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Hapten-carrier conjugates for use in drug-abuse therapy and methods for preparation of same

A hapten and conjugate technology, which can be used in drug combinations, carrier-binding antigen/hapten components, antibodies, etc., to solve the problems of complex neurochemical events, insufficient to overcome addiction, and limited efficacy.

Inactive Publication Date: 2006-08-09
XENOVA RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Current therapies for cocaine addiction have at least four major limitations that lead to high relapse rates
First and foremost, the resulting neurochemical events in cocaine abuse and addiction are complex (Carroll et al., (1994), supra)
As a result, neuropharmacological approaches acting alone, such as inhibition of dopamine uptake, are not sufficient to overcome the phenomenon of addiction
Second, drugs currently used to treat cocaine addiction generally have significant side effects that limit their efficacy
Third, compliance with drug therapy is problematic in these patient populations
Fourth, due to the complexity of the chemistry issues involved in pharmacological treatments, many of them are not compatible with other therapies currently in use or with clinical trials
However, the reference neither teaches nor suggests the use of nicotine carrier conjugates as a vaccine against nicotine abuse
[0021] Effective treatments for drug addiction, especially cocaine, heroin, and nicotine, are not yet available

Method used

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  • Hapten-carrier conjugates for use in drug-abuse therapy and methods for preparation of same
  • Hapten-carrier conjugates for use in drug-abuse therapy and methods for preparation of same
  • Hapten-carrier conjugates for use in drug-abuse therapy and methods for preparation of same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 3

[0144] Example 3, Method A).

[0145] Conjugate

Carrier protein

Hapten / Monomer

Conjugation method

PS-54

PS-54

PS-55

PS-55

PS-56

PS-56

PS-57

PS-57

PS-58

BSA

HEL

BSA

HEL

BSA

HEL

BSA

HEL

BSA

19.5

3.2

33.2

1.09

27

2.2

81

8

66.8

Example 1, Method B

Example 1, Method B

Example 3, Method A

Example 3, Method A

Example 3, Method A

Example 3, Method A

Example 3, Method A

Example 3, Method A

Example 3, Method A

PS-58

HEL

7.4

Example 3, Method A

[0146] This is a non-limiting list of conjugates. Other conjugates are made with more than one hapten linked to a carrier containing T cell epitopes. Preferably, 1-100 haptens are linked to a carrier containing T cell epitopes. More preferably, 1-70 haptens are linked to a carrier containing T cell epitopes.

[0147] The examples disclose the synthesis methods of the compounds PS-54, P...

Embodiment 1

[0190] Preparation of nicotine conjugate

[0191] Method A To a solution of nornicotine (50 mmol) in dichloromethane was added triethylamine (75 mmol) followed by succinic anhydride (100 mmol). The solution was heated at reflux for 18 hours. The reaction mixture was washed with 10% aqueous hydrochloric acid, saturated sodium bicarbonate solution, brine and water in this order. Dry (MgSO 4 After removing the solvent under reduced pressure, the residue is purified by silica gel flash chromatography to obtain the expected product.

[0192] Method B The succinylated nornicotine was then used to synthesize the nicotine conjugate PS-54 (Figure 7). To the succinylated nornicotine (5 μm) DMF solution (0.1 ml), diisopropylethylamine (10 μm) and HATU (5.5 μm) were sequentially added. After 10 minutes, the light yellow solution was added dropwise to a solution (0.9 ml) of HEL or BSA (500 μg) in a 0.1 M sodium borate buffer at pH 8.8, and the mixture was stirred at room temperature for 18 hou...

Embodiment 2

[0210] Method A (S)-N’-butyric acid adduct of nicotine

[0211] Under argon, at ice water temperature, ethyl 4-bromobutyrate (0.0341 mol) was added dropwise to (S)-nicotine (0.031 mol) in anhydrous methanol solution (50 ml) within 10 minutes. The resulting orange solution was returned to room temperature and stirred for 18 hours. The solvent was removed under reduced pressure, and the remaining brown residue was precipitated with hexane to obtain an analytically pure sample of the expected ester.

[0212] The ester (36mg) was dissolved in methanol (3ml) and 1M sodium hydroxide solution (5ml) and stirred at room temperature for 18 hours. The solvent was removed under reduced pressure, and the residue was dissolved in 10% hydrochloric acid and extracted with ethyl acetate. Dry (MgSO 4 After ), the solvent was removed under reduced pressure to obtain the expected compound.

[0213] Method B (S)-N'-valeric acid adduct of nicotine

[0214] Under argon, at ice water temperature, 1-bromo...

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Abstract

The invention discloses hapten-carrier conjugates comprising at least a hapten which is a drug of abuse and at least a carrier comprising a T cell epitope. Also disclosed is a therapeutic composition containing the conjugate which is particularly useful in the treatment of a drug addiction and a method for producing the conjugate.

Description

[0001] The present invention is a divisional application of a Chinese patent application filed on September 30, 1997 with the application number 97199363.7 and the title of the invention "Hapten carrier conjugate for drug abuse treatment and its preparation method". Technical field [0002] The present invention relates to the treatment of drug abuse. More specifically, the present invention relates to a method for treating drug abuse using a drug / hapten carrier conjugate that elicits an antibody response and / or an antibody using the drug / hapten carrier conjugate. Background technique [0003] The widespread use and abuse of drugs all over the world, especially in the United States, has reached a prevalent level. The surplus and abuse of legal and illegal drugs have become a serious focus issue in public policy, and its obvious medical and social consequences have affected all levels of society. Some users live in high-risk groups associated with poverty and illegal behavior. Othe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K47/34A61K39/385A61P25/30A61K39/395A61P37/04A61P39/02
CPCA61K47/48261A61K39/0013A61K47/48276A61K47/4833A61K2039/6037A61K47/6415A61K47/6425A61K47/646A61P25/30A61P25/34A61P37/04A61P39/02Y02A50/30
Inventor P·A·斯温J·L·格林斯泰恩M·A·艾克丝雷B·S.·福克斯S·P·帕沃斯M·L·格夫特
Owner XENOVA RES
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