Loxoprofen sodium dispersible tablet and preparation method thereof

Abstract

The invention relates to a loxoprofen sodium dispersible tablet and a preparation method thereof. The dispersible tablet comprises loxoprofen sodium, a disintegrating agent, a filling agent, a flow aid and a lubricating agent. According to the prescription and the prepared product, the dissolution rate is improved, the effect can be quickly achieved, the technological operation is simple and convenient, the product yield is improved, the production cost is saved, and the method is suitable for industrial mass production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and relates to an antipyretic, analgesic and anti-inflammatory dispersible tablet and a preparation method thereof. More specifically, it relates to a loxoprofen sodium dispersible tablet and a preparation method thereof. Background Art

[0002] Loxoprofen Sodium is the first propionic acid type prodrug non-steroidal anti-inflammatory drug (NSAIDs). It was first developed by Sankyo Co., Ltd. (now Daiichi Sankyo Co., Ltd.) in Japan and was launched in Japan in 1986 under the trade name After oral administration, this drug is metabolized into the trans-OH type active drug in the body, which inhibits the biosynthesis of prostaglandins. That is, by binding to cyclooxygenase and covering the active center of the enzyme, it blocks the metabolism of arachidonic acid catalyzed by this enzyme into prostaglandins, thereby exerting analgesic, anti-inflammatory and antipyretic effects.

[0003] Loxoprofen Sodium, the chemical name is sodium 2-[4-(2-oxocyclopentan-1-ylmethyl)phenyl]propionate, and the molecular formula is C 15 H 17 NaO3, and its chemical structure is as follows:

[0004]

[0005] At present, the loxoprofen sodium preparations on the domestic market mainly include tablets and capsules. The reference preparations and commercially available tablets are mostly ordinary tablets. The process in Patent CN201210123938.3 (a patent for an invention of a loxoprofen sodium composition applied by Disha Pharmaceutical Group Co., Ltd.) is as follows: (1) The raw and auxiliary materials are sieved through a 100-mesh sieve; (2) Weigh the prescribed amounts of loxoprofen sodium dihydrate, microcrystalline cellulose, silicon dioxide, and cross-linked polyvinylpyrrolidone XL-10 and dry-mix them in a wet granulator for 5 minutes; (3) Add 95% ethanol to make soft materials; (4) Screen through a 24-mesh sieve; (5) Dry the wet granules at 60°C with forced air until the weight loss is less than 3%; (6) Screen the dry granules through a 20-mesh sieve, add magnesium stearate and mix evenly. (7) Press tablets according to the main drug content and package to obtain the product.

[0006] The ordinary tablets prepared by this process include wet granulation, drying and screening, with cumbersome processes, easy material loss, long production cycle, large kinetic energy loss and labor cost. As ordinary tablets, it is difficult to meet the needs of the elderly, children, stroke patients and patients with difficulty in swallowing. The present invention prepares loxoprofen sodium dispersible tablets by direct powder compression, reduces the production process, reduces the material loss in the intermediate process, improves the product yield, and reduces the production cost.

[0007] Since this product is a dispersible tablet, it can be taken in two ways. When swallowed, it is taken in the same way as ordinary tablets. In addition, it can also be dispersed in warm water for oral administration, which can conveniently meet the needs of the elderly, children, stroke patients and those who have difficulty swallowing ordinary tablets, thus improving the competitive advantage of the product. Summary of the Invention

[0008] The object of the present invention is to provide a loxoprofen sodium dispersible tablet and its preparation method. The dispersible tablet has good dispersion uniformity, quick onset of action, stable properties, and a simple preparation method.

[0009] The problems to be solved by the present invention are achieved through the following technical solutions:

[0010] A loxoprofen sodium dispersible tablet, wherein the dispersible tablet comprises loxoprofen sodium, a disintegrant, a filler, a glidant and a lubricant.

[0011] Preferably, the filler is one or more of starch, lactose monohydrate or microcrystalline cellulose, and further preferably, a combination of microcrystalline cellulose and lactose monohydrate.

[0012] Preferably, the disintegrant is one or more of low-substituted hydroxypropyl cellulose, crospovidone or sodium carboxymethyl starch, and further preferably, a combination of low-substituted hydroxypropyl cellulose and crospovidone.

[0013] Preferably, the glidant is silicon dioxide.

[0014] Preferably, the lubricant is magnesium stearate.

[0015] Preferably, the mass percentage of loxoprofen sodium in the tablet weight of each dispersible tablet is 13-29%, the filler accounts for 43-48% of the tablet weight, the disintegrant accounts for 21-39% of the tablet weight, the glidant accounts for 0.5-2% of the tablet weight, and the lubricant accounts for 0.5-2% of the tablet weight.

[0016] Preferably, the mass percentage of loxoprofen sodium in the tablet weight is 13-29%; the lactose monohydrate as the filler accounts for 26-34% of the tablet weight, and the microcrystalline cellulose as the filler accounts for 14-17% of the tablet weight; the low-substituted hydroxypropyl cellulose as the disintegrant accounts for 19-29% of the tablet weight, and the crospovidone as the disintegrant accounts for 2-11% of the tablet weight; the glidant accounts for 0.5-2% of the tablet weight; the lubricant accounts for 0.5-2% of the tablet weight.

[0017] The present invention provides another technical solution, a preparation method of a loxoprofen sodium dispersible tablet, comprising the following steps:

[0018] (1) Pretreatment of raw and auxiliary materials: Weigh the prescribed amounts of loxoprofen sodium, lactose monohydrate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone, silicon dioxide, and magnesium stearate; among them, dry loxoprofen sodium and sieve it; sieve lactose monohydrate;

[0019] (2) Premixing: Premix the loxoprofen sodium, lactose monohydrate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone, and silicon dioxide prepared in step (1) for 10 - 60 min;

[0020] (3) Final mixing: Add magnesium stearate to the powder obtained in the previous step and perform final mixing for 5 - 30 min;

[0021] (4) Tabletting: Mix the raw and auxiliary materials evenly, perform tabletting, inspection, and packaging;

[0022] (5) Packaging: Package the tablets.

[0023] Preferably, for the preparation method of the dispersible tablets, use PVDC (polyvinyl chloride / polyethylene / polyvinylidene chloride solid pharmaceutical composite hard sheet) and pharmaceutical aluminum foil for inner packaging, and use polyester / aluminum / polyethylene pharmaceutical composite film and bag for outer packaging.

[0024] The advantages and positive effects of the present invention are as follows:

[0025] (1) In the technical solution provided by the present invention, low-substituted hydroxypropyl cellulose and crospovidone are used as combined disintegrants, and lactose monohydrate and microcrystalline cellulose are used as fillers. By regulating the dosage ratio, the dispersion uniformity is improved;

[0026] (2) In the technical solution of the present invention, PVDC (polyvinyl chloride / polyethylene / polyvinylidene chloride solid pharmaceutical composite hard sheet) and pharmaceutical aluminum foil are used for inner packaging, and polyester / aluminum / polyethylene pharmaceutical composite film and bag are used for outer packaging. The double packaging improves the stability of the dispersible tablets;

[0027] (3) For the prescription provided by the present invention and the prepared product, the dissolution is improved, it can take effect quickly, and the analgesic effect can be achieved;

[0028] (4) The present invention adopts the powder direct compression process, and its preparation is simpler, more convenient to operate, reduces material loss, improves product yield, saves production cost, and is more suitable for industrial large-scale production compared with other processes such as wet granulation and dry granulation. Specific embodiments

[0029] The beneficial effects of the present invention will be further described through the following embodiments. The embodiments are for illustrative purposes only and do not limit the scope of the present invention. At the same time, obvious changes and modifications made by those of ordinary skill in the technical field to which the present invention pertains are also included within the scope of the present invention. The technical content not described in detail in the present invention is well-known technology.

[0030] Example 1:

[0031] A dispersible tablet of loxoprofen sodium is prepared from the following raw and auxiliary materials for 1000 tablets:

[0032]

[0033] Preparation method:

[0034] (1) Pretreatment of raw and auxiliary materials: Weigh the prescribed amounts of loxoprofen sodium, lactose monohydrate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone, silicon dioxide, and magnesium stearate as raw and auxiliary materials; among them, dry the loxoprofen sodium and sieve it after drying; sieve the lactose monohydrate and set it aside.

[0035] (2) Premixing: Directly premix the loxoprofen sodium, lactose monohydrate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone, and silicon dioxide prepared in step (1).

[0036] (3) Final mixing: Add magnesium stearate to the powder obtained in the previous step for final mixing.

[0037] (4) Tableting: Mix the raw and auxiliary materials evenly, carry out tableting, inspection, and packaging.

[0038] (5) Packaging: Inner package the base tablets with PVDC (solid pharmaceutical composite hard sheet of polyvinyl chloride / polyethylene / polyvinylidene chloride) and pharmaceutical aluminum foil, and outer package with polyester / aluminum / polyethylene pharmaceutical composite film and bag.

[0039] Example 2:

[0040] A dispersible tablet of loxoprofen sodium is prepared from the following raw and auxiliary materials for 1000 tablets:

[0041]

[0042] Preparation method:

[0043] (1) Pretreatment of raw and auxiliary materials: Weigh the prescribed amounts of loxoprofen sodium, lactose monohydrate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone, silicon dioxide, and magnesium stearate as raw and auxiliary materials; among them, dry the loxoprofen sodium and sieve it after drying; sieve the lactose monohydrate and set it aside.

[0044] (2) Premixing: Directly premix the loxoprofen sodium, lactose monohydrate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone, and silicon dioxide prepared in step (1).

[0045] (3) Final mixing: Add magnesium stearate to the powder obtained in the previous step for final mixing.

[0046] (4) Tabletting: Mix the raw and auxiliary materials evenly, conduct tabletting, inspection, and packaging.

[0047] (5) Packaging: Use PVDC (polyvinyl chloride / polyethylene / polyvinylidene chloride solid pharmaceutical composite hard sheet) and pharmaceutical aluminum foil for inner packaging of the substrate tablets, and use polyester / aluminum / polyethylene pharmaceutical composite film and bags for outer packaging.

[0048] Example 3:

[0049] A dispersible loxoprofen sodium tablet is prepared from the following raw and auxiliary materials for 1000 tablets:

[0050]

[0051] Preparation method:

[0052] (1) Pretreatment of raw and auxiliary materials: Weigh the prescription amounts of loxoprofen sodium, lactose monohydrate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone, silicon dioxide, and magnesium stearate; among them, dry the loxoprofen sodium and sieve it after drying; sieve the lactose monohydrate and set aside.

[0053] (2) Premixing: Directly premix the loxoprofen sodium, lactose monohydrate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone, and silicon dioxide prepared in step (1).

[0054] (3) Final mixing: Add magnesium stearate to the powder obtained in the previous step for final mixing.

[0055] (4) Tabletting: Mix the raw and auxiliary materials evenly, conduct tabletting, inspection, and packaging.

[0056] (5) Packaging: Use PVDC (polyvinyl chloride / polyethylene / polyvinylidene chloride solid pharmaceutical composite hard sheet) and pharmaceutical aluminum foil for inner packaging of the substrate tablets, and use polyester / aluminum / polyethylene pharmaceutical composite film and bags for outer packaging.

[0057] Comparative Example 1:

[0058] A dispersible loxoprofen sodium tablet is prepared from the following raw and auxiliary materials for 1000 tablets:

[0059]

[0060] Preparation method:

[0061] (1) Pretreatment of raw and auxiliary materials: Weigh the prescription amounts of loxoprofen sodium, lactose monohydrate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone, silicon dioxide, and magnesium stearate as raw and auxiliary materials; among them, dry loxoprofen sodium and sieve it after drying; sieve lactose monohydrate and set aside.

[0062] (2) Premixing: Directly premix the loxoprofen sodium, lactose monohydrate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone, and silicon dioxide prepared in step (1).

[0063] (3) Total mixing: Add magnesium stearate to the powder obtained in the previous step for total mixing.

[0064] (4) Tabletting: Mix the raw and auxiliary materials evenly, carry out tabletting, inspection, and sub-packaging.

[0065] (5) Packaging: Use PVDC (polyvinyl chloride / polyethylene / polyvinylidene chloride solid pharmaceutical composite hard sheet) and pharmaceutical aluminum foil for inner packaging of the tablets, and use polyester / aluminum / polyethylene pharmaceutical composite film and bags for outer packaging.

[0066] Comparative Example 2:

[0067] A dispersible loxoprofen sodium tablet is prepared from the following raw and auxiliary materials for 1000 tablets:

[0068]

[0069] Preparation method:

[0070] (1) Pretreatment of raw and auxiliary materials: Weigh the prescription amounts of loxoprofen sodium, lactose monohydrate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone, silicon dioxide, and magnesium stearate as raw and auxiliary materials; among them, dry loxoprofen sodium and sieve it after drying; sieve lactose monohydrate and set aside.

[0071] (2) Premixing: Directly premix the loxoprofen sodium, lactose monohydrate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone, and silicon dioxide prepared in step (1).

[0072] (3) Total mixing: Add magnesium stearate to the powder obtained in the previous step for total mixing.

[0073] (4) Tabletting: Mix the raw and auxiliary materials evenly, carry out tabletting, inspection, and sub-packaging.

[0074] (5) Packaging: Use PVDC (polyvinyl chloride / polyethylene / polyvinylidene chloride solid pharmaceutical composite hard sheet) and pharmaceutical aluminum foil for inner packaging of the tablets, and use polyester / aluminum / polyethylene pharmaceutical composite film and bags for outer packaging.

[0075] Comparative Example 3:

[0076] A dispersible tablet of loxoprofen sodium is prepared from the following raw and auxiliary materials for 1000 tablets:

[0077]

[0078] Preparation method:

[0079] (1) Pretreatment of raw and auxiliary materials: Weigh the prescription amounts of loxoprofen sodium, lactose monohydrate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone, silicon dioxide and magnesium stearate as raw and auxiliary materials; among them, dry loxoprofen sodium and sieve it after drying; sieve lactose monohydrate and reserve it.

[0080] (2) Premixing: Directly premix the loxoprofen sodium, lactose monohydrate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone and silicon dioxide prepared in step (1).

[0081] (3) Total mixing: Add magnesium stearate to the powder obtained in the previous step for total mixing.

[0082] (4) Tableting: Mix the raw and auxiliary materials evenly, carry out tableting, inspection and packaging.

[0083] (5) Packaging: The base tablets are inner packaged with PVC (solid pharmaceutical hard tablets of polyvinyl chloride) and pharmaceutical aluminum foil, and outer packaged with polyester / aluminum / polyethylene pharmaceutical composite film and bags.

[0084] Test example 1: Investigation on compressibility during tableting

[0085] Statistically compare the compressibility during tableting of the samples in the examples and comparative examples. The results are as follows:

[0086] Table 1: Investigation results during tableting

[0087]

[0088] Experimental data show that: The compressibility during tableting of the examples is good, there is no sticking phenomenon, the tablet surface is smooth, there is obvious sticking in Comparative Example 1, although there is no sticking in Comparative Example 2, but the compressibility is poor and there is an obvious sense of jerk during tableting, that is, the tableting process of the examples of the present invention is superior to the comparative examples.

[0089] Test example 2: Investigation on dispersion uniformity

[0090] Take 6 test samples, and they should all disintegrate and pass through the sieve within 3 minutes. If a small amount cannot pass through the sieve, but has softened into a light floating mass without a hard core, it meets the requirements.

[0091] Table 2: Inspection results of dispersion uniformity

[0092]

[0093] The test data shows that: all of the dispersible tablets of the example passed through a 710 μm sieve within 2.6 min, while the dispersible tablets of the comparative example passed through the 710 μm sieve within 2.8 min to 3.5 min. That is, the dispersing effect of the example of the present invention is better than that of the comparative example.

[0094] Test Example 3: Stability test

[0095] (1) Stress testing

[0096] Take the loxoprofen sodium dispersible tablets obtained by packaging in Example 2 and Comparative Example 3 of the present invention, and place them under the conditions of high temperature (60°C ± 2°C), high humidity (25°C ± 2°C / RH 75% ± 5%), and light (4500 lx ± 500 lx) for stress testing. Samples were taken at 10 days and 30 days to detect appearance, moisture, hardness, related substances and content. The results are shown in the following table:

[0097] Table 3: Results of stress testing of loxoprofen sodium dispersible tablets

[0098]

[0099]

[0100] As shown in Table 3, within 30 days of stress testing, there were no obvious changes in the appearance, hardness, moisture, related substances and content of Example 2; the moisture of Comparative Example 3 increased significantly and the hardness decreased significantly under high humidity conditions (25°C ± 2°C / RH 90% ± 5%). It shows that the packaging method of using PVDC (polyvinyl chloride / polyethylene / polyvinylidene chloride solid pharmaceutical composite hard sheet) and pharmaceutical aluminum foil for inner packaging, and polyester / aluminum / polyethylene pharmaceutical composite film and bag for outer packaging can significantly improve the product stability.

[0101] (2) Accelerated and long-term stability testing

[0102] Place the dispersible tablets prepared and packaged in Example 2 and Comparative Example 3 under the conditions of accelerated test (40°C ± 2°C / RH 75% ± 5%) and long-term (25°C ± 2°C / RH 65 ± 5%) for investigation. Appearance, hardness, moisture, related substances and content were investigated at 0, 1, and 3 months respectively. Related substances and content were determined by HPLC method. The results are shown in the following table.

[0103] Table 4: Results of accelerated and long-term stability testing of loxoprofen sodium dispersible tablets

[0104]

[0105]

[0106] As shown in Table 3, within 3 months of the accelerated and long-term tests, there were no significant changes in the properties, hardness, moisture content, related substances, and content of Example 2; significant changes in the moisture content and hardness of Comparative Example 3 were observed compared with those at month 0. It shows that the packaging method of using PVDC (solid medicinal composite hard sheet of polyvinyl chloride / polyethylene / polyvinylidene chloride), medicinal aluminum foil for inner packaging, and polyester / aluminum / polyethylene medicinal composite film and bag for outer packaging can significantly improve the product stability.

[0107] Test Example 4: Dissolution curve investigation

[0108] The dissolution curves of the dispersible tablets of loxoprofen sodium in Example 2 were compared with those of the reference preparation ( produced by Daiichi Sankyo (Shanghai) Co., Ltd.) in hydrochloric acid medium, acetic acid medium, phosphoric acid medium, and water medium, and the results are as follows:

[0109] (1) pH 1.2 hydrochloric acid solution (paddle method, 900 ml, 75 rpm)

[0110] The dissolution behaviors of the dispersible tablets of loxoprofen sodium in this product and the reference preparation in hydrochloric acid medium are shown in the following table.

[0111] Table 5: Dissolution comparison results in pH 1.2 hydrochloric acid solution

[0112]

[0113] (2) pH 4.0 acetate solution (paddle method, 900 ml, 75 rpm)

[0114] Table 6: Dissolution comparison results in pH 4.0 acetate solution

[0115]

[0116] (3) pH 6.8 phosphate solution (paddle method, 900 ml, 75 rpm)

[0117] Table 7: Dissolution comparison results in pH 6.8 phosphate solution

[0118]

[0119]

[0120] (4) Water (paddle method, 900 ml, 75 rpm)

[0121] Table 8: Dissolution comparison results in water

[0122]

[0123] The above dissolution results show that: the cumulative dissolution of all samples in each medium reached over 85% at 20 minutes. The dissolution of the sample in Example 2 was faster than that of the reference preparation, reaching over 85% in 10 minutes, indicating that the product in Example 2 can dissolve and release rapidly, with a faster onset of action than the reference preparation.

Claims

1. A loxoprofen sodium dispersible tablet, characterized in that, The described dispersible tablets comprise loxoprofen sodium, disintegrants, fillers, glidants and lubricants.

2. The dispersible tablets according to claim 1, characterized in that, The filler is one or more of starch, lactose monohydrate or microcrystalline cellulose, preferably a combination of microcrystalline cellulose and lactose monohydrate.

3. The dispersible tablets according to claim 1, characterized in that, The disintegrant is one or more of low-substituted hydroxypropyl cellulose, crospovidone or sodium carboxymethyl starch, preferably a combination of low-substituted hydroxypropyl cellulose and crospovidone.

4. The dispersible tablets according to claim 1, characterized in that, The glidant is silicon dioxide and the lubricant is magnesium stearate.

5. The dispersible tablets according to claim 1, characterized in that, In each of the dispersible tablets, the mass percentage of loxoprofen sodium in the tablet weight is 13 - 29%, the filler accounts for 43 - 48% of the tablet weight, the disintegrant accounts for 21 - 39% of the tablet weight, the glidant accounts for 0.5 - 2% of the tablet weight, and the lubricant accounts for 0.5 - 2% of the tablet weight.

6. The dispersible tablets according to claim 1, characterized in that, The mass percentage of loxoprofen sodium in the tablet weight is 13 - 29%; the lactose monohydrate as the filler accounts for 26 - 34% of the tablet weight, and the microcrystalline cellulose as the filler accounts for 14 - 17% of the tablet weight; the low-substituted hydroxypropyl cellulose as the disintegrant accounts for 19 - 29% of the tablet weight, and the crospovidone as the disintegrant accounts for 2 - 11% of the tablet weight; the glidant accounts for 0.5 - 2% of the tablet weight; the lubricant accounts for 0.5 - 2% of the tablet weight.

7. The preparation method of the dispersible tablets according to claim 1, characterized in that, It includes the following steps: (1) Pretreatment of raw and auxiliary materials: Weigh the prescribed amounts of loxoprofen sodium, lactose monohydrate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone, silicon dioxide and magnesium stearate; among them, dry and sieve loxoprofen sodium; sieve lactose monohydrate. (2) Premixing: Premix the loxoprofen sodium, lactose monohydrate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone and silicon dioxide prepared in step (1) for 10 - 60 min. (3) Final mixing: Add magnesium stearate to the powder obtained in the previous step and conduct final mixing for 5 - 30 min. (4) Tableting: Mix the raw and auxiliary materials evenly, conduct tableting, inspection and sub-packaging. (5) Packaging: Package the base tablets.

8. The preparation method of the dispersible tablets according to claim 7, characterized in that, For inner packaging, use PVDC (solid pharmaceutical composite hard sheet of polyvinyl chloride / polyethylene / polyvinylidene chloride) and pharmaceutical aluminum foil; for outer packaging, use polyester / aluminum / polyethylene pharmaceutical composite film and bags.

Images