CN111632029A - Methocarbamol injection and preparation method thereof - Google Patents

Methocarbamol injection and preparation method thereof Download PDF

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CN111632029A
CN111632029A CN202010601342.4A CN202010601342A CN111632029A CN 111632029 A CN111632029 A CN 111632029A CN 202010601342 A CN202010601342 A CN 202010601342A CN 111632029 A CN111632029 A CN 111632029A
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methocarbamol
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liquid medicine
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filter
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CN111632029B (en
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高怡蓉
陈燕
李宁
孙静怡
李喜峰
顾静燕
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Suzhou Pharmaceutical Factory Jiangsu Wuzhong Pharmaceutical Group Corp
Jiangsu Wuzhong Pharmaceutical Group Corp
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Abstract

The invention provides a methocarbamol injection and a preparation method thereof. The pH value of the methocarbamol injection is 4.2-4.5. When the pH value of the methocarbamol injection is adjusted to 4.2-4.5, the impurity C, other single impurities and total impurity fluctuation of the methocarbamol injection are obviously reduced compared with a reference preparation, so that the stability of the preparation is obviously improved, and the quality of the methocarbamol injection variety is further improved.

Description

Methocarbamol injection and preparation method thereof
Technical Field
The invention relates to the field of pharmacy, and in particular relates to a methocarbamol injection and a preparation method thereof.
Background
Methocarbamol (also known as Shujinling, Methoxid) of the formula (+/-) -3- [ o-methoxyphenoxy group]-1, 2-propanediol-1-carbamate of formula C11H15NO5The structural formula is as follows:
Figure BDA0002558658710000011
the methocarbamol is a muscle relaxant, and the administration mode of the methocarbamol mainly comprises oral administration and injection, and the dosage forms comprise tablets, capsules, injections and the like. The methocarbamol injection is a medicine which is widely used clinically and is used for treating diseases such as joint muscle sprain, lumbar muscle strain, sciatica and the like. The impurities mainly involved in the quality control of the methocarbamol injection are shown in table 1.
TABLE 1 Methocarbamol injection quality control mainly related impurities
Figure BDA0002558658710000012
Figure BDA0002558658710000021
The chemical imitation pharmaceutical reference preparation catalog (twenty-seventh batch) published by the current national Center for Drug Evaluation (CDE) publishes the imitation pharmaceutical reference preparation of methocarbamol injection, with the trade name Robaxin, specification 100mg/mL, and the certificate holder: hikma pharmaceuticals International Ltd. Stability tests on the imitation pharmaceutical reference preparation of the methocarbamol injection find that the impurity C, the rest single impurities and the total impurities have larger growth range in the test process, and the stability of the injection needs to be improved.
Disclosure of Invention
Therefore, the technical problem to be solved by the present invention is to improve the stability of the methocarbamol injection, thereby providing a methocarbamol injection and a preparation method thereof.
In a first aspect, the invention provides a methocarbamol injection, wherein the pH value of the methocarbamol injection is 4.2-4.5.
Further, the pH of the methocarbamol injection is adjusted with hydrochloric acid.
Further, the methocarbamol injection comprises the following raw and auxiliary materials: methocarbamol, cosolvent, hydrochloric acid and water for injection.
Further, the methocarbamol injection comprises the following components in 1 mL: 100mg of methocarbamol and 0.5mL of cosolvent, wherein the cosolvent is polyethylene glycol 300 or polyethylene glycol 400.
In a second aspect, the invention provides a preparation method of the methocarbamol injection, which is characterized by comprising the steps of weighing, preparing, filtering, encapsulating and sterilizing.
Further, in the step of potting, comprising: filling liquid medicine, filling nitrogen on the liquid surface, and sealing, wherein the nitrogen is filled on the liquid surface until the headspace oxygen residue is less than 5% (the headspace oxygen residue is the volume percentage of oxygen in the headspace air).
Further, in the step of formulating, comprising:
heating the cosolvent to 60-65 ℃, adding the methocarbamol and completely dissolving, adding water for injection to 70% -90% of the total amount, adding the pH value regulator to regulate the pH value of the liquid medicine to 4.0-4.4, cooling the liquid medicine to 35-45 ℃, adding water for injection to the total amount, stirring for 3-10 minutes, and standing for 0-10 minutes.
Further, the filtering comprises:
the prepared liquid medicine is subjected to pre-stage filtration through a first liquid medicine filter;
and sequentially filtering the liquid medicine filtered by the front stage by a second liquid medicine filter and a third liquid medicine filter for post-stage filtration, wherein the first liquid medicine filter, the second liquid medicine filter and the third liquid medicine filter all adopt polyether sulfone filter elements with the aperture of 0.45 mu m and the length of 10 inches, and the pressure difference between the second liquid medicine filter and the third liquid medicine filter is less than or equal to 0.2 MPa.
Further, the step of encapsulation is carried out in an A/B grade clean area, the ambient temperature is 18-26 ℃, the humidity is 45-65%, and the pressure difference is more than or equal to 10 Pa.
Further, in the sterilization step, the sterilization temperature is 121 ℃, and the sterilization time is 12-15 min.
Further, the preparation method of the methocarbamol injection also comprises the steps of quality inspection and packaging.
The technical scheme of the invention has the following advantages:
1. the pH value of the imitation-pharmaceutical reference preparation of the methocarbamol injection is 3.6-3.7, the applicant finds that the impurity C, the rest single impurities and the total impurities of the preparation are obviously increased in the stability test for the first time through the stability test, and the applicant finds that the fluctuation amplitude of the impurity C, the rest single impurities and the total impurities of the methocarbamol injection is obviously reduced when the pH value of the methocarbamol injection is adjusted to 4.2-4.5, so that the stability of the preparation is obviously improved, and the quality of the methocarbamol injection variety is further improved.
2. The preparation method of the methocarbamol injection provided by the invention comprises the following steps of: filling liquid medicine, filling nitrogen on the liquid surface, and sealing, wherein the nitrogen is filled on the liquid surface until the headspace residual oxygen content is less than 5%, which is beneficial to reducing the aldehyde content in the methocarbamol injection, thereby further improving the quality of the methocarbamol injection variety.
Detailed Description
The following examples are provided to further understand the present invention, not to limit the scope of the present invention, but to provide the best mode, not to limit the content and the protection scope of the present invention, and any product similar or similar to the present invention, which is obtained by combining the present invention with other prior art features, falls within the protection scope of the present invention.
The reagent and equipment information in examples and experimental examples are shown in tables 2 and 3, respectively.
TABLE 2 reagent information
Name (R) Origin of origin Batch number
Purified water Milli-Q Direct 8 of Milli-Cribo water purifier /
Potassium dihydrogen phosphate Shanghai Lingfeng Chemicals Co., Ltd 20190103
Phosphoric acid SINOPHARM CHEMICAL REAGENT Co.,Ltd. 20190326
Potassium hydroxide Shanghai Lingfeng Chemicals Co., Ltd 20171229
Methanol Tedia 19065100
Sodium hydroxide XILONG SCIENTIFIC Co.,Ltd. 1811202
Hydrochloric acid Shanghai Lingfeng Chemicals Co., Ltd 20181029
Phenylhydrazine hydrochloride MACKLIN C10401940
Potassium ferricyanide Aladdin G1802039
Ethanol Subson chemical Co Ltd of Wuxi City 20181215
TABLE 3 Instrument Equipment information
Figure BDA0002558658710000051
The examples do not show the specific experimental steps or conditions, and can be performed according to the conventional experimental steps described in the literature in the field. The reagents or apparatus used are all conventional products commercially available, including but not limited to those used in the examples of the present application.
Example 1
The methocarbamol injection is prepared by the following steps:
Figure BDA0002558658710000052
the preparation method of the methocarbamol injection comprises the following steps:
(1) washing the bottle: washing bottles (medium borosilicate glass ampoules) by using a vertical ultrasonic cleaner, wherein the sterilization temperature is 340 ℃, and the mesh belt frequency is less than or equal to 50 Hz;
(2) weighing: weighing methocarbamol, polyethylene glycol 300 and hydrochloric acid according to the prescription amount respectively;
(3) preparation: putting the weighed polyethylene glycol 300 into a batching tank, starting a stirrer, stirring at the speed of 45Hz, opening a steam valve of the batching tank, heating the solution, controlling the temperature to be 60-65 ℃, and closing the steam valve of the batching tank; adding the weighed methocarbamol under the stirring state, stirring until the methocarbamol is completely dissolved, clarifying the liquid medicine, and closing the stirrer; adding injection water to 90% of the total amount, starting a stirrer to continue stirring, simultaneously starting a cooling water valve of a batching tank, cooling the liquid medicine to 35-45 ℃, and closing the cooling water valve of the batching tank; gradually adding hydrochloric acid to adjust pH to 4.0, and adding water for injection to full dose; starting a stirrer, stirring for 10 minutes, standing for 5 minutes, and keeping the temperature of the liquid medicine at 35-45 ℃;
(4) and (3) filtering: a. pre-stage filtration: the liquid medicine is pre-filtered by a liquid medicine filter; b. and (3) post-stage filtration: filtering the liquid medicine sequentially through a liquid medicine mixing filter and a liquid medicine filling and sealing filter, and filtering the liquid medicine into a material bottle, wherein the pressure difference between the front and the back of the liquid medicine filter (the pressure of the liquid medicine mixing filter and the pressure of the liquid medicine filling and sealing filter) is controlled to be less than or equal to 0.2MPa, and a bubble point test is carried out before and after the filter element is used, and the bubble point value is not less than 0.2 MPa;
(5) encapsulating: performing in an A/B grade clean area by using an ampoule filling and sealing machine, controlling the room temperature at 18-26 ℃, the humidity at 45-65%, and the pressure difference at least equal to 10Pa, filling nitrogen (the nitrogen flow is 5-8L/min, the speed is 230) at 240 bottles/min, the headspace residual oxygen content is less than 5%) in the liquid level after the liquid medicine is filled and before the liquid medicine is sealed, wherein the filling amount is 10.7mL, and the detection qualification standard is 10.0-10.7 mL;
(6) sterilization and leak detection: an ampoule sterilizer is used for sterilizing at 121 ℃ for 15 minutes; leak detection pressure: -80KPa, leak detection time: 15 minutes; cleaning time: 4 minutes, number of washes: 2, sterilizing the intermediate product by first filling and sealing according to the filling and sealing sequence, wherein the filling and sealing is carried out until the sterilization time is not more than 4 hours;
(7) and (4) lamp inspection: using an automatic checking machine for foreign matters in the ampoule injection, and performing appearance inspection: detecting unqualified products such as a sharp head, a bubble head, a coke head and the like; machine inspection: detecting unqualified products such as unqualified loading amount and visible foreign matters;
(8) and (6) packaging.
The pH of the methocarbamol injection prepared in this example was found to be 4.2.
Example 2
The methocarbamol injection is prepared according to the formula in example 1, and the preparation method comprises the following steps:
(1) washing the bottle: washing bottles (medium borosilicate glass ampoules) by using a vertical ultrasonic cleaner, wherein the sterilization temperature is 340 ℃, and the mesh belt frequency is less than or equal to 50 Hz;
(2) weighing: weighing methocarbamol, polyethylene glycol 300 and hydrochloric acid according to the prescription amount respectively;
(3) preparation: putting the weighed polyethylene glycol 300 into a proportioning tank, starting a stirrer, stirring at the speed of 50Hz, opening a steam valve of the proportioning tank, heating the solution, controlling the temperature to be 60-65 ℃, and closing the steam valve of the proportioning tank; adding the weighed methocarbamol under the stirring state, stirring until the methocarbamol is completely dissolved, clarifying the liquid medicine, and closing the stirrer; adding injection water to 70% of the total amount, starting a stirrer to continue stirring, simultaneously starting a cooling water valve of a batching tank, cooling the liquid medicine to 35-45 ℃, and closing the cooling water valve of the batching tank; gradually adding hydrochloric acid to adjust pH to 4.1, and adding water for injection to full dose; starting a stirrer, stirring for 3 minutes, standing for 10 minutes, and keeping the temperature of the liquid medicine at 35-45 ℃;
(4) and (3) filtering: a. pre-stage filtration: the liquid medicine is pre-filtered by a liquid medicine filter; b. and (3) post-stage filtration: filtering the liquid medicine sequentially through a liquid medicine mixing filter and a liquid medicine filling and sealing filter, and filtering the liquid medicine into a material bottle, wherein the pressure difference between the front and the back of the liquid medicine filter (the pressure of the liquid medicine mixing filter and the pressure of the liquid medicine filling and sealing filter) is controlled to be less than or equal to 0.2MPa, and a bubble point test is carried out before and after the filter element is used, and the bubble point value is not less than 0.2 MPa;
(5) encapsulating: performing in an A/B grade clean area by using an ampoule filling and sealing machine, controlling the room temperature at 18-26 ℃, the humidity at 45-65%, and the pressure difference at least equal to 10Pa, filling nitrogen (the nitrogen flow is 5-8L/min, the speed is 230) at 240 bottles/min, the headspace residual oxygen content is less than 5%) in the liquid level after the liquid medicine is filled and before the liquid medicine is sealed, wherein the filling amount is 10.7mL, and the detection qualification standard is 10.0-10.7 mL;
(6) sterilization and leak detection: sterilizing with an ampoule sterilizer at 121 deg.C for 12 min; leak detection pressure: -80KPa, leak detection time: 15 minutes; cleaning time: 4 minutes, number of washes: 2, sterilizing the intermediate product by first filling and sealing according to the filling and sealing sequence, wherein the filling and sealing is carried out until the sterilization time is not more than 4 hours;
(7) and (4) lamp inspection: using an automatic checking machine for foreign matters in the ampoule injection, and performing appearance inspection: detecting unqualified products such as a sharp head, a bubble head, a coke head and the like; machine inspection: detecting unqualified products such as unqualified loading amount and visible foreign matters;
(8) and (6) packaging.
The pH of the methocarbamol injection prepared in this example was found to be 4.4.
Example 3
The methocarbamol injection is prepared according to the formula in example 1, and the preparation method comprises the following steps:
(1) washing the bottle: washing bottles (medium borosilicate glass ampoules) by using a vertical ultrasonic cleaner, wherein the sterilization temperature is 340 ℃, and the mesh belt frequency is less than or equal to 50 Hz;
(2) weighing: weighing methocarbamol, polyethylene glycol 300 and hydrochloric acid according to the prescription amount respectively;
(3) preparation: putting the weighed polyethylene glycol 300 into a proportioning tank, starting a stirrer, stirring at the speed of 50Hz, opening a steam valve of the proportioning tank, heating the solution, controlling the temperature to be 60-65 ℃, and closing the steam valve of the proportioning tank; adding the weighed methocarbamol under the stirring state, stirring until the methocarbamol is completely dissolved, clarifying the liquid medicine, and closing the stirrer; adding injection water to 90% of the total amount, starting a stirrer to continue stirring, simultaneously starting a cooling water valve of a batching tank, cooling the liquid medicine to 35-45 ℃, and closing the cooling water valve of the batching tank; gradually adding hydrochloric acid to adjust pH to 4.4, and adding water for injection to full dose; starting a stirrer, stirring for 8 minutes, standing for 0 minute, and keeping the temperature of the liquid medicine at 35-45 ℃;
(4) and (3) filtering: a. pre-stage filtration: the liquid medicine is pre-filtered by a liquid medicine filter; b. and (3) post-stage filtration: filtering the liquid medicine sequentially through a liquid medicine mixing filter and a liquid medicine filling and sealing filter, and filtering the liquid medicine into a material bottle, wherein the pressure difference between the front and the back of the liquid medicine filter (the pressure of the liquid medicine mixing filter and the pressure of the liquid medicine filling and sealing filter) is controlled to be less than or equal to 0.2MPa, and a bubble point test is carried out before and after the filter element is used, and the bubble point value is not less than 0.2 MPa;
(5) encapsulating: performing in an A/B grade clean area by using an ampoule filling and sealing machine, controlling the room temperature at 18-26 ℃, the humidity at 45-65%, and the pressure difference at least equal to 10Pa, filling nitrogen (the nitrogen flow is 5-8L/min, the speed is 230) at 240 bottles/min, the headspace residual oxygen content is less than 5%) in the liquid level after the liquid medicine is filled and before the liquid medicine is sealed, wherein the filling amount is 10.7mL, and the detection qualification standard is 10.0-10.7 mL;
(6) sterilization and leak detection: an ampoule sterilizer is used for sterilizing at 121 ℃ for 15 minutes; leak detection pressure: -80KPa, leak detection time: 15 minutes; cleaning time: 4 minutes, number of washes: 2, sterilizing the intermediate product by first filling and sealing according to the filling and sealing sequence, wherein the filling and sealing is carried out until the sterilization time is not more than 4 hours;
(7) and (4) lamp inspection: using an automatic checking machine for foreign matters in the ampoule injection, and performing appearance inspection: detecting unqualified products such as a sharp head, a bubble head, a coke head and the like; machine inspection: detecting unqualified products such as unqualified loading amount and visible foreign matters;
(8) and (6) packaging.
The pH of the methocarbamol injection prepared in this example was found to be 4.5.
Example 4
The methocarbamol injection is prepared according to the formula in example 1, and the preparation method comprises the following steps:
(1) washing the bottle: washing bottles (medium borosilicate glass ampoules) by using a vertical ultrasonic cleaner, wherein the sterilization temperature is 340 ℃, and the mesh belt frequency is less than or equal to 50 Hz;
(2) weighing: weighing methocarbamol, polyethylene glycol 300 and hydrochloric acid according to the prescription amount respectively;
(3) preparation: putting the weighed polyethylene glycol 300 into a proportioning tank, starting a stirrer, stirring at the speed of 50Hz, opening a steam valve of the proportioning tank, heating the solution, controlling the temperature to be 60-65 ℃, and closing the steam valve of the proportioning tank; adding the weighed methocarbamol under the stirring state, stirring until the methocarbamol is completely dissolved, clarifying the liquid medicine, and closing the stirrer; adding injection water to 90% of the total amount, starting a stirrer to continue stirring, simultaneously starting a cooling water valve of a batching tank, cooling the liquid medicine to 35-45 ℃, and closing the cooling water valve of the batching tank; gradually adding hydrochloric acid to adjust pH to 4.1, and adding water for injection to full dose; starting a stirrer, stirring for 10 minutes, standing for 10 minutes, and keeping the temperature of the liquid medicine at 35-45 ℃;
(4) and (3) filtering: a. pre-stage filtration: the liquid medicine is pre-filtered by a liquid medicine filter; b. and (3) post-stage filtration: filtering the liquid medicine sequentially through a liquid medicine mixing filter and a liquid medicine filling and sealing filter, and filtering the liquid medicine into a material bottle, wherein the pressure difference between the front and the back of the liquid medicine filter (the pressure of the liquid medicine mixing filter and the pressure of the liquid medicine filling and sealing filter) is controlled to be less than or equal to 0.2MPa, and a bubble point test is carried out before and after the filter element is used, and the bubble point value is not less than 0.2 MPa;
(5) encapsulating: performing in an A/B grade clean area by using an ampoule filling and sealing machine, controlling the room temperature at 18-26 ℃, the humidity at 45-65%, and the pressure difference at least equal to 10Pa, filling nitrogen (the nitrogen flow is 5-8L/min, the speed is 230) at 240 bottles/min, the headspace residual oxygen content is less than 5%) in the liquid level after the liquid medicine is filled and before the liquid medicine is sealed, wherein the filling amount is 10.7mL, and the detection qualification standard is 10.0-10.7 mL;
(6) sterilization and leak detection: an ampoule sterilizer is used for sterilizing at 121 ℃ for 15 minutes; leak detection pressure: -80KPa, leak detection time: 15 minutes; cleaning time: 4 minutes, number of washes: 2, sterilizing the intermediate product by first filling and sealing according to the filling and sealing sequence, wherein the filling and sealing is carried out until the sterilization time is not more than 4 hours;
(7) and (4) lamp inspection: using an automatic checking machine for foreign matters in the ampoule injection, and performing appearance inspection: detecting unqualified products such as a sharp head, a bubble head, a coke head and the like; machine inspection: detecting unqualified products such as unqualified loading amount and visible foreign matters;
(8) and (6) packaging.
The pH of the methocarbamol injection prepared in this example was found to be 4.4.
Example 5
A methocarbamol injection which differs from example 4 only in that no nitrogen charging operation is performed in the step of potting.
Comparative example
A methocarbamol injection, which is different from the example 4 only in that hydrochloric acid is added in the preparation step to adjust the pH of the liquid medicine to 3.4, and the pH of the methocarbamol injection prepared in the comparative example is measured to be 3.7.
Experimental example 1 influence factor test
1. Test method
The home-made formulation of methocarbamol injection prepared in example 1 of the present application and the reference formulation of methocarbamol injection (manufacturer: West-Ward Pharmaceuticals Corp., Eatontown, N.J. 07724USA) were each tested under the conditions of ① 40 ℃ for 30 days, ② 60 ℃ for 30 days, and ③ were respectively packaged without package and with package under light (total illumination was not less than 1.2 × 10)6Lux.hr, near ultraviolet energy not less than 200w.hr/m2) The mixture is placed for 30 days, the properties and the color of the mixture are observed on 0 day, 5 days, 10 days and 30 days under the condition ① and the condition ② respectively, the pH value, related substances (impurity A, impurity B, impurity C, other single impurities and total impurities except the impurity A) and aldehyde are detected, and the detection items are also detected under the condition ③, wherein the detection method comprises the following steps:
(1) measuring the pH value of the methocarbamol injection by adopting a pH meter;
(2) detecting aldehyde by adopting an ultraviolet-visible spectrophotometry, wherein:
phenylhydrazine hydrochloride solution: is used newly. An appropriate amount of phenylhydrazine hydrochloride is weighed, dissolved by adding 20% ethanol and diluted to prepare a solution containing 10mg of phenylhydrazine hydrochloride per 1 mL.
Potassium ferricyanide solution: is used newly. An appropriate amount of potassium ferricyanide was weighed, dissolved in water and diluted to make a solution containing about 10mg per 1 mL.
Formaldehyde solution: a proper amount of formaldehyde solution is taken and diluted by water to prepare a solution containing 10 mu g of formaldehyde per 1 mL.
Precisely measuring a proper amount (about 0.4g of methocarbamol) of the product, putting the product into a 25mL measuring flask, adding 2mL of phenylhydrazine hydrochloride diluted ethanol (1 → 5) solution (1 → 100) (fresh preparation for clinical application), shaking uniformly, standing for 10 minutes, adding 1mL of potassium ferricyanide solution (1 → 100) (fresh preparation for clinical application), shaking uniformly, standing for 5 minutes, adding 4mL of hydrochloric acid, diluting to a scale with ethanol, and shaking uniformly to obtain a sample solution. Separately, 4mL of formaldehyde solution (1 → 100000) was precisely measured and placed in a 25mL measuring flask, and the same procedure was carried out to obtain a control solution. The absorbance was measured at 515nm by UV-visible spectrophotometry (four parts general rule 0401 in Chinese pharmacopoeia 2015 edition) and corrected with a blank. The absorbance of the test solution should not be greater than that of the control solution (0.01%).
(3) Detecting related substances by adopting a high performance liquid chromatography, wherein:
a chromatographic column: COSMOSIL 5-C18-MS-II, 4.6X 250mm, 5 μm
Column temperature: 30 deg.C
A detector: UV at 274nm
Sample introduction volume: 20 μ L
Flow rate: 1mL/min
Operating time: 50min
Mobile phase A: phosphate buffer (taking 6.8g of monopotassium phosphate, adding water to dissolve and dilute to 1000mL, adjusting pH to 4.50 +/-0.05 by 10% phosphoric acid or 0.1mol/L potassium hydroxide)
Mobile phase B: methanol
Diluent agent: mobile phase A-mobile phase B (70:30)
Elution procedure:
Figure BDA0002558658710000131
taking a proper amount of the methocarbamol and an impurity A reference substance respectively, adding a diluent to dissolve and dilute the methocarbamol and the impurity A reference substance to prepare solutions containing 2mg and 20 mu g of the methocarbamol in each 1mL of the reference substance respectively, taking 20 mu L of the solutions as system applicability solutions, injecting the solutions into a liquid chromatograph, recording a chromatogram, wherein the separation degree of the impurity A (the relative retention time is about 0.84) and the methocarbamol peak is not less than 3.5; precisely measuring a reference substance solution (taking a proper amount of methocarbamol reference substance, precisely weighing, adding a diluent for dissolving, quantitatively diluting to prepare a solution containing about 2 mug of methocarbamol per 1ml, and using the solution as the reference substance solution) by 20 muL, injecting into a liquid chromatograph, recording a chromatogram, wherein the signal-to-noise ratio of the peak height of the main component is not less than 20; precisely measuring sample solution (precisely measuring appropriate amount of the product, adding diluent (mobile phase under content determination term) to dilute into solution containing 2mg of methocarbamol per 1ml, injecting into liquid chromatograph, recording chromatogram, and calculating according to external standard method and peak area of methocarbamol in control solution). Impurity a (multiplied by a correction factor of 0.81) should not exceed 1.0%, impurity B (relative retention time of about 0.90) should not exceed 0.1%, impurity C (relative retention time of about 1.24) should not exceed 0.2%, the remaining individual impurities should not exceed 0.1%, and the total amount of impurities other than impurity a should not exceed 0.5%.
The limit requirements for each item under investigation are shown in table 4.
TABLE 4 Methocarbamol injection Limit requirements for research projects
Figure BDA0002558658710000141
2. Test results
The test results for the home-made formulation and the reference formulation are shown in tables 5 and 6, respectively.
TABLE 5 statistics of the experimental results of the influencing factors of the self-made preparation of methocarbamol injection
Figure BDA0002558658710000142
Figure BDA0002558658710000151
TABLE 6 statistics of the test results of the influencing factors of the reference formulation of methocarbamol injection
Figure BDA0002558658710000152
As shown in tables 5 and 6, (1) the self-made preparation and the reference preparation are placed at 40 ℃ for 30 days, the total impurities except the impurity A are slightly increased, other indexes are not obviously changed, and the increase levels of the self-made preparation and the reference preparation are equivalent; (2) placing the self-made preparation and the reference preparation at 60 ℃ for 30 days, wherein related substances of the self-made preparation slightly increase, the impurity C increases from 0.02% to 0.08%, and the total impurities increase from 0.04% to 0.18%; the related substances of the reference preparation increase remarkably, the impurity C increases from 0.04% to 0.15%, and the total impurities increase from 0.11% to 0.41%; the pH value is slightly increased, and the aldehyde is slightly reduced and is within the standard specified range; the other indexes have no obvious change, and the stability of the self-made preparation is superior to that of a reference preparation; (3) the aldehyde is obviously increased under the illumination condition, the self-made preparation is increased from 0.004% to 0.010%, the reference preparation is increased from 0.007% to 0.016%, the standard specified range is exceeded, the other indexes are not obviously changed, the self-made preparation and the reference preparation are equivalent in level, the product is sensitive to illumination, and the outer package is made of a shading material.
Experimental example 2 accelerated test
1. Test method
The methocarbamol injection self-made preparation prepared in the examples 2-4 of the application, the methocarbamol injection reference preparation prepared in the comparative examples of the application and the methocarbamol injection reference preparation are placed in a stability test box under the following conditions for 6 months: shading, wherein the temperature is 40 ℃ plus or minus 2 ℃, the relative humidity is 75 percent plus or minus 5 percent RH, the properties and the color of the product are observed in 0 month, 1 month, 2 months, 3 months and 6 months respectively, the pH value, related substances (impurity A, impurity B, impurity C, other single impurities and total impurities except the impurity A) and aldehyde are detected, and the detection method of each detection item refers to the experimental example 1. The limit requirements for each item under investigation are shown in table 4.
2. Test results
The results of the tests on the home-made, control and reference formulations are shown in tables 7-13.
TABLE 7 statistics of accelerated test results for the home-made formulation of methocarbamol injection (example 2)
Figure BDA0002558658710000161
Figure BDA0002558658710000171
TABLE 8 statistics of accelerated test results for the home-made formulation of methocarbamol injection (example 3)
Figure BDA0002558658710000172
TABLE 9 statistics of accelerated test results for the home-made formulation of methocarbamol injection (example 4)
Figure BDA0002558658710000173
Figure BDA0002558658710000181
TABLE 10 statistics of accelerated test results for the home-made formulation of methocarbamol injection (example 5)
Figure BDA0002558658710000182
TABLE 11 statistics of accelerated test results for reference formulation of methocarbamol injection
Figure BDA0002558658710000191
TABLE 12 statistics of accelerated test results for methocarbamol injection control formulation (comparative)
Figure BDA0002558658710000192
Figure BDA0002558658710000201
TABLE 13 Mesobamol injection 0 hour and 6 month impurity change trend table
Figure BDA0002558658710000202
As shown in tables 7-10, the self-made preparation was left under accelerated conditions for 6 months, the property changed from colorless and slightly viscous clear liquid to almost colorless and slightly viscous clear liquid, the color changed from colorless to less than yellow No. 0.5, and the pH value and aldehyde slightly increased; related substances, namely impurity B, impurity C and total impurities are slightly increased, but other impurities are not obviously increased and other indexes are not obviously changed within the range specified by the quality standard. As can be seen from tables 9 and 10, the nitrogen-charging operation is omitted in the step of encapsulation, and the content of aldehyde in the methocarbamol injection is increased, which proves that the aldehyde content can be effectively reduced and the quality of the methocarbamol injection can be improved by performing nitrogen-charging protection on the drug solution in the step of encapsulation.
As shown in table 11, the reference formulation changed from colorless and slightly viscous clear liquid to almost colorless and slightly viscous clear liquid, changed from colorless to less than yellow No. 0.5, and slightly increased in pH and aldehyde, when left under accelerated conditions for 6 months; related substances, namely impurity C, other single impurities and total impurities are remarkably increased, the impurity C is increased from 0.04% to 0.13%, the other single impurities are increased from 0.01% to 0.09%, the total impurities are increased from 0.11% to 0.44%, and the other indexes are not remarkably changed within the range specified by the quality standard.
As shown in table 12, the control formulation changed from colorless to slightly viscous clear liquid to almost colorless to slightly viscous clear liquid, the color changed from colorless to less than yellow No. 0.5, and the pH increased slightly when left under accelerated conditions for 6 months; related substances, namely impurity C, other single impurities and total impurities are obviously increased, the impurity C is increased from 0.05% to 0.14%, the other single impurities are increased from 0.01% to 0.04%, the total impurities are increased from 0.05% to 0.38%, and the impurities are still in the range specified by the quality standard, other impurities are not obviously increased, and other indexes are not obviously changed.
As shown in table 13, the fluctuation of the impurity a from 0.01 to 0.03% in the reference preparation, the control preparation and the self-made preparation up to 6 months of acceleration was stable; the fluctuation of the impurity C reference preparation is 0.09%, the detected amount exceeds 0.1%, the fluctuation of the reference preparation is 0.09%, the detected amount also exceeds 0.1%, and the fluctuation of the self-made preparation is 0.04-0.05%; the maximum single impurity of other medicines is 0.08 percent of the amplitude of the reference preparation, 0.03 percent of the amplitude of the reference preparation and basically unchanged from the self-made preparation; the total impurities except the impurity A comprise 0.33% of the reference preparation, 0.33% of the reference preparation and 0.08-0.10% of the self-made preparation. It can be seen that the adjustment of the pH of the methocarbamol injection to 4.2-4.5 is more advantageous than the stability of the reference and control formulations.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.

Claims (10)

1. The methocarbamol injection is characterized in that the pH value of the methocarbamol injection is 4.2-4.5.
2. The methocarbamol injection according to claim 1, wherein the pH of the methocarbamol injection is adjusted with hydrochloric acid.
3. The methocarbamol injection according to claim 1 or 2, characterized in that the raw materials and auxiliary materials comprise: methocarbamol, cosolvent, hydrochloric acid and water for injection.
4. The methocarbamol injection according to claim 3, wherein based on 1mL of the methocarbamol injection, comprising: 100mg of methocarbamol and 0.5mL of cosolvent, wherein the cosolvent is polyethylene glycol 300 or polyethylene glycol 400.
5. A process for the preparation of the methocarbamol injection according to any of claims 1 to 4, comprising the steps of weighing, formulating, filtering, encapsulating and sterilizing.
6. The method for preparing methocarbamol injection according to claim 5, wherein in the step of encapsulating, comprising: filling liquid medicine, filling nitrogen on the liquid surface, and sealing, wherein the nitrogen is filled on the liquid surface until the headspace residual oxygen amount is less than 5%.
7. The process for the preparation of the methocarbamol injection according to claim 5 or 6, characterized in that in the step of formulating, it comprises:
heating the cosolvent to 60-65 ℃, adding the methocarbamol and completely dissolving, adding water for injection to 70% -90% of the total amount, cooling the liquid medicine to 35-45 ℃, adding the pH value regulator to regulate the pH value of the liquid medicine to 4.0-4.4, adding water for injection to the total amount, stirring for 3-10 minutes, standing for 0-10 minutes, and keeping the temperature of the liquid medicine at 35-45 ℃.
8. The process for the preparation of methocarbamol injection according to any one of claims 5 to 7, wherein the filtration comprises:
the prepared liquid medicine is subjected to pre-stage filtration through a first liquid medicine filter;
and sequentially filtering the liquid medicine filtered by the front stage by a second liquid medicine filter and a third liquid medicine filter for post-stage filtration, wherein the first liquid medicine filter, the second liquid medicine filter and the third liquid medicine filter all adopt polyether sulfone filter elements with the aperture of 0.45 mu m and the length of 10 inches, and the pressure difference between the second liquid medicine filter and the third liquid medicine filter is less than or equal to 0.2 MPa.
9. The process for the preparation of the methocarbamol injection according to any one of claims 5 to 8, wherein the step of encapsulating is carried out in a class A/B clean zone, the ambient temperature is between 18 ℃ and 26 ℃, the humidity is between 45% and 65%, and the pressure difference is greater than or equal to 10 Pa.
10. The process for preparing a methocarbamol injection according to any one of claims 5 to 9, wherein in the sterilization step, the sterilization temperature is 121 ℃ and the sterilization time is 12 to 15 min.
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Citations (1)

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Publication number Priority date Publication date Assignee Title
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105392469A (en) * 2013-04-02 2016-03-09 西弥斯医疗有限公司 Compositions of pharmaceutical actives containing diethylene glycol monoethyl ether or other alkyl derivatives

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