RU2343908C1 - Agent for prevention and treatment of alcoholism and method of its application - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: agent for prevention and alcoholism treatment contains admixture of amidocyanogen and polylactide in the ratio (wt) from 10:90 till 40:60. The method of prevention and alcoholism treatment consists that to the patient, as a rule, enter intramusculary a solution containing an admixture amidocyanogen and polylactide in a single dose of 0.5-1.5 g once a month.

EFFECT: appreciable effect of delay and slow liberation of the operating beginning.

4 cl, 3 dwg, 2 tbl, 3 ex

Description

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

For Russia, alcohol abuse, alcoholism is 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) and is one of the highest in the world (Nemtsov A.V. Alcoholic damage to Russian regions. 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. Alcohol is the most important destructive factor in the demographic, social and economic development of Russia. Studies show that severe alcohol problems are the main reason that the mortality rate of Russians is catastrophically high. (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; AV Nemtsov 2006. Geography of alcohol-related mortality in Russia. Report at the All-Russian Conference "The Concept of Alcoholic Policy in Russia, Moscow, May 18, 2006).

The basis of therapeutic measures for alcoholism, as in any other chronic disease, is the formation and maximum prolongation of therapeutic remissions, that is, periods of complete abstinence of patients from drinking alcohol. 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 (Krupitsky E.M., Zvartau E.E. Pharmacological agents used to stabilize remissions and prevent relapses in acogolism. St. Petersburg State Medical University named after Academician I.P. Pavlov. St. Petersburg, 2003. T.X. No. 2. S.12-23). Failure occurs in 75% of patients in the first year, and in 50% in the first three months of treatment (Eryshev O.F., Rybakova T.G., Shabanov P.D. Alcohol dependence: formation, course, anti-relapse therapy. - St. Petersburg .: Publishing house "ELBI-SPb", 2002. - 192 c .; Niederhofer, H., Staffen, W. and Mair, A. (2003) Comparison of cyanamide and placebo in the treatment of alcohol dependence of adolescents. Alcohol and Alcoholism 38, 50-53).

Currently, the main drugs used in the treatment of alcoholism are naltrexone, acamprosate, disulframum, cyanamide and a number of other drugs that have not been adequately studied due to the limited amount of reasonable data from clinical observations (Krupitsky E.M., Zvartau E.E. pharmacological agents for stabilization of remissions and prevention of relapses in acogolism. Scientific notes of St. Petersburg State Medical University named after Academician IP Pavlov. St. Petersburg, 2003. T.X. No. 2. S.12-23).

NALTREXONE. 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 the duration of the period of complete withdrawal (i.e., complete abstinence from alcohol) did not differ significantly from placebo. There are studies indicating that naltrexone is more effective than placebo, stabilizes remission and prevents 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. Apparently, the low compliance with the drug they noted is due to the presence of an undesirable side effect. A multicenter, double-blind, randomized study conducted in the USA by Yale scientists in several war veteran hospitals for patients with severe alcohol dependence, also did not reveal advantages in naltrexone compared with placebo (Volpicelli JR, et al. Naltrexone in the treatment of alcohol dependence Arch Gen Psychiatry 1992; 49 (11): 876-880; Volpicelli JR, et al. Naltrexone and alcohol dependence: role of subject compliance Arch Arch Psychiatry 1997; 54: 737-742; Mason BJ, et al. A double -blind, placebo-controlled pilot study to evaluate the efficacy and safety of oral nalmefene HCl for alcohol dependence. Alcohol Clin Exp Res 1994; 18 (5): 1162-1167; Oslin D, et al. Naltrexone as an adjunctive treatment for older patients with alcohol dependence. Am J Geriatr Psychiatry 1997; 5 (4): 324-332; Anton RF, et al. Naltrexone and cognitive behavioral therapy for the treatment of outpatient alcoholics: results of a placebo-controlled trial. Am J Psychiatry 1999; 156 (11): 1758-1764; Kranzler HR, et al. Naltrexone vs. Nefazodone for treatment of alcohol dependence. A placebo-controlled trial. Neuropsychopharmacology 2000; 22 (5): 493-503 .; Krysati J.H., et al. Naltrexone in the treatment of alcohol dependence. New England Journal of Medicine 2001; 345 (24): 1734-1739; Krupitsky E.M. Different strategies for using naltrexone for the treatment of alcoholism: a brief review of research findings. New drugs. M., 2006. Issue 2. S.44-47).

In 2006, the long-acting drug Vivitrol by Alkermes ^®, based on the naltrexone opiate antagonist as a treatment for alcoholism, was registered in the United States. Multicenter studies show that depending on the dose of the drug and the sex of patients, the incidence of heavy drinking decreases by 20-35%, 30% of patients receiving Vivitrol for 3 months remained in remission (James C. Garbutt, Henry R. Kranzler, Stephanie S. O'Malley, David R. Gastfriend, Helen M. Pettinati, Bernard L. Silverman, John W. Loewy, Elliot W. Ehrich, for the Vivitrex Study Group. JAMA, April 6, 2005 - Vol 293, No. 13, 1617-1625).

ACAMPROSATE is officially registered as a treatment for alcoholism in most European countries, as well as in Australia and South Africa. Acamprosate (calcium acetyl homotaurinate) has structural similarities with GABA and taurine. In numerous laboratory studies, it has been shown that, in addition to the system of opioid neuropeptides, ethanol directly affects GABAergic and glutamatergic neurotransmission, and especially N-methyl-D-aspartate (NMDA) receptors (Berton F, et al. Acamprosate enhances N -methyl-D-apartate receptor-mediated neurotransmission but inhibits presynaptic GABA (B) receptors in nucleus accumbens neurons. Alcohol Clin Exp Res 1998; 22 (1): 183-191 .; Dahchour A, et al. Central effects of acamprosate: part 1. Acamprosate blocks the glutamate increase in the nucleus accumbens microdialysate in ethanol withdrawn rats. Psychiatry Res 1998; 82 (2): 107-114).

Preclinical studies have shown that the ligand of the acamprosate NMDA receptors causes a dose-dependent decrease in animal ethanol consumption and completely suppresses it at a dose of 400 mg / kg (Wilde MI, Wagstaff AJ. Acamprosate. A review of its pharmacology and clinical potential in the management of alcohol dependence after detoxification. Drugs 1997; 53 (6): 1038-53).

The clinical efficacy of acamprosate has been studied in a fairly large number of double-blind, randomized clinical trials. (Lhuintre JP, et al. Acamprosate appears to decrease alcohol intake in weaned alcoholics. Alcohol Alcohol 1990; 25 (6): 613-622 .; Paille FM, et al. Double-blind randomized multicentre trial of acamprosate in maintaining abstinence from alcohol .Alcohol Alcohol 1995; 30 (2): 239-247 .; Sass H, et al. Relapse prevention by acamprosate. Results from a placebo-controlled study on alcohol dependence. Arch Gen Psychiatry 1996; 53 (8): 673-680 .; Whitworth AB, et al. Comparison of acamprosate and placebo in long-term treatment of alcohol dependence. Lancet 1996; 347 (9013); 1438-1442 .; Roussaux JP, Hers D, Ferauge M. Does acamprosate diminish the appetite for alcohol in weaned alcoholics? J Pharm Beig 1996; 51 (2): 65-68 .; Geerlings PJ, Ansoms C, van den Brink W. Acamprosate and prevention of relapse in alcoholics. Eur Addict Res 1997; 3: 129-137. ; Barrias JA, et al. Acamprosate: multicenter Portugese efficacy and tolerance evaluation study. Psiquiatr Clin 1997; 18: 149-160 .; Pelc I, et al. Efficacy and safety of acamprosate in the treatment of detoxified alcohol-dependent patients. A 90-day placebo-controlled dose-finding study. Br J Psychiatry 1997; 171: 73-77 .; Poldrugo F. Acamprosate treatment in a long-term community-based alcohol rehabilitation program. Addiction 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 access for 3 months remain in remission (Lhuintre JP, et al. Acamprosate appears to decrease alcohol intake in weaned alcoholics. Alcohol Alcohol 1990; 25 (6): 613-622; Ladewig D, et al. Acamprosate-a stabilizing actor in long-term withdrawal of alcoholic patients. Ther Umsch 1993; 50 (3): 182-188 .; Paille FM, et al. Double-blind randomized multicentre trial of acamprosate in maintaining abstinence from alcohol Alcohol Alcohol 1995; 30 (2): 239-247 .; Roussaux JP, Hers D, Ferauge M. Does acamprosate diminish the appetite for alcohol in weaned alcoholics? J Pharm Beig 1996; 51 (2): 65-68 .; Geerlings PJ, Ansoms C, van den Brink W. Acamprosate and prevention of relapse in alcoholics. Eur Addict Res 1997; 3: 129-137 .; Barrias JA, et al. Acamprosate: multicenter Portugese efficacy and tolerance evaluation study. Psiquiatr Clin 1997 ; 18: 149-160 .; Peic I, et al. Calcium acetyl homotaurinate for maintaining abstinence in weaned alcoholic patients; a placebo controlled double-blind multi-center study. In: Naranjo C, Sellers E, eds. Novel pharmacological interventions for alcoholism. New York: Springer-Verlag, 1992: 348-352 .; Poldrugo F. Acamprosate treatment in a long-term community-based alcohol rehabilitation program. Addiction 1997; 92 (11) 1537-1546).

DISULFRAMUM is an aversive drug used in narcological practice since the mid-20th century. Disulfiram inhibits aldehyde dehydrogenase, which catalyzes the oxidation of acetaldehyde, an ethanol oxidation product that 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, there are relatively few correct scientific studies of its effectiveness. 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, first of all, to low compliance with therapy (Fuller RK, et al. Disulfiram treatment of alcoholism. A Veterans Administration cooperative study. 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 (Chick J, et al. Disulfiram treatment of alcoholism. Br J Psychiatry 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 (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.

CIANAMIDE (Temposil, Dipsan, Abstem, Coime). Like disulfiram, the drug inhibits the activity of acetaldehyde dehydrogenase, which is involved in the two-unit oxidative metabolism of ethanol: ethanol-acetaldehyde acetate (Sina JF, Bean CL, Dysart GR, et al. Evaluation of the alkaline elution / rat hepatocyte assay as a predictor of carcinogenic / mutagenic potential. Mutat Res 1983; 113: 357-91 .; Brien JF, Loomis CW. Disposition and pharmacokinetics ofdisulfiram and calcium carbimide (calcium cyanamide). Drug Metab Rev 1983; 14: 113-26; Colom, H., Prunonosa, J., Peraire, C., Domenech, J., Azcona, O., Torrent, J. and Obach, R. (1999) Absolute bioavailability and absorption profile of cyanamide in man. Journal of Pharmacokinetic Biopharmacology 27, 421-436. )

Cyanamide 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 .: Clinical study on the anti-alcoholic action of Cyanamide (I). The Journal of the Kurume Medical Association. 22, 1632. 1959; Mokasa. H. : Studies on the physiological anti alcoholic effects of Cyanamide and its clinical application. 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 (Altshuler V.B., Kravchenko S.L., Rusinov A.V. The drug Colme (Colme) as a means of obverse therapy for patients with alcoholism. NTSN Roszdrav. 2006. www.colme.ru). Cyanamide stabilizes remission better than disulfiram, thereby reducing the number of relapses (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 main advantage of cyanamide over disulfiram is its lower intrinsic toxicity and greater specificity of action. Unlike disulfiram, cyanamide does not have a hypotensive effect (Biochem. Pharmacol. 25: 2733-2737), inhibits only aldehyde dehydrogenase, does not affect dopamine-beta-hydroxylase, thereby not causing psychosis (Ivanets N.N. Report on the results of 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). Double-blind, randomized, placebo-controlled trials showed greater efficacy of cyanamide compared to placebo in terms of the duration of the complete withdrawal period (Niederhofer, H., Staffen, W. and Mair, A. (2003) Comparison of cyanamide and placebo in the treatment of alcohol dependence of adolescents. Alcohol and 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.

The closest in technical essence 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 is 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.

The technical problem solved by the authors was the creation of a long-acting agent for the prevention and treatment of alcoholism, no less effective and more convenient to use.

This problem was solved by creating a composition based on cyanamide, administered intramuscularly.

The technical result was achieved by the creation of an agent based on cyanamide containing a mixture of cyanamide and polylactide in a ratio (wt.) 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 .

The resulting mixture, which is a microcapsule from cyanamide, 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 wt.% 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 can be administered more often (for example, once in 1-2 weeks) or more rarely (1 time in 2 months).

It is optimal for administration to use a solution containing carboxymethyl cellulose - 0.3-1.0 wt.%, Tween 80-0.05-0.2 wt.%, Mannose - 3-10 wt.%, Sodium chloride 0.5-2.0 wt.%, A mixture of cyanamide and polylactide 20- 40 wt.%, 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.

The essence of the claimed invention is illustrated by the following examples.

Example 1. Receiving funds.

1.1. Preparation of polylactide solution. A sample of 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 + 40 ° C for 2 hours. The polylactide concentration was 5%.

1.2. Preparation of a solution of polyvinyl alcohol. A portion of polyvinyl alcohol (MM ~ 80 kDa) weighing 4.2 g was dissolved in 200 ml of pyrogen-free water when heated in a water bath to a temperature of + 900 ° 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 and the upper layer of a solution of cyanamide base was selected.

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 vials, after which they were frozen for 5 minutes by placing the container with the vials in liquid nitrogen. Frozen vials with microcapsules were dried in a sublimation machine for 24 hours.

Samples with cyanamide contents of 10%, 25% and 40% were obtained.

Example 2. Preparation of a suspension for injection.

In 200 ml of pyrogen-free water, weighed portions of carboxymethyl cellulose (CMC), tween 80, mannose, and sodium chloride were successively dissolved. After all components were dissolved, the solution was sterilely filtered through a filter with 0.44 μm pores. 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 Composition The content of the component, wt.% Sample 1 Sample 2 Sample 3 Sample 4 Sample 5 CMC 0.3 0.5 0.5 0.5 1.0 Twin 8 0.05 0.1 0.1 0.2 0.2 Mannose 5.0 10.0 5.0 5.0 5.0 NaCl 0.5 1.0 0.9 2.0 1.0 Cyanamide 2.0 5.0 7.5 10.0 16.0 Polylactide 18.0 15.0 22.0 20.0 24.0 Water 74.15 68.4 64.0 62.3 52.8

Example 3. The experiments were conducted 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 a.m. / 12 hours dark), air temperature 22: 1: 1 ° C and humidity 60%.

Each experimental group consisted of 6 animals. There were 4 groups of animals: control group 1 (solvent with repeated administration of isotonic NaCl 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 per day) and group 4 (a single intramuscular injection of sample 3 at a dose of 60 mg / kg).

The effect of drug administration was evaluated using high performance liquid chromatography with the preliminary derivatization of cyanamide by converting it to a danil derivative (J. Chromatogr. 1991 Sep 27; 558 (1) p. 141-146).

The animals of the control groups were injected intramuscularly (IM) with a solution of pyrogen-free water containing 0.5 wt.% CMC; 0.1 wt.% Tween 80; 5.0 wt.% Mannose, 0.9% NaCl, animals of the experimental groups — solutions of the drug, the composition of which is indicated in Table 1.

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 2 as a percentage of the initial cyanamide preparation administered.

Table 2.
Data on the prolonged action of the proposed drug Group of animals Plasma cyanamide after 1 day 7 days 14 days 21 days 28 days 1 (control) no no no no no 2 (cyanamide) one hundred 12 no no no 3 (Sample 1) one hundred 68 65 60 56 4 (Sample 2) one hundred 74 70 55 52 5 (Sample 3) one hundred 87 67 56 54 6 (Sample 4) one hundred 87 70 64 57 7 (Sample 5) one hundred 92 72 62 59 8 (Sample 3) one hundred 98 76 75 68

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 (4)

1. The tool for the prevention and treatment of alcoholism, containing an active principle based on cyanamide and excipients, characterized in that it contains a mixture of cyanamide and polylactide in a ratio (wt.) From 10:90 to 40:60. 2. A method for the prevention and treatment 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 according to claim 1 in a single dose of 0.5-1.5 g. 3. The method according to claim 2, characterized in that the tool is administered 1 time per month. 4. The method according to claim 2, characterized in that the tool is administered in the form of a solution containing carboxymethyl cellulose - 0.3-1.0 wt.%, Tween 80 - 0.05-0.2 wt.%, Mannose - 3- 10 wt.%, Sodium chloride 0.5-2.0 wt.%, A mixture of cyanamide and polylactide 20-40 wt.%, Pyrogen-free water - the rest.