Application of hydroxypropyl-β-cyclodextrin in preparing solid preparation of Vericipiracil, solid preparation and preparation method

Abstract

The present invention belongs to the technical field of drug preparation, and particularly relates to the application of hydroxypropyl-β-cyclodextrin in the preparation of a solid preparation of Vericipiragua, a solid preparation and a preparation method. The present invention focuses on the application of hydroxypropyl-β-cyclodextrin in the preparation of a Vericipiragua cyclodextrin inclusion complex with Vericipiragua, and then combines it with other raw materials to prepare a Vericipiragua solid preparation with excellent solubilization effect. The average degree of substitution of the above-mentioned hydroxypropyl-β-cyclodextrin is 3.5~5.5, which is one of the keys of the present invention. The present invention has conducted a large number of experiments, including comparing different types of β-cyclodextrins and β-cyclodextrins with different degrees of substitution. Finally, hydroxypropyl-β-cyclodextrin with an average degree of substitution of 3.5~5.5 was selected to include Vericipiragua. Compared with hydroxypropyl-β-cyclodextrins with other degrees of substitution or other solubilizers, the solubilization effect is more excellent, and the stability is good. After accelerating for 3 months, the total impurities are almost unchanged.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug preparation, and particularly relates to the application of hydroxypropyl-β-cyclodextrin in the preparation of a solid preparation of Vericipirax, a solid preparation and a preparation method. Background Art

[0002] Vericipirat is a drug used to treat recent heart failure. Its solubility has a great influence on absorption. Therefore, it is necessary to increase its solubility and thus improve its bioavailability.

[0003] At present, the common and commonly used methods to increase drug solubility mainly include reducing particle size, using solid dispersion technology to prepare amorphous crystals to increase solubility, etc., but these methods have high requirements for equipment and are not easy to apply in actual production. For example, there is a document that uses a wet grinding process to prepare a nanosuspension, and then uses a fluidized bed for granulation and tableting. In this process, the raw materials are made into a nanosuspension and added. Although it can increase solubility, its preparation process has high requirements for equipment, and its suspension has the risk of Ostwald ripening such as precipitation and aggregation. At the same time, the fluidized bed granulation is used in this scheme to spray the suspension, which may cause uneven dispersion of the sprayed suspension and affect the uniformity of the content. At the same time, poor dispersion or precipitation of the suspension will cause gun blockage, affecting the granulation effect. Fluidized bed granulation is very likely to cause uneven particle size, affecting tableting (unstable tablet weight), resulting in large intra-batch differences. According to the dissolution determination of the listed product, it can also be seen that the dissolution RSD of the listed product is too large.

[0004] Spray drying is a common method for preparing solid dispersions to increase solubility. However, for Vericipiracil in the present application, spray drying is not possible due to its low solubility in various solvents. Therefore, finding a suitable solvent for dissolution becomes an important factor restricting the use of this method.

[0005] Hot melt extrusion of a drug with a suitable carrier is also a common method to increase the solubility of the drug. However, the inventors have conducted multiple experiments and found that the related substances of the sample prepared by hot melt extrusion after Vericipiraguat was mixed with a carrier significantly increased, and the degradation rate of the active ingredient was greater than 40%. Therefore, the above method is also not suitable for the present invention.

[0006] Therefore, it is necessary to invent a method that can effectively improve the solubility of Vericipirat according to its own characteristics, so that it is more conducive to human absorption and thus exerts a better drug effect. Summary of the invention

[0007] In order to solve the above technical problems, the present invention selects hydroxypropyl-β-cyclodextrin with an average degree of substitution of 3.5-5.5 as a solubilizer, and uses it in combination with acetone under specific temperature environment and pH conditions to improve the solubilization effect of the solid preparation of Vericipirax.

[0008] The application of hydroxypropyl-β-cyclodextrin in the preparation of the solid preparation of Vericipiracil is mainly to dissolve hydroxypropyl-β-cyclodextrin and then form a Vericipiracil-cyclodextrin inclusion complex to achieve the effect of solubilizing the product. The average degree of substitution of hydroxypropyl-β-cyclodextrin used in this application is 3.5 to 5.5.

[0009] The Vericipirat solid preparation prepared in the present application mainly comprises the following raw materials in parts by weight: Vericipirat-cyclodextrin inclusion compound 20-40, filler 70-90, binder 3-6, disintegrant 6-10, lubricant 0.5-1.5;

[0010] The filler is a combination of lactose and microcrystalline cellulose;

[0011] The binder is selected from at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose and sodium carboxymethyl cellulose;

[0012] The disintegrant is selected from at least one of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, and cross-linked polyvinylpyrrolidone;

[0013] The lubricant is selected from at least one of magnesium stearate, talc and sodium stearyl fumarate.

[0014] The preparation process of the above-mentioned Vericipirat-cyclodextrin inclusion compound is as follows:

[0015] (1) Add hydroxypropyl-β-cyclodextrin with an average degree of substitution of 3.5 to 5.5 to a citric acid aqueous solution of 4 times its weight, and stir to dissolve at a constant temperature of 50 to 60° C., wherein the pH of the citric acid aqueous solution is 2.0 to 3.0;

[0016] (2) Add Vericipiracil to 8 times its weight of acetone and stir evenly;

[0017] (3) Slowly add the sample stirred in (2) to the solution in (1) so that the weight ratio of vericipirat to hydroxypropyl-β-cyclodextrin is 1:4-6, and keep the temperature at 50-60°C during the addition process while stirring. After the addition is completed, continue stirring for 1 hour until the inclusion complex is completely formed;

[0018] (4) The inclusion complex formed in (3) is freeze-dried, and then crushed through a 100-mesh sieve to obtain a viriciguat-cyclodextrin inclusion complex.

[0019] The method for preparing a solid preparation of Vericipiracil comprises the following steps:

[0020] (1) Prepare the raw and auxiliary materials according to the following weight proportions: 20-40 parts of Vericipirat-cyclodextrin inclusion compound, 70-90 parts of filler, 3-6 parts of binder, 6-10 parts of disintegrant, and 0.5-1.5 parts of lubricant;

[0021] (2) The Vericipirax-cyclodextrin inclusion complex in (1) is added to a wet granulator with a filler, a binder, and an internal disintegrant. The granules are sieved and dried, and the granules are sieved again. The external disintegrant is added and mixed evenly. A lubricant is then added and mixed evenly to obtain granules. The granules are tableted to obtain a Vericipirax solid preparation.

[0022] There are many documents reporting on the use of cyclodextrin in drug solubilization. However, the inventors have found through experiments that not all cyclodextrins are suitable for the production of the solid preparation of Vericiguat of the present invention. For example, γ-cyclodextrin, on the one hand, has a high price and is not suitable for large-scale production and use. If it is applied to the present application, it will significantly increase the production cost; on the other hand, the cavity structure of γ-cyclodextrin is too large and is not suitable for the drug production in the present application. For another example, the cavity structure of α-cyclodextrin is relatively small, while the molecular weight of the product of the present invention is relatively large (426), and the cavity structure is too small to be suitable for encapsulating drug molecules.

[0023] The characteristic of the hydroxypropyl-β-cyclodextrin used in this application is that its solubility can increase by hundreds of times when the temperature is slightly increased (above 50°C). This dissolution mode is conducive to the drug and cyclodextrin. The solubility is significantly increased at a slightly higher temperature to achieve full inclusion, and it can be quickly precipitated when the temperature is lowered to reduce losses. However, through experiments, the inventors also found that even if they are all hydroxypropyl-β-cyclodextrin, the hydroxypropyl-β-cyclodextrin purchased from different manufacturers or different models has different solubilization effects on Vericipiragua. Regarding this phenomenon, the inventors have analyzed it and found that the reason may be that the degree of substitution of hydroxypropyl-β-cyclodextrin will affect the solubilization effect. There is currently no corresponding literature disclosure on the range of substitution degree for which hydroxypropyl-β-cyclodextrin has a better solubilization effect on Vericipiragua.

[0024] In addition, when preparing the inclusion complex of Vericipirax-cyclodextrin, whether the solubilization effect will be affected by the inclusion conditions, such as whether the solubilization effect will be affected by the pH value, or the inclusion temperature or the solvent used for inclusion, and whether these external conditions will have a significant effect on the solubilization effect, there is also no corresponding literature disclosure. The examples in this application investigated the effect of the type of hydroxypropyl-β-cyclodextrin (different degrees of substitution) on the solubilization effect, temperature, pH value and other factors, and obtained the conditions and parameters that are most conducive to the preparation of the inclusion complex of Vericipirax-cyclodextrin. The experiment also proved that the above conditions may affect the solubilization effect of the product.

[0025] Compared with the prior art, the present invention has the following advantages and effects:

[0026] (1) Compared with the solubilization method using a ball mill, the preparation process of the present invention does not require grinding, and does not require the use of equipment such as a ball mill. The following effects can be achieved by simply combining cyclodextrin inclusion with wet granulation: the raw materials are mixed evenly, the prepared particles are of uniform size, which is conducive to tableting or capsule filling, the prepared samples can achieve rapid release and have small intra-batch differences, and their release rate is higher than that of marketed varieties, which can effectively increase drug absorption; at the same time, the inclusion of the raw material in cyclodextrin can also increase drug stability; compared with the spray drying method, the present invention has the obvious advantage of low cost, and there is no need to try various different solvents; compared with the extrusion method, the present invention has the characteristics of stable active ingredients and not easy to degrade; regardless of which existing solubilization method is compared, the method of the present invention has the advantages of excellent solubilization effect, good product stability, and not easy to degrade;

[0027] (2) The present invention has conducted a large number of experiments and selected hydroxypropyl-β-cyclodextrin with a degree of substitution of 3.5-5.5 to include Vericipiraguat. Compared with hydroxypropyl-β-cyclodextrin with other degrees of substitution or other solubilizers, the solubilization effect is better. Figure 3 As shown, three different concentrations of solubilizers were used, and the results showed that hydroxypropyl-β-cyclodextrin had higher solubility than methyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin;

[0028] (3) The cumulative dissolution rate of the solid preparation of Vericipiracil prepared by the method of the present invention is significantly higher than that of the commercially available product. Figure 1 shown. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 Cumulative dissolution curves of the products in Examples 1 to 3;

[0030] Figure 2 Cumulative dissolution comparison for different samples;

[0031] Figure 3 To compare the solubilization effects of different β-cyclodextrins;

[0032] Figure 4 Dissolution profile of the relevant substances in Example 10. DETAILED DESCRIPTION

[0033] In order to enable those skilled in the art to better understand the present invention, the present invention is further described in conjunction with specific implementation methods.

[0034] The raw materials in this application are all commercially available products, such as acetone, hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin, etc.

[0035] Example 1

[0036] The preparation method of the solid preparation of Vericipiracil is as follows:

[0037] (1) Prepare the raw and auxiliary materials according to the ratio in Table 1;

[0038] (2) Preparation of cyclodextrin inclusion complex:

[0039] Add 20 g of cyclodextrin (hydroxypropyl-β-cyclodextrin with an average degree of substitution of 4.5) to 80 mL of a citric acid aqueous solution at pH 3.0, and stir and dissolve at about 55°C to form a hydroxypropyl-β-cyclodextrin solution;

[0040] (3) Add Vericipirab to acetone in an amount of about 8 times its weight and stir evenly. Then, slowly add the stirred Vericipirab sample in small amounts and multiple times to the hydroxypropyl-β-cyclodextrin solution in (2). Continue stirring for 1 hour until the inclusion is complete. Cool, freeze-dry at a temperature of about -50°C, and grind through a 100-mesh sieve to obtain a Vericipirab-cyclodextrin inclusion complex.

[0041] (4) The Vericipirax-cyclodextrin inclusion complex in (3) is added to a wet granulator with lactose, microcrystalline cellulose, hypromellose, and cross-linked sodium carboxymethyl cellulose (internal addition method), granulated with purified water, and then granulated through a 20-mesh sieve, dried at 60° C., and then granulated through a 30-mesh sieve, and cross-linked sodium carboxymethyl cellulose (external addition method) is added and mixed evenly, and then magnesium stearate is added and mixed evenly to obtain granules, and the granules are compressed to obtain a Vericipirax solid preparation.

[0042] Table 1 Formula of raw materials and auxiliary materials of the drug in Example 1

[0043]

[0044] Example 2

[0045] (1) Prepare the raw materials according to the ratio in Table 2;

[0046] (2) Preparation of cyclodextrin inclusion complex:

[0047] Add 25g of cyclodextrin (hydroxypropyl-β-cyclodextrin with an average degree of substitution of 4.5) to 100ml of pH 3.0 citric acid aqueous solution, maintain the temperature at about 60°C, and stir to dissolve to form a cyclodextrin solution;

[0048] (3) (4) Steps are the same as those in Example 1.

[0049] Table 2 Drug raw material formula in Example 2

[0050]

[0051] Example 3

[0052] (1) Prepare the raw materials according to the ratio in Table 3;

[0053] (2) Preparation of cyclodextrin inclusion complex: Add 30 g of cyclodextrin (hydroxypropyl-β-cyclodextrin with an average degree of substitution of 4.5) to 120 ml of a citric acid aqueous solution at pH 3.0, maintain the temperature at about 50°C, and stir to dissolve to form a cyclodextrin solution;

[0054] (3) (4) Steps are the same as those in Example 1.

[0055] Table 3 Drug raw material formula in Example 3

[0056]

[0057] In Example 4-7, the method is exactly the same as that in Example 1, except that the hydroxypropyl-β-cyclodextrin selected in Example 4-7 is from different manufacturers, and their substitution degrees are different. The specific substitution degrees are as follows:

[0058] In Example 4, hydroxypropyl-β-cyclodextrin with an average degree of substitution of 3.5 was used;

[0059] In Example 5, hydroxypropyl-β-cyclodextrin with an average degree of substitution of 4 was used;

[0060] In Example 6, hydroxypropyl-β-cyclodextrin with an average degree of substitution of 5 was used;

[0061] In Example 7, hydroxypropyl-β-cyclodextrin with an average degree of substitution of 6 is used.

[0062] Example 8

[0063] The samples in Examples 1-3 were compared with commercially available products. The same prescription process as listed in Example 2 was used to prepare samples using hydroxypropyl-β-cyclodextrin with different degrees of substitution. The dissolution was determined using the first method (basket method) in the four dissolution test methods of the Chinese Pharmacopoeia 2020 edition (see Appendix). Figure 1 , where listed products refer to similar products on the market), the dissolution results are as follows in Tables 4-1 and 4-2 (corresponding to the attached Figure 2 ) as shown:

[0064] Table 4-1 RSD values ​​of commercially available products and the products of Examples 1-3 detected at different dissolution times (%)

[0065]

[0066] Table 4-2 RSD values ​​of the products of Example 4-7 detected at different dissolution times (%)

[0067]

[0068] It can be seen from the above data that the samples prepared in each embodiment can be dissolved more completely than the marketed product, and the intra-batch difference is significantly smaller than the marketed product (RSD is smaller). At the same time, differences can also be seen between different degrees of substitution. The endpoint dissolution (120 min) of the samples prepared in Examples 4 and 5 is more complete.

[0069] Example 9

[0070] The prepared samples were tested for related substances and stability, accelerated for 3 months, with the storage conditions of 40°C and 75% relative humidity. The results are as follows:

[0071] Table 5 Performance evaluation of samples in Examples 1-3 after 3 months of acceleration

[0072]

[0073] It can be seen from the above data that the quality attributes of the samples in Examples 1-3 are not lower than those of the marketed products and have good stability. The specific results are that after the product in Example 1 is accelerated for 3 months, the total impurities change from 0.22% to 0.23%; after the product in Example 2 is accelerated for 3 months, the total impurities of the product are still 0.23%; after the product in Example 3 is accelerated for 3 months, the total impurities of the product change from 0.22% to 0.24%.

[0074] Example 10

[0075] When developing the solution of the present application, the inventors also used spray drying (DMSO as solvent) and melt extrusion (copolyvidone as carrier) to solubilize Vericiguat. The following are the corresponding experiments and data:

[0076] Table 6 Comparison of different solubilization methods

[0077] Preparation method Spray drying Melt extrusion Single miscellaneous 3.5 57.1 Total Miscellaneous 10.7 62.3 content 86.5 41.2

[0078] From the above data, it can be seen that the samples prepared by these two methods have too high related substances and serious degradation of raw materials. These two methods are not suitable for preparing the solid preparation of the present invention. Figure 4 It can be seen that the blue is the main peak of the sample (content 100%), and the black is the melt extrusion sample. It can be clearly seen that the area of ​​the main peak is greatly reduced, and there are larger impurities behind it, which exceed the main peak. Therefore, hot melt extrusion is not suitable for sample preparation.

[0079] Embodiment 11

[0080] In the present invention, the inventors first studied the effect of the solubility of the drug itself on the inclusion rate. One of the effective ways to increase the inclusion rate is to increase the solubility of the drug itself and increase the inclusion with cyclodextrin. However, the solubility of Vericipiraguat in various solvents is relatively low. Therefore, it is particularly important to screen a solvent that can make Vericipiraguat disperse better and include better. The cyclodextrin was dissolved in an acidic solution, acetone, methanol, and water, and then the raw materials were added and stirred evenly. The inclusion rate was measured. The inclusion rates in hydrochloric acid solution (pH 2.0), citric acid solution (pH 3.0), acetone and methanol were measured, respectively, as shown in Table 7.

[0081] Table 7 Comparison of different types of solvent solubilization methods

[0082] Drug inclusion solvent Hydrochloric acid solution (pH 2.0) Citric acid solution (pH 3.0) acetone Methanol water Inclusion rate (%) 66.3 64.7 88.5 77.6 43.7

[0083] It can be seen from Table 7 that the sample prepared with acetone as the solvent has the highest inclusion rate, which can reach 88.5%. Therefore, acetone is selected as the inclusion solvent in this application.

[0084] Example 12

[0085] The derivatives formed by substitution at different positions of β-cyclodextrin have slightly different spatial structures and hydrophilicity. Therefore, it is necessary to study the inclusion effects of different β-cyclodextrin derivatives and screen the most suitable β-cyclodextrin derivatives. The formation of inclusion complexes increases the water solubility of the drug from 0.83μg / ml to about 30μg / ml (25℃), effectively improving the dissolution rate of the drug. Figure 3 As shown in Table 8 (preparation method and dosage refer to Example 1).

[0086] Table 8 Comparison of solubilization effects of inclusion complexes at different concentrations (solubility, μg / mL)

[0087] Inclusion complex concentration (W / W) Methyl-β-cyclodextrin Hydroxypropyl-β-cyclodextrin Sulfonbutyl-β-cyclodextrin 5 0.83 0.88 0.76 10 5.01 5.21 4.38 15 18.28 19.10 17.33 20 26.73 28.60 24.98 25 28.80 29.87 27.24 30 28.12 29.79 27.33 35 27.85 28.00 27.68 40 26.96 27.51 26.91 45 12.88 12.73 13.13 50 6.13 10.10 4.98

[0088] Embodiment 13

[0089] Considering that the product of the present invention has good solubility in acidic solution, but cyclodextrin is easily degraded in acidic solution, thereby affecting the inclusion and solubilization effect, the stability and inclusion effect of the acetone solution of the raw material in different cyclodextrin solutions are compared:

[0090] Table 9 Comparison of the stability and inclusion effect of acetone solutions of raw materials in different cyclodextrin solutions

[0091]

[0092] Unexpectedly, Vericipirat and hydroxypropyl-β-cyclodextrin can be stably present in an acidic solution for more than 24 hours, and the inclusion rate of the raw material and hydroxypropyl-β-cyclodextrin is effectively increased in the acidic solution.

[0093] Embodiment 14

[0094] The solubility of the API in hydroxypropyl-β-cyclodextrin solutions with different degrees of substitution (20% (w / w) pH 3.0 citric acid aqueous solution) was determined, and the results are as follows:

[0095] Table 10 Solubility of API in hydroxypropyl-β-cyclodextrin solutions with different degrees of substitution

[0096] Average degree of substitution of hydroxypropyl-β-cyclodextrin 3.5 4.0 4.5 5.0 5.5 6.0 Solubility (μg / ml) 15.3 22.1 28.9 25.6 16.7 8.3

[0097] From the above data, it can be seen that the solubility of hydroxypropyl β-cyclodextrin with a degree of substitution of 3.5-5.5 is significantly increased, among which 4.0-5.0 hydroxypropyl β-cyclodextrin has the best solubility-enhancing effect, and the drug has the highest solubility in cyclodextrin with this degree of substitution.

[0098] Embodiment 15

[0099] The effects of inclusion temperature and inclusion time on the inclusion rate were investigated. When the inclusion temperature was selected at 40℃, 50℃, 55℃, and 60℃, the inclusion time was set to 2 hours.

[0100] When the inclusion time is set to 0.5h, 1h, 2h, and 3h, and the inclusion temperature is set at 55°C, the specific test results are shown in the following table:

[0101] Table 11 Effect of inclusion temperature and inclusion time on product inclusion rate

[0102]

[0103] From the above data, it can be seen that the inclusion rate of the inclusion compound prepared by using acetone as the drug solvent is the highest, the inclusion rate is higher when the inclusion temperature is between 50-60°C, and a good inclusion rate can be achieved with a stirring time of 1h.

[0104] Comparative Example 1

[0105] Generally, the more appropriate ratio for drug inclusion by cyclodextrin is 1:1 in molar ratio. The molecular weight of Vericipirab is 426, and the molecular weight of hydroxypropyl-β-cyclodextrin is about 1300. When the molar ratio of the two is 1:1, the mass ratio is about 1:3. It is necessary to verify whether this conventional ratio is suitable for inclusion of this API with cyclodextrin. Therefore, different raw material-cyclodextrin ratios are studied, mainly evaluated by inclusion rate, as follows:

[0106] Raw material: Hydroxypropyl-β-cyclodextrin (w:w) 1:2 1:3 1:4 1:5 1:6 1:7 Inclusion rate (%) 61.1 78.2 90.5 88.7 92.1 83.1

[0107] It can be seen from the above data that when the ratio of Vericipirat to cyclodextrin is in the range of 1:4-6, the inclusion effect is the best. When the ratio of Vericipirat to cyclodextrin is 1:2, 1:3, or 1:7, the effect is not as good as when the ratio is in the range of 1:4-6.

Claims

1. The use of hydroxypropyl-β-cyclodextrin as a solubilizer in the preparation of a solid preparation of Vericipiracil, characterized in that: The hydroxypropyl-β-cyclodextrin is used to form a vericipirat-cyclodextrin inclusion complex with vericipirat; The Vericipiracil solid preparation is prepared by the following method: (1) Prepare the raw materials according to the ratios in the table below; ； (2) Preparation of hydroxypropyl-β-cyclodextrin solution: Add 25 g of cyclodextrin to 100 mL of pH 3.0 citric acid aqueous solution, maintain the temperature at 60°C, and stir to dissolve to form a cyclodextrin solution, wherein the cyclodextrin is hydroxypropyl-β-cyclodextrin with an average degree of substitution of 4.5; (3) Add Vericipirab to 8 times its weight of acetone and stir evenly. Then slowly add the stirred Vericipirab sample to the hydroxypropyl-β-cyclodextrin solution in (2), continue stirring for 1 hour until it is completely included, cool, freeze-dry at -50°C, and grind through a 100-mesh sieve to obtain the Vericipirab-cyclodextrin inclusion complex; (4) The Vericipirax-cyclodextrin inclusion complex in (3) is added to a wet granulator with lactose, microcrystalline cellulose, hypromellose, and cross-linked sodium carboxymethyl cellulose by internal addition, granulated with purified water, sieved through a 20-mesh sieve, dried at 60° C., and then sieved through a 30-mesh sieve. Cross-linked sodium carboxymethyl cellulose is added by external addition, mixed evenly, and then magnesium stearate is added and mixed evenly to obtain granules. The granules are compressed into tablets to obtain a Vericipirax solid preparation.

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