Drug preparation tilorone in suppositories

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical industry, and concerns making a preparation Tilorone in the form of rectal suppositories 125 mg, being an antiviral immunostimulant.

EFFECT: making a new antiviral immunostimulant.

The invention relates to the field of pharmaceutical industry and relates to the dihydrochloride 2,7-bis-[2-(diethylamino)ethoxy]-fluoren-9-she medicinal product based on it Celoron, made in the form of rectal suppositories.

Pharmaceutical drug Tilaran (dihydrochloride 2,7-bis-[2-(diethylamino)ethoxy]-fluoren-9-it) - low molecular weight synthetic inducer of interferon stimulated in the body of α-, β - and γ-interferons. The main producers of interferon in response to the introduction of Tilorone are cells of the intestinal epithelium, hepatocytes, T-lymphocytes, neutrophils and granulocytes. Tilaran immunomodulatory effect: stimulates the stem cells in the bone marrow, depending on the dose increases antibody production, reduces the degree of immunosuppression, restores the ratio of T-suppressor and T-helper cells. The antiviral mechanism of action is associated with inhibition of translation of virus-specific proteins in infected cells, resulting in suppression of reproduction of viruses.

Tilaran used for the treatment of viral hepatitis a, b, C, herpes infection, cytomegalovirus infection, in the complex therapy of urogenital and respiratory chlamydia, for the treatment and prevention of influenza and other acute respiratory viral infections.

Tilaran was first synthesized in the United States is 1968 group of authors (U.S. patent No. 3592819). Synthesis of 2,7-bis-[2-(diethylamino)ethoxy]-fluoren-9-it was made after. USSR Academy of Sciences A.V. Bogatsky and staff in 1975 in Odessa (laboratory Institute of the Academy of Sciences of the USSR) developed by the authors of the original method (Avigate and others, DAN USSR, 1976, series B, No. 7, s-612). In Russia, industrial production of drug Amiksin in the form of tablets, coated tablets, containing tilorone 125 mg, developed by JSC "Dalkhimpharm" in 1998, pills dosage 60 mg - in 2002

To reduce side effects by oral administration of the drug, especially for patients with diseases of the gastrointestinal tract, developed dosage form in the form of rectal suppositories containing 125 mg of tilorone as the active ingredient and the rest of the mass - suppozitornyj the basis weight of one suppository 2,0, Preference to use as the basis of given solid fat type And, as is well compatible with the active ingredient and is available to the agent.

The choice of the dosage form in the form of suppositories explains the advantages of this form.

Suppositories are solid at room temperature and rasplyvshuyusya or dissolve at body temperature dosage form. The first mention of suppositories refers to 2600 BC in the Papi is truncated Bersa described laxatives and suppositories for the treatment of hemorrhoids. Suppositories General actions - anti-asthma containing anise, myrrh, honey, goose fat, introduced by Hippocrates. Were created soap suppositories, widely practiced instead of cleansing enemas.

Depending on the structure and characteristics of body cavities suppositories give appropriate geometric shapes and sizes. There are suppositories rectal (suppositories), vaginal and sticks. Rectal suppositories are inserted into the rectum, vaginal, vagina, sticks in the urinary and other channels (cervix, ear canal, and fistulous wound moves). In addition there are suppositories General and local actions. Suppositories General steps designed for rapid absorption of active substances in the blood. Suppositories local actions apply mainly to facilitate defecation, with the aim of the local action of medicinal substance at one time or another inflammatory process, to relieve pain, etc. currently, vaginal suppositories are used primarily for local action - disinfectant, astringent, cauterizing, anesthetic, oral and rectal is in most cases considered as a medicinal form of joint action. The latter is prescribed for the violation of cardiovascular activity, neuro-psychiatric disorders and d Application in such cases is due to the rapidity of the effects of drugs prescribed in the form of suppositories. As you know, drugs absorbed through the mucous membrane of the rectum, fall within the hemorrhoidal veins, from her into the inferior Vena cava and then into the General bloodstream, bypassing the protective barrier of the liver. It is believed that the rapidity of action of drugs suppositories are not only equal, but in some cases even exceed the dosage forms for oral, subcutaneous or intramuscular injection. Of the other benefits of suppositories as dosage forms can be noticed a decrease of the degree and frequency allerleirauh of action of the drug, the reduction or disappearance of side effects of drugs; the independence of the suction effect from the filling of the digestive tract. In the form of suppositories you can enter a substance having an unpleasant organoleptic properties, as well as incompatible in other dosage forms.

The high effectiveness of this dosage form allows its use in Pediatrics, geriatrics, psychiatry, liver problems, the system of the digestive tract, disorders of the processes of ingestion, absorption. In addition, the positive properties of the suppositories are easy and painless injection (rivers the social introduction requires no special tools and is done without compromising the integrity of the skin), there is no danger of introducing infection, and the possibility of combining in suppositories ingredients with different pharmacological and physico-chemical properties, compactness.

Thanks to a series of benefits suppositories are widely used in medical practice. So the annual world production of suppositories reached more than 150 billion pieces, up to 9-17% of the nomenclature of modern drugs and being present in almost all pharmacological groups. Item suppositories in each of the leading European countries (France, Spain, Italy, Germany) is 100 or more items. Especially suppositories are used in pediatric practice, where they comprise approximately 20% of all used in paediatric dosage forms.

Tilaran as suppozitornoj form up to the present time has not been applied.

A study was conducted General toxicity of the drug "Tilaran rectal suppositories 125 mg.

Acute toxicity of the drug has been studied in nonlinear white rats weighing 150-170, the Drug was administered rectally once daily for 14 days at doses of 1000 mg/kg or more. The results of toxicomanie, observations of experimental animals after acute application and data pathomorphological studies allow us to classify "Tilaran suppositories R is stalnye 125 mg" to the V class is practically non-toxic drugs.

The study of subacute and chronic toxicity studies were conducted on rats of both sexes of Wistar weighing 160-180 g single introduction rectal doses of 100 mg/kg (exceeding therapeutic dose for a person more than 3 times), 500 mg/kg (exceeding therapeutic dose for a person more than 20 times), and mongrel dogs aged 3-4 years weighing 8 to 15 kg in a dose of 500 mg/kg for 90 days.

Physiological, hematological and biochemical investigations were carried out before the start of the experiment and at the end of the introduction (30 and 90 days). Bone marrow, macroscopic and histological examination of internal organs was performed posthumously 90 days.

Throughout the period of drug administration "Tilaran rectal suppositories 125 mg no marked signs of changes in the clinical status of Wistar rats. Long-term administration of the drug had no effect on the cardiovascular system functional state of the kidneys, hematological indices of peripheral blood, blood-forming organs. Conducted postmortem examination is not installed morphological signs of toxic effects on the organism of animals.

Daily application of the drug in the rectum within 90 days dogs of both sexes did not cause changes in their behavior, integralnym indicators of the General condition, as well as shifts in biochemical composition and morphology of blood. The mucous membrane of the rectum at the point of application of the drug was without inflammatory changes and signs of irritation.

Study of the pharmacokinetics of the drug "Tilaran rectal suppositories 125 mg" was carried out on rabbits male breed Chinchilla weight to 3.02±0.15 kg in the dose of 41.9±2.3 mg/kg single introduction rectal in the morning on an empty stomach.

The results of pharmacokinetic studies of the drug have shown:

- maximum concentration level tilorone (within 280-400 mg/ml) in blood of experimental animals is achieved within 1 h after rectal administration;

the total average time of presence of the drug in the body is an indicator of MRT approximately 33 h;

the half - life of the drug T¹/₂amounted to about 47 hours;

- the value of the apparent stationary distribution capacity amounted to about 32 ml/kg

Evidence of the accumulation of the drug in the body and the possibility of cumulation studies not identified.

Experiments for the study of allergic effects of the drug were carried out on outbred rats and Guinea pigs of both sexes with a single introduction in rectal therapy (50 mg/kg) and 10 times therapeutic (500 mg/kg) doses within 30 days.

The results showed that toprepare does not have any local irritation, no allergenic effects. It was also shown that the drug has no allergenic properties identified in the reaction of General anaphylaxis, indirect degranulation of mast cells and conjunctival sample.

For new members suppositories developed technology of production of suppositories in the molten base is added to the active substance - tilaran, stirred until a uniform distribution of the component and the weight moves suppozitornaja on an automated line to obtain suppositories weighing 2.0 g±5% in units from a polyvinylchloride film.

In clinical studies (clinical infectious diseases, RMAPO CCH them. Botkin, Moscow) the use of the drug for the treatment of viral hepatitis b (125 mg 2 times on the first day, then 125 mg every 48 hours, at the rate of 1.25-1.5 g) revealed that patients had significant improvement in all clinical and biochemical parameters, as well as normalization parameters interferon status at discharge patients. In the complex treatment of viral hepatitis C and mixed HCV+In the same dose at the end of treatment Tilorone PCR HCV RNA was not detected in 50% of patients with hepatitis C, while in the control group, only 20% of patients. When mixed infection (+) positive dynamics in relation to markers of HBV, as well as reducing deletelinesstarting period from 14.8 to 8.1 days, the reduced duration of cytolysis from 19.8 to 14.5 days.

The use of the drug in the treatment of treatment of genital herpes (Department of obstetrics and gynecology, Saint-Petersburg state medical University. Acad. Ilhabela) showed that the treatment leads to a more rapid clinical cure herpes infection and is not accompanied by any unwanted effects.

The results of clinical studies allow to conclude that Tilaran rectal suppositories 125 mg in therapeutic doses is characterized by high efficiency and safety.

Antiviral agent, characterized in that it is made in the form of a suppository and contains the active substance (dihydrochloride 2,7-bis-[2-(diethylamino)ethoxy]-fluoren-9-it) and excipients - solid fat, the type And in the following ratio of ingredients on one candle weighing 2.0 g: