Cyclodextrin inclusion compound and preparation method thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a cyclodextrin inclusion compound and a preparation method thereof.The cyclodextrin inclusion compound comprises voriconazole, a cosolvent and sulfobutyl-beta-cyclodextrin, by increasing use of the cosolvent polysorbate 80 (II), the use amount of sulfobutyl ether-beta-cyclodextrin in voriconazole for injection is reduced, and the content of the sulfobutyl ether-beta-cyclodextrin in voriconazole for injection is reduced; the invention aims at remarkably reducing cyclodextrin accumulation in the body and provides guarantee for medication safety of patients with moderate to severe renal function impairment. Meanwhile, the preparation process is simple, industrial production is facilitated, and the inclusion effect of the inclusion compound and the stability of the product can be guaranteed.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and in particular relates to a cyclodextrin inclusion compound and a preparation method thereof. Background Art

[0002] Voriconazole is a broad-spectrum triazole antifungal drug with a chemical name of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol and a structural formula of C 16 H 14 F 3 N 5 O, whose structural formula is shown below:

[0003] Voriconazole can effectively control and treat invasive aspergillosis, a progressive, potentially life-threatening infection in immunocompromised patients. As a broad-spectrum triazole antifungal drug, it has broad clinical application prospects and huge international market demand. Intravenous injection can quickly control infection, but the clinical application of voriconazole is limited by its low solubility in water (only 0.2 mg / ml), unstable chemical properties, and easy hydrolysis.

[0004] Since its discovery, cyclodextrin has been widely used to solubilize poorly soluble drugs. Its unique cage structure can form a complex with drug molecules: non-polar drug molecules are located in the hydrophobic cage structure, and the polyhydroxyl groups on the outside of cyclodextrin have a strong affinity with the surrounding polar water molecules, thereby achieving a solubilization effect. Among them, β-cyclodextrin (β-CD) is more commonly used. Currently, Pfizer's voriconazole for injection uses sulfobutyl ether-β-cyclodextrin (SBE-β-CD) as the main excipient to improve the solubility of voriconazole. However, when using a single cyclodextrin for inclusion, the amount of cyclodextrin is large. The molar ratio of voriconazole to sulfobutyl ether-β-cyclodextrin (SBE-β-CD) in Pfizer's voriconazole for injection reached 1:4. Cyclodextrin derivatives accumulate in large quantities in the patient's body, causing severe nephrotoxicity to patients with moderate and severe renal dysfunction during clinical application, seriously threatening the health of patients.

[0005] Therefore, how to improve the solubility of voriconazole in water and reduce the amount of sulfobutyl ether-β-cyclodextrin in voriconazole injection is a technical problem that needs to be solved urgently by those skilled in the art. Summary of the invention

[0006] In order to overcome the deficiencies of the above-mentioned prior art, the object of the present invention is to provide a voriconazole injection that reduces the amount of sulfobutyl ether-β-cyclodextrin used in voriconazole injection, significantly reduces the accumulation of cyclodextrin in the body, and provides a guarantee for the medication safety of patients with moderate to severe renal impairment.

[0007] To achieve the above purpose, the technical solution adopted by the present invention is: The invention provides a sulfobutyl-β-cyclodextrin inclusion compound, which contains an active ingredient voriconazole, a cosolvent, sulfobutyl-β-cyclodextrin and a pH regulator. The inclusion compound exists in a liquid form, and the solvent is water.

[0008] According to an embodiment of the present invention, in the inclusion compound, the co-solvent is selected from one or more of polysorbate 80 (II), poloxamer, and sodium dodecyl sulfate; preferably polysorbate 80 (II).

[0009] According to an embodiment of the present invention, in the inclusion complex, the mass ratio of polysorbate 80 (II) to sulfobutyl-β-cyclodextrin is selected from 1:0.5 to 1:2, and the molar ratio of voriconazole to sulfobutyl-β-cyclodextrin is selected from 6:1 to 1:1.

[0010] Preferably, the mass ratio of polysorbate 80 (II) to sulfobutyl-β-cyclodextrin is selected from 3:2; and the molar ratio of voriconazole to sulfobutyl-β-cyclodextrin is selected from 3:1 to 1:1.

[0011] According to an embodiment of the present invention, the average degree of substitution of sulfobutyl-β-cyclodextrin in the inclusion compound is preferably 6.1 to 6.9.

[0012] According to an embodiment of the present invention, the pH adjuster is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, sodium hydroxide, and sodium citrate, preferably hydrochloric acid or sodium hydroxide.

[0013] The present invention also provides a method for preparing a sulfobutyl-β-cyclodextrin inclusion compound, comprising preparation, sterilization filtration, filling and freeze drying to obtain voriconazole for injection, specifically 1) Add voriconazole and cosolvent to 20% water for injection and stir in a 30-50℃ water bath for 0.5-2 hours; 2) Dissolve sulfobutyl-β-cyclodextrin in 60% of the total amount of water for injection; 3) Add the liquid obtained in step 1) to the liquid in step 2) and stir for 0.5 to 2 hours; 4) Control the pH range of the solution, control the dissolution temperature, and add water for injection to the total amount; 5) Filter through a 0.2 μm sterilizing filter, fill into 20 ml bottles, and freeze-dry.

[0014] According to an embodiment of the present invention, during the preparation of the inclusion compound, the pH control range is selected from 5.5 to 7.5, and the dissolution temperature is selected from 30° C. to 50° C.

[0015] Compared with the prior art, the present invention has the following beneficial effects: 1) The combination of non-ionic surfactant polysorbate 80 (II) and sulfobutyl-β-cyclodextrin surprisingly found that it can achieve a synergistic solubilization effect on voriconazole. This combination makes full use of the solubilization effect of polysorbate 80 (II) on voriconazole to first molecularize voriconazole, and then includes voriconazole with sulfobutyl-β-cyclodextrin, effectively improving the solubility of voriconazole and significantly reducing the dosage of sulfobutyl-β-cyclodextrin, thereby significantly reducing the accumulation of cyclodextrin in the body and the renal toxicity caused by cyclodextrin, providing guarantees for the development of low nephrotoxic voriconazole injection and the safety of medication for patients with moderate to severe renal impairment.

[0016] 2) The cyclodextrin inclusion compound and the preparation method thereof provided by the present invention ensure the stability of the inclusion compound by controlling the molar ratio of voriconazole to cyclodextrin, the degree of substitution of cyclodextrin, and the parameters in the inclusion process; the preparation process is simple and convenient for industrial production, while being able to ensure the inclusion effect of the inclusion compound and the stability of the product. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 : The solubility curves of voriconazole at different ratios of different co-solvents to sulfobutyl-β-cyclodextrin. SBECD is sulfobutyl-β-cyclodextrin.

[0018] Figure 2 The R value changes under different ratios of different co-solvents and sulfobutyl-β-cyclodextrin.

[0019] Figure 3 These are DSC diagrams of voriconazole, sulfobutyl-β-cyclodextrin, physical mixture of voriconazole and sulfobutyl-β-cyclodextrin, and multiple batches of inclusion complexes. SBECD is sulfobutyl-β-cyclodextrin, and API is voriconazole raw material. DETAILED DESCRIPTION

[0020] Example 1: Polysorbate 80 (II): sulfobutyl-β-cyclodextrin = 1:1

[0021] Preparation method: 1) Under stirring conditions, add voriconazole and cosolvent into 20% of the total volume of water for injection, and stir in a water bath at 30℃~50℃ for 1 hour; 2) Add sulfobutyl-β-cyclodextrin to 60% of the total volume of water for injection under continuous stirring and stir until completely dissolved; 3) Add the liquid obtained in step 1) to the liquid in step 2), control the temperature at 30°C to 50°C, and stir continuously for more than 1 hour until completely dissolved; 4) Use 1% hydrochloric acid to adjust the pH of the solution to 5.5-7.5, and add water for injection to the total amount; 5) Filter the obtained solution through a 0.2 μm sterilizing filter; 6) For turbid solutions, filter the solution through a 0.2 μm sterilizing filter and determine the voriconazole content; for clear solutions, continue to add excess voriconazole, stir for 60 minutes, and then filter through a 0.2 μm sterilizing filter and determine the voriconazole content.

[0022] Example 2: Polysorbate 80 (II): sulfobutyl-β-cyclodextrin = 1:2, the preparation method is the same as Example 1.

[0023]

[0024] Example 3: Polysorbate 80 (II): sulfobutyl-β-cyclodextrin = 2:3, the preparation method is the same as that of Example 1.

[0025]

[0026] Example 4: Polysorbate 80 (II): sulfobutyl-β-cyclodextrin = 3:2, the preparation method is the same as that of Example 1.

[0027]

[0028] Example 5: Polysorbate 80 (II): sulfobutyl-β-cyclodextrin = 2:1, the preparation method is the same as that of Example 1.

[0029]

[0030] Example 6: Poloxamer: sulfobutyl-β-cyclodextrin = 1:1, the preparation method is the same as Example 1.

[0031]

[0032] Example 7: Poloxamer: sulfobutyl-β-cyclodextrin = 2:1, the preparation method is the same as Example 1.

[0033]

[0034] Example 8: Sodium dodecyl sulfate: sulfobutyl-β-cyclodextrin = 1:1, the preparation method is the same as that of Example 1.

[0035]

[0036] Example 9: Sodium dodecyl sulfate: sulfobutyl-β-cyclodextrin = 2:1, the preparation method is the same as that of Example 1.

[0037]

[0038] According to the results of prescriptions 3, 4, 7, 8, 11 and 12 in Examples 1 to 3, the ratio of polysorbate 80 (II) to sulfobutyl-β-cyclodextrin is 1:1 to 1:2, and the molar ratio of voriconazole to sulfobutyl-β-cyclodextrin can be increased to 1:2 to 1:1; according to the results of prescriptions 15, 16, 18, 19 and 20 in Examples 4 to 5, it can be seen that further increasing the ratio of polysorbate 80 (II) to sulfobutyl-β-cyclodextrin to 1:1 to 2:1 can increase the molar ratio of voriconazole to sulfobutyl-β-cyclodextrin to 1:1 to 3.07:1. According to the above results, it can be judged that by increasing the ratio of polysorbate 80 (II), the amount of sulfobutyl-β-cyclodextrin used in the prescription can be significantly reduced.

[0039] The results of Examples 6 to 9 show that when the ratio of poloxamer, sodium dodecyl sulfate and sulfobutyl-β-cyclodextrin is in the range of 1:1 to 2:1, voriconazole cannot be dissolved and the dosage of sulfobutyl-β-cyclodextrin cannot be significantly reduced.

[0040] According to the voriconazole content results of Examples 1 to 9, solubility curves of different co-solvents and different ratios of sulfobutyl-β-cyclodextrin were drawn ( Figure 1 ), through the slope calculation, it can be seen that the synergistic solubilization effect of voriconazole at different ratios is different. Figure 1 It can be seen that polysorbate 80 (II) and sulfobutyl-β-cyclodextrin have a stronger synergistic solubilization effect, while poloxamer and sodium dodecyl sulfate have no obvious synergistic solubilization effect.

[0041] Draw the R value of the synergistic solubilization strength at different ratios in the prescription Figure 2 According to the R value, polysorbate 80 (II) is significantly stronger than poloxamer and sodium dodecyl sulfate. According to the change pattern of the R value, the R value is the largest when the ratio of polysorbate 80 (II): sulfobutyl-β-cyclodextrin is 3:2, indicating that the synergistic solubilization effect of the two is the strongest at this time.

[0042] Using this ratio, polysorbate 80 (II): sulfobutyl-β-cyclodextrin = 3:2, voriconazole solution was prepared as follows.

[0043] Example 10

[0044] Preparation method: 1) Under stirring conditions, add voriconazole and polysorbate 80 (II) to 20% of the total volume of water for injection, and stir in a water bath at 30℃~50℃ for 1 hour; 2) Add sulfobutyl-β-cyclodextrin to 60% of the total volume of water for injection under continuous stirring and stir until completely dissolved; 3) Add the liquid obtained in step 1) to the liquid in step 2), control the temperature at 30°C to 50°C, and stir continuously for more than 1 hour until completely dissolved; 4) Use 1% hydrochloric acid to adjust the pH of the solution to 5.5-7.5, and add water for injection to the total amount; 5) Filter the obtained solution through a 0.2 μm sterilizing filter.

[0045] Comparative Example 1 Voriconazole for injection, with the trade name of Weifan, has a specification of 200 mg. The license holder is Pfizer Pharmaceuticals Co., Ltd. It is a marketed drug in China with batch number Z537901.

[0046]

[0047] The inclusion constants of the solutions under the above different preparation parameters were studied, and the results are as follows.

[0048] (1) Inclusion constants of sulfobutyl-β-cyclodextrin with different degrees of substitution and voriconazole

[0049] The results show that the degree of substitution requirement (6.1-6.9) for sulfobutyl-β-cyclodextrin in the present invention can meet the requirements for the formation of a stable inclusion complex of the product.

[0050] (2) Inclusion constant of voriconazole with sulfobutyl-β-cyclodextrin under different pH conditions

[0051] The results show that the pH requirement range of 5.5 to 7.5 under the present invention can satisfy the formation of a stable inclusion complex of the product.

[0052] (3) Inclusion constant of voriconazole by sulfobutyl-β-cyclodextrin at different dissolution temperatures

[0053] The results show that the dissolution temperature requirement range of 30℃~50℃ is sufficient for the product to form a stable inclusion complex.

[0054] (4) Inclusion constant of homemade preparation and comparative example 1

[0055] The inclusion constants of prescriptions 37 to 39 were consistent with those of the reference preparations, indicating that a stable inclusion constant could still be maintained when the dosage of polysorbate 80 (II) was increased and the dosage of sulfobutyl ether-β-cyclodextrin was reduced.

[0056] See also Figure 3 DSC measurements were performed on voriconazole, sulfobutyl-β-cyclodextrin, a physical mixture of voriconazole and sulfobutyl-β-cyclodextrin, and multiple batches of inclusion complexes. The results showed that voriconazole had an absorption peak at 133°C, which was consistent with the melting point of voriconazole. The physical mixture also had an absorption peak at 133°C, while the inclusion complex had no absorption peak at 133°C, which was consistent with the thermodynamic characteristics of sulfobutyl-β-cyclodextrin, indicating that the product formed a stable inclusion complex. This shows that under the conditions of polysorbate 80 (II): sulfobutyl-β-cyclodextrin = 3:2, voriconazole solution can form a stable inclusion complex under different preparation parameters.

[0057] Prescriptions 37 to 39 and comparative example 1 were subjected to accelerated tests (40°C, 75%RH) and left for 6 months. The related substances and enantiomers were tested. The results are shown in the following table:

[0058] Conclusion: By adding polysorbate 80 (II) to sulfobutyl-β-cyclodextrin to solubilize voriconazole, the results of the accelerated 6-month test of the samples were all below the limit requirements (related substances ≤ 1.0%, enantiomers ≤ 0.4%), which can prove that the use of polysorbate 80 (II) does not affect the stability of the product. This lays a good foundation for reducing the dosage of sulfobutyl ether-β-cyclodextrin in voriconazole injection and developing low nephrotoxic voriconazole injection.

Claims

1. A sulfobutyl-β-cyclodextrin inclusion compound, characterized in that: The inclusion compound contains active ingredient voriconazole, a cosolvent, sulfobutyl-β-cyclodextrin and a pH regulator. The inclusion compound exists in liquid form, the solvent is water, and the molar ratio of voriconazole to sulfobutyl-β-cyclodextrin is 6:1 to 1:

1.

2. A sulfobutyl-β-cyclodextrin inclusion compound according to claim 1, characterized in that: The cosolvent is selected from one or more of polysorbate 80 (II), poloxamer and sodium dodecyl sulfate.

3. A sulfobutyl-β-cyclodextrin inclusion compound according to claim 2, characterized in that: The cosolvent is selected from polysorbate 80 (II).

4. A sulfobutyl-β-cyclodextrin inclusion compound according to claim 3, characterized in that: The mass ratio of polysorbate 80 (II) to sulfobutyl-β-cyclodextrin is selected from 1:0.5 to 1:2, and the molar ratio of voriconazole to sulfobutyl-β-cyclodextrin is selected from 6:1 to 1:

1.

5. A sulfobutyl-β-cyclodextrin inclusion compound according to claim 4, characterized in that: The mass ratio of polysorbate 80 (II) to sulfobutyl-β-cyclodextrin is selected from 3:2, and the molar ratio of voriconazole to sulfobutyl-β-cyclodextrin is selected from 3:1 to 1:

1.

6. The sulfobutyl-β-cyclodextrin inclusion compound according to claim 1, characterized in that: The average degree of substitution of the sulfobutyl-β-cyclodextrin is selected from 6.1 to 6.

9.

7. The sulfobutyl-β-cyclodextrin inclusion compound according to claim 1, characterized in that: The pH regulator is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, sodium hydroxide, and sodium citrate, preferably hydrochloric acid or sodium hydroxide.

8. A method for preparing a sulfobutyl-β-cyclodextrin inclusion compound, characterized in that: The preparation method comprises: 1) Add voriconazole and cosolvent to 20% water for injection and stir in a 30-50℃ water bath for 0.5-2 hours; 2) Dissolve sulfobutyl-β-cyclodextrin in 60% of the total amount of water for injection; 3) Add the liquid obtained in step 1) to the liquid in step 2) and stir for 0.5 to 2 hours; 4) Control the pH range of the solution, control the dissolution temperature, and add water for injection to the total amount; 5) Filter through a 0.2 μm sterilizing filter, fill into 20 ml bottles, and freeze-dry.

9. The method for preparing a sulfobutyl-β-cyclodextrin inclusion compound according to claim 8, characterized in that: The pH control range is selected from 5.5 to 7.

5.

10. The method for preparing a sulfobutyl-β-cyclodextrin inclusion compound according to claim 8, characterized in that: The dissolving temperature is selected from 30 to 50°C.

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