Meclofenoxate hydrochloride capsule and preparation method thereof

Abstract

The invention discloses a pharmaceutical composition containing meclofenoxate hydrochloride, which is characterized by comprising meclofenoxate hydrochloride, a filling agent, a flow aid, a lubricant, a stabilizer and an antioxidant, the mass ratio of meclofenoxate hydrochloride to the stabilizer to the antioxidant is 1: (0.005-0.015): (0.001-0.005), the mass ratio of meclofenoxate hydrochloride to the filling agent to the flow aid is 1: (0.3-0.7): (0.1-0.5), and the lubricant is a lubricant. The stabilizer is benzoic acid. Benzoic acid is selected as a stabilizing agent, and the hygroscopicity is obviously lower than that of citric acid, in RHlt; and when the content is 80%, moisture is not absorbed basically, so that the meclofenoxate hydrochloride is effectively prevented from being hydrolyzed due to moisture absorption.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, specifically to a meclofenoxate hydrochloride capsule and its preparation method, which solves the problems of the raw materials of meclofenoxate hydrochloride capsules being prone to moisture absorption and hydrolysis and chemical instability during storage. Background Technology

[0002] Meclofenoxate hydrochloride (also known as chlorphenoxate acetate) is a central nervous system stimulant and brain metabolism improver. Its chemical name is dimethylaminoethyl ethyl p-chlorophenoxyacetic acid hydrochloride. It primarily works by promoting brain cell metabolism, increasing glucose utilization, and improving neurotransmission. Clinically, it is used to treat central nervous system dysfunctions such as post-traumatic brain injury coma, Alzheimer's disease, and intellectual developmental delay in children. However, while the ester bonds in its molecular structure endow it with pharmacological activity, they also result in its susceptibility to hydrolysis. Meclofenoxate hydrochloride is sensitive to humidity, light, and pH. Especially under alkaline conditions, the ester bonds readily hydrolyze to form p-chlorophenoxyacetic acid, thus rendering it ineffective. Furthermore, it is easily oxidized and degraded, limiting its formulation stability and clinical application. The molecular formula of meclofenoxate hydrochloride is C1. 12 H 17 C l2 NO3 has a molecular weight of 294.1743. The structure of meclofenac hydrochloride is as follows:

[0003]

[0004] Chinese patent CN200610122516.9 discloses a hydrolysis-resistant meclofenoxate hydrochloride pharmaceutical composition. This composition includes the active ingredient meclofenoxate hydrochloride, pharmaceutical excipients, and a lubricant. The composition further contains a stabilizer (citric acid), which is a substance capable of maintaining the pharmaceutical composition in a weakly acidic state. Preferred stabilizers are organic acids with multiple functional groups, such as organic acids with two or more carboxyl groups. Using an acidic stabilizer can maintain a weakly acidic local environment, which is beneficial for preventing the hydrolysis of meclofenoxate hydrochloride. Furthermore, citric acid also acts as a trace metal chelating agent, which can delay the occurrence of metal-catalyzed hydrolysis reactions. However, this only solves the problem of meclofenoxate hydrolysis and does not address the problem of meclofenoxate's susceptibility to moisture absorption and instability during long-term storage. Additionally, citric acid irritates the gastrointestinal tract, which is an additional burden for patients taking the medication long-term.

[0005] Chinese patent CN201310144366.1 discloses a meclofenac hydrochloride capsule, which mainly increases the stability of meclofenac by changing its crystal form, and has specific requirements for the raw materials of meclofenac.

[0006] Chinese patent CN200710036878.0 discloses a gastric floating sustained-release capsule of meclofenac hydrochloride. The capsule core contains (1) the active ingredient meclofenac hydrochloride, (2) microspheres made of gastric floating skeleton material, and (3) a sustained-release coating material layer. This patent uses gastric floating sustained-release technology to overcome the adverse effects of the gradually increasing pH value in the gastrointestinal tract on the stability of the drug in the capsule, and avoids the degradation of meclofenac hydrochloride in the capsule by human intestinal fluid, so as to ensure that the drug achieves stable, slow and complete release. However, it has high process requirements and is difficult to industrialize.

[0007] Meclofenac hydrochloride is unstable and contains ester bonds in its molecule, making it prone to hydrolysis in aqueous solutions. The hydrolysis rate accelerates as the pH of the aqueous solution increases. To address this issue, current technologies generally attempt to improve its stability through formulation, using methods such as adding excipients and employing complex processes. While existing technologies have shown some effectiveness in improving the stability of meclofenac hydrochloride at the formulation level, their research on long-term stability, especially under high temperature and high humidity conditions, has been limited. The more complex formulations, while having some effect, have limited scope, restricting the application of meclofenac hydrochloride and requiring extremely stringent storage conditions. Summary of the Invention

[0008] In view of the shortcomings of the prior art, the purpose of this invention is to provide a pharmaceutical composition containing meclofenac hydrochloride, which has low irritation, high stability, minimal changes in impurities during long-term storage, and is suitable for large-scale production.

[0009] To achieve the above objectives, the present invention, through extensive experimental research and improvement on existing formulations and processes, has obtained the following technical solution: a pharmaceutical composition containing meclofenoxate hydrochloride, comprising meclofenoxate hydrochloride, a filler, a flow aid, a lubricant, a stabilizer, and an antioxidant, wherein the mass ratio of meclofenoxate hydrochloride, stabilizer, and antioxidant is 1:0.005-0.015:0.001-0.005, and the mass ratio of meclofenoxate hydrochloride, filler, and flow aid is 1:0.3-0.7:0.1-0.5, and the stabilizer is benzoic acid.

[0010] In this invention, the proportions of meclofenac hydrochloride, stabilizers, and antioxidants, as well as the types of stabilizers, are key technical factors in achieving the desired technical effects. The hydrolysis of meclofenac hydrochloride follows first-order reaction kinetics. Experimental data show that its hydrolysis rate is significantly affected by pH: under acidic conditions of 20℃ and pH = 2.35, the hydrolysis rate constant is only 0.183 × 10⁻⁶. -4 At this point, it takes 94.7 hours for the drug to decompose by 10%; however, under neutral conditions (pH = 7.54), the rate constant increases sharply to 134.0 × 10⁻⁶. -4The same proportion of compounds decomposes in just 7.7 minutes. This 100-fold difference in rate indicates that the compound is significantly more stable in acidic environments than in neutral environments. Notably, the hydrolysis reaction accelerates significantly when the pH exceeds 5, demonstrating the crucial importance of pH control for the stability of pharmaceutical formulations. Therefore, maintaining an acidic environment (pH < 5) in the formulation system is a key measure to ensure the stability of meclofenac hydrochloride in actual production. Chinese patent CN200610122516.9 uses citric acid as a stabilizer, which can temporarily maintain a weakly acidic local environment, helping to prevent the hydrolysis of meclofenac hydrochloride. However, during long-term storage, citric acid gradually absorbs moisture and transforms into citric acid monohydrate. Citric acid monohydrate is more hygroscopic and may further deliquesce at RH > 75%, even forming a viscous liquid. Moisture will accelerate the hydrolysis of meclofenac, and the local pH will change after citric acid absorbs moisture, affecting the drug degradation rate. Therefore, using citric acid as a stabilizer is not recommended. Citric acid, as a stabilizer, temporarily prevents the hydrolysis of meclofenac hydrochloride, but hydrolysis still occurs under long-term storage conditions. Compared to citric acid, benzoic acid is slightly weaker and less irritating to the gastrointestinal tract. Under these conditions, benzoic acid still has a better pH regulation ability, lowering the local pH, promoting the dissolution of meclofenac, and improving gastrointestinal absorption. More importantly, benzoic acid is significantly less hygroscopic than citric acid, and it is essentially non-hygroscopic at RH < 80%, making it more suitable for humidity-sensitive formulations and reducing the risk of capsule softening or clumping. Antioxidants mainly prevent the oxidative degradation of meclofenac, thereby improving the chemical stability and shelf life of the formulation. Because the molecular structure of meclofenac contains easily oxidized groups (such as ester bonds and benzene rings), it may undergo oxidation reactions under light, oxygen, or metal ion catalysis, leading to reduced efficacy or the generation of impurities. Meclofenac may be affected by light or metal ions (such as Fe). 2+ Cu 2+ The catalyst generates free radicals, initiating auto-oxidation. Adding antioxidants can inhibit the free radical chain reaction, eliminate trace metal ions from raw materials or excipients, and eliminate their catalytic effect. When the mass ratio of meclofen hydrochloride, stabilizer, and antioxidant is 1:0.005-0.015:0.001-0.005, the stabilizer benzoic acid can maintain the system pH 4-5 at low dosage, effectively inhibiting the hydrolysis of meclofen hydrochloride (first-order reaction). The addition of trace amounts of antioxidant can block the free radical chain reaction, prevent oxidative degradation, and avoid impurity accumulation. Simultaneously, the acidic environment of the stabilizer enhances the effect of the antioxidant, while reducing the amount of antioxidant used and saving production costs. Preferably, the mass ratio of meclofen hydrochloride, stabilizer, and antioxidant is 1:0.01:0.002.

[0011] In this invention, the content ratio of meclofenoxate hydrochloride, filler, and flow aid, as well as the type of stabilizer, are among the key technical factors for achieving the desired technical effect. Excessive filler leads to delayed dissolution and excessively large capsule volume; excessive flow aid increases capsule brittleness and affects disintegration. Conversely, insufficient filler and flow aid result in excessive filler content variation and low production efficiency. When the mass ratio of meclofenoxate hydrochloride, filler, and flow aid is 1:0.3-0.7:0.1-0.5, the capsule filling volume meets the standard, avoiding empty capsules or insufficient filler content. Simultaneously, it improves powder flowability, and the flow aid significantly reduces inter-particle friction, increases filling speed, and reduces filler content variation. In the meclofenoxate hydrochloride capsule formulation, the active ingredient, filler, and flow aid interact and constrain each other. The amount of filler directly determines the capsule filling volume and mixing uniformity, but excessive filler can dilute the drug and may introduce hygroscopic or pH instability risks. Gliding agents improve filling efficiency by enhancing powder flowability. When the mass ratio of meclofenac hydrochloride, filler, and gliding agent is 1:0.4:0.2, the amount of gliding agent can be reduced. Meanwhile, the hygroscopicity of the filler or the surface adsorption of the gliding agent indirectly affects drug dissolution and chemical stability. Through the "flowability-volume-stability" triangular balance, the three factors ultimately determine the feasibility of formulation production, content uniformity, and product quality.

[0012] In this invention, the type of antioxidant is one of the key technical factors in achieving the desired technical effect. Ascorbyl palmitate or ascorbyl stearate, as antioxidants, can effectively penetrate lipid systems and scavenge free radicals. They are particularly suitable for protecting the ester bond structure of meclofenac hydrochloride and preventing oxidative degradation. Compared with ordinary ascorbic acid, their esterified form is less acidic (pH neutral), almost non-hygroscopic, and will not exacerbate the hydrolysis risk of meclofenac in acidic environments. They also have better compatibility with acid-base stabilizers and possess both antioxidant and mild surface-active effects, promoting the wetting and dissolution of the hydrophobic drug meclofenac and improving bioavailability. Preferably, the antioxidant in this invention is ascorbyl palmitate.

[0013] In this invention, the particle size of meclofenoxate hydrochloride is one of the key technical factors for achieving the desired technical effect. In meclofenoxate hydrochloride capsule formulations, the particle size and distribution range of the meclofenoxate active pharmaceutical ingredient (API) directly affect the physicochemical properties, formulation process, and in vivo behavior of the drug. When the particle size of the meclofenoxate API is too large, the mixing uniformity between the raw materials and excipients is poor, and stratification is easy. When the particle size is too small, the flowability of the raw materials and excipients is poor, requiring the addition of more flow aids. Simultaneously, a small particle size increases the specific surface area of ​​the drug, increasing the contact area with water or oxygen, accelerating its hydrolysis and oxidation rates. Furthermore, fine particles are prone to electrostatic aggregation, leading to clumping during long-term storage. When the particle size of meclofenoxate hydrochloride is 20μm≤D90≤50μm, the overall performance of the meclofenoxate hydrochloride capsules can be significantly optimized. This particle size range provides sufficient specific surface area to ensure rapid dissolution while maintaining good powder flowability, requiring only a small amount of flow aid to meet industrial filling requirements (RSD < 5%). Compared to finer particles (D90 < 10 μm), this particle size range significantly reduces the risk of hygroscopicity, decreases the amount of antioxidant required, and ensures uniform content. Furthermore, this particle size can be achieved through conventional pulverization processes, reducing production energy consumption and achieving an optimal balance between dissolution efficiency, process feasibility, and stability. Preferably, the particle size of meclofenac hydrochloride is 25 μm ≤ D90 ≤ 40 μm.

[0014] In this invention, the choice of formulation is one of the factors in achieving the technical effect. In meclofenac hydrochloride capsule formulations, when the filler is microcrystalline cellulose, anhydrous calcium hydrogen phosphate, or mannitol, the gliding agent is talc or colloidal silica, and the lubricant is sodium stearate fumarate, stearic acid, or hydrogenated vegetable oil, the negative hydrolytic effects caused by the moisture absorption of excipients can be reduced. The preferred combination of microcrystalline cellulose as a filler, talc as a gliding agent, and sodium stearate fumarate as a lubricant has significant advantages. Microcrystalline cellulose possesses excellent compressibility and low hygroscopicity, providing stable filling volume and preventing moisture from affecting drug stability. Talc, as a natural mineral-derived flow aid, not only effectively improves powder flowability, but its flake-like structure also reduces inter-particle friction of meclofenac hydrochloride and is less prone to drug adsorption compared to colloidal silica. Sodium stearate combines lubrication and pH buffering functions; its weak acidity (pH≈5.5) matches the stable pH range of meclofenac (4-6), reducing capsule friction without accelerating drug hydrolysis like magnesium stearate (pH≈8) due to its alkalinity. The synergistic effect of these three components significantly improves production process stability and long-term storage reliability while ensuring content uniformity and dissolution efficiency.

[0015] In this invention, the mass ratio of meclofenoxate hydrochloride to lubricant is also one of the factors contributing to the technical effect. In meclofenoxate hydrochloride capsule formulations, controlling the mass ratio of meclofenoxate hydrochloride to lubricant at 1:0.025-0.050 offers multiple advantages. This ratio range ensures that the lubricant (such as sodium stearate fumarate) forms a complete monolayer covering the particle surface, improving capsule filling efficiency, while avoiding the hydrophobic film effect caused by excessive lubricant, thus guaranteeing capsule dissolution. This optimized ratio achieves the best balance between lubrication effect, dissolution performance, and stability, making it particularly suitable for industrial production needs. Preferably, the mass ratio of meclofenoxate hydrochloride to lubricant is 1:0.032.

[0016] Specifically, the present invention also provides a pharmaceutical composition containing meclofenac hydrochloride, comprising the following components:

[0017] name Quality Meclofenac Hydrochloride 1 microcrystalline cellulose 0.4 talcum powder 0.2 Sodium stearate 0.032 benzoic acid 0.01 Ascorbyl palmitate 0.002

[0018] The meclofenac hydrochloride has a D90 of 25 μm ≤ 40 μm.

[0019] This invention also provides a preparation process for the above-mentioned meclofenac hydrochloride pharmaceutical composition. The meclofenac hydrochloride capsules prepared by this process have low hygroscopicity, no hydrolysis, high long-term storage stability, and low gastric irritation. The process is simple and ensures the feasibility of production scale-up. The process includes the following steps:

[0020] (1) Premixing: Place meclofenac hydrochloride and dried talc powder in a premixing position, set the mixing speed to 10-20 rpm, and mix for 10-30 min;

[0021] (2) Granulation and sieving: The above mixture is granulated and sieved using a pulverizer and granulator with a granulation screen of Ф3.0mm and a granulation frequency of 25Hz;

[0022] (3) Premixing: Add the dried microcrystalline cellulose to the mixing tank for premixing. Set the mixing speed to 15-25 rpm and mix for 40 min.

[0023] (4) Total mixing: Add sodium stearate fumarate, benzoic acid and ascorbate palmitate to the total mixing tank for total mixing. Set the mixing speed to 15-20 rpm and mix for 10 min to obtain the total mixed powder.

[0024] (5) Capsule filling: The total powder mixture is filled into capsules using a capsule filling machine to obtain meclofenac hydrochloride capsules.

[0025] Compared with the prior art, the present invention has the following outstanding advantages and beneficial effects:

[0026] (1) Benzoic acid is selected as a stabilizer. Its hygroscopicity is significantly lower than that of citric acid. It does not absorb moisture at RH<80%, which effectively prevents meclofenac hydrochloride from being hydrolyzed due to moisture absorption, reduces the risk of capsules softening or clumping, and causes less irritation to the gastrointestinal tract.

[0027] (2) The rational combination of meclofenac hydrochloride, stabilizer (benzoic acid) and antioxidant effectively inhibits the hydrolysis of meclofenac, the antioxidant blocks the free radical chain reaction and prevents oxidative degradation, the acidic environment of the stabilizer can enhance the effect of the antioxidant, and at the same time reduce the amount of antioxidant used and save production costs.

[0028] (3) The meclofenac hydrochloride capsules prepared by the present invention have high stability, good dissolution, etc., and the preparation process is simple and suitable for large-scale industrial production. Detailed Implementation

[0029] The present invention will be further described in detail below with reference to embodiments, but the implementation of the invention is not limited thereto.

[0030] Example 1: Preparation of Meclofenac Hydrochloride Capsules

[0031] The formulation for preparing a drug containing 100 mg of the active ingredient meclofenac hydrochloride per capsule is as follows:

[0032]

[0033]

[0034] The preparation method is as follows:

[0035] (1) Premixing: Using a three-dimensional motion mixer or a V-type mixer, place meclofenac hydrochloride and dried talc powder in a container for premixing. Set the mixing speed to 10-20 rpm and mix for 10-30 min. The relative humidity should be ≤40% and the temperature should be below 25℃.

[0036] (2) Granulation and sieving: The above mixture is granulated and sieved using a pulverizer and granulator with a granulation screen of Ф3.0mm and a granulation frequency of 25Hz;

[0037] (3) Premixing: Add the dried microcrystalline cellulose to the mixing tank for premixing. Set the mixing speed to 15-25 rpm and mix for 40 min.

[0038] (4) Total mixing: Add sodium stearate fumarate, benzoic acid and ascorbate palmitate to the total mixing tank for total mixing. Set the mixing speed to 15-20 rpm and mix for 10 min to obtain the total mixed powder.

[0039] (5) Capsule filling: The total powder mixture is filled into capsules using a capsule filling machine. The relative humidity is ≤40% and the temperature is below 25℃ to obtain meclofenac hydrochloride capsules.

[0040] Example 2: Preparation of meclofenac hydrochloride capsules

[0041] The formulation for preparing a drug containing 100 mg of the active ingredient meclofenac hydrochloride per capsule is as follows:

[0042]

[0043] The preparation method is as described in Example 1.

[0044] Example 3: Preparation of Meclofenac Hydrochloride Capsules

[0045] The formulation for preparing a drug containing 100 mg of the active ingredient meclofenac hydrochloride per capsule is as follows:

[0046]

[0047] The preparation method is as described in Example 1.

[0048] Example 4: Preparation of Meclofenac Hydrochloride Capsules

[0049] The formulation for preparing a drug containing 100 mg of the active ingredient meclofenac hydrochloride per capsule is as follows:

[0050]

[0051] The preparation method is as described in Example 1.

[0052] Example 5: Preparation of Meclofenac Hydrochloride Capsules

[0053] The formulation for preparing a drug containing 100 mg of the active ingredient meclofenac hydrochloride per capsule is as follows:

[0054]

[0055] The preparation method is as described in Example 1.

[0056] Comparative Example 1: Preparation of Meclofenac Hydrochloride Capsules

[0057] The formulation for preparing a drug containing 100 mg of the active ingredient meclofenac hydrochloride per capsule is as follows:

[0058]

[0059] The preparation method is as in Example 1. Compared with Example 1, Comparative Example 1 uses less benzoic acid, ascorbate palmitate, microcrystalline cellulose, talc, and sodium stearate fumarate.

[0060] Comparative Example 2: Preparation of Meclofenac Hydrochloride Capsules

[0061] The formulation for preparing a drug containing 100 mg of the active ingredient meclofenac hydrochloride per capsule is as follows:

[0062]

[0063]

[0064] The preparation method is the same as in Example 1. Compared with Example 1, Comparative Example 2 uses more benzoic acid, ascorbate palmitate, microcrystalline cellulose, talc, and sodium stearate fumarate.

[0065] Comparative Example 3: Preparation of Meclofenac Hydrochloride Capsules

[0066] The formulation for preparing a drug containing 100 mg of the active ingredient meclofenac hydrochloride per capsule is as follows:

[0067]

[0068] The preparation method is the same as in Example 1. Compared with Example 1, the particle size of the meclofenac hydrochloride raw material in Comparative Example 3 is larger.

[0069] Comparative Example 4: Preparation of Meclofenac Hydrochloride Capsules

[0070] The formulation for preparing a drug containing 100 mg of the active ingredient meclofenac hydrochloride per capsule is as follows:

[0071]

[0072]

[0073] The preparation method is the same as in Example 1. Compared with Example 1, the stabilizer used in Comparative Example 4 is citric acid.

[0074] Comparative Example 5: Preparation of Meclofenac Hydrochloride Capsules

[0075] The formulation for preparing a drug containing 100 mg of the active ingredient meclofenac hydrochloride per capsule is as follows:

[0076]

[0077] The preparation method is the same as in Example 1. Compared with Example 1, no antioxidant was used in Comparative Example 5.

[0078] Comparative Example 6: Preparation of Meclofenac Hydrochloride Capsules

[0079] The formulation for preparing a drug containing 100 mg of the active ingredient meclofenac hydrochloride per capsule is as follows:

[0080]

[0081]

[0082] The preparation method is the same as in Example 1. Compared with Example 1, in Comparative Example 6, the antioxidant is ascorbic acid, the filler is pregelatinized starch, and the lubricant is magnesium stearate.

[0083] Example 7

[0084] Meclofenac hydrochloride capsules prepared in Examples 1-5 and Comparative Examples 1-6 were examined for their properties, identification, content uniformity, dissolution rate, related substances content, microbial limits, and total content. The results are shown in Tables 1 and 2.

[0085] Table 1. Evaluation of the formulation performance of meclofenac hydrochloride capsules in Examples 1-5

[0086]

[0087] Table 2. Evaluation of formulation performance of meclofenac hydrochloride capsules in Comparative Examples 1-6

[0088]

[0089]

[0090] The test results in Tables 1 and 2 show that the meclofenac hydrochloride capsules prepared in Examples 1-5 all meet the requirements in terms of appearance, identification, content uniformity, dissolution, related substances content, microbial limits, and content. In Comparative Example 1, due to the low content of stabilizer and antioxidant, some meclofenac hydrochloride underwent hydrolysis, resulting in some impurities. In Comparative Example 2, the high content of stabilizer, antioxidant, and other excipients, while reducing impurities, negatively impacted dissolution due to uneven mixing. In Comparative Example 3, the larger particle size of meclofenac hydrochloride slowed dissolution. Examples 1-5 are preferred solutions in this scheme, and all parameters in Example 1, including the types and proportions of excipients, are optimal. For example, meclofenoxate hydrochloride, benzoic acid, antioxidants, etc. are in appropriate proportions, and are combined with appropriate amounts of other excipients. The overall combination of the above conditions results in meclofenoxate hydrochloride capsules with high dissolution rate, high content, and no "hydrolysis" phenomenon.

[0091] Example 8

[0092] This embodiment examines the stability of the meclofenac hydrochloride capsules provided by the present invention. Stability tests were conducted on meclofenac hydrochloride capsules prepared in Examples 1-5 and Comparative Examples 4-6.

[0093] This experiment was conducted in accordance with the guidelines for stability testing of active pharmaceutical ingredients and preparations, Part IV, of the 2025 edition of the Chinese Pharmacopoeia. Accelerated testing was performed under the following conditions: 40℃±2℃, 75%RH±5%RH. The results are shown in Tables 3 and 4.

[0094] Table 3 Results of accelerated test content determination

[0095]

[0096]

[0097] Table 4. Results of long-term test content determination

[0098] 0 months 3 months 6 months 9 months 15 months 24 months Example 1 99.99％ 99.98％ 99.97％ 99.96％ 99.95％ 99.92％ Example 2 99.99％ 99.97％ 99.96％ 99.93％ 99.92％ 99.90％ Example 3 99.99％ 99.97％ 99.96％ 99.94％ 99.92％ 99.91％ Example 4 99.99％ 99.98％ 99.95％ 99.93％ 99.92％ 99.89％ Example 5 99.99％ 99.98％ 99.97％ 99.94％ 99.93％ 99.91％ Comparative Example 4 99.70％ 98.65％ 97.60％ 96.52％ 95.45％ 93.15％ Comparative Example 5 99.72％ 98.68％ 97.60％ 96.55％ 95.50％ 94.42％ Comparative Example 6 99.82％ 98.77％ 97.70％ 96.50％ 94.41％ 92.28％

[0099] As shown in Tables 3 and 4, the meclofenac hydrochloride capsules prepared in Examples 1-5 exhibited stable properties during both accelerated and long-term tests over 12 months, indicating good long-term stability. Comparative Example 4 used citric acid as a stabilizer. During long-term storage, citric acid gradually absorbs moisture and transforms into citric acid monohydrate. Citric acid monohydrate has stronger hygroscopicity, accelerating the hydrolysis of meclofenac hydrochloride. Comparative Example 5 did not use an antioxidant, resulting in oxidative degradation of meclofenac hydrochloride during long-term storage. Oxidation reactions occurred under light, oxygen, or metal ion catalysis, producing impurities. Comparative Example 6 did not use the formulation defined in this invention. The antioxidant used was ascorbic acid, which has certain hygroscopic properties and easily causes hydrolysis of meclofenac hydrochloride. The lubricant used was magnesium stearate, which contains magnesium ions. Under long-term storage, magnesium ions catalyze oxidation reactions, producing impurities, thus also hindering the long-term storage of meclofenac hydrochloride. Examples 1-5 are preferred solutions in this scheme, and the various parameters in Example 1, including the types and proportions of excipients, are optimal. For example, meclofenac hydrochloride, benzoic acid, antioxidants, etc. are in appropriate proportions, and with appropriate amounts of other excipients, the overall combination of the above conditions ensures that the prepared meclofenac hydrochloride capsules do not undergo hydrolysis and oxidation, and remain stable during long-term storage.

[0100] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A pharmaceutical composition containing meclofenac hydrochloride, characterized in that, The product comprises meclofen hydrochloride, a filler, a flow aid, a lubricant, a stabilizer, and an antioxidant. The mass ratio of meclofen hydrochloride, the stabilizer, and the antioxidant is 1:0.005-0.015:0.001-0.005, and the mass ratio of meclofen hydrochloride, the filler, and the flow aid is 1:0.3-0.7:0.1-0.

5. The stabilizer is benzoic acid.

2. The pharmaceutical composition according to claim 1, characterized in that, The mass ratio of meclofenac hydrochloride, stabilizer, and antioxidant is 1:0.01:0.

002.

3. The pharmaceutical composition according to claim 1, characterized in that, The mass ratio of meclofenac hydrochloride, filler, and flow aid is 1:0.4:0.

2.

4. The pharmaceutical composition according to claim 1, characterized in that, The antioxidant is ascorbyl palmitate or ascorbyl stearate, preferably ascorbyl palmitate.

5. The pharmaceutical composition according to claim 1, characterized in that, The particle size of the meclofenac hydrochloride is 20μm≤D90≤50μm, preferably 25μm≤D90≤40μm.

6. The pharmaceutical composition according to claim 1, characterized in that, The filler is microcrystalline cellulose, anhydrous calcium hydrogen phosphate, or mannitol; the flow aid is talc or colloidal silica; and the lubricant is sodium stearate fumarate, stearic acid, or hydrogenated vegetable oil. Preferably, the filler is microcrystalline cellulose, the flow aid is talc, and the lubricant is sodium stearate fumarate.

7. The pharmaceutical composition according to claim 1, characterized in that, The mass ratio of meclofenac hydrochloride to lubricant is 1:0.025-0.

050.

8. The pharmaceutical composition according to claim 1, characterized in that, The mass ratio of meclofenac hydrochloride to lubricant is 1:0.

032.

9. A pharmaceutical composition containing meclofenac hydrochloride, characterized in that, It contains the following components: The meclofenac hydrochloride has a D90 of 25 μm ≤ 40 μm.

10. A method for preparing a pharmaceutical composition of meclofenac hydrochloride according to any one of claims 1-9, characterized in that, Includes the following steps: (1) Premixing: Place meclofenac hydrochloride and dried talc powder in a premixing position, set the mixing speed to 10-20 rpm, and mix for 10-30 min; (2) Granulation and sieving: The above mixture is granulated and sieved using a pulverizer and granulator with a granulation screen of Ф3.0mm and a granulation frequency of 25Hz; (3) Premixing: Add the dried microcrystalline cellulose to the mixing tank for premixing. Set the mixing speed to 15-25 rpm and mix for 40 min. (4) Total mixing: Add sodium stearate fumarate, benzoic acid and ascorbate palmitate to the total mixing tank for total mixing. Set the mixing speed to 15-20 rpm and mix for 10 min to obtain the total mixed powder. (5) Capsule filling: The total powder mixture is filled into capsules using a capsule filling machine to obtain meclofenac hydrochloride capsules.

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