CN105769755A - Methyhaaltrexone bromide injection and preparation method thereof - Google Patents

Abstract

The invention provides a methyhaaltrexone bromide injection, which comprises a methyhaaltrexone bromide bulk drug and a proper amount of auxiliary materials. The invention also provides a preparation method of the methyhaaltrexone bromide injection. The injection is highly stable, and is basically stable under situations such as illumination, high temperature, and the like.

Description

A kind of methylnaltrexone bromide injection and preparation method thereof

technical field

The invention relates to methylnaltrexone bromide injection and a preparation method thereof, belonging to the technical field of chemical pharmaceutical preparations.

Background technique

Methylnaltrexone bromide (MNTX), English name: Methylnaltrexonebromid, is a selective mu opioid receptor antagonist. As a quaternary ammonium salt, it limits the ability of methylnaltrexone bromide to pass through the blood-brain barrier, allowing methylnaltrexone bromide to act as a peripherally acting opioid receptor antagonist in tissues such as the gastrointestinal tract. Therefore, Methylnaltrexone bromide reduces the opioid-constipating effects without affecting the analgesic effects of opioids on the central nervous system.

Methylnaltrexone bromide has the following characteristics: 1) It acts on peripheral μ receptors, but does not activate opioid receptors in the central nervous system, and may play a competitive antagonistic role; 2) It is safe, and a series of tests have not found its It has serious toxic and side effects, and the common adverse reactions are abdominal pain, diarrhea, flatulence and dizziness; 3) the effect is fast, and it can take effect within a few minutes; 4) the effect of treating constipation is better than that of stool laxatives and softeners; 5) the route of action Not only, it can directly bind to opioid receptors on the gastrointestinal tract, and can also bind to opioid receptors throughout the body through blood distribution. Therefore, bromomethylnaltrexone can not only treat gastrointestinal side effects of opioids, but also treat parenteral adverse reactions; 6) it does not pass through the blood-brain barrier and does not weaken the central analgesic effect of opiates.

The structural formula of methylnaltrexone bromide is as follows:

Original research manufacturer: Wyeth Pharmaceuticals Inc. Methylnaltrexone bromide injection has been approved by the FDA and EMEA as an opioid peripheral receptor antagonist, but it is not currently on the market in China.

Contents of the invention

The object of the present invention is to provide a kind of bromidenaltrexone injection, comprising bromidenaltrexone crude drug and appropriate amount of auxiliary materials. The invention also provides a preparation method of the methylnaltrexone bromide injection.

Technical scheme of the present invention is as follows:

The invention discloses a methylnaltrexone bromide injection, which is composed of a methylnaltrexone bromide raw material and auxiliary materials, wherein the auxiliary materials include disodium edetate and glycine, an antioxidant.

Preferably, the methylnaltrexone bromide injection of the present invention is composed of methylnaltrexone bromide crude drug and auxiliary materials, and the auxiliary materials include sodium chloride, disodium edetate, glycine and water for injection.

More preferably, the methylnaltrexone bromide injection of the present invention is mainly composed of the following raw materials and auxiliary materials: 12 parts by weight of methylnaltrexone bromide, 3-5 parts by weight of sodium chloride, 0.1-5 parts by weight of disodium edetate 0.3 parts by weight, 0.1-0.2 parts by weight of glycine, water for injection is added to 600 parts by volume, and the unit ratio of weight to volume is g:mL.

Further, the methylnaltrexone bromide injection of the present invention mainly consists of the following raw materials and auxiliary materials: 12 parts by weight of methylnaltrexone bromide, 3.5-4.5 parts by weight of sodium chloride, 0.2-0.25 parts by weight of disodium edetate Parts by weight, glycine 0.1-0.15 parts by weight, water for injection is added to 600 parts by volume, and the unit ratio of weight to volume is g:mL.

Further, the methylnaltrexone bromide injection of the present invention mainly consists of the following raw materials and auxiliary materials: 12 parts by weight of methylnaltrexone bromide, 3.9 parts by weight of sodium chloride, 0.22 parts by weight of disodium edetate, glycine 0.12 parts by weight, water for injection is added to 600 parts by volume, and the unit ratio of weight to volume is g:mL.

Preferably, methylnaltrexone bromide injection of the present invention, every 1000 injections are made up of the following raw materials and auxiliary materials: methylnaltrexone bromide 12g, sodium chloride 3.9g, disodium edetate 0.22g, glycine 0.12g, add water for injection to 600mL.

The preparation method of methylnaltrexone bromide injection of the present invention comprises the following steps:

(1) adding sodium chloride, disodium edetate, and glycine to water for injection, and stirring to dissolve;

(2) add methylnaltrexone bromide, stir and dissolve;

(3) Coarse filtration: Add 0.05% (W/V) activated carbon for needles, stir and adsorb at 50-70°C, and filter to remove activated carbon;

(4) Fine filtration: adjust the pH value of the filtrate after the coarse filtration to 3.0-5.0, and use a filter membrane for fine filtration;

(5) Filling, sealing and sterilizing the fine filter filtrate.

The above-mentioned step (3) uses a 0.45 μm filter membrane for coarse filtration; step (4) uses a 0.22 μm filter membrane for fine filtration.

Preferably, the above step (4) uses 1 mol/L hydrochloric acid or 1 mol/L sodium hydroxide solution to adjust the pH value to 4.0.

The advantages of the present invention are:

1. The present invention adopts the combination of the metal complexing agent edetate disodium and the antioxidant glycine to achieve an unexpected stable effect of the injection. The injection of the present invention is highly stable, even under the conditions of high temperature and light, the injection of the present invention is also basically stable; it is also basically stable under different pH conditions.

2. The cost of the injection of the present invention is low, and the auxiliary materials used are domestic commonly used pharmaceutical auxiliary materials.

3. The preparation process of the injection solution of the present invention is simple, and the product quality is high.

detailed description

The present invention is specifically described below from the aspects of prescription screening and pH value selection, and describes the technical solution of the present invention in detail through examples, but this is not a limitation of the present invention. Those skilled in the art can make Various modifications or improvements are within the scope of the present invention as long as they do not depart from the basic idea of the present invention.

1. Prescription screening:

1. Antioxidant selection and dosage screening:

As can be seen from the oxidative forced degradation test of methylnaltrexone bromide naltrexone bulk drug, bromethylnaltrexone solution is prone to oxidation and degradation in a strong oxidative environment, so a certain amount of antioxidant should be added to the formulation prescription.

Considering that there are not many excipients that can be used as antioxidants in injections, and generally have certain pharmacological activities or side effects, glycine is selected as an antioxidant, and its dosage is screened to evaluate the effect of different glycines on The protective ability of the preparation to optimize the optimal glycine dosage.

Method: add the main and auxiliary materials according to the prescription design table, operate according to the general process regulations of the preparation, add H2O2 as the source of oxygen atoms appropriately, carry out the accelerated test at a high temperature of 80 ℃, take samples at _{0, 2 ,} and 4 hours respectively, and measure according to the methyl bromide Naltrexone raw material drug has developed a related substance method to measure the change of impurities, which is used to screen the appropriate dosage of glycine. The results are shown below.

Glycine Dosage Screening Table

Screening test results of brommethylnaltrexone antioxidant dosage

Conclusion: Adding glycine to the prescription can improve the antioxidant capacity of the preparation; under the oxidative damage environment, the antioxidant capacity of the nitrogen filling process and the process without adding glycine are weak. Therefore, 12 mg of glycine is selected as the antioxidant of this prescription, that is, the glycine content in each injection is 0.12 mg.

2. Selection and dosage screening of metal complexing agents:

Because methylnaltrexone bromide injection is easy to contact with metal utensils during the production process, metal ions are introduced. In order to verify the influence of metal ions on the stability of methylnaltrexone bromide injection, the metal ion complexing agent and dosage were screened.

Method: add the main and auxiliary materials according to the formula design table, operate according to the general process regulations of the preparation, and properly add FeCl ₃ solution as the source of metal ions in the prescription, and conduct accelerated tests at a high temperature of 60°C, and take samples at 0, 4, and 8 hours respectively According to the related substance method of methylnaltrexone bromide raw materials, the change of impurities is determined, which is used to screen the metal ion complexing agent and its dosage.

The result is as follows:

Screening test results of metal complexing agent dosage

Conclusion: As can be seen from the test results, metal ions can cause the instability of methylnaltrexone bromide; adding a metal ion complexing agent can increase the stability of the preparation; the amount of complexing agent is positively correlated with the stability of the preparation; EDTA- The effect of 2Na is better than that of sodium citrate. EDTA-2Na is selected as the complexing agent of this preparation, and the dosage is 0.22 mg per tube.

2. pH value selection

Add the prescribed amount of sodium chloride, disodium EDTA, and glycine into the water for injection, and stir to dissolve. Add the prescribed amount of methylnaltrexone bromide into the auxiliary material solution, and stir to dissolve. Divide the injection solution into three parts and adjust the pH to 3.0, 4.0 and 5.0 with 1 mol/L hydrochloric acid respectively.

The above solution was taken at 0, 2, 4, 6, 8, and 24 hours for determination according to the proposed detection method for related substances of methylnaltrexone bromide, and the stability of methylnaltrexone bromide in solutions with different pH values was investigated. The result is as follows:

Investigation results of impurities in methylnaltrexone bromide injection under different pH conditions

Conclusion: Based on the above measured data, it can be seen that bromidenaltrexone injection has no significant changes in the main peak area, impurities, and appearance under the conditions of pH 3.0, 4.0, and 5.0. Therefore, the pH value of this product should be controlled between 3.0 and 5.0.

Example 1:

making process:

(1) Add sodium chloride, disodium edetate, and glycine into 600mL of water for injection, and stir to dissolve.

(2) Add methylnaltrexone bromide and stir to dissolve.

(3) Coarse filtration: add 0.05% (W/V) activated carbon for needles, stir and adsorb at 70° C. for 30 minutes, and filter out activated carbon with a 0.45 μm filter membrane.

(4) Fine filtration: adjust the pH value to 4.0 with 1 mol/L hydrochloric acid or 1 mol/L sodium hydroxide solution, and fine filter with a 0.22 μm filter membrane.

(5) Filling, sealing, and sterilization.

Stability comparison experiment:

The sample is subjected to the influence factor test, and the total amount of impurities on the 10th day is measured.

sample:

1. Embodiment 1 of the present invention

2. According to the prescription in column 2 of the first table on page 27 of the superscript of Chinese patent 200780009723.6 and the method in 200780009723.6, a comparative example was prepared.

The samples of methylnaltrexone bromide injection were placed in the light, 40°C and 60°C influencing factor test chambers for 10 days to measure the changes in the total amount of impurities, and compared with 0 days, the specific data See the table:

It can be seen from the above experimental results that the stability of the embodiment of the present invention is better than that of the comparative example.

Claims (10)

1. a methyhaaltrexone bromide injection, is made up of methylnaltrexone bromide crude drug and adjuvant, and wherein adjuvant includes metal chelating agent disodiumedetate and antioxidant glycine.

2. methyhaaltrexone bromide injection according to claim 1, it is characterised in that adjuvant includes sodium chloride, disodiumedetate, glycine and water for injection.

3. methyhaaltrexone bromide injection according to claim 2, it is characterized in that, mainly comprising of this injection is as follows: methylnaltrexone bromide 12 weight portion, sodium chloride 3～5 weight portion, disodiumedetate 0.1～0.3 weight portion, glycine 0.1～0.2 weight portion, water for injection adds to 600 parts by volume, and wherein weight is g: mL with the unit ratio of volume.

4. methyhaaltrexone bromide injection according to claim 3, it is characterized in that, mainly comprising of this injection is as follows: methylnaltrexone bromide 12 weight portion, sodium chloride 3.5～4.5 weight portion, disodiumedetate 0.2～0.25 weight portion, glycine 0.1～0.15 weight portion, water for injection adds to 600 parts by volume, and the unit ratio of weight and volume is g: mL.

5. methyhaaltrexone bromide injection according to claim 4, it is characterized in that, mainly comprising of this injection is as follows: methylnaltrexone bromide 12 weight portion, sodium chloride 3.9 weight portion, disodiumedetate 0.22 weight portion, glycine 0.12 weight portion, water for injection adds to 600 parts by volume, and the unit ratio of weight and volume is g: mL.

6. the methyhaaltrexone bromide injection according to any one in Claims 1 to 5, it is characterised in that the pH value of this injection is between 3.0～5.0.

7. methyhaaltrexone bromide injection according to claim 6, it is characterised in that the pH value of this injection is 4.0.

8. the preparation method of methyhaaltrexone bromide injection described in any one in claim 1～7, comprises the following steps:

1) sodium chloride, disodiumedetate and glycine are joined in water for injection, stirring and dissolving；

2) methylnaltrexone bromide, stirring and dissolving are added；

3) coarse filtration: in step 2) gained solution adds the needle-use activated carbon of 0.05% (W/V), 50～70 DEG C of stirring and adsorbing, with membrane filtration except activated carbon；

4) fine straining: coarse filtration gained filtrate is regulated pH value to 3.0～5.0, use filter membrane fine straining；

5) by fine straining filtrate fill, sealing, sterilizing.

9. preparation method according to claim 8, it is characterised in that described step 4) sodium hydroxide solution of the hydrochloric acid of middle 1mol/L or 1mol/L regulates pH value to 4.0.

10. preparation method according to claim 8, it is characterised in that step 3) coarse filtration is with 0.45 μm of membrane filtration；Step 4) fine straining is with 0.22 μm of membrane filtration.