Betahistine lyophilized powder and process for its preparation

Abstract

The application provides a betahistine lyophilized powder and a preparation method thereof. The 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 with pH-sensitive polymer layers and nanometer particles of citric acid. The lyophilized matrix comprises histidine, citrate and a lyophilized skeleton agent. The histidine and citrate in the lyophilized matrix maintain the overall pH stability (3.5-4.5) during the storage period, preventing pH drift. If the moisture invades during the storage period and the pH rises to 5.0 or above, the pH-sensitive polymer layer dissolves, and the internal nanometer particles of citric acid further adjust the pH value as an emergency buffer. Through the synergistic effect of the endogenous emergency buffer microcapsules and the exogenous active buffer matrix, the pH stability requirement during the storage period is covered.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparation, more particularly to a betahistine lyophilized powder and a preparation method thereof. BACKGROUND

[0002] Betahistine is a commonly used drug for treating Meniere's disease and dizziness, but it is prone to oxidative and hydrolytic degradation in aqueous solution, especially at pH>5.0, the degradation rate increases significantly. The prior art stabilizes the solution pH at about 4.0 by adding a single buffer (such as citrate), but it cannot cover the risk of sudden pH drift during storage or reconstitution. The single buffer system has inherent defects: first, the buffer capacity is limited, and it is difficult to cope with abnormal pH of the solvent during reconstitution or local pH drift caused by moisture penetration and CO2 escape during long-term storage; second, the compatibility of the buffer with the drug is insufficient, and high concentration of citric acid may accelerate the oxidative side reaction of the drug. Therefore, further improvement and development are needed. SUMMARY

[0003] In view of the deficiencies of the prior art and to solve the above problems, a betahistine lyophilized powder and a preparation method thereof are provided, and the following technical solutions are provided:

[0004] A betahistine lyophilized powder, comprising 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 material with citrate nanoparticles through a pH-sensitive polymer layer, and the lyophilized matrix comprises histidine, citrate, and a lyophilized scaffold.

[0005] Further, the concentration of betahistine raw material 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.

[0006] Further, the mass ratio of betahistine raw material to citrate nanoparticles is 85-92:8-15.

[0007] Further, the thickness of the pH-sensitive polymer layer is 5-10 μm.

[0008] Further, the pH-sensitive polymer layer is Eudragit L 100-55.

[0009] Further, isopropyl alcohol is used as the coating solvent for coating the betahistine raw material with the pH-sensitive polymer layer, and triethyl citrate is used as the plasticizer.

[0010] Further, the particle size of the citrate nanoparticles is 200-500 nm.

[0011] In addition, the application further provides a method for preparing the betahistine lyophilized powder, comprising the following steps: mixing betahistine raw materials with citric acid nanoparticles, and then coating with a pH-sensitive polymer layer to obtain drug-loaded microcapsules; dissolving the drug-loaded microcapsules, histidine, citrate and lyophilized matrix agent in water for lyophilization treatment.

[0012] Further, the pH-sensitive polymer layer is coated by using a fluidized bed process, with an inlet air temperature of 30-40 DEG C and a liquid spraying rate of 2-5 mL / min.

[0013] Further, the lyophilization treatment comprises pre-freezing, primary drying and secondary drying, wherein the pre-freezing temperature is -60 to -40 DEG C, the pre-freezing time is 1.5-3 hours, the primary drying temperature is -30 to -20 DEG C, the primary drying time is 20-24 hours, the secondary drying temperature is 20 to 25 DEG C, and the secondary drying time is 5-8 hours.

[0014] Due to the above technical solutions, the application has the following beneficial technical effects:

[0015] 1. The application provides a betahistine lyophilized powder with dynamic pH regulation capability, wherein the histidine and citrate in the lyophilized matrix release buffer capacity during the storage period to maintain the overall pH stability (3.5-4.5) and prevent pH drift; if the moisture invades during the storage period and the pH rises 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, thereby covering the pH stability requirement during the storage period through the synergistic effect of the endogenous emergency buffer microcapsules and the exogenous active buffer matrix.

[0016] 2. During reconstitution, the pH-sensitive polymer layer dissolves the citric acid nanoparticles together with the histidine and citrate to prevent the oxidation and degradation of betahistine during reconstitution. DETAILED DESCRIPTION

[0017] In order to enable those skilled in the art to better understand the technical solutions of the application, the technical solutions of the application will be described clearly and completely below in combination with the embodiments of the application. Based on the embodiments in the present application, other similar embodiments obtained by those skilled in the art without making any creative efforts should all fall within the scope of protection of the present application.

[0018] A betahistine lyophilized powder comprises drug-loaded microcapsules and a lyophilized matrix, wherein the drug-loaded microcapsules and the lyophilized matrix are dissolved in water to form a lyophilized liquid for lyophilization, the drug-loaded microcapsules are formed by coating betahistine raw materials with citric acid nanoparticles through a pH-sensitive polymer layer, and the lyophilized matrix comprises histidine, citrate and a lyophilized matrix agent.

[0019] pH dynamic regulation mechanism:

[0020] 1. Shelf life

[0021] Normal condition (pH < 5.0): Eudragit L 100-55 coating remains intact, isolating betahistine from the external environment, avoiding moisture, oxygen or alkaline substances from entering.

[0022] Dual buffering system (citrate + histidine) maintains the internal microenvironment pH at 3.5-4.5 in the lyophilized powder:

[0023] Citrate preferentially buffers in the pH 3.5-4.0 range (OH - is neutralized by citrate);

[0024] Histidine buffers in the pH 4.0-4.5 range (covers higher pH excursion risks).

[0025] Abnormal condition (local pH ≥ 5.0):

[0026] If moisture enters due to poor packaging during storage, causing local pH to rise above 5.0, the Eudragit L100-55 coating dissolves, releasing internal citrate nanoparticles, quickly neutralizing alkaline substances, preventing drug degradation.

[0027] 2. Reconstitution process (lyophilized powder dissolved into injection solution)

[0028] Initial reconstitution (pH < 5.0):

[0029] The coating remains intact, and the dual buffering system directly dissolves in water for injection / normal saline, stabilizing the initial solution pH at 4.0±0.2 (coordinated by citrate-histidine).

[0030] After reconstitution (solution exposed to the external environment):

[0031] After reconstitution, the pH rises above 5.0, the Eudragit L100-55 coating dissolves, releasing more citrate nanoparticles, quickly pulling the pH back into a safe range (3.5-4.5), reducing local pH fluctuations, preventing betahistine degradation.

[0032] Example 1

[0033] 1. Drug-loaded microcapsule preparation

[0034] Betahistine and citric acid nanoparticles with a particle size of 300 nm (mass ratio 90:10) were ball milled for 30 minutes (at a speed of 200 rpm) to obtain a mixture; then isopropyl alcohol was used as a coating solvent, and citric acid triethyl ester was used as a plasticizer, and Eudragit L 100-55 was added to prepare a coating solution, the mass ratio of isopropyl alcohol, citric acid triethyl ester and Eudragit L 100-55 was 88:2:10, and the coating solution was sprayed on the surface of the mixture by fluidized bed technology to coat, the inlet air temperature was 35°C, the liquid spraying rate was 3 mL / min, and drug-loaded microcapsules were obtained, and the coating thickness was 8μm.

[0035] 2. Preparation of the freeze-drying solution

[0036] Histidine, citrate and mannitol were dissolved in water, the concentration of histidine in the freeze-drying solution was 0.05 M, the concentration of citrate in the freeze-drying solution was 0.1 M, the concentration of mannitol was 0.2 M, and the drug-loaded microcapsules were added, the concentration of betahistine raw material in the freeze-drying solution was 10 mg / ml, and the freeze-drying solution was ultrasonically dispersed for 5 minutes at an ultrasonic power of 40 kHz.

[0037] 3. Freeze-drying process

[0038] The freeze-drying solution was pre-frozen, primary dried and secondary dried, 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.

[0039] Example 2

[0040] 1. Preparation of drug-loaded microcapsules

[0041] Betahistine and citric acid nanoparticles with a particle size of 200 nm (mass ratio 85:15) were ball milled for 30 minutes (at a speed of 200 rpm) to obtain a mixture; then isopropyl alcohol was used as a coating solvent, and citric acid triethyl ester was used as a plasticizer, and Eudragit L 100-55 was added to prepare a coating solution, the mass ratio of isopropyl alcohol, citric acid triethyl ester and Eudragit L 100-55 was 92:1:7, and the coating solution was sprayed on the surface of the mixture by fluidized bed technology to coat, the inlet air temperature was 35°C, the liquid spraying rate was 3 mL / min, and drug-loaded microcapsules were obtained, and the coating thickness was 5μm.

[0042] 2. Preparation of the freeze-drying solution

[0043] Histidine, citrate, mannitol were dissolved in water, the concentration of histidine in the freeze-dried liquid was 0.04 M; the concentration of citrate in the freeze-dried liquid was 0.08 M, and the concentration of mannitol was 0.2 M. The drug-loaded microcapsules were added, and the concentration of betahistine raw material in the freeze-dried liquid was 8 mg / ml. The freeze-dried liquid was ultrasonically dispersed for 5 minutes, and the ultrasonic power was 40 kHz.

[0044] 4. Freeze-drying process

[0045] The freeze-dried liquid was pre-frozen, primary dried and secondary dried, the pre-freezing temperature was -40℃, the pre-freezing time was 3 hours, the primary drying temperature was -20℃, the primary drying time was 24 hours, the secondary drying temperature was 20℃, and the secondary drying time was 8 hours.

[0046] Example 3

[0047] 1. Preparation of drug-loaded microcapsules

[0048] Betahistine and citric acid nanoparticles with a particle size of 500 nm (mass ratio 92:8) were ball milled for 30 minutes (rotation speed 200 rpm) to obtain a mixture; then isopropyl alcohol was used as a coating solvent, citric acid triethyl ester was used as a plasticizer, and Eudragit L 100-55 was added to prepare a coating solution, the mass ratio of isopropyl alcohol, citric acid triethyl ester and Eudragit L 100-55 was 85:2:13, and the coating solution was sprayed on the surface of the mixture by fluidized bed technology to coat, the inlet air temperature was 35℃, the spraying rate was 3 mL / min, and drug-loaded microcapsules were obtained, and the coating thickness was 10 μm.

[0049] 2. Preparation of freeze-dried liquid

[0050] Histidine, citrate, mannitol were dissolved in water, the concentration of histidine in the freeze-dried liquid was 0.06 M; the concentration of citrate in the freeze-dried liquid was 0.12 M, and the concentration of mannitol was 0.3 M. The drug-loaded microcapsules were added, and the concentration of betahistine raw material in the freeze-dried liquid was 12 mg / ml. The freeze-dried liquid was ultrasonically dispersed for 5 minutes, and the ultrasonic power was 40 kHz.

[0051] 5. Freeze-drying process

[0052] The freeze-dried liquid was pre-frozen, primary dried and secondary dried, the pre-freezing temperature was -60℃, the pre-freezing time was 1.5 hours, the primary drying temperature was -30℃, the primary drying time was 20 hours, the secondary drying temperature was 25℃, and the secondary drying time was 5 hours.

[0053] Comparative Example 1

[0054] Compared with Example 1, no citric acid nanoparticles, histidine, and citrate were added, and the other steps were the same.

[0055] Comparative Example 2

[0056] Compared with Example 1, no sodium citrate nanoparticles were added, and other steps were the same.

[0057] Comparative Example 3

[0058] Compared with Example 1, no histidine, citrate were added, and other steps were the same.

[0059] Comparative Example 4

[0060] Compared with Example 1, no isopropanol, triethyl citrate, Eudragit L 100-55 were used for coating, and other steps were the same.

[0061] The products obtained in Examples 1-3 and Comparative Examples 1-4 were subjected to pH dynamic capability test.

[0062] (1) Storage period simulation: the freeze-dried powder was placed under 40℃ / 75% RH accelerated conditions for 30 days, and the pH change was detected.

[0063] (2) Reconstitution simulation: reconstituted in normal saline (initial pH = 5.5), and the pH change within 0-60 minutes was recorded.

[0064] The test results are shown in Table 1.

[0065] Table 1 PH dynamic capability test results

[0066]

[0067] All examples can stabilize the pH in the range of 3.9-4.3 during storage and reconstitution, which is significantly better than the pH stability performance of each comparative example.

[0068] The products obtained in Examples 1-3 and Comparative Examples 1-4 were subjected to drug stability test.

[0069] The products obtained in Examples 1-3 and Comparative Examples 1-4 were stored under 40℃ / 75% RH conditions for 6 months, and the content of betahistine main component and oxidative impurities (using HPLC method) were detected, and the test results are shown in Table 2.

[0070] Table 2 Drug stability test results

[0071]

[0072] The content of oxidative impurities in each example is reduced compared with each comparative example, indicating that the betahistine freeze-dried powder system designed in the present application has high stability and can ensure the production of less impurities.

[0073] Application Example:

[0074] Six guinea pigs with a weight of 300-350 g were selected as the first group of blank control group, and injected with normal saline. Meniere's disease guinea pigs were selected as the model: 66 guinea pigs with a weight of 300-350 g were injected with kanamycin (400 mg / kg / d x 7 days) in the abdominal cavity to induce inner ear microcirculation disorder. The 66 guinea pigs were divided into 11 groups; the second group was the model group without treatment; the third group was the single drug group, and an equivalent dose of betahistine (10 mg / kg / d) was injected intravenously every day; the fourth to tenth groups were the drug administration groups, and the drug reconstitution solutions of examples 1 to 3 and comparative examples 1 to 4 were injected intravenously every day at an equivalent dose (10 mg / kg / d). After 7 days of administration, the cochlear blood flow was detected. A PeriFlux 5000 laser Doppler flowmeter (Perimed AB, Sweden) was used, equipped with a cochlear special probe (tip diameter 0.5 mm). Anesthetics: urethane (1.5 g / kg, intraperitoneal injection).

[0075] Specific operation steps are as follows:

[0076] Anesthesia: After the guinea pigs were anesthetized, they were fixed on a stereotaxic instrument, and the body temperature was maintained at 37°C (controlled by a heating pad).

[0077] Surgical exposure of the cochlea: the skin behind the ear was incised, the muscle tissue was separated, and the auditory bubble was exposed.

[0078] Under a microscope, drill a hole (diameter 1 mm) to the cochlear bone wall to avoid damaging the inner ear structure.

[0079] Blood flow detection:

[0080] Gently touch the surface of the cochlear bone wall with the LDF probe (avoid pressing the blood vessels), and record the baseline blood flow value (PU, Perfusion Unit) for 5 minutes. Detection parameters: laser wavelength 780 nm, sampling frequency 32 Hz, time constant 0.2 seconds.

[0081] Data recording: continuously record the average blood flow value in the stable state (eliminate the motion artifact interference section). Take the blank group as 100% as the basis, and calculate the recovery percentage after modeling and treatment.

[0082] The results of the blood flow recovery rate are shown in Table 3 below.

[0083] Table 3 Results of cochlear blood flow recovery rate

[0084]

[0085] The blood flow recovery rate of the second group of models was only 45.3%, indicating that the modeling was successful. The blood flow recovery rate of the single drug group was 78.6%, which was significantly higher than that of the model group, but lower than that of each administration group. The blood flow recovery rates of Examples 1-3 were close to the level of the blank group, indicating that the drug efficacy of Examples 1-3 was obvious. In addition, compared with the corresponding drugs of the comparative examples, whether the sodium citrate nanoparticles were added was also a key factor affecting the drug efficacy. The sodium citrate nanoparticles had a synergistic effect with betahistine, which could jointly improve the drug efficacy.

[0086] In addition, it should be understood that although the present specification is described in terms of embodiments, not every embodiment contains only one independent technical solution, and the description of the specification is only for the sake of clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can be appropriately combined to form other embodiments that those skilled in the art can understand.

Claims

1. A betahistine lyophilized powder, characterized in that, The product includes drug-loaded microcapsules and a lyophilized matrix. The drug-loaded microcapsules and the lyophilized matrix are dissolved in water to form a lyophilized solution and then lyophilized. The drug-loaded microcapsules are formed by encapsulating betahistine active pharmaceutical ingredient and citrate nanoparticles with a pH-sensitive polymer layer. The lyophilized matrix includes histidine, citrate, and a lyophilized matrix agent. The concentration of betahistine active pharmaceutical ingredient in the lyophilization solution is 8-12 mg / ml, the concentration of histidine in the lyophilization solution is 0.04-0.06 M, and the concentration of citrate in the lyophilization solution is 0.08-0.12 M. The mass ratio of betahistine active pharmaceutical ingredient to citrate nanoparticles is 85-92:8-15; The thickness of the pH-sensitive polymer layer is 5-10 μm; The pH-sensitive polymer layer is Eudragit L 100-55.

2. The betahistine lyophilized powder according to claim 1, characterized in that, The pH-sensitive polymer layer coating of tasting active pharmaceutical ingredient uses isopropanol as the coating solvent and triethyl citrate as the plasticizer.

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

4. A method for preparing betahistine lyophilized powder as described in any one of claims 1-3, characterized in that, Includes the following steps: Betahistine active pharmaceutical ingredient was mixed with citrate nanoparticles and then coated with a pH-sensitive polymer layer to obtain drug-loaded microcapsules; the drug-loaded microcapsules, histidine, citrate and lyophilized matrix were dissolved in water and then lyophilized.

5. The method according to claim 4, characterized in that, When coating pH-sensitive polymer layers, a fluidized bed process is used with an inlet air temperature of 30-40℃ and a spray rate of 2-5 mL / min.

6. The method according to claim 4, characterized in that, The freeze-drying process includes pre-freezing, primary drying, and secondary drying. The pre-freezing temperature is -60 to -40°C and the pre-freezing time is 1.5 to 3 hours. The primary drying temperature is -30 to -20°C and the primary drying time is 20 to 24 hours. The secondary drying temperature is 20 to 25°C and the secondary drying time is 5 to 8 hours.

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