Letrozole-cyclodextrin compound tablet and stability optimization process

Abstract

The invention relates to a letrozole-cyclodextrin compound as well as a tablet and a stability optimization process thereof, and belongs to the technical field of pharmaceutical preparations. The letrozole-cyclodextrin compound disclosed by the invention is prepared from letrozole, cyclodextrin and a stable solubilizer through a high-temperature wet grinding process and an inclusion process. The invention also provides a tablet prepared from the compound and pharmaceutical auxiliary materials, the problems of poor water solubility and low bioavailability of letrozole are effectively improved, compared with the prior art, the compound is high in encapsulation efficiency and strong in stability, the dissolution rate of the tablet is remarkably improved, and a better pharmaceutical preparation is provided for breast cancer treatment.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a letrozole-cyclodextrin complex tablet and a stability optimization process. Background Art

[0002] Letrozole is a drug widely used in the treatment of breast cancer. Its mechanism of action is to inhibit the activity of aromatase, reduce the synthesis of estrogen, and thus inhibit the growth of estrogen-dependent breast cancer. However, its poor water solubility (0.01mg / mL) and low bioavailability pose severe challenges to the formulation process. In the prior art, the dissolution rate and stability are mainly improved through excipient optimization and process improvement, but there are still the following limitations: Chinese patents with publication numbers CN107737112A and CN103933004A respectively disclose a letrozole tablet and its preparation method. Although micronization technology can improve dissolution, there are problems such as powder floating and uneven mixing caused by too small particle size, and the dissolution rate at 15 minutes is difficult to exceed 85%; the dissolution rate of the wet granulation process is relatively slow, and the dissolution rate of direct tableting without comminution is only 75%. Chinese patent with publication number CN 103356495A discloses a letrozole tablet and its preparation method. The main excipients included in the letrozole tablet are: microcrystalline cellulose, lactose, sodium carboxymethyl starch, L-HPC, sodium lauryl sulfate, Tween 80, magnesium stearate, and starch, but the problem of the light stability of letrozole has still not been solved.

[0003] In the existing improvement schemes, by optimizing the disintegrant (such as the ratio of sodium carboxymethyl starch to corn starch), lubricant (synergy of magnesium stearate and colloidal silica), and adding stabilizers (such as magnesium hydrogen phosphate), the shelf life can be extended and the dissolution rate of letrozole can be improved. However, these methods still rely on physical mixing and do not fundamentally solve the problem of direct contact between drug molecules and environmental factors.

[0004] Cyclodextrin is a class of cyclic structure compounds composed of glucose molecules, which can improve the solubility of poorly soluble drugs through inclusion. However, the preparation and stability optimization of the letrozole-cyclodextrin complex still face some challenges. First, the preparation process of the letrozole-cyclodextrin complex is complex and may be affected by environmental factors (such as humidity, temperature) and other additives, resulting in unsatisfactory stability of the complex. Second, in the preparation process, how to effectively optimize the type of cyclodextrin, the complex ratio, and the preparation process parameters to obtain the best drug release characteristics and stability is still an issue worthy of in-depth discussion.

[0005] Therefore, how to improve the stability, solubility and bioavailability of letrozole-cyclodextrin complex tablets through process optimization has become an important topic in the field of drug research and development. This patent aims to conduct in-depth research on the preparation process of letrozole-cyclodextrin complex tablets, propose a new optimization process, and thus solve the problems of poor stability and slow dissolution rate existing in the current complex preparation process, in order to provide more effective drug preparations for clinical treatment. Summary of the Invention

[0006] To overcome the deficiencies of the prior art, the present invention provides a letrozole-cyclodextrin complex and its tablets. By optimizing the types of cyclodextrin, the components and ratios of stabilizing solubilizers, and the preparation process parameters, the problems of poor water solubility, low bioavailability of letrozole, and poor stability of the complex are effectively solved.

[0007] Specifically, the letrozole-cyclodextrin complex is composed of 2.5 parts by weight of letrozole, 13 - 41 parts by weight of cyclodextrin, and 0.5 - 2.1 parts of histidine and sodium alginate as stabilizing solubilizers; its preparation process is to grind sodium alginate and histidine by wet method at high temperature, react with the saturated aqueous solution of cyclodextrin, then inject the letrozole solution, and perform inclusion to obtain the letrozole-cyclodextrin complex.

[0008] Furthermore, the stabilizing solubilizer is histidine and sodium alginate with a mass ratio of 1:2 - 1:8. Preferably, the stabilizing solubilizer is histidine and sodium alginate with a mass ratio of 1:5. The cyclodextrin is selected from at least one of β-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, and sulfobutyl-β-cyclodextrin. Preferably, the cyclodextrin is hydroxypropyl-β-cyclodextrin.

[0009] Specifically, the preparation process of the letrozole-cyclodextrin complex is as follows: (1) Dissolve cyclodextrin in water to form a saturated aqueous solution; (2) Add a small amount of water to sodium alginate and histidine, grind them together at 45°C - 55°C for 15 - 30 min, and after cooling, add them to the saturated aqueous solution of cyclodextrin; (3) Dissolve letrozole in an organic solvent, ultrasonicate it, and slowly inject it into the solution in step (2) at 60°C - 80°C, stir at a constant temperature for 4 - 6 h, let it stand at room temperature for 12 - 18 h, filter, wash, and dry to obtain the product.

[0010] Furthermore, the organic solvent is ethyl acetate, and in step (2), sodium alginate and histidine are ground together with a small amount of water at 50°C for 20 min.

[0011] The present invention also provides a letrozole-cyclodextrin complex tablet, which is composed of the above-mentioned letrozole-cyclodextrin complex and pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients include fillers, disintegrants, lubricants, flavoring agents, binders, and coating agents.

[0012] The present invention screens out hydroxypropyl-β-cyclodextrin as the inclusion cyclodextrin, which has good inclusion performance with letrozole; determines histidine and sodium alginate with a mass ratio of 1:2 - 1:8 (preferably 1:5) as the stabilizing solubilizers, and the two act synergistically to significantly improve the stability of the complex under high temperature, high humidity, and light conditions; optimizes the preparation process, including specific grinding temperature, time, letrozole injection temperature, stirring and standing time, etc., to ensure full inclusion of letrozole and cyclodextrin and improve the encapsulation efficiency. On this basis, the complex is combined with pharmaceutically acceptable excipients to prepare tablets, further improving the dissolution rate and stability of letrozole.

[0013] It should be noted that the specification only shows some measurement data of the high temperature, high humidity, and light experiments, and the remaining data can be provided if needed.

[0014] Compared with the prior art, the technical effects of the present invention are as follows: (1) By selecting the appropriate type of cyclodextrin and optimizing the preparation process, the present invention significantly improves the encapsulation efficiency of the prepared letrozole-cyclodextrin complex, which has obvious advantages compared with the comparative examples and is beneficial to improving the utilization rate of the drug.

[0015] (2) By utilizing the synergistic effect of the stabilizing solubilizers histidine and sodium alginate, the complex shows good stability under high temperature (40 ± 2°C), high humidity (relative humidity 75% ± 5%), and light (illuminance 4500 lx ± 500 lx) conditions, effectively ensuring the drug quality.

[0016] (3) The dissolution rate of the letrozole-cyclodextrin complex tablet prepared by the present invention is significantly improved, and the dissolution rate within 30 minutes is significantly higher than that of the comparative examples and commercially available tablets, which helps to improve the bioavailability of the drug and give full play to the drug efficacy. Brief Description of the Drawings

[0017] Figure 1 : Letrozole content curves of letrozole-cyclodextrin complexes in Examples 1 - 3 and letrozole-cyclodextrin complexes in Comparative Examples 1 - 6.

[0018] Figure 2 : In vitro dissolution of Examples 4 - 5, Comparative Examples 7 - 8, and commercially available letrozole tablets. Detailed Description of the Invention

[0019] To make the objectives and technical solutions of the present invention clearer and more understandable, the following provides further explanations of the present invention in combination with embodiments. However, the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain the present invention. Those skilled in the art should understand that any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0020] Single-factor experiment 1. Selection of cyclodextrin types and ratios α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin, and γ-cyclodextrin were respectively selected as the inclusion guests. Based on the molar ratios of letrozole to cyclodextrin of 1:1, 1:2, and 1:3, the entrapment efficiency (the percentage of the amount of letrozole drug encapsulated in the complex to the total mass of the complex) of different types of cyclodextrins was compared, and other conditions were the same as in Example 1.

[0021] Table 1 Screening of cyclodextrin types and ratios As can be seen from the experimental data in Table 1, when the molar ratios of letrozole to α-cyclodextrin were 1:1, 1:2, and 1:3, the entrapment efficiencies were 63.84%, 70.15%, and 75.03% respectively, which were significantly lower than those of other cyclodextrins as a whole. The entrapment efficiency of the inclusion complex prepared from letrozole and γ-cyclodextrin was between 66.20% and 79.60%. Although it was slightly higher than that of α-cyclodextrin, it was still lower than that of β-cyclodextrin and its derivatives. In contrast, the entrapment efficiency of hydroxypropyl-β-cyclodextrin was the highest, reaching 95.51%, and the entrapment efficiencies of β, methyl-β, and sulfobutyl-β were also all above 80%, even close to 90%. Therefore, due to the structural size mismatch and solubility defects of α-cyclodextrin and γ-cyclodextrin, the efficiency of encapsulating letrozole is low and they are not suitable as its inclusion carriers. While β-cyclodextrin and its derivatives (such as hydroxypropyl-β-cyclodextrin) have appropriate cavity sizes, better solubility and stability, and show higher inclusion performance.

[0022] 2. Screening of the ratio of the stabilizing solubilizer After determining histidine and sodium alginate as the stabilizing solubilizers of letrozole, the single-factor experiment was used to screen their ratios, and the stability of letrozole-cyclodextrin complexes with different ratios of the stabilizing solubilizer was measured, and other conditions were the same as in Example 1. Test conditions: temperature 40±2°C, relative humidity 75%±5%, illuminance 4500lx±500lx, and samples were taken for detection on the 0th day, 30th day, 90th day, and 180th day (only part of the data is shown in the table).

[0023] Determination of Letrozole Content It is determined according to the high performance liquid chromatography method (General Rule 0512) in Chinese Pharmacopoeia. Test solution: Take about 25 mg of this product, accurately weigh, place it in a 50-ml volumetric flask, add 15 ml of acetonitrile, shake to dissolve, dilute to the scale with water, and shake well; accurately measure 2 ml, place it in a 100-ml volumetric flask, dilute to the scale with the solvent, and shake well. Reference solution: Take about 25 mg of letrozole reference substance, accurately weigh, place it in a 50-ml volumetric flask, add 15 ml of acetonitrile, shake to dissolve, dilute to the scale with water, and shake well; accurately measure 2 ml, place it in a 100-ml volumetric flask, dilute to the scale with the solvent, and shake well. Solvent: Acetonitrile-water (30:70). System suitability solution: Dissolve with acetonitrile and dilute with the solvent to prepare a solution containing about 0.1 mg of letrozole per 1 ml. Chromatographic conditions: Use octadecylsilane chemically bonded silica gel as the filler (Zorbax SB-C18, 4.6 mm×150 mm, 5 μm or a chromatographic column with equivalent efficiency); use water as mobile phase A and acetonitrile as mobile phase B, and perform linear gradient elution according to Table 2; the detection wavelength is 230 nm; the injection volume is 20 μl.

[0024] Table 2 Linear Gradient Elution Parameters System suitability requirements: In the chromatogram of the system suitability solution, the retention time of the letrozole peak is 8 - 10 minutes, and the resolution between the impurity I peak (relative retention time is about 0.67) and the letrozole peak should be not less than 5.0. Assay method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram. Calculate by the external standard method based on the peak area.

[0025] Table 3 Screening of the Ratio of Histidine and Sodium Alginate It can be seen from the data in Table 2 that when the ratio of the stable solubilizer histidine to sodium alginate is in the range of 1:2 - 1:8, through their synergistic effect, the stability of letrozole-cyclodextrin complex under high temperature, high humidity and light conditions is significantly improved.

[0026] Example 1 Letrozole-Cyclodextrin Complex Formula: Preparation method: (1) Dissolve cyclodextrin in water to form a saturated aqueous solution of cyclodextrin.

[0027] (2) Mix sodium alginate and histidine, add 5 ml of water, grind together at 50 °C for 20 min, cool to 25 °C, and add to the saturated aqueous solution of cyclodextrin.

[0028] (3) Dissolve letrozole in 6 ml of ethyl acetate, sonicate to dissolve it, slowly inject it into the solution of step (2) at 70 °C, stir at a constant temperature for 5 h, let it stand at room temperature for 14 h, filter, wash 1 - 3 times, and dry to obtain the product.

[0029] Example 2 Letrozole - Cyclodextrin Complex Formulation: Preparation method: (1) Dissolve cyclodextrin in water to form a saturated aqueous solution of cyclodextrin.

[0030] (2) Mix sodium alginate and histidine, add 3 ml of water, grind them together at 45 °C for 15 min, cool to 25 °C, and add them to the saturated aqueous solution of cyclodextrin.

[0031] (3) Dissolve letrozole in 4 ml of ethyl acetate, sonicate to dissolve it, slowly inject it into the solution of step (2) at 60 °C, stir at a constant temperature for 4 h, let it stand at room temperature for 12 h, filter, wash 1 - 3 times, and dry to obtain the product.

[0032] Example 3 Letrozole - Cyclodextrin Complex Formulation: Preparation method: (1) Dissolve cyclodextrin in water to form a saturated aqueous solution of cyclodextrin.

[0033] (2) Mix sodium alginate and histidine, add 8 ml of water, grind them together at 55 °C for 30 min, cool to 25 °C, and add them to the saturated aqueous solution of cyclodextrin.

[0034] (3) Dissolve letrozole in 10 ml of ethyl acetate, sonicate to dissolve it, slowly inject it into the solution of step (2) at 80 °C, stir at a constant temperature for 6 h, let it stand at room temperature for 18 h, filter, wash 1 - 3 times, and dry to obtain the product.

[0035] Comparative Example 1 Letrozole - Cyclodextrin Complex Formulation: Preparation method: (1) Dissolve cyclodextrin in water to form a saturated aqueous solution of cyclodextrin.

[0036] (2) Add 5 ml of water to sodium alginate, grind it at 50 °C for 20 min, cool to 25 °C, and add it to the saturated aqueous solution of cyclodextrin.

[0037] (3) Dissolve letrozole in 6 ml of ethyl acetate, sonicate to dissolve it, slowly inject it into the solution of step (2) at 70 °C, stir at a constant temperature for 5 h, let stand at room temperature for 14 h, filter, wash 1 - 3 times, and dry to obtain the product.

[0038] Comparative Example 2 Letrozole - Cyclodextrin Complex Formula: Preparation method: (1) Dissolve cyclodextrin in water to form a saturated aqueous solution of cyclodextrin.

[0039] (2) Add 5 ml of water to histidine, grind at 50 °C for 20 min, cool to 25 °C, and add it to the saturated aqueous solution of cyclodextrin.

[0040] (3) Dissolve letrozole in 6 ml of ethyl acetate, sonicate to dissolve it, slowly inject it into the solution of step (2) at 70 °C, stir at a constant temperature for 5 h, let stand at room temperature for 14 h, filter, wash 1 - 3 times, and dry to obtain the product.

[0041] Comparative Example 3 Letrozole - Cyclodextrin Complex Formula: Preparation method: (1) Dissolve cyclodextrin in water to form a saturated aqueous solution of cyclodextrin.

[0042] (2) Dissolve letrozole in 6 ml of ethyl acetate, sonicate to dissolve it, slowly inject it into the saturated aqueous solution of cyclodextrin at 70 °C, stir at a constant temperature for 5 h, let stand at room temperature for 14 h, filter, wash 1 - 3 times, and dry to obtain the product.

[0043] Comparative Example 4 Letrozole - Cyclodextrin Complex Formula: Preparation method: (1) Dissolve cyclodextrin in water to form a saturated aqueous solution of cyclodextrin.

[0044] (2) Mix sodium alginate and L - arginine, add 5 ml of water, co - grind at 50 °C for 20 min, cool to 25 °C, and add it to the saturated aqueous solution of cyclodextrin.

[0045] (3) Dissolve letrozole in 6 ml of ethyl acetate, sonicate to dissolve it, slowly inject it into the solution of step (2) at 70 °C, stir at a constant temperature for 5 h, let stand at room temperature for 14 h, filter, wash 1 - 3 times, and dry to obtain the product.

[0046] Comparative Example 5 Letrozole - Cyclodextrin Complex Formula: Preparation method: (1) Dissolve cyclodextrin in water to form a saturated aqueous solution of cyclodextrin.

[0047] (2) Mix sodium alginate and histidine, and add them to the saturated aqueous solution of cyclodextrin.

[0048] (3) Dissolve letrozole in 6 ml of ethyl acetate, ultrasonically dissolve it, slowly inject it into the solution of step (2) at 70 °C, stir at a constant temperature for 5 h, let it stand at room temperature for 14 h, filter, wash 1 - 3 times, and dry to obtain the product.

[0049] Comparative Example 6 Letrozole - Cyclodextrin Complex Formula: Preparation method: (1) Dissolve cyclodextrin in water to form a saturated aqueous solution of cyclodextrin.

[0050] (2) Mix sodium alginate and histidine, add 5 ml of water, grind them together at 25 °C for 20 min, cool to 25 °C, and add them to the saturated aqueous solution of cyclodextrin.

[0051] (3) Dissolve letrozole in 6 ml of ethyl acetate, ultrasonically dissolve it, slowly inject it into the solution of step (2) at 70 °C, stir at a constant temperature for 5 h, let it stand at room temperature for 14 h, filter, wash 1 - 3 times, and dry to obtain the product.

[0052] Stability and Encapsulation Efficiency of Examples and Comparative Examples Verify the stability and encapsulation efficiency of letrozole - cyclodextrin complexes in Examples 1 - 3 and letrozole - cyclodextrin complexes in Comparative Examples 1 - 6. Test conditions: temperature 40 ± 2 °C, relative humidity 75% ± 5%, illuminance 4500 lx ± 500 lx, sample and detect on the 0th day, 30th day, 90th day, and 180th day.

[0053] Table 4 Stability of Encapsulation Efficiency Figure 1 For the letrozole content curves of letrozole - cyclodextrin complexes in Examples 1 - 3 and letrozole - cyclodextrin complexes in Comparative Examples 1 - 6, combined with the experimental data of the encapsulation efficiency of letrozole - cyclodextrin complexes in Table 4, it shows that the letrozole - cyclodextrin complexes in Examples 1 - 3 of the present invention have higher encapsulation efficiency and stronger stability.

[0054] Example 4 Letrozole Tablets Take the letrozole - cyclodextrin complex in Example 1 (containing 2.5 g of letrozole), add starch, mannitol, microcrystalline cellulose, sucrose, magnesium stearate, and sodium carboxymethyl starch to prepare letrozole tablets (specification 2.5 mg).

[0055] Example 5 Letrozole Tablets The letrozole-cyclodextrin complex (containing 2.5 g of letrozole) prepared in Example 1 was added with starch, dextrin, microcrystalline cellulose, lactose, low-substituted hydroxypropyl methylcellulose, and micropowdered silica gel to prepare letrozole tablets (specification 2.5 mg).

[0056] Comparative Example 7 Letrozole Tablets The letrozole-cyclodextrin complex of Comparative Example 3 (containing 2.5 g of letrozole) was added with starch, mannitol, microcrystalline cellulose, sucrose, magnesium stearate, and sodium carboxymethyl starch to prepare letrozole tablets (specification 2.5 mg).

[0057] Comparative Example 8 Letrozole Tablets The letrozole-cyclodextrin complex of Comparative Example 5 (containing 2.5 g of letrozole) was added with starch, mannitol, microcrystalline cellulose, sucrose, magnesium stearate, and sodium carboxymethyl starch to prepare letrozole tablets (specification 2.5 mg).

[0058] Commercially available letrozole tablets (approval number: National Medicine Standard H19991001) Stability and dissolution verification of Examples 4-5 and Comparative Examples 7-8 Dissolution was determined according to the dissolution and release method (General Chapter 0931, Method 2) in the Chinese Pharmacopoeia. Dissolution conditions: Use 500 ml of 0.1 mol / L hydrochloric acid solution as the dissolution medium, rotate at 75 rpm, and operate according to the method. Samples were collected after 30 minutes. Test solution: Take an appropriate amount of the solution, filter, and collect the filtrate. Reference solution: Accurately weigh an appropriate amount of letrozole reference substance, dissolve it in the dissolution medium, and quantitatively dilute it to a solution containing approximately 5 μg per 1 ml. System suitability solutions, chromatographic conditions, and system suitability requirements are described under Assay. The assay method is described under Assay. Calculate the dissolution rate for each tablet.

[0059] Figure 2 The in vitro dissolution of Examples 4-5, Comparative Examples 7-8, and commercially available letrozole tablets shows that Examples 4-5 of the present invention have high solubility.

[0060] Table 5 Content of Examples 4-5, Comparative Examples 7-8, and Commercially Available Letrozole Tablets Examples 4-5, Comparative Examples 7-8, and commercially available letrozole tablets were placed in commercial packaging at a temperature of 40±2°C, a relative humidity of 75%±5%, and an illumination of 4500lx±500lx. Samples were taken on day 0, day 30, day 90, and day 180 to detect the letrozole content. Table 5 shows the content stability of Examples 4-5, Comparative Examples 7-8, and commercially available letrozole tablets. Under high temperature, high humidity, and light conditions, the letrozole tablets of the present invention can maintain the stability of the active ingredient content.

Claims

1. A letrozole-cyclodextrin complex, characterized in that, The letrozole-cyclodextrin complex consists of 2.5 parts by weight of letrozole, 13-41 parts by weight of cyclodextrin, and 0.5-2.1 parts of histidine and sodium alginate as a stabilizing solubilizer; Its preparation process is to wet grind sodium alginate and histidine at high temperature, react with a saturated aqueous solution of cyclodextrin, and then inject a letrozole solution for inclusion to obtain the letrozole-cyclodextrin complex.

2. The letrozole-cyclodextrin complex according to claim 1, characterized in that, The stabilizing solubilizer is histidine and sodium alginate with a mass ratio of 1:2 to 1:

8.

3. The letrozole-cyclodextrin complex according to claim 1, characterized in that, The stabilizing solubilizer is histidine and sodium alginate with a mass ratio of 1:

5.

4. The letrozole-cyclodextrin complex according to claim 1, characterized in that, The cyclodextrin is selected from at least one of β-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, and sulfobutyl-β-cyclodextrin.

5. The letrozole-cyclodextrin complex according to claim 1, wherein The cyclodextrin is hydroxypropyl-β-cyclodextrin.

6. The letrozole-cyclodextrin complex according to claim 1, wherein The preparation process of the letrozole-cyclodextrin complex is as follows: (1) Dissolve cyclodextrin in water to form a saturated aqueous solution; (2) Add a small amount of water to sodium alginate and histidine and co-grind at 45°C to 55°C for 15-30 min, and then add to the saturated aqueous solution of cyclodextrin after cooling; (3) Dissolve letrozole in an organic solvent, sonicate, and slowly inject it into the solution in step (2) at 60°C to 80°C, stir at a constant temperature for 4-6 h, stand at room temperature for 12-18 h, filter, wash, and dry to obtain the product.

7. The letrozole-cyclodextrin complex according to claim 6, wherein The organic solvent is ethyl acetate.

8. The letrozole-cyclodextrin complex according to claim 6, wherein, In step (2), sodium alginate and histidine are co-ground with a small amount of water at 50°C for 20 min.

9. A letrozole-cyclodextrin complex tablet, characterized in that, The letrozole-cyclodextrin complex tablet is composed of the letrozole-cyclodextrin complex as claimed in claim 1 and pharmaceutically acceptable excipients.

10. The letrozole-cyclodextrin complex tablet according to claim 9, wherein, The pharmaceutically acceptable excipients include fillers, disintegrants, lubricants, flavoring agents, binders, and coating agents.

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