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Enzymatic preparation of naloxone and pharmaceutical composition thereof

A technology of enzymatic preparation and composition, applied in the field of medicine, can solve the problems of severe conditions, great harm to the human body of reagents, and no jumping out

Inactive Publication Date: 2014-09-17
SUMAAZ CHENGDU BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, Chinese patents (applications) 200710039118.5 and 201010211706.4 involve the preparation technology of naloxone and its intermediates, but they still use chemical synthesis technology and have not jumped out of the framework of using hydrobromic acid or chloroformic acid to synthesize since the 1980s, that is, using Thebacine is oxidized and hydrogenated as a raw material to produce 14-hydroxy-7,8-dihydrocodone, and then undergoes a complicated process, under the condition of adding a protecting group, using reagents such as hydrobromic acid or chloroformic acid to demethylate , and then remove the protecting group, and finally generate naloxone through alkylation, where the reaction (especially the demethylation process) conditions are severe, and the reagents and their residues are very harmful to the human body

Method used

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  • Enzymatic preparation of naloxone and pharmaceutical composition thereof
  • Enzymatic preparation of naloxone and pharmaceutical composition thereof
  • Enzymatic preparation of naloxone and pharmaceutical composition thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1 Expression of Demethylase Gene

[0042] Based on our platform technology, we designed a new enzyme gene, and commissioned Shenggong Bioengineering (Shanghai) Co., Ltd. to synthesize a codon-expression optimized demethylase gene. Its nucleotide sequence is shown in SEQ ID No:1 in the sequence table. The amino acid sequence encoded by this gene is shown in SEQ ID No: 2. Then, a yeast secreting and expressing the enzyme was constructed according to the "Molecular Cloning Experiment Guide", that is, using the synthetic gene as a template, using primer 1 (SEQ ID No: 3, introducing EcoR I endonuclease site) and primer 2 (SEQ ID No: 4, the Not I endonuclease site was introduced) After PCR amplification, it was digested with EcoR I and Not I, and combined with the pPIC3.5 plasmid (available from Invitrogen) digested with these two endonucleases. ) Connect with T4DNA ligase and transform into E. coli DH5α. Pick out the positive clones and extract the plasmids. After the...

Embodiment 2

[0044] Example 2 Production of Naloxone

[0045] (1) Chemical synthesis of 14-hydroxy-7,8-dihydrocodeinone

[0046] Basically follow the prior art oxidative hydrogenation synthesis, the specific improvement is as follows: Weigh 50g thebaine into 100mL of anhydrous formic acid in an ice bath, stir to dissolve, add 30% (V / V) peroxide dropwise under ice bath conditions 22 mL of hydrogen solution, then stirred for 1 hour, then warmed to room temperature 37°C and continued stirring for 2.5 hours. Then, 60mL of acetone and 60mL of water were added to the reaction solution, and then 20% (W / W) sodium hydroxide solution was added dropwise until the pH reached 8.2. After the addition was completed, let it stand for 0.5 hours, during which precipitation would be precipitated. After filtration, it was dried to obtain a white powder. (14-hydroxycodeinone) 44.3g. The white powder was dissolved in 200 mL of 10% (W / W) acetic acid solution, 4 g of Pd / C catalyst was added, and hydrogen was introdu...

Embodiment 3

[0051] Example 3 Pharmacodynamic and safety test of naloxone composition

[0052] Experimental drug: The naloxone composition prepared in Example 2 was directly neutralized with hydrochloric acid and administered without high-cost purification.

[0053] Control drug: Naloxone Hydrochloride Injection (Yiqiao (Hunan) Pharmaceutical Co., Ltd.).

[0054] Experimental method: BALB / c mice (body weight 18-22g, male and female) were randomly divided into the following 6 groups, each with 10 animals: 1) blank control group (administered distilled water); 2) model group (gavage 50% ethanol solution 1mL); 3) high-dose control drug group (0.5 mg / kg as naloxone for injection + 1 mL of 50% ethanol solution for intragastric administration); 4) low-dose control drug group (for injection The drug is naloxone 0.1mg / kg·day + intragastric administration 50% ethanol solution 1mL); 5) Experimental drug high-dose group (injection administration is naloxone and 14-hydroxy-7,8-dihydro The total amount of c...

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Abstract

The invention provides a method for enzymatic preparation of naloxone. The enzyme is mild in reaction condition and free of harm to a human body. In addition, the invention also provides a naloxone composition prepared by the method and application thereof. The composition contains 14-hydroxy-7,8-dihydro codein ketone impurities, but the medicine performance can not be affected. Furthermore, the invention also provides an identification method of the naloxone composition and enzyme and the like for preparation.

Description

Technical field [0001] The present invention belongs to the technical field of medicine. Specifically, the present invention relates to a naloxone composition prepared by an enzymatic method. Although it contains impurities, it does not affect its pharmaceutical properties. Background technique [0002] Naloxone, the chemical name is 17-allyl-4,5a-epoxy-3,14-dihydroxymorphinan-6-one, usually in the form of hydrochloride, is an opioid receptor antagonist It is mainly used to reverse narcotic analgesia and respiratory depression caused by morphine substances (drugs), and can be used to rescue poisoning caused by alcohol and other substances. [0003] In recent years, research on naloxone has mainly focused on its pharmaceutical preparations and its combination with other drugs. For example, see Chinese Patent (application) 03807796.5, 200680005969.1, 200510080479.5, 201180023192.2, 200880006847.3, etc. In addition, Chinese patents (applications) 200710039118.5 and 201010211706.4 rel...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12P17/18A61K31/485A61P39/02A61P25/00A61P9/10A61P7/04A61P11/16A61P1/16A61P25/18C12N9/02C12N15/53C12N15/63
Inventor 刘军杨春玮
Owner SUMAAZ CHENGDU BIOTECHNOLOGY CO LTD
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