A preparation method of a butylphthalide injection

Abstract

The application 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, wherein the cholate is prepared by the 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%.Butylphthalide, cholate and phospholipid are mixed in a certain concentration and mass ratio, and cholic acid in the cholate and phospholipid are mixed in a certain molar ratio to prepare the butylphthalide injection in a clear solution.The preparation process of the butylphthalide injection is simple, the stability of the injection is further improved by multiple dissolving and stirring, the clinical drug demand is met, and the industrialized production is facilitated.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a butylphthalide injection and its preparation method. Background Technology

[0002] 3-n-butylphthalide (NBP), also known as 3-butyl-1(H)-isobenzofuranone, has the chemical formula C1. 12 H 14 O2 is the levorotatory isomer extracted from celery seeds; a racemic mixture can also be synthesized artificially. Butylphthalide is an oily liquid, insoluble in water, with a strong celery odor. Its molecule contains one chiral carbon atom, therefore it exists in two optical isomers: levorotatory butylphthalide and dextrorotatory butylphthalide. Butylphthalide is a drug used to treat ischemic stroke, and can also be used to treat hypertension. It has neuroprotective effects, shrinks infarct foci after focal cerebral ischemia, reduces the degree of neurological function damage, and improves brain energy metabolism after global cerebral ischemia.

[0003] Currently, most butylphthalide injection products utilize cyclodextrin inclusion technology. For example, Chinese invention patent CN109985035A discloses a butylphthalide sodium chloride injection containing hydroxypropyl-β-cyclodextrin. The prepared injection has a relatively large 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. Calculations show that the prescribed amount of hydroxypropyl-β-cyclodextrin in 100mL of injection is 0.51-0.9g. According to the butylphthalide sodium chloride injection instructions, a daily dose of 200mL is given, which is close to the maximum daily exposure (the US FDA approved drug inactive ingredient database requires a maximum daily exposure of 1333mg of hydroxypropyl beta-cyclodextrin administered intravenously and intramuscularly). Hydroxypropyl beta-cyclodextrin is cleared by glomerular filtration, and the instructions clearly limit the patient's renal function. Moreover, the butylphthalide injection prepared by this technology has a volume of 100mL, which can only be administered intravenously and cannot adequately meet the needs of clinical medication.

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

[0005] Chinese invention patent CN114869848A discloses a butylphthalide micelle composition, which can be used as an injection solution or a lyophilized powder for injection. Its raw materials include butylphthalide, phospholipids, cholic acid or its salts, a stabilizer, and an organic solvent. This patent involves dissolving butylphthalide, phospholipids, or cholic acid / cholesterol in an organic solvent, rotary evaporating to form a loose film, dissolving it in a stabilizer solution to obtain a clear solution, and then lyophilizing it after adjusting the volume. Alternatively, butylphthalide, phospholipids, or cholic acid / cholesterol can be dissolved in an organic solvent or a mixture of an organic solvent and water for injection, lyophilized, and then the lyophilized block can be dissolved in a stabilizer solution. While this method avoids the use of other surfactants such as cyclodextrin, thus improving clinical safety to some extent, the use of organic solvents raises concerns about the safety of organic solvent production and their recycling.

[0006] Chinese invention patent CN107970208A discloses a butylphthalide injection and its preparation method. The butylphthalide injection contains butylphthalide or its derivatives, a surfactant, and water for injection. This invention indicates that a relatively large amount of surfactant is used, and a stabilizer is also added to maintain the stability of the injection.

[0007] Therefore, existing butylphthalide injections still have safety concerns due to the influence of organic solvents, and the excessive use of surfactants such as cyclodextrin can damage the kidneys. Stabilizers and other components need to be added to the injection to maintain its long-term stability. Furthermore, the effects of the formulation of each component in butylphthalide injection on the quality, stability, and efficacy of the injection are unclear. These issues urgently need to be addressed. Summary of the Invention

[0008] This invention addresses the problems existing in the prior art by providing a butylphthalide injection and its preparation method. The butylphthalide injection comprises butylphthalide, bile salt, phospholipid, and water for injection. The drug concentration of butylphthalide in the injection is 2.5-10 mg / mL. Butylphthalide, bile salt, and phospholipid are mixed under certain concentration and mass ratio conditions to prepare a clear solution of butylphthalide injection. The preparation process is simple, suitable for industrial production, and the obtained sample has stable quality, high encapsulation rate, high safety, and good stability, meeting the needs of clinical drug use.

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

[0010] On one hand, the present invention provides an injection of butylphthalide, comprising the following components: butylphthalide, bile salt, phospholipid and water; wherein the molar ratio of phospholipid to bile acid is 0.3-1.2:1; the mass fraction of butylphthalide in the injection is 0.025%-1%; and the mass fraction of bile 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, which includes any range, real number and endpoint value within the numerical range, such as, 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] More preferably, the molar ratio of phospholipid to cholic acid is 0.5-0.96:1; this molar ratio includes any range, real number and endpoint value within the numerical range, such as, 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 solution is 0.5-1%.

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

[0016] Preferably, the butylphthalide injection comprises, by mass fraction: 0.5-1% butylphthalide, 4.933%-5.918% cholate, 3.51-8.00% phospholipid and the balance water.

[0017] More preferably, the butylphthalide injection comprises, by mass fraction: 0.5% butylphthalide, 4.933%-5.918% cholate, 7-7.56% phospholipid and the balance water.

[0018] Preferably, the cholate salt can be a commercially available product or a self-prepared product; the preparation method of the cholate salt includes the steps of mixing cholic acid with sodium hydroxide solution and stirring to obtain the product.

[0019] More preferably, the method for preparing cholate salts includes the following steps: dissolving sodium hydroxide in 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 obtaining cholate salts.

[0020] More preferably, in the preparation method of bile salts, 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, such as, but not limited to, 5-59%, 6-50%, 5-10%, 10-20%, 20-35%, 35-50%, 50-59%; within the above-described dosage range of the present invention, the prepared butylphthalide injection solution can achieve the technical effect of the present invention, and there is no 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, such as, but not limited to, 6-50%, 12-50%, 6-20%, 20-35%, 35-50%; within the above-described amount range of the present invention, the prepared butylphthalide injection solution can achieve the technical effect of the present invention, and there is no 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, such as, but not limited to, 12-50%, 12-40%, 40-50%, 26-50%; within the above-described dosage range of the present invention, the prepared butylphthalide injection solution can achieve the technical effect of the present invention, and there is no significant difference.

[0023] Preferably, the cholate 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 phospholipids, lecithin, and hydrogenated phospholipids.

[0026] In this invention, all water used is water for injection.

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

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

[0029] (1) Mix the bile salt solution with phospholipids and butylphthalide, stir, and prepare a mixture system;

[0030] (2) Depending on the viscosity of the mixture system, keep it at a constant temperature or continue stirring to obtain mixture A;

[0031] (3) Mixture A with some water and stir to obtain mixture B;

[0032] (4) Mixture B is diluted to a certain volume, filtered, and filled to obtain butylphthalide injection.

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

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

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

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

[0037] Preferably, in step (2), the viscous state is divided into a viscous state or a solution state of the mixture system; when it is viscous, it is kept at 50-65℃ and left to stand for 1-12 hours; when it is a solution state, it is kept at 50-65℃ and stirred for 3-21 hours.

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

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

[0040] More preferably, the substance used to adjust the pH of 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℃; even more preferably, the operating temperature of step (3) is 25-60℃.

[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 at 110-130℃ for 10-20 minutes.

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

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

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

[0047] The technical effects of the injection solutions prepared under the conditions within the scope of this invention are not significantly different.

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

[0049] 1. The butylphthalide injection prepared by this invention does not use cyclodextrin or other synthetic surfactants in its components, nor does it contain any stabilizers. No organic solvents are added during the preparation of the injection. This invention can produce a butylphthalide injection with stable properties, stable particle size, high quality, low cost, high safety performance, and easy dilution by commonly used diluents in the field without affecting the quality of the injection, using only water for injection.

[0050] 2. The butylphthalide injection of the present invention improves the stability of the injection and reduces the occurrence of demulsification by using butylphthalide with bile salts and phospholipids at a certain concentration and mass ratio. At the same time, the bile acids and phospholipids in the bile salts work synergistically at a certain molar ratio to increase the solubility and stability of the injection, while improving bioavailability and drug encapsulation rate.

[0051] 3. The butylphthalide injection of the present invention has a high content and can be packaged into small-volume formulations to meet clinical drug administration needs; at the same time, the preparation process of the injection of the present invention is simple, and the stability of the injection is further improved by multiple dissolution and stirring; the preparation method of the present invention is highly operable and conducive to industrialization. Attached Figure Description

[0052] Figure 1 This is a particle size distribution diagram of butylphthalide injection solution according to Example 1 of the present invention;

[0053] Figure 2 This is a particle size distribution diagram of butylphthalide injection solution according to Example 2 of the present invention;

[0054] Figure 3 This is a particle size distribution diagram of butylphthalide injection solution according to Example 3 of the present invention;

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

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

[0057] Figure 6 This is a particle size distribution diagram of the butylphthalide injection solution (Comparative Example 4) of this invention.

[0058] Figure 7 This is a particle size distribution diagram of the intermediates of the butylphthalide injection solution before sterilization according to the present invention. Detailed Implementation

[0059] The following non-limiting embodiments are intended to provide a more comprehensive understanding of the invention by those skilled in the art, but do not limit the invention in any way. The following description is merely an exemplary illustration of the scope of protection claimed by the invention. Those skilled in the art can make various changes and modifications to the invention based on the disclosed content, and these should also fall within the scope of protection claimed by the invention. When numerical ranges are given in the embodiments, it should be understood that, unless otherwise stated in the invention, the two endpoints of each numerical range and any value between the two endpoints may be selected. Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by those skilled in the art to which this invention pertains.

[0060] The present invention will be further described below by way of specific embodiments. Unless otherwise specified, all chemical reagents used in the embodiments of the present invention are obtained through conventional commercial channels. In the present invention, reagent products from different manufacturers do not have a significant impact 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] Butylphthalide Injection (5mL), the composition of the butylphthalide injection product (20 vials) is as follows:

[0064]

[0065]

[0066] ① A method for preparing butylphthalide injection 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), including the following steps:

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

[0068] (2) Weigh the prescribed amount of soybean lecithin and butylphthalide into the above cholate solution and continue stirring for 4 hours to obtain mixture A;

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

[0070] (4) Continue to add water for injection to make up to 100 mL, filter through a 0.2 μm PES filter membrane and fill into 5 mL vials. The solution is colorless and clear, and butylphthalide injection is obtained.

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

[0072] ② A method for preparing butylphthalide injection when the molar ratio of soybean phosphatidylcholine to glycocholic acid is 0.70:1 (Examples 1-6), 0.85:1 (Examples 1-7), 0.96:1 (Examples 1-8), and 1.2:1 (Examples 1-9), including the following steps:

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

[0074] (2) Weigh out the prescribed amount of soybean lecithin and butylphthalide into the above cholate solution and continue stirring for about 15 minutes to obtain mixture A;

[0075] (3) After mixture A is left to stand for 4 hours, continue to add water for injection to about 80% of the total volume, measure the pH, and obtain mixture B;

[0076] (4) Continue to add water for injection to make up to 100 mL, filter through a 0.2 μm PES filter membrane and fill into 5 mL vials. The solution is colorless and clear, and butylphthalide injection is obtained.

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

[0078] Example 2

[0079] Unlike Examples 1-7, the temperature in step (1) is 25°C (room temperature). Everything else is the same as in Examples 1-7.

[0080] Both the sterilized and sterilized butylphthalide injection solutions obtained were clear and stable.

[0081] Example 3

[0082] The initial amount of water for injection was changed, and the amounts of water for injection in step (1) were 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).

[0083] Butylphthalide Injection (5mL), Butylphthalide Drug Injection Product (20 vials) Composition:

[0084]

[0085] The remaining parameters and preparation methods of Example 3-1 are the same as those of Examples 1-7. The remaining parameters and preparation methods of Examples 3-2, 3-3, 3-4, 3-5, and 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), respectively, while the other parameters and preparation methods were the same as in Example 1-1. The prepared butylphthalide injection solutions were all clear and stable injection solutions.

[0088] Butylphthalide Injection (5mL), Butylphthalide Drug Injection Product (20 vials) Composition:

[0089]

[0090] Example 5

[0091] The dosage of butylphthalide in step (2) was changed to 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 includes the following steps:

[0095] The preparation methods for Examples 5-2, 5-3, and 5-4 are the same as those for Examples 1-7;

[0096] In the preparation method of Example 5-1, in step (4), water for injection is added to mixture B and the volume is adjusted to 1000 mL. The mixture is filtered and filled with 0.2 μm PES filter membrane, 10 mL / vial. The mixture is colorless and clear. The remaining steps are the same as in Examples 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 other parameters and preparation methods were the same as in Examples 1-7.

[0099]

[0100] Both the sterilized and sterilized butylphthalide injection solutions obtained were clear and stable.

[0101] Comparative Example 1

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

[0103] A butylphthalide injection (5 mL), butylphthalide drug injection product (20 vials) composition:

[0104]

[0105]

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

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

[0108] Comparative Example 2

[0109] The differences from Examples 1-7 are as follows: 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 in Examples 1-7.

[0112] Comparative Example 3

[0113] A butylphthalide injection (5 mL), butylphthalide drug injection product (20 vials) composition:

[0114] Sodium hydroxide 0.116 0.116 Glycinecholic acid 1.388 1.388 Soybean phospholipids 3.496 3.496 Butylphthalide 0.5 0.5 Total proportion of auxiliary materials 4.884 4.884 Water for Injection Add to 100mL margin

[0115] Of the above components, the concentration of butylphthalide is 5 mg / mL (mass fraction of 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 includes the following steps:

[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 at 60°C, and mechanically stir at about 200 rpm to dissolve it, so as to obtain a cholate solution with a pH of 5.66.

[0118] (2) Weigh out the prescribed amount of soybean lecithin and butylphthalide and stir in the above cholate solution for 40 minutes until a viscous emulsion is formed, and obtain mixture A;

[0119] (3) Mixture A was left to stand overnight and remained a viscous emulsion. 12 mL of water for injection was added and stirred at 60 °C for 5 h. After standing, it remained a viscous emulsion.

[0120] Comparative Example 4

[0121] The addition of mannitol specifically refers to: a butylphthalide injection (5 mL), and the composition of the butylphthalide drug injection product (20 vials):

[0122]

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

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

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

[0126] (2) Weigh out the prescribed amount of soybean lecithin, butylphthalide and mannitol and stir in the cholate solution in step (1) for 4 hours at 200 rpm to obtain mixture A;

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

[0128] Both the sterilized and sterilized butylphthalide injection solutions obtained were clear and stable.

[0129] Experiment 1 Particle size distribution

[0130] The particle size of the prepared butylphthalide injection solution before and after sterilization was measured using a Malvern Zetasizer PRO nanoparticle size analyzer. The detection 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] As shown in Table 1 above, the butylphthalide injection of this application exhibits minimal particle size change before and after sterilization, demonstrating high high-temperature resistance and stability. In Table 1, Peak1 represents the first peak; Peak2 represents the second peak; and Peak3 represents the third peak. When the molar ratio of soybean lecithin to glycocholic acid is 0.20:1, the butylphthalide injection becomes turbid, making particle size detection impossible; when the molar ratio of soybean lecithin to glycocholic acid is 1.5:1, the butylphthalide injection also becomes turbid, making particle size detection impossible.

[0139] The particle size distribution test results of the butylphthalide injection in Example 3 are shown in Table 2 below. When the amount of water for injection in step (1) is 60 mL (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 in Example 4 are shown in Table 3 below.

[0144] Table 3

[0145]

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

[0147] Table 4

[0148]

[0149] Particle size distribution diagrams were plotted for the butylphthalide injection solutions of each embodiment and comparative example. The particle size distribution diagram for the butylphthalide injection solution of Example 1 is shown below. Figure 1 Example 2: Particle size distribution diagram of butylphthalide injection is shown below. Figure 2 Example 3: Particle size distribution diagram of butylphthalide injection is shown below. Figure 3 Example 4: Particle size distribution diagram of butylphthalide injection is shown below. Figure 4 Example 5: Particle size distribution diagram of butylphthalide injection is shown below. Figure 5 The particle size distribution diagram of butylphthalide injection (Comparative Example 4) is shown below. Figure 6 ; Figure 7 This is a particle size distribution diagram of the intermediates of the butylphthalide injection solution before sterilization according to the present invention.

[0150] The injection solutions prepared in the comparative example were emulsions or turbid liquids and did not form stable solutions, so it was not necessary to test the particle size and stability of the injection solutions.

[0151] Test 2 Dilution Stability Test

[0152] The butylphthalide injection solutions of the examples and comparative examples were diluted 20-fold with 0.9% sodium chloride injection and 20-fold with 5% glucose injection, respectively. The appearance stability of the diluted solutions was observed after 9 hours, and the results are shown in Table 5.

[0153] Table 5

[0154]

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

[0156] Summarize:

[0157] 1. The phosphatidylcholine molar ratio is clear within the range of 0.3-1.2;

[0158] 2. Based on particle size distribution, the molar ratio of phosphatidylcholine is relatively concentrated in the range of 0.7-1.2;

[0159] 3. Based on the dilution test results of 0.9% sodium chloride injection, it is preliminarily speculated that the injection prepared with a formula that has a smaller total amount of excipients or a lower molar ratio of phospholipids and bile salts that forms fewer mixed micelles will be closer to a clear state after dilution with 0.9% sodium chloride.

[0160] 4. Based on the particle size distribution of the intermediate and the sterilized product, there was no significant difference in particle size distribution before and after sterilization;

[0161] 5. Clear and transparent injection solutions can be prepared at temperatures ranging from 25°C to 90°C, and there is no significant difference in particle size distribution among solutions of the same formulation. However, when the solution temperature is 25°C, it needs to be prepared overnight, which takes a long time. Therefore, 60°C is preferred.

[0162] 6. A clear injection solution can be prepared with an initial water volume of 6-50% of the total volume;

[0163] 7. The concentration range of the encapsulated drug is 2.5-10 mg / mL;

[0164] 8. After the raw materials are added, the mixture is stirred and reacted for more than 1 hour to obtain a clear injection solution;

[0165] 9. The addition of mannitol as a stabilizer has no significant effect on the stability of the injection solution.

[0166] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A butylphthalide injection solution, characterized in that, It is composed of 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 solution is 0.546%-5.88%; Bile salts are prepared as injection solutions, and water accounts for 12%-50% of the injection volume during the preparation of the bile salt solution. The preparation method of the injection solution includes the following steps: (1) Mix the bile salt solution with phospholipids and butylphthalide, stir, and prepare a mixture system; (2) Depending on the viscosity of the mixture system, keep it at a constant temperature and let it stand or continue stirring to obtain mixture A; (3) Mixture A is mixed with some water and stirred to obtain mixture B; (4) Mixture B is diluted to a certain volume, filtered, and filled to obtain butylphthalide injection solution; In step (1), the pH of the bile salt solution is 5.4-5.8; in step (1), the stirring temperature is 25-70℃ and the stirring time is 10-20min; in step (2), the viscous state is divided into the mixture system being viscous or in solution form; when it is viscous, it is kept at 50-65℃ and allowed to stand for 1-12h; when it is in solution form, it is kept at 50℃ and stirred for 3-21h; in step (3), mixture A is mixed with some water until the volume of mixture B is 75-85% of the total volume of the butylphthalide injection product; the operating temperature of step (3) is 25-90℃.

2. The injection solution according to claim 1, characterized in that, The molar ratio of phospholipids to bile acids is 0.5-0.96:

1.

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

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

5. The injection solution according to claim 1, characterized in that, The preparation method of cholate salts includes the following steps: dissolving sodium hydroxide in an appropriate amount of water for injection, adding the prescribed amount of glycocholic acid, heating at 50-65℃, and stirring at 200-600 rpm to dissolve, thus obtaining the product.

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

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

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

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