RU2421228C1 - Agent for prevention and treatment of alcoholic dependence - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, and concerns an agent for prevention and treatment of alcoholic dependence.

EFFECT: invention provides the efficacy of the offered agent and the presence of a considerable delay and slow release effect of an active principle after introduced.

6 cl, 4 ex, 3 tbl

Description

The invention relates to medicine, namely to means for the prevention and treatment of alcoholism.

For Russia, alcohol abuse has long been a national problem. According to official figures, in 2001 in Russia per capita consumed 10.7 liters of pure alcohol per year (World Health Organization. Global Alcohol Database. 2006), which is one of the highest in the world (Nemtsov A.V. Alcohol damage to regions Russia. M.:"NALEX ", 2003).

In 2005, Roszdrav specialized institutions registered 3 million 445 thousand patients with drug addiction disorders, or 2.4% of the total population. 84.2% of the total number of registered patients are alcohol addicts (Khalturina D.A., Korotaev A.V. Russian Cross. Factors, mechanisms and ways to overcome the demographic crisis in Russia. M .: URSS, 2006; Nemtsov A.V. Alcohol mortality in Russia 1980-90s M: "NALEX", 2001; Nemtsov AV 2006. Geography of alcohol-related mortality in Russia. Report at the All-Russian Conference "The Concept of Alcoholic Policy of Russia", Moscow, 18 May 2006).

The main problem in the treatment of alcoholism is the prevention of relapse and the formation and maximum prolongation of therapeutic remissions, that is, periods of complete abstinence of patients from drinking alcohol. However, despite the variety of psychotherapeutic methods and social programs aimed at stabilizing remissions in patients with alcoholism, the effectiveness of the treatment of this disease continues to be insufficient. Failure occurs in 75% of patients in the first year, and 50% in the first three months of treatment (Krupitsky E.M., Zvartau E.E. Scientific notes of St. Petersburg State Medical University named after academician I.P. Pavlov. St. Petersburg ., 2003. T.X. No. 2. S.12-23; Eryshev OF, Rybakova TG, Shabanov PD Alcohol dependence: formation, course, anti-relapse therapy. - St. Petersburg: Publishing House " ELBI-SPb ", 2002. - 192 p.)

Currently, drugs such as disulfiram, cyanamide and naltrexone are widely used in the treatment of alcoholism (Krupitsky E.M., Zvartau E.E. Scientific notes of St. Petersburg State Medical University named after academician I.P. Pavlov. St. Petersburg, 2003. T.X. No. 2. S.12-23).

Disulfiram is an aversive drug used in narcological practice since the mid-20th century. Disulfiram inhibits aldehyde dehydrogenase, which catalyzes the oxidation of acetaldehyde, a product of the oxidation of ethanol, which has a toxic effect. Thus, the use of alcoholic beverages against the background of the action of disulfiram leads to acetaldehyde intoxication and aversive effects. In randomized controlled clinical trials performed in the 80s in the USA, it was shown that in the absence of direct monitoring of the drug, disulfiram does not differ significantly in clinical efficacy from placebo, which may be due primarily to low compliance with the therapy ( Fuller RK, et al. JAMA, 1986; 256 (11): 1449-1455). As an alternative to such methods of improving compliance, it was proposed to use a prolonged form of disulfiram in the form of an implant (Esperal drug). However, in none of the studies conducted, the effectiveness of prolonged forms of disulfiram was not demonstrated, possibly due to the fact that the implant did not provide a stable and high concentration of disulfiram in the blood, sufficient for the development of a disulfiram-alcohol reaction. In addition, during oral treatment with disulfiram, a number of drawbacks have been identified: 1) its effect is very slow; 2) difficult to predict, overly strong reactions "disulfiram-alcohol"; 4) a tolerant amount of alcohol is difficult to determine; 5) if the dose is exceeded, disulfiram psychoses may occur (Johnsen J, Morland J. Disulfiram implant: a double-blind placebo controlled follow-up on treatment outcome. Alcohol Clin Exp Res, 1991; 15 (3): 532-536; Wilson A, et al. Disulfiram implantation: a dose response trial. J Clin Psychiatry, 1984; 45 (6): 242-247).

It is important to note that the creation of prolonged forms of drugs based on disulfiram is technologically difficult, since in the formation of a long-acting depot it is necessary to use a large amount (tens and hundreds of grams, depending on the duration) of the drug substance. There is also a high risk of disulfiramic psychosis with an uneven release of the drug.

Cyanamide (Temposil, Dipsan, Abstem, Colme) has a reliable and fast, in comparison with disulfiram, anti-alcohol effect. Alcohol intake during treatment with this drug causes an aversive reaction (flushing, nausea, tachycardia, shortness of breath, etc.). Cyanamide is safe and causes less harmful side effects than disulfiram (Mokasa. H. The Journal of the Kurume Medical Association. 22, 1632. 1959; Mokasa. H. Psychiatr. Neurol. Jap., 64, 469. 1962; Lancet (Apr 24, 1976): 911-912).

A comparative study of the clinical efficacy of cyanamide and disulfiram revealed: faster formation of sensitization to alcohol, mild but sufficient severity of an aversive reaction, the absence of gross side effects, suppression of craving for alcohol (Ivanets N.N. Report on the results of a comparative open clinical and follow-up study of the drug KOLME in the complex treatment of patients with alcohol dependence. National Scientific Center. 2006, p.26).

The sensitizing effect of cyanamide on alcohol appears after about 45-60 minutes and lasts about 12 hours. The disadvantages of the drug is the need for daily intake, as well as the thermolability of the active principle, which is easily destroyed by hot food. Long-acting registered dosage forms of cyanamide currently do not exist in the world. In the treatment of drug addiction, cyanamide is used as part of complex therapy.

More promising is the use of opiate receptor antagonists such as naloxone, naltrexone, diprenofin, etazocine levalofan metazocine, nalofin, or their salts (US 5086058, US 4882335). The most common of them were naloxone and naltrexone. Naloxone is used, as a rule, in the form of injections at a dose of 0.4-10.0 mg per day, naltrexone - orally at a dose of 50 to 200 mg before taking alcohol. The efficacy of naltrexone, an opiate receptor antagonist, in the treatment of alcoholism has been studied in numerous double-blind, randomized, placebo-controlled trials. The greater efficacy of naltrexone compared with placebo was revealed in such indicators as the period of time before alcoholism recurrence and the percentage of sober days. There are studies showing that naltrexone is more effective than placebo, stabilizes remission and prevents the onset of a recurrent relapse of alcoholism after a breakdown (a single episode of alcohol consumption). In 2006, the long-acting drug Vivitrol by Alkermes ^® , based on naltrexone, as a treatment for alcoholism, was registered in the USA.

Multicenter studies show that depending on the dose of the drug and the sex of patients, the incidence of heavy drinking is reduced by 20-35%, 30% of patients receiving Vivitrol for 3 months remained in remission (J.C. Garbutt et al., JAMA, April 6, 2005 .-- Vol. 293, no.13, 1617-1625). However, a multicenter, double-blind, randomized trial conducted by Yale scientists in the United States on patients with chronic severe alcohol dependence did not reveal advantages in naltrexone compared with placebo (Volpicelli JR, et al. Arch Gen Psychiatry, 1992; 49 (11): 876- 880; Volpicelli JR, et al. Arch Gen Psychiatry, 1997; 54: 737-742).

The closest in technical essence and the achieved effect to the claimed invention is the preparation S- (N, N-diethylcarbomoyl) -glutathione, further DECT (US Pat. US No. 7250401, 2005), which has a neuroprotective effect, which can be used for the prevention and treatment of alcoholism in in the form of solutions, capsules, suspensions, suspensions, etc. The specific technology of application and the achieved results on the treatment of alcoholism with its use in the scanned scientific and technical literature are absent. As the experiments showed, the disadvantage of using DECT in this direction is the relative short duration of its action. Already 24 hours after administration to the body, its content in the blood plasma becomes insignificant.

The objective of the invention is the development of a drug based on DECT for the treatment of alcohol dependence with a prolonged effect, i.e. providing maintenance of the dosed therapeutic concentration of the drug in the biological fluids of the patient at the required level throughout the treatment period (30-45 days or more).

The technical result was achieved by creating a drug in the form of microgranules, which is a suspension of 20-500 nm nanoparticles in vegetable oil, consisting of a mixture of DEKT and polyglucin in a mass ratio of 1: 4 to 3: 7.

The use of smaller nanoparticles is difficult for technological reasons, the use of larger particles reduces the effectiveness of the impact and the duration of storage of the suspension. The experiments (Table 2) showed that an increase or decrease in the content of DECT is possible, but reduces the duration of the drug.

The most convenient suspension is a suspension containing 20-25 wt.% Nanoparticles, which is stable for several months. The use of higher concentrations of nanoparticles reduces the storage time of the drug. Less concentrated suspensions require the introduction of large quantities of used funds.

As a vegetable oil, the suspension contains a pharmaceutically acceptable vegetable oil, for example olive, sesame or coconut oil.

The inventive tool is prepared by mixing the ingredients, grinding in a DECT ballistic mill to form particles with a size of 20-500 nm, followed by suspending the nanoparticles in a polyglucin solution, freeze drying the resulting solution, grinding it again in a ballistic mill and suspending in oil.

The essence of the claimed invention and its industrial applicability are illustrated by the following examples.

Example 1. DEKT was ground in a ballistic mill to form nanoparticles with a size of 20-500 nm. A weighed mass of 2 g of DECT was suspended in 100 ml of a 6% aqueous solution of polyglucin. Then, the resulting suspension was subjected to freezing at -70 ° C and subjected to freeze drying. The obtained substance was additionally subjected to grinding in a ballistic mill to obtain a fraction of 20-250 nm containing 25% DECT. 1 g of the resulting dry mixture was dispersed in 4 g of coconut oil, obtaining a suspension containing 20% nanoparticles (5 wt.% DECT).

Example 2. The experiments were carried out on male rats of the Wistar strain weighing 190-240 grams. Animals were obtained from the Rappolovo breeding station (St. Petersburg). Rats were housed in 6 animals in standard cages. The animals got used to the laboratory conditions for at least 1 week with unlimited access to food (granular food) and water in a vivarium with adjustable light mode (12 hours light - from 8:00 a.m. / 12 hours dark), air temperature 22 ± 1 ° С and humidity 60%.

Each experimental group consisted of 6 animals. There were 5 animal groups in total: control group 1 (solvent with isotonic NaCl solution), group 2 (single intramuscular injection of saline with DECT powder with an average particle size of 0.1 mm at a dose of DECT 20 mg / kg), group 3 (single intramuscular injection saline with a powder of a mixture of DECT with polyglucin in a ratio of 20:80 with an average particle size of 0.1 mm in a dose of DECT of 20 mg / kg), group 4 (a single intramuscular injection of saline with nanoparticles of DECT (after the first grinding) at a dose of DECT of 20 mg / kg), group 5 (single intramuscular injection in administration of saline with drug 1 at a dose of DECT 20 mg / kg) and group 6 (a single intramuscular injection of drug 1 in the form of a suspension in coconut oil at a dose of DECT 20 mg / kg).

The effect of drug administration was evaluated using high performance liquid chromatography.

Processing of the obtained results was carried out using the INSTAT application program. The experimental results were analyzed using a Repeated Measures Analysis of Variance followed by identification of significant differences between the groups (Post hoc analysis using the Tukey-Kramer Multiple Comparisons test). The results for groups of animals were averaged. The results are shown in table 1 as a percentage of the input substance.

Table 1 Data on the effect of ingredients on the prolonged action of the proposed drug Group of animals The plasma DEKT content as a percentage of the starting material 4 hours 3 days 14 days 21 days 45 days 1 (control) no no no no no 2 (DECT particles 0.1 mm) one hundred 3.2 <2 no no 3 (DECT + polyglucin - 0.1 mm particles) one hundred 8.2 3,7 no no 4 (DECT - nanoparticles) one hundred 12 <2 no no 5 (DECT + polyglucin sample 1) one hundred 49.1 14.2 4.8 <2 6 (suspension in oil sample 1) one hundred 39.2 20.1 15,2 5.2

The results obtained indicate that the introduction of the proposed drug provides a prolongation of the effect of DECT to 45 days.

Example 3. In the conditions of example 1, changing the ratio of ingredients, samples were obtained with different ratios of polyglucin and DECT, which were dispersed in vegetable oil with a concentration of 25% nanoparticles. The results are shown in table 2.

table 2 The effect of the ratio DECT: polyglucin (PLGA) on the prolonged effect with the introduction of a suspension based on nanoparticles Composition 15% DECT + 85% PGA * 20% DECT + 80% PLGA ** 25% DECT + 75% PGA * 28% DECT + 72% PLGA *** 30% DECT + 70% PGA * 34% DECT + 66% PLGA ** The plasma DEKT content 1 hour after administration 56.7 56.7 56.7 56.7 56.7 56.7 The plasma DEKT content 4 hours after administration one hundred one hundred one hundred one hundred one hundred one hundred The plasma DEKT content 24 hours after administration 33.1 45.3 57.6 64.9 79.7 84.7 The plasma DEKT content 3 days after administration 18.7 26.6 38.8 43.6 41.9 63.7 The plasma DEKT content 7 days after administration 3.9 17,2 24.6 26.3 21,2 31.7 The plasma DEKT content 14 days after administration 2,4 14.8 18.5 21.9 17.3 12.7 The plasma DEKT content 21 days after administration <2 11.6 13,4 14.7 10,2 6.7 The plasma DEKT content 30 days after administration <2 8.3 10,4 9.7 8.1 <2 The plasma DEKT content 45 days after administration <2 6.9 5.8 4,5 3,7 <2 The plasma DEKT content 60 days after administration <2 4.9 3,7 2.7 2.0 <2 The plasma DEKT content 75 days after administration <2 3.4 2.7 <2 <2 <2 * suspension in olive oil; ** suspension in coconut oil; *** suspension in sesame oil;

The results obtained indicate that the greatest prolonging effect has a tool containing 20-25 wt.% DECT.

Example 4. A group of 5 rabbits was injected intramuscularly with a suspension of sample 1 in coconut oil at a dose of 10 mg / kg. The concentration of DECT in the bloodstream of rabbits was determined by HPLC. The results are shown in table 3.

Table 3 Dependence of the concentration of DEKT in the bloodstream of rabbits on time with intramuscular administration of a prolonged form №№ Circulation time The concentration of DECT according to HPLC, nanograms / ml one 24 hours 126 2 2 days 83 3 3 days 64 four 4 days 53 5 5 days 51 6 6 days 47 7 7 days 46 8 2 weeks 44 9 3 weeks 41 10 4 weeks 37 eleven 5 weeks 35 12 6 weeks 32 13 7 weeks 26 fourteen 8 weeks 23 fifteen 9 weeks 21

The results of the study confirmed the effectiveness of the proposed drug and the presence of a significant effect of delay and slow release of the active principle with the introduction of the claimed form of the claimed drug.

Claims (6)

1. The tool for the prevention and treatment of alcohol dependence based on S- (N, N-diethylcarbamoyl) -glutathione and excipients, characterized in that it additionally contains polyglucin in a mass ratio of S- (N, N-diethylcarbamoyl) -glutathione: polyglucin from 1: 4 to 3: 7, and the resulting composition consists of particles with sizes of 20-500 nm and suspended in oil. 2. The tool according to claim 1, characterized in that the suspension contains 20-25 wt.% Nanoparticles of a mixture of S- (N, N-diethylcarbamoyl) -glutathione and polyglucin. 3. The tool according to claim 1, characterized in that as the oil it contains a pharmaceutically acceptable vegetable oil. 4. The tool according to claim 3, characterized in that it contains olive oil as an oil. 5. The tool according to claim 3, characterized in that it contains coconut oil as an oil. 6. The tool according to claim 3, characterized in that it contains sesame oil as oil.