Derinat suppositories to be used in medical practice

FIELD: medicine.

SUBSTANCE: for treating urogenital clamidiosis, cytomegalovirus, herpes simplex, Helicobacter pylori, polyethylene oxide 1500 and polyethylene oxide 400 are melted in the ratio 9:1; the liquid melt is added with a design amount of the preservative sodium chloride; further a design amount of sodium deoxyribonucleate is added in mixing. A melted paste is mould to prepare Derinat suppositories of 1.3-2.5 g.

EFFECT: prepared suppositories provide high bioavailability and prolonged action of the active agent.

3 cl, 7 tbl, 2 ex

The invention relate to medicine, namely to Virology, immunology, gynecology and pharmacology concerns the development and creation of tools for the prevention and treatment of diseases in the form of a suppository. The invention can be used to prevent infection by viruses or other intracellular agents (herpes simplex viruses 1 and type 2 (HSV-1, HSV-2), cytomegalovirus (CMV), a virus of Apsta Bar, papillovirus, chlamydia, Mycoplasma, and various combinations thereof).

There is the possibility that alerts using the proposed means of sexual transmission of hepatitis b, and HIV infections.

Known suppositories (patent RU №2185817, A61K 9/02, A61K 35/76, 2002) with high biological activity. However, these suppositories are used only in the treatment and prevention of staphylococcal etiology and dysbacteriosis.

Close of the present invention for the effective enhancement of nonspecific resistance of the mucosa and underlying tissues are suppositories containing IINF-poludana and interferon (patent RU №2147873 1999). However, the proposed suppositories are only local antiviral effect.

The prototype of the present invention may be a system (in a/m, oral, internalnode) application Derinat (patent RU №2309759, A61K 35/60, 2006) l the treatment of genital herpes, CMV infection, chlamydia, Mycoplasma, Candida, helikobakterioza.

The objective of the invention is to provide a composition and industrial method for the production of suppositories IIIA category fast effective nonspecific antiviral actions with a high therapeutic efficacy in the treatment of urogenital chlamydiosis, cytomegaly person, herpes simplex virus human infection with Helicobacter pylori.

The problem is solved by the composition of the treatment-and-prophylactic means in the form of a suppository (Derinat-suppository), including sodium salt of native deoxyribonucleic acid (sodium deoxyribonuclease), the base of which is a mixture of oxides PEO 1500 and PEO 400 at a ratio of 9:1 and sodium chloride as a stabilizer in the following ratio, wt.%:

Therapeutic effectiveness is ensured by the fact that the suppositories contain biologically active agent with multifunctional activity - sodium salt of native is desoxyribonucleic acid (deoxyribonuclease sodium or Derinat) which stimulates the regenerative and reparative processes, increases the body's resistance to infections, etc.. the Drug activates processes of cellular and humoral immunity. Immunomodulatory effect mainly due to the stimulation of b-lymphocytes, activation of T-helper cells (http://www.rlsnet.ru/tn_derinatl.html).

As part of a suppository, in addition to the active ingredient, contains a water-soluble base, consisting of a combination of PEO (PEO - 1500 and PEO - 400 in the ratio 9:1), characterized by a complete physiological indifference, good solubility in water and the secrets of the mucous membranes, able to give the active substance. PEO is characterized by an unfavourable environment for microbial growth, long enough remains unchanged, is characterized by the ability to different production methods. Although polietilenoksidnoy bases are widely used in pharmaceutical practice, it is known that when combined with medicinal substances containing hydroxy - and carboxy groups may lose their therapeutic activity. Deoxyribonuclease sodium is derived nucleic acids that do not contain a hydroxy - and carboxy groups, therefore, not only remains high therapeutic activity, but also provides high bioavailability when using the Appl is authorized mixture in the ratio of 9:1.

In the present invention, the third component in suppositories - stabilizer and preservative, no irritant action on the mucous membrane, which is sodium chloride. Sodium chloride suppositories promotes long-term conservation of natively patterns of deoxyribonuclease sodium (prevents denaturation of DNA), in direct dependence on the state which is the biological activity of the suppository.

The presence of sodium chloride in suppositories ensures optimum pH value of the mass, which is in the range of 5.8 to 7.2.

Suppositories according to the invention as rectal (vaginal) a therapeutic agent was prepared as follows: sterile filler is heated to melt, add the calculated amount of powdered sodium chloride solution and mixed under aseptic conditions. In the resulting homogeneous mixture enter the estimated amount of the substance sodium deoxyribonuclease and continue mixing at 40°C to obtain a completely homogeneous mixture. The resulting mixture is formed into suppositories. For example, the mixture is poured into a special pre-cooled sterile form or pressed on the auto setting, under aseptic conditions.

Suppositories are torpedo-shaped form with a smooth surface weight of 1.3-2.5 g of white or pale-yellow the CSOs color.

Ready suppositories check according to the requirements of Gosfarmakapei and Packed 5 suppositories in blister packaging made of PVC film. Get suppositories IIIA category.

Example 1. Under aseptic conditions melt at 40°C 100 kg PEO 400 and PEO 1500 (ratio 1:9). With constant stirring to melt add the crushed (to the state of powder) 0.9 kg of sodium chloride. Stirring with heating continued for 30 minutes to obtain a completely homogeneous mass. Later in the melt - add 2.5 kg of sodium deoxyribonuclease, stirred for 30 minutes. The resulting mass is distributed in a special cooled to +15 to +18 degrees C° sterile form. Pre-forms are washed with detergent, rinsed with water, dried, sterilized with UV light for 30 minutes. Completed forms are cooled, assort in aseptic conditions. Ready suppositories weighing 2 g control and Packed.

Example 2. Under aseptic conditions melt at 40°C 80 kg PEO 400 and PEO 1500 (ratio 1:9). With stirring, heated add chopped (to the state of powder) 0.72 kg of sodium chloride. Stand 20 minutes at 40°C. To the resulting mixture while heating and stirring, 2.0 kg of sodium deoxyribonuclease. Cooled the mass to 38°C and pressed under aseptic conditions on the machine. Get the Derinat-torpedo-shaped suppositories forms pale yellow color weighing up to 1.3, Ready suppositories control and pack 5 suppositories in blister packaging made of PVC film.

The bioavailability of sodium deoxyribonuclease in a rectal is at the level of bioavailability of intramuscular introduction. After 5 hours, the concentration of sodium deoxyribonuclease in the blood of mice is in a rectal 30 ng/ml, and intramuscular - 40 ng/ml, after 24 hours, the sodium content of deoxyribonuclease - 20 ng/ml and 27 ng/ml, respectively. The use of other bases, such as witepsol, known for its high affinity to the tissues did not provide the same level of bioavailability.

Below the invention is illustrated with specific examples of its application.

Treating chlamydia with ureaplasmosis, Mycoplasma, Trichomonas.

A comprehensive approach in the treatment of urogenital chlamydiosis using Derinat-suppositories in long courses of antibiotic treatment allows you to completely neutralize the toxic properties of drugs used.

The use of Derinat-suppositories with multi-action allows 84,2% to achieve clinical and etiological treatment in patients with chronic urogenital chlamydiosis.

In table 1 presents the proportion of negative control tests for chlamydia before and after treatment PAC the clients.

Immunomodulatory effect Derinat-suppositories due to the ability of sodium deoxyribonuclease to penetrate into the blood and indirectly to restore and strengthen the immune response, to strengthen anti-infective activity of NK-cells and antigen-specific T-killers, to stabilize the In-link through activation of T-helper cells.

Study of antiviral activity of Derinat-suppositories against cytomegaly were performed on models of human diploid cells M-19 infected with cytomegalovirus dose of virus 2 lg TCID and 4 lg TCID. The results are presented in table 2.

As follows from table Derinat-suppositories are 100% inhibitory effect on CMV virus while drug use and infection of cell cultures, indicating the importance of its use as a preventive measure and a means of retaining the latent state of the virus in the body.

In a clinical study Derinat-suppositories for CMV are three forms of infection: latent, to the ora determined only antibody class lg G anti-CMV; reactivated, at which identify the specific antibodies of class lg M together with antibodies lg G anti-CMV; and persistent, characterized by virualization and availability of the lg G anti-CMV.

In the treatment of patients by PCR was determined by the presence of DNA of the pathogen in the saliva, urine and secret arvicolinae channel (table 3).

The study included 60 patients, whose age ranged from 22 to 34 years, 20 patients - reactivated form of current cytomegalovirus infections and 40 patients - persistent form of current cytomegalovirus infections.

Patients with reactivated form in the complex treatment received Der the NAT-suppositories for example, 11 times in 24 hours. Patients with peristiwa form CMV received Derinat-suppositories 2 times in 24 hours.

The control treatment was performed by PCR after 1 month after the last injection Derinat-suppository. The results showed that 96.4% of patients in the saliva, urine and secret arvicolinae channel virus DNA was not detected. Through treatment Derinat-suppositories jet and the persistent current cytomegalovirus infections transformed in latent form.

Antiviral activity Derinat-suppository against herpes simplex virus in humans was studied on the model of herpes encephalitis mice caused by this virus. The results took into account survival rates (%) of animals to the 15-th day and the degree of protection (in percent), which was determined in relation to the surviving animals in the control group. As a result, in the group of mice treated with Derinat-suppositories were killed by the 15th day of 70%, whereas in the control group died 96,7%. Under very hard conditions of the experiment - intracerebral infection, high infectious dose, a single peripheral introduction Derinat-suppositories detects a protective effect against lethal herpes infection. Table 4 presents therapeutic effect Derinat-suppository with herpes infections (herpes encephalitis mice strain L)

The clinical picture of genital herpes is characterized by a wide variability. Group clinical study included 30 people. The results of the verification of herpes simplex virus (HSV) is presented in table 5.

Comprehensive treatment of genital herpes was conducted Derinat-suppository in combination with Cycloferon. Patients who received integrated treatment, the clinical efficacy is 73,3%. The PCR results showed the absence of HSV DNA in 66.7%. Evaluation of the immune system of patients with genital herpes after treatment has established a positive trend of most of the indicators, which resulted in the restoration of the number of Mature T-lymphocytes, T-lymphocytes-lymphocytes, % faguoqitirute cells, their absorption capacity and the concentration of serum immunoglobulins (table 6).

After 3 months of treatment, the average ratio of the frequency of relapses decreased to 0.3, whereas before treatment he was 1,33.

In the complex treatment of ulcer and 12 duodenal ulcer Derinat-suppositories significantly increase the efficiency of basic therapy, increasing its H. pylori effect. Recovery of immune status in patients with disappearance of Helicobacter pylori infection to a certain extent explains the H. pylori activity Derinat-suppositories. The specific mechanisms by which H. pylori actions associated with the stimulation of local factors of protection, with increased production of secretory immunoglobulin A, which neutralize bacteria and viruses, as well as inhibit the adhesion of bacteria to apetalum cells. the table 7 presents the dynamics of the immune system when included in a comprehensive treatment of ulcer and 12 duodenal ulcer Derinat-suppositories.

These tables show a reliable increase in immunoregulatory index and secretory immunoglobulines A. These results indicate that the effectiveness of H. pylori action Derinat-suppository due to its immunomoduliruushim effect.

1. Treatment-and-prophylactic means in the form of a suppository, characterized in that it comprises the sodium salt of native deoxyribonucleic acid (sodium deoxyribonuclease), the base of which is a mixture of oxides PEO 1500 and PEO 400 at a ratio of 9:1 and sodium chloride as a stabilizer in the following ratio, wt.%:

2. The tool according to claim 1, characterized in that it is used in treatment of urogenitale chlamydia, cytomegalovirus and herpes infections of Helicobacter pylori infection.

3. The way to obtain therapeutic and preventive tool in the form of a suppository according to claim 1 characterized in, the oxides PEO 1500 and PEO 400 in the ratio of 9:1 is melted at 40°C. and with stirring, enter the estimated amount of the powdered sodium chloride solution, then, without stopping heating and stirring, the mixture enter the estimated amount of the sodium salt of native deoxyribonucleic acid, continue mixing for 30 min and then formed into a suppository weighing from 1.3 to 2.5 g method of pouring or pressing.