Bunazosin water-based solution preparation and preparation method

Abstract

The application belongs to the technical field of drug dissolution and dispersion, and particularly relates to a bunazosin water-based solution preparation and a preparation method. The bunazosin water-based solution preparation provided by the application comprises the following components: bunazosin, gamma-cyclodextrin, lecithin, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, aspartame and water. The above components are mixed to be homogeneous to prepare an oral solution which is uniform, clear and can be stored for a long time. The scheme of the application further enriches the dosage form of bunazosin, improves the convenience of taking bunazosin, and is expected to help improve the oral bioavailability and absorption efficiency of bunazosin. The scheme of the application also provides a reference direction for the mechanism research on the dissolution and dispersion behavior of the insoluble bunazosin macromolecule in a water medium.

Description

[0001] This application is a divisional application. The original application has the application number 202411487772.2 and the original application date is October 24, 2024. The entire contents of the original application are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of drug dissolution and dispersion technology, specifically relating to buspirone water-based solution formulations and preparation methods. Background Technology

[0003] Bronaseline is a highly selective dopamine D2 and 5-HT compound with a novel chemical structure. 2A Brenaseline, a receptor antagonist, was developed by Sumitomo Pharmaceutical Co., Ltd. of Japan and launched in Japan in 2008. It was approved for sale in China by the former China Food and Drug Administration (CFDA) in 2017. Brenaseline significantly improves positive symptoms (such as hallucinations and illusions) and negative symptoms (such as depression and motor dysfunction) of schizophrenia, reduces 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.

[0004] Clinical data show that the absolute oral bioavailability of marketed bromelain tablets (4 mg) is 55%. Comparing pharmacokinetic data between postprandial and fasting administration revealed that postprandial administration... max and AUC 0-12 The levels were increased by 2.68 times and 2.69 times respectively compared to pre-meal levels. Clinical data also indicate that alcohol consumption can improve the oral bioavailability of bromelain. All of this information suggests that there is still room for improvement in the oral bioavailability of bromelain. Furthermore, currently available bromelain formulations in China and abroad are only available in regular tablet form, which presents problems such as swallowing difficulties and inconvenience in dosage adjustment for children. Therefore, innovation in bromelain formulations, developing a solution-based bromelain oral solution, is expected not only to improve the oral bioavailability and absorption efficiency of bromelain formulations, but also to make it easier for children to take.

[0005] However, bromelain has poor water solubility, exhibiting only high solubility in organic solvents such as ethanol, and belongs to BCS class II compounds. The molecular structure of bromelain is as follows: Figure 1 As shown, the skeleton contains a piperazine ring, a benzene ring with a fluorine substituent, and a hexahydroarctopyridine skeleton. These nonpolar molecular fragments have weak interactions with water molecules and cannot effectively form hydrogen bond networks with water molecules, resulting in extremely poor solubility of bromelain in water, making it difficult to form a homogeneous bromelain oral solution that can remain stable during routine storage. Summary of the Invention

[0006] To address the aforementioned technical problems, this invention provides a water-based solution formulation of bunamserin and its preparation method, aiming to overcome the problem of low solubility of bunamserin and provide a uniform, clear bunamserin oral solution that can maintain long-term stability during daily storage.

[0007] A first aspect of the present invention is to provide a water-based solution formulation of bromelain, comprising the following components by weight:

[0008] Bunan Serin 2 ± 0.2 parts;

[0009] 45-50 parts of γ-cyclodextrin;

[0010] 15-20 parts lecithin;

[0011] 3-6 parts of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer;

[0012] Aspartame 0.08 ± 0.005 parts;

[0013] 1000 portions of water.

[0014] This Bunansserin water-based solution preparation may also include the following components by weight:

[0015] Bunan Serin 2 ± 0.2 parts;

[0016] γ-Cyclodextrin 37-50 parts;

[0017] Lecithin 16.5~20 parts;

[0018] 3-6 parts of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer;

[0019] Aspartame 0.08 ± 0.005 parts;

[0020] 1000 portions of water.

[0021] Furthermore, the above-mentioned Bunanserin water-based solution preparation also includes 1 to 3 parts of preservative.

[0022] Furthermore, the preservative used in the above-mentioned Bunanserin water-based solution preparation is sodium benzoate.

[0023] As a preferred formulation of Bunansserin water-based solution preparation, it comprises the following components by mass:

[0024] Bunan Serin 2 ± 0.2 parts;

[0025] γ-Cyclodextrin 40±0.5 parts;

[0026] Lecithin 16.5 ± 0.2 parts;

[0027] 3 ± 0.2 parts of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer;

[0028] Sodium benzoate preservative 2 ± 0.2 parts;

[0029] Aspartame 0.08 ± 0.005 parts;

[0030] 1000 portions of water.

[0031] A second aspect of this invention provides a method for preparing a water-based solution formulation of bromelain, comprising the following steps:

[0032] Step 1: Mix the total amount of bromelain, the total amount of γ-cyclodextrin, and a portion of water, grind and slurry to form mixture I;

[0033] Step 2: Dissolve the full amount of lecithin in a portion of the water to form mixture II;

[0034] Step 3: Mix and homogenize mixture I and mixture II to form mixture III;

[0035] Step 4: Dissolve the full amount of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, preservative and aspartame in a portion of the water to form mixture IV;

[0036] Step 5: Mix mixture III, mixture IV and the remaining water evenly to obtain the Bunanserin water-based solution preparation.

[0037] Further, in step 1, Brønsserin, γ-cyclodextrin and water are mixed and ground into a pulp at room temperature, and then heated to 60°C to form mixture I.

[0038] Furthermore, in step 2, lecithin is mixed with water and heated to 60°C to form mixture II.

[0039] Further, in step 3, mixture I and mixture II are mixed under shear conditions and then rapidly injected into a high-pressure homogenizer, continuously homogenized 6 times at a pressure of 80 MPa, and cooled to room temperature to form mixture III.

[0040] 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.

[0041] Beneficial effects

[0042] This invention eliminates the need for non-pharmaceutical excipients, enabling the formulation of poorly soluble bromelain into a homogeneous, clear, and long-term stable oral solution. This further enriches the dosage forms of bromelain, improves its convenience of administration, and is expected to enhance its oral bioavailability and absorption efficiency. Furthermore, experiments have revealed that components such as γ-cyclodextrin, lecithin, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and aspartame play important and complex roles in the formation of a clear and stable oral formulation of bromelain, providing a reference direction for the study of the mechanism of dissolution and dispersion behavior of poorly soluble bromelain macromolecules in aqueous media. Attached Figure Description

[0043] Figure 1 This is the molecular structure diagram of brnanserin.

[0044] Figure 2 This is a diagram showing the prescription dosage for Example 1.

[0045] Figure 3 This is a diagram showing the prescription dosage for Example 2.

[0046] Figure 4 This is a diagram showing the prescription dosage for Example 3.

[0047] Figure 5 This is a diagram showing the prescription dosage for Example 4.

[0048] Figure 6 This is a diagram showing the solution state in Example 4.

[0049] Figure 7 This is a diagram showing the prescription dosage for Example 5.

[0050] Figure 8 This is a diagram showing the solution state in Example 5.

[0051] Figure 9 This is a diagram showing the prescription dosage configuration for Example 6.

[0052] Figure 10 This is a diagram showing the solution state in Example 6.

[0053] Figure 11 This is a diagram showing the prescription dosage for Example 7.

[0054] Figure 12 This is a diagram showing the solution state in Example 7.

[0055] Figure 13 This is a diagram showing the solution state in Example 8. Detailed Implementation

[0056] The present invention is further illustrated below with specific embodiments. These embodiments are exemplary and intended to illustrate the problem and explain the present invention, and are not intended to be limiting.

[0057] In the following examples, the bromelain solution was prepared according to the following steps:

[0058] (1) Mix the total amount of bromelain and the total amount of γ-cyclodextrin, add 50 parts of water, grind and slurry at room temperature, and heat to 60°C to form mixture I;

[0059] (2) Dissolve the total amount of lecithin in 50 parts of water, heat to 60°C, and form mixture II;

[0060] (3) Mixture I and mixture II are mixed under high-speed shearing conditions and rapidly injected into a high-pressure homogenizer. The mixture is homogenized 6 times under a pressure of 80 MPa and cooled to room temperature to form mixture III.

[0061] (4) Dissolve the total amount of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SOLUPLUS®), sodium benzoate and aspartame in 50 parts of water at room temperature to form mixture IV;

[0062] (5) Mix mixture III and mixture IV, stir evenly, add the remaining water, and seal to obtain the final product.

[0063] Note: If the prescription amount of a certain component is 0, then cancel the operation steps corresponding to that component.

[0064] Example 1

[0065] The bromelain solution in this embodiment, by mass, is based on... Figure 2 The solutions were prepared according to the indicated dosage. After preparation, the solutions were allowed to stand for 1 hour, and the state of the solution was observed. The results showed that all solutions prepared according to the prescriptions contained a small amount of particulate matter deposited at the bottom and in a suspended state. This indicates that without the addition of the polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, regardless of the adjustment of the amount of γ-cyclodextrin and lecithin, it was impossible to fully encapsulate and disperse bromelain in the aqueous solution.

[0066] Example 2

[0067] The bromelain solution in this embodiment, by mass, is based on... Figure 3The solutions were prepared according to the indicated dosage. After preparation, the solutions were allowed to stand for 1 hour, and the state of the solution was observed. The results showed that all solutions prepared according to the indicated dosage contained extremely fine suspended particles, and undissolved white particles were present at the bottom of the solution. This result indicates that, without the addition of lecithin, regardless of the adjustment of the dosage of γ-cyclodextrin and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, it is impossible to fully encapsulate and disperse bromelain in aqueous solution.

[0068] Based on the experimental results of Examples 1 and 2, in this bromelain solution system, γ-cyclodextrin, a cyclic oligosaccharide, encapsulates bromelain to form an inclusion complex. Lecithin and the polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer jointly promote the full encapsulation and uniform dispersion of bromelain by γ-cyclodextrin, forming a well-dissolved clear solution. Without the participation of γ-cyclodextrin, lecithin, or the polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, bromelain cannot form a clear solution in water by adjusting the formulation amounts and employing methods such as stirring and homogenization.

[0069] Example 3

[0070] The bromelain solution in this embodiment, by mass, is based on... Figure 4 The solutions were prepared according to the indicated dosages. After preparation, the solutions were allowed to stand for 1 hour, and the state of the solution was observed. The results showed that the solutions prepared with formulations 3.1 and 3.2 contained extremely fine suspended particles, and undissolved white particles were present at the bottom of the solutions. The remaining solutions were clear. This indicates that the amount of γ-cyclodextrin added in formulations 3.1 and 3.2 was insufficient to completely encapsulate bromelain, while the other formulations, through the combined action of γ-cyclodextrin, lecithin, and the polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, effectively encapsulated and completely dispersed bromelain in the water solvent.

[0071] Example 4

[0072] The bromelain solution in this embodiment, by mass, is based on... Figure 5 The solution was prepared according to the indicated dosage. After preparation, it was placed in the dark and allowed to stand. The solution status was observed at 0, 1, 4, 12, and 24 weeks, and the results were summarized and recorded. Figure 6The results showed that formulations 4.1 and 4.2 successfully encapsulated and completely dispersed bromelain in water and remained stable for up to 3 months. However, in the 6-month stability test, fine particles appeared at the bottom of the solution. This indicates that the inclusion complex systems constructed by formulations 4.1 and 4.2 have deficiencies in long-term stability and are difficult to store for extended periods. The inclusion complex systems constructed by formulations 4.3 to 4.6 all maintained excellent stability in bromelain cyclodextrin solutions for at least 6 months, meeting the requirements for long-term stable storage.

[0073] Example 5

[0074] The bromelain solution in this embodiment, by mass, is based on... Figure 7 The solution was prepared according to the indicated dosage. After preparation, it was placed in the dark and allowed to stand. The solution status was observed at 0, 1, 4, 12, and 24 weeks, and the results were summarized and recorded. Figure 8 The results showed that after reducing the amount of lecithin in the formulation, the inclusion complex systems constructed with formulations 5.1 to 5.3, including boramine cyclodextrin solutions, remained stable for up to 3 months. However, in the 6-month stability test, fine particles appeared at the bottom of the solution, making long-term storage difficult. The inclusion complex systems constructed with formulations 5.4 to 5.6 all showed good stability in boramine cyclodextrin solutions for 6 months.

[0075] The experimental results of Examples 4 and 5 show that there is a close relationship between the amounts of γ-cyclodextrin and lecithin in the bromelain solution system. 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 the bromelain to be fully encapsulated, but also ensures that the resulting solution has long-term stability and that no bromelain precipitation occurs during storage.

[0076] Example 6

[0077] The bromelain solution in this embodiment, by mass, is based on... Figure 9 The solution was prepared according to the indicated dosage. After preparation, it was placed in the dark and allowed to stand. The solution status was observed at 0, 1, 4, 12, and 24 weeks, and the results were summarized and recorded. Figure 10 The results showed that, after increasing the amount of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer in the formulation, the inclusion complex systems constructed by formulations 6.1 to 6.6 all exhibited good stability of bromelain cyclodextrin solutions for 6 months.

[0078] Example 7

[0079] The bromelain solution in this embodiment, by mass, is based on... Figure 11The solution was prepared according to the indicated dosage. After preparation, it was placed in the dark and allowed to stand. The solution status was observed at 0, 1, 4, 12, and 24 weeks, and the results were summarized and recorded. Figure 12 Sweeteners typically do not participate in the inclusion and dispersion of drug molecules, however Figure 12 The results showed that in this bromelain inclusion system, the type of sweetener had a significant impact on the inclusion behavior and dispersion of poorly soluble bromelain molecules in γ-cyclodextrin. Four commonly used sweeteners with similar molecular weights were used in formulations 7.1 to 7.4, including aspartame, neotame, glycyrrhizin, and sucralose. However, only the system in formulation 7.1 showed long-term stability exceeding 6 months. Systems in formulations 7.2 to 7.4 all exhibited turbidity and fine particulate matter at the bottom of the solution within 1 to 3 months, making long-term stable storage difficult.

[0080] Considering the need to minimize the amount of excipients such as cyclodextrin while ensuring the solution remains physically stable for at least 6 months, a preferred formulation for a bromelain solution is: 2 parts bromelain, 40 parts γ-cyclodextrin, 16.5 parts lecithin, 3 parts polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, 2 parts sodium benzoate, 0.08 parts aspartame, and 1000 parts water.

[0081] Example 8

[0082] 1.1 Test Samples: Sample 1 was a bromelain solution prepared according to the preferred formulation with fewer excipients mentioned above; the only difference between reference 1 and sample 1 was that 2,6-dimethyl-β-cyclodextrin was used instead of γ-cyclodextrin in equal molar amounts; the only difference between reference 2 and sample 1 was that hydroxypropyl-β-cyclodextrin was used instead of γ-cyclodextrin in equal mass.

[0083] 1.2 Experimental Methods: The solution was placed at 60℃ for one week, and the state of the solution was observed on days 0, 1, 3 and 7. The sample was vortexed, 1 mL was taken, centrifuged, and the supernatant was collected. The content of bromelain in the supernatant was determined according to the method provided in the following article: Cui Jian, et al. (2020). Study on self-emulsifying preparations of bromelain. Journal of Shenyang Pharmaceutical University, 37(7), 577-584+610.

[0084] 1.3 Experimental conditions: Chromatographic column: Diamonsil C18 column (150 mm × 4.6 mm, 5 μm); mobile phase: methanol-20 mM NaH2PO4 phosphate buffer (pH 3.0) (90:10 v / v); flow rate: 1.0 mL / min; UV detection wavelength: 238 nm; column temperature: 30 ℃; injection volume: 20 μL. Under these chromatographic conditions, the elution time of Bronaseline was 8.3 min, and the excipients did not interfere with the elution of the Bronaseline peak.

[0085] 1.4 Test Results: The percentage of bromelain content in each sample relative to the labeled amount (average, %) is as follows: Figure 13 As shown.

[0086] The results of the above-mentioned high-temperature accelerated stability test showed that the three samples exhibited significant differences in performance during the accelerated test. Sample 1 remained clear throughout the one-week high-temperature accelerated test. After vortexing and centrifugation, no precipitate appeared at the bottom of the centrifuge tube, and the supernatant content analysis showed that the bromelain content was 97.3% of the labeled amount. In contrast, both control samples 1 and 2 produced fine particles at the bottom of the solution during the one-week high-temperature accelerated test. After vortexing and centrifugation, precipitates were found at the bottom of the centrifuge tube, and the supernatant content analysis showed that the bromelain content was 57.4% and 46.0% of the labeled amount, respectively, indicating that a large amount of bromelain had separated from the corresponding cyclodextrin inclusion system and formed a precipitate. The 2,6-dimethyl-β-cyclodextrin used is a modified cyclodextrin with an introduced methyl group, and the hydroxypropyl-β-cyclodextrin used is a modified cyclodextrin with an introduced hydroxypropyl group. While both can adequately encapsulate and disperse sparingly soluble bromelain in the aqueous solution system of this invention, the stability of the resulting dispersion is weaker than that prepared with γ-cyclodextrin. γ-cyclodextrin, in the solution system of this invention, can adequately encapsulate and solubilize bromelain, and effectively prolong its physical stability.

[0087] In addition, natural cyclodextrins α-cyclodextrin and β-cyclodextrin were also attempted for the inclusion and solubilization of bromelain, with the following formulation amounts: 2 parts bromelain, 40 parts cyclodextrin, 16.5 parts lecithin, 3 parts polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, 2 parts sodium benzoate, 0.08 parts aspartame, and 1000 parts water. However, the systems formed using formulations containing α-cyclodextrin and β-cyclodextrin all exhibited visible precipitation and could not exist in a clear state.

[0088] The above embodiments are exemplary and are intended to illustrate the technical concept and features of the present invention, so that those skilled in the art can understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made according to the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A water-based solution formulation of Brunazosin characterized in that: consists of, by mass: Bunazosin 2 parts; γ-cyclodextrin 45 parts; Lecithin 15-20 parts; Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer 3-6 parts; Aspartame 0.08 parts; Preservative sodium benzoate 1-3 parts; Water 1000 parts.

2. A water-based solution formulation of Brunazosin characterized in that: consists of, by mass: Bunazosin 2 parts; γ-cyclodextrin 45 parts; Lecithin 15 parts; Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer 3 parts; Aspartame 0.08 parts; Preservative sodium benzoate 1-3 parts; Water 1000 parts.

3. The buananserin water-based solution preparation according to claim 1 or 2, characterized by: The preservative is 2 parts.

4. Process for the preparation of a water-based solution formulation of Brunello according to any one of claims 1 to 3, characterized in that: The method comprises the following steps: Step 1: Mix the full amount of bunazosin, the full amount of γ-cyclodextrin and part of the water, grind and pulp to form mixture I; Step 2: Dissolve the full amount of lecithin in part of the water to form mixture II; Step 3: Mix mixture I and mixture II uniformly to form mixture III; Step 4: Dissolve the full amount of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, preservative and aspartame in part of the water to form mixture IV; Step 5: Mix mixture III, mixture IV and the remaining water uniformly to obtain the bunazosin water-based solution preparation.

5. The method for preparing the Bunansserin water-based solution formulation according to claim 4, characterized in that: In step 1, after mixing bunazosin, γ-cyclodextrin and water, grind and pulp at room temperature, then heat to 60°C to form mixture I.

6. The method of claim 5, wherein the method is characterized by: In step 2, after mixing lecithin and water, heat to 60°C to form mixture II.

7. The method for preparing the Bunansserin water-based solution formulation according to claim 6, characterized in that: In step 3, mix mixture I and mixture II under shearing conditions, then quickly inject into a high-pressure homogenizer, continuously homogenize 6 times under 80 MPa pressure, and cool to room temperature to form mixture III.

8. The method for preparing the Bunansserin water-based solution formulation according to claim 7, 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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