Betamethasone dipropionate suspension and preparation method thereof

Abstract

According to the preparation method of the betamethasone dipropionate suspension and the compound betamethasone injection, the betamethasone dipropionate suspension can be prepared through an anti-solvent crystallization method by means of self prescription components, and the obtained betamethasone dipropionate particles are appropriate in particle size, good in uniformity and high in stability. The betamethasone dipropionate suspension and the preparation method thereof have the advantages that the betamethasone dipropionate raw material does not need to be micronized firstly, other organic solvents do not need to be additionally added, the step of removing the organic solvent does not need to be added, the process is simple and convenient, and the prepared betamethasone dipropionate suspension can be used for preparing the compound betamethasone injection, is stable and uniform in physicochemical property, good in pharmacodynamic performance, easy to store and suitable for popularization and application. The product quality is stable and controllable, the cost is low, and commercial production and process amplification transfer are facilitated.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to preparation of betamethasone dipropionate suspension. BACKGROUND

[0002] Compound betamethasone injection belongs to glucocorticoid drugs, and has the effects of anti-inflammation, anti-allergy, anti-rheumatism, and immunosuppression. It is used for treating acute and chronic diseases sensitive to glucocorticoids.

[0003] The drug is a compound preparation composed of soluble betamethasone sodium phosphate and insoluble betamethasone dipropionate. In the two active ingredients, betamethasone dipropionate is in a suspended microparticle state in the preparation, and the particle size and uniformity in the suspended microparticles need to be strictly controlled, otherwise the microparticles are too large to cause safety problems such as pain, venous embolism, and influence on injection needle passing. Since betamethasone sodium phosphate has poor thermal stability, the conventional terminal high-temperature sterilization method cannot be used for sterilization of the finished product of compound betamethasone suspension injection.

[0004] Chinese patent CN101167730A discloses a preparation method of compound betamethasone injection, in which the betamethasone dipropionate raw material microparticles are first micronized to have a particle size less than 15 μm, and then are formulated into a suspension with various excipients.

[0005] Chinese patent CN101849910B discloses a method for preparing betamethasone dipropionate microparticles by anti-solvent microcrystallization. The method is to dissolve betamethasone dipropionate in an organic solvent such as acetone, dichloromethane, or ethanol, and then add it into water under stirring to obtain betamethasone dipropionate microparticles by microcrystallization. The microparticles prepared by the microcrystallization method can be further formulated into a suspension type preparation.

[0006] Chinese patent CN102526078B discloses a preparation method of compound betamethasone injection, which comprises the following steps: first, swelling carboxymethylcellulose sodium in a prescribed amount in water for injection by heating, cooling, and filtering to obtain solution I; then, dissolving benzyl alcohol, Tween 80, and nipagin methyl ester in a prescribed amount in water under stirring at 40℃ in a water bath to obtain solution II, sterilizing at 121℃ for 20 min, cooling to room temperature, and homogenizing for 5 min to obtain sterile base solution III; then, adding sterile microcrystallized betamethasone dipropionate raw material into the sterile base solution III and homogenizing for 5 min to obtain sterile suspension; then, preparing a sterile betamethasone sodium phosphate solution; and finally, mixing the sterile suspension and the sterile betamethasone sodium phosphate solution to obtain compound betamethasone injection.

[0007] Therefore, it is still necessary to provide a new solution to overcome the above shortcomings, so that the preparation method of compound betamethasone injection is simple, the product has stable physical and chemical properties, is uniform, and is easy to store. SUMMARY

[0008] In one aspect of the present application, a betamethasone dipropionate suspension A is provided, which comprises betamethasone dipropionate, benzyl alcohol, Tween 80 and water for injection.

[0009] In some embodiments, the weight ratio of betamethasone dipropionate, benzyl alcohol, Tween 80 and water for injection is: betamethasone dipropionate 643 parts, benzyl alcohol 810-990 parts, Tween 80 10-55 parts, and water for injection 35000-75000 parts.

[0010] In some embodiments, the average particle size of the betamethasone dipropionate microparticles in the betamethasone dipropionate suspension A is 5-15 μm, and the particle size distribution width Span is 1.3-1.8.

[0011] In another aspect of the present application, a preparation method of the betamethasone dipropionate suspension A of the present application is provided, which comprises the following steps:

[0012] Step a: dissolving betamethasone dipropionate in benzyl alcohol, heating and stirring to dissolve, filtering the obtained solution to obtain a sterile betamethasone dipropionate benzyl alcohol solution;

[0013] Step b: adding temperature-controlled water for injection to the sterile betamethasone dipropionate benzyl alcohol solution obtained in step a, and stirring to obtain a betamethasone dipropionate suspension A;

[0014] In step a and / or b, Tween 80 is also added. The Tween 80 can be added in step a or step b, or a part of it is added in step a and the remaining part is added in step b, as long as the total amount is unchanged.

[0015] In some embodiments, the Tween 80 is added in step a.

[0016] In some embodiments, the heating temperature in step a is 50-80°C, and the solution is filtered through a 0.22 μm filter to obtain a sterile betamethasone dipropionate benzyl alcohol solution.

[0017] In some embodiments, the temperature in step b is controlled at 25-60°C, the stirring rate is 300-1000 rpm, and the stirring time is 0.5-2 hours.

[0018] In some embodiments, the API microparticles in the sterile betamethasone dipropionate suspension A obtained in step b are prone to aggregation, and need to be uniformly dispersed by a certain granulation method, such as online shearing at a linear speed of not more than 12 m / s or homogenization granulation treatment at a pressure of not more than 50 bar, for the preparation of the next step.

[0019] The present application inventors surprisingly found that without first micronizing the betamethasone dipropionate raw material and without adding additional organic solvents, betamethasone dipropionate suspension A can be prepared by a "anti-solvent crystallization method" using only the prescription components. The average particle size of the betamethasone dipropionate microparticles in the suspension is 5-15 μm, the particle size distribution width Span is 1.2-2.2, the particle size is normally distributed, the distribution width is narrow, and the peak shape is good. In addition, the betamethasone dipropionate raw material can be non-sterile grade, and can be made sterile by filtration.

[0020] The third aspect of the present application is to provide a betamethasone dipropionate suspension B, which comprises betamethasone dipropionate suspension A, hydroxybenzyl alcohol, hydroxybenzyl propyl ester and sodium carboxymethyl cellulose.

[0021] In some embodiments, the betamethasone dipropionate suspension B has the following weight proportions: betamethasone dipropionate 643 parts, hydroxybenzyl alcohol 120-140 parts, hydroxybenzyl propyl ester 18-22 parts, and sodium carboxymethyl cellulose 450-550 parts.

[0022] In some embodiments, the betamethasone dipropionate suspension B can further comprise sodium chloride and / or polyethylene glycol.

[0023] The fourth aspect of the present application is to provide a preparation method of the betamethasone dipropionate suspension B of the present application, which comprises the following steps:

[0024] Step a: dissolving betamethasone dipropionate in benzyl alcohol, heating and stirring to dissolve, filtering and sterilizing to obtain sterile betamethasone dipropionate benzyl alcohol solution;

[0025] Step b: adding temperature-controlled water for injection to the sterile betamethasone dipropionate benzyl alcohol solution obtained in step a, stirring under temperature control, to obtain betamethasone dipropionate suspension A;

[0026] Step c: dissolving hydroxybenzyl alcohol, hydroxybenzyl propyl ester and sodium carboxymethyl cellulose in water for injection, filtering and sterilizing, and then mixing with the betamethasone dipropionate suspension A obtained in step b to obtain betamethasone dipropionate suspension B;

[0027] In step a and / or b, Tween 80 is also added. The Tween 80 can be added in step a or step b, or a part of it can be added in step a and the other part in step b, as long as the total amount is unchanged.

[0028] In some embodiments, the preparation method of the betamethasone dipropionate suspension B comprises the following steps:

[0029] Step a: dissolving betamethasone dipropionate in benzyl alcohol, heating and stirring to dissolve, filtering and sterilizing to obtain sterile betamethasone dipropionate benzyl alcohol solution;

[0030] Step b: the temperature-controlled water for injection is added to the sterile betamethasone dipropionate benzyl alcohol solution obtained in step a, and stirred to obtain betamethasone dipropionate suspension A;

[0031] Step c: the hydroxybenzoic acid ester, hydroxybenzoic acid propyl ester, sodium carboxymethyl cellulose, polyethylene glycol and sodium chloride are dissolved in water for injection, and after sterilization by filtration, the betamethasone dipropionate suspension A obtained in step b is mixed to obtain betamethasone dipropionate suspension B;

[0032] In step a and / or b, Tween 80 is also added, and the total amount of Tween 80 can be added in step a or step b, or a part of it is added in step a and the other part is added in step b.

[0033] The fifth aspect of the present application provides a preparation method of compound betamethasone injection, which comprises the following steps: step d: betamethasone sodium phosphate and related excipients are dissolved in water for injection, and sterilized by filtration to obtain a sterile betamethasone sodium phosphate solution;

[0034] Step e: the betamethasone dipropionate suspension B obtained in step c) and the sterile betamethasone sodium phosphate solution obtained in step d) are mixed uniformly to obtain compound betamethasone injection;

[0035] Step f: the compound betamethasone injection obtained above is filled into ampoule bottles, and is nitrogen-filled and fusion-sealed.

[0036] In some embodiments, the related excipients in step d) are disodium hydrogen phosphate, sodium chloride, disodium edetate, hydrochloric acid and polyethylene glycol, wherein the weight fractions are: betamethasone dipropionate 643 parts, betamethasone sodium phosphate 263 parts, disodium hydrogen phosphate 245-255 parts, sodium chloride 495-505 parts, disodium edetate 8-12 parts, and polyethylene glycol 1950-2050 parts; when the betamethasone dipropionate suspension B already contains sodium chloride and / or polyethylene glycol, step d) is to supplement the prescribed amount of sodium chloride and polyethylene glycol.

[0037] The present application has the following positive effects compared with the prior art:

[0038] (1) The present application uses its own prescription components, and can obtain betamethasone dipropionate suspension B by "anti-solvent crystallization method", and the particle size of betamethasone dipropionate microparticles obtained is suitable and uniform, without the need to micronize the betamethasone dipropionate raw material, without the need to add other organic solvents, and without the need to add a step of removing organic solvents, and the process is simple.

[0039] (2) The betamethasone dipropionate suspension A obtained by the present application can use betamethasone dipropionate raw material of non-sterile grade, which can be made sterile by simple filtration, including removing insoluble particles and visible impurities in the raw material, and the raw material does not need to be prepared under sterile conditions or the final product does not need to be sterilized by terminal high temperature, which is simple in process, low in cost and does not require special process equipment.

[0040] (3) The compound betamethasone injection prepared according to the present application has stable physical and chemical properties, is uniform, has good drug efficacy, is easy to store, has stable and controllable product quality, is low in cost, and is more conducive to commercial production and process scale-up transfer. BRIEF DESCRIPTION OF DRAWINGS

[0041] Figure 1 Figure 4 is a particle size distribution comparison chart of betamethasone dipropionate particles in the compound betamethasone injection of Example 1 and the comparative preparation, wherein the green curve represents the particle size distribution chart of Example 1, and the blue curve represents the particle size distribution chart of the comparative preparation.

[0042] Figure 2 Figure 5 is an X-ray powder diffraction (XRPD) spectrum of betamethasone dipropionate particles in the compound betamethasone injection of Examples 1 and 2, raw materials and the comparative preparation, wherein pink represents the raw drug, blue represents Example 1, green represents Example 2, and red represents the comparative preparation.

[0043] Figure 3 Figure 6 is an image of betamethasone dipropionate particles in the betamethasone dipropionate suspension B of Example 1 (after crystallization, before whole-grain) under an optical microscope.

[0044] Figure 4 Figure 7 is an image of betamethasone dipropionate particles in the betamethasone dipropionate suspension B of Example 1 after whole-grain under an optical microscope. DETAILED DESCRIPTION

[0045] The specific embodiments of the present application will be further described in detail with reference to the examples. The following examples are only used to illustrate the present application, but not to limit the scope of the present application.

[0046] All ranges recited in the present application include those endpoints between the recited ranges, whether or not expressly stated. All values recited in the present application include the degree of expected experimental error, technical error, and instrumental error for the given technique used to measure the value. When the degree of error is not recited, all values recited in the present application include a range of ±10% of the recited value.

[0047] In the present application, % is the percentage of weight / weight (w / w) unless otherwise specified.

[0048] The materials used in the present application, if not otherwise specified, can be obtained commercially.

[0049] The "betamethasone dipropionate suspension A" refers to an intermediate suspension in which betamethasone dipropionate exists in the form of microparticles, which can be understood as an intermediate of the preparation, and can be further formulated into a final product with other excipients.

[0050] The "betamethasone dipropionate suspension B" refers to a final product obtained by stirring and uniformly mixing the betamethasone dipropionate suspension A as an intermediate suspension with the remaining excipients, which can be further mixed with a betamethasone sodium phosphate solution to obtain a compound betamethasone injection.

[0051] The "average particle size", also referred to as the median particle size, is the particle size value at which 50% of the volume distribution is reached, and refers to the fact that 50% of the volume fraction of particles has a particle size less than the D50 value, and therefore, 50% of the volume fraction of particles has a particle size greater than the D50 value. The detection instrument is a Malvern 3000, the refractive index is 1.59, the obscuration is 5% to 10%, and the detection time is 10 s.

[0052] The "D90" refers to the particle size corresponding to the cumulative particle size distribution number of a sample reaching 90%, and its physical meaning is that 90% of the particles have a particle size less than it.

[0053] The "particle size distribution width Span" is a parameter commonly used in the powder industry to represent the width of the particle size distribution, and the calculation formula is Span = (D90-D10) / D50, wherein D90 and D10 are the particle sizes corresponding to 90% and 10% of the cumulative distribution curve of the volume of microparticles, respectively, and the larger the Span value, the wider the particle size distribution.

[0054] The term "μm" refers to "micrometers", i.e. 1*10 -6 meters.

[0055] The term "rpm" refers to the unit of stirring speed, i.e. revolutions per minute, indicating the number of rotations per minute of the equipment.

[0056] The X-ray diffraction spectrum detection method used in the present application is as follows: excite the Cu target, the tube current is 40 mA, the tube voltage is 45 kV, the starting angle is 4.0°, the ending angle is 40.0°, the scanning time is 38 s, and the step length is 0.013°.

[0057] The content detection method of the compound betamethasone suspension used in the present application is as follows: high performance liquid chromatography is used, octadecylsilane bonded silica gel is used as the filler, a phosphate buffer solution containing 0.3% trifluoroacetic acid is used as the mobile phase A, tetrahydrofuran-isopropyl alcohol (88:12) is used as the mobile phase B, gradient elution is performed, the flow rate is 1 ml per minute, the column temperature is 40°C, and the detection wavelength is 254 nm.

[0058] Example 1:

[0059] Preparation of betamethasone dipropionate suspension A:

[0060] Take 9 g of benzyl alcohol, 0.5 g of Tween 80, 6.43 g of betamethasone dipropionate, and stir to dissolve in a water bath at 60°C. Filter through a 0.22 μm filter to sterilize to obtain a betamethasone dipropionate benzyl alcohol solution. Take 480 g of water for injection and slowly add to the betamethasone dipropionate benzyl alcohol solution in a water bath at 60°C. Stir at 700 rpm for 1 h to obtain betamethasone dipropionate suspension A, which is ready for use after being homogenized by shearing or high pressure.

[0061] Preparation of betamethasone dipropionate suspension B:

[0062] Take 200 g of water for injection, add 5 g of sodium carboxymethyl cellulose, 1.3 g of hydroxybenzyl ester, and 0.2 g of hydroxybenzyl propyl ester, and stir to dissolve in a water bath at 70°C. After filtering and sterilizing, mix with the betamethasone dipropionate suspension A obtained in the previous step, and add water to a total weight of 750 g to obtain betamethasone dipropionate suspension B.

[0063] Preparation of sterile betamethasone sodium phosphate solution:

[0064] Take 2 g of anhydrous disodium hydrogen phosphate and add to 200 g of water for injection, stir to dissolve, and then add an appropriate amount of hydrochloric acid to adjust the pH to 7.5. Take 2.63 g of betamethasone sodium phosphate, 5 g of sodium chloride, 0.1 g of disodium edetate, and 20 g of polyethylene glycol, and add to the disodium hydrogen phosphate solution, stir to dissolve, add water to a total weight of 250 g, and filter to sterilize to obtain sterile betamethasone sodium phosphate solution.

[0065] Preparation of compound betamethasone injection:

[0066] Mix the betamethasone dipropionate suspension B and the sterile betamethasone sodium phosphate solution, stir until uniform, and then fill into ampoules under stirring, charge with nitrogen, and seal to obtain compound betamethasone injection.

[0067] Example 2:

[0068] Preparation of betamethasone dipropionate suspension A:

[0069] Take 9 g of benzyl alcohol and 6.43 g of betamethasone dipropionate, and stir to dissolve in a water bath at 60°C. Filter through a 0.22 μm filter to sterilize to obtain a betamethasone dipropionate benzyl alcohol solution. Take 0.5 g of Tween 80 and dissolve in 480 g of water for injection, and slowly add to the betamethasone dipropionate benzyl alcohol solution in a water bath at 60°C. Stir at 700 rpm for 1 h to obtain betamethasone dipropionate suspension A.

[0070] Example 3:

[0071] Preparation of betamethasone dipropionate suspension A:

[0072] Take 9 g benzyl alcohol, 0.1 g Tween 80, 6.43 g betamethasone dipropionate in a water bath at 60°C, stirring to dissolve, filter sterilization through a 0.22 μm filter to obtain sterile betamethasone dipropionate benzyl alcohol solution. Take 720 g water for injection in a water bath at 60°C, slowly add the betamethasone dipropionate benzyl alcohol solution, stirring at 700 rpm for 1 h to obtain betamethasone dipropionate suspension A.

[0073] Example 4:

[0074] Preparation of betamethasone dipropionate suspension A:

[0075] Take 9 g benzyl alcohol, 0.25 g Tween 80, 6.43 g betamethasone dipropionate in a water bath at 60°C, stirring to dissolve, filter sterilization through a 0.22 μm filter to obtain sterile betamethasone dipropionate benzyl alcohol solution. Take 0.25 g Tween 80, water for injection to 720 g, stirring to dissolve, slowly add the betamethasone dipropionate benzyl alcohol solution in a water bath at 60°C, stirring at 700 rpm for 1 h to obtain betamethasone dipropionate suspension A.

[0076] Example 5:

[0077] Preparation of betamethasone dipropionate suspension A:

[0078] Take 9 g benzyl alcohol, 0.5 g Tween 80, 6.43 g betamethasone dipropionate in a water bath at 60°C, stirring to dissolve, filter sterilization through a 0.22 μm filter to obtain sterile betamethasone dipropionate benzyl alcohol solution. Take 400 g water for injection in a water bath at 25°C, slowly add the betamethasone dipropionate benzyl alcohol solution, stirring at 700 rpm for 1 h to obtain betamethasone dipropionate suspension A.

[0079] Example 6:

[0080] Preparation of betamethasone dipropionate suspension A:

[0081] Take 9 g benzyl alcohol, 0.5 g Tween 80, 6.43 g betamethasone dipropionate in a water bath at 60°C, stirring to dissolve, filter sterilization through a 0.22 μm filter to obtain sterile betamethasone dipropionate benzyl alcohol solution. Take 400 g water for injection in a water bath at 60°C, slowly add the betamethasone dipropionate benzyl alcohol solution, stirring at 700 rpm for 1 h to obtain betamethasone dipropionate sterile suspension A.

[0082] Example 7:

[0083] Preparation of betamethasone dipropionate suspension A:

[0084] Take 9 g benzyl alcohol, 0.5 g Tween 80, 6.43 g betamethasone dipropionate in a water bath at 60°C, stirring to dissolve, filter sterilization through 0.22 μm filter to obtain sterile betamethasone dipropionate benzyl alcohol solution. Take 720 g water for injection in a water bath at 25°C, slowly add betamethasone dipropionate benzyl alcohol solution, stirring at 700 rpm for 1 h to obtain betamethasone dipropionate suspension A.

[0085] Example 8:

[0086] Preparation of betamethasone dipropionate suspension A:

[0087] Take 9 g benzyl alcohol, 0.5 g Tween 80, 6.43 g betamethasone dipropionate in a water bath at 60°C, stirring to dissolve, filter sterilization through 0.22 μm filter to obtain sterile betamethasone dipropionate benzyl alcohol solution. Take 720 g water for injection in a water bath at 60°C, slowly add betamethasone dipropionate benzyl alcohol solution, stirring at 700 rpm for 1 h to obtain betamethasone dipropionate suspension A.

[0088] Example 9:

[0089] Preparation of betamethasone dipropionate suspension A:

[0090] Take 9 g benzyl alcohol, 0.5 g Tween 80, 6.43 g betamethasone dipropionate in a water bath at 60°C, stirring to dissolve, filter sterilization through 0.22 μm filter to obtain sterile betamethasone dipropionate benzyl alcohol solution. Take 720 g water for injection in a water bath at 60°C, slowly add betamethasone dipropionate benzyl alcohol solution, stirring at 700 rpm for 1 h to obtain betamethasone dipropionate suspension A.

[0091] Preparation of betamethasone dipropionate suspension B:

[0092] Take 200 g water for injection, add 5 g sodium carboxymethyl cellulose, 1.3 g hydroxybenzyl methyl ester, 0.2 g hydroxybenzyl propyl ester in a water bath at 70°C, stirring to dissolve, then add 20 g polyethylene glycol, 5 g sodium chloride, stirring to dissolve. After sterilization, mix with betamethasone dipropionate suspension A obtained in the previous step, add water to a total weight of 750 g to obtain betamethasone dipropionate suspension B.

[0093] Preparation of sterile betamethasone sodium phosphate solution:

[0094] Take 2 g anhydrous disodium hydrogen phosphate and add to 200 g water for injection, stirring to dissolve, then add appropriate amount of hydrochloric acid to adjust pH to 7.5. Take 2.63 g betamethasone sodium phosphate, 0.1 g disodium edetate and add to the disodium hydrogen phosphate solution, stirring to dissolve, add water to a total weight of 250 g, filter sterilization to obtain sterile betamethasone sodium phosphate solution.

[0095] Preparation of compound betamethasone injection:

[0096] Mix betamethasone dipropionate suspension B with sterile betamethasone sodium phosphate solution, stir until homogeneous, fill into ampoules while stirring, fill with nitrogen, and seal to obtain compound betamethasone injection.

[0097] Example 10: Preparation of the comparative formulation:

[0098] Composition of compound betamethasone injection:

[0099]

[0100] Dissolve the prescribed amount of sodium carboxymethyl cellulose in heated water for injection with stirring until swollen, cool to room temperature, and filter to obtain solution I. Dissolve the prescribed amounts of benzyl alcohol, polysorbate 80, methylparaben, and propylparaben in water bath at 40°C with stirring until dissolved, sterilize by moist heat at 121°C for 20 minutes, then cool to room temperature at a rotation speed of 1*10. 3 After homogenization at rpm for 5 min, solution II was obtained. Then, sterile microcrystalline betamethasone dipropionate raw material was added to solution II and homogenized at 1*103 rpm for 5 min to obtain betamethasone dipropionate suspension. Finally, it was mixed with the sterile betamethasone sodium phosphate solution obtained according to Example 1 and stirred evenly to obtain compound betamethasone injection.

[0101] Example 11:

[0102] 1. Determination of particle size

[0103] Methods: Take 1 ml each of betamethasone dipropionate raw material, betamethasone dipropionate sterile suspension B prepared in Examples 1 and 9, compound betamethasone injection prepared in Examples 1 and 9, and the comparative preparation obtained in Example 10. Disperse evenly by sonication for 3 min, and slowly drop it into the sample cell of Malvern 3000 laser particle size analyzer. Water is used as the mobile carrier. The dynamic method is used for determination. The specific results are shown in Table 1.

[0104] Table 1: Results of Suspended Particle Size Measurement

[0105]

[0106] The particle size distribution of betamethasone microparticles in the compound betamethasone injection obtained in Example 1 and the comparative example is as follows: Figure 1 As shown in the figure. The results show that the betamethasone dipropionate microparticles obtained in the compound betamethasone injection obtained by the present invention have no significant changes in particle size and particle size distribution, and all exhibit a unimodal distribution, indicating good suspension state.

[0107] The D10 of betamethasone dipropionate microparticles in the compound betamethasone injection obtained in Example 1 is 3.37 um, the D50 is 7.05 um, the D90 is 13.2 um, and the span of particle size distribution is 1.394.

[0108] The D10 of betamethasone dipropionate microparticles in the compound betamethasone injection obtained in Example 9 is 3.29 um, the D50 is 6.90 um, the D90 is 12.3 um, and the span of particle size distribution is 1.306, which is not significantly different from that in Example 1. In addition, the average particle size of betamethasone dipropionate raw material can be reduced from 40-60 um to about 9-11 um by the embodiments of the present application, indicating that the technical scheme of the present application can significantly and effectively reduce the particle size of betamethasone dipropionate raw material.

[0109] Example 11: Stability investigation

[0110] 1. Crystal form stability test

[0111] The betamethasone dipropionate suspension B obtained in Examples 1 and 2 and the compound betamethasone injection of Comparative Example 10 are filtered to collect betamethasone dipropionate microparticles, which are washed with water and dried in a vacuum at 25°C, and then the powder is detected for crystal form. The X-ray powder diffraction (XRPD) spectrum is shown in Figure 2 The results show that the crystal form of the betamethasone dipropionate suspension prepared in Examples 1 and 2 is consistent with that of the raw material and the comparative preparation obtained in Example 10, and the crystallization method of the present application does not change the crystal form.

[0112] The betamethasone dipropionate suspension A obtained in Example 1 after crystallization (before granulation) and the betamethasone dipropionate microparticles after granulation are photographed by optical microscope, and the optical microscope photographs are shown in Figure 3 The betamethasone dipropionate particles after crystallization (before granulation) are block-shaped crystals with complete morphology, and the appearance and particle size of the crystal particles after granulation are not changed, and there is no obvious agglomeration phenomenon.

[0113] 2. Mass stability test

[0114] The compound betamethasone injection prepared in Examples 1 and 9 and the comparative preparation obtained in Example 10 are placed in a constant temperature and humidity box under accelerated conditions (40°C / 65% RH) for 0 days, and then sampled after 1 month, and the related substances, content and suspension microparticle size are detected. The specific results are shown in Table 2.

[0115] Table 2: Stability test results

[0116]

[0117] Results:

[0118] The comparative preparation was placed under accelerated conditions of 40°C / 65% RH for 1 month, and the related substance increased by about 0.4%, and the span of the particle size distribution changed from 1.402 to 1.46. The compound betamethasone injection prepared according to the present application was placed under the same storage conditions, and the related substance increased by about 0.24%, and the span of the particle size distribution changed from 1.394 to 1.330. According to the above results, it is shown that the stability of the compound betamethasone injection prepared according to the present application has no significant difference in the change of the particle size distribution or the quality from the comparative preparation, and is even superior to the comparative preparation.

[0119] The specific embodiments described in the present application are only for illustration of the spirit of the present application. Those skilled in the art of the technical field described in the present application can make various modifications or supplements to the described specific embodiments or replace them with similar ways, but will not deviate from the spirit of the present application or exceed the scope defined by the appended claims.

Claims

1. A betamethasone dipropionate suspension A, characterized in that, The suspension A contains betamethasone dipropionate, benzyl alcohol, Tween 80, and water for injection.

2. The suspension according to claim 1, characterized in that, The weight ratio of betamethasone dipropionate, benzyl alcohol, Tween 80 and water for injection is as follows: 643 parts betamethasone dipropionate, 810-990 parts benzyl alcohol, 10-55 parts Tween 80, and 35,000-75,000 parts water for injection.

3. The suspension according to claim 1, characterized in that, The betamethasone dipropionate suspension A contains betamethasone dipropionate microparticles with an average particle size of 5–15 μm and a particle size distribution width of 1.3–1.

8.

4. A method for preparing suspension A according to claims 1 to 3, characterized in that, The preparation method involves the following steps: Step a: Dissolve betamethasone dipropionate in benzyl alcohol, heat and stir until dissolved, filter the resulting solution to remove bacteria and obtain a sterile betamethasone dipropionate benzyl alcohol solution; Step b: Add the temperature-controlled water for injection to the sterile betamethasone dipropionate benzyl alcohol solution obtained in step a, and stir while maintaining the temperature to obtain betamethasone dipropionate suspension A; Tween 80 is also added in step a and / or step b.

5. The preparation method according to claim 4, characterized in that, The Tween 80 can be added entirely in step a, entirely in step b, or a portion can be added in step a and the remainder added in step b, as long as the total amount added remains unchanged; preferably, the Tween 80 is added entirely in step a.

6. The preparation method according to claim 4, characterized in that, The heating temperature in step a is 50-80℃, and the solution is filtered through a 0.22μm filter to obtain a sterile betamethasone dipropionate benzyl alcohol solution.

7. The preparation method according to claim 4, characterized in that, The temperature controlled in step b is 25-60℃, the stirring rate is 300-1000 rpm, and the stirring time is 0.5-2 hours.

8. The preparation method according to claim 4, characterized in that, The betamethasone dipropionate suspension A is used in the next step of preparation after shearing or high-pressure homogenization and granulation.

9. A betamethasone dipropionate suspension B, characterized in that, The suspension comprises betamethasone dipropionate suspension A, methylparaben, propylparaben, and sodium carboxymethyl cellulose.

10. The betamethasone dipropionate suspension B according to claim 9, characterized in that, The betamethasone dipropionate suspension B contains the following weight parts: 643 parts betamethasone dipropionate, 120-140 parts methylparaben, 18-22 parts propylparaben, and 450-550 parts sodium carboxymethyl cellulose.

11. The betamethasone dipropionate suspension B according to claim 10, characterized in that, The suspension B may further include sodium chloride and / or polyethylene glycol.

12. A method for preparing betamethasone dipropionate suspension B according to claims 9-10, characterized in that, The preparation method involves the following steps: Step a: Dissolve betamethasone dipropionate in benzyl alcohol, heat and stir until dissolved, filter to remove bacteria to obtain a sterile betamethasone dipropionate benzyl alcohol solution; Step b: Add the temperature-controlled water for injection to the sterile betamethasone dipropionate benzyl alcohol solution obtained in step a, stir, and obtain betamethasone dipropionate suspension A; Step c: Dissolve methylparaben, propylparaben, and sodium carboxymethyl cellulose in water for injection, filter to remove bacteria, and then mix with betamethasone dipropionate suspension A obtained in step b to obtain betamethasone dipropionate suspension B. In step a and / or b, Tween 80 is added. All of the Tween 80 can be added in step a or step b, or a portion can be added in step a and the other portion in step b, as long as the total amount added remains unchanged.

13. A method for preparing betamethasone dipropionate suspension B according to claim 11, characterized in that, The preparation method involves the following steps: Step a: Dissolve betamethasone dipropionate in benzyl alcohol, heat and stir until dissolved, filter to remove bacteria to obtain a sterile betamethasone dipropionate benzyl alcohol solution; Step b: Add the temperature-controlled water for injection to the sterile betamethasone dipropionate benzyl alcohol solution obtained in step a, stir, and obtain betamethasone dipropionate suspension A; Step c: Dissolve methylparaben, propylparaben, sodium carboxymethyl cellulose, polyethylene glycol and sodium chloride in water for injection, filter to remove bacteria, and then mix with betamethasone dipropionate suspension A obtained in step b to obtain betamethasone dipropionate suspension B. In step a and / or b, Tween 80 is added. All of the Tween 80 can be added in step a or step b, or a portion can be added in step a and the other portion in step b, as long as the total amount added remains unchanged.

14. A method for preparing compound betamethasone injection, characterized in that, The method steps are as follows: Step d: Dissolve betamethasone sodium phosphate and related excipients in water for injection, filter and sterilize to obtain sterile betamethasone sodium phosphate solution; Step e: Mix the betamethasone dipropionate suspension B obtained according to claim 12 or 13 and the sterile betamethasone sodium phosphate solution obtained in step d) evenly to obtain compound betamethasone injection; Step f: Fill the obtained compound betamethasone injection solution into ampoules, fill with nitrogen, and seal.

15. The preparation method according to claim 14, characterized in that, In step d), the relevant excipients are disodium hydrogen phosphate, sodium chloride, disodium edetate, and polyethylene glycol, wherein the weight parts are: 643 parts betamethasone dipropionate, 263 parts betamethasone sodium phosphate, 245-255 parts disodium hydrogen phosphate, 495-505 parts sodium chloride, 8-12 parts disodium edetate, and 1950-2050 parts polyethylene glycol; when the betamethasone dipropionate suspension B already contains sodium chloride and / or polyethylene glycol, step d) is to add sodium chloride and polyethylene glycol to the prescribed amount.

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