Quick-acting heart-saving freeze-dried orally disintegrating tablet and preparation method thereof

Abstract

The invention discloses a quick-acting heart-saving freeze-dried orally disintegrating tablet and a preparation method thereof, and relates to the technical field of medicines, the quick-acting heart-saving freeze-dried orally disintegrating tablet is prepared from the following materials through freeze drying: a ligusticum wallichii extract, a borneol clathrate compound, a freeze-dried proppant, and an optional sweetening agent and / or thickening agent, the borneol clathrate compound is a clathrate compound prepared from cyclodextrin or a derivative thereof through a clathration technology. According to the freeze-dried orally disintegrating tablet and the preparation method thereof, the inclusion compound of the borneol and the cyclodextrin derivative is prepared firstly, then the inclusion compound and other raw and auxiliary materials are prepared into the freeze-dried orally disintegrating tablet according to a specific process, the stability of the borneol content in a final product can be effectively guaranteed, and cyclodextrin or the cyclodextrin derivative is selected from at least one of beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin and sulfobutyl-beta-cyclodextrin. Meanwhile, the absolute ethyl alcohol for dissolving the borneol is removed during preparation of the inclusion compound, a special freeze dryer is not needed, the safety problem of equipment operation is avoided, and the production cost is reduced.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a fast-acting lyophilized orally disintegrating tablet for resuscitation and its preparation method. Background Technology

[0002] Angina pectoris is a clinical syndrome characterized by paroxysmal chest pain or discomfort, caused by insufficient blood supply to the coronary arteries and acute, temporary ischemia and hypoxia of the myocardium. Fast-acting cardiac remedies can dilate the coronary arteries, increase coronary blood flow, and improve myocardial blood supply, thereby relieving angina symptoms. Their main components are Ligusticum chuanxiong and borneol. Ligusticum chuanxiong contains tetramethylpyrazine, an alkaloid that dilates blood vessels, increasing blood supply to the heart. Simultaneously, tetramethylpyrazine has antiplatelet aggregation effects, reducing thrombus formation and lowering the risk of serious complications such as myocardial infarction in patients with coronary heart disease. Ligusticum chuanxiong can also improve microcirculation, increasing the number of open myocardial capillaries, allowing myocardial cells to receive better blood and oxygen supply. Borneol's main components are dextrorotatory borneol, which is volatile and can be absorbed by the body through the respiratory tract. Its volatile components can stimulate nerve endings, producing a certain analgesic effect. At the same time, borneol can also improve local blood circulation and assist other ingredients in promoting blood circulation and removing blood stasis.

[0003] Currently, the main dosage form of fast-acting cardiac medications on the market is drop pills, which have the following shortcomings: 1) Short shelf life. The borneol in these pills is extracted from the resin and volatile oil of the Dipterocarpus santalinus plant (family Dipterocarpaceae), and is volatile. It easily decomposes upon contact with air, or under conditions such as high temperature or light, significantly reducing its efficacy. Generally, fast-acting cardiac pills have a shelf life of 36 months when sealed, but after opening, the shelf life is usually only 3 months; 2) Inconvenient to take and use. Each drop pill is only 2.5mm in diameter, requiring 10-15 pills to be taken in an emergency, and placed under the patient's tongue. In an emergency, counting these tiny pills one by one is very inconvenient; moreover, according to statistics, about 30% of angina patients clench their teeth during an attack, making it impossible to place the drop pills under their tongue; 3) Slow dissolution. The drop pills take about 2 minutes to completely dissolve under the tongue. For emergency medications, rapid dissolution, rapid absorption, and onset of action are paramount. Summary of the Invention

[0004] The purpose of this invention is to propose a fast-acting, lyophilized, orally disintegrating tablet formulation for cardiac relief, which overcomes the following shortcomings: 1) This formulation uses a double-aluminum sealed packaging material with excellent oxygen and moisture barrier properties. Each tablet is individually packaged; opening one tablet does not affect the expiration date as the remaining tablets remain completely sealed. 2) It is convenient to take, requiring no water and dissolves instantly in the mouth. The tablets are approximately 15mm in diameter and 4mm thick, easily removed after tearing off the cap. Each tablet contains the same amount of active ingredient as 5 pills. In emergency situations, 2-3 tablets are sufficient, making it very convenient. Even when the patient's jaw is clenched, it dissolves quickly in the mouth and is rapidly absorbed by the oral mucosa for immediate effect. 3) This tablet dissolves completely under the tongue within 3-8 seconds, fully releasing the active ingredient for rapid absorption by the sublingual mucosa.

[0005] To achieve the above objectives, the present invention provides the following technical solution: a fast-acting lyophilized orally disintegrating tablet and its preparation method, comprising the following materials freeze-dried: Ligusticum chuanxiong extract, borneol inclusion complex, freeze-drying support agent, and optional sweetener and / or thickener.

[0006] Preferably, the borneol inclusion complex is an inclusion complex prepared by inclusion technology from cyclodextrin or its derivatives.

[0007] Preferably, the cyclodextrin or its derivative is selected from at least one of β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and sulfobutyl-β-cyclodextrin.

[0008] Preferably, the freeze-drying support agent includes gelatin and pullulan.

[0009] Preferably, the sweetener is D-mannitol and the thickener is xanthan gum.

[0010] Preferably, by weight, the material comprises: 9.6-16.0 parts of Ligusticum chuanxiong extract, 49.0-84.0 parts of borneol inclusion complex, 7.0-8.0 parts of gelatin, 12.0-15.0 parts of pullulan, 0.2-0.4 parts of xanthan gum, and 12.0-15.0 parts of D-mannitol.

[0011] Preferably, a method for preparing a fast-acting, lyophilized, orally disintegrating tablet includes the following steps: S1. Preparation of borneol inclusion complex: Dissolve borneol in an organic solvent to obtain a borneol solution; Cyclodextrin or its derivatives are dissolved in water to obtain a cyclodextrin solution; Under stirring conditions, the borneol solution was added to the cyclodextrin solution to carry out an inclusion reaction, followed by drying to obtain the borneol inclusion complex; S2. Preparation of suspension: The borneol inclusion complex, chuanxiong extract, freeze-dried support agent, and optional sweetener and / or thickener are dispersed in water and mixed evenly to obtain a suspension; S3. Filling and freeze-drying: The suspension is filled into the bubble holes of the blister pack, and then quick-frozen and freeze-dried to obtain freeze-dried tablet cores; S4. Packaging: Seal the blister pack containing the freeze-dried tablet core with aluminum foil to obtain individually packaged fast-acting lyophilized orthotic tablets.

[0012] Preferably, in step S1, the mass ratio of borneol to cyclodextrin or its derivative is 1:1 to 1:4, and the organic solvent is anhydrous ethanol; the drying is vacuum drying under reduced pressure; in step S2, the uniform mixing includes stirring for 20-40 minutes at a speed of 500-1000 rpm, and the temperature of the liquid is controlled at 20-26°C; in step S3, the quick-freezing is pre-freezing in a liquid nitrogen environment at -80°C to -100°C for 5-15 minutes; the freeze-drying process curve includes: maintaining at -35°C to -30°C for 150-200 minutes; maintaining at -30°C to -25°C for 150-200 minutes; maintaining at -25°C to -20°C for 150-200 minutes; maintaining at -20°C to -5°C for 100-150 minutes; and maintaining at -5°C to 25°C for 50-70 minutes.

[0013] The technical effects and advantages of this invention are as follows: This invention employs a method of first preparing an inclusion complex of borneol and a cyclodextrin derivative, and then using it along with other raw materials and excipients to prepare freeze-dried ortholytic tablets according to a specific process. This effectively ensures the stability of the borneol content in the final product. Simultaneously, the anhydrous ethanol used to dissolve the borneol is removed during the preparation of the inclusion complex, eliminating the need for a special freeze dryer, avoiding equipment safety issues, and reducing production costs. Detailed Implementation

[0014] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0015] This invention provides a fast-acting, lyophilized, orally disintegrating tablet for cardiac relief and its preparation method: Example

[0016]

[0017] Preparation process: 1.1 Grind borneol into a fine powder, accurately weigh the borneol, and dissolve it in anhydrous ethanol; 1.2 Accurately weigh β-cyclodextrin, add purified water, and dissolve the β-cyclodextrin solution in an 80℃ water bath; 1.3 At 40℃, add borneol-anhydrous ethanol solution dropwise while stirring; stop stirring after the addition is complete. 1.4 Place 1.3 in the refrigerator and let it stand for 12-24 hours; 1.5 Place 1.4 into a vacuum drying oven and dry it to obtain a white, loose, powdery inclusion complex. Example

[0018]

[0019] The preparation process is the same as in Example 1. Example

[0020]

[0021] Preparation process: 1.1 Grind borneol into a fine powder, accurately weigh the borneol, and dissolve it in anhydrous ethanol; 1.2 Accurately weigh hydroxypropyl β-cyclodextrin, add purified water, and dissolve by magnetic stirring; 1.3 Add borneol-anhydrous ethanol solution dropwise while stirring; stop stirring after the addition is complete; 1.4 The borneol hydroxypropyl-β-cyclodextrin solution was dried in a vacuum drying oven to obtain a white, loose, powdery inclusion complex. Example

[0022]

[0023] The preparation process is the same as in Example 3.

[0024] Testing was conducted according to the General Rules for Gas Chromatography (General Rule 0521) of the 2020 edition of the Pharmacopoeia. Borneol content = (borneol content / 0.96) * 100%; Borneol inclusion rate % = (bornol content * inclusion mass / borneol addition amount) * 100%.

[0025] Experimental results Serial Number Example 1 Example 2 Example 3 Example 4 Borneol inclusion rate % 42 50 41 48 Borneol content % 28.1 10.55 27.63 10.17 Screening of Formula Ratios for Fast-Acting Cardiotonic Freeze-Dried Orally Disintegrating Tablets Example

[0026]

[0027] The above formula makes 1000 tablets.

[0028] Sources of raw materials and auxiliary materials: Material Name factory Remark Ligusticum chuanxiong extract Anguo City Ronghua Herbal Medicine Co., Ltd. Ligusticum chuanxiong extract was prepared by procuring raw medicinal materials, extracting and concentrating the extract, and determining the ferulic acid content to be 0.5% according to the high performance liquid chromatography method (General Rule 0512) of the 2020 edition of the Chinese Pharmacopoeia. Borneol Hunan Songyuan Biotechnology Co., Ltd. Borneol content 96% gelatin Rousselot (Da'an) Gelatin Co., Ltd. / pullulan Shandong Kangnaxin Biotechnology Co., Ltd. / Xanthan Gum Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd. / D-Mannitol Shandong Tianli Pharmaceutical Co., Ltd. / β-Cyclodextrin Anhui Shanhe Pharmaceutical Excipients Co., Ltd. / Hydroxypropyl-β-cyclodextrin Shandong Binzhou Zhiyuan Biotechnology Co., Ltd. / Preparation process: Step 1: Measure an appropriate amount of purified water into a beaker and heat it in a water bath at 50°C. Weigh the prescribed amount of pullulan and gelatin into a beaker and stir with a glass rod in the water bath until completely dissolved. Step 2: Weigh the prescribed amount of other materials and mix them with the materials from Step 1. Subtract the amount of borneol inclusion complex and add purified water to make up to the final volume. Step 3: Emulsification: Add the liquid from Step 2 into the emulsifier at 10,000 rpm and emulsify for 5 minutes. Then add the borneol inclusion complex powder and stir at 500 rpm for 30 minutes. During the entire emulsification process, control the temperature of the liquid at 20-26℃. Step 4: Filling: Dispense the prepared liquid solution at 0.5ml / piece into the pores of the aluminum-plastic blister pack; Step 5: Quick-freezing: Place the blister packs after filling with liquid material into a liquid nitrogen tunnel at -80 to -100°C for pre-freezing for 10 minutes; Step Six: Freeze-drying: Transfer the pre-frozen blister packs onto the freeze dryer trays and run the following freeze-drying curve: Temperature (°C) time min -35℃~--30℃ 180 -30℃~-25℃ 180 -25℃~-20℃ 180 -20℃~-5℃ 120 -5℃~25℃ 60 Step 7: Sealing: After the freeze-drying curve is completed, remove the blister pack from the freeze dryer, and seal and package it on the sealing machine. Example

[0029] Prescription composition:

[0030] Make 1000 pieces.

[0031] Preparation process: Same as in Example 1. Example

[0032] Prescription composition:

[0033] Make 1000 pieces.

[0034] Preparation process: Same as in Example 1. Example

[0035] Prescription composition:

[0036] Make 1000 pieces.

[0037] Preparation process: Same as in Example 1.

[0038] Comparative Example 1 Prescription composition:

[0039] Make 1000 pieces.

[0040] Comparative Example 2 Prescription composition:

[0041] Make 1000 pieces.

[0042] Preparation process: Same as in Example 1.

[0043] Comparative Example 3 Prescription composition:

[0044] Make 1000 pieces.

[0045] Comparative Example 4 Prescription composition:

[0046] Make 1000 pieces.

[0047] Preparation process: Same as in Example 1.

[0048] Comparative Example 5 Prescription composition: Same as in Example 1.

[0049] Preparation process: basically the same as in Example 1, the difference being the freeze-drying curve; run the following freeze-drying curve: Temperature (°C) time min -35℃~--30℃ 120 -30℃~-25℃ 120 -25℃~-20℃ 120 -20℃~-5℃ 90 -5℃~25℃ 60 Experiments and Results 1. Experiment on the formation of fast-acting lyophilized orally disintegrating tablets.

[0050] 1.1 Experimental Objective: To observe the effect of different proportions of borneol inclusion complex on the formability of lyophilized flash-release tablets; 1.2 Experimental Methods: After the samples were removed from the chamber, they were visually inspected for cracking, sticking to the bottom, or collapse. Samples that passed the appearance test were placed in a stability test chamber (temperature 40℃±2℃, humidity 75%±5%) for 3 and 6 months. Afterward, they were removed and visually inspected for cracking, sticking to the bottom, or collapse.

[0051] 1.3 Experimental Results: 1.3.1 Observation results after unpacking: sample Is it cracked? Does it stick to the bottom? Whether it has collapsed Example 1 no no no Example 2 no no no Example 3 no no no Example 4 no no no Comparative Example 1 no no no Comparative Example 2 no yes no Comparative Example 3 no no no Comparative Example 4 no yes no Comparative Example 5 no no yes 1.3.23-month observation results: sample Is it cracked? Does it stick to the bottom? Whether it has collapsed Example 1 no no no Example 2 no no no Example 3 no no no Example 4 no no no Comparative Example 1 no no no Comparative Example 3 no no no 1.3. Observation results at 36 months: sample Is it cracked? Does it stick to the bottom? Whether it has collapsed Example 1 no no no Example 2 no no no Example 3 no no no Example 4 no no no Comparative Example 1 no no no Comparative Example 3 no no no 2. Determination of disintegration time of lyophilized orally disintegrating tablets for quick-acting cardiac relief.

[0052] 2.1 Experimental objective: Determination of disintegration time of lyophilized flash-release tablets for rapid-acting cardiac remedies.

[0053] 2.2 Experimental method: The disintegration basket was fixed on the support and immersed in a 1000ml cup containing about 900g of water at a temperature of 37±1℃. The bottom of the basket was 15±1mm below the water surface. One sample with acceptable appearance was placed in the disintegration basket, and the time it took for the sample to completely disintegrate and pass through a 710μm sieve was recorded.

[0054] 2.3 Experimental Results: sample Disintegration timeout (s) Example 1 3 Example 2 8 Example 3 3 Example 4 8 Comparative Example 1 20 Comparative Example 3 19 3. Stability test of rapid-acting lyophilized orally disintegrating tablets.

[0055] 3.1 The samples of the fast-acting cardiolytic tablets prepared in Examples 1, 2, 3 and 4 were placed in a stability test chamber at a temperature of 30℃±2℃ and a humidity of 65%±5% for 12 months.

[0056] 3.2 The changes in borneol content were determined according to the General Rules for Gas Chromatography (General Rule 0521) of the 2020 edition of the Chinese Pharmacopoeia.

[0057] 3.3 The changes in ferulic acid content in lyophilized orally disintegrating tablets were determined according to the high performance liquid chromatography method (General Rule 0512) of the 2020 edition of the Pharmacopoeia; Borneol / ferulic acid content calculation: Content % = (Actual detected content / Theoretical addition amount) * 100% Calculation of relative content of borneol / ferulic acid: Relative content % = (content in 3, 6, 9, 12 months / content in 0 months) * 100% 3.40-month content test results sample Time / Month 0 Example 1 Borneol content % 99.9 Ferulic acid content % 99.8 Example 2 Borneol content % 99.9 Ferulic acid content % 99.9 Example 3 Borneol content % 99.8 Ferulic acid content % 99.9 Example 4 Borneol content % 99.9 Ferulic acid content % 99.9 Content test results at 3, 6, 9, and 12 months: sample Time / Month 3 6 9 12 Example 1 relative content of borneol (%) 99.8 99.7 99.6 99.5 relative content of ferulic acid (%) 99.8 99.8 99.7 99.6 Example 2 relative content of borneol (%) 99.7 99.8 99.7 99.5 relative content of ferulic acid (%) 99.8 99.7 99.6 99.7 Example 3 relative content of borneol (%) 99.8 99.7 99.6 99.6 relative content of ferulic acid (%) 99.9 99.8 99.7 99.7 Example 4 relative content of borneol (%) 99.8 99.8 99.5 99.5 relative content of ferulic acid (%) 99.9 99.8 99.6 99.6 4. Conclusion: 4.1 The lyophilized orally disintegrating tablets prepared with an inclusion complex of borneol and cyclodextrin derivative at a mass ratio of 1:1 disintegrated faster. Although the inclusion complex at a mass ratio of 1:4 had a higher borneol inclusion rate, the borneol content decreased, requiring a larger mass of inclusion complex to be added. This increased the solid content in the lyophilized orally disintegrating tablet solution and slowed down disintegration.

[0058] 4.2 A two-step method was used to prepare lyophilized orally disintegrating tablets of a traditional Chinese medicine compound for rapid cardiac relief. After stability testing, the contents of borneol and ferulic acid in the sample were stable, which solved the problem of unstable borneol content.

[0059] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A fast-acting, lyophilized, orally disintegrating tablet for cardiac relief, characterized in that... It is composed of the following materials by freeze-drying: Ligusticum chuanxiong extract, borneol inclusion complex, freeze-dried support agent, and optional sweetener and / or thickener.

2. The rapid-acting, lyophilized, orthotically disintegrating tablet according to claim 1, characterized in that, The borneol inclusion complex is an inclusion complex prepared by inclusion technology from cyclodextrin or its derivatives.

3. The rapid-acting, lyophilized, orthotically disintegrating tablet according to claim 2, characterized in that, The cyclodextrin or its derivatives are selected from at least one of β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and sulfobutyl-β-cyclodextrin.

4. The rapid-acting, lyophilized, orthotically disintegrating tablet according to claim 1, characterized in that, The freeze-dried support agent includes gelatin and pullulan.

5. The rapid-acting, lyophilized, orally disintegrating tablet for cardiac relief according to claim 1, characterized in that, The sweetener is D-mannitol, and the thickener is xanthan gum.

6. The rapid-acting, lyophilized, orally disintegrating tablet for cardiac relief according to any one of claims 1-5, characterized in that, By weight, the material comprises: 9.6-16.0 parts of Ligusticum chuanxiong extract, 49.0-84.0 parts of borneol inclusion complex, 7.0-8.0 parts of gelatin, 12.0-15.0 parts of pullulan, 0.2-0.4 parts of xanthan gum, and 12.0-15.0 parts of D-mannitol.

7. The method for preparing a fast-acting, lyophilized, orally disintegrating tablet according to any one of claims 1-6, characterized in that, Includes the following steps: S1. Preparation of borneol inclusion complex: Dissolve borneol in an organic solvent to obtain a borneol solution; Cyclodextrin or its derivatives are dissolved in water to obtain a cyclodextrin solution; Under stirring conditions, the borneol solution was added to the cyclodextrin solution to carry out an inclusion reaction, followed by drying to obtain the borneol inclusion complex; S2. Preparation of suspension: The borneol inclusion complex, chuanxiong extract, freeze-dried support agent, and optional sweetener and / or thickener are dispersed in water and mixed evenly to obtain a suspension; S3. Filling and freeze-drying: The suspension is filled into the bubble holes of the blister pack, and then quick-frozen and freeze-dried to obtain freeze-dried tablet cores; S4. Packaging: Seal the blister pack containing the freeze-dried tablet core with aluminum foil to obtain individually packaged fast-acting lyophilized orthotic tablets.

8. The method for preparing a fast-acting, lyophilized, orally disintegrating tablet according to claim 7, characterized in that, In step S1, the mass ratio of borneol to cyclodextrin or its derivative is 1:1 to 1:4, and the organic solvent is anhydrous ethanol; the drying is vacuum drying under reduced pressure.

9. The method for preparing a fast-acting, lyophilized, orally disintegrating tablet according to claim 7, characterized in that, In step S2, the mixing process includes stirring for 20-40 minutes at a speed of 500-1000 rpm, and controlling the temperature of the liquid at 20-26℃.

10. The method for preparing a fast-acting, lyophilized, orally disintegrating tablet according to claim 7, characterized in that, In step S3, the quick-freezing is pre-freezing in a liquid nitrogen environment at -80℃ to -100℃ for 5-15 minutes; the freeze-drying process curve includes: maintaining at -35℃ to -30℃ for 150-200 minutes; maintaining at -30℃ to -25℃ for 150-200 minutes; maintaining at -25℃ to -20℃ for 150-200 minutes; maintaining at -20℃ to -5℃ for 100-150 minutes; and maintaining at -5℃ to 25℃ for 50-70 minutes.

Images