Dexketoprofen trometamol sustained release tablet and preparation method thereof

Abstract

The invention discloses a dexketoprofen trometamol sustained release tablet and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The dexketoprofen trometamol sustained-release tablet is prepared from dexketoprofen trometamol, a sustained-release framework material, a stabilizer, a filler, an adhesive and a lubricant, wherein the sustained-release framework material is selected from a combination of hydroxypropyl methylcellulose, polyethylene glycol 6000, tragacanth and shellac, and the stabilizer is a compound system of glucamine, vitamin E and proline; the composition is prepared by adopting a wet granulation process. The sustained release tablet provided by the invention can present a stable release trend in different pH environments, has no release stagnation or burst release phenomenon, has excellent storage stability, can meet clinical medication requirements, and improves medication compliance and safety of patients.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a dexketoprofen tromethamine sustained-release tablet and its preparation method. Background Technology

[0002] Dextromethorphan tromethamine is a nonsteroidal anti-inflammatory drug (NSAID) that exerts significant anti-inflammatory, analgesic, and antipyretic effects by selectively inhibiting the activity of cyclooxygenase-2 (COX-2). Simultaneously, it has a weaker inhibitory effect on cyclooxygenase-1 (COX-1), which maintains normal gastrointestinal and renal physiological functions. Therefore, compared to traditional non-selective NSAIDs, its incidence of gastrointestinal adverse reactions is significantly reduced by 30%-40%, resulting in higher safety. Clinically, it is mainly used to treat joint pain caused by rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, gouty arthritis, etc., as well as various acute and chronic pains such as dysmenorrhea, toothache, postoperative pain, cancer pain, acute sprains or soft tissue contusions, and systemic pain caused by colds and fever. It can also be used as an adjunct to opioid analgesics for acute moderate to severe postoperative pain in adults who are not suitable for oral administration.

[0003] Currently, the marketed dosage forms of dexketoprofen tromethamine mainly include tablets, capsules, and injections. Tablets and capsules are rapidly absorbed after oral administration; in healthy subjects, peak plasma concentrations are reached within 0.25-0.75 hours after a single dose of 12.5 mg or 25 mg. However, their short half-life (approximately 1.6-1.9 hours) necessitates frequent dosing (usually 3-4 times daily), which not only reduces patient adherence but also causes significant fluctuations in plasma drug concentrations. Peak concentrations may increase the risk of adverse reactions, while trough concentrations may fail to effectively control pain symptoms. While injections have a rapid onset of action, they require administration by qualified medical personnel and are limited to short-term use, making them unsuitable for long-term treatment of chronic pain. Furthermore, they carry risks of adverse reactions such as injection site pain and inflammation.

[0004] To address the aforementioned issues, developing sustained-release formulations has become a crucial direction for improving the dosage form of dextroketoprofen tromethamine. In the prior art, Chinese patent CN106137997A discloses a sustained-release tablet of dextroketoprofen tromethamine, composed of a matrix material, lubricant, glidant, PC-10, and EPO, prepared using a direct compression method. Chinese patent CN108542889A discloses a gastric retention sustained-release tablet of dextroketoprofen tromethamine, composed of dextroketoprofen tromethamine, hydrophilic gelling excipients, microcrystalline cellulose, and magnesium stearate. After oral administration, it is fully absorbed by gastric juice, expands to form a hydrogel, controls the drug release rate and gastric retention effect, achieving a sustained-release effect. However, the following problems exist: (1) The release behavior varies greatly in different pH environments. In particular, the drug release stops in acidic media and is suddenly released after entering neutral or alkaline media; (2) Existing sustained-release formulations have not been specifically designed to address the instability of dexketoprofen tromethamine and lack effective stabilization methods, resulting in a short shelf life of the formulations, which is difficult to meet the needs of large-scale production, long-term storage and long-term clinical use.

[0005] Therefore, developing a stable and reliable dexketoprofen tromethamine sustained-release tablet that can be released smoothly in different pH environments is of great significance for meeting clinical needs and improving patient medication safety and compliance. It is also a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0006] This invention overcomes the technical defects of existing dexketoprofen tromethamine sustained-release formulations, such as the release behavior being greatly affected by pH and insufficient formulation stability. It provides a dexketoprofen tromethamine sustained-release tablet that can release stably in different pH environments and has excellent storage stability, as well as its preparation method, to meet clinical medication needs and improve patient medication compliance and safety.

[0007] To achieve the above-mentioned objectives, the present invention adopts the following technical solution: (I) Formulation of Dexketoprofen Tromethamine Extended-Release Tablets The dextromethorphan tromethamine sustained-release tablets comprise the following components by weight: Active ingredient: 8-15 parts of dextromethorphan tromethamine; sustained-release matrix material: 20-35 parts, selected from at least one of hydroxypropyl methylcellulose, polyethylene glycol 6000, tragacanth gum, and shellac, preferably one of the following two combinations: Combination 1: polyethylene glycol 6000 Combination 1: 10-20 parts, 4-6 parts, shellac 4-6 parts; Combination 2: 10-20 parts, 4-6 parts, shellac 4-9 parts; Stabilizer: 1-3 parts, composed of 0.25-0.5 parts, vitamin E 0.5-1.5 parts, and proline 0.25-1 parts; Filler: 30-50 parts, selected from at least one of lactose, microcrystalline cellulose, and mannitol; Adhesive: 2-5 parts, selected from one of povidone K30 and hydroxypropyl cellulose; Lubricant: 0.3-1.5 parts, selected from at least one of micronized silica gel, talc, and magnesium stearate.

[0008] (II) Preparation method of dexketoprofen tromethamine sustained-release tablets The sustained-release tablets are prepared using a wet granulation process, the specific steps of which are as follows: Raw material pretreatment: Dextromethorphan tromethamine, sustained-release matrix material (except for preheated polyethylene glycol 6000), stabilizer, and filler are pulverized separately using a universal pulverizer, passed through an 80-mesh standard sieve, and placed in a desiccator for later use; magnesium stearate is passed through an 80-mesh sieve separately and sealed for later use; povidone K30 is passed through a 100-mesh sieve for later use; if polyethylene glycol 6000 is selected as a component of the sustained-release matrix material, it needs to be preheated and softened in a 45°C water bath before being mixed with other solid excipients.

[0009] Adhesive preparation: If the adhesive is polyvinyl ketone K30, add anhydrous ethanol to prepare an ethanol solution with a mass concentration of 4-8%, stir at 300 r / min at room temperature until completely dissolved, and let stand for 30 min to remove bubbles; if the adhesive is hydroxypropyl cellulose, prepare a 4-8% aqueous solution, and the preparation conditions are the same as above.

[0010] Dry mixing: Add the pretreated dextromethorphan tromethamine, sustained-release skeleton material, stabilizer, and filler into a wet granulator, set the stirring speed to 150 r / min and the cutter speed to 800 r / min, and dry mix for 12 minutes until the materials are evenly mixed.

[0011] To prepare the soft material: Keep the stirring speed of the wet granulator at 120 r / min and the cutting speed at 600 r / min. Slowly and evenly add the above-mentioned binder solution to the dry-mixed material. Control the adding time to 8-10 min. After the adding is completed, continue to shear and mix for 3 min until the material forms a soft material that can be formed into a ball by hand and dispersed by light pressure.

[0012] Granulation: Transfer the soft material to a gyratory granulator and granulate it using an 18-mesh nylon screen to collect the wet granules.

[0013] Drying: Spread the wet granules evenly on the drying trays of a hot air circulating oven, with a layer thickness of ≤2cm. Set the drying temperature to 48℃ and the air speed to 2m / s. Dry until the moisture content of the granules is 3%-5%. Turn the material over once every 30 minutes during the drying process.

[0014] Granulation: After drying, the granules are cooled to room temperature and transferred to a swing granulator. A 20-mesh nylon sieve is used for granulation to collect dry granules with uniform particle size.

[0015] Total mixing: Put the sized dry particles into a three-dimensional motion mixer, premix at 20 r / min for 3 min, then add the pretreated lubricant and continue mixing for 6 min until the mixture is uniform.

[0016] Tableting: The mixed granules are transferred into a rotary tablet press and compressed into tablets according to the prescription tablet weight settings. This yields dexketoprofen tromethamine sustained-release tablets.

[0017] Compared with the prior art, the present invention has the following beneficial effects: (1) Stable release behavior: The present invention uses a combination of sustained-release matrix materials in a specific ratio (polyethylene glycol 6000 / hydroxypropyl methylcellulose, tragacanth gum and shellac synergistic effect) to enable the formulation to show a gradually increasing and stable release trend in four different pH environments: pH1.2 (acidic), pH4.5 (weakly acidic), pH6.8 (neutral), and pH7.4 (weakly alkaline), without release stagnation or sudden release. The cumulative dissolution rate reaches about 90% in 24 hours, which is adapted to the pH difference of the human gastrointestinal tract and ensures stable clinical efficacy.

[0018] (2) Excellent storage stability: The present invention uses a composite stabilizer system of meglumine, vitamin E and proline to specifically solve the instability problem of dexketoprofen tromethamine. After being placed for 6 months under accelerated test conditions of 40℃±2℃ and relative humidity of 75%±5%, the drug content is still maintained above 98.5%, which meets the needs of large-scale production, long-term storage and long-term clinical use. Attached Figure Description

[0019] Figure 1 Example 1: Cumulative dissolution of dexketoprofen tromethamine sustained-release tablets at different pH values.

[0020] Figure 2 Example 3: Cumulative dissolution of dexketoprofen tromethamine sustained-release tablets at different pH values.

[0021] Figure 3 Accelerated test to change the content of dextromethorphan and tromethorphan. Detailed Implementation

[0022] To make the objectives and technical solutions of this invention clearer, the following embodiments are provided for further explanation. However, the scope of protection of this invention is not limited to these embodiments; the embodiments are merely for illustrative purposes. Those skilled in the art should understand that any changes or equivalent substitutions that do not depart from the concept of this invention are included within the scope of protection of this invention.

[0023] Preparation process of dextromethorphan tromethamine sustained-release tablets 1. Pretreatment of raw and auxiliary materials The main and auxiliary materials, including dextromethorphan tromethamine, hydroxypropyl methylcellulose, tragacanth gum, shellac, meglumine, vitamin E, proline, microcrystalline cellulose, and lactose, were pulverized separately using a universal pulverizer, passed through an 80-mesh standard sieve, and the sieve-underfill material was collected and placed in a desiccator for later use. Magnesium stearate was passed through an 80-mesh sieve separately and sealed for later use. Povidone K30 was passed through a 100-mesh sieve for later use.

[0024] 2. Adhesive preparation Take the prescribed amount of povidone K30, add anhydrous ethanol to the povidone K30 mass concentration to 4-8%, place on a magnetic stirrer, stir at 300 r / min at room temperature until the povidone K30 is completely dissolved, let stand for 30 min to remove bubbles, and set aside.

[0025] 3. Dry Mixing The pretreated dextromethorphan tromethamine, sustained-release skeleton material, stabilizer, and filler were put into a wet granulation machine. The stirring speed was set to 150 r / min and the cutter speed to 800 r / min. The mixture was dry-mixed for 12 minutes until the materials were evenly mixed.

[0026] 4. Making soft materials Keep the stirring speed of the wet granulator at 120 r / min and the cutting speed at 600 r / min. Slowly and evenly add 4-8% povidone K30 ethanol binder solution to the dry-mixed material. Control the adding time to 8-10 min. After the addition is completed, continue shearing and mixing for 3 min until the material forms a soft material that can be formed into a ball by hand and dispersed by light pressure.

[0027] 5. Granulation The prepared soft material is quickly transferred to a gyratory granulator, granulated using an 18-mesh nylon screen, and the wet granules are collected.

[0028] 6. Drying Spread the wet granules evenly on the drying trays of the hot air circulating oven, with a layer thickness of ≤2cm. Set the drying temperature to 48℃ and the air speed to 2m / s. Dry until the moisture content of the granules is 3%-5%. Turn the material over every 30 minutes during the drying process to ensure uniform drying.

[0029] 7. Whole grains After drying, the granules are cooled to room temperature and transferred to a gyratory granulator. A 20-mesh nylon sieve is used to granulate the granules, removing coarse particles and fine powder, and collecting dry granules with uniform particle size for later use.

[0030] 8. Total Mixture The granulated dry particles were put into a three-dimensional motion mixer. The mixing speed was set to 20 r / min. After premixing for 3 min, the pretreated magnesium stearate was added and the mixture was continued for 6 min until the lubricant and dry particles were evenly mixed.

[0031] 9. Tableting The mixed granules are transferred into a rotary tablet press, and the tableting parameters are set according to the prescription tablet weight to compress them into tablets, thus obtaining dexketoprofen tromethamine sustained-release tablets.

[0032] Remark: If the slow-release skeleton material combination one (15 parts polyethylene glycol 6000 + 5 parts tragacanth gum + 7 parts shellac) is selected, the polyethylene glycol 6000 needs to be preheated and softened in a 45°C water bath before being mixed with other solid excipients, while the other process parameters remain unchanged. The lubricant can be replaced with micronized silica gel, talc, or a combination thereof as needed, and the addition method is the same as that of magnesium stearate, which is to be added at the end of the total mixture. If hydroxypropyl cellulose is selected as the binder, it can be prepared into a 4-8% aqueous solution, and the drip rate and mixing time remain unchanged when preparing the soft material.

[0033] Example 1: Dexketoprofen and tromethamine sustained-release tablets formulation Example 2: Dexketoprofen and tromethamine sustained-release tablets formulation Example 3: Dexketoprofen and tromethamine sustained-release tablet formulation Comparative Example 1: Dexketoprofen and tromethamine sustained-release tablets formulation Comparative Example 2: Dexketoprofen and tromethamine sustained-release tablets formulation Comparative Example 3: Dexketoprofen and tromethamine sustained-release tablets formulation Comparative Example 4: Dexketoprofen and tromethamine sustained-release tablets formulation Comparative Example 5: Dexketoprofen and tromethamine sustained-release tablets formulation Comparative Example 6: Dexketoprofen and tromethamine sustained-release tablets formulation Comparative Example 7: Dexketoprofen and tromethamine sustained-release tablets formulation Comparative Example 8: Dexketoprofen and tromethamine sustained-release tablets prescription Comparative Example 9: Dexketoprofen and tromethamine sustained-release tablets prescription Sustained-release effect experiment Dissolution medium: pH 1.2 hydrochloric acid solution: Take 3.6 ml of hydrochloric acid, dilute with water to 1000 ml, shake well, and calibrate the pH meter.

[0034] pH 4.5 Acetic Acid-Sodium Acetate Buffer: Take 18g of sodium acetate, dissolve it in water and dilute it to 1000ml, add glacial acetic acid to adjust the pH to 4.5, and shake well.

[0035] pH 6.8 phosphate buffer: Take 6.8g of potassium dihydrogen phosphate, dissolve and dilute with water to 1000ml, add sodium hydroxide solution to adjust the pH to 6.8, and shake well.

[0036] pH 7.4 phosphate buffer: Dissolve 1.36g of potassium dihydrogen phosphate in water and dilute to 1000ml. Adjust the pH to 7.4 with sodium hydroxide solution and shake well.

[0037] Media pretreatment: Take 900 ml of each of the above 4 dissolution media and add them to 4 dissolution cups respectively. Degas the media (ultrasonic degassing for 15 min or boiling degassing for 5 min followed by cooling). Adjust the water temperature of the dissolution apparatus to 37℃±0.5℃.

[0038] Sample placement: Take 6 tablets of each batch of samples and put them into dissolution cups of 4 different pH media. Use the paddle method with a rotation speed of 50 r / min and start timing.

[0039] Sampling time points: 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 24h.

[0040] Sampling method: Accurately aspirate 10 ml of the dissolution solution at each time point, and simultaneously add an equal volume of dissolution medium at the same temperature and pH (to keep the volume constant).

[0041] Sample preparation: The extracted leaching solution was filtered through a 0.45 μm filter membrane. 5 ml of the filtrate was taken and diluted with methanol to 10 ml (adjust the dilution factor according to the concentration). The solution was shaken well and used as the test solution. At the same time, a blank leaching medium control solution was prepared.

[0042] HPLC determination: The peak areas of the test solution and blank control solution were determined under the above chromatographic conditions, and the drug concentration in the dissolution solution was calculated by substituting the peak areas into the regression equation, and then the cumulative dissolution rate was calculated.

[0043] Table 1. Cumulative dissolution at different pH values Table 1 shows that the dexketoprofen tromethamine sustained-release tablets of Examples 1-3 exhibited a steady, gradually increasing cumulative dissolution rate in four different pH dissolution media: pH 1.2 (acidic), pH 4.5 (weakly acidic), pH 6.8 (neutral), and pH 7.4 (weakly alkaline), with no release stagnation or sudden burst release. The dissolution rate differences at the same time point were small in each medium, and the cumulative dissolution rate reached approximately 90% after 24 hours, meeting the dissolution requirements for sustained-release formulations. This indicates that the formulation can stably release the drug in different pH environments of the gastrointestinal tract, adapting to the pH differences in the human gastrointestinal tract. Comparative Examples 1, 2, and 3 showed significantly lower cumulative dissolution rates in the early stages (0.5h, 1h, 2h) in acidic media (pH 1.2, pH 4.5), exhibiting a "release stagnation" characteristic in acidic environments. However, in neutral / alkaline media (pH 6.8, pH 7.4), the dissolution rate increased rapidly in the later stages, exhibiting a "burst release" phenomenon with large fluctuations in release behavior. This demonstrates that the synergistic effect of sustained-release materials can improve drug release in acidic environments and prevent the release behavior from being excessively affected by pH, which is the core of achieving stable release of formulations across pH levels.

[0044] Accelerated testing to verify stability The accelerated test was designed according to the requirements of "Accelerated Test" in General Chapter 9001 (Guiding Principles for Stability Testing of Drug Preparations) of Part IV of the 2020 edition of the Chinese Pharmacopoeia. The accelerated test conditions were 40℃±2℃, relative humidity (RH) 75%±5%, and the samples were placed for 6 months. Samples were taken for testing at 0 months, 1 month, 2 months, 3 months and 6 months.

[0045] Table 2. Accelerated Test Results of Dexketoprofen and Tromethamine Content Table 2 shows that after 6 months of accelerated storage at 40℃±2℃ and 75%±5% relative humidity, the sustained-release tablets of Examples 1-3 still maintained a dexketoprofen tromethamine content of over 98.5%, indicating that the formulations exhibited good stability under accelerated storage conditions and could meet the needs of large-scale production, long-term storage, and long-term clinical use. The formulations of Comparative Examples 4-9 showed a significant decrease in content during the accelerated test: after 6 months, the content was only 88.7%-92.1%. This indicates that the combination of meglumine, vitamin E, and proline in the original formulation can specifically address the instability of dexketoprofen tromethamine and synergistically improve the storage stability of the formulation.

Claims

1. A dextrokeprofen tromethamine sustained-release tablet, characterized in that, The dextromethorphan tromethorphan sustained-release tablets are calculated in the following parts by weight: 8-15 parts dextromethorphan tromethorphan, 20-35 parts sustained-release matrix material, 1-3 parts stabilizer, 30-50 parts filler, 2-5 parts binder, and 0.3-1.5 parts lubricant.

2. The dextrokeprofen tromethamine sustained-release tablets according to claim 1, characterized in that, The filler is at least one of lactose, microcrystalline cellulose, and mannitol.

3. The dexketoprofen tromethamine sustained-release tablets according to claim 1, characterized in that, The adhesive is one of polyvinylpyrrolidone K30 and hydroxypropyl cellulose.

4. The dextrokeprofen tromethamine sustained-release tablets according to claim 1, characterized in that, The lubricant is at least one of micronized silica gel, talc, and magnesium stearate.

5. The dextrokeprofen tromethamine sustained-release tablet according to claim 1, characterized in that, The sustained-release matrix material is at least one of hydroxypropyl methylcellulose, polyethylene glycol 6000, tragacanth gum, and shellac.

6. The dexketoprofen tromethamine sustained-release tablet according to claim 1, characterized in that, The stabilizers are meglumine, vitamin E, and proline.

7. The dextrokeprofen tromethamine sustained-release tablet according to claim 6, characterized in that, The stabilizer is 0.25-0.5 parts of meglumine, 0.5-1.5 parts of vitamin E, and 0.25-1 parts of proline.

8. The dextrokeprofen tromethamine sustained-release tablet according to claim 1, characterized in that, The sustained-release matrix material is: Combination 1: Polyethylene glycol 6000, tragacanth gum, shellac; Combination 2: Hydroxypropyl methylcellulose, tragacanth gum, shellac.

9. The dextrokeprofen tromethamine sustained-release tablet according to claim 8, characterized in that, The sustained-release matrix material is: Combination 1: 10-20 parts polyethylene glycol 6000, 4-6 parts tragacanth gum, 6-9 parts shellac; Combination 2: 10-20 parts hydroxypropyl methylcellulose, 4-6 parts tragacanth gum, and 6-9 parts shellac.

10. The dextrokeprofen tromethamine sustained-release tablet according to claim 1, characterized in that, The preparation method of the dextromethorphan tromethamine sustained-release tablets is wet granulation.

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