Betahistine freeze-dried powder and preparation method thereof

Abstract

The invention provides betahistine freeze-dried powder and a preparation method thereof.The betahistine freeze-dried powder comprises a drug-loaded microcapsule and a freeze-drying matrix, the drug-loaded microcapsule and the freeze-drying matrix are dissolved in water to form freeze-drying liquid for freeze-drying, the drug-loaded microcapsule is formed by coating a betahistine raw material medicine and citric acid nanoparticles through a pH-sensitive polymer layer, and the pH-sensitive polymer layer is coated with the freeze-drying liquid. The freeze-dried matrix comprises histidine, citrate and a freeze-dried skeleton agent. Histidine and citrate in the freeze-dried matrix release buffer capacity in the storage period to maintain the overall pH stable (3.5-4.5), and pH drift is prevented; if moisture invades in the storage period and the pH value is increased to 5.0 or above, the pH sensitive polymer layer is dissolved, the citric acid nanoparticles inside serve as an emergency buffer agent to further adjust the pH value, and the requirement for pH stability in the storage period is met through the synergistic effect of the endogenous emergency buffer microcapsules and the exogenous active buffer matrix.

Description

Technical Field

[0001] The present invention relates to the field of lithium battery additives, and more particularly to betahistine freeze-dried powder and a preparation method thereof. Background Art

[0002] Betahistine is a commonly used drug for the treatment of Meniere's disease and vertigo, but it is susceptible to oxidative and hydrolytic degradation in aqueous solutions, with the degradation rate increasing significantly at pH levels above 5.0. Existing technologies stabilize the solution pH at around 4.0 by adding a single buffer (such as citrate), but this cannot mitigate the risk of sudden pH shifts during storage or reconstitution. Single buffer systems have inherent drawbacks: first, their limited buffering capacity makes it difficult to address abnormal solvent pH during reconstitution or localized pH shifts caused by moisture penetration and CO2 evolution during long-term storage; second, the buffer is not compatible with the drug, and high concentrations of citric acid may accelerate drug oxidation side reactions. Therefore, further improvement and development are needed. Summary of the Invention

[0003] In view of the various deficiencies of the existing technology and to solve the above problems, a betahistine lyophilized powder and a preparation method thereof are proposed, and the following technical solutions are provided: A betahistine lyophilized powder comprises drug-loaded microcapsules and a lyophilized matrix. The drug-loaded microcapsules and the lyophilized matrix are dissolved in water to form a lyophilized solution for lyophilization. The drug-loaded microcapsules are formed by coating betahistine raw materials and citric acid nanoparticles with a pH-sensitive polymer layer. The lyophilized matrix comprises histidine, citrate, and a lyophilized skeleton agent.

[0004] Furthermore, the concentration of betahistine API in the lyophilized solution is 8-12 mg / ml, the concentration of histidine in the lyophilized solution is 0.04-0.06 M; and the concentration of citrate in the lyophilized solution is 0.08-0.12 M.

[0005] Furthermore, the mass ratio of betahistine API to citric acid nanoparticles is 85-92:8-15.

[0006] Furthermore, the pH-sensitive polymer layer has a thickness of 5-10 μm.

[0007] Furthermore, the pH-sensitive polymer layer is Eudragit L 100-55.

[0008] Furthermore, the pH-sensitive polymer layer coated with the tahistine raw material drug uses isopropyl alcohol as a coating solvent and triethyl citrate as a plasticizer.

[0009] Furthermore, the particle size of the citric acid nanoparticles is 200-500 nm.

[0010] In addition, the present invention also provides a method for preparing the above-mentioned betahistine freeze-dried powder, comprising the following steps: mixing the betahistine raw material with citric acid nanoparticles and then coating them with a pH-sensitive polymer layer to obtain drug-loaded microcapsules; dissolving the drug-loaded microcapsules, histidine, citrate and freeze-dried skeleton in water and performing freeze-drying treatment.

[0011] Furthermore, the pH-sensitive polymer layer is coated using a fluidized bed process with an inlet air temperature of 30-40° C. and a spray rate of 2-5 mL / min.

[0012] Furthermore, the freeze-drying process includes pre-freezing, primary drying and secondary drying, wherein the pre-freezing temperature is -60 to -40°C, the pre-freezing time is 1.5-3 hours, the primary drying temperature is -30 to -20°C, the primary drying time is 20-24 hours, the secondary drying temperature is 20 to 25°C, and the secondary drying time is 5-8 hours.

[0013] Due to the adoption of the above technical solution, the beneficial technical effects of the present invention are: 1. The present invention provides a betahistine lyophilized powder with dynamic pH regulation capabilities. The histidine and citrate in the lyophilized matrix release buffering capacity during storage to maintain overall pH stability (3.5-4.5), preventing pH drift. If moisture intrusion during storage raises the pH to 5.0 or above, the pH-sensitive polymer layer dissolves, and the internal citric acid nanoparticles act as an emergency buffer to further adjust the pH value. Through the synergistic effect of endogenous emergency buffer microcapsules and the exogenous active buffer matrix, the pH stability requirement during storage is met. 2. During re-dissolution, the pH-sensitive polymer layer of the present invention dissolves the citric acid nanoparticles together with histidine and citrate to prevent betahistine from being oxidatively degraded during re-dissolution. DETAILED DESCRIPTION

[0014] In order to enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention is clearly and completely described below in conjunction with the embodiments of the present invention. Based on the embodiments in this application, other similar embodiments obtained by ordinary technicians in this field without making any creative work should fall within the scope of protection of this application.

[0015] A betahistine lyophilized powder comprises drug-loaded microcapsules and a lyophilized matrix. The drug-loaded microcapsules and the lyophilized matrix are dissolved in water to form a lyophilized solution for lyophilization. The drug-loaded microcapsules are formed by coating betahistine raw materials and citric acid nanoparticles with a pH-sensitive polymer layer. The lyophilized matrix comprises histidine, citrate, and a lyophilized skeleton agent.

[0016] pH dynamic control mechanism: 1. Storage period Normal conditions (pH < 5.0): The Eudragit L 100-55 coating remains intact, isolating betahistine from the external environment and preventing the intrusion of moisture, oxygen or alkaline substances.

[0017] The dual buffer system (citrate + histidine) maintains the microenvironmental pH at 3.5-4.5 within the lyophilized powder: Citrate preferentially buffers in the pH range of 3.5-4.0 (e.g., OH⁻ is generated locally due to trace amounts of water and is neutralized by citric acid); Histidine buffers in the pH range 4.0-4.5 (covering higher risk of pH excursions).

[0018] Abnormal conditions (local pH ≥5.0): If moisture intrudes during storage due to poor packaging sealing, causing the local pH to rise above 5.0, the Eudragit L100-55 coating will dissolve, releasing the internal citric acid nanoparticles to quickly neutralize alkaline substances and prevent drug degradation.

[0019] 2. Reconstitution process (lyophilized powder dissolved into injection solution) Initial stage of reconstitution (pH < 5.0): The coating remains intact and the dual buffer system dissolves directly in water for injection / normal saline, stabilizing the initial pH of the solution at 4.0 ± 0.2 (co-regulated by citrate-histidine).

[0020] After reconstitution (solution exposed to the external environment): After reconstitution, the pH rises to above 5.0, the Eudragit L 100-55 coating dissolves, releasing more citric acid nanoparticles, quickly bringing the pH back to a safe range (3.5-4.5), reducing local pH fluctuations, and preventing betahistine degradation.

[0021] Example 1 1. Preparation of drug-loaded microcapsules Betahistine and 300 nm citric acid nanoparticles (mass ratio 90:10) were ball-milled for 30 minutes (rotation speed 200 rpm) to obtain a mixture. Isopropyl alcohol was then used as the coating solvent, triethyl citrate was used as the plasticizer, and Eudragit L 100-55 was added to prepare a coating solution. The mass ratio of isopropyl alcohol, triethyl citrate, and Eudragit L 100-55 was 88:2:10. The coating solution was sprayed onto the surface of the mixture using fluidized bed technology for coating. The inlet air temperature was 35°C and the spray rate was 3 mL / min. Drug-loaded microcapsules with a coating thickness of 8 μm were obtained.

[0022] 2. Preparation of freeze-dried solution Histidine, citrate, and mannitol were dissolved in water. The concentration of histidine in the lyophilized solution was 0.05 M; the concentration of citrate in the lyophilized solution was 0.1 M, and the concentration of mannitol in the lyophilized solution was 0.2 M. Drug-loaded microcapsules were added. The concentration of betahistine API in the lyophilized solution was 10 mg / ml. The lyophilized solution was ultrasonically dispersed for 5 minutes at an ultrasonic power of 40 kHz.

[0023] 3. Freeze-drying process The lyophilized liquid was pre-frozen, dried once and dried twice, wherein the pre-freezing temperature was -50°C, the pre-freezing time was 2 hours, the primary drying temperature was -25°C, the primary drying time was 22 hours, the secondary drying temperature was 23°C, and the secondary drying time was 6 hours.

[0024] Example 2 1. Preparation of drug-loaded microcapsules Betahistine and 200 nm citric acid nanoparticles (mass ratio 85:15) were ball-milled for 30 minutes (rotation speed 200 rpm) to obtain a mixture. Isopropyl alcohol was then used as the coating solvent, triethyl citrate was used as the plasticizer, and Eudragit L 100-55 was added to prepare a coating solution. The mass ratio of isopropyl alcohol, triethyl citrate, and Eudragit L 100-55 was 92:1:7. The coating solution was sprayed onto the surface of the mixture using fluidized bed technology for coating. The inlet air temperature was 35°C and the spray rate was 3 mL / min. Drug-loaded microcapsules with a coating thickness of 5 μm were obtained.

[0025] 2. Preparation of freeze-dried solution Histidine, citrate, and mannitol were dissolved in water. The concentration of histidine in the lyophilized solution was 0.04 M; the concentration of citrate in the lyophilized solution was 0.08 M, and the concentration of mannitol in the lyophilized solution was 0.2 M. Drug-loaded microcapsules were added. The concentration of betahistine API in the lyophilized solution was 8 mg / ml. The lyophilized solution was ultrasonically dispersed for 5 minutes at an ultrasonic power of 40 kHz.

[0026] 4. Freeze-drying process The freeze-dried liquid was pre-frozen, dried once and dried twice, wherein the pre-freezing temperature was -40°C, the pre-freezing time was 3 hours, the primary drying temperature was -20°C, the primary drying time was 24 hours, the secondary drying temperature was 20°C, and the secondary drying time was 8 hours.

[0027] Example 3 1. Preparation of drug-loaded microcapsules Betahistine and citric acid nanoparticles with a particle size of 500 nm (mass ratio of 92:8) were ball-milled for 30 minutes (rotation speed of 200 rpm) to obtain a mixture. Then, isopropyl alcohol was used as the coating solvent, triethyl citrate was used as the plasticizer, and Eudragit L 100-55 was added to prepare a coating solution. The mass ratio of isopropyl alcohol, triethyl citrate, and Eudragit L 100-55 was 85:2:13. The coating solution was sprayed on the surface of the mixture using fluidized bed technology for coating. The inlet air temperature was 35°C and the spray rate was 3 mL / min. Drug-loaded microcapsules with a coating thickness of 10 μm were obtained.

[0028] 2. Preparation of freeze-dried solution Histidine, citrate, and mannitol were dissolved in water. The concentration of histidine in the lyophilized solution was 0.06 M; the concentration of citrate in the lyophilized solution was 0.12 M, and the concentration of mannitol in the lyophilized solution was 0.3 M. Drug-loaded microcapsules were added. The concentration of betahistine API in the lyophilized solution was 12 mg / ml. The lyophilized solution was ultrasonically dispersed for 5 minutes at an ultrasonic power of 40 kHz.

[0029] 5. Freeze-drying process The lyophilized liquid was pre-frozen, dried once and dried twice, wherein the pre-freezing temperature was -60°C, the pre-freezing time was 1.5 hours, the primary drying temperature was -30°C, the primary drying time was 20 hours, the secondary drying temperature was 25°C, and the secondary drying time was 5 hours.

[0030] Comparative Example 1 Compared with Example 1, citric acid nanoparticles, histidine, and citrate were not added, and other steps were the same.

[0031] Comparative Example 2 Compared with Example 1, no citric acid nanoparticles were added, and the other steps were the same.

[0032] Comparative Example 3 Compared with Example 1, histidine and citrate were not added, and other steps were the same.

[0033] Comparative Example 4 Compared with Example 1, isopropyl alcohol, triethyl citrate and Eudragit L 100-55 were not used for coating, and other steps were the same.

[0034] The products obtained in Examples 1-3 and Comparative Examples 1-4 were subjected to a pH dynamic capacity test.

[0035] (1) Storage period simulation: The freeze-dried powder was placed under accelerated conditions of 40°C / 75% RH for 30 days and the pH change was detected.

[0036] (2) Redissolution simulation: Redissolve in physiological saline (initial pH = 5.5) and record the pH change from 0 to 60 minutes.

[0037] The test results are shown in Table 1.

[0038] Table 1 PH dynamic capacity test results All examples were able to stabilize the pH within the range of 3.9-4.3 during storage and reconstitution, which was significantly better than the pH stability of each comparative example.

[0039] The products obtained in Examples 1-3 and Comparative Examples 1-4 were subjected to drug stability tests.

[0040] The products obtained in Examples 1-3 and Comparative Examples 1-4 were stored at 40°C / 75% RH for 6 months, and the content of the main component of betahistine and oxidized impurities were detected (using HPLC). The test results are shown in Table 2.

[0041] Table 2 Drug stability test results The content of oxidized impurities in each example is lower than that in each comparative example, indicating that the betahistine lyophilized powder system designed in this application has high stability and can ensure that less impurities are produced.

[0042] Application examples: Six guinea pigs weighing 300-350g were selected as the first blank control group and injected with normal saline. Using the Meniere's disease guinea pig model, 66 guinea pigs weighing 300-350g were selected and intraperitoneally injected with kanamycin (400 mg / kg / day for 7 days) to induce inner ear microcirculatory impairment. The 66 animals were divided into 11 groups: Group 2 served as the model group and received no treatment; Group 3 served as the single-drug group and received an equivalent dose of betahistine (10 mg / kg / day) intravenously daily; and Groups 4 through 10 served as the drug-treated groups, receiving the reconstituted solutions of Examples 1 through 3 and Comparative Examples 1 through 4, respectively, at an equivalent dose (10 mg / kg / day) intravenously daily. Cochlear blood flow was measured 7 days after drug administration using a PeriFlux 5000 laser Doppler flowmeter (Perimed AB, Sweden) equipped with a cochlear-specific probe (tip diameter 0.5 mm). Urethane (1.5 g / kg, intraperitoneal injection) was used as the anesthetic.

[0043] Specific steps: Anesthesia: Guinea pigs were anesthetized and fixed in a stereotaxic apparatus, and the body temperature was maintained at 37°C (controlled by a heating pad).

[0044] Surgical exposure of the cochlea: incision of the skin behind the ear, separation of the muscle tissue, and exposure of the auditory bulla.

[0045] A hole (1 mm in diameter) was drilled into the cochlear bone wall under a microscope to avoid damaging the inner ear structure.

[0046] Blood flow testing: The LDF probe was gently placed on the cochlear bony wall (avoiding compression of blood vessels) and baseline blood flow (PU, Perfusion Unit) was recorded for 5 minutes. Measurement parameters included a laser wavelength of 780 nm, a sampling frequency of 32 Hz, and a time constant of 0.2 seconds.

[0047] Data recording: Continuously record the average blood flow value in a stable state (excluding the segment with motion artifact interference). Calculate the recovery percentage after modeling and treatment, taking the blank group as 100%.

[0048] The results of blood flow recovery rate are shown in Table 3 below.

[0049] Table 3 Results of cochlear blood flow recovery rate The blood flow recovery rate in the second model group was only 45.3%, indicating successful modeling. The blood flow recovery rate in the single-drug group was 78.6%, significantly higher than that in the model group, but lower than that in each of the drug-treated groups. The blood flow recovery rates in Examples 1-3 were all close to those in the blank group, indicating that Examples 1-3 exhibited significant efficacy. Furthermore, compared with the corresponding drugs in the comparative example, the addition of citric acid nanoparticles also significantly impacted efficacy; citric acid nanoparticles and betahistine exhibited a synergistic effect, enhancing efficacy.

[0050] In addition, it should be understood that although this specification is described in terms of implementation methods, not every implementation method contains only one independent technical solution. This narrative method of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment can also be appropriately combined to form other implementation methods that can be understood by those skilled in the art.

Claims

1. A betahistine lyophilized powder, characterized in that: The invention comprises a drug-loaded microcapsule and a freeze-dried matrix. The drug-loaded microcapsule and the freeze-dried matrix are dissolved in water to form a freeze-dried liquid for freeze-drying. The drug-loaded microcapsule is formed by coating betahistine raw material and citric acid nanoparticles with a pH-sensitive polymer layer. The freeze-dried matrix comprises histidine, citrate and a freeze-dried skeleton agent.

2. A betahistine lyophilized powder according to claim 1, characterized in that The concentration of the betahistine raw material in the lyophilized solution is 8-12 mg / ml, the concentration of the histidine in the lyophilized solution is 0.04-0.06 M; and the concentration of the citrate in the lyophilized solution is 0.08-0.12 M.

3. A betahistine lyophilized powder according to claim 1, characterized in that The mass ratio of betahistine raw material to citric acid nanoparticles is 85-92:8-15.

4. The betahistine lyophilized powder according to claim 1, characterized in that The pH-sensitive polymer layer has a thickness of 5-10 μm.

5. The betahistine lyophilized powder according to claim 1, characterized in that: The pH-sensitive polymer layer was Eudragit L 100-55.

6. The betahistine lyophilized powder according to claim 1, characterized in that The pH-sensitive polymer layer coated with the tahistine raw material drug uses isopropyl alcohol as a coating solvent and triethyl citrate as a plasticizer.

7. The betahistine lyophilized powder according to claim 1, characterized in that: The particle size of citric acid nanoparticles is 200-500 nm.

8. A method for preparing the betahistine lyophilized powder according to any one of claims 1 to 7, characterized in that: The following steps are involved: The betahistine raw material and citric acid nanoparticles are mixed and then coated with a pH-sensitive polymer layer to obtain drug-loaded microcapsules; the drug-loaded microcapsules, histidine, citrate and a freeze-dried skeleton are dissolved in water and freeze-dried.

9. The method for preparing betahistine lyophilized powder according to claim 8, wherein: The pH-sensitive polymer layer is coated using a fluidized bed process with an inlet air temperature of 30-40° C. and a spray rate of 2-5 mL / min.

10. The method for preparing betahistine lyophilized powder according to claim 8, wherein: The freeze-drying process includes pre-freezing, primary drying and secondary drying. The pre-freezing temperature is -60 to -40°C, the pre-freezing time is 1.5-3 hours, the primary drying temperature is -30 to -20°C, the primary drying time is 20-24 hours, the secondary drying temperature is 20 to 25°C, and the secondary drying time is 5-8 hours.

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