WO2021137738A1

WO2021137738A1 - Compositions for treating inflammatory diseases of the throat

Info

Publication number: WO2021137738A1
Application number: PCT/RU2020/050398
Authority: WO
Inventors: Марк Mаркович ШАМЦЯН; Валентина Георгиевна КОНУСОВА; Евгений Владимирович ВОРОБЕЙЧИКОВ; Евгения Валерьевна БЕЗРУКОВА; Андрей Семенович СИМБИРЦЕВ; Владимир Евгеньевич ГАВРИЛОВ; Валерий Николаевич ЖИЖИКОВ
Original assignee: Марк Mаркович ШАМЦЯН; Валентина Георгиевна КОНУСОВА; Евгений Владимирович ВОРОБЕЙЧИКОВ; Евгения Валерьевна БЕЗРУКОВА; Андрей Семенович СИМБИРЦЕВ; Владимир Евгеньевич ГАВРИЛОВ; Валерий Николаевич ЖИЖИКОВ
Priority date: 2019-12-30
Filing date: 2020-12-28
Publication date: 2021-07-08
Also published as: RU2019145564A; RU2019145564A3

Abstract

The invention relates to medicine, more particularly to creating drugs based on plant raw materials, and can be used in prophylaxis and treatment of infectious and inflammatory diseases of the throat. Provided is a composition for treating inflammatory diseases of the throat, which includes as an active ingredient a basidial fungi extract comprising from 7.5 wt% to 15.0 wt% of β-D-glucans in the final product and one or more auxiliary substances. Said composition is intended for treating inflammatory diseases of the throat, it extends the range of drugs based on plant raw materials, is therapeutically effective and has no contraindications.

Description

COMPOSITIONS FOR THE TREATMENT OF INFLAMMATORY DISEASES OF THE PHOTO

FIELD OF TECHNOLOGY

The invention relates to medicine, namely to the creation of medicines based on plant raw materials, and can be used for the prevention and treatment of infectious and inflammatory diseases of the pharynx.

LEVEL OF TECHNOLOGY

Infectious and inflammatory diseases of the pharynx often occur as a phenomenon accompanying colds and acute respiratory diseases, as well as in the form of independent diseases. Such inflammatory processes in the oral cavity and pharynx are often accompanied by unpleasant painful sensations.

Diseases such as pharyngitis and chronic tonsillitis are among the most common reasons for patients seeking medical attention. Treatment of inflammatory diseases of the pharynx, depending on their severity, in general, consists in local therapy, and in some cases, with the course of the disease in a more severe form, in additional systemic therapy. Therapeutic tactics for such diseases of the mucous membrane of the oral cavity and pharynx include the appointment of drugs with anti-inflammatory, analgesic, immunocorrective action, the use of local antiseptics, decongestants and hyposensitizing drugs (Morozova S.V. Pain in the throat: causes and possibilities of drug therapy. Breast cancer, volume 13, N ° 21, 2005, pp. 1447-1452).

Typically, antiseptics and inflammation-inhibiting substances are used, for example, anti-inflammatory antiphlogistics, topical antibiotics, etc., which can be used, for example, in the form of rinses, sprays (aerosols) or tablets for sucking in the mouth.

In particular, a spray for topical application is known, which is a dosed antiseptic Antiangin containing chlorhexidine gluconate in the form of a 20% solution, tetracaine hydrochloride and excipients: glycerol 85% ethanol, aspartame, mint flavor, propyl parahydroxybenzoate, citric acid, water.

Currently, a drug is produced in the form of tablets for resorption for the treatment of infectious and inflammatory diseases of the pharynx "Grammidin with anesthetic neo", which includes gramicidin C, oxybuprocaine hydrochloride and cetylpyridine. nium chloride. However, these components have only a short-term antiseptic and analgesic effect.

In practical medicine for the treatment of throat inflammation tablet- ki widely used for sucking in the mouth "Lizobakt ^®», containing as active principle lizo- tsima hydrochloride and -20.0 mg -10.0 mg of pyridoxine hydrochloride and excipients: lactose monohydrate - 155.4 mg; gum tragacanth - 10 mg; magnesium stearate - 4 mg; sodium saccharinate - 0.5 mg; vanillin - 0.1 mg. However, this remedy is not effective enough and is used after rinsing the throat with a furacilin solution.

There are also known antiseptic lozenges (ATC) in the form of lozenges or lozenges, which contain one or more active antiseptic substances in a caramel-like or caramel mass, in particular, the use of Anatol and 2,4-dichlorobenzalcohol as active substances (Antisept Dr. Tais, Register of Medicines of Russia, M., "RLS-2000", 1999, p. 935), chlorhexidine (Drill sore throat, ibid., p. 980), diclonin hydrochloride (Coldrex Larry Plus, ibid., p. . 1033), 4-dichlorobenzyl alcohol and amylmetacresol (Faringopils, ibid., P. 701). The disadvantage of these drugs is the development of allergic reactions to the contained organochlorine ingredient and the low efficiency of the extracts. In addition, some of these drugs cause disorders of the gastrointestinal tract, nausea, and vomiting.

The use of herbal preparations is of particular interest in the treatment of inflammatory diseases of the pharynx, which is associated with the variety of their pharmacological properties and the possibility of creating the most effective combinations, since they contain a whole spectrum of biologically active substances and have a multidirectional effect on the pathogenesis of inflammatory diseases.

It is known to use active substances of natural origin, for example, mucus-producing medicinal plants (so-called mucus-containing medicinal plants) or their extracts, such as Icelandic moss and the like. (UA78642, 2005). A known agent containing extracts of licorice, marshmallow and menthol, gramicidin C and auxiliary substances - polyethylene oxide, sugar, calcium stearate (RU 2160088, 2000). However, such drugs do not always allow achieving the required therapeutic effect, because they, in general, do not have the proper effect on pain symptoms in inflammatory diseases of the pharynx.

There is a known agent for the prevention and treatment of infectious and inflammatory diseases of the pharynx, containing dry extract of St. nickel, licorice roots and rose hips, ascorbic acid, and as auxiliary substances beet pectin, food agar, sodium carboxymethyl cellulose, sugar, calcium stearic acid (RU 2216320, 2003). However, the product contains a large amount of ingredients that can cause allergic reactions in children and adults.

Closest to the claimed invention is an agent for the prevention and treatment of infectious and inflammatory diseases of the pharynx in the form of a lozenge for resorption, containing as an active component the extract of licorice and rose hips, peppermint, myrtle, leaves of medicinal rosemary and refined sugar in the ratio extract of medicinal plants to refined sugar 1: 2 using flower honey, or raspberry, or lemon as a flavoring agent 1% of the total weight of the candy (ЕА 027691, 2016). The disadvantage of this product is its relatively low efficiency.

DESCRIPTION OF THE INVENTION

The technical problem solved by the authors is to expand the range of drugs for the treatment of inflammatory throat diseases by creating a more effective pharmaceutical anti-inflammatory immunostimulating composition.

The technical result is achieved by creating a composition for resorption in the mouth, in the caramel mass of which an extract of basidiomycetes is included as an active principle, containing PI-glucans in an amount from 7.5% to 15.0% of the mass.

The authors of the present invention have found that the herbal remedies of basidiomycetes contain biologically active substances that are close to the metabolites of the body and are biologically compatible with it, showing a normalizing effect on the altered functions of the body without affecting other parameters. These properties, as well as the use of low doses of herbal components, make it possible to practically eliminate toxic and undesirable side effects.

Currently, b-glucans isolated from lichen are offered as an antitumor agent (RET 2121839, 1998); composition of b-glucans from Saccharomyces cerevisiae, ginseng extract and Reishi mushroom extract (RU 2 693 022, 2018) is proposed to enhance immunity, beta-glucan derivatives in the form of carboxymethyl beta-glucan sodium salt and iota carrageenan are offered as an antiviral agent active against an infection caused by the herpes virus (RU 2701514, 2019). The use of P-O-glucans and other preparations based on basidiomycetes for the treatment of inflammatory diseases of the throat is unknown in the art.

Thus, according to the present invention, there is provided a composition for resorption in the mouth, containing an effective amount of an extract of basidiomycetes containing P-O-glucans in an amount from 7.5% to 15.0% by weight, and an excipient.

According to one embodiment of the invention, the content of P-D-glucans in the composition is from 7.5% to 14%, from 10% to 12%, from 8% to 11%, from 9% to 13%.

According to a preferred embodiment of the present invention, the extract is an extract of Oyster mushroom (Pleurotus ostreatus). In another embodiment, the basidiomycete extract is a Reishi (Ganoderma lucidum) extract. In another embodiment, the basidiomycete extract is a Shiitake extract (Lentinula edodes).

In a further embodiment, the compositions of the present invention may contain extracts of other edible basidiomycetes as a source of P-O-glucans.

In one embodiment, caramels and flavoring and flavoring agents are used as adjuvants, including, but not limited to, raspberry, cherry, anise, etc. flavor additives.

The inventors of the present invention have surprisingly found that the use of a drug with a concentration of P-O-glucans less than 7.5% by weight. is ineffective, while the use of a drug with a concentration of P-D-glucans of more than 15.0% does not lead to a significant improvement in therapeutic properties, while deteriorating the taste and organoleptic characteristics of the composition.

In a preferred embodiment, the composition of the present invention is for oral administration. In a further embodiment, the composition of the present invention may be in the form of a lozenge, tablet or lozenge.

Specialists of the Clinic for Ear, Throat and Nose Diseases, MMA named after THEM. Sechenov (ЕА 027691, 2016) believe that therapeutic "suckers" are the only group of drugs used today intended for self-medication, because has practically no side effects. In addition, the lozenges will not interfere with other medications that may be prescribed by the attending physician. Thanks to the sugar base, the medicinal substance remains on the mucous membrane of the oropharynx longer. In addition, the lollipop resorption process results in the production of saliva, which lubricates the throat and reduces pain and discomfort experienced by the individual.

The essence and practical applicability of the proposed method (means) is illustrated by the following examples.

Preparation of the composition according to the present invention.

It should be understood that the compositions of the present invention can be prepared by any of the conventional methods for the preparation of lozenges, for example, by adding the extract to a melted caramel with flavoring and flavoring additives, and then granulating the resulting product.

It should also be understood that specific treatment regimens and dosages of the composition of the present invention for the treatment of inflammatory throat diseases may be prescribed by the attending physician depending on the physiological parameters of the patient and the severity of his condition.

In the examples below, the following treatment regimen was used: 1 lozenge 2-3 times a day, for 5-7 days, depending on the characteristics of the disease.

Example 1. For the treatment of patients with a diagnosis of acute catarrhal pharyngitis (OP), exacerbation of chronic catarrhal pharyngitis, an immunostimulating agent in the form of lozenges for resorption was used, consisting of an extract of basidiomycetes of Oyster mushroom (Pleurotus ostreatus) containing P-O-glucans 10% of the mass and filler in the form of caramel with raspberry flavor and aroma. The inventive agent was used 1 lozenge 2 times a day, lasting 5 days. As a comparison method, a traditional method was used, which included rinsing the throat with a furacilin solution (2 times a day) in combination with Lizobakt lozenges (2 tablets 3 times a day). The total duration of treatment was 5 days.

Patients diagnosed with OB were divided into 2 groups. Patients in group No. 1 received conventional therapy. Patients of group No. 2 received the claimed treatment. The number of patients in groups N ° 1 and N ° 2 consisted of 20 people in each group.

The statistical evaluation of the treatment results was carried out using the nonparametric criterion c ² Pearson, which makes it possible to determine the significance of statistical changes in pathological signs in patients of groups N ° 1 and N ° 2 in the form of their presence or absence against the background of traditional therapy and proposed for treatment of an immunostimulating agent. Using the parametric Student's t test and the nonparametric criterion Riya Mann-Whitney determined the reliability of differences in the mean values of the severity of a number of symptoms in patients against the background of traditional therapy and the claimed immunostimulating agent.

As a subjective criterion for patient complaints, a score was used to assess pain and sore throat, as well as the presence of cough. The severity of these complaints was determined in points (0-5). The pharyngoscopic picture of the pharyngeal mucosa was visually assessed by the following indicators: presence or absence of hyperemia; drainage of discharge along the posterior wall of the pharynx, the degree of edema of the lateral lymphoid ridges of the pharynx. The integral indicator of the effectiveness of treatment was the number of cases of complete clinical recovery.

Tables 1, 2, 3 present data on the subjective assessment of their condition in patients of groups JVT1 and N ° 2.

Table 1.

Significance of differences in the mean values of the severity of sore throat (scores from 0 to 5) in patients with OP during therapy.

Group Group T-test Criterion

Time * N ° 1 N ° 2 Student Mann-Whitney hour M ± Sd M ± Sd T; Tcr .; p U; Z; R

0 4.38 ± 0.74 4.38 ± 0.81 0.00; 2.02; p> 0.05 216.5; -0, 10; p> 0.05

2 4.35 ± 0.49 3.10 ± 0.45 8.43; 2.02; p <0.01 19.50; -4.88; p <0.01

24 4.30 ± 0.47 3.05 ± 0.39 9.11; 2.02; p <0.01 14.00; -5.03; p <0.01

48 3.60 ± 0.50 2.10 ± 0.64 8.24; 2.02; p <0.01 20.00; -4.89; p <0.01

72 2.75 ± 0.44 1.35 ± 0.49 9.47; 2.02; p <0.01 17.50; -4.94; p <0.01

96 2.10 ± 0.64 0.65 ± 0.48 8.04; 2.02; p <0.01 19.50; -4.88; p <0.01

120 1.45 ± 0.51 0.20 ± 0.41 8.54; 2.02; p <0.01 22.00; -4.81; p <0.01

Note: * - observation time

Table 2.

Significance of differences in the mean values of the severity of sore throat (scores from 0 to 5) in patients with OP during therapy. Group Group T-test Criterion

Time * N ° 1 F Student Mann-Whitney hour M ± Sd M ± Sd T; Tcr .; p U; Z; R

0 4.43 ± 0.51 4.47 ± 0.51 -0.30; 2.02; p> 0.05 210.00; -0.31; p> 0.05

2 4.00 ± 0.79 2.90 ± 0.44 5.08; 2.02; p <0.01 62.00; -4.04; p <0.01

24 3.60 ± 0.50 3.25 ± 0.45 2.33; 2.02; p <0.05 130.00; -2.21; p> 0.05

48 3.50 ± 0.61 2.50 ± 0.51 5.63; 2.02; p <0.01 55.00; -4.21; p <0.01

72 3.50 ± 0.51 1.95 ± 0.51 9.58; 2.02; p <0.01 10.00; -5.40; p <0.01

96 2.50 ± 0.51 1.20 ± 0.42 8.85; 2.02; p <0.01 20.00; -5.19; p <0.01

120 1.40 ± 0.50 0.10 ± 0.31 9.86; 2.02; p <0.01 12.00; -5.49; p <0.01

Note: * - observation time

Table 3.

Significance of differences in the mean values of the severity of cough (scores from 0 to 5) in patients with OP during therapy.

Group Group T-test Criterion

Time * F F Student Mann-Whitney hour M ± Sd M ± Sd T; Tcr .; p U; Z; R

0 3.81 ± 0.87 3.80 ± 0.81 0.00; 2.02; p> 0.05 219.50; -0.03; p> 0.05

2 3.80 ± 0.89 3.70 ± 0.73 0.38; 2.02; p> 0.05 189.00; -0.32; p> 0.05

24 3.60 ± 0.68 3.05 ± 0.51 2.89; 2.02; p <0.05 117.00; -2.62; p <0.05

48 2.85 ± 0.67 2.45 ± 0.51 2.12; 2.02; p <0.05 136.50; -1.92; p> 0.05

72 2.72 ± 0.72 2.15 ± 0.37 3.33; 2.02; p <0.01 105.50; -2.99; p <0.05

96 1.80 ± 0.41 1.90 ± 0.71 -0.54; 2.02; p> 0.05 188.00; -0.38; p> 0.05

120 1.15 ± 0.67 0.65 ± 0.59 2.51; 2.02; p <0.05 122.50; -2.33; p <0.05

Note: * - observation time.

Comparative analysis of the results obtained shows a pronounced efficacy of the claimed agent, in comparison with the standard therapy of OP. Moreover, in contrast to the standard treatment regimen for OP, the claimed agent has an analgesic effect. Patients noted a decrease in sore throat, starting from the second hour after taking the drug.

Tables 4-7 present the data of visual examination of patients during treatment.

Table 4. Evaluation of the effectiveness of the therapy by the presence of hyperemia of the pharyngeal mucosa in patients.

Table 5.

Criteria for the statistical significance of differences between the number of cases of the presence and absence of hyperemia of the pharyngeal mucosa in patients of groups N ° 1 and N ° 2 against the background of traditional treatment and the claimed agent.

The results in Tables 4 and 5 demonstrate that the differences between the number of cases of the presence and absence of hyperemia of the pharyngeal mucosa in patients of groups J1 and N ° 2 with OP have statistical significance (p <0.05), which indicates the effectiveness of the claimed funds.

Table 6.

Evaluation of the effectiveness of the therapy by the presence of a symptom of discharge along the posterior pharyngeal wall in patients.

Table 7.

Criteria for the statistical significance of differences between the number of cases of presence and absence of a symptom of drainage along the posterior pharyngeal wall.

The results in Tables 6-7 demonstrate that the differences between the number of cases of the symptom of drainage along the posterior pharyngeal wall in patients of groups N ° 1 and N ° 2 with OP have statistical reliability (p <0.05), which also demonstrates the effectiveness of the claimed funds.

Thus, as follows from the above data, the agent according to the present invention, in comparison with the standard treatment regimen, including the instillation of furacilin in combination with the antibacterial drug Lizobact, by the end of the treatment reliably reduces inflammatory manifestations in the throat: hyperemia and mucus formation ... The great advantage of the drug is its pronounced analgesic effect.

The integral effectiveness of treatment was assessed by the number of cases of “complete clinical recovery”, determined by the sum of positive results of visual examination and the absence of patient complaints. The results are shown in Table 8. Table 8.

The number of cases of complete clinical recovery of patients with OB against the background of traditional treatment and the declared remedy.

Table 9.

Criteria for the statistical significance of differences between the number of complete and incomplete clinical recovery of patients with OP against the background of traditional treatment and the proposed remedy.

The results in Tables 8 and 9 demonstrate that the differences between the number of cases of complete and incomplete clinical recovery of patients in groups N ° 1 and N ° 2 are statistically significant (p <0.05). This means that the use of the claimed agent in the form of lozenges for absorption in the oral cavity in patients of group N ° 2 for the treatment of OP, increases the likelihood of a positive therapeutic effect, because reduces the incidence of incomplete clinical recovery. The use of traditional treatment of patients with ONF does not give such an effect.

Example 2. Patient A, 27 years old. Complaints of sore throat when swallowing, feeling of dryness in the throat, fever. In the blood leukocytosis, accelerated ESR. Diagnosis of acute tonsillopharyngitis. I took lollipops 3 times a day according to example 1. On the 4th day it was stopped a feeling of dry mouth, pain when swallowing, the temperature dropped to normal (36.6 ° C), the patient's general condition returned to normal.

Example 3. Patient S. 36 years old. Complaints about fever, sore throat, sweating. In the blood leukocytosis, accelerated ESR. Diagnosis of acute catarrhal pharyngitis.

Within 6 days, along with the medicines prescribed by the attending physician, I took 3 times a day before meals according to example 1. On the third day, the sore throat passed, the temperature returned to normal. The condition has stabilized. No side effects were observed.

Example 4. Were tested preparations obtained from different sources of b-D-glucans. The drug was taken for 5 days. The test results are shown in Table 10.

Table 10.

Influence of P-O-glucan preparations on the effectiveness of treatment of diseases of the oral cavity and pharynx.

The results in Table 10 demonstrate that the number of cases of complete recovery of patients is practically independent of the source.

P-O-glucans contained in the inventive agent, which makes it possible to use various types of edible basidiomycetes for its production.

Example 5. Prophylaxis in the autumn and spring was carried out in 64 patients with various chronic periodontal diseases using the drug according to example 1. The result is positive in 80% of cases. Only 2% of patients did develop an exacerbation.

Example 6. Treatment of chronic compensated tonsillitis (simple form).

The effectiveness of therapy for chronic compensated tonsillitis (simple form) was determined after 6 months by the presence or absence of caseous plugs in the tonsils lacunae. Patients diagnosed with chronic compensated tonsillitis (simple form) were divided into the following groups:

Group of patients No. 1 (control group) received traditional therapy - washing the lacunae of the tonsils with saline in combination with the drug Miramistin daily for 10 days;

Patient group No. 2 (experimental group) received lacunae washing of the tonsils with saline daily for 10 days in combination with lozenges for absorption in the mouth with raspberry flavor and aroma 3 times a day, 1 lozenge for 10 days ... Then, the 10-day course of lozenges was repeated for 2 months;

Group N ° 3 patients (treatment group) received washing gaps tonsils saline daily for 10 days in combination with preparative that Ismigen ^®, used in the form of tablets for sucking in the mouth, the complex containing antigenic bacterial lysates frequent pathogens of respiratory diseases ... The mode of administration of Ismigen ^® is once a day for 10 days. Then, a 10-day course of the drug Ismigen ^® was repeated for 2 months. The results of treatment of patients in these groups were assessed using the nonparametric Chi-square test.

Treatment results

Table 11 shows the results of treatment of chronic compensated tonsillitis (simple form) in patients of groups N ° 1 and N ° 2.

Table 11.

The number of cases of absence and presence of caseous plugs in patients with chronic compensated tonsillitis (simple form) 6 months after traditional therapy (group N ° l) and the claimed agent (group N ° 2).

Table 12 presents the criteria for the statistical significance of the differences between the number of cases of absence and presence of caseous plugs in patients of groups N ° 1 HN ° 2 against the background of traditional treatment and the claimed agent.

Table 12.

Criteria for the statistical significance of differences between the number of cases of absence and presence of caseous plugs in patients of groups N ° 1 HN ° 2 after traditional treatment and the claimed agent.

The results in Tables 11 and 12 demonstrate that the differences between the number of cases of absence and presence of caseous plugs in patients with chronic compensated tonsillitis volume (simple form) 6 months after traditional therapy (group No. 1) and the claimed agent (group No. 2) have statistical significance (p <0.05). This means that the use in patients of group No. 2 for the treatment of chronic compensated tonsillitis (simple form) of the claimed agent in the form of lozenges for absorption in the oral cavity increases the likelihood of developing a positive therapeutic effect, because reduces the number of cases of caseous plugs in the lacunae of the tonsils. The use of traditional therapy does not give such an effect.

Table 13 shows the results of treatment of chronic compensated tonsillitis (simple form) in patients of groups N ° 2 and N ° 3.

Table 13.

The number of cases of absence and presence of caseous plugs in patients with chronic compensated tonsillitis (simple form) 6 months after immunostimulating therapy (group No. 3) and the claimed agent (group No. 2).

Table 14 presents criteria for the statistical significance of differences between the number of cases of absence and presence of caseous plugs in patients of groups N ° 2 pN ° 3 after immunostimulating therapy and the claimed treatment.

Table 14.

Criteria for the statistical significance of differences between the number of cases of absence and presence of caseous plugs in patients of groups N ° 2 pN ° 3 after traditional treatment and the claimed agent.

The results in Tables 13 and 14 demonstrate that the differences between the number of cases of absence and presence of caseous plugs in patients with chronic compensated tonsillitis (simple form) 6 months after the claimed immunostimulating therapy (group N ° 2) and immunostimulating therapy based on Ismigen preparation ^® (group N ° 3) have no statistical significance (p> 0.05). This means that the use of at patsien- comrade group N ° 2 for the treatment of chronic tonsillitis compensated (simple shape) of the inventive means as a candy lozenge in the buccal cavity and an immunological lating drug Ismigen ^® provide similar effectiveness of treatment of a chronic inflammatory process. Therefore, washing the lacunae of the palatine tonsils in combination with immunostimulating agents gives a positive clinical effect, which makes it possible to use, inter alia, the composition according to the present invention for the treatment of chronic compensated tonsillitis (simple form).

Thus, the new drug, which is a composition according to the present invention, is beneficial and effective for the treatment of inflammatory diseases of the pharynx and chronic inflammation of the palatine tonsils, expanding the arsenal of herbal medicines, has no contraindications.

Claims

CLAIM

1. Composition for the treatment of inflammatory diseases of the pharynx, containing, as an active principle, a component of plant raw materials, which is an extract of basiodial fungi, and one or more auxiliary substances, wherein the content of bD-glucans in the final product ranges from 7.5% to 15.0% masses.

2. A composition according to claim 1, characterized in that said extract of basiodial mushrooms contains an extract of Oyster mushroom.

3. A composition according to claim 1, characterized in that said extract of basiodial mushrooms comprises Reishi extract.

4. A composition according to claim 1, wherein said basiodial mushroom extract comprises Shiitake extract.

5. Composition according to any one of paragraphs. 1-4, characterized in that one or more adjuvants are selected from the group consisting of caramel and flavoring and flavoring additives.