CN112891301B - Scopolamine butylbromide injection and preparation method thereof - Google Patents
Scopolamine butylbromide injection and preparation method thereof Download PDFInfo
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Abstract
The invention provides scopolamine butylbromide injection and a preparation method thereof, the scopolamine butylbromide injection comprises 200mg of scopolamine butylbromide, 10-100mg of pH buffer pair, 1.2-36mg of stabilizer, 10ml of water for injection, the pH value of the injection is 4.8-5.4, and the preparation method comprises the following steps: (1) adding 60-80% of water for injection into prescription amount of pH buffer pair, stirring for 10-30min to dissolve completely, and controlling pH to 4.8-5.2; (2) adding scopolamine butylbromide with the formula ratio, and stirring for dissolving; adding the formula amount of stabilizer and the rest water for injection, and stirring for 15-45 min; (3) filtering with 0.22 μm microporous membrane, bottling, introducing nitrogen gas for protection, and sterilizing at 121 deg.C for 12 min. The scopolamine butylbromide injection can effectively promote smooth muscle spasmolysis of patients, and has small adverse reaction; high storage stability, simple process and low production cost.
Description
Technical Field
The invention relates to the technical field of medicinal preparations, in particular to scopolamine butylbromide injection and a preparation method thereof.
Background
Scopolamine is an alkaloid extracted from plants such as flos Daturae Metelis, belladonna and hyoscyami, and is a hydrobromide and butyl bromide derivative commonly used in clinic. Wherein, the scopolamine butylbromide is a choline receptor blocking drug, and the chemical name of the scopolamine butylbromide is as follows: brominated 6 beta, 7 beta-epoxy-3 alpha-hydroxy-8-butyl-l alpha-H, 5 alpha H-tropane (-) -tropinate of the formula: C21H30BrNO4, developed in 1950 by Boehringer, Germany, and marketed in 1956 in 2 months. The compound has effects of relieving spasm of smooth muscle, inhibiting ganglion conduction, acting on parasympathetic nervous system, and treating gastrointestinal spasm, biliary colic, renal colic or gastrointestinal hyperkinesia caused by various reasons; in addition, the medicine is also clinically used for preoperative preparation of fiberendoscopy of stomach, duodenum and colon, endoscopic retrograde cholangiopancreatography, and preoperative preparation of barium hypotrophy radiography or CT scanning of gastroduodenum and colon, can reduce or inhibit gastrointestinal peristalsis, and is a commonly used digestive system spasmolytic medicine.
Compared with medicines such as atropine and anisodamine, the scopolamine butylbromide has low adverse reaction rate and wide clinical application range. The Chinese pharmacopoeias of 2000, 2005 and 2010 are loaded with scopolamine butylbromide raw materials, capsules and injections. The scopolamine butylbromide contains ester bonds, is sensitive to pH, temperature and illumination, and has poor storage stability; at present, freeze-dried powder is used as a main injection preparation, and related researches on injection are less. The freeze-dried powder has the defects of complex preparation process, re-dissolution in use, complex operation and the like.
Therefore, the preparation of scopolamine butylbromide injection with high stability is a technical problem which needs to be addressed by the technical personnel in the field.
Disclosure of Invention
In view of this, the present invention aims to provide a scopolamine butylbromide injection and a preparation method thereof, so as to overcome the defects of the prior art, and provide a scopolamine butylbromide injection which has high stability, especially stability under illumination and storage conditions, less impurities and low cost.
In order to achieve the purpose, the technical scheme of the invention is realized as follows:
a scopolamine butylbromide injection comprises scopolamine butylbromide 200mg, pH buffer pair 10-100mg, stabilizer 1.2-36mg, water for injection 10ml, and pH value of the injection is 4.8-5.4. The pH of the scopolamine butylbromide injection can be 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4. Preferably, the pH of the scopolamine butylbromide injection is 4.9-5.1.
Preferably, the pH buffer pair is an acid-base buffer pair consisting of salts of weak acid and strong base weak acid root, accounts for 0.1-1% of the total amount of the solution, and can be any one or more of citric acid-disodium hydrogen phosphate, citric acid-sodium citrate and phosphoric acid-disodium hydrogen phosphate. Preferably, the weak acid content is 4-12mg/10ml, and the salt content of the weak acid radical of the strong base is 12-18mg/10 ml. Preferably, the pH buffer pair is citric acid-disodium hydrogen phosphate. Preferably, the amount of the pH buffer pair is 15-60mg/10ml, and more preferably, 18-36mg/10 ml.
Preferably, the stabilizer comprises at least one of valine, isoleucine, leucine, phenylalanine, methionine, tryptophan, threonine, lysine and tyrosine. Preferably, the amino acid monomer is an aromatic amino acid, such as tryptophan, tyrosine, phenylalanine. Preferably, the amount of the stabilizer is 15-25mg/10ml, and more preferably, the amount of the stabilizer is 18-22.2mg/10 ml.
Preferably, the stabilizer further comprises glutathione.
More preferably, the stabilizer comprises tryptophan, phenylalanine, glutathione-25: 5: 7. Preferably, the stabilizer consists of tryptophan, phenylalanine, glutathione and glucose selenite, wherein the weight ratio of the tryptophan to the phenylalanine to the glutathione to the glucose selenite is 75:15:11: 10. Preferably, the glucose selenite is prepared by the following method: s31, weighing 0.45g of glucose, adding 100ml of 1.2% (W/V) nitric acid, stirring at 240rpm for 15min, and standing for 8 h; performing nitrogen protection in the reaction; s32, adding 1.1g of barium chloride and 0.3g of selenious acid under ultrasound, heating to 68 ℃, reacting for 24min, and cooling to room temperature; wherein the ultrasonic conditions are as follows: the power is 4.8kW, and the frequency is 25 kHz; s33, carrying out vacuum filtration, stirring and dripping 20ml of 1.5mol/L sulfuric acid into the filtrate, standing for 5min, and centrifuging at 30 ℃ and 4000rpm for 10 min; s34, taking the supernatant, adjusting the pH value to 6-7, performing ultrafiltration, replacing 15-30 times volume of the supernatant with purified water until 2% (M/M) ascorbic acid solution is detected to have no red color, concentrating under reduced pressure (50 ℃, 0.06Mpa) to 1/10 of the original volume, adding 0.8 times (v/v) ethanol for precipitation, standing for 3h, centrifuging, and freeze-drying the precipitate to obtain the compound. Preferably, the freeze-drying condition is-50 ℃ and 0.01 MPa.
Preferably, the scopolamine butylbromide injection further comprises an osmotic pressure regulator. The content of the osmotic pressure regulator is 80-84mg/10ml, and the osmotic pressure regulator can be any one of fructose, sodium chloride and glucose.
A preparation method of scopolamine butylbromide injection comprises the following steps:
(1) adding 60-80% of water for injection into prescription amount of pH buffer pair, stirring for 10-30min to dissolve completely, and controlling pH to 4.8-5.2; preferably, the injection water is used for removing residual oxygen by adopting a physical means through simultaneously regulating and controlling temperature and pressure and introducing nitrogen.
(2) Adding scopolamine butylbromide with the formula ratio, and stirring for dissolving; adding the formula amount of stabilizer and the rest water for injection, and stirring for 15-45 min;
(3) filtering with 0.22 μm microporous membrane, bottling, introducing nitrogen gas for protection, and sterilizing at 121 deg.C for 12 min.
Preferably, the water for injection is pretreated by the following method: s11, filling nitrogen in the stirring kettle in advance, adding injection water, heating to 50-65 ℃, vacuumizing to 0.015-0.045Mpa, and stirring under reduced pressure for 30-60 min; for example, a vacuum is applied to 0.035 MPa; s12, slowly reducing the temperature to 4-10 ℃ at the speed of 8-10 ℃/h, introducing nitrogen into the stirring kettle to 0.15-0.35Mpa, pressurizing, stirring for 20-40min, and standing to normal temperature and normal pressure for later use. Preferably, the step S11 is vacuumized to 0.035MPa, and the step S12 is aerated with nitrogen to 0.15 MPa.
More preferably, the water for injection is pretreated by the following method: s11, filling nitrogen in the stirring kettle in advance, adding injection water, heating to 50-65 ℃, vacuumizing to 0.015-0.045Mpa, and stirring under reduced pressure for 30-60 min; s12, slowly reducing the temperature to 4-10 ℃ at the speed of 8-10 ℃/h, introducing nitrogen into the stirring kettle to 0.15-0.35Mpa, and stirring for 30min under pressure; s13, slowly heating to 50-65 deg.C at a speed of 12-15 deg.C/h, and slowly reducing pressure to 0.015-0.045MPa, such as 0.025MPa, and stirring for 30-60 min; s14, slowly reducing the temperature to 4-10 ℃ at the speed of 10 ℃/h, simultaneously slowly introducing nitrogen into the stirring kettle at the speed of 0.04Mpa/h, pressurizing to 0.15-0.35Mpa, pressurizing and stirring for 20-40min, and standing to normal temperature and normal pressure for standby.
Preferably, the scopolamine butylbromide in the step (2) is refined by the following method: s21 in the scopolamine butylbromide (200mg) as 1: 4-7 (m/v, g/ml) of ethanol aqueous solution with the concentration of 95% (v/v); s22, heating to 55-65 ℃, and refluxing to fully dissolve; s23, cooling to 10-15 ℃ within 20-30min, stirring and preserving heat for 1 h; then cooling to-2-5 ℃ within 30min, standing for 3-5h, and filtering; s24, washing the crystal with 0.8-3 times (v/m) of ice-cold absolute ethyl alcohol, drying by pumping, and drying in vacuum to obtain the product. More preferably, the scopolamine butylbromide in the step (2) is purified by the following method: s21 in the scopolamine butylbromide (200mg) as 1: 4-7 (m/v, g/ml) of ethanol aqueous solution with the concentration of 95% (v/v); s22, heating to 55-65 ℃, adding tryptophan with the amount of the prescription under stirring, and refluxing to be fully dissolved; s23, cooling to 12 ℃ within 20-30min, stirring and preserving heat for 1 h; then cooling to-2-5 ℃ within 30min, standing for 3-5h, and filtering; s24, washing the crystal with 0.8-3 times (v/m) of ice-cold absolute ethyl alcohol, drying by pumping, and drying in vacuum to obtain the product.
Compared with the prior art, the scopolamine butylbromide injection and the preparation method thereof have the following advantages: (1) the scopolamine butylbromide injection disclosed by the invention is optimized in formula, the pH of the injection is kept stable by using the acid-base buffering capacity of a pH buffering pair, and meanwhile, the amino acid is used as a stabilizer, particularly aromatic amino acid, so that the ultraviolet light has the maximum light absorption, and the stability of the injection is improved; (2) the scopolamine butylbromide injection removes residual oxygen in the solution by a physical method, and has the advantages of simple components, stable quality and low adverse reaction rate in use; meanwhile, the method avoids the use of less nitrogen, proper heating temperature and low cost; (3) the scopolamine butylbromide injection disclosed by the invention utilizes a pH buffer pair to control the pH of the solution to be always within 4.8-5.2, the pH buffer pair is dissolved in water for injection, the pH of the solution is adjusted to be acidic, and the scopolamine butylbromide is prevented from being degraded due to overhigh and overlow local pH; meanwhile, the adding sequence of the auxiliary material tryptophan is changed, the purity of the raw material, namely scopolamine butylbromide, is improved, and the product has good stability and high safety.
Detailed Description
It should be noted that the embodiments and features of the embodiments may be combined with each other without conflict.
Although scopolamine butylbromide has obvious clinical curative effect, the related research on the storage stability of the injection is less. In the prior art, scopolamine butylbromide injection is sensitive to pH, temperature and illumination, and tropine acid which is an impurity generated in the storage process can influence the pH of the injection and accelerate the degradation of a main drug, so that poor storage stability is caused, and finally impact is generated on the safety of the drug. The applicant has found that; in particular, ultraviolet light with shorter wavelength is easy to destroy ester bonds contained in scopolamine butylbromide, and the oxidation effect and the illumination condition have strong synergistic effect.
Further research by the applicant finds that: the stability and the safety of the preparation are influenced by the formula and the process; specifically, the formula of the preparation can protect the main medicine, effectively inhibit the degradation of the main medicine and avoid generating new impurities; the process determines the content of impurities in the preparation and the production cost. The present invention will be described in detail with reference to examples.
Example 1
A scopolamine butylbromide injection contains scopolamine butylbromide 200mg, glutathione 4.2mg, and water for injection 10ml, with pH of 5.05.
The preparation method comprises the following steps: (1) taking 70% of the formula amount of water for injection, and adjusting the pH value to 5.1 by using 0.1M hydrochloric acid; (2) adding scopolamine butylbromide with the formula ratio, and stirring for 30min at 150 rpm; (3) adding glutathione and the rest water for injection, stirring for 25min, filtering with 0.22 μm microporous membrane, bottling, introducing nitrogen gas for protection, and sterilizing at 121 deg.C for 12 min.
Example 2
A scopolamine butylbromide injection contains scopolamine butylbromide 200mg, tryptophan 15mg, phenylalanine 3mg, disodium hydrogen phosphate 19mg, and citric acid 7mg, and is added to 10ml of water for injection, with pH of 4.92.
The preparation method comprises the following steps: (1) taking 60% formula amount of water for injection, adding formula amount of disodium hydrogen phosphate and citric acid, stirring at 180rpm for 12min to completely dissolve; (2) adding scopolamine butylbromide with the formula ratio, and stirring for 30min at 120 rpm; (3) adding tryptophan, phenylalanine and the rest water for injection, controlling pH to 4.9, stirring for 20min, filtering with 0.22 μm microporous membrane, bottling, introducing nitrogen gas for protection, and sterilizing at 121 deg.C for 12 min.
Example 3
A scopolamine butylbromide injection contains scopolamine butylbromide 200mg, tryptophan 15mg, phenylalanine 3mg, disodium hydrogen phosphate 19mg, and citric acid 7mg, and is added to 10ml of water for injection, with pH of 4.9.
The procedure of example 2 was otherwise the same as for the pretreatment of the water for injection of scopolamine butylbromide injection. The pretreatment specifically comprises the following steps: pre-filling nitrogen into the stirring kettle, adding water for injection, heating to 62 deg.C, vacuumizing to 0.035Mpa, and stirring under reduced pressure for 30 min; slowly cooling to 4 deg.C at a speed of 8 deg.C/h, introducing nitrogen gas to 0.25Mpa, pressurizing, stirring for 30min, and standing at normal temperature and normal pressure.
Example 4
A scopolamine butylbromide injection contains scopolamine butylbromide 200mg, tryptophan 15mg, phenylalanine 3mg, disodium hydrogen phosphate 19mg, and citric acid 7mg, and is added to 10ml of water for injection, with pH of 4.9.
The procedure of example 2 was otherwise the same as for the pretreatment of the water for injection of scopolamine butylbromide injection. The pretreatment specifically comprises the following steps: pre-filling nitrogen into the stirring kettle, adding water for injection, heating to 60 deg.C, vacuumizing to 0.035Mpa, and stirring under reduced pressure for 45 min; slowly reducing the temperature to 8 ℃ at the speed of 10 ℃/h, introducing nitrogen into the stirring kettle to 0.25Mpa, and stirring for 30min under pressure; slowly heating to 60 deg.C at a speed of 15 deg.C/h, slowly reducing pressure to 0.035Mpa at a speed of 0.04Mpa/h, stirring for 40min, slowly reducing temperature to 4-10 deg.C at a speed of 8 deg.C/h, slowly introducing nitrogen gas into the stirring kettle at a speed of 0.04Mpa/h to pressurize to 0.25Mpa, stirring for 25min, and standing at room temperature and normal pressure.
Example 5
A scopolamine butylbromide injection contains scopolamine butylbromide 200mg, tryptophan 15mg, phenylalanine 3mg, glutathione 4.2mg, disodium hydrogen phosphate 19mg, citric acid 7mg, and water for injection is added to 10ml, and pH value is 4.9.
The preparation method comprises the following steps: (1) the method of example 4 is used to pretreat water for injection; (2) taking 60% formula amount of water for injection, adding formula amount of disodium hydrogen phosphate and citric acid, stirring at 200rpm for 10min to completely dissolve; (2) adding scopolamine butylbromide with the formula ratio, and stirring at 150rpm for 15 min; (3) adding tryptophan, phenylalanine, glutathione and the rest water for injection, controlling pH to 4.9, stirring for 20min, filtering with 0.22 μm microporous membrane, bottling, introducing nitrogen gas for protection during the whole preparation and bottling process, and sterilizing at 121 deg.C for 12 min.
Example 6
A scopolamine butylbromide injection contains scopolamine butylbromide 200mg, tryptophan 15mg, phenylalanine 3mg, glutathione 4.2mg, disodium hydrogen phosphate 19mg, citric acid 7mg, and water for injection is added to 10ml, and pH value is 4.9.
The preparation method comprises the following steps: (1) the method of example 4 is used to pretreat water for injection; (2) scopolamine butylbromide was purified-S21 in a ratio of 1: 4-7 (m/v, g/ml) of ethanol aqueous solution with the concentration of 95% (v/v); s22, heating to 60 ℃, and refluxing to fully dissolve; s23, cooling to 15 ℃ within 20min, stirring and preserving heat for 1 h; then cooling to-2-5 ℃ within 30min, standing for 5h, and filtering; s24, washing and crystallizing with 2 times (v/m) of ice-cold absolute ethyl alcohol, and performing suction drying and vacuum drying to obtain the crystal; (3) adding 72% of formula amount of water for injection into the formula amount of disodium hydrogen phosphate and citric acid, and stirring at 150rpm for 20min to completely dissolve; (4) adding the scopolamine butylbromide drying substance prepared in the step (2), and stirring for 16min at 220 rpm; (5) adding tryptophan, phenylalanine, glutathione and residual water for injection, controlling pH to 4.9, stirring for 25min, filtering with 0.22 μm microporous membrane, bottling, introducing nitrogen gas for protection, and sterilizing at 121 deg.C for 12 min.
Example 7
A scopolamine butylbromide injection contains scopolamine butylbromide 200mg, tryptophan 15mg, phenylalanine 3mg, glutathione 4.2mg, disodium hydrogen phosphate 19mg, citric acid 7mg, and water for injection is added to 10ml, and pH value is 4.9.
The preparation method comprises the following steps: (1) the method of example 4 is used to pretreat water for injection; (2) scopolamine butylbromide was purified-S21 in a ratio of 1: 4-7 (m/v, g/ml) of ethanol aqueous solution with the concentration of 95% (v/v); s22, heating to 62 ℃, adding phenylalanine with the amount according to the prescription under stirring, and refluxing to be fully dissolved; s23, cooling to 12 ℃ within 20min, stirring and preserving heat for 1 h; then cooling to-2-5 ℃ within 30min, standing for 3h, and filtering; s24, washing and crystallizing with 2.5 times (v/m) of ice-cold absolute ethyl alcohol, pumping, and drying in vacuum to obtain the product; (3) adding 78% of injection water according to the formula amount into the disodium hydrogen phosphate and citric acid according to the formula amount, and stirring at 150rpm for 20min to completely dissolve the disodium hydrogen phosphate and the citric acid; (4) adding the scopolamine butylbromide drying substance prepared in the step (2), and stirring at 180rpm for 20 min; (5) adding tryptophan, glutathione and the rest water for injection, controlling pH to 4.9, stirring for 25min, filtering with 0.22 μm microporous membrane, bottling, introducing nitrogen gas for protection, and sterilizing at 121 deg.C for 12 min.
Example 8
A scopolamine butylbromide injection contains scopolamine butylbromide 200mg, tryptophan 15mg, phenylalanine 3mg, glutathione 4.2mg, disodium hydrogen phosphate 19mg, citric acid 7mg, and water for injection is added to 10ml, and pH value is 4.9.
The preparation method comprises the following steps: (1) the method of example 4 is used to pretreat water for injection; (2) scopolamine butylbromide was purified-S21 in a ratio of 1: 4-7 (m/v, g/ml) of ethanol aqueous solution with the concentration of 95% (v/v); s22, heating to 62 ℃, adding tryptophan with the amount of the prescription under stirring, and refluxing to be fully dissolved; s23, cooling to 12 ℃ within 20min, stirring and preserving heat for 1 h; then cooling to-2-5 ℃ within 30min, standing for 3h, and filtering; s24, washing and crystallizing with 2.5 times (v/m) of ice-cold absolute ethyl alcohol, pumping, and drying in vacuum to obtain the product; (3) adding 78% of injection water according to the formula amount into the disodium hydrogen phosphate and citric acid according to the formula amount, and stirring at 150rpm for 20min to completely dissolve the disodium hydrogen phosphate and the citric acid; (4) adding the scopolamine butylbromide drying substance prepared in the step (2), and stirring at 180rpm for 20 min; (5) adding phenylalanine, glutathione and residual water for injection, controlling pH to 4.9, stirring for 25min, filtering with 0.22 μm microporous membrane, bottling, introducing nitrogen gas for protection, and sterilizing at 121 deg.C for 12 min.
Example 9
A scopolamine butylbromide injection contains scopolamine butylbromide 200mg, tryptophan 15mg, phenylalanine 3mg, glutathione 2.2mg, glucose selenite 2mg, disodium hydrogen phosphate 19mg, and citric acid 7mg, and is added to 10ml of water for injection, with pH value of 5.0.
Wherein the glucose selenite is prepared by the following method: (1) weighing 0.45g of glucose, adding 100ml of 1.2% (W/V) nitric acid solution, stirring at 240rpm for 15min, and standing for 8 h; performing nitrogen protection in the reaction; (2) adding 1.1g of barium chloride and 0.3g of selenious acid under ultrasound, heating to 68 ℃, reacting for 24min, and cooling to room temperature; wherein the ultrasonic conditions are as follows: the power is 4.8kW, and the frequency is 25 kHz. (3) Vacuum filtering, stirring the filtrate, adding 1.5mol/L sulfuric acid 20ml dropwise, standing for 5min, centrifuging at 30 deg.C and 4000rpm for 10 min; (4) adjusting the pH of the supernatant to 6-7, performing ultrafiltration, replacing 15-30 times volume of 2% (M/M) ascorbic acid solution with purified water until no red appears, concentrating under reduced pressure (50 ℃, 0.06Mpa) to 1/10 of the original volume, adding 0.8 times (v/v) ethanol for precipitation, standing for 3h, centrifuging, and freeze-drying the precipitate at-50 ℃ and 0.01MPa to obtain the compound;
and (3) adding glucose selenite and glutathione in the step (5), wherein other preparation methods are the same as those in the example 8 and are not described herein.
Comparative example 1
A commercial scopolamine butylbromide injection (manufactured by Shandong Weifang pharmaceutical factory Co., Ltd., Jingkang Suo brand).
Experimental example 1 group optimization
A great deal of research on the formula of scopolamine butylbromide injection shows that the stability of scopolamine butylbromide injection can be influenced by the difference of the formula, especially the stability under the illumination condition. Amino acid is used as an essential component of a human body, and has good biocompatibility; has antioxidant effect, and can be added into injection as adjuvant. The applicant sets and experiments the amino acid components and the dosage in the scopolamine butylbromide injection according to the following table 1:
the recipe for preparing the injection sample is as follows: scopolamine butylbromide 200mg, amino acid antioxidant 10-25mg, disodium hydrogen phosphate 19mg, citric acid 7mg, water for injection added to 10ml, pH 5.1, the preparation method is the same as example 2, and details are not repeated herein.
Placing the injection sample for the experiment in a clean container, and taking the comparative example 1 as a control; placing the glass at the illumination of 60lx for 12h every day, and then keeping out of the sun for 12 h; the sample was kept at 25. + -. 0.5 ℃ for 6 days, and samples were taken on day 3 and day 6, and examined according to the stability stress test items, and the results were compared with those on day 0, and are shown in Table 1.
TABLE 1 Effect of different Components on the stability of the injection
The prior art has pointed out that: scopolamine butylbromide is sensitive to pH, temperature and illumination, and scopolamine butylbromide injection has poor stability, especially stability under illumination conditions; the storage condition is improper, impurities are easily generated, the safety problem of the medicine is caused, and even serious medical accidents occur. The applicant researches and discovers that: the existing scopolamine butylbromide injection has simple components and poor pH buffering capacity; the tropine acid generated by degradation is easy to cause the pH value of the injection to fluctuate, and even accelerate the degradation of the medicine.
To this end, the applicant added a pH buffer pair to the scopolamine butylbromide injection to ensure that the pH of the injection was stable throughout storage. Secondly, the applicant researches and discovers that: the amino acid antioxidant can consume residual oxygen in the injection, protect scopolamine butylbromide in the injection and effectively avoid the synergistic effect of the residual oxygen and the illumination condition; in addition, the results of screening commonly used amino acids are shown in table 1; the applicants have surprisingly found that: aromatic amino acids such as tryptophan, tyrosine and phenylalanine have better protection effect on scopolamine butylbromide in the injection; wherein, tryptophan and tyrosine both contain conjugated double bonds, and have maximum light absorption at 280nm and 275nm, respectively, and phenylalanine has maximum absorption peak at 257nm, and the prior art generally utilizes the principle to determine protein content. After a plurality of tests, the following results are determined: tryptophan: phenylalanine 5:1, when the total content is 18mg/10ml, the stability of the scopolamine butylbromide injection is obviously superior to that of the comparative example 1.
Experimental example 2 product stability test
The scopolamine butylbromide injections of examples 3, 5, 6, 9 and 10 and comparative example 1 were subjected to stability tests under conditions of 25 ℃ and 55% RH for 6 months, and samples were taken at 0 th, 3 th and 6 th months, respectively, to determine properties, pH, and related substances and contents thereof, and the related substances and contents were determined by reference to the contents of scopolamine butylbromide injections in "second part of chinese pharmacopoeia 2015 edition", with the test results shown in tables 2 and 3.
TABLE 2 stability test results for scopolamine butylbromide injection
TABLE 3 stability test results of scopolamine butylbromide injection
The applicant finds in research that impurities of scopolamine butylbromide injection have two sources, one of the impurities is the residual impurities of the raw material namely scopolamine butylbromide after refining, and the impurities are usually removed by multiple or multiple refining operations, and the production cost is increased by the additional refining operation; and secondly, the scopolamine butylbromide injection is newly generated due to factors such as light, heat, pH and the like in the storage process, wherein the degradation of scopolamine butylbromide by residual oxygen and illumination in the solution also has a synergistic effect. At present, in the production of injection preparations, nitrogen is used for obstructing the contact of a solution and oxygen and/or antioxidants such as sodium metabisulfite, ascorbic acid, nicotinamide and the like are added to consume the residual oxygen in the solution so as to improve the stability; however, other added components easily cause adverse reactions of patients, and the quality of the medicine is difficult to control.
Through a large number of experiments, the following results are found: compared with other amino acids, the aromatic amino acid can absorb ultraviolet light with shorter wavelength, so that the stability of the scopolamine butylbromide injection is effectively improved; wherein the ratio of tryptophan: phenylalanine is expressed as 5:1 the effect of the composite addition is optimal (example 2); secondly, in order to reduce the content of residual oxygen in the injection, the applicant pretreats the injection water, namely controls the temperature and the pressure to cooperatively play a role so as to effectively remove the residual oxygen, improves the stability of the solution by a physical method, does not need to use a chemical antioxidant, and has low cost, good biocompatibility and low adverse reaction rate (example 3); the storage stability of the injection water was also affected by the positive correlation between the number of pretreatments and the residual oxygen content in the injection solution (example 5). On the basis, the applicant further studies the formula of scopolamine butylbromide injection, and finds that a small amount of glutathione can further improve the stability (example 5), and the combination and matching effect of the glutathione and chitosan selenite is the best (example 9), and the possible reason is that the glutathione is polypeptide and can play a role in protecting scopolamine butylbromide; the chitosan selenite has strong inoxidizability, further consumes trace residual oxygen in water, and avoids oxidative degradation of scopolamine butylbromide. Furthermore, the applicant found that: further impurities can be removed by refining operations; and tryptophan is added in the crystallization, the tryptophan and scopolamine butylbromide can form a crystalline material which is regularly arranged in the same crystal lattice through a certain acting force in the crystallization process, an eutectic phenomenon exists between the tryptophan and scopolamine butylbromide, the refining effect is better (examples 6, 7 and 8), the adding sequence of auxiliary materials, namely tryptophan, is only changed in the production, and the operation is simple.
As can be seen from tables 2 and 3, the residual oxygen content in the scopolamine butylbromide injection is reduced by a physical method, the generation of new impurities is reduced, and the stability of the injection is improved; meanwhile, the feeding sequence of the auxiliary materials is changed, so that the content of impurities in the raw materials is reduced, and the storage stability and the medication safety of the medicine are improved together.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (4)
1. A scopolamine butylbromide injection is characterized by comprising 200mg of scopolamine butylbromide, 10-100mg of pH buffer pair, 1.2-36mg of stabilizer, 10ml of water for injection, and the pH value of the injection is 4.8-5.4; the stabilizer contains tryptophan, phenylalanine and glutathione, wherein the weight ratio of the tryptophan to the phenylalanine is 5:1, the total content is 18mg/10 ml;
the preparation method comprises the following steps:
(1) adding 60-80% of water for injection into prescription amount of pH buffer pair, stirring for 10-30min to dissolve completely, and controlling pH to 4.8-5.2;
the water for injection is pretreated by the following method: s11, filling nitrogen in the stirring kettle in advance, adding injection water, heating to 50-65 ℃, vacuumizing to 0.015-0.045Mpa, and stirring under reduced pressure for 30-60 min; s12, slowly reducing the temperature to 4-10 ℃ at the speed of 8-10 ℃/h, introducing nitrogen into the stirring kettle to 0.15-0.35Mpa, and stirring for 30min under pressure; s13, slowly heating to 50-65 ℃ at the speed of 12-15 ℃/h, and slowly reducing the pressure to 0.015-0.045MPa at the speed of 0.04MPa/h, and stirring for 30-60 min; s14, slowly reducing the temperature to 4-10 ℃ at the speed of 10 ℃/h, simultaneously slowly introducing nitrogen into the stirring kettle at the speed of 0.04Mpa/h, pressurizing to 0.15-0.35Mpa, pressurizing and stirring for 20-40min, and standing to normal temperature and normal pressure for standby;
(2) adding scopolamine butylbromide with the formula ratio, and stirring for dissolving; adding the rest formula amount of stabilizer and the rest water for injection, and stirring for 15-45 min;
the scopolamine butylbromide is refined by adopting the following method: s21 in scopolamine butylbromide at a ratio of 1: adding 95% (v/v) ethanol water solution into 4-7 g/ml; s22, heating to 55-65 ℃, adding tryptophan with the amount of the prescription under stirring, and refluxing to be fully dissolved; s23, cooling to 12 ℃ within 20-30min, stirring and preserving heat for 1 h; then cooling to-2-5 ℃ within 30min, standing for 3-5h, and filtering; s24, washing and crystallizing with 0.8-3 times of v/m ice-cold absolute ethyl alcohol, pumping, and drying in vacuum to obtain the product;
(3) filtering with 0.22 μm microporous membrane, bottling, introducing nitrogen gas for protection, and sterilizing at 121 deg.C for 12 min.
2. The scopolamine butylbromide injection according to claim 1, wherein the pH buffer pair is an acid-base buffer pair consisting of a salt of a weak acid with a strong base weak acid root, comprising any one or more of citric acid-disodium hydrogen phosphate, citric acid-sodium citrate, phosphoric acid-disodium hydrogen phosphate.
3. The scopolamine butylbromide injection of claim 1, wherein said stabilizer further comprises glucose selenite.
4. The scopolamine butylbromide injection of claim 1, wherein the vacuum is drawn to 0.035Mpa in step S11, and the nitrogen is bubbled to 0.15Mpa in step S12.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102146079A (en) * | 2011-02-28 | 2011-08-10 | 广州瑞尔医药科技有限公司 | Preparation method of scopolamine butylbromide |
| CN102366402A (en) * | 2011-09-28 | 2012-03-07 | 河南辅仁怀庆堂制药有限公司 | Scopolamine hydrobromide injection and production technology |
| JP2016029029A (en) * | 2014-07-23 | 2016-03-03 | エスエス製薬株式会社 | Oral composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102146079A (en) * | 2011-02-28 | 2011-08-10 | 广州瑞尔医药科技有限公司 | Preparation method of scopolamine butylbromide |
| CN102366402A (en) * | 2011-09-28 | 2012-03-07 | 河南辅仁怀庆堂制药有限公司 | Scopolamine hydrobromide injection and production technology |
| JP2016029029A (en) * | 2014-07-23 | 2016-03-03 | エスエス製薬株式会社 | Oral composition |
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| Title |
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| pH值对丁溴东莨菪碱溶液稳定性的影响;云晓琳等;《今日药学》;20130131;第23卷;第19-22页 * |
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