FR2859633A1 - Synthetic immunogen for therapy and prophylaxis of addiction with narcotic and psychoactive substances - Google Patents

Abstract

Synthetic immunogen represents conjugate as the natural or artificial protein as a carrier and haptene - narcotic or psychotropic compound taken among the following groups of low-molecular compounds. Conjugate is modified with an immunocompetent polyelectrolyte - polyoxidonium in the ratio, weight %: conjugate : polyoxidonium = 1:(1.5-5.0). Invention can be used for treatment of narcomania, intoxication with different poisons in industry and in homes, in technogenic catastrophe and so on. Synthetic immunogen represents conjugate as the natural or artificial protein (egg albumin or human gamma-globulin, or bacterial toxins) as a carrier and haptene - narcotic or psychotropic compound taken among the following groups of low-molecular compounds: aromatic propaneamines or isoquinolines, or diphenylmethanes, or indoleamines, or derivatives of barbituric acid, or derivatives of substituted piperidines. Conjugate is modified with an immunocompetent polyelectrolyte - polyoxidonium in the ratio, weight %: conjugate : polyoxidonium = 1:(1.5-5.0).

Description

Synthetic immunogen for the treatment and prevention of abuse of

products

  The invention relates to the field of medicine, in particular to immunology and can be used for the treatment of addictions, poisoning by various poisons in industry and in everyday life, during technogenic accidents. etc. At present national practical medicine widely uses synthetic immunogens comprising a vehicle which is a polyoxydonium (a high molecular weight N-oxidized polyethylene piperazine derivative) and a hapten which is a macromolecular compound, for example a hyaluronidase enzyme or a mixture of haemagglutinin and neuramidase, or a cholera toxin, or a tritonic extract (glycopeptide) of BCG microbacterial cell walls, or others.

  [see, for example, Application No. 97103034, CIB A 61K 38/43, filed on 28. 02.1997, published 10.09.1998; Patent No. 1580617, CIB A 61K 39/145, dep. 13.05.1988, publ. 10.02.1997; Patent No. 2021816, CIB A 61K 39/106, dep. 05.06.1991, publ. 30.10.1994, Patent No. 2153354, CIB A 61K 39/04, dep.

  31.03.1999, publ. 27.07.2000; the journal "Immunology" No 6, 2002, p. 324333; the journal "Attending Physician" No 4, 1998].

  Despite the fact that the polyoxydonium forming part of the known immunogens has remarkable properties (reproductivity of chemical structure, absence of weighting impurities, pronounced immunostimulatory activity, apparent properties of detoxification, antioxidants and stabilization of membranes), these preparations can not be used only for the treatment of acute and chronic bacterial and viral infections, because they contain specific heptanes.

  It is known a synthetic immunogen that is closest to the technical nature and the intended result of the claimed invention, which is used for the treatment and prevention of narcotic abuse (including, opioid addiction) and which represents a conjugated in the form of a vehicle which is a natural or synthetic protein and a hapten which is a narcotic or psychotropic compound. As a vehicle it contains bovine serum albumin or synthetic polypeptides and glycoproteins, and as hapten, it contains morphine, or codeine, or heroin, or methadone, or the like.

  [Cf. Kovalev I.E., Polévaïa O.Y. "Biochemical Bases of Immunity Against Low Molecular Weight Chemicals", Moscow, "Naouka", 1985]. The drawbacks of this prior art are the following: R: \ Patents 23000 \ 23050.doc - 15 September 2004 - 1116 presence of ballast impurities; weak therapeutic activity (immunostimulant); need for large doses (up to 20 mg / kg) and short immunization (up to 6 months); impossibility of ensuring stable and / or lasting immunity.

  The object of the present invention is to provide a synthetic immunogen which is easily reproducible, accessible and harmless, able to protect the human being against the effects of a wide range of toxic products and to form a stable and prolonged immune reaction in his body.

  The objective is achieved by virtue of the fact that in the known synthetic immunogen used for the treatment of narcotic and psychoactive substance abuse, which is represented by a conjugate in the form of a vehicle which is a natural or synthetic protein and of a hapten which is a narcotic or psychotropic compound, according to the invention, the conjugate is modified by an immunocompetent polyelectrolyte, polyoxydonium, the weight ratio in% being equal to: conjugate / polyoxydonium = 1: 1.5 to 5.0, the conjugate containing ovalbumin, or human gamma-globulin, or microbial toxins as a carrier, and containing as haptenes compounds of low molecular weight selected from the following groups: aromatic propanamines, or isochinolines, or diphenylmethanes , or indolamines, or barbituric acid derivatives, or derivatives of substituted piperidines.

  Modification of the claimed conjugate by the polyoxydonium ensures the absence of weighting impurities in the synthetic immunogen, the claimed conjugate / polyoxydonium ratio being necessary and sufficient to provide stable and prolonged immunostimulatory activity.

  The use in the proposed synthetic immunogen of particular vehicles and haptens protects the human body against the effects of a wide range of toxic products (including narcotics, industrial poisons, various carcinogens).

  The claimed synthetic immunogen stimulates processes within the immune system, such as migration and co-operation between T-lymphocytes and B-lymphocytes, antibody production in response to foreign antigens, functioning of NC cells and macrophages. It contributes to increase the synthesis of antibodies whose number increases in geometric progression from the first two weeks, and at the end of the second month from the beginning of the administration, the body accumulates antibodies likely to fix the doses of narcotic or toxic substances in general from 2/1 to 10 times higher than lethal doses. In particular, the production of anti-heroin antibodies is accompanied simultaneously by the formation of mononuclear spleen cells binding the heroin. Thus, the immunization of the patient using the proposed formulation allows to develop the tolerance vis-à-vis the specific products in the absence of any negative effect.

  To prepare the claimed synthetic immunogen the following commercial or in situ synthesized components were used: Products Supplier NPOs "Biochimréactivy" Olaïn's chemical reagent plant Ovalbumin freeze-dried Company producing bacterial preparations Bel. NIIEM, certificate No. 17 Moscow Chemical Society "Laverna", packaging by ZAO "Indikator", cat. No human gamma globulin Microbial toxins Extracted from cultures (diphtheria, tetanus toxin, streptococci, botulinum) Synthetic polypeptides Independent synthesis from amino acids consisting of amino acids I or produced by the company "Reanal", Bulgaria D spontaneously polymerized Haptenes Aromatic propanamines : Independent synthesis from ephedrine Amphetamine Independent synthesis from saffron Pervitin Extasy R: 1Brevets123000123050.doc - September 15, 2004 - 3/16 Isochinolines: Independent synthesis by steam distillation Nicotine from tobacco Mescaline Independent synthesis from gallic Morphine acid Heroin Independent synthesis by successive codeine transformations of terpinecode Ethorphine - "- Dihydroethorphine -" Naltrexone - "- -" - OAO "Pharmaceutical Factory of Moscow"; "Du Pont, France;" Diosynt BV ", Netherlands, in the form of 50 mg capsules or tablets Diphenylmethanes: Independent synthesis by successive Methadone transformations of terpincode Indolamines: Independent synthesis from ergometrine LSD-25 Summary independent from treptophane Psylocin "- Ibogaine" - Garmine Derivatives of the Novokuznetsk barbiturate PO "Organika" acid: barbiturates and Chemical and pharmaceutical Corporation of their possible analogues Kazan "Tatkhimpharmpreparaty" Derivatives of substituted NPO piperidines Ukrmedbioprom "Zdorovie": Synthesis independent from benzene, Phentanyl piperidine and cyclohexanol Phencyclidine Independent synthesis from phentanyl Carphentanyl - "- 3-methylphentanyl" Suphentanyl "- Alphentanyl" - Lophentanyl Polyoxydonium CNG "Institute of Imunnology" R1 Patents 23000 \ 23050 .doc - 15 September 2004 - 4/16 The preparation of the synthetic immunogen has been carried out according to known traditional methods.

Method 1.

  To the mixture of 1.2 g of benzidine, 2 ml of formic acid and 70 ml of water was added 1 g of sodium nitride in 2 ml of water. The reaction mixture was cooled and stirred for one hour. The solution thus obtained was then added to the solution of 2 g of phentanyl (carphentanyl, methadone, cocaine, nicotine, heroin, etc.) in 15 ml of water, maintaining pH at 7.0-8.0 with addition of a 10% solution of sodium hydroxide. The deposit was filtered and washed with water and several times with chloroform.

  To 200 mg of the para-aminodiphenylazopentanyl (-carphentanyl, -methadone, cocaine, -nicotine, -heroin etc.) prepared and 10 ml of concentrated hydrochloric acid at minus 10 C was added 20 mg of sodium nitride in 2 mg of 'water. The reaction mixture was cooled and stirred for 30 minutes. The resulting solution was added cold to an aqueous solution of human gamma globulin or synthetic polypeptide while maintaining pH at 7.0-8.0 by the addition of sodium hydroxide. The mixture was stored in the refrigerator for 12 hours. Purification of the obtained conjugate was carried out through semipermeable membranes against the current of distilled water for 5 days or sefadex. The conjugate was modified with the polyoxydonium previously activated by a known method (see, for example, Patent No. 1580617), the conjugate / polyoxidonium ratio being 1: 1.5-5.0.

  The structural formula of the synthetic immunogen obtained is presented in the Appendix.

Method 2

  Stoichiometric amounts of naltrexone (morphine, codeine etc.) of 0.01 mole (3.8 g) in 0.01 mole (0.08 g) of pyridine and succinyl dichloride of 0.01 mole were taken. (1.6 g). Pyridine is used in the reaction as a scavenger of the hydrogen chloride evolved during the addition of naltrexone to one of the chlorocarboxyl functions of succinyl chloride. The second function remains free for subsequent addition to a protein which is human gamma globulin or synthetic polypeptide. Purification of the conjugate and its modification were performed as described in Method 1.

  The structural formula of the synthetic immunogen obtained is presented in the Appendix.

  The claimed synthetic immunogen was synthesized under the laboratory conditions of the chair of pharmacology of the Ural Academy of Medicine with authorization from the Ministry of Health to carry out research. R: \ Patents - 23000123050.doc - 15 September 2004 5116 scientists with narcotic and psychotropic substances in accordance with the following documents: the Ordinance of the Ministry of Health of the USSR No. 1311 of 30.12.1982 and the Federal Law "Narcotic Means and Psychotropic Drugs" No 3-FZ of 08.01.1998. The synthesized immunogens were subjected to multiple testing in mice, as well as to groups of volunteers in accordance with Article 124 of the Criminal Code of the Russian Federation, Article 43 of the Principles of Legislation in the Field of protection of the health of citizens and Article 21, part 2 of the Constitution of the Russian Federation.

  The synthetic immunogen was administered to patients by subcutaneous injection in the form of a 0.5 ml solution. After two weeks, the procedure was repeated and the immunogen was administered for six weeks at one injection per week. The duration of the active immune reaction was determined according to the standard methods: PHA, RPHA, IFA, RIA. Patients were monitored continuously for 5 years to monitor their improved health.

  Synthetic immunogen for the treatment and prevention of abuse of narcotic and psychoactive products The synthetic immunogen consists of a conjugate in the form of a vehicle which is a human gamma globulin protein and a hapten which is a compound of low molecular weight selected from the group consisting of isochinoline and naltrexone.

  The conjugate is modified with an immunocompetent polyelectrolyte, the polyoxydonium, the weight ratio in% being: Conjugate: polyoxydonium = 1: 1.5 10.0 mg 15.0 mg Examples 2 to 8 illustrate the synthetic immunogen in which the vectors , the haptens and the ratio (conjugate / polyoxydonium) vary within the claimed limits.

  The compositions of the synthetic immunogen and the known immunogen taken for the prototype [cf. Kovalev I.E., Polévaïa O.Y. "Biochemical Bases of Immunity Against Low Molecular Weight Chemicals", Moscow, "Naouka", 1985], as well as their pharmacological effects are illustrated in the table below.

  The examples and data presented in the table demonstrate that the use of the claimed synthetic immunogen provides the following technical and social advantages over the known immunogen taken for the prototype [cf. Kovalev I.E., Polévaïa O.Y. "Biochemical bases R: \ Patents \ 23000 \ 23050.doc September 2004 - 6/16 immunity against low molecular weight chemical compounds", Moscow, "Naouka", 1985]: - easy reproductivity without ballast impurities; - accessibility and absence of negative effects; high immunological activity; - reduction of doses and cure time; - prolonged stable immunity; - protection against the effects of a wide range of toxic substances (narcotics and psychoactive substances).

Preclinical trials.

  A series of appropriate tests using the biological sample collection method demonstrated the possibility of neutralizing the toxic effect of heroin on animals. An absolutely lethal heroin dose of 100 mg / kg (LD100) was administered to a reference animal group consisting of four non-immunized rabbits and a group of test animals consisting of four immunized rabbits. It was determined that all four rabbits in the reference group were killed by these doses. Among the immunized rabbits no fatal cases are recorded, i.e., a clear immunological protection has been found.

  The blood serum of the immunized animals was also tested.

  Eight rabbits weighing 2 kg each were immunized with the preparation consisting of polyoxydonium 3-hemisuccinylnaltrexone-gamma globulin and containing 45 moles of 3-hemisuccinylnaltrexone and 3 moles of polyoxydonium per molecule of protein, which was administered by intramuscular injections at 30 mg / kg twice weekly for 8 weeks. The presence of antibodies in animal blood serum was determined before and after immunization and their specificity was examined in the passive haemagglutination inhibition reaction by conventional methods.

  R: \ Patents \ 23000 \ 23050.doc - 15 September 2004 - 7/16

Board.

  Compositions of Synthetic Immunogens and Their Pharmacological Effects Exem- Composition of Report Pharmacological Effect on Immunogen Conjugate / 1. polyoxidonium vehicle 2. hapten 3. polyoxydonium 1. 1.gamma-globulin 1: 1.5 Antibody synthesis, human stability humoral immunity of 12 2. naltrexone month; any technique 3. + administration, absence of allergic reactions, lifetime immunity 2. 1.gamma-globulin 1: 3.0 Antibody synthesis, human stability of humoral immunity of 12 2. naltrexone month; any technique 3. + administration, absence of allergic reactions, cellular immunity for life, improvement of the detoxicative function of the body 3. 1.gamma-globulin 1: 5.0 Antibody synthesis, human stability of the body humoral immunity of 12 2. naltrexone month; any technique 3. + administration, absence of allergic reactions, cellular immunity for life, improvement of the detoxicative function of the body: sorption of metabolites and xenobiotics 4. 1. ovalbumin 1: 3.0 - "- 2. amphetamine 3. + 5. 1. ovalbumin 1: 3.0 - "- 2. methadone 3. + R: \ Patents \ 23000 \ 23050.doc - 15 September 2004 - 8/16 6. 1.toxin 1: 3, 0 diphtheria 2. garmine 3. + 7. 1.gamma-globulin 1: 3.0 - "- human 2. phenobarbital 3. + 8. 1.gamma-globulin 1: 3.0 -" - human 2. carphentanyl 3 + Serum proto-1.albumin - Antibody synthesis, typical beef stability of humoral immunity of 4-6 2. heroin month, intravenous injection, 3. + allergic reactions from eruption to anaphylactic shock Observations : 1. Apart from the vehicles shown in the table, it is possible to use microbial toxins (tetanotoxin, streptococcal toxin, botulinum toxin) or synthetic polypeptides (L- or D-amino acids to pol spontaneous ymerization).

  2. Apart from the haptens mentioned in the table, it is possible to use compounds of low molecular weight chosen from the following groups: aromatic propanamines (pervitin, ecstasy), or isochinolines (morphine, cocaine, nicotine, etharphin, dihydroethaphfin) or diphenylmethanes, or indolamines (LSD-25, psylocin, ibogaine, lysergic acid diethylamide), or barbituric acid derivatives (barbiturates or their possible analogues), or substituted piperidine derivatives (phentanyl, lophentanyl, 3-methylphentanyl, suphentanyl, alphentanyl, phencyclidine).

  3. The pharmacological effects of the synthetic immunogens comprising the various vehicles and haptens specified in (1) and (2) are characterized by the synthesis of specific antibodies for each hapten.

  Immunization of the rabbits with the preparation according to the presented scheme contributed to the appearance in the blood serum of high titers of antibodies against the immune complex consisting of 3 haemisuccinylnaltrexone / gamma globulin R: 1Brevets123000123050.doc September 2004 - 9/16 human / polyoxudonium (1: 2560). In the haemagglutination inhibition reaction, the antibodies formed were found to bind heroin and 3-hemisuccinylnaltrexone: the antibody titer to the immune complex decreased to 1 : 320 when the concentration of heroin and 3-hemisuccinylnaltrexone was used equal to 0.001 mole, which indicates the presence of antibodies to these compounds.

  Thus, the synthesized immune complex specifically binds heroin not only in vitro but also in vivo in the body.

  Antibodies obtained from the blood serum of rabbits were examined for the specificity of opiate attachment of the phenanthrene series. Examination of the specificity of the antibodies, i.e., their ability to bind to morphine, heroin, or other opioid receptor ligands, was performed by means of inhibition of immune fermentation. As inhibitors, morphine, heroin, codeine, N-allylmorphine and methadone were used. The results obtained testify to the fact that the active immunization of the animals by the immune assembly 3-hemisuccinylnaltrexone / gamma-globulin human / polyoxydonium makes it possible to induce antibodies specifically binding morphine, heroin, codeine, N-allylmorphine but hardly reacting with methadone.

  Specificity of antibodies against heroin in rabbit blood serum.

  Narcotic Specificity of antibodies,% Morphine 95.0 Heroin 100.0 Codeine 65.0 N-allylmorphine 92.0 Methadone 0.08 These data demonstrate that opiate attachment is a function of the presence of the groups and the radicals determined in their molecules. Thus, in particular, a high specificity of antibodies to heroin is conditioned by the presence in the immune system of an ester linkage between naltrexone and succinic acid, and towards Nallylmorphine by the presence of the cyclopropylmethyl radical bound to the nitrogen atom in the chemical structure of naltrexone. Thus, the antibodies formed have high specificity only towards opiates of the phenanthrene series (heroin and its structural analogues).

  In view of the results of tests, the inventors have found that 3-hemisuccinylnaltrexone is suitable for the synthesis of the immunogen. SUMMARY OF THE INVENTION Its chemical structure has branched radicals to ensure the immune response and for the synthesis of high affinity antibodies to opiates of the phenanthrene series.

Clinical tests.

  Similar specificity tests were performed with antibodies extracted from the blood serum of volunteers with drug addiction and immunized with the synthesized immunogen.

  The immunogen was administered to 22 opioid-positive volunteers aged 21 to 36 years. The age of poisoning by narcotics is 2 to 13 years. The immunogen was administered by subcutaneous injection into the upper third of the right and left arms alternately once a week, from 8 to 10 injections during a course of treatment.

  For the 22 sera taken from narcotics, the antibodies against opiates were extracted from all the samples. According to the FIA data, the sera contain the IgG and IgM antibodies against morphine, heroin and codeine reacting identically with each of the metabolites.

  Specificity of antibodies against heroin in human immune serum.

  Narcotic Specificity of antibodies,% IgG IgM Morphine 100, 0 100.0 Heroin 100.0 100.0 Codeine 100.0 25.0 N-allylmorphine 100.0 17.0 Methadone 0.05 - As with antibodies against opiates extracted from rabbits, the antibodies extracted from the blood serum of drug addicts practically did not react with the non-phenanthrene narcotic substances. The antibodies extracted from the blood serum of drug addicts have a wider range of specificity compared to antibodies extracted from rabbit blood sera.

  Additional information is presented below to confirm the data in the table "Compositions of synthetic immunogens and their pharmacological effects" (see the description of the invention, the table on page 12).

  Examples of particular applications of synthetic immunogens shown in the table.

  Example 9 (corresponds to composition 1 of the table) The patient is 25 years old, the seniority of drug addict is 7 years, opiate addiction.

  Initial laboratory data: 1 ml of blood plasma 2570 pmole of heroin-binding antibody determined by radioimmunoassay (RIA).

  The patient was immunized with the synthetic immunogen: gamma globulin human naltrexone (isochinolines group hapten) polyoxydonium.

  Laboratory data (9 weeks after start of immunogen treatment): RIA 1 ml 77550 pmole synthesis of heroin-binding antibodies. After 8 weeks, T-lymphocytes are matured and stimulation of the formation of antibodies contributing to the maturation of B-lymphocytes, the appearance of cellular immunity for life, the absence of allergic reactions.

  Data from the control test (12 months after the start of immunogen treatment): RIA 1 ml 50120 pmol.

Example 10

  The age of the patient: 32 years old. He has been suffering from opium addiction for 9 years.

  Initial laboratory data: 1 ml 1520 pmole; erythrocyte sorption capacity (ESC) detoxification function of the body 64.1 5.7% (method for the rapid determination of the sorption of vital dyes (methylene blue), by the erythrocytes, see the review "Work in Laboratory ", 1988, No. 9, article of AATogayayayev, AV Kuryukzina et al" Method of diagnosis of endogenous intoxication ").

  The patient was immunized with the synthetic immunogen: human gamma globulin naltrexone polyoxydonium.

  Laboratory data: RIA 1 ml 78610 pmole, CSE 44.1 5.8%, improving the detoxicative function of the body. The other characteristics are identical to those of Example 1.

  Data from the control test: RIA 1 ml 51100 pmol.

Example 11

  The patient is 21 years old and has opioids for 4 years.

  Initial laboratory data: RIA 1 ml 1680 pmole; CSE: 63.8 5, 6%; determination of opiates (immunochromatographic tests of urine): positive.

  The patient was immunized with the synthetic immunogen: gamma-globulin 35 human naltrexone polyoxydonium.

  Laboratory data: RIA 1 ml 78900 pmole; CSE: 42.4 5.8%; opiate determination: negative, that is to say, the improvement of sorption of metabolytes and xenobiotics is observed. The other characteristics are identical to those of Examples 1 and 2.

  Data from the control test: RIA 1 ml 52600 pmole.

  Observations for Examples 1 to 3: The data presented were recorded in the patient files.

Example 12.

  Six unscented mature rats of both sexes were immunized with the synthetic immunogen: ovalbumin amphetamine (aromatic propanamine hapten) polyoxydonium at 50 mg / kg.

  They injected a lethal dose of a psychoactive substance, pervitine.

  Laboratory data: RIA 1 ml 76500 pmole. The other characteristics are identical to those of Examples 1 to 3.

  Data from the control test: RIA 1 ml 51200 pmol.

Example 13

  Six unscented mature rats of both sexes were immunized with the synthetic immunogen: ovalbumin-methadone (diphenylmethane group hapten) polyoxydonium, 50 mg / kg.

  They injected a lethal dose of a psychoactive substance, heroin.

  Laboratory data: RIA 1 ml 75300 pmoles. The other characteristics are identical to those of Examples 1 to 3.

  Data from the control test: RIA 1 ml 52600 pmoles.

Example 14.

  Six unscented mature rats of both sexes were immunized with synthetic immunogen: diphtheria toxin-garmine (indolamine gaptene group) polyoxydonium at 50 mg / kg.

  They injected a lethal dose of a psychoactive substance, pervitine.

  Laboratory data: RIA 1 ml 77900 pmole. The other characteristics are identical to those of Examples 1 to 3.

  Data from the control test: RIA 1 ml 54700 pmol.

Example 15

  Six unscented mature rats of both sexes were immunized with synthetic immunogen: phenobarbital human gamma globulin (barbituric acid group hapten) polyoxydonium at 50 mg / kg.

  They injected a lethal dose of a sleeping substance, barbiturate.

  Laboratory data: RIA 1 ml 72300 pmole. The other characteristics are identical to those of Examples 1 to 3.

  Data from the control test: RIA 1 ml 51100 pmol.

  R: \ Patents123000123050.doc - September 15, 2004 - 13/16

Example 16

  Six unscented mature rats of both sexes were immunized with the synthetic immunogen: diphtheria human gamma globulin carphentanyl (substituted piperidine derivative hapten) polyoxydonium at 50 mg / kg.

  They injected a lethal dose of a narcotic substance, morphine.

  Laboratory data: RIA 1 ml 75400 pmole. The other characteristics are identical to those of Examples 1 to 3.

  Data from the control test: RIA 1 ml 57200 pmole.

Prototype.

  Six unscented mature rats of both sexes were immunized with the immunogen: bovine serum diphtheria serum albumin at 50 mg / kg.

  They were administered a lethal dose of a narcotic substance, morphine, only by intravenous injection.

  Laboratory data: RIA 1 ml 70100 pmole. A high allergic potential related to the formation of IgE class IgE immunoglobulins. The animals died three months after anaphylactic shock during a second immunization.

  R: \ Patents123000 \ 23050.doc - September 15, 2004 - 14/16

Claims (1)

CLAIM   1. Synthetic immunogen for the treatment and prevention of abuse of narcotic and psychoactive products represented by a conjugate consisting of a vehicle which is a natural or synthetic protein and a hapten which is a narcotic or psychotropic compound, characterized in that the conjugate is modified by an immunocompetent polyelectrolyte, polyoxydonium, the weight ratio in% being equal to: conjugate / polyoxydonium = 1: 1.5 to 5.0, the conjugate containing as vehicle ovalbumin, or gamma-globulin human, or microbial toxins and containing as low molecular weight compounds selected from the following groups: aromatic propanamines, or isochinolines, or diphenylmethanes, or indolamines, or derivatives of barbituric acid, or derivatives of substituted piperidines.   A: 1Brevets12 3 0 0012 3 050.doc - 15 September 2004 - 15/16