CN1245968C - Method for preparing naproxen sodium release tablet - Google Patents
Method for preparing naproxen sodium release tablet Download PDFInfo
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- CN1245968C CN1245968C CN 02137348 CN02137348A CN1245968C CN 1245968 C CN1245968 C CN 1245968C CN 02137348 CN02137348 CN 02137348 CN 02137348 A CN02137348 A CN 02137348A CN 1245968 C CN1245968 C CN 1245968C
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- naproxen sodium
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- release tablet
- hypromellose
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Abstract
The present invention specifically relates to a preparation method of a naproxen sodium sustained-release tablet, which belongs to the field of chemical medicine preparation. In the present invention, the naproxen sodium sustained-release tablet for relieving pains and resisting inflammation is obtained through a scientific design by adopting hydroxypropyl methyl cellulose (HPMC) as a high molecular substance as a framework material and naproxen sodium as an active ingredient and adding a certain quantity of release velocity regulating agent. The naproxen sodium sustained-release tablet of the present invention has the characteristics of quick effect taking, powerful medicinal effects, acting time prolongation and few toxic and side effects. Both the property of the naproxen sodium sustained-release tablet in vivo and the property of the naproxen sodium sustained-release tablet in vitro are similar to those of Naprelan as a reference substance. Compared with a tabletting process of coated granules, the present invention has the advantages of simple operation, low cost, easy control and easy industrialized production.
Description
Technical field
The invention belongs to chemical pharmacy field, relate to a kind of pharmaceutical methods, be specifically related to a kind of preparation method of naproxen sodium release tablet.
Background technology
Naproxen is the antipyretic analgesic that U.S. Xin Disi drugmaker (Syntex Co.) succeeds in developing, and belongs to NSAID (non-steroidal anti-inflammatory drug), because its good medical effect and lower toxic reaction and be subjected to patient's welcome deeply.Naproxen sodium (Naproxen Sodium) is the sodium salt of naproxen, has stronger anti-inflammatory and analgesic effect.Its chemical structural formula is as follows,
The clinical pain that is mainly used in treatment rheumatism, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, prolapse of lumbar intervertebral disc and various light, moderate.The same naproxen of naproxen sodium curative effect, but after it enters stomach is scattered in the gastric juice immediately and is precipitated as the granule naproxen, thus than the easier absorption of naproxen, prove effective fast, effect is strong and toxic and side effects is low.
Domesticly began to manufacture experimently naproxen sodium in 1985, synthetic simple based on it, have characteristics such as good water solubility, absorption is rapid, rapid-action, toxic and side effects is low, develop in succession and gone on the market naproxen sodium crude drug, conventional tablet, capsule, suppository and injection.Wherein naproxen sodium crude drug and naproxen sodium tablet are recorded by Chinese Pharmacopoeia version in 2000.But the ordinary tablet dosage is big, needs day clothes 2～3 times, causes the fluctuation of blood drug level in the body bigger, the patient Yi Yinfa gastrointestinal tract toxic and side effects that needs are taken medicine for a long time.
The release of existing naproxen slow releasing preparation is slower on the domestic market, and clinical performance curative effect is slower.The U.S. released naproxen sodium release tablet by Wyeth-Ayerst company in 1996, was that compacting is in blocks after adopting the enteric material crylic acid resin with the medicine-containing particle coating, trade name Naprelan.This product has rapid release and slow release dual function, and 30min can onset in vivo, and alleviating pain, and blood concentration rapidly is stable, and sustainable 24 hours of analgesic activity liked by the patient, but complicated process of preparation costs an arm and a leg.
Summary of the invention
The purpose of this invention is to provide a kind of rapid-action, strong drug action, prolong action time and toxic and side effects low, analgesia, anti-inflammatory preparation naproxen sodium release sheet that inside and outside character is all similar to the Naprelan reference substance.
The present invention adopts polymer substance hypromellose (HPMC) as framework material, is active component with the naproxen sodium, adds a certain amount of rate of release regulator, makes the naproxen sodium release sheet through the science design.
The hydroxy propyl cellulose prime system hydrophilic gel material that the present invention adopts has and expands and adhesion property, the time of staying that can prolong drug middle part on gastrointestinal tract.The matrix type sustained-release preparation that the present invention adopts is more simple to operate than coated granule tablet forming technique, and cost is low, is easy to control, is easy to suitability for industrialized production.
Characteristics such as this medical instrument has the dual characteristics of rapid release and slow release, takes every day once, and is rapid-action, and the length of holding time has blood drug level and stablizes, and toxic and side effects is little.
The present invention prepares as follows.
1. moist granulation method tabletting
Get sustained-release matrix material hypromellose (K4M) 6%～12%, naproxen sodium 83%～92%, rate of release regulator carboxymethyl starch sodium 0.5%～5% is behind the mix homogeneously, add adhesive polyvidone alcoholic solution system soft material, sieve system wet granular, drying, granulate, add 0.5%～2% magnesium stearate as lubricant, tabletting is made the slow releasing tablet that contains naproxen sodium 200～1000mg.
2. direct powder compression
Get sustained-release matrix material hypromellose K4M 6%～12%, naproxen sodium 80%～92%, rate of release regulator carboxymethyl starch sodium 0.5%～5%, filler microcrystalline Cellulose 0～8%, behind the mix homogeneously, add 0.5%～2% magnesium stearate as lubricant, direct compression is made the slow releasing tablet that contains naproxen sodium 200～1000mg.
Also available sustained-release matrix material is hypromellose K15M, hypromellose K100M, hypromellose E4M, hypromellose F4M in the above-mentioned preparation method, ethyl cellulose, carbomer 934 P, Acritamer 940 P, sodium alginate, chitosan and stearic acid.Also available rate of release regulator is a polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose and microcrystalline Cellulose.Also available adhesive is to be the ethyl cellulose solution and the hypromellose solution of solvent with 50%～100% ethanol.Also available filler is a calcium sulfate, lactose, polyvidone and amylum pregelatinisatum.
The present invention adopts rat to study the absorption site and the absorption dynamics feature of naproxen sodium in body intestinal perfusion absorption experiment, it is good that the result shows that naproxen sodium absorbs at the small intestinal position, infiltration rate descends successively by the order of jejunum, ileum, duodenum, colon, medicine presents one-level absorption dynamics feature and mechanism of absorption is passive absorption in the absorption of intestinal, and the absorption window of medicine is that colon is with the upper part.Experimental result shows that also the infiltration rate constant of colon is about 3/10 of little intestinal segment, when the slow releasing preparation of obeying design naproxen sodium day once, should prolong the holdup time at preparation middle part on gastrointestinal tract.
Naproxen sodium release tablet of the present invention is that reference substance has carried out bioavailability test in test of release in vitro degree and the body with external product Naprelan 375, and the result is as follows,
1, release in vitro degree test
Experimental condition: carry out rotating speed 50rpm by Chinese Pharmacopoeia version release test in 2000 oar method.37 ℃ ± 0.5 ℃ of temperature.
The result: the naproxen sodium release matrix tablet of above-mentioned preparation, its pH-at pH1.2 hydrochloric acid solution+0.05% tween 80, pH5.0 phosphate buffer+0.05% tween 80, pH6.8 and pH7.4 phosphate buffer discharges percentage rate-time graphics and sees Fig. 1.Be reference substance with external product Naprelan 375 simultaneously, measured its release profiles in corresponding release medium, the release result f of comparison film Naprelan and test film
2The similar factors method is to verifying, the result confirms naproxen sodium release tablet of the present invention and the release all similar of reference substance in external each pH medium.
Medicine of the present invention carries out external pH gradient experiment at the intravital environment of simulation, changes the medium of different pH value in the regular hour.Wherein o～2h release medium is pH1.2 hydrochloric acid solution+0.05% tween 80, and 2～3h release medium is pH5.0 phosphate buffer+0.05% tween 80, and 3～5h release medium is the pH6.8 phosphate buffer, and 5～6h release medium is the pH7.4 phosphate buffer.f
2The similar factors statistical test is the result show, two kinds of preparation release profiles all similar in various media.Naproxen sodium release sheet of the present invention release in 36 minutes in the pH6.8 phosphate buffer discharged greater than 90% in about 25%, 2 hour about 70%, 6 hour.
Table 1 is the release result of naproxen sodium test film in the pH gradient solution.
Table 2 is f
2Similar factors method result of determination.
Wherein criterion: f
2Value＞50 o'clock two release profiles are similar.
Table 1
| Time (h) | 1 | 2 | 3 | 4 | 5 | 6 | Meansigma methods | SD |
| 0.5 1 1.5 2 3 4 6 | 12.38 16.50 19.97 28.13 60.88 83.56 90.57 | 12.87 18.09 22.72 30.73 64.19 86.59 91.96 | 12.60 18.09 22.53 30.92 61.63 85.61 92.24 | 13.07 18.75 22.15 31.31 67.43 84.75 91.25 | 12.53 18.28 20.99 31.11 64.33 85.72 92.61 | 13.18 18.63 23.69 30.93 65.74 84.92 91.75 | 12.77 18.06 22.01 30.52 64.03 85.19 91.73 | 0.32 0.81 1.33 1.19 2.46 1.03 0.73 |
Table 2
| T(h) | pH＝1.2 | pH＝5.0 | pH＝6.8 | pH＝7.4 | The pH gradient | |||||
| Contrast | Test | Contrast | Test | Contrast | Test | Contrast | Test | Contrast | Test | |
| 0.5 1 1.5 2 3 4 6 | 13.84 18.68 22.89 30.62 37.25 38.07 38.40 | 12.08 16.96 21.54 29.41 34.85 36.73 37.36 | 23.95 28.99 39.12 54.86 60.37 62.75 65.17 | 20.53 25.98 35.87 51.52 59.60 67.21 71.94 | 25.16 48.86 56.62 68.62 83.10 89.82 93.55 | 25.37 45.34 56.90 70.54 83.06 89.75 92.26 | 28.85 45.92 59.20 71.09 83.76 89.50 92.71 | 29.18 46.47 58.38 71.44 84.14 89.33 92.63 | 13.10 17.78 20.79 28.18 65.19 85.97 92.27 | 12.77 18.06 22.01 30.52 64.03 85.19 91.73 |
| f 2Value | 86.87 | 91.02 | 86.21 | 98.03 | 90.76 | |||||
2. bioavailability test in the body
Experimental rabbit is oral external reference substance Naprelan 375 respectively, and every contains naproxen sodium 412.5mg and is equivalent to naproxen 375mg and naproxen sodium release test film of the present invention (dosage is the same).Result of the test shows slow releasing tablet of the present invention and external its inside and outside feature similarity of reference substance Naprelan.The bioequivalence statistic analysis result shows, the AUC of slow releasing tablet of the present invention
0-∞And C
Max90% confidence interval drop on respectively reference substance 86.7%～116.3% and 75.1%～100.6% between, relative bioavailability is 101.6%, according to bioequivalence criterion, i.e. AUC
0-∞And C
Max90% confidence interval should drop on respectively reference substance 80%～125% and 70%～145% between, can judge two preparation bioequivalences.
Pharmaceutic adjuvant that the present invention adopts is commercially available.
Description of drawings
The three-dimensional release profiles of this naproxen sodium of Fig. 1 tablet
Fig. 2 is the average blood drug level behind oral naproxen sodium release sheet of rabbit and the comparison film Naprelan
Wherein ▲ be this naproxen sodium release sheet
■ is comparison film naprelan 375
The specific embodiment
Embodiment 1
Get sustained-release matrix material hypromellose K4M 7%, naproxen sodium 90%, rate of release regulator carboxymethyl starch sodium 2% is behind the mix homogeneously, add adhesive 5% polyvidone alcoholic solution system soft material, sieve system wet granular, drying, granulate, add 1% magnesium stearate as lubricant, tabletting is made the slow releasing tablet that contains naproxen sodium 412.5mg.
Embodiment 2
Get sustained-release matrix material hypromellose K15M 7%, naproxen sodium 90%, rate of release regulator polyvinylpolypyrrolidone 2% is behind the mix homogeneously, add adhesive 5% ethyl cellulose alcoholic solution system soft material, sieve system wet granular, drying, granulate, add 1% magnesium stearate as lubricant, tabletting is made the slow releasing tablet that contains naproxen sodium 500mg.
Embodiment 3
Get sustained-release matrix material hypromellose K100M 10%, naproxen sodium 84%, rate of release regulator carboxymethyl starch sodium 2%, filler microcrystalline Cellulose 3% behind the mix homogeneously, adds 1% magnesium stearate as lubricant, direct compression is made the slow releasing tablet that contains naproxen sodium 412.5mg.
Embodiment 4
Get sustained-release matrix material hypromellose K4M 10%, naproxen sodium 84%, rate of release regulator carboxymethyl starch sodium 2%, filler lactose 3% behind the mix homogeneously, adds 1% magnesium stearate as lubricant, direct compression is made the slow releasing tablet that contains naproxen sodium 500mg.
Claims (4)
1, a kind of preparation method of naproxen sodium release tablet, it is characterized in that adopting the polymer substance hypromellose as framework material, with the naproxen sodium is active component, add the rate of release regulator, adhesive and filler make the naproxen sodium release sheet, its content of described hypromellose is 6%～12%/gross weight, is selected from hypromellose K4M, hypromellose K15M or hypromellose K100M; Described its content of rate of release regulator is 0.5%～5%/gross weight, is selected from carboxymethyl starch sodium, polyvinylpolypyrrolidone or microcrystalline Cellulose.
2, by the method for claim 1, it is characterized in that it is the povidone solution of solvent that described adhesive is selected from 50%～100%g/ml ethanol, ethyl cellulose solution or hypromellose solution.
3, by the method for claim 1, it is characterized in that described filler is selected from microcrystalline Cellulose, calcium sulfate, lactose, polyvidone or amylum pregelatinisatum.
4, by the process of claim 1 wherein that described hypromellose content is 7%～10%/gross weight.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02137348 CN1245968C (en) | 2002-10-09 | 2002-10-09 | Method for preparing naproxen sodium release tablet |
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| CN 02137348 CN1245968C (en) | 2002-10-09 | 2002-10-09 | Method for preparing naproxen sodium release tablet |
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| CN1404826A CN1404826A (en) | 2003-03-26 |
| CN1245968C true CN1245968C (en) | 2006-03-22 |
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| EP2177215A1 (en) | 2008-10-17 | 2010-04-21 | Laboratorios Del. Dr. Esteve, S.A. | Co-crystals of tramadol and NSAIDs |
| CN102532033A (en) * | 2012-02-29 | 2012-07-04 | 江西杏林白马药业有限公司 | Telmisartan salifying process |
| CN106880614A (en) * | 2017-04-06 | 2017-06-23 | 地奥集团成都药业股份有限公司 | A kind of Naproxen Sustained Release Tablet and preparation method thereof |
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