The use of amyl-metacresol to obtain drugs for the local treatment of inflammation and medicinal product containing the alcohol dichlorobenzoyl


(57) Abstract:

The invention can be used to treat local inflammation on the skin and/or mucosa. The stated use of amyl-metacresol, preferably 2,4-dihlorbenzilovy, as an active ingredient of a medicinal product for the local treatment of inflammation, eliminating the inflammation caused by Helicobacter pylori. The tool can optionally include bioadhesive materials and provide a solution, ointment, cream or gel. The tool can be applied in the mouth or applied on the skin. The invention extends the range of anti-inflammatory drugs for external use. 6 C.p. f-crystals, 4 PL.

The present invention relates to the use of amyl-metacresol, in particular 2,4-amyl-metacresol, to obtain drugs for the local treatment of inflammation. In addition, the invention relates to anti-inflammatory drugs, containing dichlorobenzoyl alcohol, including 2,4-dichlorobenzoyl alcohol, in the form of ointment, cream, solution or gel for topical use on the skin and/or mucosa.

Known application of 2,4-amyl-metacresol (hereinafter referred to the traveler yeast, fungi, skin mushrooms, and some gram-positive and gram-negative bacteria. Thus, for more than 30 years was known application of 2,4-DHBS in combination with other antibacterial agents, antiseptic tablets.

2,4-DHBS were also successfully used as an antimicrobial agent in the treatment of infections in the mouth and throat, antiseptic skin preparations for disinfection and treatment of small cuts and abrasions, and creams/lotions for the feet to treat the fungus.

In U.S. patent 3123528 disclosed pharmaceutical preparation for oral administration which comprises 2,4-DHBS and a pharmaceutically acceptable diluent or carrier. Compositions, inter alia, include liquids for mouth rinses, toothpastes, lozenges, pills, lotions, ear drops, these compositions are used to fight infections caused by bacteria and fungi in the ear, throat and on the skin. If desired, the composition may also contain saligenin (o-hydroxybenzoyl alcohol), which is a local anesthetic, introduced to make the compositions for oral administration as antibacterial and analgesic actions.

In patent application EP 161898 disclosed is UNT for the treatment of plaque (bacterial coating) for example, 2,4-DHBS.

Furthermore, in U.S. patent 4167583 disclosed antimicrobial compositions for disinfection of the skin of humans and animals, these compositions among other things can include dichlorobenzoyl alcohol, for example 2,4-DHBS. The composition can also be used for disinfection of surgical instruments and equipment. The compositions are particularly suitable for the disinfection of hands, for example, in surgery.

In WO 95/26134 described composition for use on surfaces such as the surface of the apparatus or instruments, clothing, gloves, condoms, or the surface of the skin containing the agent for inactivation of the so-called irritant means and substance, which effectively prevents the agent inactivating irritant tool from binding to the surface. Antimicrobial agents, including 2,4-DHBS are marked as examples, inactivating irritant tool agents.

In WO 92/1811 disclosed an antimicrobial agent, such as 2,4-DHBS, to obtain drugs for the treatment of gastric diseases caused by microorganism Helicobacter pylori.

In WO 96/32934 described the use of a composition containing 2,4-DHBS and amylmetacresol, for receiving the s pharmaceutical compositions for topical application in the form of a thixotropic gel, these compounds in addition to the active component contains from 2 to 15% of colloidal silica, water and, optionally, one or more excipients. As examples of active ingredients specified non-steroidal anti-inflammatory agents Antibacterials/antibiotics. Along with other noted composition containing 2,4-DHBS.

In addition, it is known the use of 2,4-DHBS to prevent the growth of bacteria/fungi for example, in cosmetic products, toiletry products, including shampoos and destroy plaque toothpaste, household products, textiles, wood products, leather products, paper, etc.

The invention is based on the discovery that dichlorobenzoyl alcohol, and in particular 2,4-DHBS, has a surprisingly good effect in inflammation.

Inflammation is the result of alien caused damage to the cells or tissue. Such damage can be caused by chemical and/or physical effects on the skin of humans and animals. Examples of physical effects include shock, heat, cold, radiation, electric shock, and examples of chemical exposure are contact with acids, bases and allergens. Inflammation can also be wytwarzania microorganisms in the human body or animal.

In other words, inflammation is a protective mechanism of invasive alien-induced effects on the skin or fabric. Symptoms can be one or more of the following: pain, increased surface temperature, swelling, erythema and reduced or impaired function, for example, the ability to chewing.

Thus, the invention relates to the use of amyl-metacresol, and, in particular, 2,4-DHBS to obtain drugs for the local treatment of inflammation, including inflammation caused by Helicobacter pylori.

It turned out that the use of 2,4-DHBS at low concentrations irritating inflammatory action on the skin and mucosa. The skin reactions were studied by direct application solutions in propylene glycol under the bandage stomachs Guinea pigs for 4-5 hours. Concentrations up to 1% did not cause or has caused minor damage, whereas higher concentrations caused inflamed state.

Although 2,4-DHBS has a very limited solubility in water, this substance can be efficiently introduced into the water system. Its solubility in organic solvents - good.

For optimum effectiveness of the active compounds (amyl-metacresol, 2,4-DHBS) it is important that it remained at the site of inflammation over an extended period of time. For these purposes, can advantageously be used bioadhesive, which are substances that bind with biological materials, including proteins, cells or tissue. Therefore, bioadhesive can be defined as a compound capable of contact with biological material and stay connected for a specified period of time. When biological material is a mucous membrane, it is about mucoadhesive materials. Mucoadhesive materials in the form of polymers typically are capable of forming hydrogels.

In one embodiment of the invention the active compound together with one or more substances, which provide controlled release and/or prolonged retention amyl-metacresol at the place of treatment.

In another embodiment of the invention the active compound together with one or more bioadhesive materials.

Examples bioadhesive materials include hydrocolloids such in methyl cellulose and gum Arabic.

A distinctive feature of bioadhesive materials is that they are macromolecular organic hydrocolloids with hydrophilic functional groups capable of forming hydrogen bonds with, for example, the corresponding functional groups of the biological material. Strength bioadhesive material increases with increasing molecular weight up to more than 100,000 daltons.

As noted above, when using bioadhesive longer retention time of the active agent to hell/absorbent surface. To control release of the active agent can be used many different types bioadhesive materials, both natural and synthetic.

It was found that the compound 2,4-DHBS effective against various skin diseases, including itching and psoriasis. In addition, it was found that the compound is effective for the treatment of bites/acute pain from insect bites (an inflammatory condition).

The invention also relates to a drug for topical treatment of inflammation, which can be applied to the skin and/or mucous membranes and which as active komponentnogo component bioadhesive thickening agent and water.

In the preferred embodiment of the medicines it consists of 0.05 to 2 weight. %, preferably about 1 wt.%, amyl-metacresol, 0.1 to 10 weight. %, preferably about 2 wt.%, bioadhesive material and 90-99 wt.%, preferably about 97 wt.%, water.

Since the new drug is as a disinfectant, anti-inflammatory and analgesic (boleuspokaivajushchee), and when used for oral administration in the form of a composition for caring for the oral cavity, it is useful for treatment and pain relief for a variety of painful conditions such as gum disease, inflammation during the eruption of the wisdom tooth after tooth, for preventive disinfection of the oral cavity of patients patients who are not able to maintain adequate oral hygiene, periodontal abscess, inflammation of the oral mucosa as a result of pressure exerted by the prosthesis, fungal infections and for treatment of the exposed surface of the bone in the alveolar sicca dolorosa, which is a painful condition that can occur after tooth extraction.

Composition for oral care mouth, depending on the content of the thickening agent (bioadhesive), is left in the form of a dental gel thickening agent together with water forms a gel phase in which the dispersed undissolved particles of the active agent, such as 2,4-DHBS.

Hereinafter the invention is described in more detail with reference to the following examples.

Example 1

The action of the medicinal product according to the invention for inflammation of the oral cavity was tested clinically.

For clinical trial received three variants of the medicinal product containing 2,4-DHBS (Myracid SP), carboxymethylcellulose sodium Ph. Eur. and treated water Ph.Eur.


1. 2,4-Dichlorobenzoyl alcohol (Myacid SP) - 5 grams

2. Carboxymethylcellulose sodium Ph.Eur. 0.9 g

3. Purified water Ph.Eur. - 994,1 g

Dental gel (liquid)

1. 2,4-Dichlorobenzoyl alcohol (Myacid SP) - 1%

2. Carboxymethylcellulose sodium Ph.Eur. - 2%

3. Purified water Ph.Eur. - 97%

The above percentages are given by weight.

Dental gel (thick)

1. 2,4-Dichlorobenzoyl alcohol (Myacid SP) - 1%

2. Carboxymethylcellulose sodium Ph.Eur. - 4%

3. Purified water Ph.Eur. - 95%

The above percentages are given by weight.

The two types of gel filled tubes with the tip (rectal) for extrusion of the drug to ease packa.

Patients for the survey were recruited five practitioners in private dentists.

Inclusion criteria for treatment gel: patients aged over 18 years with an inflamed painful condition of the mouth that does not respond to conventional treatment. In addition, there was a requirement to separate the patient was a regular patient of the dentist carrying out the treatment.

Exclusion criteria: patients were treated solely in the event of unforeseen acute treatment. Patients under the age of 18 years.

Treatment of patients with three variants of the medicinal product consisted partly in the local application of the drug dentist, partly in the distribution of medicines for independent home use by the patient.

The study involved approximately 60 patients, 41 of whom responded to the proposed questionnaire (see form 1).

The majority of patients felt pain or soreness in connection with the state, because of which they treated.

The result of the study showed that 39 patients noted a positive effect of the drug. As for bol the t was observed during the first day. However, 2 patients with total caries effect is not noted. None of the patients did not report discomfort during or after treatment.

In addition to using the gel in inflammatory painful conditions of the oral cavity, some of the patients also used the gel for the treatment of skin inflammatory conditions associated with the stings of bees and mosquitoes, contact allergies, mechanical/physical injuries and various chemical actions. It also appeared that the drug has a positive effect in the treatment of these painful conditions (see questionnaire 2).

Dentists engaged in the treatment, agreed that the medicinal product is easy to apply and has good adhesive ability. Dentists used the gel for the treatment of inflammatory conditions of the mouth and throat. All types of inflammation showed a positive reaction for pain, erythema, swelling, fever, and reduced function, such as reduced chewing ability. It turned out that in the case of RAS gel has a remarkable healing effect.

Based on the results of clinical studies and their own observations of dentists, you can do what the duty to regulate healing, for example, mechanical injury, reduced the risk of recurrent infections.

Analgesic action of the medicinal product is of great importance in the treatment of inflammatory conditions. This applies both to the physical aspect, and largely to the mental aspect, as the absence of, for example, pain plays an important role in adaptation/regulation of new prostheses. In such situations, there are often problems of irritation (inflammation) of the mucous membrane, and may be formed of wounds, and for this reason the patient is not inclined to use the prosthesis because of the pain, the consequence of which often are changes in adjacent bone structures or displacement of teeth, in that case, when talking about adaptation to the partial denture.

Form 1:

Questionnaire for patients (41 patients)

What are the symptoms You felt before the last visit to the dentist?

Pain or soreness - 34 (83%)

One or more teeth lost - 4 (10%)

Difficulties with chewing - 6 (15%)

Bleeding when brushing teeth - 1 (17%)

Soreness of the gums, tongue or similar - 6 (15%)

Soreness at the corners of the mouth - 3 (7%)

Burning, for example, sky - 3 (7%)

Other unpleasant sensationso

Have You ever felt any effect as a result of processing a mouthwash or tooth gel?

Yes - 39 (95%)

No - 2 (5%)

If You feel any effect in the processing, as soon as this effect was observed after the start of treatment?

Almost instantly - 32 (78%)

During the first day - 7 (17%)

After treatment - 2 (5%)o< / BR>
oin the first week

Did You have any discomfort during or after treatment with mouthwash or tooth gel?

Yes - 1(2%)o< / BR>
No - 40 (98%)

ounpleasant taste

Initially I spent a processing

The mouthwash - 8 (20%)

Dental gel 15 (37%)

Large equal quantities - 18 (44%)

Form 2:

Treatment of skin inflammatory painful conditions

(The numbers indicate the number of people, regardless of how many times the drug was used by the same user)

The bite of a mosquito - 8

Bee sting - 3

Flea bite - 1

Sunburn - 2

Thermal eczema - 1

Contact Allergy - 3

Psoriasis - 2

Erysipelas - 1

Acne - 2

Inflammation of the nail - 3

Cuts - 3

Burns from ovens or hot plates is Denia results noted in example 1 in a clinical study of anti-inflammatory action of 2,4-DHBS were carried out controlled laboratory studies.

The objective of this laboratory study was to determine the anti-inflammatory action of 2,4-DHBS against chronic toxic skin inflammation of the ear in mice induced by 12-0-deletion-phorbol-13-acetate (TN).

Mice were chosen as test objects, in the case when they were approached for the study of ear inflammation.

As a carrier for the test compounds, 2,4-DHBS, used acetone, which is commonly used in experiments on mice ears of the type in question.

Used 24 female mice having a body weight between 19 and 22 d before the study. Mice were kept in the room for animals with filtered air at room temperature for 24+/-3oC, relative humidity 55%+/-15% and the air was replaced 10 times per hour. The lighting was held on a 24-hour cycle with 12 hours light and 12 hours of darkness. Thus, the light was from 6 o'clock till 18 o'clock.

Mice contained groups in polycarbonate cages with an area of 810 cm2. Tile the CTL. Examination to detect any intrusion conducted regularly.

Mice had free access to food in the form of balls "altromin-1314" and containers with water with addition of hydrochloric acid to achieve a pH of 2.5.

Both solid and liquid food regularly examined for contamination.

The mice were divided into 4 groups in accordance with the principle of random sampling and pasted labels on tails.

Groups and numbers of animals are given in table.A.

It should be noted that group 4 was included only to demonstrate the validity of the model. Thus, the goal was not to compare the action of 2,4-DHBS with known highly effective anti-inflammatory betamethasone-valerate.

Mice in groups 2-4 were induced with 0.1 ml of TN (0.1 mg/ml) in the left ear at 1, 3, 5, 7 and 9 days, it was developed toxic inflammation. 8, 9, 10 and day 11 mice in groups 3 and 4 was treated with 2,4-DHBS (0.1 ml/ear 1% aqueous solution) and a control drug (0.1 ml/ear), respectively, twice a day in the left ear.

6 hours after treatment on day 11 measured thickness of the left ear of mice using a measuring screw. The measurement stick with the right ear for establishing the presence or absence of erythema, called TN-processing and subsequent processing of 2,4-DHBS and a control substance or in the absence of any processing at all, as in groups 1 and 2. The body weight of mice was determined on day 12 and compared with body weight in 1 day. Thus obtained results are presented in table. 1.

For all 4 groups was calculated the average thickness of the left ear of mice and performed the statistical calculations for the measured thickness using the program SAS (Version 6.12). The results presented in table 2, show that there is a statistically significant difference (p<0.05) in the ear thickness of mice in group 2 and mice of groups 3 and 4 at the last measurement.

When determining ear erythema was observed that mice in group 3 had less ear erythema on day 12 compared with mice in group 2.

When determining the body weight of mice shows that only mouse in group 1 had gained weight during the experiment. Weight loss was observed for the remaining groups, the lowest it has been in group 3. Weight loss in group 4 was a factor 4 higher compared to group 3, see table.3.

1. The use of amyl-metacresol as an active ingredient in a medicinal product for the local treatment of vocal the alcohol is a 2,4-dichlorobenzoyl alcohol.

3. Application under item 1, in which dichlorobenzoyl alcohol combined with one or more substances, which provide controlled release and/or prolonged retention amyl-metacresol at the place of treatment.

4. Application under item 3, at which dichlorobenzoyl alcohol combined with one or more bioadhesive materials.

5. Use PP. 3 and 4, in which bioadhesive materials selected among hydrocolloids, such as carboxymethylcellulose sodium, Carbopol, Tragakant, Karaeva gum, Karaya gum, sodium alginate, gelatin, methyl cellulose and gum Arabic.

6. Application under item 1, in which the drug is intended for application to the skin or mucous membrane.

7. Application under item 3, at which the drug is intended for use in the oral cavity and/or external use.


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