WO2009031919A1

WO2009031919A1 - Alcoholism recurrence preventing agent and method for the use thereof

Info

Publication number: WO2009031919A1
Application number: PCT/RU2008/000235
Authority: WO
Inventors: Ruslan Dmitrievich Ilyuk; Evgeny Michailovich Krupitsky; Sergey Vasilievich Martyushin
Original assignee: Ruslan Dmitrievich Ilyuk; Evgeny Michailovich Krupitsky; Sergey Vasilievich Martyushin
Priority date: 2007-09-05
Filing date: 2008-04-15
Publication date: 2009-03-12
Also published as: RU2343908C1

Abstract

The invention relates to medicine, in particular to alcoholism recurrence preventing agents and to methods for the use thereof. The inventive alcoholism recurrence preventing agent contains a cyanamide and polylactide mixture with a component ratio (mass) ranging from 10:90 to 40:60. The inventive method for preventing alcoholism recurrences consists in intramuscularly injecting to a patient, in general once per month, a solution containing the cyanamide and polylactide mixture in a single dose of 0.5-1.5 g. The agent produces a substantial retardation effect and a low effective agent release.

Description

MEANS FOR PREVENTION OF RECIDENTS OF ALCOHOLISM AND

METHOD OF ITS APPLICATION

FIELD OF TECHNOLOGY

The invention relates to medicine, namely to means for the prevention of relapse of alcoholism and methods for their use. BACKGROUND OF THE INVENTION

Currently, the main drugs used in the prevention of alcoholism are paltrehop, asmrrososate, disulframate, suapamide, and a number of other drugs that have not been adequately studied due to the limited amount of evidence from clinical observations (Krupitsky EM, Zvartau E. E. Use of pharmacological agents to stabilize remissions and prevention of relapse in acogolism. Scientific notes of St. Petersburg State Medical University named after Academician I. P. Pavlov. St. Petersburg, 2003. TX Ns 2. P. 12-23)

NALTREHONE. The efficacy of naltrexone, an opiate receptor antagonist, in the treatment of alcoholism has been studied in numerous double-blind, randomized, placebo-controlled trials. Naltrexone was found to be more effective than placebo in such indicators as the period before alcoholism recurrence and the percentage of sober days, while opiate antagonists did not significantly differ from placebo in the duration of the period of complete withdrawal (i.e., complete abstinence from alcohol). There are studies indicating that naltrexone is more effective than placebo in stabilizing remission and preventing the onset of a relapse of alcoholism following a breakdown (a single episode of alcohol use). However, in a recent randomized trial comparing naltrexone, nefazodone, and placebo, negative results were obtained regarding the effectiveness of naltrexone. A multicenter, double-blind, randomized study conducted in the USA by Yale scientists in several hospitals for war veterans in patients with chronic heavy alcohol dependence, also did not reveal advantages in naltrexone compared with placebo. (Volcelli JR, et al. Nalthekhope i tе tretatmept оf аlcohоl redepеse. Arсh Gep Рсусhiаtru 1992; 49 (11): 876-880; Vоlpесеlеreхеpеlеreсеreхепепелепелереепелепелереепелепелепелепелепелепелепелепелепелепелепелепелепелепелепелепелепелепелепелепелепелепелепелепелепелепелепелеcommunicating with the rest of the world. 54: 737-742; Masop BJ, et al. And doublebpd, first-best-res studio, the last one was optimized HCI felo-elocelso-elocelsohlcelohllsohlsohlsohlsohlsohlsohlsohlsohlsohlsohlohlohlsohlohlohlohlsohlsohlohlohlsohlsohlohlsohlsohlohlsohlsohlohlhlsohlsohlsohlsohlohlhlsohlsohlsohlsohlsohlsohlsohlsohlsohlsohlohl. ; Oslip D, et al Naltrehope AS adjupstive treatmept for an older ratiepts with alsohol derepdepse Am J Geriatr Rsushiatru 1997; 5 (4):.. 324-332; Aptop RF, et al Naltrehope apd sogpitive behavioral theraru for the treatmept outratiept ° F. alcoholis: results of and a caselo-triled tri. Am J Psihiatru 1999; 156 (11): 1758-1764; Крапзлер HR, et al. Natltope vs. Nefazodop fortolepteptef. Al.Naltrehopope tе treаtmеpt оf аlсохол reredepse.Неw Епglапd Jоurпal оf Медісіпе 2001; 345 (24): 1734-1739 .; Krupitsky EM Various strategies for the use of naltrexone for the treatment of alcoholism: a brief review of research results. New drugs. M., 2006. Issue. 2, p. 44-47).

In 2006, the long-acting drug Vivitrol of Alkhermes ^{® was} registered in the USA, based on the naltrexone opiate antagonist, as a treatment for alcoholism. Multicenter studies show that depending on the dose of the drug and the sex of patients, the number of cases of heavy drinking decreases by 30-35%, 30% of patients who received Vivitrol for 3 months remained in remission (James S. Garbutt, Henry R. Kräzler, Stephanie S O'Malleuw, David R. Gastfriepd, Helen M. Reptipti, Bernard L. Silvermap, Joh W. W. Loeu, Ell W. W. Eric, Forte Vivit Stud Jouma, Aril 6, 2005 — VoI 293, No. 13, No. 13, 2005. 1617-1625).

ASAMRROSATE is officially registered as a drug for the treatment of alcoholism in most countries of Europe, as well as in Australia and South Africa. Acamprosate (calcium acetyl homotaurinate) has structural similarities with GABA and taurine. Numerous laboratory studies have shown that, in addition to the opioid system of neuropeptides, ethanol directly affects GABAergic and glutamatergic neurotransmission, and in particular N-methyl-D-aspartate (NMDA) receptors (Vegtop F, et al. Acamphase epitopes N-methul-

D-aparte geserto-mediad neurotransmission but iPhibits Respartis GABA (B) Reseptors IP Pusleus Assumbeps Peru. Alcohol CNn Exp Res 1998;

22 (1): 183-191 .; Dahshour A, et al. Septal Effects Of Asmrroset: Part 1.

Asmrrosace blosse the glutamate ipseas ip tusulus assumbeps mirodialus ip etapol withdraw gats. Psihiathu Res 1998; 82 (2): 107-114).

Preclinical studies have shown that the ligand of the NMDA receptor akamprosat causes a dose-dependent decrease in ethanol consumption by animals and completely suppresses it at a dose of 400 mg / kg (Wild Ml, Wagstaff AJ. Acamroptate. Dgugs 1997; 53 (6): 1038-53.) The clinical efficacy of acamprosate has been studied in a fairly large number of double-blind, randomized clinical trials. (Lhuiptre JP, et al Asamrrosate arrears to desrease alsohol iptake Ip weaped alsoholiss Alsohol Alsohol 1990; 25 (6):.. 613-622 .; Raille FM, et al Double-blipd gapdomized multiseptre trial asamrrosate ° F Ip maiptaipipg abstipepse from alsohol. Alcohol Alcohol 1995; 30 (2): 239-247 .; Sass H, et al. Relarse reptiop. .; Whitworth AB, et al. Сomparisop оf асаmрrосаtе аd rlаsеbо іp lopg-termеtеmpt оf аlсохеl relеpеpе. Lapset 1996; 347 (9013): 14осеpеptеpеmpеm J. alcohol ip waped alcoholis? J PHARM BeIg 1996; 51 (2): 65-68 .; Geerliпgs PJ, Apсoms C, vap d Brupp W. W. Asmroset apd rereveptiop of reelars and alcohols. Eur Addis Res 1997; 3: 129-137 .; Vargos Ja, alp. ; PeIc I, et al. Eficasu apd saffetu of asmatroset ip tétatmept of detohyphed alcohol-rapept patt. And the 90-day rlasebo-soptrоllеd dose-fiпdiпg studу. Br J Psychiati 1997; 171: 73-77 .; Paulrugo F. Asmrrosace treatept ip and lopg-term socialipitu-based alcohol rehabilitioprogram. Addictop 1997; 92 (11): 1537-1546.)

Most studies demonstrated the double superiority of acamprosate over placebo in such parameters as the duration of the period of complete abstinence (the time from inclusion in the study to the first case of alcohol consumption) and the total number of days of total sobriety. 30% of patients receiving acomprasate for 3 months remain in remission. (Lhuiptre JP, et al Asamrrosate arrears to desgease alsohol iptake Ip weaped alsoholiss Alsohol Alsohol 1990; 25 (6):.. 613-622 .; Ladewig D, et al Asamrrosate- and stabilizipg astog Ip lopg-terpl withdgawal alsoholis ratiepts ° F. . Umssh Theg 1993; 50 (3): 182-188 .; Raille FM, et al Double-blipd rapdomized multiseptre trial asamrrosate ° F Ip maiptaipipg abstipepse from alsohol alsohol alsohol 1995; 30 (2):.. 239-247 .; Roussauh JP, Hers D, Ferauge M. Dös asämrrosaté dimipish té arretité foralsoholip, wäpäd alcoholis? J PHARM BeIg 1996; 51 (2): 65-68. Ip alcoholis. Euro Addic Res 1997; 3: 129-137 .; Barrias JA, et al. Asmrosace: multiceptor Portuges effcu apd tolerapse evaluatiop studu Rsiquiatr CNn 1997; 18:. 149-160 .; PeIc I, et al Salsium asetul homotaugipate for maiptaipipg abstipepse Ip weaped alsoholis ratiepts; and rlasebo soptrolled double-blipd multiseptre studu In:. Naraηjo C Sellers E, EDS. .Novel pharmacologic iptegveptiops for alcoholism. New York: Springer-Verlag, 1992: 348-352 .; Paulrugo F. Asmatrocetipt and lopg-therm com-pasad alcohl rehabilitatrogram. Addictop 1997; 92 (11): 1537-1546. DISULFRAMUM is an aversive drug used in narcological practice since the middle of the 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. Despite the continued use of disulfiram in the treatment of alcoholism, sound scientific research into effectiveness its application is relatively small. In randomized controlled clinical trials performed in the 1980s 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 (Fullеr RK, et al. Disulfiram tegetmof of alcoholism, and Veteraps Admirostiopore cooperative stud. JAMA 1986; 256 (11): 1449-1455).

In the case of compliance control and the use of special patient rewards for regular administration of disulfiram, the effectiveness of treatment was significantly increased (Chiсk J, et al. Disulfiram tatempt оf alcoholism. Br J Рсусhiаtru 1992; 161: 84-89).

As an alternative to such methods of improving compliance, it was proposed to use the disulfiram prolong in the form of an implant (the preparation "Esperal"). 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 "diphilfiram-alcohol" are possible; 4) a tolerant amount of alcohol is difficult to determine; 5) if the dose is exceeded, disulfiram psychoses may occur. (Johpsep J, Morland J. Disulfiram imprpt: a dubble-blupdoplopod follow-up ontomptutcom. Alcohl Slip Exp Reps 1991; 15 (3): 532-536tloptil; Resource Trial. J Slip Psihiatrou 1984; 45 (6): 242-247).

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 term action) drug substance. There is also a high risk of disulfiramic psychosis with an uneven release of the drug.

CIANAMIDE (Temrosil, Dirsap, Abstem, Colmе). Like disulfiram, the drug inhibits the activity of acetaldehyde dehydrogenase, which takes part in the two-unit oxidative metabolism of ethanol: ethanol - acetaldehyde acetate (Sipa JF, Bean CL, Dusagt GR, et al. Rottepal. Mutat Res 1983; 113: 357-91 .; Vgiep JF, Loomis CW. Disrosiop apd rhagmasocipitis ap disulfirum ap Calcium carbimide (Calcium suapamide). , J., Repaire, C, Home, J., Azsopa, O., Torpept, J. apd Obashe, R. (1999) Absolute bioavailabilit apd absorptiof pofofile suapamide ip map. PHARMACOKIPETIS VIORHAGMASOLOGU 27, 421-436.) Cyanamide has a reliable and quick, 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 fewer harmful side effects than disulfiram. (Mokasa. H .: Slipisal studu on thе apti-alcoholis astiop оf Suapamide (I). Thе Jurpal оf thе Kurume Medisal Assosioptiop. 22, 1632. 1959 .; Mokasa. its сіlipisal arrlisatiop. Psushiatr. Neurol. Jar., 64,469. 1962.; Laсcet (Arr. 24, 1976): 911-912)

A comparative study of the clinical efficacy of cyanamide and disulfiram yielded: a more rapid formation of sensitization to alcohol, a mild but sufficient severity of an aversive reaction, the absence of gross side effects, and suppression of craving for alcohol. Cyanamide stabilizes remission better than disulfiram, thereby reducing the number of relapses. The main advantage of cyanamide over disulfiram is its lower intrinsic toxicity and greater specificity of action. Unlike disulfiram, cyanamide does not have hypotensive effect (Biochem. Pharmacol. 25: 2733-2737), inhibits only aldehyde dehydrogenase, does not affect dopamine-beta-hydroxylase, thereby not causing psychosis. In double-blind, randomized, placebo-controlled trials, cyanamide was found to be more effective than placebo in terms of the duration of the period of complete withdrawal (Niederhofoff, H., Staffep, W. ap. Alcohol défépéps of adolesceps. Alcohol apd Alcoholism 38, 50-53)

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. Closest to the claimed tool is the drug cyamide, used in the form of tablets, and which is a mixture of 0.05 mg of calcium cyanamide (active principle) and 0.1 g of citric acid. The drug is taken orally daily for 1-2 tablets for several months. (Mashkovsky M.D. Medicines. - M.: Medicine, 1985, v. 2, p. 197).

The disadvantages of the drug are the need for a long daily intake of tablets, as well as the thermolability of the active principle. Cyanamide is used orally, in the form of a solution, twice a day, 36-75 mg, for a period of 1-6 months or more. SUMMARY OF THE INVENTION

The invention is directed to the development of a long-acting agent for the prevention of relapse of alcoholism, effective and convenient to use.

A tool based on cyanamide containing a mixture of cyanamide and polylactide in a ratio (mass.) From 10:90 to 40:60 and a method for its administration into the body by intramuscular injection of a suspension containing this mixture in a single dose of 0.5-1.5 g was developed. The resulting mixture, which is a microcapsule from cyanamide and polylactide, provides a slow release of cyanamide into the body, which creates a stable prolonging effect for at least 30 days. The use of lower concentrations of cyanamide in the mixture does not provide the necessary concentration in the body after administration. The use of a mixture with a polylactide concentration of less than 60% of the mass does not allow to obtain a stable suspension and reduces the prolonging effect of the drug. As a rule, the drug is administered 1 time per month, however, in some cases, according to individual indications, it is possible that it is administered more often (for example, once every 1-2 weeks) or more rarely (once every 2 months).

It is optimal for administration to use a solution containing carboxymethyl cellulose -0.3-1, 0% mass, tween 80-0.05-0.2% mass, mannose 3-10% mass, sodium chloride 0.5-2.0% mass, a mixture of cyanamide and polylactide 20- 40% of the mass, pyrogen-free water - the rest. The specified solution ensures the stability of the suspension when it is introduced into the body and consists of components approved for use in healthcare for intramuscular administration. EMBODIMENTS FOR CARRYING OUT THE INVENTION.

Example 1. Receiving funds.

1.1. Preparation of polylactide solution.

A portion of a polylactide weighing 1 gram was dissolved in 20 ml of ethyl acetate with stirring on a magnetic stirrer in a cold cabinet at a temperature of + 40c for 2 hours. The polylactide concentration was 5%.

1.2. Preparation of a solution of polyvinyl alcohol.

A weighed portion of polyvinyl alcohol (MM ~ 80 kfla) weighing 4.2 g was dissolved in 200 ml of pyrogen-free water when heated in a water bath to a temperature of + 90 ° C with occasional stirring. Then the solution was cooled to room temperature and filtered through a vacuum filter with a transmission of 0.44 μm.

1.3. Preparation of cyanamide solution A portion of cyanamide weighing 360 mg was suspended in 15 ml of ethyl acetate with stirring on a magnetic stirrer at room temperature. Then, 20 ml of distilled water was added to the solution and titrated with 1 N sodium hydroxide to pH 8.2 with stirring. After stabilization of pH 8.2, the suspension was centrifuged at a rotation speed of 1000 rpm, selecting the upper layer of a solution of cyanamide base.

1.4. Cooking tools. The cyanamide solutions obtained in stages 1.1 and 1.3 were combined in a predetermined ratio and the total volume was adjusted to 40 ml by adding ethyl acetate. To the resulting solution was added 200 ml of a solution of polyvinyl alcohol obtained according to Claim 1.2 and stirred on a mechanical stirrer at a speed of 500 rpm for 2 hours. The resulting microcapsule suspension was centrifuged at a rotation speed of 5000 rpm for 15 minutes. The microcapsules were then washed with pyrogen-free water by suspension and subsequent centrifugation. The supernatant was discarded. The washing cycle was repeated 3 times. After the last centrifugation, 30 ml of pyrogen-free water was added to the microcapsules, shaken vigorously and placed in sterile polypropylene bottles, then frozen for 5 minutes by placing the container with the bottles in liquid nitrogen. Frozen vials with microcapsules were dried in a sublimation machine for 24 hours. Samples were obtained with a cyanamide content of 10%, 25% and 40%. Example 2. Preparation of a suspension for injection. Samples of carboxymethyl cellulose (CMC), tween 80, mannose, and sodium chloride were successively dissolved in 200 ml of pyrogen-free water. After all components were dissolved, the solution was sterile filtered through a filter with 0.44 μm spores. The solution was stored at room temperature. Before introducing the agent into the body, the specified amount of the mixture obtained in Example 1 was introduced into the solution at the rate of 1 g of microcapsules per 3 ml of solution and mixed thoroughly. Suspensions of the following composition were obtained (Table 1)

Table 1.

The composition of the compositions

INDUSTRIAL APPLICABILITY

The experiments were conducted on male Wistar rats weighing 190-240 grams. Animals were obtained from the Rappolovo breeding station (St. Petersburg). Rats were housed in 6 animals in standard cages. Animals got used to 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 a.m. / 12 hours dark), air temperature 22: 1: 1 os and humidity 60%.

Each experimental group consisted of 6 animals. There were 4 animal groups in total: control group 1 (solvent with repeated administration of isotonic NaCI solution), control group 2 (solvent with repeated administration of cyanamide, groups 3-7 (single intramuscular injection of samples 1-5 at a dose of 30 mg / kg s) and group 4 (single intramuscular administration of sample 3 at a dose of 60 mg / kg).

The effect of administration of the drug was evaluated using high performance liquid chromatography with preliminary derivatization of cyanamide by converting it into a danil derivative (J. Chemogatogr. 1991 Ser 27; 558 (1) p. 141-146). Control animals were intramuscularly administered once.

(v / m) pyrogen-free water solution containing 0.5% by weight of CMC; 0.1% of the mass of tween 80; 5.0% of the mass of mannose, 0.9% NaCI, for animals of the experimental groups — solutions of the product, the composition of which is indicated in Table 1.

Processing of the obtained results was carried out using the INSTAT application program. The results of the experiments were analyzed using analysis of variance (Reserved Меаsureеs Apаlуsis оf Vagiapse) followed by identification of significant differences between the groups (Post hoc analysis using the Tukeu-Krameg Multirle Сomrarisops test). The results for groups of animals were averaged. The results obtained are shown in table 2 as a percentage of the initial cyanamide preparation administered.

Table 2.

Data on the prolonged action of the proposed drug.

The results of a study of the effect of the prolongation of cyanamide, presented in the table, show a significant effect of the delay and slow release of the active principle during intramuscular administration of a microgranulated form of an anti-alcohol agent.

Claims

CLAIM

1. The tool for the prevention of relapse of alcoholism, containing an active principle based on cyanamide and excipients, characterized in that it contains a mixture of cyanamide and polylactide in the ratio (mass.) From 10:90 to 40:60.

2. A method for the prevention of relapse of alcoholism by introducing into the body a mixture containing cyanamide, characterized in that the patient is injected intramuscularly with a solution containing a mixture of cyanamide and polylactide taken in a ratio (mass.) From 10:90 to 40:60 in a single dose of 0.5- 1, 5 g.

3. The method according to claim 2, characterized in that the agent is administered once a month.

4. The method according to claim 2, characterized in that the agent is administered in the form of a solution containing carboxymethyl cellulose - 0.3 - 1.0% by mass, tween 80 - 0.05-0.2% by mass, mannose - 3-10% by mass, sodium chloride 0.5 -2.0% of the mass, a mixture of cyanamide and polylactide 20-40% of the mass, pyrogen-free water - the rest.