Butylphthalide injection and preparation method thereof

Abstract

The invention provides a butylphthalide injection and a preparation method thereof, and relates to the technical field of medicines.The butylphthalide injection comprises butylphthalide, cholate, phospholipid and water for injection, the cholate is prepared through a reaction of cholic acid and sodium hydroxide; the molar ratio of the phospholipid to the cholic acid is (0.3-1.2): 1. The mass fraction of butylphthalide in the butylphthalide injection is 0.025%-1%, the butylphthalide, cholate and phospholipid are mixed and proportioned under the conditions of certain concentration and mass ratio and cholic acid and phospholipid in the cholate under the condition of certain molar ratio, and the butylphthalide injection of a clear solution is prepared; the preparation process of the butylphthalide injection is simple, the stability of the injection is further improved through repeated dissolving and stirring, clinical medication requirements are met, and industrial production is facilitated.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and in particular relates to a butylphthalide injection and a preparation method thereof. Background Art

[0002] 3-n-butylphthalide (NBP), full name 3-butyl-1(H)-isobenzofuranone, also known as apigenin, has a chemical formula of C 12 H 14 O 2 , is the L-isomer extracted from celery seeds, and the racemate can also be synthesized artificially. Butylphthalide is an oily liquid that is insoluble in water and has a strong celery smell. It contains a chiral carbon atom in the molecule, so it has two optical isomers, namely L-butylphthalide and D-butylphthalide. Butylphthalide is a drug for the treatment of ischemic stroke and can be used to treat hypertension. It has a neuroprotective effect, shrinks the infarct focus after focal cerebral ischemia, reduces the degree of neurological damage, and improves brain energy metabolism after global cerebral ischemia.

[0003] At present, the injection products of butylphthalide mostly adopt cyclodextrin inclusion technology. For example, Chinese invention patent CN109985035A discloses a butylphthalide sodium chloride injection containing hydroxypropyl-β-cyclodextrin. The prepared injection has a maximum volume of 100mL, including 25mg of butylphthalide and 0.9g of sodium chloride. The molar ratio of hydroxypropyl-β-cyclodextrin to butylphthalide is 3-5:1. After calculation, the prescription amount of hydroxypropyl-β-cyclodextrin in 100mL injection is 0.51-0.9g. Combined with the instructions for butylphthalide sodium chloride injection, 200mL is administered daily, that is, the amount of hydroxypropyl-β-cyclodextrin is close to the maximum daily exposure (the US FDA approved drug inactive ingredient database requires that the maximum daily exposure of hydroxypropyl-β-cyclodextrin when administered by intravenous and intramuscular injection is 1333mg). Hydroxypropyl-β-cyclodextrin is cleared by glomerular filtration, and its instructions have clear restrictions on the patient's renal function. Moreover, the volume of butylphthalide injection prepared by this technology is 100 mL, which can only be administered by intravenous drip and cannot meet the clinical medication needs well.

[0004] Phospholipids and bile salts can significantly improve the solubility of poorly soluble drugs and have been successfully used to solubilize drugs such as diazepam, vitamin K1, and multivitamins (12). The phospholipid and bile salt system has good safety and biocompatibility. It is a biocompatible medium and is called a "physiological excipient."

[0005] Chinese invention patent CN114869848A discloses a butylphthalide micelle composition, which can be an injection or a freeze-dried powder injection, and its raw materials include butylphthalide, phospholipids, bile acid or its salt, stabilizer and organic solvent. The patent dissolves butylphthalide, phospholipids or bile acid / bile salt in an organic solvent, forms a loose film by rotary evaporation, dissolves it with a stabilizer solution to obtain a clear solution, and freeze-dries it after constant volume. Butylphthalide, phospholipids or bile acid / bile salt are dissolved in an organic solvent or a mixed solvent of an organic solvent and water for injection, freeze-dried, and the freeze-dried block is dissolved with a stabilizer solution; although the use of other surfactants such as cyclodextrin is avoided, the clinical safety is improved to a certain extent, but the patent method uses an organic solvent, and the production safety and recycling of the organic solvent are still problematic.

[0006] Chinese invention patent CN107970208A discloses a butylphthalide injection and a preparation method thereof, wherein the butylphthalide injection comprises butylphthalide or its derivatives, a surfactant and water for injection. The invention indicates that the dosage of the active agent is relatively large, and a stabilizer is also added to maintain the stability of the injection.

[0007] Therefore, the butylphthalide injection in the prior art still has the problems of organic solvents affecting safety, excessive use of surfactants such as cyclodextrin causing damage to the kidneys, and the need to add stabilizers and other ingredients to the injection to maintain the long-term stability of the butylphthalide injection. Moreover, it is not clear what effect the formula of each ingredient in the butylphthalide injection has on the quality, stability and efficacy of the injection. The above problems need to be solved urgently. Summary of the invention

[0008] The invention aims at the problems existing in the prior art and provides a butylphthalide injection and a preparation method thereof. The butylphthalide injection comprises butylphthalide, cholate, phospholipid and water for injection; the drug concentration of butylphthalide in the injection is 2.5-10 mg / mL; butylphthalide, cholate and phospholipid are mixed under certain concentration and mass ratio conditions to prepare the butylphthalide injection of a clear solution; the preparation process is simple and suitable for industrial production; the obtained sample has stable quality, high encapsulation rate, high safety and good stability, and meets the clinical drug use needs.

[0009] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0010] On the one hand, the present invention provides a butylphthalide injection, comprising components: butylphthalide, cholate, phospholipid and water; the molar ratio of the phospholipid to cholic acid is 0.3-1.2:1; the mass fraction of butylphthalide in the injection is 0.025%-1%; the mass fraction of cholic acid in the injection is 0.546%-5.88%.

[0011] Preferably, the molar ratio of phospholipid to bile acid is 0.3-1.2:1, and the molar ratio includes any range, real number and endpoint value within the numerical range, for example but not limited to 0.3-1.2:1, 0.3-0.7:1, 0.7-1.2:1, 0.5-0.96:1.

[0012] Further preferably, the molar ratio of phospholipid to bile acid is 0.5-0.96:1; the molar ratio includes any range, real number and endpoint value within the numerical range, for example but not limited to 0.5-0.96:1, 0.5-0.7:1, 0.7-96:1.

[0013] More preferably, the molar ratio of phospholipid to bile acid is 0.85:1.

[0014] Preferably, the mass fraction of butylphthalide in the injection is 0.5-1%.

[0015] Preferably, the mass fraction of the phospholipid in the injection is 0.756%-10.67%.

[0016] Preferably, the butylphthalide injection comprises the following components by mass fraction: 0.5-1% butylphthalide, 4.933%-5.918% bile salt, 3.51-8.00% phospholipids and the remainder water.

[0017] Further preferably, the butylphthalide injection comprises the following components by mass fraction: 0.5% butylphthalide, 4.933%-5.918% bile salt, 7-7.56% phospholipids and the remainder water.

[0018] Preferably, the bile salt can be a common commercial product or a self-prepared product; the preparation method of the bile salt comprises the steps of: mixing bile acid with sodium hydroxide solution and stirring to obtain the bile salt.

[0019] Further preferably, the method for preparing bile salt comprises the steps of: dissolving sodium hydroxide with an appropriate amount of water for injection, adding a prescribed amount of glycocholic acid, heating at 50-65° C., and stirring at 200-600 rpm to dissolve, thereby preparing bile salt.

[0020] Further preferably, in the method for preparing bile salt, the amount of water for injection is 5-59% of the volume of the injection solution; the amount of water for injection includes any range, real number and endpoint value within the numerical range, for example but not limited to 5-59%, 6-50%, 5-10%, 10-20%, 20-35%, 35-50%, 50-59%; within the above-mentioned dosage range of the present invention, the prepared butylphthalide injection can achieve the technical effect of the present invention without significant difference.

[0021] More preferably, the amount of water for injection accounts for 6-50% of the volume of the injection solution; the amount of water for injection includes any range, real number and endpoint value within the numerical range, for example but not limited to 6-50%, 12-50%, 6-20%, 20-35%, 35-50%; within the above-mentioned dosage range described in the present invention, the prepared butylphthalide injection can achieve the technical effect of the present invention without significant difference.

[0022] More preferably, the amount of water for injection accounts for 12-50% of the volume of the injection solution; the amount of water for injection includes any range, real number and endpoint value within the numerical range, for example but not limited to 12-50%, 12-40%, 40-50%, 26-50%; within the above-mentioned dosage range of the present invention, the prepared butylphthalide injection can achieve the technical effect of the present invention without significant difference.

[0023] Preferably, the bile salt is selected from at least one of sodium glycocholate, sodium glycodeoxycholate and sodium taurocholate.

[0024] More preferably, the pH of the bile salt is 5.4-5.8; even more preferably, it is 5.48-5.68.

[0025] Preferably, the phospholipid is selected from at least one of soybean lecithin, egg choline and hydrogenated phospholipids.

[0026] In the present invention, the water is water for injection.

[0027] In the present invention, the injection solution is an undiluted injection solution, an injection solution diluted with glucose injection solution, or an injection solution diluted with water for injection.

[0028] On the other hand, the present invention provides a method for preparing the above-mentioned butylphthalide injection, comprising the steps of:

[0029] (1) mixing a bile salt solution with phospholipids and butylphthalide, and stirring to prepare a mixture system;

[0030] (2) The mixture system is kept at a temperature and allowed to stand or continue to be stirred, depending on the viscosity, to obtain a mixture A;

[0031] (3) Mixing mixture A with part of water and stirring to obtain mixture B;

[0032] (4) Mixture B is fixed to volume, filtered, and bottled to obtain a butylphthalide injection.

[0033] Preferably, in step (1), the pH of the bile salt solution is 5.4-5.8.

[0034] Further preferably, the pH of the bile salt solution is 5.48-5.68.

[0035] Preferably, in step (1), the stirring temperature is 25-70° C., the stirring speed is 200-600 rpm, and the stirring time is 10-20 min.

[0036] More preferably, in step (1), the stirring temperature is 25-60°C.

[0037] Preferably, in step (2), the viscous state is divided into the mixture system being viscous or solution-like; when it is viscous, it is kept at 50-65° C. for 1-12 hours; when it is solution-like, it is kept at 50-65° C. for 3-21 hours with continuous stirring.

[0038] Preferably, in step (3), mixture A is mixed with part of water, and the mixing needs to be carried out in batches, the number of batches is 1-3 times, until the volume of mixture B is 75-85% of the total volume of the finished product of butylphthalide injection, and the operating temperature of step (3) is 25-90°C.

[0039] Further preferably, mixture A is first mixed with part of the water, stirred into a solution state, and continued to stir for 1-16 hours; then mixed with the remaining part of the water until the volume of mixture B is 75-85% of the total volume of the finished injection solution of butylphthalide, and the pH of mixture B is adjusted to 4.5-6.5; the speed of continued stirring is 200-1200rpm.

[0040] More preferably, the substance for adjusting the pH of the mixture B is at least one selected from sodium hydroxide solution and hydrochloric acid solution.

[0041] More preferably, the operating temperature of step (3) is 25-70°C; even more preferably, the operating temperature of step (3) is 25-60°C.

[0042] Preferably, in step (4), the filtration is performed through a 0.2 μm PES filter membrane.

[0043] After filling, the present invention can be terminally sterilized, and the sterilization is maintained at 110-130° C. for 10-20 minutes.

[0044] In step (3) of the present invention, before mixing with the remaining water until the volume of mixture B is 75-85% of the total volume of the finished injection solution of butylphthalide, if there is a large amount of foam, it is necessary to stand and defoam.

[0045] In the present invention, the filling specification is 2.5-100mL / vial.

[0046] In the present invention, the injection solution may be an undiluted injection solution, an injection solution diluted with glucose injection solution, or an injection solution diluted with water for injection.

[0047] The injections prepared under various conditions within the scope of the present invention have no significant differences in technical effects.

[0048] Compared with the prior art, the present invention has the following beneficial effects:

[0049] 1. The butylphthalide injection prepared by the present invention does not use cyclodextrin and other synthetic surfactants in the components, nor does it add stabilizer components, and no organic solvent is added in the process of preparing the injection; the present invention only uses injection water to prepare the butylphthalide injection with stable properties, stable particle size, high quality, low cost, high safety performance, easy to be diluted by commonly used diluents in the field and does not affect the quality of the injection.

[0050] 2. The injection of butylphthalide of the present invention improves the stability of the injection and reduces the occurrence of demulsification by the action of butylphthalide, bile salt and phospholipid at a certain concentration and mass ratio; at the same time, the bile acid and phospholipid in the bile salt act synergistically in a certain molar ratio, increasing the solubility and stability of the injection while improving the bioavailability and the encapsulation rate of the drug.

[0051] 3. The injection of butylphthalide of the present invention has a high content and can be packaged into small-volume preparations to meet clinical drug administration requirements; at the same time, the injection of the present invention has a simple preparation process, and multiple dissolution and stirring are used to further improve the stability of the injection; the preparation method of the present invention has strong operability and is conducive to industrialization. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Figure 1 is a particle size distribution diagram of butylphthalide injection in Example 1 of the present invention;

[0053] Figure 2 is a particle size distribution diagram of butylphthalide injection in Example 2 of the present invention;

[0054] Figure 3 is a particle size distribution diagram of butylphthalide injection in Example 3 of the present invention;

[0055] Figure 4 is a particle size distribution diagram of butylphthalide injection in Example 4 of the present invention;

[0056] Figure 5 is a particle size distribution diagram of butylphthalide injection in Example 5 of the present invention;

[0057] Figure 6 is a particle size distribution diagram of butylphthalide injection in comparative example 4 of the present invention;

[0058] Figure 7 It is a particle size distribution diagram of the intermediate of the butylphthalide injection before sterilization of the present invention. DETAILED DESCRIPTION

[0059] The following non-limiting examples can make those of ordinary skill in the art understand the present invention more comprehensively, but do not limit the present invention in any way. The following content is merely an exemplary description of the scope of the present invention, and those skilled in the art can make various changes and modifications to the present invention according to the disclosed content, and it should also belong to the scope of the present invention. When the embodiment gives a numerical range, it should be understood that, unless otherwise specified in the present invention, the two endpoints of each numerical range and any numerical value between the two endpoints can be selected. Unless otherwise defined, all technical and scientific terms used in the present invention have the same meanings as those of ordinary skill in the technical field to which the present invention belongs.

[0060] The present invention is further described below by way of specific examples. The various chemical reagents used in the examples of the present invention are obtained through conventional commercial channels unless otherwise specified. In the present invention, reagent products from different manufacturers have no significant effect on the effect.

[0061] Example 1

[0062] The molar ratio of soybean phosphatidylcholine to glycocholic acid was changed to 0.3:1 (Example 1-1), 0.48:1 (Example 1-2), 0.5:1 (Example 1-3), 0.64:1 (Example 1-4), 0.70:1 (Example 1-5), 0.70:1 (Example 1-6), 0.85:1 (Example 1-7), 0.96:1 (Example 1-8) and 1.2:1 (Example 1-9).

[0063] The composition of butylphthalide injection (5mL) and butylphthalide injection (20 vials) is as follows:

[0064]

[0065]

[0066] ① When the molar ratio of soybean phosphatidylcholine to glycocholic acid is 0.3:1 (Example 1-1), 0.48:1 (Example 1-2), 0.5:1 (Example 1-3), 0.64:1 (Example 1-4) and 0.70:1 (Example 1-5), the preparation method of butylphthalide injection comprises the steps of:

[0067] (1) Weigh a prescribed amount of sodium hydroxide into a three-necked flask, add an appropriate amount of water for injection to dissolve it, add a prescribed amount of glycocholic acid, stir at 200 rpm to dissolve it, and prepare a bile salt solution;

[0068] (2) Weighing the prescribed amount of soybean lecithin and butylphthalide into the above bile salt solution and continuing to stir for 4 hours to prepare a mixture A;

[0069] (3) After the mixture A is allowed to stand, water for injection is continuously added to about 80% of the total volume, and the pH is measured to obtain a mixture B;

[0070] (4) Continue to add injection water to make up to 100 mL, filter and fill with 0.2 μm PES filter membrane, 5 mL / vial, colorless and clear, to obtain butylphthalide injection;

[0071] (5) The above injection solution was sterilized at 121° C. for 15 min to obtain a sterilized butylphthalide injection solution.

[0072] ② When the molar ratio of soybean phosphatidylcholine to glycocholic acid is 0.70:1 (Example 1-6), 0.85:1 (Example 1-7), 0.96:1 (Example 1-8) and 1.2:1 (Example 1-9), the preparation method of butylphthalide injection comprises the steps of:

[0073] (1) Weigh a prescribed amount of sodium hydroxide into a three-necked flask, add an appropriate amount of water for injection to dissolve it, add a prescribed amount of glycocholic acid, stir at 200 rpm to dissolve it, and prepare a bile salt solution;

[0074] (2) weighing the prescribed amount of soybean lecithin and butylphthalide into the above bile salt solution and continuing to stir for about 15 minutes to prepare a mixture A;

[0075] (3) After the mixture A was allowed to stand for 4 hours, water for injection was continuously added to about 80% of the total volume, and the pH was measured to obtain a mixture B;

[0076] (4) Continue to add injection water to make up to 100 mL, filter and fill with 0.2 μm PES filter membrane, 5 mL / vial, colorless and clear, to obtain butylphthalide injection;

[0077] (5) The above injection solution was sterilized at 121° C. for 15 min to obtain butylphthalide injection solution.

[0078] Example 2

[0079] The difference from Example 1-7 is that the temperature in step (1) is room temperature 25° C. The rest is the same as Example 1-7.

[0080] The prepared butylphthalide injections before and after sterilization are both clear and stable injections.

[0081] Example 3

[0082] The amount of initial water for injection was changed, and the amount of water for injection in step (1) was 6 mL (Example 3-1), 12 mL (Example 3-2), 26 mL (Example 3-3), 40 mL (Example 3-4), and 50 mL (Example 3-5), respectively.

[0083] Butylphthalide injection (5mL), Butylphthalide injection product (20 vials) composition:

[0084]

[0085] The remaining parameters and preparation method of Example 3-1 are the same as those of Example 1-7, and the remaining parameters and preparation method of Example 3-2, Example 3-3, Example 3-4, Example 3-5, and Example 3-6 are the same as those of Example 1-1.

[0086] Example 4

[0087] The stirring time in step (2) of the preparation method was changed to 1 h (Example 4-1), 3 h (Example 4-2), 4 h (Example 4-3), 6 h (Example 4-4) and 21 h (Example 4-5), and the other parameters and preparation method were the same as those in Example 1-1. The prepared butylphthalide injections were all clear and stable injections.

[0088] Butylphthalide injection (5mL), Butylphthalide injection product (20 vials) composition:

[0089]

[0090] Example 5

[0091] By changing the dosage of butylphthalide in step (2), the drug concentrations were 0.25 mg / mL (Example 5-1), 2.5 mg / mL (Example 5-2), 5 mg / mL (Example 5-3) and 10 mg / mL (Example 5-4).

[0092]

[0093]

[0094] The preparation method of butylphthalide injection comprises the steps of:

[0095] The preparation steps of Example 5-2, Example 5-3 and Example 5-4 are the same as those of Example 1-7;

[0096] In the preparation method of Example 5-1, in step (4), water for injection is continuously added to mixture B to adjust the volume to 1000 mL, and the mixture is filtered through a 0.2 μm PES filter membrane and filled at 10 mL / vial, colorless and clear. The remaining steps are the same as those of Example 1-7.

[0097] Example 6

[0098] The pH in step (3) was changed to 4.5 (Example 6-1), 5.0 (Example 6-2), 5.5 (Example 6-3), 6.0 (Example 6-4) and 6.5 (Example 6-5), respectively. The remaining parameters and preparation method were the same as those of Examples 1-7.

[0099]

[0100] The prepared butylphthalide injections before and after sterilization are both clear and stable injections.

[0101] Comparative Example 1

[0102] The molar ratios of soybean phosphatidylcholine to glycocholic acid are respectively glycocholic acid single excipient (Comparative Example 1-1), 0.2:1 (Comparative Example 1-2) and 1.5:1 (Comparative Example 1-3).

[0103] A butylphthalide injection (5 mL), a butylphthalide drug injection product (20 vials) is composed of:

[0104]

[0105]

[0106] When the molar ratio of soybean phosphatidylcholine to glycocholic acid is 0.2:1 (Comparative Example 1-2) respectively, the preparation method and steps are the same as those in Example 1-1;

[0107] When the molar ratio of soybean phosphatidylcholine to glycocholic acid is 1.5:1 (Comparative Example 1-3), the preparation method and steps are the same as those of Example 1-7.

[0108] Comparative Example 2

[0109] The difference from Example 1-7 is that the drug concentration of butylphthalide, the mass fraction of each component, and the molar ratio of soybean lecithin to glycocholic acid are different, specifically:

[0110]

[0111] The preparation method and other parameters of butylphthalide injection are the same as those of Example 1-7.

[0112] Comparative Example 3

[0113] A butylphthalide injection (5 mL), a butylphthalide drug injection product (20 vials) is composed of:

[0114] Components Weight, g Component mass fraction, % Sodium hydroxide 0.116 0.116 Glycocholic acid 1.388 1.388 Soybean lecithin 3.496 3.496 Butylphthalide 0.5 0.5 Total proportion of auxiliary materials 4.884 4.884 Water for injection Make up to 100mL margin

[0115] In the above components, the concentration of butylphthalide is 5 mg / mL (mass fraction is 0.5%), the molar ratio of soybean lecithin to glycocholic acid is 0.8:1; and the mass ratio of glycocholic acid to butylphthalide is 2.776:1.

[0116] The preparation method of butylphthalide injection comprises the steps of:

[0117] (1) Weigh the above-prescribed amount of sodium hydroxide into a three-necked flask, add 5 mL of water for injection to dissolve it, add the prescribed amount of glycocholic acid, heat to 60° C., and mechanically stir at about 200 rpm to dissolve it to prepare a bile salt solution with a pH of 5.66;

[0118] (2) weighing the prescribed amount of soybean lecithin and butylphthalide and stirring them in the above bile salt solution for 40 minutes until a viscous emulsion is formed, thereby preparing a mixture A;

[0119] (3) After the mixture A was allowed to stand overnight, it was still in the form of a viscous emulsion. 12 mL of water for injection was added and the mixture was stirred at 60° C. for 5 h. After standing, it was still in the form of a viscous emulsion.

[0120] Comparative Example 4

[0121] Mannitol is added, specifically: a butylphthalide injection (5 mL), a butylphthalide drug injection product (20 vials) composed of:

[0122]

[0123] In the above components, the concentration of butylphthalide drug is 5.0 mg / mL (mass fraction is 0.5%).

[0124] The preparation method of butylphthalide injection comprises the steps of:

[0125] (1) Same as in Examples 1-7;

[0126] (2) weighing the prescribed amount of soybean lecithin, butylphthalide and mannitol into the bile salt solution in step (1) and stirring at 200 rpm for 4 h to prepare a mixture A;

[0127] (3)-(4) Same as Examples 1-7.

[0128] The prepared butylphthalide injections before and after sterilization are both clear and stable injections.

[0129] Test 1 Particle size distribution

[0130] The particle size of the prepared butylphthalide injection was tested before and after sterilization using the Malvern ZETASIZER PRO nanoparticle size analyzer. The test parameters were set as follows:

[0131] Material: Polystyrene latex (RI: 1.59, Absorption: 0.01);

[0132] Dispersant:water(Temperature:25℃,RI:1.330);

[0133] Cell Name:DTS0012.

[0134] The particle size distribution test results of butylphthalide injection are shown in Table 1 below.

[0135] Table 1

[0136]

[0137]

[0138] It can be seen from Table 1 above that the particle size of the butylphthalide injection of the present application changes little before and after sterilization, and the butylphthalide injection has high high temperature resistance and stability. In Table 1, Peak1 represents the first peak; Peak2 represents the second peak; Peak3 represents the third peak. When the molar ratio of soybean lecithin to glycocholic acid is 0.20:1, the butylphthalide injection is turbid and the particle size cannot be detected; when the molar ratio of soybean lecithin to glycocholic acid is 1.5:1, the butylphthalide injection is turbid and the particle size cannot be detected.

[0139] The particle size distribution test results of the butylphthalide injection of Example 3 are shown in Table 2 below. When the amount of water for injection in step (1) is 60 mL (accounting for 60% of the total volume), the butylphthalide injection is turbid and the particle size cannot be detected.

[0140] Table 2

[0141]

[0142]

[0143] The particle size distribution test results of the butylphthalide injection of Example 4 are shown in Table 3 below.

[0144] Table 3

[0145]

[0146] The particle size distribution test results of the butylphthalide injection of Example 5 are shown in Table 4 below.

[0147] Table 4

[0148]

[0149] The particle size distribution diagram of the butylphthalide injection of each embodiment and comparative example is drawn, wherein the particle size distribution diagram of the butylphthalide injection of embodiment 1 is shown in FIG. Figure 1 ; The particle size distribution diagram of embodiment 2 butylphthalide injection is shown in Figure 2 ; The particle size distribution diagram of Example 3 butylphthalide injection is shown in Figure 3 ; The particle size distribution diagram of embodiment 4 butylphthalide injection is shown in Figure 4 ; The particle size distribution diagram of Example 5 butylphthalide injection is shown in Figure 5 ; Particle size distribution diagram of comparative example 4 butylphthalide injection is shown in Figure 6 ; Figure 7 It is a particle size distribution diagram of the intermediate of the butylphthalide injection before sterilization of the present invention.

[0150] The injection prepared in the comparative example was an emulsion or a turbid liquid and did not form a stable solution. Therefore, it was not necessary to test the particle size and the stability of the injection.

[0151] Test 2 Dilution stability test

[0152] The butylphthalide injections of the embodiment and the comparative example were diluted 20 times with 0.9% sodium chloride injection and 20 times with 5% glucose injection, respectively. After 9 hours, the appearance stability of the diluted solutions was observed. The test results are shown in Table 5:

[0153] Table 5

[0154]

[0155] It can be seen from Table 5 above that the butylphthalide injection of the present application still maintains a high particle size stability after being diluted 20 times with 5% glucose injection.

[0156] Summarize:

[0157] 1. Phosphatidylcholic acid molar ratio is clarified in the range of 0.3-1.2;

[0158] 2. According to the particle size distribution, the molar ratio of phosphatidylcholic acid is concentrated in the range of 0.7-1.2;

[0159] 3. Based on the results of the dilution test of 0.9% sodium chloride injection, it is preliminarily inferred that the injection prepared by the prescription with less total excipients or the molar ratio of phospholipid bile salt with less mixed micelles formed will be closer to a clear state after dilution of 0.9% sodium chloride injection;

[0160] 4. According to the particle size distribution of the intermediate and after sterilization, there is no significant difference in particle size distribution before and after sterilization;

[0161] 5. When the preparation temperature is 25-90℃, clear and transparent injection can be prepared, and there is no significant difference in particle size distribution between the same prescriptions. However, when the preparation temperature is 25℃, it needs to be prepared overnight, which takes a long time, so 60℃ is preferred;

[0162] 6. The initial water volume can be 6-50% of the total volume to prepare a clear injection solution;

[0163] 7. Encapsulated drug concentration range is 2.5-10 mg / mL;

[0164] 8. After adding the raw materials, stir and react for more than 1 hour to obtain a clear injection solution;

[0165] 9. Adding the stabilizer mannitol has no significant effect on the stability of the injection.

[0166] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A butylphthalide injection, characterized in that: The invention comprises the following components: butylphthalide, cholate, phospholipid and water; the molar ratio of the phospholipid to the cholic acid is 0.3-1.2:1; The mass fraction of butylphthalide in the injection solution is 0.025%-1%; The mass fraction of bile acid in the injection is 0.546%-5.88%.

2. The injection according to claim 1, characterized in that: The molar ratio of the phospholipid to bile acid is 0.5-0.96:

1.

3. The injection according to claim 1, characterized in that: The mass fraction of the butylphthalide in the injection is 0.5-1%.

4. The injection according to any one of claims 1 to 3, characterized in that: The components include, by mass fraction, 0.5%-1% butylphthalide, 4.933%-5.918% bile salt, 3.51%-8.00% phospholipids and the balance water.

5. The injection according to claim 1, characterized in that: The preparation method of cholate comprises the steps of: dissolving sodium hydroxide with an appropriate amount of injection water, adding a prescribed amount of glycocholic acid, heating at 50-65 DEG C, and stirring at 200-600 rpm to dissolve the cholate.

6. The injection according to claim 1, characterized in that: The bile salt is selected from at least one of sodium glycocholate, sodium glycodeoxycholate, and sodium taurocholate; the phospholipid is selected from at least one of soybean lecithin, egg choline, and hydrogenated phospholipid.

7. The method for preparing the injection according to any one of claims 1 to 6, characterized in that: Includes steps: (1) mixing a bile salt solution with phospholipids and butylphthalide, and stirring to prepare a mixture system; (2) The mixture system is kept at a temperature and allowed to stand or continue to be stirred, depending on the viscosity, to obtain a mixture A; (3) Mixing mixture A with part of water and stirring to obtain mixture B; (4) Mixture B is fixed to volume, filtered, and bottled to obtain a butylphthalide injection.

8. The preparation method according to claim 7, characterized in that: In step (1), the pH of the bile salt solution is 5.4-5.8; in step (1), the stirring temperature is 25-70°C and the stirring time is 10-20 minutes; in step (2), the viscous state is divided into the mixture system being viscous or solution-like; when it is viscous, it is kept at 50-65°C for 1-12 hours; when it is a solution, it is kept at 50-65°C and stirred for 3-21 hours; in step (3), the mixture A is mixed with part of the water until the volume of the mixture B is 75-85% of the total volume of the finished injection solution of butylphthalide, and the operating temperature of step (3) is 25-90°C.

9. The preparation method according to claim 8, characterized in that: In step (1), the pH of the bile salt solution is 5.48-5.68; in step (3), the mixture A is first mixed with part of the water, stirred into a solution state, and continued to stir for 1-16 hours; then mixed with the remaining part of the water until the volume of the mixture B is 75-85% of the total volume of the finished injection solution of butylphthalide, and the pH of the mixture B is adjusted to 4.5-6.5; the rotation speed of the continued stirring is 200-1200rpm; in step (4), the filtration is filtration through a 0.2μm PES filter membrane.

10. The injection according to claim 1, characterized in that: The injection solution is an undiluted injection solution, an injection solution diluted with glucose injection solution, or an injection solution diluted with injection water.

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