DE3510531A1 - Process for the preparation of a composition which is suitable for the prophylaxis and therapy of adverse changes in the hygiene on epithelial cells and can be used as specific and accelerated in vivo nutrient medium - Google Patents

Abstract

The essence of the invention is, for specific multiplication of the Lactobacillus acidophilus living on epithelial tissues, where appropriate Lactobacillus bifidus, Propionibacterium and/or Corynebacterium etc, that an in vivo utilisable carbon source of 0-50% by weight, preferably one or more carbohydrates, lactic acid and/or glycerol, a nitrogen source of 0-20% by weight, preferably proteins, protein breakdown products or urea, and additional materials of 0-20% by weight, preferably salts, vitamins, growth factors, antiviral or antiphage agents and/or immunity-increasing or immunity-inhibiting agents are mixed and diluted 0-20-fold with the carrier materials customary in pharmaceutical formulation, these being added to the amount of the carbon or nitrogen source; the acidity of the mixture is adjusted by an acid, preferably by lactic acid, to a pH of 3.0-6.5; where appropriate the mixture is heat-treated between 30 and 120 DEG C and then converted by a process known per se into a therapeutic composition, preferably suppositories, tablets, ointment, chewing gum, coated tablets, injection or spray.

Description

Process for the preparation of a, for prophylaxis

and therapy of negative changes in hygiene on epithelia suitable, as a specific and accelerated in vivo nutrient medium usable preparation subject The invention is a method for the production of a, for prophylaxis and therapy negative changes in hygiene on epithelia suitable, possibly known Medicines and also containing living or killed microorganisms the epithelia useful as a specific and accelerated in vivo nutrient medium Preparation.

"Hygiene" means the current distribution of the physiological or pathogenic microflora of the epithelial surfaces or epithelial cells.

The negative ones that occur on the various surfaces of the body Hygiene changes usually arise from the decline in populations of the Physiological microorganisms located in epithelial cells (mostly lactobacilli), which live in symbiosis with the epithelial cells and also play a protective role there.

The view of pathogenesis, which is still valid today, is wrong. the The cause of the negative changes in hygiene is not an exogenous infection, but rather the deterioration of the nutrient medium of the biological microorganisms.

Numerous known antimicrobial agents have been and are in use with which one wanted to influence these changes. These are the most varied anti- septics, chemotherapy drugs, antibiotics, etc .; there there are two principal disadvantages: a) there is no specific prophylaxis; b) the Therapy can only be resolved through potentially harmful chemicals.

The known antimicrobial agents have a rough impact on ecology of the organism and on the other hand exert other potentially damaging effects - e.g. allergy, toxicity, carcinogenic and teratogenic effects.

That is why these funds can only be used under strict control. Its use is contraindicated for pregnant women; so you can use them for prophylaxis do not consider.

Typical examples of antimicrobial agents are the nitro derivatives, those often used on the epithelia of the oral cavity, the intestines and the vagina are: e.g. metroindazole 1- (2-hydroxyethyl) -2-methyl-5-nitroimidazole; see US-PS 2 944 061). This remedy should primarily be used against Trichomonas species and anaerobic Bacteria be effective. The application of this remedy is on the infectious components one-sided, even only focused on a part of it, creating the effect is partial and only works with newer infections.

In addition, Metroindazole represents potential harm, as it was shown to be carcinogenic in mice and probably also carcinogenic in rats is.

In addition to therapies with antimicrobial agents, there have been attempts to the really missing biological microorganisms, mainly the lactobacilli the Supplement epithelial surfaces by feeding.

According to FR-PS M 7 414, living lactic acid bacteria are acidified entered the scabbard. The solution according to FR-PS 2 043 483 should be a prophylaxis form of enteritis. The procedure of FR-PS M 4 430 aims at restoration the intestinal flora through the simultaneous use of antibiotics.

A common endeavor of this and other attempts is that Avoid using harmful antimicrobials. However, these have the common mistake of view that they denote the ubiquitous character of microorganisms "forget" and "want to bring in" something that is available there in advance stands.

In the treatment of the mucous membranes therefore means a fundamental Change the solution announced in HU-PS 172 501, with the cause of the destruction of biological microorganisms recognized in the deficiency of the nutrient medium will.

The inadequacy of this last document is that The effect and success of the produced nutrient medium are uncertain and the decisive factor Moment is not taken. On the other hand, it is true that only production of the "Döderlein bacillus" or the "Döderlein group" in the patent cited is described.

The acid-producing capacity of the various lactobacilli is not identical: the largest is that of the normal inhabitant of the vagina, the intestine and the oral cavity, i.e. that of Lactobacillus acidophilus. (This value can be a pH of about 3.6 under in vitro conditions reach.) This acid concentration is not only for the acid-sensitive pathogens, but also for other Lactobacillus species incompatible. The hygiene of the epithelial surfaces is ensured by the antiseptic capacity the lactic acid produced by the lactobacilli has a decisive influence.

The prerequisite leading to the present invention was that a culture of Lactobacillus acidophilus, which is about the strongest antiseptic (antagonistic) ability is produced on the corresponding epithelial surfaces shall be. For this purpose, an ordinary "lactobacillus nutrient medium" is not suitable. Lactobacillus acidophilus, which is particularly sensitive to nutrient media requires a specifically adequate nutrient medium.

The invention is based on the following findings: a) On the On the epithelial surface, the microorganism is produced, which is the most effective there Ability.

b) This task is being solved in an accelerated process.

The production of the uncertain in its composition, from several Laktobacillus-kinds existing "Döderlein group" is expedient by an imperfect Medium dissolved. According to the invention, the situation is reversed: the specific nutrient medium for Lactobacillus acidophilus is complete.

Similarly, as with the in vitro nutrient media, the in vivo Culture media can be "general" or "specific" lactobacillus culture media.

The selectivity can also be positive or negative.

The corresponding lactobacillus species be created with a complete nutrient medium, while the latter is based on the Competitor acts (R. Schröder et al .: Uterus and vagina as a source of fluorine genitalis, Arch. f. Gynäkologie, 128, 165 (1926)) and an important source of nutrients in in an unusable form (e.g. lactose, which is derived from glycogen not exploited by Candida species).

The latter type of culture media can also consist of a single component exist.

It has now been found that for the prophylaxis and therapy of hygiene on epithelial tissues suitable, possibly active pharmaceutical ingredients as well as living ones or containing killed microorganisms on the epithelial tissues as specific and accelerated nutrient medium useful compositions are obtained when one for the specific reproduction of the Lactobacillus living on the epithelial tissues acidophilus, possibly Lactobacillus bifidus, Propionibacterium and / or Corynebacterium, etc.

an amount of 0-50% by weight of a carbon source that can be used in vivo, preferably one or more carbohydrates, lactic acid and / or glycerin, a nitrogen source from 0-20% by weight, preferably proteins, protein breakdown products or urea and additional materials from 0-20% by weight, preferably inorganic salts, vitamins, growth factors, antivirals or anti-phage agents and / or immunity-increasing or immunity-inhibiting agents, mixes with the usual carrier materials in the drug formulation and 0-20 times diluted, this being added to the amount of the carbon or nitrogen source the acidity of the mixture by an acid, preferably by lactic acid, adjusts to a pH value of 3.0-6.5, optionally the mixture between 30 and 120 "C heat treated and then after one per se known procedures for therapeutic composition, preferably for suppositories, tablets, ointments, Formed chewing gum, coated tablets, injection or spray.

The nutrient medium according to the invention can be used as an assimilable source of carbon simple or compound sugars, sugar derivatives, starch or starch derivatives as well as other carbohydrates, honey, lactic acid, glycerin and other alcohols. Preferred carbon sources are glucose, lactose, sucrose, fructorns, xylose, Maltose, dextrin, glycerin and ethanol; particularly preferred carbon sources are glucose, lactose and glycerin.

The amount of the carbon source is usually 2-30% by weight, preferably 2-18% by weight, in particular 2-8% by weight.

Proteins, protein degradation products, Amino acids, peptones, nucleotides, amines, peptides, polypeptides and urea derivatives be used. A preferred source of nitrogen is tryptic digested casein (Tripcasin), acid-digested casein (Lactacid), liver extract (Neoperhepar), Mushroom extract (yeast extract), purine and pyrimidine bases, gelatin and urea, the liver extract and the purine and pyrimidine bases are particularly preferred.

The amount of the nitrogen source is usually 1-30% by weight, preferably 1-10% by weight, in particular 1-3% by weight.

Known active pharmaceutical ingredients can also be used in the nutrient media according to the invention use when indicated by therapy.

Those optionally used in the nutrient media according to the invention Active pharmaceutical ingredients are appropriate antiseptics, antibiotics, trichomonacides, Fungicides, antiviral and anti-phage agents, cytostatics, immunity-enhancing or immunosuppressive and similar agents. Of these active ingredients is generally sufficient the delivery of a fraction of the usual therapeutic dose.

As antiseptics or antibiotics, chlorogen, metronidazole, Clotrimazole, sulfathiazole urea, oxacillin sodium, neomycin, polymixin, ampicillin, Oxytetracycline, Moroxide, Cefalexin, Natamycin, Amantadine, Hexachlorophene, Chloramphenicol and azathioprine can be used. Metronidazole, clotromazole, Neomycin, oxytetracycline, natamycin and hexachlorophene.

The amount of active pharmaceutical ingredients is usually 0.1-25% by weight, preferably 0.5-20% by weight, in particular 0.5-15% by weight.

The compositions according to the invention can also be one or more Additional materials, e.g. salts, trace elements, vitamins, growth factors, propolis and other similar substances. The individual types of additives can be applied as such or together.

The salts of lactic acid, acetic acid, Use phosphoric acid, citric acid, succinic acid and boric acid. As growth factors you generally need Tween 80, oleic acid, ethyl p-aminobenzoate and Sodium acetate.

The vitamins are thiamine hydrochloride, riboflavin, Nicotinamide, Pyridoxine hydrochloride, folic acid, ascorbic acid and B12 preferred.

The amount of additional materials can vary between widths, depending on the type Limits can be varied. Usually 0.01-10% by weight is used, preferably 0.1-5 % By weight, in particular 1-4% by weight, of the additional materials.

Taking into account the particular sensitivity of lactobacilli and especially that of Lactobacillus acidophilus against the composition of the nutrient medium one should take into account that the amount of carbon and nitrogen of the other Components are included in the amount of carbon and nitrogen source should.

The compositions according to the invention are basically specific, expediently complete in vivo nutrient media, which are at least twice as concentrated are like the ready-to-use in vitro nutrient media, which means that the topographically current The physiological leading role of the epithelial tissue, primarily that of the Lactobacillus acidophilus, guaranteed or created.

The compositions according to the invention can be used immediately or in the form of one suitable for external and / or internal administration bring pharmaceutical composition.

The specific nutrient media prepared as described above - taking into account their nature and their effect - are also without the addition well-known active pharmaceutical ingredients full prophylactic and therapeutic pharmaceutical compositions.

Although when using the composition according to the invention the therapy the destruction of the microorganisms is, however, this effect arises through a indirect, biological way. The benefits of this biological effect can be can be summarized as follows: - Appear after applying the composition and the beneficial biological microorganisms multiply, especially the Lactobacillus acidophilus, and at the same time the other or pathogenic microorganisms disappear.

- The clinical symptoms, such as redness, pain, itching, etc. can be heard within a few hours after use.

The nutrient media prepared according to the invention can be in any pharmaceutical formatting, e.g. as a solution, emulsion, suspension, foam, spray, Powder, granulate, ointment, liniment, paste, suppository, capsule, tampon, tablet, Chewing gum, injection, etc. can be used.

The lactobacilli are hygienic organisms.

This ability is used worldwide by huge branches of industry, such as plant materials, preservation and processing of milk and milk products. Through the purposeful use of the useful bacilli of the epithelial cells (biotechnology) one could create a new branch of industry of similar dimensions, that of the biological Hygiene, educate.

The composition of the present invention can be used in the following fields can be applied: - Preserving, maintaining and supporting the physiological Flora (decisive is the Lactobacillus acidophilus population) of the epithelial surface, i.e. the maintenance and prophylaxis on the epithelial surface.

- Correction of the hygienically negative changes in the body cavities (Oral cavity, throat, intestines, vagina, vulva, etc.).

- Treating digestive irregularities (e.g.

Diarrhea, constipation, flatulence) by changing the mood of the intestinal flora and the displacement of the beneficiaries from the small intestine segments (i.e. the in loco realization the "Acidophilus milk").

- The prophylaxis of periodontal disease and caries in dentistry, partly by correcting the oral flora and basically by correcting it the negative consequences of "modern" eating habits.

- The vaginal hygienic care for women and the expansion of the obstetric asepsis in the form of functional antisepsis at any age. Dodging the antimicrobial pathway could affect a sensitive group, such as for pregnant women, children and the elderly, be particularly useful.

- There are none in the intestinal flora of old people or in the seriously ill Lactobacilli, therefore it is advisable to study the flora of the lactobacilli (Lactobacillus acidophilus, lactobacillus bifidus in infants) and on a high Maintain population level.

- The prevention or therapy of the negative effects of broad-spectrum antibiotics on the physiological flora.

- The culture of Lactobacillus acidophilus is practically odorless, this removes the putrid smell of bacteria, the unpleasant smell of fungi and removes the odor of the Trichomonas species reminiscent of rotting wood.

- Sexual hygiene should be corrected on two important points. These are, on the one hand, keeping away the pathogens and correcting the tasting Effects.

These are spontaneous events of the leading role of the Lactobacillus acidophilus.

- In veterinary medicine, as the intestinal flora of mammals - similar to the of human infants - consists of approximately 90% lactobacilli. In prevention the early deaths (e.g. the consequences of enteritis caused by viruses or bacteria are) and in therapy the restoration of the physiological flora can be a play a significant role.

The following examples explain the process according to the invention.

Example 1 Lactacid (lactalbumin, manufacturer: vaccine production and Research Institute HUMAN) 4.00 g dextrose 2.00 g Polybe tablets, powdery (Manufacturer: Chemische Fabrik Gedeon Richter AG.) 8 pieces of potassium dihydrogen phosphate 0.40 g Tween 80 (polyoxyethylene sorbitan monooleate) 1.00 g agar powder 2.00 g urea 0.50 g The above components are homogenized and the powder mixture or the granulate made from it is put into a gelatin capsule or filled into an enteric gelatin capsule.

Example 2 Gelatin 0.50 g -Tryptcasin (manufacturer: vaccine production and research institute HUMAN) 4.00 g Polybe tablets, dusty (manufacturer: Chemische Fabrik Gedeon Richter AG.> 5 pieces of sucrose 1.00 g dextrose 1.00 g lactose 2.20 g sodium chloride 2.00 g folic acid tablets, in powder form (manufacturer: ALKALOIDA Chemische Werke) 15 pieces of lactic acid 2.00 g The above components are homogenized, mixed with 150 g of cocoa butter and after a heat treatment suppositories are made with a weight of 5 g each.

For the purpose of prophylaxis, the effect of the suppositories thus obtained was used in 160 women (age 12-50 years) daily with a vaginal suppository examined. After a 1-7 days of treatment, the leading role of the Lactobacillus could acidophilus in the vagina is proven in 70% of the treated women. By the systematic application of the composition fluorine disease be prevented.

For the purpose of therapy, 200 women (age 12-50 years) were through the application of one suppository per day. It was possible for 50% of the sick the pure culture of Lactobacillus acidophilus detected in the vagina after 8-14 days will. At the same time, the negative changes in vaginal hygiene and stopped both the objective and the subjective symptoms of fluorine disease.

Example 3 Lactic Acid 3.00 g Sodium Acetate 3.00 g Glycerin 4.50 g ethyl p-aminobenzoate 2.00 g lactose 15.00 g The components are mixed with 100 g cocoa butter homogenized, the pH of the mixture is adjusted to 4.00 and after appropriate stirring, suppositories weighing 3 g each are prepared.

Example 4 Lactose 10.00 g oleic acid 1.00 g glycerine 1.50 g peptone (manufacturer: Difco) 2.00 g lactic acid 2.00 g ammonium chloride 2.00 g urea 2.00 g ethyl p-aminobenzoate 3.00 g Sodium acetate 4.00 g manganese chloride 0.05 g calcium lactate 0.50 g magnesium carbonate 0.50 g folic acid tablets, dusty (manufacturer: ALKALOIDA Chemical factory) 15 pieces Hydroxykobalamin 2.00 g The components are homogenized, suspended in 150 g of cocoa butter, the pH is adjusted to 4.2-5.0 and from Suppositories weighing 5 g each are prepared from the mixture.

Example 5 Vitamin B12 200 gamma oleic acid 1.00 g ethyl p-aminobenzoate 5.00 g lactic acid 1.00 g diethyl stilböstrol 0.015 g peptone (manufacturer: Difco) 0.50 g sodium acetate 1.50 g ascorbic acid 0.50 g The components given above are homogenized, the pH of the mixture is adjusted to 4.0-4.5 and A homogeneous ointment is prepared with 100 g of zinc paste.

Example 6 Trypeasin (manufacturer: Vaccine Production and Research Institute HUMAN) 20.00 g mushroom extract (manufacturer: Bacto) 5.00 g gelatin 2.50 g Dextrose 5.00 g lactose 5.00 g sucrose 5.00 g sodium chloride 4.00 g sodium acetate 1.50 g ascorbic acid 0.50 g The components are homogenized, the mixture is at 1200C and 1.5 atm. sterilized, the ascorbic acid becomes the cooled mixture Stirred in and the pH value is adjusted to 4.0-4.5. Finally there is a suspension of Lactobacillus acidophilus (2 x 106 / spleen added.

Example 7 Tryptis Digested Casein 15.00 g agar powder 6.00 g sodium chloride 5.00 g sodium thioglycolate 0.50 g lactose 15.00 g lactic acid 1.00 g gelatin 10.00 g After homogenization and suitable heat treatment, 0.5 ml of a suspension of Lactobacillus bifidus (2 x 10 / mol) are added, then the mixture is put into gelatin capsules filled.

Example 8 Peptone (manufacturer: Difco 15.00 g Lactacid (manufacturer: Vaccine Production and Research Institute HUMAN) 10.00 g agar powder 15.00 g the Components are mixed, the mixture is shaken for 20 minutes and then 5 Maintained at 80 ° C. for minutes. After cooling, 25 g are sterilized and filtered Paradise juice is added, the pH is adjusted to 4.0 with lactic acid and Enteric coated tablets are produced from the mixture.

Example 9 ethyl p-aminobenzoate 5.00 g magnesium sulfate 2.00 g pyridoxine 0.01 g potassium hydrogen sulfate 2.00 g glycine 0.02 g pepsin 0.10 g theophylline 2.00 g citric acid 1.00 g Tween 80 3.00 g oleic acid 1.00 g thymidine 0.01 g iron sulfate 0.50 g Podophyllin 0.01 g The components are mixed, heat treated, the pH is adjusted to 3.5, after cooling, 0.20 g of ascorbic acid is added and the mixture is mixed with an inert ointment base.

Example 10 Lactic acid 2.00 g glycerol 4.50 g ethyl p-aminobenzoate 2.00 g Folic acid tablets, dusty (manufacturer: ALKALOIDA Chemische Factory) 10 pieces oleic acid 2.00 g Polybe tablets, powdery (manufacturer: Chemical Factory Gedeon Richter AG.) 5 pieces Propolis 0.02 g Lactose 15.00 g The components are homogenized with 150 g of cocoa butter, after heat treatment and cooling 0.10 mg of ascorbic acid are added to the mixture, homogenized and 50 pieces of suppositories are produced.

Claims (1)

Process for producing a negative, for prophylaxis and therapy Changes in hygiene on epithelia appropriate, as more specific and accelerated In vivo nutrient medium usable preparation Patent claims 1. Process for the preparation of, for the prophylaxis and therapy of negative changes in hygiene on epithelia suitable on the epithelia as a specific and accelerated in vivo nutrient medium useful compositions, indicated that one for specific increase of the Lactobacillus acidophilus living on the epithelial tissues, optionally Lactobacillus bifidus, Propionibacterium and / or Corynebacterium, etc., a 0-50 wt% carbon source useful in vivo, preferably one or more carbohydrates, lactic acid and / or glycerin, a source of nitrogen from 0-20% by weight, preferably proteins, protein breakdown products or urea, and additional materials from 0-20% by weight, preferably salts, vitamins, growth factors, or antivirals Antiphage agents and / or immunity-increasing or immunity-inhibiting Middle, mixes with the usual carrier materials in the drug formulation and 0-20 times diluted, this being added to the amount of the carbon or nitrogen source will; the acidity of the mixture by an acid, preferably by lactic acid, adjusts to pH 3.0-6.5; optionally the mixture between 30 and 1200C and then heat-treated by a method known per se into one therapeutic composition, preferably for suppositories, tablets, ointments, Formed chewing gum, coated tablets, injection or spray. A method according to claim 1 for the preparation of an accelerated composition, by using vitamins, growth factors and salts of 10-20% by weight applies and dilutes 1-5 times.