A kind of water-based solution preparation of Bunananserin and preparation method thereof

Abstract

The present invention belongs to the technical field of drug dissolution and dispersion, and specifically relates to a water-based solution preparation of blonanserin and a preparation method thereof. The water-based solution preparation of blonanserin provided by the present invention comprises components such as blonanserin, γ-cyclodextrin, lecithin, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, aspartame, and water. The above components are mixed and homogenized to form a uniform, clear, and long-term stable storage oral liquid. The scheme of the present invention further enriches the dosage form of blonanserin, improves the convenience of taking blonanserin, and is expected to help improve the oral bioavailability and absorption efficiency of blonanserin. The scheme of the present invention also provides a reference direction for the mechanism study of the dissolution and dispersion behavior of poorly soluble blonanserin macromolecules in aqueous media.

Description

Technical Field

[0001] The invention belongs to the technical field of drug dissolution and dispersion, and particularly relates to a blonanserin water-based solution preparation and a preparation method thereof. Background Art

[0002] Blonanserin is a highly selective dopamine D2 and 5-HT inhibitor with a novel chemical structure. 2A Blonanserin is a receptor antagonist developed by Sumitomo Pharma Co., Ltd. and launched in Japan in 2008. The drug was approved by the former China Food and Drug Administration (CFDA) in 2017 and launched in China. Blonanserin can significantly improve the positive symptoms (such as hallucinations, delusions, etc.) and negative symptoms (such as depression, motor dysfunction, etc.) of schizophrenia, reduce the incidence of extrapyramidal side effects (Parkinson's syndrome, acute dystonia, akathisia, etc.) and other adverse reactions, and its safety and tolerability are significantly better than traditional antipsychotic drugs.

[0003] Clinical data showed that the absolute oral bioavailability of the marketed blonanserin tablets (4 mg) was 55%. Comparison of the pharmacokinetic data of post-meal administration and fasting administration revealed that post-meal C max and AUC 0-12 They were 2.68 times and 2.69 times higher than before meals, respectively. There are also clinical data showing that drinking alcohol can increase the oral bioavailability of blonanserin. The above information shows that there is still room for further improvement in the oral bioavailability of blonanserin. In addition, the only blonanserin preparations currently on the market at home and abroad are ordinary tablets, which have problems such as difficulty in swallowing and inconvenient dosage adjustment for children. Therefore, innovation of blonanserin preparations and development of a solution-based blonanserin oral solution are expected to not only improve the oral bioavailability and absorption efficiency of blonanserin preparations, but also make it easier for children to take.

[0004] However, blonanserin has poor water solubility and only has high solubility in organic solvents such as ethanol, and belongs to BCS class II compounds. Figure 1 As shown in the figure, the skeleton contains a piperazine ring, a benzene ring with a fluorine substituent, and a hexahydrooctanopyridine skeleton. These non-polar molecular fragments have weak interactions with water molecules and cannot effectively form a hydrogen bond network with water molecules, resulting in extremely poor solubility of blonanserin drug molecules in water, making it difficult to form a uniform blonanserin oral solution that can remain stable during daily storage. Summary of the invention

[0005] In view of the above technical problems, the present invention provides a water-based solution preparation of blonanserin and a preparation method thereof, aiming to overcome the problem of low solubility of blonanserin and provide a uniform, clear blonanserin oral solution that can maintain long-term stability during daily storage.

[0006] The first aspect of the present invention is to provide a water-based solution preparation of blonanserin, comprising the following components by mass:

[0007] Blonanserin 2 ± 0.2 copies;

[0008] γ-cyclodextrin 45-50 parts;

[0009] 15-20 parts of lecithin;

[0010] 3-6 parts of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer;

[0011] Aspartame 0.08 ± 0.005 parts;

[0012] 1000 parts of water.

[0013] This water-based solution preparation of Blonanserin may also include the following components by mass:

[0014] Blonanserin 2 ± 0.2 copies;

[0015] γ-cyclodextrin 37-50 parts;

[0016] 16.5-20 parts of lecithin;

[0017] 3-6 parts of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer;

[0018] Aspartame 0.08 ± 0.005 parts;

[0019] 1000 parts of water.

[0020] Furthermore, the above-mentioned blonanserin water-based solution preparation also includes 1 to 3 parts of a preservative.

[0021] Furthermore, the preservative used in the above-mentioned blonanserin water-based solution preparation is sodium benzoate.

[0022] As a preferred formulation of the water-based solution of Blonanserin, the following components are included by mass:

[0023] Blonanserin 2 ± 0.2 copies;

[0024] γ-cyclodextrin 40±0.5 parts;

[0025] Lecithin 16.5 ± 0.2 parts;

[0026] Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer 3±0.2 parts;

[0027] Preservative sodium benzoate 2±0.2 parts;

[0028] Aspartame 0.08 ± 0.005 parts;

[0029] 1000 parts of water.

[0030] The second aspect of the present invention is to provide a method for preparing a water-based solution of blonanserin, comprising the following steps:

[0031] Step 1: Mix the whole amount of blonanserin and the whole amount of γ-cyclodextrin with a portion of water, grind and slurry to form a mixture I;

[0032] Step 2: dissolving the whole amount of lecithin in part of the water to form a mixture II;

[0033] Step 3: Mixing mixture I and mixture II to form mixture III;

[0034] Step 4: dissolving the whole amount of the polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, the preservative and aspartame in a portion of the water to form a mixture IV;

[0035] Step 5: Evenly mix the mixture III, the mixture IV and the remaining amount of water to obtain the blonanserin water-based solution preparation.

[0036] Further, in step 1, blonanserin, γ-cyclodextrin and water are mixed and ground and slurried at room temperature, and then heated to 60° C. to form a mixture I.

[0037] Further, in step 2, lecithin and water are mixed and then heated to 60° C. to form mixture II.

[0038] Further, in step 3, mixture I and mixture II are mixed under shear conditions, then quickly injected into a high-pressure homogenizer, homogenized continuously for 6 times at a pressure of 80 MPa, and cooled to room temperature to form mixture III.

[0039] Furthermore, in step 1, the amount of water added is 50 parts; in step 2, the amount of water added is 50 parts; in step 4, the amount of water added is 50 parts.

[0040] Beneficial Effects

[0041] The solution of the present invention does not use non-pharmaceutical excipients, and can make the poorly soluble blonanserin into a uniform, clear, and long-term stable storage oral liquid, further enriching the dosage form of blonanserin, improving the convenience of taking blonanserin, and is expected to help improve the oral bioavailability and absorption efficiency of blonanserin. In addition, experiments have found that components such as γ-cyclodextrin cavity, lecithin, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and aspartame play an important and complex key role in the process of forming a clear and stable oral preparation of blonanserin, providing a reference direction for the mechanism study of the dissolution and dispersion behavior of poorly soluble blonanserin macromolecules in aqueous media. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 This is the molecular structure of blonanserin.

[0043] Figure 2 This is the prescription quantity configuration diagram of Example 1.

[0044] Figure 3 This is the prescription quantity configuration diagram of Example 2.

[0045] Figure 4 This is the prescription quantity configuration diagram of Example 3.

[0046] Figure 5 This is the prescription quantity configuration diagram of Example 4.

[0047] Figure 6 This is a solution state record diagram of Example 4.

[0048] Figure 7 This is the prescription quantity configuration diagram of Example 5.

[0049] Figure 8 This is a solution state record diagram of Example 5.

[0050] Fig. 9 This is the prescription quantity configuration diagram of Example 6.

[0051] Fig.10 This is a solution state record diagram of Example 6.

[0052] Fig.11 This is the prescription quantity configuration diagram of Example 7.

[0053] Fig.12 This is a solution state record diagram of Example 7.

[0054] Fig.13 This is a solution state record diagram of Example 8. DETAILED DESCRIPTION

[0055] The present invention is further illustrated by specific examples below. These examples are exemplary and are intended to illustrate the problem and explain the present invention, but are not intended to be limiting.

[0056] The blonanserin solution in the following examples was prepared according to the following steps:

[0057] (1) Mix the whole amount of blonanserin and the whole amount of γ-cyclodextrin, add 50 parts of water, grind and slurry at room temperature, and heat to 60° C. to form a mixture I;

[0058] (2) dissolving the whole amount of lecithin in 50 parts of water and heating the mixture to 60°C to form mixture II;

[0059] (3) Mixing mixture I and mixture II under high-speed shear conditions, and rapidly injecting them into a high-pressure homogenizer, homogenizing them continuously for 6 times at a pressure of 80 MPa, and cooling them to room temperature to form mixture III;

[0060] (4) dissolving the entire amount of poly(ethylene caprolactam)-poly(vinyl acetate)-poly(ethylene glycol) graft copolymer (SOLUPLUS®), sodium benzoate and aspartame in 50 parts of water at room temperature to form a mixture IV;

[0061] (5) Mix mixture III and mixture IV, stir evenly, add remaining amount of water, and seal to obtain.

[0062] Note: If the prescription quantity of a component is 0, cancel the operation steps corresponding to the component.

[0063] Example 1

[0064] The blonanserin solution of this embodiment is measured by mass according to Figure 2 After the preparation, the solution was allowed to stand for 1 hour and the state of the solution was observed. The results showed that a small amount of particles deposited at the bottom and suspended in the solution prepared by all the prescriptions existed, indicating that without the addition of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, no matter how the amount of γ-cyclodextrin and lecithin was adjusted, blonanserin could not be fully included and dispersed in the aqueous solution.

[0065] Example 2

[0066] The blonanserin solution of this embodiment is measured by mass according to Figure 3After the preparation, the solution was allowed to stand for 1 hour and the state of the solution was observed. The results showed that there were extremely fine particles in suspension inside the solutions prepared by all the prescriptions, and there were undissolved white particles at the bottom of the solution. The results showed that in the absence of lecithin, no matter how the amount of γ-cyclodextrin and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer was adjusted, blonanserin could not be fully included and dispersed in the aqueous solution.

[0067] Based on the experimental results of Example 1 and Example 2, in the blonanserin solution system, γ-cyclodextrin is a cyclic oligosaccharide, which is used to encapsulate blonanserin to form an inclusion complex; lecithin and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer jointly promote the full inclusion and uniform dispersion of blonanserin by γ-cyclodextrin to form a well-dissolved clear solution. In the absence of γ-cyclodextrin, lecithin or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, blonanserin cannot form a clear solution in water by adjusting the prescription amount and using stirring, homogenization and other means.

[0068] Example 3

[0069] The blonanserin solution of this embodiment is measured by mass according to Figure 4 The solution was prepared according to the formula shown in the formula. After preparation, the solution was allowed to stand for 1 hour and the state of the solution was observed. The results show that the solutions prepared by formula 3.1 and formula 3.2 contained extremely fine particles in suspension, and there were undissolved white particles at the bottom of the solution. The remaining solutions were all clear solutions. This shows that the amount of γ-cyclodextrin added in formula 3.1 and formula 3.2 was not enough to completely encapsulate blonanserin, while the other formulas fully encapsulated blonanserin and completely dispersed it in the solvent water under the joint action of γ-cyclodextrin, lecithin, and polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0070] Example 4

[0071] The blonanserin solution of this embodiment is measured by mass according to Figure 5 After preparation, the solution was kept away from light and the state of the solution was observed at 0, 1, 4, 12, and 24 weeks, and the results were summarized and recorded in Figure 6. The results showed that Prescription 4.1 and Prescription 4.2 could successfully fully include bunanserin and completely disperse it in the solvent water, and could remain stable within 3 months. However, in the 6-month stability experiment, fine particles appeared at the bottom of the solution. This shows that the inclusion system constructed by Prescription 4.1 and Prescription 4.2 has defects in long-term stability and is difficult to store for a long time. The inclusion system constructed by Prescription 4.3 to Prescription 4.6, the bunanserin cyclodextrin solution can maintain excellent stability for at least 6 months, meeting the needs of long-term stable storage.

[0072] Example 5

[0073] The blonanserin solution of this embodiment is measured by mass according to Figure 7 After preparation, the solution was kept away from light and the state of the solution was observed at 0, 1, 4, 12, and 24 weeks, and the results were summarized and recorded in Figure 8 The results showed that after reducing the amount of lecithin in the prescription, the inclusion system constructed by prescriptions 5.1 to 5.3, the cyclodextrin solution of blonanserin could remain stable within 3 months, but in the 6-month stability experiment, fine particles appeared at the bottom of the solution, making it difficult to store for a long time. The inclusion system constructed by prescriptions 5.4 to 5.6, the cyclodextrin solution of blonanserin could show good stability for 6 months.

[0074] The experimental results of Example 4 and Example 5 show that in the blonanserin solution system, there is a close correlation between the amounts of γ-cyclodextrin and lecithin. When the amount of γ-cyclodextrin is 45 parts, the amount of lecithin is preferably ≥15 parts, and when the amount of γ-cyclodextrin is 37 parts, the amount of lecithin is preferably ≥16.5 parts. This not only allows blonanserin to be fully included, but also the formed solution has long-term stability, and no precipitation of blonanserin occurs during storage.

[0075] Example 6

[0076] The blonanserin solution of this embodiment is measured by mass according to Fig. 9 After preparation, the solution was kept away from light and the state of the solution was observed at 0, 1, 4, 12, and 24 weeks, and the results were summarized and recorded in Fig.10 The results showed that after increasing the amount of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, the inclusion complex system constructed from prescription 6.1 to prescription 6.6 and the cyclodextrin solution of blonanserin showed good stability for 6 months.

[0077] Example 7

[0078] The blonanserin solution of this embodiment is measured by mass according to Fig.11After preparation, the solution was kept away from light and the state of the solution was observed at 0, 1, 4, 12, and 24 weeks, and the results were summarized and recorded in Fig.12 Sweeteners usually do not participate in the inclusion and dispersion of drug molecules, however Fig.12 The results showed that in the blonanserin inclusion system, the type of sweetener has a significant effect on the inclusion behavior and dispersion of the poorly soluble blonanserin molecule in γ-cyclodextrin. Four commonly used sweeteners with similar molecular weights were used in prescriptions 7.1 to 7.4, including aspartame, neotame, glycyrrhizin, and sucralose, but only the system of prescription 7.1 showed long-term stability for more than 6 months. The systems of prescriptions 7.2 to 7.4 all became turbid within 1 to 3 months and had fine particles at the bottom of the solution, making it difficult to store them stably for a long time.

[0079] Taking into account the need to minimize the amount of auxiliary materials such as cyclodextrin and to maintain the physical stability of the solution for at least 6 months, a more preferred formula of blonanserin solution is: 2 parts of blonanserin, 40 parts of γ-cyclodextrin, 16.5 parts of lecithin, 3 parts of polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, 2 parts of sodium benzoate, 0.08 parts of aspartame, and 1000 parts of water.

[0080] Example 8

[0081] 1.1 Test samples: Sample 1 is a blonanserin solution prepared according to the above preferred formula with less excipients; the difference between reference substance 1 and sample 1 is only that an equal molar amount of 2,6-dimethyl-β-cyclodextrin is used to replace γ-cyclodextrin; the difference between reference substance 2 and sample 1 is only that an equal mass of hydroxypropyl-β-cyclodextrin is used to replace γ-cyclodextrin.

[0082] 1.2 Test method: Place at 60℃ for 1 week and observe the solution state at 0, 1, 3 and 7 days. Vortex the sample, take 1 mL of the sample, centrifuge and take the supernatant. The content of blonanserin in the supernatant was determined based on the method provided by the following article: Cui Jian, et al. (2020). Study on self-emulsifying preparation of blonanserin. Journal of Shenyang Pharmaceutical University, 37(7), 577-584+610.

[0083] 1.3 Experimental conditions: Chromatographic separation column: Diamonsil C18 column (150 mm × 4.6 mm, 5 μm), mobile phase: methanol-20 mM NaH2PO4 phosphate buffer (pH 3.0) (volume ratio 90:10), flow rate: 1.0 mL / min, UV detection wavelength: 238 nm, column temperature: 30 °C, injection volume: 20 μL. When blonanserin was determined using this chromatographic condition, the peak time was 8.3 min, and the excipients had no interference with the peak of blonanserin.

[0084] 1.4 Test results: The percentage of blonanserin content in each sample to the labeled amount (average value, %) is as follows: Fig.13 shown.

[0085] The results of the above-mentioned high-temperature accelerated stability experiment show that the performance of the three samples in the accelerated experiment is quite different. Sample 1 remained in a clear state during the one-week high-temperature accelerated experiment. After vortexing and centrifugation, no precipitation appeared at the bottom of the centrifuge tube. The supernatant content determination showed that the content of blonanserin was 97.3% of the labeled amount. In contrast, both reference substance 1 and reference substance 2 produced fine particles at the bottom of the solution during the one-week high-temperature accelerated experiment. After vortexing and centrifugation, precipitation was found at the bottom of the centrifuge tube. The supernatant content determination showed that the content of blonanserin was 57.4% and 46.0% of the labeled amount, indicating that a large amount of blonanserin has been separated from the corresponding cyclodextrin inclusion system and formed precipitation. The 2,6-dimethyl-β-cyclodextrin used is a modified cyclodextrin with a methyl group introduced, and the hydroxypropyl-β-cyclodextrin used is a modified cyclodextrin with a hydroxypropyl group introduced. Although both can fully include and disperse the poorly soluble blonanserin in the aqueous solution in the blonanserin solution system of the present invention, the stability of the formed dispersion is weaker than that prepared by γ-cyclodextrin. γ-cyclodextrin can fully include and solubilize blonanserin in the solution system of the present invention, and can also effectively prolong its physical stability.

[0086] In addition, natural cyclodextrins α-cyclodextrin and β-cyclodextrin were also tried for inclusion and solubilization of blonanserin, with the following dosage: 2 parts of blonanserin, 40 parts of cyclodextrin, 16.5 parts of lecithin, 3 parts of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, 2 parts of sodium benzoate, 0.08 parts of aspartame, and 1000 parts of water. However, the systems formed by the prescriptions of cyclodextrins α-cyclodextrin and β-cyclodextrin all showed visible precipitation and could not exist in a clear state.

[0087] The above embodiments are exemplary, and their purpose is to illustrate the technical concept and features of the present invention so that people familiar with the technology in this field can understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A water-based solution preparation of blonanserin, characterized in that: The components by mass are: Blonanserin 2 ± 0.2 copies; γ-cyclodextrin 45-50 parts; 15-20 parts of lecithin; 3-6 parts of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; Aspartame 0.08 ± 0.005 parts; 1000 parts of water.

2. A water-based solution preparation of blonanserin, characterized in that: The components by mass are: Blonanserin 2 ± 0.2 copies; γ-cyclodextrin 37-50 parts; 16.5-20 parts of lecithin; 3-6 parts of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; Aspartame 0.08 ± 0.005 parts; 1000 parts of water.

3. The water-based solution preparation of blonanserin according to claim 1 or 2, characterized in that: It also contains 1 to 3 parts of preservatives.

4. The water-based solution preparation of blonanserin according to claim 3, characterized in that: The preservative is sodium benzoate.

5. A water-based solution preparation of blonanserin, characterized in that: The components by mass are: Blonanserin 2 ± 0.2 copies; γ-cyclodextrin 40±0.5 parts; Lecithin 16.5 ± 0.2 parts; Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer 3±0.2 parts; Preservative sodium benzoate 2±0.2 parts; Aspartame 0.08 ± 0.005 parts; 1000 parts of water.

6. The method for preparing the water-based solution of blonanserin according to any one of claims 3 to 5, characterized in that: The following steps are involved: Step 1: Mix the whole amount of blonanserin and the whole amount of γ-cyclodextrin with a portion of water, grind and slurry to form a mixture I; Step 2: dissolving the whole amount of lecithin in part of the water to form a mixture II; Step 3: Mixing mixture I and mixture II to form mixture III; Step 4: dissolving the whole amount of the polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, the preservative and aspartame in a portion of the water to form a mixture IV; Step 5: Evenly mix the mixture III, the mixture IV and the remaining amount of water to obtain the blonanserin water-based solution preparation.

7. The method for preparing the water-based solution of blonanserin according to claim 6, characterized in that: In step 1, blonanserin, γ-cyclodextrin and water are mixed and ground and slurried at room temperature, and then heated to 60° C. to form a mixture I.

8. The method for preparing the water-based solution of blonanserin according to claim 7, characterized in that: In step 2, lecithin and water are mixed and heated to 60°C to form mixture II.

9. The method for preparing the water-based solution of blonanserin according to claim 8, characterized in that: In step 3, mixture I and mixture II are mixed under shear conditions, and then quickly injected into a high-pressure homogenizer, homogenized continuously for 6 times at a pressure of 80 MPa, and cooled to room temperature to form mixture III.

10. The method for preparing the water-based solution of blonanserin according to claim 9, characterized in that: In step 1, the amount of water added is 50 parts; in step 2, the amount of water added is 50 parts; in step 4, the amount of water added is 50 parts.

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