CN100536848C - Stable nalmefene hydrochloride injection and preparation method thereof - Google Patents

Abstract

A high-stability nalmefene hydrochloride injection is prepared from nalmefene hydrochloride (0.005-0.2 W/v %) and the medicinal carrier chosen from sodium chloride, glucose, beta-cyclodextrin, dextran, pectose, sorbitol, etc. Its preparing process is also disclosed.

Description

Stable nalmefene hydrochloride injection and preparation method thereof

Technical field:

The invention relates to a nalmefene injection and a preparation method thereof, belonging to the technical field of medicines.

technical background:

Nalmefene hydrochloride was designed and developed on the basis of transforming and optimizing the structure of the parent compound during the in-depth study of naloxone and naltrexone in the 1970s to address the shortcomings of existing opioid receptor antagonists. new compound. Nalmefene hydrochloride completely retains the characteristics of naloxone and naltrexone as a pure antagonist, has no agonistic effect on opioid receptors, and does not produce dependence. Compared with naloxone and naltrexone, it has the advantages of long action time, high oral bioavailability, small dosage, and wide safety range. Therefore, nalmefene hydrochloride has the characteristics of high efficiency and low toxicity, and has become a new generation of opioid recipients. It is the species with the most potential for development among body antagonists.

As a new generation opioid receptor antagonist, nalmefene hydrochloride was officially launched in the United States in April 1995. The FDA-approved indications for nalmefene hydrochloride can be used to fully or partially reverse the effects of opioids, including respiratory depression caused by natural and synthetic opioids. And can be used for confirmed or suspected opioid overdose.

In March 2001, the U.S. market for naloxone injection was out of stock due to the reduction in production. FDA specially approved Canada’s Sabex company for emergency supply to relieve the urgent need. naloxone. It can be seen that nalmefene is an ideal substitute for naloxone.

Nalmefene, like naloxone, is a pure opioid receptor antagonist. In the absence of opioid substances, it does not produce any other side effects, and is a relatively safe variety among chemical drugs. Compared with naloxone, the route of administration of nalmefene is more extensive and more convenient. The oral solid formulation of nalmefene is more suitable for non-emergency treatment. Finland's ContrAlPharma (merged with BioTie) started Phase III clinical research of Nalmefene Tablets in Finland and the UK in January 2002. The new indications developed are the treatment of chronic alcoholism and alcohol dependence. It is estimated that in 2003 Preliminary results will be available in the second quarter of this year. Early clinical trials have proved that nalmefene has a better alcohol withdrawal effect than naltrexone, especially suitable for alcoholics with a family history, and there is no hepatotoxic side effect of naltrexone in large doses. The treatment of nalmefene for impulse control disorders (Impulse control disorders) has entered phase II clinical trials in the United States, and the subjects are pathological gambling patients. Preliminary results are expected in the first half of 2003. The indications of nalmefene in small-scale trials are also the rapid withdrawal of opioid-dependent patients.

的盐酸纳美芬注射液处方资料，处方中除活性药物外只加了pH调节剂盐酸及等渗调节剂氯化钠，生产采用充氮工艺。In the process of 0.1mol/L sodium hydroxide solution of nalmefene hydrochloride and hydrogen peroxide damage test, influencing factor test and stability research, it was found that more than half of the degradation products of nalmefene hydrochloride injection were mainly with a relative retention time of about According to the chromatographic peak of 2 times of the drug, according to the research results of liquid mass spectrometry, it can be known that the degradation substance is the dimer of nalmefene, that is, dinalmefene. Trade name in FDA

According to the prescription data of Nalmefene Hydrochloride Injection, in addition to the active drug, only the pH regulator hydrochloric acid and the isotonic regulator sodium chloride are added in the prescription, and the production adopts nitrogen filling process.

The Chinese patent with the application number 200410022782.5 titled "Nalmefene Powder Injection Preparation and Its Preparation Method" describes a nalmefene powder injection, which uses nalmefene as the raw material and mannitol as the filling agent, freeze-dried. Although freeze-dried powder injection can improve the stability of the preparation, the freeze-drying process of more than 30 hours has greatly increased the production cost, and nalmefene is mainly used for first aid, and the powder injection needs to be dissolved in water for injection during clinical use. Use, make clinical use more loaded down with trivial details.

The present invention uses appropriate additives, and the quality of the nalmefene hydrochloride injection produced is stable, and after 10 days of strong light irradiation and high temperature placement and 6 months of accelerated testing, the injection appearance properties, pH value, content and various indicators of related substances are all stable. There is no obvious change, and the production process is easy to control.

Invention content:

The object of the present invention is to provide a nalmefene injection with remarkable curative effect and stable quality and a preparation method thereof. The nalmefene injection provided by the present invention can improve the stability of the drug and make it safer and more effective. The problems existing in the prior art can be solved.

The nalmefene hydrochloride injection of the present invention basically consists of a therapeutically effective dose of nalmefene hydrochloride and an appropriate amount of pharmaceutical carrier.

Nalmefene hydrochloride injection according to the present invention, wherein the concentration of nalmefene hydrochloride can be 0.001% to 2.0%, preferably 0.005% to 1.0%, more preferably 0.01% to 0.1% in weight/volume .

The pharmaceutical carrier contained in the nalmefene hydrochloride injection of the present invention is not particularly limited, as long as it is a carrier that can be used in the preparation of injections, for example, the osmotic pressure regulator can be selected from sodium chloride, glucose, β- One or more of cyclodextrin, dextran, fructose, sorbitol, etc., preferably sodium chloride and/or glucose. The pH regulator can be selected from hydrochloric acid, acetic acid, phosphoric acid, malic acid, citric acid, maleic acid, succinic acid, etc., preferably hydrochloric acid. The antioxidant can be selected from sulfurous acid, sodium bisulfite, sodium sulfite, sodium pyrosulfite, vitamin C, cysteine, etc., preferably sodium sulfite. The stabilizer (chelating agent) is preferably disodium edetate. The content of the pharmaceutical carrier in the formulation is also not particularly limited, and the pharmaceutical carrier can be used arbitrarily within the range that does not impair the effect of the present invention.

Because the injection is usually divided into easy-to-break ampoules and administered in unit dose form, so the nalmefene hydrochloride injection of the present invention, every unit dose, that is, every injection contains nalmefene hydrochloride can be 0.1mg～4mg; pharmaceutical carrier such as sodium chloride can be 4.5mg～90mg, or glucose can be 25mg～400mg; sodium bisulfite can be 0.005mg～0.5mg; edetate disodium can be 0.001mg ~0.5mg; appropriate amount of hydrochloric acid or acetic acid, adjust the pH value of the solution before dispensing this product to 3.5~5.5.

The nalmefene hydrochloride injection of the present invention contains sodium chloride in the preparation of each unit dose, preferably 7mg～60mg, more preferably, contains 9mg～36mg of sodium chloride in the preparation of each unit dose; The sodium bisulfite contained in the preparation may preferably be 0.01 mg to 0.1 mg, more preferably 0.02 mg to 0.05 mg; the disodium ethylenediamine tetraacetate contained in the preparation per unit dose is preferably 0.002 mg to 0.25 mg, Optimally, it is 0.004 mg to 0.1 mg.

The nalmefene hydrochloride injection of the present invention has a pH value of 3.5-5.5, preferably 4.0-5.0.

The sterilization conditions of the nalmefene hydrochloride injection in the present invention can be sterilized at 105°C for 45 minutes, or autoclaved at 115°C for 20 minutes, or autoclaved at 121°C for 15 minutes. Preferably it is autoclaved at 115°C for 20 minutes.

The technical scheme of the present invention is achieved in that it is made by adding nalmefene hydrochloride with water for injection and an appropriate amount of antioxidant and stabilizer. Specifically, calculated by weight ratio: 0.1-4g nalmefene, 0.0005-0.05% sodium bisulfite, sodium sulfite or sulfur dioxide (sulfurous acid), 0.0001-0.05% edetate disodium, 0.9% Sodium chloride, prepared by adding sterile water for injection to 2000ml. The preparation is an injection; the preparation method of the nalmefene hydrochloride injection: a nitrogen filling process is adopted in the whole preparation process. Take nalmefene hydrochloride and add 60% of the total amount of water for injection, stir until completely dissolved; add 0.0005-0.05% sodium bisulfite, sodium sulfite or sulfur dioxide and 0.0001-0.05% disodium edetate, stir to dissolve, add 1.0mol/L hydrochloric acid solution to adjust the pH to 3.7-4.1; add 0.05% (w/v) activated carbon activated at 115-120°C for 2 hours, keep stirring at 80°C for 30 minutes, coarse filter, and decarbonize; The composite filter membrane composed of 0.45μm and 0.22μm is filtered until clear, and it is packaged in a clean environment of 100 grades. Autoclave at 115°C for 20 minutes.

The clinical administration method of nalmefene hydrochloride injection of the present invention is: intravenous injection or intramuscular injection. When it is used to partially reverse the effect of opioids after surgery, the total dose should not exceed 1.0 μg/kg body weight, and the dose used for opioid overdose treatment should not exceed 20 μg/kg body weight. Exceeding this dose will not increase the therapeutic effect.

The nalmefene hydrochloride injection of the invention has reasonable prescription, simple process and good stability. After 10 days of investigation of the influencing factors under the conditions of high temperature, high humidity and strong light irradiation and 6 months of accelerated testing at 40°C, the appearance, pH, content of active ingredients and related substances of the samples did not change significantly.

Detailed ways:

The present invention is further illustrated by the following examples, but these examples do not limit the present invention in any way.

Example 1

prescription:

Nalmefene Hydrochloride 0.1g

Sodium chloride 9g

Proper amount of hydrochloric acid to pH3.6

Process: 1) Take 1000ml of water for injection and put it in the liquid mixing tank, add the full amount of sodium chloride prescribed, and stir until dissolved; 2) Add the prescribed amount of nalmefene hydrochloride, stir until dissolved; then use a 0.22 μm microporous filter membrane Fine filtration until clarity; 3) filling in a glass ampoule (filling 1ml of liquid in a glass ampoule with a volume of 2ml); 4) melting and sealing. 5) Sterilize at 115°C for 20 minutes. 5) Capping, labeling, packaging, and the finished product after passing the inspection. PH value after sterilization: Take 10 sticks of this product, combine them, and measure according to the law (Appendix VI H of Part II of Chinese Pharmacopoeia Edition in 2000), and the pH value is 3.9.

Example 2

prescription:

Nalmefene Hydrochloride 1g

Sodium chloride 9g

Proper amount of hydrochloric acid to pH3.8

Technology: with embodiment 1. 2ml glass ampoules are used for dispensing, and the dispensing volume is 2ml.

PH value: measuring method is the same as embodiment 1, gets the solution in 5 ampoules to merge, and the result of measuring pH value is 3.9.

Example 3

prescription:

Nalmefene Hydrochloride 1g

Sodium chloride 9g

Proper amount of hydrochloric acid to pH3.8

Technology: with embodiment 1. 5ml glass ampoules are used for dispensing, and the dispensing volume is 4ml.

PH value: measuring method is the same as embodiment 1, gets the solution in 3 ampoules to merge, and the result of measuring pH value is 3.9.

Example 4

prescription:

Nalmefene Hydrochloride 0.1g

Sodium chloride 9g

Sodium bisulfite 0.02g

Proper amount of hydrochloric acid to pH3.8

Process: 1) Take 1000ml of water for injection and place it in a liquid dispensing tank, add the full amount of sodium chloride and sodium bisulfite in the prescription, and stir until dissolved; other steps are the same as in Example 1.

PH value: measuring method is the same as embodiment 1, and pH value is 3.9.

Example 5

prescription:

Nalmefene Hydrochloride 0.1g

Sodium chloride 9g

Sodium bisulfite 0.02g

Disodium edetate 0.005g

Appropriate amount of hydrochloric acid to pH3.8

Process: 1) Take 1000ml of water for injection and put it in a liquid mixing tank, add the full amount of sodium chloride, sodium bisulfite and disodium ethylenediaminetetraacetate in the prescription, and stir until dissolved; other steps are the same as in Example 1.

pH value: measuring method is the same as embodiment 1, and pH value is 3.9.

The injection prepared in Example 5 was subjected to an influencing factor test for 10 days and an accelerated test at 40°C ± 2°C for 6 months. The results of the influencing factor test are shown in Table 1, and the accelerated test results are shown in Table 2:

Table 1 Determination results of influencing factors of nalmefene hydrochloride injection after 5 and 10 days

There is no change in appearance and properties after being placed under strong light and high temperature conditions, and it remains a colorless and clear liquid. There was no change in pH after exposure to light. The content and the amount of related substances are almost unchanged. Confirm that the prescription of embodiment 5 is all more stable to strong light and high temperature.

Table 2 Accelerated test results of nalmefene hydrochloride injection at 40°C±2°C

time/month Appearance, traits Clarity pH value content/% relative substance/% 0 colorless clear liquid qualified 3.9 99.1 0.32 1 colorless clear liquid qualified 3.9 98.9 0.34 2 colorless clear liquid qualified 3.9 98.9 0.28 3 colorless clear liquid qualified 3.9 98.6 0.40 6 colorless clear liquid qualified 3.9 98.3 0.46

The results of the accelerated test of the sample at 40°C±2°C for 6 months showed that there was no significant change in the content of related substances, all less than 2.0%, the content and pH value of nalmefene hydrochloride were stable, and the sterility, endotoxin and clarity inspection The results also meet the requirements. Taken together, the key inspection items all meet the quality standards.

Claims (14)

1. a Nalmefene hydrochloride injection is characterized in that containing nalmefene hydrochloride and pharmaceutical carrier, and wherein pharmaceutical carrier comprises antioxidant sodium sulfite and chelating agen Calcium Disodium Versenate.

2. the injection of claim 1, wherein pharmaceutical carrier also comprises one or more in osmotic pressure regulator and the pH regulator agent.

3. the injection of claim 1, the concentration of nalmefene hydrochloride counts 0.001%～2.0% with concentration in the preparation.

4. the injection of claim 2, wherein osmotic pressure regulator is selected from one or more in sodium chloride, glucose, beta-schardinger dextrin-, dextran, fructose, the sorbitol.

5. the injection of claim 5, wherein osmotic pressure regulator is a sodium chloride.

6. the injection of claim 2, wherein the pH regulator agent is selected from hydrochloric acid, acetic acid, phosphoric acid, malic acid, citric acid, maleic acid or succinic acid.

7. the injection of claim 6, wherein the pH regulator agent is a hydrochloric acid.

8. the injection of claim 1, wherein the consumption of the Calcium Disodium Versenate in the preparation of per unit dosage is in the scope of 0.002mg～0.25mg.

9. the injection of claim 8, wherein the consumption of the Calcium Disodium Versenate in the preparation of per unit dosage is in the scope of 0.004mg～0.1mg.

10. the injection of claim 5, wherein the amount of sodium chloride in the per unit dosage is in the scope of 4.5mg～90mg.

11. according to the injection of claim 7, wherein the consumption of hydrochloric acid in right amount the solution pH value to the injection packing in 3.5～5.5 scope.

12. according to the injection of claim 1, wherein the consumption of the antioxidant sodium sulfite in the preparation of per unit dosage is in the scope of 0.005mg～0.5mg.

13. the injection of claim 12, wherein the sodium sulfite consumption in the preparation of per unit dosage is in the scope of 0.02mg～0.05mg.

14. according to the injection of claim 1, its preparation process is used and is filled nitrogen technology; Sterilization process is selected from 105 ℃ ± 2 ℃ 45min, 115 ℃ ± 2 ℃ 20min, or 120 ℃ ± 2 ℃ 15min.