Carbamazepine and disodium glycyrrhizinate co-amorphous compound and preparation method thereof

Abstract

The invention discloses a carbamazepine and disodium glycyrrhizinate co-amorphous compound and a preparation method of the carbamazepine and disodium glycyrrhizinate co-amorphous compound. The co-amorphous compound is a single-phase amorphous mixture prepared from carbamazepine and disodium glycyrrhizinate. The composition can be prepared by adopting a spray drying method. The thermodynamic property of the carbamazepine and disodium glycyrrhizinate co-amorphous compound is verified through DSC, and it is shown that a co-amorphous system is formed. The dissolution rate of the carbamazepine and disodium glycyrrhizinate co-amorphous compound is obviously superior to that of a single crystal medicine and a physical mixture thereof, and the carbamazepine and disodium glycyrrhizinate co-amorphous compound shows excellent physical stability and has the potential of improving the bioavailability of carbamazepine. Meanwhile, the preparation method is simple to operate, the use of an auxiliary material carrier is omitted, and a new preparation thought is provided for the drug combination of other insoluble compounds.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to a carbamazepine and disodium glycyrrhizinate co-amorphous complex and a preparation method thereof. Background Art

[0002] Carbamazepine, with the chemical name of 5H-dibenz[b,f]azepine-5-carboxamide, is an organic compound with the chemical formula of C 15 H 12 N2O. The chemical structure is shown as follows:

[0003]

[0004] Carbamazepine is a common anti-epileptic drug and is the first choice for treating grand mal epilepsy and partial seizures. It is also commonly used in the treatment of trigeminal neuralgia, glossopharyngeal neuralgia, diabetes insipidus, and painful symptom groups. However, carbamazepine is almost insoluble in water and belongs to the typical BCS class II drug, that is, a drug with low solubility and high permeability. Therefore, improving the solubility of carbamazepine has always been a research hotspot for its oral preparations. Currently, the research on carbamazepine oral preparations mainly includes solid dispersions, co-crystals, etc. Although the bioavailability of carbamazepine has been improved to a certain extent, most of the preparations use non-pharmacologically active polymers as carriers, with low drug loading and easy moisture absorption, and prone to recrystallization during dissolution and storage, which limits their application to a certain extent. In addition, carbamazepine is also classified by the Liver tox website as a drug that significantly causes liver damage clinically. Long-term use may cause an increase in alanine aminotransferase and aspartate aminotransferase in the serum, resulting in drug-induced liver injury. These all limit the clinical application of carbamazepine and make its application have certain limitations.

[0005] Disodium glycyrrhizinate, as a salt form of glycyrrhizic acid, is a lupane-type pentacyclic triterpenoid saponin extracted from Glycyrrhiza uralensis Fisch., which has similar pharmacological effects to glycyrrhizic acid: antibacterial, anti-inflammatory, anti-tumor, immune regulation, liver protection, etc. These multiple effective pharmacological effects also make glycyrrhizic acid drugs such as disodium glycyrrhizinate become commonly used liver protection drugs in clinical practice and play an important role in the prevention and treatment of drug-induced liver injury. In addition, disodium glycyrrhizinate is a natural surfactant that can self-assemble to form micelles, encapsulate some poorly soluble drugs, and thus can improve the solubility of poorly soluble drugs, enhance drug bioavailability and efficacy.

[0006] Co-amorphous complex, which is a single-phase amorphous binary system, has the potential to improve the solubility and dissolution rate of drugs. Moreover, combining two drugs with synergistic effects can produce synergistic pharmacological effects, improve clinical efficacy, and reduce the toxic and side effects of drugs. Therefore, the co-amorphous system of drugs is of great significance for pre-formulation research and dosage form design of drug preparations. Preparing co-amorphous complex by spray drying means that the mixed solution of drugs is pumped into the drying chamber through a nozzle. At the nozzle orifice, the liquid droplets are atomized and come into contact with the hot gas in the drying chamber. After the transfer of energy and mass, particles are finally formed. The spray drying preparation process is simple, the drying is mild, the particle size distribution of the obtained particles is narrow. At the same time, the active ingredients in the prepared solid dispersion are mainly uniformly dispersed in the amorphous form, with a high Gibbs energy, so less energy is required during dissolution. In addition, better porosity, wettability, and small particle size structure with a large surface area are all important reasons for the improvement of its bioavailability. Summary of the Invention

[0007] The object of the present invention is to provide a co-amorphous complex of carbamazepine and disodium glycyrrhizinate and its preparation method in view of the deficiencies of the prior art. The present invention aims to use the co-amorphous complex of carbamazepine and disodium glycyrrhizinate to improve the solubility of carbamazepine and produce potential synergistic therapeutic effects, thereby improving the bioavailability and clinical application of carbamazepine. The method for preparing the co-amorphous complex of carbamazepine and disodium glycyrrhizinate provided by the present invention can effectively improve the solubility / dissolution rate of carbamazepine. Moreover, when carbamazepine and disodium glycyrrhizinate are used in combination, it is expected to utilize the pharmacological effects of disodium glycyrrhizinate such as immunomodulation and protecting the liver from drug-induced liver injury, enhance the oral absorption and therapeutic advantages of carbamazepine, and improve the drug-induced liver injury of carbamazepine. It is of great significance for promoting the practical application of carbamazepine.

[0008] In order to achieve the above invention object, the technical solutions adopted by the present invention are as follows:

[0009] The co-amorphous complex of carbamazepine and disodium glycyrrhizinate is prepared from carbamazepine and disodium glycyrrhizinate according to a mass ratio of 1:(1-5).

[0010] Preferably, according to the mass ratio, carbamazepine:disodium glycyrrhizinate = 1:(2.5-5); most preferably, according to the mass ratio, carbamazepine:disodium glycyrrhizinate = 1:2.5.

[0011] The co-amorphous complex of carbamazepine and disodium glycyrrhizinate is prepared by spray drying.

[0012] Preparing the co-amorphous complex of carbamazepine and disodium glycyrrhizinate by spray drying includes the following steps:

[0013] (1) Mix carbamazepine and disodium glycyrrhizinate evenly according to the mass ratio to prepare a carbamazepine and disodium glycyrrhizinate mixture;

[0014] (2) Dissolve the carbamazepine and disodium glycyrrhizinate mixture in step (1) in a 70% ethanol - aqueous solution with a solid content of 1% (w / v). After ultrasonic treatment, a carbamazepine and disodium glycyrrhizinate mixed solution is obtained.

[0015] (3) Use a spray dryer to spray - dry the carbamazepine and disodium glycyrrhizinate mixed solution in step (2). The working parameters of spray - drying are an inlet temperature of 105 °C, a spraying speed of 5 mL / min, and an air volume of 100%. Collect the dried powder to obtain a solid powder of the carbamazepine and disodium glycyrrhizinate co - amorphous complex.

[0016] The carbamazepine and disodium glycyrrhizinate co - amorphous complex prepared by the method of the present invention is analyzed by differential scanning calorimetry (DSC). The spectrum shows that there is only one glass transition temperature and the melting peak of the drug disappears.

[0017] Advantages of the present invention:

[0018] The carbamazepine and disodium glycyrrhizinate co - amorphous complex prepared by the method of the present invention can significantly improve the solubility, dissolution rate and stability of carbamazepine, and realize the combination of drugs in a single homogeneous system.

[0019] The carbamazepine and disodium glycyrrhizinate co - amorphous complex prepared by the method of the present invention analyzes the thermodynamic properties of the co - amorphous by differential scanning calorimetry (DSC). There is one and only one glass transition temperature on the DSC spectrum and the crystal melting point peak disappears, indicating the formation of a single carbamazepine and disodium glycyrrhizinate co - amorphous complex.

[0020] The carbamazepine and disodium glycyrrhizinate co - amorphous complex prepared by the method of the present invention shows through in vitro dissolution tests that the solubility and dissolution rate of the carbamazepine and disodium glycyrrhizinate co - amorphous complex are significantly improved compared with the crystalline API and physical mixtures, solving the problem of poor solubility of carbamazepine.

[0021] The present invention prepares a co - amorphous complex of poorly soluble carbamazepine and disodium glycyrrhizinate, an active ingredient in traditional Chinese medicine licorice, by spray - drying method, which improves the physicochemical property defects of carbamazepine (such as solubility, dissolution rate, stability, etc.), eliminates the use of excipient carriers, has a high drug - loading capacity, is simple to prepare, has good miscibility, and has the potential to improve the bioavailability of carbamazepine and achieve synergistic treatment. It provides a new formulation idea for better application of carbamazepine and solving problems such as combination of drugs in the future. Description of the Drawings

[0022] Figure 1It is the DSC comparison chart of carbamazepine, disodium glycyrrhizinate, the physical mixture of carbamazepine and disodium glycyrrhizinate in Example 1, and the co-amorphous complex of carbamazepine and disodium glycyrrhizinate in Example 1;

[0023] Figure 2 It is the dissolution curve chart of carbamazepine, disodium glycyrrhizinate, the physical mixture of carbamazepine and disodium glycyrrhizinate in Example 1, and the co-amorphous complex of carbamazepine and disodium glycyrrhizinate in Example 1;

[0024] Figure 3 It is the dissolution curve chart of the co-amorphous complex of carbamazepine and disodium glycyrrhizinate in Example 2 and Example 3;

[0025] Figure 4 It is the PXRD diagram of the co-amorphous complex of carbamazepine and disodium glycyrrhizinate in Example 1 under the conditions of 40 °C and 75% RH; Detailed implementation mode

[0026] The present invention is further elaborated through the following examples.

[0027] Example 1

[0028] Weigh 571 mg of carbamazepine and 1429 mg of disodium glycyrrhizinate respectively and place them in a 50 mL centrifuge tube. Then use a vortex mixer to vortex and mix for 10 min to obtain the physical mixture of carbamazepine and disodium glycyrrhizinate. Dissolve the physical mixture of carbamazepine and disodium glycyrrhizinate in 200 ml of 70% ethanol-aqueous solution. After ultrasonic treatment, a mixed solution is obtained. Use a spray dryer to spray-dry the mixed solution. The working parameters of the spray dryer are an inlet temperature of 105 °C, a spray speed of 5 mL / min, and an air volume of 100%. Collect the dried powder to obtain the solid powder of the co-amorphous complex of carbamazepine and disodium glycyrrhizinate. The powder is stored in a desiccator containing color-changing silica gel.

[0029] Example 2

[0030] Weigh 1000 mg of carbamazepine and 1000 mg of disodium glycyrrhizinate respectively and place them in a 50 mL centrifuge tube. Then use a vortex mixer to vortex and mix for 10 min to obtain the physical mixture of carbamazepine and disodium glycyrrhizinate. Dissolve the physical mixture of carbamazepine and disodium glycyrrhizinate in 200 ml of 70% ethanol-aqueous solution. After ultrasonic treatment, a mixed solution is obtained. Use a spray dryer to spray-dry the mixed solution. The working parameters of the spray dryer are an inlet temperature of 105 °C, a spray speed of 5 mL / min, and an air volume of 100%. Collect the dried powder to obtain the solid powder of the co-amorphous complex of carbamazepine and disodium glycyrrhizinate. The powder is stored in a desiccator containing color-changing silica gel.

[0031] Example 3

[0032] Weigh 333 mg of carbamazepine and 1667 mg of disodium glycyrrhizinate separately and place them in a 50 mL centrifuge tube. Then vortex and mix for 10 min to obtain a physical mixture of carbamazepine and disodium glycyrrhizinate. Dissolve the physical mixture of carbamazepine and disodium glycyrrhizinate in 200 ml of 70% ethanol - aqueous solution. After ultrasonic treatment, a mixed solution is obtained. Use a spray dryer to spray - dry the mixed solution. The working parameters of spray - drying are: inlet temperature 105 °C, spraying speed 5 mL / min, and air volume 100%. Collect the dried powder to obtain the solid powder of the co - amorphous complex of carbamazepine and disodium glycyrrhizinate. The powder is stored in a desiccator containing silica gel for color change.

[0033] Test Example 1: Conduct a characterization test on the co - amorphous complex of carbamazepine and disodium glycyrrhizinate in Example 1 as follows:

[0034] Instrument: DSC 200F3 differential scanning calorimeter (NETZSCH, Germany), range: 10 - 300 °C, heating rate: 10 °C / min.

[0035] Detect carbamazepine, disodium glycyrrhizinate, the physical mixture of carbamazepine and disodium glycyrrhizinate, and the co - amorphous complex of carbamazepine and disodium glycyrrhizinate respectively. The corresponding DSC spectra are as Figure 1 shown.

[0036] As Figure 1 shown, in the DSC spectrum of the co - amorphous complex of carbamazepine and disodium glycyrrhizinate in Example 1, the endothermic melting peak of carbamazepine crystals disappears, and there is a single glass transition temperature, which is 53.9 °C.

[0037] Test Example 2: Conduct an in vitro dissolution test on the co - amorphous complex of carbamazepine and disodium glycyrrhizinate in Examples 1, 2, and 3 as follows:

[0038] According to the third method of General Chapter 0931, Volume IV of the Chinese Pharmacopoeia 2020 Edition, the small - cup method is used for in vitro dissolution evaluation. At 37 °C ± 0.5 °C, add carbamazepine, the physical mixture of carbamazepine and disodium glycyrrhizinate, and the co - amorphous complex of carbamazepine and disodium glycyrrhizinate into 250 mL of phosphate buffer solution (pH 5.8), and stir at 100 rpm. Take 2 mL samples at 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 h and place them in EP tubes, and simultaneously supplement the same volume of dissolution medium at the same temperature. Filter with a 0.45 μm microporous filter membrane, discard the initial filtrate, and then dilute with methanol by an appropriate multiple. Use high - performance liquid chromatography to determine and analyze the drug concentration in the sample. Each sample is measured in parallel 3 times, and the dissolution curve is plotted. The corresponding dissolution curves are as Figure 2 , Figure 3 shown.

[0039] The high performance liquid chromatography conditions are as follows: Instrument: e2695 high performance liquid chromatograph (Waters, USA), chromatographic column: Hedera C18 chromatographic column (4.6 mm × 250 mm, 5 μm), mobile phase: acetonitrile - 0.1% phosphoric acid water = 35:65 (V / V); flow rate: 1 mL / min; column temperature: 35 °C; injection volume: 10 μL; detection wavelength: 285 nm.

[0040] As Figure 2 shown, there was no significant difference (P > 0.05) in the dissolution of the physical mixture of carbamazepine and disodium glycyrrhizinate in Example 1 compared with that of carbamazepine raw material drug, and the dissolution concentration was relatively low. Compared with the former two, the dissolution of the co-amorphous complex of carbamazepine and disodium glycyrrhizinate in Example 1 was significantly improved (11 times that of carbamazepine raw material drug at 24 h), and the supersaturated dissolution concentration showed no downward trend within 24 h. As Figure 3 shown, the co-amorphous complexes of carbamazepine and disodium glycyrrhizinate in Examples 2 and 3 also showed significantly increased dissolution concentrations at different time points, but the dissolution amount of the co-amorphous complex of carbamazepine and disodium glycyrrhizinate in Example 2 gradually decreased after 30 min.

[0041] Test Example 3: A stability test was carried out on the co-amorphous complex of carbamazepine and disodium glycyrrhizinate in Example 1, and the specific steps are as follows:

[0042] In order to investigate the physical stability of the co-amorphous preparation, an appropriate amount of the newly prepared co-amorphous complex of carbamazepine and disodium glycyrrhizinate was placed in a drug comprehensive stability test chamber at 40 °C and 75% RH for a three-month stability test. Samples were taken out at 30, 60, and 90 days, and the stored samples were evaluated by PXRD.

[0043] As Figure 4 shown, the co-amorphous complex of carbamazepine and disodium glycyrrhizinate in Example 1 was stored at 40 °C and 75% RH for 90 days, and no characteristic diffraction peaks were shown in the PXRD diffraction pattern. The results indicate that the co-amorphous complex of carbamazepine and disodium glycyrrhizinate has high physical stability.

Claims

1. A carbamazepine and disodium glycyrrhizinate co-amorphous complex, characterized in that, The co-amorphous complex is prepared from carbamazepine and disodium glycyrrhizinate, and the molecules of both exist in an amorphous form in the co-amorphous complex.

2. The carbamazepine and disodium glycyrrhizinate co-amorphous complex according to claim 1, characterized in that, In the co-amorphous substance, the mass ratio of carbamazepine to disodium glycyrrhizinate is 1:(1 - 5), preferably 1:(2.5 - 5).

3. The carbamazepine and disodium glycyrrhizinate co-amorphous complex according to claim 1, wherein The co-amorphous complex is prepared from carbamazepine and disodium glycyrrhizinate by spray drying.

4. The preparation method of the carbamazepine and disodium glycyrrhizinate co-amorphous complex according to claim 3, characterized in that, It includes the following steps: (1) Mix carbamazepine and disodium glycyrrhizinate evenly according to the mass ratio to form a carbamazepine and disodium glycyrrhizinate mixture. (2) Dissolve the carbamazepine and disodium glycyrrhizinate mixture in step (1) in a solvent, and after ultrasonic treatment, obtain a carbamazepine and disodium glycyrrhizinate mixed solution. (3) Use a spray dryer to spray dry the carbamazepine and disodium glycyrrhizinate mixed solution in step (2). Collect the dried powder to obtain a solid powder of the carbamazepine and disodium glycyrrhizinate co-amorphous complex.

5. The preparation method of the carbamazepine and disodium glycyrrhizinate co-amorphous complex according to claim 4, wherein The solvent in step (2) is a 70% ethanol-aqueous solution with a solid content of 1% (w / v).

6. The preparation method of the carbamazepine and disodium glycyrrhizinate co-amorphous complex according to claim 4, characterized in that, The spray drying operating parameters in step (3) are an inlet temperature of 105 °C, a spray rate of 5 mL / min, and an air volume of 100%.

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