in the frequency of diarrhea occurs as shown in the following table ■. For patients infected with AIDS , each day for 10 days with the preparation IDg according to the invention.

Diarrhea per day Weight - kg Patient Before treatment Day after start of treatment Before After 1 3 5 10 Juice, (1) 10 5 1 1 1 42. On,t.

(2) 6 6 1 1 Q umbrella Q* Q umbrella 84.4 85.5 (3) 10 5 2 2 1 62.36 2.8*Regular delivery The preparation according to the invention alone or as an antidiarrheal or other therapeutically essential or can be administered in combination with suitable agents and reduce the frequency of diarrhea in the shortest possible time. and at the same time a significant improvement in the patient's general condition.

Tsukuda The preparation according to the invention is suitable for the treatment of so-called traveler's diarrhea and infantile diarrhea of toxin-induced origin. Also surprisingly suitable.

In laboratory tests, the preparation according to the invention was found to be particularly effective against ferrotoxin (Verotoxin). x in) Contains antibodies against 40KD-protein of 1 (VT+) I found out that - VT+ or Cigar-like (Shiga-1ike)) Ki Syn1, together with ferroxin2, is the most important component of infantile pathogenic E. coli (EPEC). It is a cytotoxic exotoxin.

Furthermore, the preparation according to the invention eliminates exotoxins, which are one of the causes of traveler's diarrhea. Intestinal W (ETEC) heat-labile exotoxin 30KD- and 20xD-proteins Contains antibodies against.

The preparation according to the invention therefore contains enteropathogenic E. coli (exotoxin, ETEC, milk). against almost the entire spectrum of toxins (e.g. infantile pathogenic EPEC, enterohemorrhagic 1EHEC). Contains antibodies for This is therefore a particularly significant advantage. Because this disease Illness often occurs and can be at least partially the result of antibiotic treatment or The administration of antibiotics often produces adverse effects on the patient due to toxin withdrawal. It is from.

carried out by immunoblot (Ia + munoblot) method at various concentrations. The results of the tests are depicted in FIG.

5 U The formation of ulcers in the duodenum and stomach, which are related to gastritis, is reported in Special Table 13-504718 ( 5) Conventionally treated with bismuth salts or antibiotics. A simple treatment with few side effects (Bisma) (salts) have only marginal efficacy; in contrast, effective antibiotic combinations Although drug regimens are reliable, their intended use is rarely followed due to side effects. I can't do it.

Therefore, there is a need for a treatment that is simple, has few side effects, and is effective at the same time. . Regarding this disease as well as regarding non-ulcer dyspepsia, Campylobacter According to recent findings, loli (Caa+pylobacter pylori) is a disease. has primary significance. For C. pylori, 120 KD adventitial protein, 6' It is characterized by a 3KD specific flagellar antigen (flagellin) and a 45KD urease. It is.

It is now surprising that the preparation according to the invention is effective against these three proteins in high concentrations. It was also found that it contains antibodies that

The test is performed by immunoblotting.

The preparation according to the invention with a protein content of 4 + ag/- was added to the undiluted Test at dilutions of 1:10 and 1:100. Detection is based on alkaline phosphater This is done by bovine-TgG conjugated using enzymes. The dirt depicted in Figure 5 As is clear from the above, all the drugs according to the present invention have a 1:1 ratio of the three above-mentioned proteins. At a dilution of 0 and at a dilution of 1:100 still clearly associated with flagellin and urease. react.

Furthermore, the preparation according to the invention also contains a large number of antibodies that react with the C. pylori preparation. Ru.

Surprisingly, therefore, the preparation according to the invention is effective against Campylobacter pylori. Excellently suited for the treatment of infections caused by.

Yersinia infections not only cause an acute intestinal infection course, but also particularly subacute and chronic infections. Disease forms also occur.

This is generally accompanied by unfavorable culture findings. However, in this case, immunohistologically pathogenic bacteria can be detected. IgA-antibody detection as a convenient indication of existing infection The most important diseases that use it are active arthritis, erythema nodosum, uveitis, chronic enteritis etc.

Experience shows that Yersinia, regardless of the species, contains the so-called yop-antigen ( In particular: YOP2b with 47KD, YOP3.26KD with 37KD YOP5). Using this isolated antigen, the preparation according to the invention is Inspect at the Westernblot.

To this the preparation was added undiluted (protein content 4+ag/-) and 1:10 and Use with dilution of t:ioo.

The preparations contain all three antigens and all concentrations used, as seen in Figure 6. Reacts with degrees. The coloration is then caused by a specific anti-antibody conjugated with alkaline phosphatase. 1:1500 and 1:3000 using bovine 1gG (H- and L-chain) This is done at a dilution of

The antigens recognized accordingly are independent of serotype and Yersinia species. The preparation according to the invention is therefore excellently suited for the treatment of Yersinia infections.

±river The preparations according to the invention are suitable for use in protozoa, such as kutobutosporidiene (Crypt. osporidien), Isospora belli Or for the eradication of Toxoplasma gondii. Surprisingly suitable. Conventionally, there are no known therapeutic drugs for treating these diseases. It wasn't.

Kutobutosboridien is used for immunocompromised patients treated with conventionally known medicines. It causes severe diarrhea that can't be cured. Kutobutosborijen was detected in the stool. 4 patients with severe diarrhea were each given 10 g of the preparation according to the invention for 10 consecutive days. Administer as a drinking solution. After completion of this treatment, none of these patients should Borisien-specific antigen was not detected.

Figure 1 10/2030 4050 6070 Father 11 mark immunoglobulin 1:10 dilution Figure 2 10°20 30 4050 6070 eo 90100 immunoglobulin 1:10 dilution Figure 3 Figure 4a Anti-ferrotoxy contained in lactoglobin in INOBROD Body detection MC,’W Figure 4b M.C.W. Figure 5 M(, W The scope of the claims 1. a) Dilute colostrum with distilled water b) Pasteurize the diluted colostrum C〉Separate the fat d) casein precipitates and then separates e) Concentrate colostrum f) Stabilize colostrum immunization during the first 30 minutes, preferably the first 10 hours, after delivery. Of all the drugs with antibody activity obtained from the colostrum of non-codified mammals, this At least 50%, preferably at least 80% of the immunoglobulin content relative to the protein content. Lobulin in the form of a mixture consisting of IgG, IgA and IgM and broad toxin neutralization The above characterized in that it contains an antibody having an action as well as an antibody against protozoa. Preparation.

2. Preparation according to claim 1, characterized in that it is obtained from bovine colostrum.

3. Characterized by additionally performing octanoic acid treatment before or after stabilization Preparation according to claim 1 or 2.

4. Consisting of or containing the preparation according to one of claims 1 to 3. for the treatment of toxin-induced diarrhea in immunocompromised patients.

5. The agent according to claim 4 for the treatment of toxin-induced diarrhea in AIDS.

Note table flat 3-504718 (g) 6. The agent according to claim 4 for the treatment of infantile diarrhea caused by toxins.

7. The agent according to claim 4 for the treatment of toxin-induced traveler's diarrhea.

8. The claimed invention is applied to the manufacture of a drug for the treatment of toxin-induced diarrhea in immunocompromised patients. Use of the preparation according to one of the following.

9. consisting of or containing a preparation according to one of claims 1 to 3; An agent for treating Yersinia infectious diseases.

10. Claims 1 to 3 for the manufacture of an agent for the treatment of Yersinia infectious disease. Use of the preparation by one of them.

11. consisting of or containing a preparation according to one of claims 1 to 3; Agents for treating gastric and intestinal ulcers and non-ulcer indigestion caused by toxins .

12. Agents for treating gastric and intestinal ulcers and non-ulcer indigestion caused by toxins Use of a preparation according to one of claims 3 to 3 for the manufacture of.

13. consisting of or containing a preparation according to one of claims 1 to 3; agents for the treatment of infections caused by protozoa.

14. Claims 1 to 3 are applicable to the manufacture of a drug for the treatment of protozoal infections. Use of the preparation by one of them.

international search report international search report DE 8900233 SA 27976

Claims (27)

[Claims] 1. a) Dilute colostrum with distilled water b) Pasteurize the diluted colostrum c) Separate the fat d) casein precipitates and then separates e) Concentrate colostrum f) Stabilize colostrum may be obtained from the colostrum of non-immunized mammals during the first 30 minutes after parturition. A preparation with antibody activity. 2. Claim 1, characterized in that colostrum from the first 10 hours after delivery is used. Preparation by. 3. Claim 1 or 2, characterized in that the colostrum is sterile filtered for stabilization. Preparation according to 2. 4. Claim 1 or 2, characterized in that the colostrum is spray-dried for stabilization. Preparation according to 2. 5. The preparation according to one of claims 1-4, characterized in that it is obtained from bovine colostrum. product. 6. characterized by an additional octanoic acid treatment before or after stabilization Preparation according to one of claims 1-5. 7. Based on the total protein content, at least 50%, preferably at least 80% % immunoglobulin. Preparation by. 8. Use of a preparation according to one of claims 1-7 for oral administration. 9. For intravenous administration in the field of veterinary medicine, according to one of claims 1-8 Use of preparations according to 10. Claim 1- for the treatment of diarrhea in AIDS or other immunodeficiency conditions 7. 11. Claim 1- for the treatment of diarrhea in AIDS or other immunodeficiency conditions 7. 12. Claims for the manufacture of agents for the prevention of diarrhea in AIDS or other immunocompromised conditions Use of the preparation according to one of ranges 1 to 7. 13. Traveler's diarrhea comprising a preparation according to one of claims 1 to 7. Agent for treatment. 14. Traveler's diarrhea containing a preparation according to one of claims 1 to 7 agent for the treatment of. 15. For the manufacture of an agent for the treatment of traveler's diarrhea, one of claims 1 to 7. Use of the preparation by one person. 16. A toxin-causing agent comprising a preparation according to one of claims 1 to 7. Agent for the treatment of infantile diarrhea. 17. A toxin-causing agent containing a preparation according to one of claims 1 to 7. agent for the treatment of infantile diarrhea. 18. One of claims 1 to 7 for treating toxin-caused infantile diarrhea Use of the preparation by one person. 19. Gastric and intestinal ulcers consisting of a preparation according to one of claims 1 to 7. Agents for treating ulcers and non-ulcer indigestion. 20. Stomach- and intestines containing a preparation according to one of claims 1 to 7 Agents for treating ulcers as well as non-ulcer indigestion. 21. For the manufacture of agents for the treatment of gastric and intestinal ulcers and non-ulcer dyspepsia, Use of a preparation according to one of claims 1 to 7. 22. Chronic and acute preparations consisting of a preparation according to one of claims 1 to 7. Agent for treating Yersinia infectious disease. 23. Chronic and acute products containing a preparation according to one of claims 1 to 7. Agent for treating Yersinia infectious disease. 24. Claims for the manufacture of agents for the treatment of chronic and acute Yersinia infectious diseases Use of the preparation according to one of 1 to 7. 25. A method for combating protozoa consisting of a preparation according to one of claims 1 to 7. An agent for annihilation. 26. of protozoa containing a preparation according to one of claims 1 to 7. Agent for eradication. 27. One of claims 1 to 7 for the production of an agent for eradicating protozoa. Use of preparations by.