Diclofenac sodium sustained release tablet and preparation method thereof

Abstract

The invention relates to the field of pharmaceutical preparations, in particular to a diclofenac sodium sustained release tablet and a preparation method thereof. The diclofenac sodium sustained release tablet is prepared from the following components: diclofenac sodium, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, mannitol, organic acid salt, a flow aid and a lubricant. The diclofenac sodium sustained-release tablet provided by the invention can be stably released, has an excellent sustained-release effect, and is simple in preparation process, low in cost and suitable for industrial mass production.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a diclofenac sodium sustained-release tablet and a preparation method thereof. Background Art

[0002] Diclofenac sodium is a non-steroidal anti-inflammatory drug and is a first-line drug for the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and gouty arthritis. Its chemical name is [o-(2,6-dichloroaniline)] phenylacetate sodium, and its molecular formula is C 14 H 10 C l2 NNaO2, the molecular structure is as follows:

[0003]

[0004] It has the advantages of good efficacy and few adverse reactions, but due to its short half-life after oral administration (about 1 to 2 hours), its ordinary tablets (25 mg) need to be taken three times a day, resulting in obvious peaks and valleys in blood drug concentrations, and can cause gastrointestinal reactions such as headache and abdominal pain, constipation, diarrhea, stomach burning, nausea, and indigestion. Diclofenac sodium sustained-release tablets can overcome the above shortcomings and maintain a stable blood drug concentration. Diclofenac sodium sustained-release tablets were developed by Novartis Pharmaceuticals and are traded under the name Voltaren Retard (100 mg / tablet). The formula contains hexadecanol, sucrose, povidone, hydroxypropyl methylcellulose, silicon dioxide, magnesium stearate, Tween-80, polyethylene glycol, iron oxide, titanium dioxide, and talc.

[0005] At present, the gel-type and erosion-type skeleton diclofenac sodium sustained-release tablets on the domestic market are released and dissolved in the stomach. Diclofenac sodium is irritating to the stomach, causing patients to experience side effects such as stomach pain, burning sensation, acid reflux, poor appetite, and nausea.

[0006] Most oral sustained-release preparations of diclofenac sodium are produced by wet granulation process, direct tableting process, or coating with membrane controlled release process. In the wet granulation process, hydropropyl methylcellulose is currently mainly used as the gel sustained-release skeleton, and the disadvantages are: water or ethanol is used as the solvent to prepare the binder for granulation. Hydroxypropyl methylcellulose is a sustained-release material. Hydroxypropyl methylcellulose is very easy to form micelles and become sticky after contacting water or ethanol, and it is easy to agglomerate. The dried particles are very hard and not easy to granulate, which is not conducive to production operation. The existing diclofenac sodium sustained-release preparations prepared only with hydropropyl methylcellulose as the gel sustained-release skeleton have the problem of fast drug release in the early stage, and the sustained-release effect is unstable. The direct tableting process is adopted, which has high requirements on the fluidity of the mixed powder and the particle size distribution of the main drug, sustained-release material and other materials. The particle size distribution of different materials is very different, the fluidity is poor, and there is a tendency of stratification during the descent process, resulting in large differences in dissolution between batches and unstable product quality. The coating process has many preparation steps and is complicated, resulting in a low production yield. In addition, the obtained oral sustained-release preparation of diclofenac sodium has the problem of fast drug release in the early stage or incomplete release in the later stage, and the release is relatively unstable.

[0007] Patent application CN112587493A discloses an oral sustained-release tablet of diclofenac sodium and a preparation process thereof. Diclofenac sodium and an inner layer carrier are dissolved in an inner layer solvent, and an outer layer carrier is dissolved in an outer layer solvent. Diclofenac sodium microcapsules are prepared by a coaxial electrostatic spray method, and then a filler is added and mixed, granulated, and other pharmaceutical excipients are added to obtain tablets. The production process is complicated and prone to sudden release.

[0008] Therefore, it is very necessary to develop a diclofenac sodium sustained-release tablet with stable release, simple preparation process and suitable for large-scale industrial production. Summary of the invention

[0009] In order to solve the problems existing in the prior art, the present invention provides a diclofenac sodium sustained-release tablet, which comprises the following components: diclofenac sodium, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, mannitol, an organic acid salt, a glidant and a lubricant.

[0010] The hydroxypropyl methylcellulose is preferably K4M or K15M.

[0011] The organic acid salt is sodium citrate or sodium tartrate, preferably sodium citrate.

[0012] The glidant is silicon dioxide or talc, preferably silicon dioxide.

[0013] The lubricant is magnesium stearate, calcium stearate or sodium stearyl fumarate, preferably magnesium stearate. In a preferred technical solution, the diclofenac sodium sustained-release tablet comprises the following components by weight:

[0014]

[0015] In a preferred technical solution, the diclofenac sustained-release tablet comprises the following components by weight:

[0016]

[0017]

[0018] In a preferred technical solution, the diclofenac sustained-release tablet comprises the following components by weight:

[0019]

[0020] In a preferred embodiment, the diclofenac sodium sustained-release tablets comprise the following components by weight:

[0021]

[0022] The present invention provides a method for preparing the diclofenac sodium sustained-release tablets, comprising the steps of:

[0023] Pretreatment: Weigh each component of the prescription and pass it through a 40-mesh sieve for later use.

[0024] Premixing: Place diclofenac sodium, hypromellose, sodium carboxymethylcellulose, mannitol and organic acid sodium in a wet granulator and mix well.

[0025] Granulation: Add appropriate amount of water directly to the wet mixer granulator to prepare soft material, and sieve to granulate.

[0026] Drying: The granules obtained after wet granulation are placed in a fluidized bed and dried to a moisture content of ≤3%.

[0027] Whole grain: The dried granules are sieved and whole grained.

[0028] Total mixing: Add glidant and lubricant and mix well.

[0029] Tableting: Tableting is performed.

[0030] Coating: Add coating premix for coating.

[0031] In a preferred embodiment, the present invention adopts the following preparation method:

[0032] The components are weighed according to the prescription amount, passed through a 40-mesh sieve, diclofenac sodium, hypromellose, sodium carboxymethylcellulose, mannitol and an organic acid salt are placed in a wet granulator and mixed evenly, a proper amount of water is directly added to the wet mixing granulator to prepare a soft material, and the wet granulation is performed through a 10×10 mm square hole sieve, the granules obtained after the wet granulation are placed in a fluidized bed and dried at room temperature until the moisture content is ≤3%, the dried granules are passed through a 1.5 mm sieve, a glidant and a lubricant are added, and the mixture is evenly mixed and then tableted, with the diclofenac sodium being 100 mg / tablet, to obtain a sustained-release tablet with a white appearance, a smooth surface and an average hardness of 100 N, and a film coating premix (gastric soluble type) is added for coating, and the tablet weight is increased by 2-4%.

[0033] The diclofenac sodium sustained-release tablet provided by the present invention is hardly released in an acidic medium, and the sustained-release tablet provided by the present invention can stably release, has an excellent sustained-release effect, can achieve a 24-hour sustained-release effect, and has a simple preparation process, low cost, and is suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 The release curve is drawn based on the results of the study on skeleton materials and dosage in Example 2.

[0035] Figure 2 The curve is drawn based on the experimental results of Example 3 to investigate the effects of the amount of filler and sodium citrate on the release of diclofenac sodium sustained-release tablets.

[0036] Figure 3 The release curves of Formulation 1 and the reference in aqueous medium were investigated for Example 4.

[0037] Figure 4 The release curves of Formulation 1 and the reference in pH 4.5 acetate buffer medium were investigated for Example 5.

[0038] Figure 5 The release curves of the medium 0.1N hydrochloric acid formulation 1 and the reference were investigated for Example 6. DETAILED DESCRIPTION

[0039] In order to better understand the technical solution of the present invention, the technical solution of the present invention is further described below in conjunction with specific embodiments. The embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0040] All raw materials of the present invention are purchased commercially, among which the film coating premix (gastric soluble type) is Opadry 13F640004-CN, which is used for film coating and has the main components of hypromellose, polysorbate 80, titanium dioxide, red iron oxide, yellow iron oxide, talc, and polyethylene glycol, purchased from Shanghai Colorcon Coating Technology Co., Ltd. LP was purchased from NOVARTIS FARMA SPA.

[0041] Example 1: Diclofenac Sodium Sustained Release Tablets (Prescription 1)

[0042]

[0043]

[0044] Preparation process:

[0045] Weigh each component according to the prescription amount, pass through a 40-mesh sieve, place diclofenac sodium, hypromellose, sodium carboxymethylcellulose, mannitol and sodium citrate in a wet granulator and mix them evenly, directly add an appropriate amount of water in the wet mixing granulator to prepare a soft material, pass through a 10×10mm square hole sieve for wet granulation, place the granules obtained after wet granulation in a fluidized bed and dry at room temperature until the moisture content is ≤3%, pass through a 1.5mm sieve for granulation after drying, add silicon dioxide and magnesium stearate, mix evenly and then compress the granules, with 100 mg / tablet of diclofenac sodium as the calculation, to obtain a sustained-release tablet with a white appearance, a smooth surface and an average hardness of 100N. Add a film coating premix (gastric soluble type) for coating, and the tablets gain 2-4% in weight.

[0046] Example 2: Research on framework materials and dosage

[0047] The effects of matrix materials and dosage on tablet release were investigated while other components remained unchanged. The formulation ingredients are shown in Table 1.

[0048] Table 1

[0049]

[0050]

[0051] Note: API is diclofenac sodium, HPMC is hydroxypropyl methylcellulose, and CMC-Na is carboxymethyl cellulose sodium.

[0052] Release measurement method: Take this product and use the first basket method of the fourth general rule 0931 of the Chinese Pharmacopoeia 2020 to measure the dissolution rate. Use 900ml of pH7.5 phosphate buffer as the release medium, the rotation speed is 100r / min, the medium temperature is 37±5℃, and 10ml is sampled at 0.5, 1, 3, 5, 8, 10, 12, 16, 20, and 24h, respectively, and filter with a 0.45um microporous membrane, and replenish the release medium of the same temperature and volume in time. Use the UV-visible spectrophotometry method of the fourth general rule 0401 of the Chinese Pharmacopoeia 2020, use pH7.5 buffer as the reference solution, and measure the absorbance at a wavelength of 276nm to calculate the cumulative release of the drug at each point. The measured values ​​are shown in Table 2.

[0053] Table 2

[0054]

[0055]

[0056] Test conclusion:

[0057] When the skeleton material is only hydroxypropyl methylcellulose or sodium carboxymethylcellulose, the 12-hour cumulative release is 98%. When the skeleton material is a composite skeleton composed of hydroxypropyl methylcellulose and sodium carboxymethylcellulose, the sustained release effect is better than that of a single skeleton, and the dosage of hydroxypropyl methylcellulose and sodium carboxymethylcellulose also has a significant effect on the sustained release effect. Prescriptions 1, 4, 5, 6-8 can all achieve excellent sustained release effects, among which the dissolution curve of prescription 1 is most similar to the reference, and the sustained release effects of prescriptions 4, 5 and 6 are similar and better than those of prescriptions 7 and 8.

[0058] Example 3: Study on excipients and dosage

[0059] The effects of fillers and sodium citrate on the release of diclofenac sodium sustained-release tablets were investigated. The prescription ingredients are shown in Table 3.

[0060] Table 3

[0061]

[0062] The release rate was measured in the same manner as in Example 2. The test results are shown in Table 4.

[0063] Table 4

[0064]

[0065]

[0066] Test conclusion:

[0067] When sucrose and sorbitol were used as fillers, the release was too fast compared to the reference preparation, with the cumulative release exceeding 90% in 12 hours. When sodium citrate was not added, the release was too slow and the final release was incomplete.

[0068] Example 4: Aqueous medium release test

[0069] The release rate was measured in the same manner as in Example 2, with water being the release medium. The test results are shown in Table 5.

[0070] Table 5

[0071]

[0072] Example 5: pH 4.5 acetate buffer medium release test

[0073] The release rate was measured in the same manner as in Example 2, with the release medium pH being 4.5. The test results are shown in Table 6.

[0074] Table 6

[0075]

[0076]

[0077] Example 6: 0.1N salt release test in medium

[0078] The release rate was measured in the same manner as in Example 2, with the release medium being 0.1N hydrochloric acid. The test results are shown in Table 7.

[0079] Table 7

[0080]

[0081] Experimental Conclusion

[0082] According to the above test results, it can be seen that prescription 1 is almost not released in acidic medium.

Claims

1. A diclofenac sodium sustained-release tablet comprising the following components: diclofenac sodium, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, mannitol, an organic acid salt, a glidant and a lubricant.

2. The sustained-release tablet according to claim 1, wherein the hydroxypropyl methylcellulose is K4M or K15M; the organic acid salt is sodium citrate or sodium tartrate; the glidant is silicon dioxide or talc; and the lubricant is magnesium stearate, calcium stearate or sodium stearyl fumarate.

3. The sustained-release tablet according to claim 1, wherein the diclofenac sodium sustained-release tablet comprises the following components by weight:

4. The sustained-release tablet according to claim 1, wherein the diclofenac sustained-release tablet comprises the following components by weight:

5. The sustained-release tablet according to claim 4, wherein the diclofenac sustained-release tablet comprises the following components by weight:

6. The sustained-release tablet according to claim 5, wherein the diclofenac sodium sustained-release tablet comprises the following components by weight:

7. A method for preparing the diclofenac sodium sustained-release tablets according to any one of claims 1 to 6, comprising the steps of: Pretreatment: weigh each component of the prescription and pass it through a 40-mesh sieve for later use; Premixing: Diclofenac sodium, hypromellose, sodium carboxymethylcellulose, mannitol and organic acid sodium are placed in a wet granulator and mixed evenly; Granulation: Add appropriate amount of water directly to the wet mixer granulator to prepare soft material, and sieve to granulate; Drying: The granules obtained after wet granulation are placed in a fluidized bed and dried to a moisture content of ≤3%; Whole grain: The dried granules are sieved and whole grained; Total mixing: add glidant and lubricant and mix evenly; Tableting: tableting; Coating: Add coating premix for coating.

8. The preparation method according to claim 7, comprising the steps of: weighing each component according to the prescription amount, passing through a 40-mesh sieve, placing diclofenac sodium, hypromellose, sodium carboxymethyl cellulose, mannitol and an organic acid salt in a wet granulator and mixing them evenly, directly adding an appropriate amount of water in the wet mixing granulator to prepare a soft material, passing through a 10×10 mm square hole sieve for wet granulation, placing the granules obtained after the wet granulation in a fluidized bed and drying at room temperature to a moisture content of ≤3%, passing through a 1.5 mm sieve for granulation, adding a glidant and a lubricant, and tableting after mixing evenly, with the diclofenac sodium being 100 mg / tablet, to obtain a sustained-release tablet with a white appearance, a smooth surface and an average hardness of 100N, adding a film coating premix (gastric soluble type) for coating, and the tablet weight gain is 2-4%.

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