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Enzymatic preparation of naloxone and pharmaceutical composition thereof

A technology of enzymatic preparation and naloxone, which is applied in the field of medicine, can solve the problems of reagents that are harmful to the human body, severe conditions, and not jumping out.

Inactive Publication Date: 2014-04-02
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] The expression of embodiment 1 demethylase gene

[0042] A new enzyme gene was designed according to our platform technology, and Sangon Bioengineering (Shanghai) Co., Ltd. was commissioned to synthesize a demethylase gene optimized for codon expression. Its nucleotide sequence is shown in SEQ ID No: 1 in the sequence table , the amino acid sequence encoded by the gene is shown in SEQ ID No:2. Then, construct the yeast that secretes and expresses the enzyme according to the "Molecular Cloning Experiment Guide", that is, use the synthetic gene as a template, use primer 1 (SEQ ID No: 3, introduces the EcoR I endonuclease site) and primer 2 (SEQ ID No:4, the Not I endonuclease site was introduced) After PCR amplification, EcoR I and Not I were double-digested, and the pPIC3.5 plasmid (available from Invitrogen Corporation) digested with these two endonucleases ) were ligated with T4 DNA ligase and transformed into Escherichia coli DH5α. Pick out the positive clones and e...

Embodiment 2

[0044] The production of embodiment 2 naloxone

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

[0046] Basically according to the existing technology of hydrogen oxidation synthesis, the specific improvement is as follows: Weigh 50g of thebaine and add it to 100mL of anhydrous formic acid in an ice bath, stir and dissolve, and add 30% (V / V) peroxide under ice bath conditions 22 mL of hydrogen solution, then stirred for 1 hour, then warmed up to room temperature 37°C and continued to stir for 2.5 hours. Then, add 60mL of acetone and 60mL of water to the reaction solution, then add dropwise 20% (W / W) sodium hydroxide solution until the pH reaches 8.2, and stand still for 0.5 hours after the dropwise addition, during which precipitation will precipitate, filter and dry to obtain a white powder (14-hydroxycodeinone) 44.3g. The above white powder was dissolved in 200mL of 10% (W / W) acetic acid solution, 4g of Pd / C catalyst was added, and hydrogen gas was introduc...

Embodiment 3

[0051] Drug efficacy and safety test of embodiment 3 naloxone composition

[0052] Experimental drug: the naloxone composition prepared in Example 2 was directly administered after being neutralized with hydrochloric acid 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, half male and half female) were randomly divided into the following 6 groups, with 10 animals in each group: 1) blank control group (administered with distilled water); 2) model group (administered with distilled water) 50% ethanol solution 1mL); 3) high-dose control group (injection 0.5 mg / kg naloxone + 1 mL 50% ethanol solution for intragastric administration); 4) low-dose control group (injection 0.1 mg / kg·day as naloxone + 1 mL of 50% ethanol solution for intragastric administration); 5) high-dose experimental drug group (administered with naloxone and The total a...

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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 invention belongs to the technical field of medicine, in particular, the invention relates to a naloxone composition prepared by an enzymatic method, which does not affect its drug-forming performance although it contains impurities. Background technique [0002] Naloxone, chemically known as 17-allyl-4,5a-epoxy-3,14-dihydroxymorphinan-6-one, usually available as the hydrochloride salt, is an opioid receptor antagonist , mainly used to reverse narcotic analgesia and respiratory depression caused by morphine-like substances (drugs), and can be used to rescue poisoning caused by ethanol 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 patents (applications) 03807796.5, 200680005969.1, 200510080479.5, 201180023192.2, 200880006847.3, etc. In addition, Chinese patents (applications) 200710039118.5 and 201010211706.4 i...

Claims

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Application Information

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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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