CN103655504B - Dexketoprofen trometamol quick-release and slow-release double-layer tablet and preparation technology thereof - Google Patents
Dexketoprofen trometamol quick-release and slow-release double-layer tablet and preparation technology thereof Download PDFInfo
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Abstract
The present invention relates to dexketoprofen trometamol quick-release and slow-release double-layer tablet and preparation technology thereof, it is characterised in that provide one process of preparing simply and easily, the double-layer tablet that compacting is collectively constituted by release layer and slow release layer.Release layer of the present invention is mainly by dexketoprofen trometamol, disintegrating agent, diluent, binding agent, and lubricant forms, and slow release layer is mainly made up of dexketoprofen trometamol, slow-release material, diluent, binding agent, lubricant.In the dexketoprofen trometamol quick-release and slow-release double-layer tablet of the present invention, the release of immediate release section can make medicine reach effective blood drug concentration quickly, and slow-released part slowly discharges, and can reach to take once the sustainable release dexketoprofen trometamol effect of 12 hours.Can overcome the disadvantages that existing dexketoprofen trometamol preparation is taken often clinically, the jiggly deficiency of blood drug level, thus increase patient's compliance and stable curative effect, effect that toxic and side effects is little.This product preparation method is simple, and supplementary material used is easy to get, and is suitable for industrialized production, has good application prospect.
Description
Technical field
The present invention relates to the new drug formulation preparation of a kind of nonsteroidal anti-inflammatory drug preparation category, preparation technology particularly to dexketoprofen trometamol quick-release and slow-release double-layer tablet, it is characterized in that the double-layer tablet being jointly pressed into by release layer and slow release layer, belong to field of medicaments.
Background technology
Double-layer sustained release tablets, is that one or both medicines are made the Tabules collectively constituted by release layer and slow release layer two parts.Release layer and slow release layer can be same drug, it is also possible to be two kinds and have synergistic medicine.Disease can be played a rapid recovery or therapeutical effect by release layer at short notice, reduces seizure of disease and brings the harm of patient, and slow release layer is used for maintaining internal blood drug level, and symptom plays an effect continuing to curative effect.This preparation is possible not only to reduce medicining times, it is also possible to allow patient that some drugs will not produce bigger dependence effect, and can reduce the peak valley difference of medicine, rapid release and slow release effect is perfectly combined
Ketoprofen belongs to NSAID (non-steroidal anti-inflammatory drug), it is adaptable to antipyretic, alleviates moderate pain such as arthritis, neuralgia, myalgia, headache, migraine, toothache, flu and flu-like symptom；Its raceme is often used to treat all types of arthritis, postoperative pain, cancer pain and acute gout etc. clinically；But there are some researches prove, left-handed ketoprofen is the nonactive laevoisomer of ketoprofen, without antipyretic, analgesia and antiinflammatory action, it it is the raceme KPF main cause that gastrointestinal reaction occurs；And d-isomer is the main component playing therapeutical effect, its activity is 2 times of racemic modification；But owing to dexketoprofen is insoluble drug, now prepare its water soluble drug, i.e. dexketoprofen trometamol, it can absorb rapidly and be distributed in vivo, and specific activity free acid is high, its Cmax specific ionization acid is high, Tmax specific ionization acid is little, is beneficial to the treatment of acute sharp pain, and additionally it is little to gastrointestinal toxicity specific ionization acid, patient is had better toleration, there is wide potential applicability in clinical practice.
But the existing dexketoprofen trometamol preparation half-life is short clinically, and general formulation needs to take day three to four times, blood concentration fluctuation is relatively big, and its slow releasing preparation release is slow, it is impossible to discharges rapidly active constituents of medicine, makes maximum plasma concentration relatively low；And the dexketoprofen trometamol Fast Stripping in release layer and quick symptom relief after the double-layer sustained release preparation oral that we develop, slow release layer is slow releasing then, makes easing pain and diminishing inflammation effect maintain 12 hours as long as, reduces medicining times, improve the compliance of patient, and alleviate untoward reaction.
Summary of the invention
It is an object of the invention to provide a kind of dexketoprofen trometamol quick-release and slow-release double-layer tablet, wherein the release of immediate release section can make medicine reach effective blood drug concentration quickly, and slow-released part slowly discharges, and plays and maintains effective blood drug concentration steady, uniform.Thus reaching to reduce medicining times, increase patient's compliance and stable curative effect, effect that toxic and side effects is little.
For solving above-mentioned technical problem, present invention provide the technical scheme that
The double-layer sustained release tablets of dexketoprofen trometamol provided by the invention includes slow release layer and release layer, it is characterized in that: described slow release layer is mainly made up of dexketoprofen trometamol, disintegrating agent, diluent, binding agent, lubricant forms, and described slow release layer is mainly made up of dexketoprofen trometamol, slow-release material, diluent, binding agent, lubricant.
Described double-layer sustained release tablets, the effective dose of dexketoprofen trometamol is 10mg～120mg.
Described double-layer sustained release tablets, its release layer and the slow release layer ratio containing principal agent amount is 1: (1～5).
Described double-layer sustained release tablets, it is characterized in that described slow-release material can be selected for one or more in hydroxypropyl methylcellulose, ethyl cellulose, methylcellulose, phthalic acid hydroxypropyl methylcellulose, cellulose acetate-phthalate, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, cellulose acetate, cellulose diacetate, Triafol T, hexadecanol, glyceryl monostearate, Brazil wax, hydroxymethyl cellulose, it is preferable that hydroxypropyl methylcellulose and ethyl cellulose.
Described double-layer sustained release tablets, it is characterised in that described disintegrating agent can be selected for cross linked polyvinyl pyrrolidone, carboxymethyl starch is received, low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose are received one or more, it is preferable that cross-linked carboxymethyl cellulose is received.
Described double-layer sustained release tablets, it is characterized in that described diluent can be selected for one or more in lactose, pregelatinized Starch, microcrystalline Cellulose, mannitol, low-substituted hydroxypropyl cellulose, polyvinyl alcohol, poly-O-phthalic acid ethyl acetate, Polyethylene Glycol, ethanol, it is preferable that lactose, microcrystalline Cellulose.
Described double-layer sustained release tablets, it is characterized in that described binding agent can be selected for one or more in water, ethanol, dehydrated alcohol, starch slurry, polyvidone, cross linked polyvinyl pyrrolidone, hydroxypropyl methylcellulose and/or other cellulose families, it is preferable that cross linked polyvinyl pyrrolidone.
Described double-layer sustained release tablets, it is characterised in that described lubricant can be selected for one or more in magnesium stearate, micropowder silica gel, Pulvis Talci, hydrogenated vegetable oil, polyethylene glycols, sodium laurylsulfate, it is preferable that magnesium stearate.
Described double-layer sustained release tablets, it is characterised in that count by weight percentage, it consists of:
Release layer:
Slow release layer:
The dexketoprofen trometamol preferred prescription of quick-release and slow-release double-layer tablet provided by the present invention is:
Described release layer mainly comprises the following composition accounting for release layer percentage by weight:
Release layer:
Described slow release layer mainly comprises the following composition accounting for slow release layer percentage by weight:
Slow release layer:
The preparation method that present invention also offers dexketoprofen trometamol quick-release and slow-release double-layer tablet, it is characterised in that: the method comprises the following steps:
1, prepared by immediate-release granules
The each component weighing recipe quantity crosses 100 mesh sieves respectively, then by crude drug, diluent, disintegrating agent mix homogeneously, with binding agent soft material, 20 mesh sieve wet granulars, 60 DEG C of forced air dryings, 20 mesh sieve granulate, adds lubricant mixing, obtains release layer granule.
2, prepared by slow-releasing granules
The each component weighing recipe quantity crosses 100 mesh sieves respectively, then by crude drug, slow-release material, diluent, mix homogeneously, with binding agent soft material, 20 mesh sieve wet granulars, 60 DEG C of forced air dryings, 20 mesh sieve granulate, adds lubricant mixing, obtains slow release layer granule.
3, tabletting
First light pressure release layer granule becomes loose, adds slow release layer granule extrusion forming, obtains double-layer tablet.
Process chart is shown in Fig. 1.
Described double-layer sustained release tablets, it is characterised in that described double-layer sustained release tablets is according to the device of dissolution method (2010 editions two annex XD the second methods of Chinese Pharmacopoeia), 900mL is solvent, rotating speed is 100 turns per minute, and temperature is 37 DEG C, operates in accordance with the law, respectively at 5min, 15min, 0.5,1.0,2.0,4.0,6.0,8.0,12.0h sampling, each 5mL, with the filtering with microporous membrane in 0.8 μm of aperture, and in process container, supplement the above-mentioned solvent of same volume in time；Discarding just filtrate, precision measures subsequent filtrate 2mL and puts in 10mL volumetric flask, dilute constant volume, as need testing solution；Separately take distilled water (pH7) as reference substance solution, according to spectrophotography, measure trap respectively at the wavelength place of 260nm, calculate the every burst size at different time respectively.Slow releasing tablet prepared by the present invention is in the accumulative release 15%～35% of 30min, 6h cumulative release 60%～85%, 12h cumulative release more than 90%.
Accompanying drawing explanation
Fig. 1 is the dexketoprofen trometamol quick-release and slow-release double-layer tablet preparation technology flow chart of the present invention.
Fig. 2 is dexketoprofen trometamol quick-release and slow-release double-layer tablet hydroxypropyl methylcellulose (HPMC) different size of the present invention influence curve figure to slow release layer release.
The different amounts of the dexketoprofen trometamol quick-release and slow-release double-layer tablet HPMCK4M that Fig. 3 is the present invention influence curve figure to slow release layer release.
Fig. 4 is the different amounts of the dexketoprofen trometamol quick-release and slow-release double-layer tablet EC of the present invention influence curve figure to slow release layer release.
Fig. 5 is the different amounts of the dexketoprofen trometamol quick-release and slow-release double-layer tablet MCC of the present invention influence curve figure to slow release layer release.
Fig. 6 is the different amounts of the dexketoprofen trometamol quick-release and slow-release double-layer tablet lactose of the present invention influence curve figure to slow release layer release.
Fig. 7 is the dexketoprofen trometamol quick-release and slow-release double-layer tablet binding agent variety classes of the present invention influence curve figure to slow release layer release.
Fig. 8 is the dexketoprofen trometamol quick-release and slow-release double-layer tablet Different Preparation of the present invention influence curve figure to slow release layer release.
Fig. 9 is the dexketoprofen trometamol quick-release and slow-release double-layer tablet difference compression force of the present invention influence curve figure to slow release layer release.
Figure 10 be the dexketoprofen trometamol quick-release and slow-release double-layer tablet of the present invention in different release medium, the influence curve figure of slow release layer release.
Figure 11 be the dexketoprofen trometamol quick-release and slow-release double-layer tablet of the present invention under different device, the influence curve figure of slow release layer release.
Figure 12 be the dexketoprofen trometamol quick-release and slow-release double-layer tablet of the present invention under different rotating speeds, the influence curve figure of slow release layer release.
Figure 13 is the dexketoprofen trometamol quick-release and slow-release double-layer tablet optimum prescribed study result curve figure of the present invention.
Specific embodiment
Data below in conjunction with embodiment and formulation study, checking are expanded on further technical scheme:
Embodiment:
Prescription (by 1000)
Release layer:
Slow release layer:
In pharmaceutical preparation, principal agent is mutual with the impact of adjuvant, briefly, it is simply that the characteristic of principal agent determines the selection of adjuvant, and the characteristic of adjuvant determines the drug effect of principal agent.This interactional relation is studied always present in pharmaceutical preparation in the whole process of Clinical practice.
Hereinafter experiments show that: the present invention is by the every experiment to adjuvant, thus selecting to be suitable for the object of the invention adjuvant, determining the dosage of each component of tablet, improving the process of production technology.
Test the impact that 1 disintegrating agent CMS-Na and MCC mixing uses
When investigation CMS-Na and MCC ratio is 0: 10,2: 8,4: 6,6: 4,8: 2,10: 0 respectively, the disintegration time of prepared release layer, its disintegrate is characterized as:
From the above results, when CMS-Na and MCC ratio is 2: 8, disintegration time is the shortest.
Test the impact of 2 variety classes disintegrating agents
Prepare CMS-Na and L-HPC and MCC ratio and be the release layer of 2: 8, measure disintegration time.Result is 58s and 302s respectively, therefore selects CMS-Na as the disintegrating agent in release layer.
Test the impact of 3 lactose different specific weights
Prepare release layer when lactose accounts for tablet weight 40%, 50%, 60% respectively, and measure disintegration time.Result is 62s, 58s, 65s.
The impact of the different binding agent of experiment 4
Prepare the release layer making binding agent with 95% alcoholic solution of 10%PVPK30,95% alcoholic solution, 75% alcoholic solution respectively, and measure disintegration time.Result is 58s, 35s, 85s respectively.
Test 5 release layer orthogonal experiments
According to above-mentioned experiment of single factor, select the disintegration time bigger ratio (A) of CMS-Na and MCC of impact, lactose consumption (B), three factors of binding agent kind (C) are carried out orthogonal design, and carried out 9 experiments, to determine optimum prescription.
Test 6 tablet making technology
The optimum prescription that release layer is determined, has investigated wet granule compression tablet and direct powder compression respectively.
Wet granulation: weigh recipe quantity and cross the crude drug of 80 mesh sieves and each adjuvant, fully mixing, with 10%PVPK3095% ethanol alcoholic solution soft material, 20 mesh sieves are granulated, 50 DEG C of drying, then with 20 mesh sieve granulate, add magnesium stearate mixing, obtain release layer granule, use single punch tablet machine tabletting.
Direct powder compression: weigh recipe quantity and cross the crude drug of 80 mesh sieves and each adjuvant, fully mixing, directly use single punch tablet machine tabletting.
Result wet granulation institute tablet agent disintegration time is 35s, powder formulation tabletting disintegration time is 32s, both difference is little, but in tableting processes, direct powder compression be can be observed, tablet corner angle are easily broken off, and consider that the preparation of later stage slow release layer needs wet granulation, therefore select wet granule compression tablet preparation technology.
Test the impact on release layer disintegration time of 7 hardness
When investigating hardness respectively 2-4,4-6,6-8kg, the disintegration time of release layer, its disintegrate is characterized as:
It is shown that the disintegration time of release layer is had difference by the pressure within the scope of investigate 3, hardness is tablet gloss appearance when 4-6kg, good moldability, and disintegration time is suitable for.
Test the impact on disintegration time of 8 punch dies
It is respectively adopted the punch die compacting release layer of 8mm, 10mm, and measures its disintegration time, its result respectively 63s, 35s.It is shown that select the punch die of 10mm can better meet the requirement of experiment.
The experiment 9HPMC model impact on slow release layer drug release
According to embodiment adopt different size HPMC prepare slow release layer, its release characteristic is:
And the release profiles of the slow releasing tablet of these three different size HPMC is shown in Fig. 2.
Experiment 10 according to embodiment adopt different amounts of HPMCK4M prepare slow release layer, its release characteristic is:
And the release profiles of the slow releasing tablet of the HPMCK4M of these three different amounts is shown in Fig. 3.
Experiment 11 according to embodiment adopt different amounts of EC prepare slow release layer, its release characteristic is:
And the release profiles of the slow releasing tablet of the EC of these three different amounts is shown in Fig. 4.
Experiment 12 adopts the MCC of the different amounts slow release layer prepared according to embodiment, and its release characteristic is:
And the release profiles of the slow releasing tablet of the MCC of these three different amounts is shown in Fig. 5.
The slow release layer that experiment 13 is prepared according to the lactose of embodiment employing different amounts, its release characteristic is:
And the release profiles of the slow releasing tablet of the lactose of these three different amounts is shown in Fig. 6.
Experiment 14 according to embodiment adopt variety classes binding agent (70% ethanol, 95% ethanol, 10%PVPK30 95% alcoholic solution) slow release layer prepared, its release characteristic is:
Adopting slow releasing tablet prepared by both the above binding agent, its rate of release there was no significant difference.But in pelletization, it has been found that when with 70% alcoholic solution as binding agent, it can make HPMC rapid gellation, viscosity is relatively big, and not easily uniformly and difficulty of sieving, dried pellet hardness is big, and the tablet pressed has mottle, therefore gives up for humidity；And adopt 95% ethanol as binding agent prepare the easy friability of granule, particle size distribution is uneven, and mobility is bad, and tablet weight variation is big；The granule strength prepared when 95% ethanol of employing 10%PVPK30 is as binding agent is moderate, and even particle size distribution, good fluidity, the tablet hardness pressed is big and bright and clean.Therefore select 95% alcoholic solution of 10%PVPK30 as binding agent.
And the release profiles of the slow releasing tablet of the different types of binding agent of both is shown in Fig. 7.
Test the impact that slow release layer is discharged by 15 preparation technologies
According to embodiment, being respectively adopted wet granule compression tablet (95% alcoholic solution of 10%PVPK30 is binding agent) and two kinds of technique tablettings of direct powder compression, measure the release of different time, its release characteristic is:
By above-mentioned result of the test it can be seen that direct powder compression is fast compared with the matrix tablet rate of releasing drug of wet granule compression tablet gained, this adds binding agent when being due to wet granulation, makes the viscosity of gel layer become big, reduces the corrosion speed of skeleton, so that rate of release slows down.And find in tableting processes, poor compressibility during direct compression of full-powder, tablet outer surface is rough, easy dry linting.Full powder tabletting powder interparticle cohesion is weak, and slice, thin piece is easily loose, and the tablet weight variation prepared is relatively big, and uniformity of dosage units and release homogeneity are not as wet granule compression tablet, and environment can be caused certain pollution by dust, is not suitable for large-scale production.Therefore select wet granule compression tablet as the tablet making technology of slow release layer.
And the release profiles of slow releasing tablet prepared by both Different Preparation is shown in Fig. 8.
The impact that slow release layer is discharged by the different compression force of experiment 16
Select 3 horizontal film-makings of different pressures respectively according to embodiment, its release characteristic is:
And the release profiles of the slow releasing tablet of preparation is shown in Fig. 9 under these three different pressures.
The impact that slow release layer is discharged by the different release medium of experiment 17
According to double-layer sustained release tablets prepared by embodiment, measuring its release in the HCL solution of 0.1mol/L, the phosphate buffer of pH6.8 and distilled water, its release characteristic is:
And the release profiles of the slow releasing tablet under three kinds of different release medium is shown in Figure 10.
The impact that slow release layer is discharged by the different release device of experiment 18
According to double-layer sustained release tablets prepared by embodiment, being respectively adopted the first method in drug release determination method (basket method) and the second method (slurry processes) carries out dissolution test, rotating speed is 100r/min respectively, 50r/min, and its release characteristic is:
And the release profiles of the slow releasing tablet under different device is shown in Figure 11.
Test the impact that slow release layer is discharged by 19 different rotating speeds
According to double-layer sustained release tablets prepared by embodiment, with distilled water for dissolution medium, investigating release when corbeil method 50r/min, 100r/min, its release characteristic is:
And the release profiles of the slow releasing tablet under different device is shown in Figure 12.
The double-layer sustained release tablets that experiment 20 is prepared according to embodiment, its release characteristic is:
Concrete release profiles is shown in Figure 13.
Test 21 Exploration of Mechanisms
The cumulative release of dexketoprofen trometamol quick-release and slow-release double-layer tablet is calculated as follows: F=Q+Mt/M∞, F is the apparent release of dexketoprofen trometamol (%) in 0～t time, and Q is dexketoprofen trometamol dissolution (%), M in release layert/M∞For dexketoprofen trometamol cumulative release percentage rate (%) in t time slow release layer.The release profiles data of final for dexketoprofen trometamol slow releasing tablet prescription are used zero level, one-level and Higuchi models fitting 0～1h, the drug release behavior of 1～12h and 0～12h respectively, and fitting result is:
As can be known from the results, dexketoprofen trometamol quick-release and slow-release double-layer tablet (0～1h) release behavior is close to Peppas equation, and slow release layer (1～12h) and double-layer tablet (0～12h) drug release behavior are closer to First-order equation.Fitting result shows that first dexketoprofen trometamol quick-release and slow-release double-layer tablet is that the medicine of release layer quickly discharges in release process, followed by the medicine in slow release layer by spreading slow releasing, has obvious rapid release and Controlled release release characteristic.
Claims (3)
1. dexketoprofen trometamol quick-release and slow-release double-layer tablet, including slow release layer and release layer, it is characterised in that: it consists of: by 1000,
Described release layer is made up of following components: dexketoprofen trometamol 20g, lactose 62.5g, microcrystalline Cellulose 35g, carboxymethyl starch sodium 8.75g, 10%PVPK30 95% alcoholic solution is appropriate and magnesium stearate 1.25g；
Described slow release layer is made up of following components: dexketoprofen trometamol 55g, lactose 27g, microcrystalline Cellulose 63g, HPMCK4M88g, ethyl cellulose 22g, 10%PVPK30 95% alcoholic solution is appropriate and magnesium stearate 2.55g.
2. dexketoprofen trometamol quick-release and slow-release double-layer tablet, including slow release layer and release layer, it is characterised in that: by 1000,
Prepared by immediate-release granules: weigh dexketoprofen trometamol 20g, lactose 62.5g, microcrystalline Cellulose 35g, carboxymethyl starch sodium 8.75g and magnesium stearate 1.25g and cross 100 mesh sieves respectively, then mix homogeneously, add the 95% alcoholic solution soft material processed in right amount of 10%PVPK30,20 mesh sieve wet granulars, 60 DEG C of forced air dryings, 20 mesh sieve granulate, add lubricant mixing, obtain release layer granule；
Prepared by slow-releasing granules: weigh dexketoprofen trometamol 55g, lactose 27g, microcrystalline Cellulose 63g, HPMCK4M88g, ethyl cellulose 22g and magnesium stearate 2.55g and cross 100 mesh sieves respectively, mix homogeneously, add the 95% alcoholic solution soft material processed in right amount of 10%PVPK30,20 mesh sieve wet granulars, 60 DEG C of forced air dryings, 20 mesh sieve granulate, add lubricant mixing, obtain slow release layer granule；
Tabletting: first light pressure release layer granule becomes loose, adds slow release layer granule extrusion forming, obtains double-layer tablet.
3. dexketoprofen trometamol quick-release and slow-release double-layer tablet as claimed in claim 1 or 2, it is characterized in that, described sustained-release double-layer tablet is according to the device of dissolution method, and 900mL is solvent, and rotating speed is 100 turns per minute, temperature is 37 DEG C, operate in accordance with the law, sample respectively at 5min, 15min, 0.5h, 1.0h, 2.0h, 4.0h, 6.0h, 8.0h, 12.0h, each 5mL, with the filtering with microporous membrane in 0.8 μm of aperture, and in process container, supplement the above-mentioned solvent of same volume in time；Discarding just filtrate, precision measures subsequent filtrate 2mL and puts in 10mL volumetric flask, dilute constant volume, as need testing solution；Separately take distilled water as reference substance solution, according to spectrophotography, measure trap respectively at the wavelength place of 260nm, calculate the every burst size at different time respectively；Described slow releasing tablet is in the accumulative release 15%～35% of 30min, 6h cumulative release 60%～85%, 12h cumulative release more than 90%.
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| CN101623280A (en) * | 2008-07-10 | 2010-01-13 | 广东肇庆星湖生物科技股份有限公司 | Compound sustained release preparation for easing pain and preparation method thereof |
| CN102000032A (en) * | 2010-11-23 | 2011-04-06 | 四川奇力制药有限公司 | Method for preparing ketoprofen slow release preparation |
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| CN101623280A (en) * | 2008-07-10 | 2010-01-13 | 广东肇庆星湖生物科技股份有限公司 | Compound sustained release preparation for easing pain and preparation method thereof |
| CN102000032A (en) * | 2010-11-23 | 2011-04-06 | 四川奇力制药有限公司 | Method for preparing ketoprofen slow release preparation |
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