ANTIMICROBIAL AGENT CONTAINING ISOTHIOCYANATES

Description

[0001] The invention relates to an antimicrobial agent based on an active ingredient combination of isothiocyanates.

[0002] Isothiocyanates are found in a variety of plants, especially those of the Brassicaceae (cruciferous) family and the nasturtium family. Of particular note are cabbage varieties such as Brussels sprouts, red cabbage, broccoli, kohlrabi, and the like, as well as radishes, radishes, mustard seeds, horseradish, and cress, as well as nasturtiums. In these plants, isothiocyanates are components of the pungent principle. They are often collectively referred to as mustard oils. These compounds are known for their antibacterial and fungicidal effects and have long been used in medicine, particularly in the form of phytotherapeutics, which contain them as prodrugs together with components for their activation. Efficacy in cancer therapy has also been demonstrated.

[0003] To exert their effect, these ingredients must enter the human body in their active form. Their extraordinary reactivity and sensitivity make this impossible. Isothiocyanates are sensitive to light and oxygen and hydrolyze in both alkaline and acidic media. Their use in their pure form is therefore problematic.

[0004] In the state of the art, the ingredients are used in the form of plant powders containing the ingredients as glucosinolates together with the enzyme myrosinase, the latter hydrolyzing the glucosinolates to active isothiocyanates.

[0005] Glucosinolates, the precursors of isothiocyanates, are present in varying concentrations in individual plants of the Brassicaceae family. Furthermore, individual plants contain different glucosinolates. The glucosinolates are released when the plants are crushed and converted into free isothiocyanates by the enzyme myrosinase, which is also released. Examples of isothiocyanates include methyl isothiocyanate, phenyl isothiocyanate, benzyl isothiocyanate, allyl isothiocyanate, sulforaphane, and the like. Each of these substances has its own flavor and spectrum of effects.

[0006] One problem with administering isothiocyanates in the form of plant products is the lack of standardization and packaging. The active ingredient content of the processed plants varies, thus hampering standardized therapy. Furthermore, the plant product requires activation by the enzyme that first releases the active ingredient, which also exposes it to chemical degradation. Therefore, the proportion of mustard oils contained in a plant product is only partially beneficial to the patient after ingestion.

[0007] In addition, the individual isothiocyanates have a specific spectrum of activity and therefore require tailoring to the specific microorganism to be combated. It would be helpful to provide a combination of active ingredients that is effective against a wide range of microorganisms.

[0008] The "Angocin Anti-Infekt N" product information dated July 1, 2015, discloses an antimicrobial agent containing allyl, benzyl, and phenethyl isothiocyanate in the form of glucosinolates. The "OTC Advisory Card 76 Angocin Anti-Infekt N Film-Coated Tablets" dated September 6, 2017, discloses an antimicrobial agent based on powder from nasturtium herb and horseradish root. The antimicrobial activity of this agent is investigated in C. Andreas et al., "In-Vitro Studies on the Antibacterial Efficacy of a Combination of Nasturtium Herb and Horseradish Root," Arzneimittelforschung / Drug Research, January 1, 2006, pp. 842 ff. SJ Kaiser et al "Natural isothiocyanates express antimicrobial activity against developing and mature biofilms of Pseudomonas aeruginosa", Fitoterapia, Milan, IT, Vol. 119, 5:April 2017, p.57 ff discloses that the phytomedicinal antimicrobial agent Angocin derives its efficacy from the isothiocyanates present in nasturtium herb powder and horseradish root powder.

[0009] The object of the invention is to provide an active ingredient combination of isothiocyanates with a broad spectrum of activity. This active ingredient combination should also be protected against chemical changes / decomposition and be released only at the site of action.

[0010] This object is achieved with an antimicrobial composition which contains as active ingredients a combination of 45 to 55 wt.% benzyl isothiocyanate, 33 to 43 wt.% allyl isothiocyanate and 7 to 17 wt.% 2-phenylethyl isothiocyanate, the total amount of isothiocyanates being 100 wt.%, bound to a carrier and enclosed hermetically in an enteric-coated administration means, the active ingredient combination bound to the inert carrier being pelletized and microencapsulated with chitosan.

[0011] The active ingredients used in the invention can be readily obtained synthetically. Extraction from the corresponding plants is possible, but complex.

[0012] Since each of the plant-derived isothiocyanates has a specific spectrum of activity, combining several of these active ingredients is beneficial to achieve the broadest possible spectrum of activity. The combination of approximately 50% by weight benzyl isothiocyanate, 38% by weight allyl isothiocyanate, and 12% by weight 2-phenylethyl isothiocyanate has proven particularly effective against a wide range of microorganisms, including both Gram-positive and Gram-negative bacteria. Isothiocyanates are also effective against viral and fungal infections.

[0013] The active ingredient combination according to the invention is bound to a conventional inert carrier. Suitable carriers include gypsum, calain carbonate, finely divided diatomaceous earth, and silica gel, but any other carriers proven effective in pharmaceuticals can also be used. The amount of carrier depends on the sorption capacity for the liquid active ingredients. Diatomaceous earth or silica gel is preferred.

[0014] The means of administration are oral medications commonly used in pharmacy, such as tablets, dragees or capsules, which meet the requirements.

[0015] It is important that the active ingredients are sealed airtight. Isothiocyanates are highly reactive and particularly sensitive to moisture and oxygen. The airtight seal is achieved in the usual way by packaging, for example, in a film-coated tablet or an airtight capsule. In principle, however, any administration form that ensures airtight packaging of the active ingredient combination according to the invention is suitable.

[0016] The inventive form of air exclusion is the microencapsulation of the active ingredient combination bound to the inert carrier. This is pelletized and coated with the encapsulating agent, chitosan. The pellets can then be filled into a standard medication capsule and administered.

[0017] Such a film-coated tablet or capsule advantageously contains 0.1 to 100 mg of the active ingredient combination, in particular 0.5 to 50 mg, and particularly preferably 1.0 to 20 mg. Administration three times daily, preferably with meals, has been shown to be sufficient. Administration should continue for a maximum of one week.

[0018] The amounts of carrier are preferably 0.1 to 1.0 g per film-coated tablet or capsule, in particular 0.2 to 0.5 g, depending on the amount of active ingredients.

[0019] Due to the reactivity of isothiocyanates, the active ingredient combination is presented in enteric-coated tablets or capsules. Pharmacists are familiar with suitable polymers for this purpose, particularly polymethacrylates (Eudragit). Film-coated tablets or capsules made from these pass through the stomach undamaged and dissolve only in the small intestine, releasing the active ingredient combination.

[0020] To stabilize the active ingredient combination, the agent according to the invention may additionally contain vitamin E. Vitamin E increases oxidation resistance. Chitosan serves as an additional barrier to oxygen.

[0021] The amount of vitamin E per film-coated tablet or capsule is advantageously 0.01 to 0.5 g, especially 0.01 to 0.30 g. Chitosan is contained in the microencapsulation in amounts of 0.1 to 0.5 g, preferably 0.1 to 0.25 g.

[0022] To promote the absorption of the active ingredient combination in the patient's intestine, the agent according to the invention may contain medium-chain triglycerides. Miglyol is preferred, as its absorption-promoting properties have been proven. Such triglycerides may be present in an amount of up to 1.0 ml per capsule.

[0023] The efficacy of an active ingredient combination according to the invention containing 50 wt.% benzyl isothiocyanate, 37.9 wt.% allyl isothiocyanate, and 12.1 wt.% 2-phenylethyl isothiocyanate was determined in vitro against a range of pathogens. The minimum inhibitory concentrations (MIC 90) (in % v / v) and minimum bactericidal concentrations (MBC 90) (% v / v) determined in each case are shown in Table 1. Strain / bacterium MHK90 (% v / v) MBK90 (% v / v) Staphylococcus aureus 0.004 0.5 Streptococcus pneumoniae 0.008 0.03 S. pyogenes 0.008 0.25 Enterococcus faecalis 0.015 >1 E. faecium 0.015 >1 Pseudomonas aeruginosa 0.03 0.06 Escherichia coli 0.015 0.25 Klebsiella pneumoniae 0.125 0.125 Common Proteus 0.004 0.015 Serratia marcescens 0.004 0.004 H. influenzae ≤0,005 ≤0.0005 Candida spp. 0.004 0.004

[0024] Isothiocyanates are metabolized by the body after absorption. The metabolite of benzyl isothiocyanate, N-acetyl-5-(N-benzylthiocabamoyl)-L-cysteine, is excreted via the kidneys and can be quantitatively detected in the urine. In volunteers, an excretion rate of 53% (mean) was observed. Excretion occurred rapidly, with a maximum concentration 2 to 6 hours after administration and was completed after 10 to 12 hours. The same applies to other isothiocyanates.

[0025] The active ingredient combinations according to the invention were well tolerated by the test subjects.

Claims

1. Antimicrobial agent containing as active ingredient a combination of 45 to 55% by weight benzyl isothiocyanate, 33 to 43% by weight allyl isothiocyanate and 7 to 17% by weight 2-phenylethyl isothiocyanate, wherein the total amount of the active ingredients adds up to 100% by weight, characterized in that the active ingredients are bound to an inert carrier substance and are enclosed in an airtight manner in an administration agent resistant to gastric juice, wherein the active ingredient combination bound to the inert carrier substance is pelletized and microencapsulated with chitosan.

2. Antimicrobial agent according to claim 1 in the form of a film-coated tablet or capsule.

3. Antimicrobial agent according to any one of the preceding claims 1 or 2, characterized in that it contains 0.1 to 100 mg of the active ingredient combination.

4. Antimicrobial agent according to claim 3, characterized in that it contains 0.5 to 50 mg of the active ingredient combination.

5. Antimicrobial agent according to any one of the preceding claims, comprising about 50% by weight benzyl isothiocyanate, 38% by weight allyl isothiocyanate and 12% by weight 2-phenylethyl isothiocyanate.

6. Antimicrobial agent according to any one of the preceding claims, characterized in that the carrier material is gypsum, calcium carbonate diatomaceous earth or silica gel in finely divided form.

7. Antimicrobial agent according to any one of the preceding claims, characterized in that it contains vitamin E.

8. Antimicrobial agent according to any one of the preceding claims, characterized in that it contains medium-chain triglycerides, in particular a miglyol.