CN101185640B - Lornoxicam sustained-release tablet and preparation method thereof - Google Patents
Lornoxicam sustained-release tablet and preparation method thereof Download PDFInfo
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- CN101185640B CN101185640B CN2006101184258A CN200610118425A CN101185640B CN 101185640 B CN101185640 B CN 101185640B CN 2006101184258 A CN2006101184258 A CN 2006101184258A CN 200610118425 A CN200610118425 A CN 200610118425A CN 101185640 B CN101185640 B CN 101185640B
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- lomoxicam
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- 229960002202 lornoxicam Drugs 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title abstract description 37
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a lornoxicam sustained release tablet and the preparation method thereof. The sustained release tablet includes 2.0-60.00 parts of lornoxicam by weight and 10.00-95.00 parts of sustained release block material by weight; wherein, the sustained release block material includes hydroxypropyl methyl cellulose or compound of hydroxypropyl methyl cellulose and other celluloses. The preparation method is that raw material prescription doses of lornoxicam, sustained release block material and filler are evenly mixed, then added with adhesive to be prepared into soft material; pelletization, drying and finishing granule are carried out according to the conventional technique of the tablet preparation, and the dry grain after finishing granule is added with lubricant, evenly mixed and pressed to make the preparation. Compared with conventional oral lornoxicam preparation, the lornoxicam sustained release tablet can maintain a longer effect after oral administration of the drug.
Description
Technical field
The present invention relates to slow releasing preparation of a kind of nonsteroidal antiinflammatory drug and preparation method thereof, specifically Lomoxicam sustained release tablet and preparation method thereof.
Background technology
Lornoxicam, chemical name are 6-chloro-4-hydroxy-2-methyl-3-(2-pyridine carbamoyl)-2H-thieno [2,3-e]-1,2-thiazines-1, and the 1-dioxide belongs to oxygen former times health non-steroid anti-inflammation analgesia medicine.It has stronger analgesia and antiinflammatory action, to severe pain, acute sciatica and lumbago, ache in late cancer, also can be used for the treatment of chronic back pain, osteoarthritis, rheumatoid arthritis and ankylosing spondylitis in can be used for that department of obstetrics and gynecology, oral cavity exodontia, orthomorphia and surgical postoperative acute pain, wound cause.
The lornoxicam parenteral administration is the same with morphine, pethidine and tramadol effective aspect the alleviation postoperative pain, but the toleration of lornoxicam is better than morphine and tramadol.The cancer pain patient, lornoxicam can also reduce the consumption of morphine as auxiliary analgesic.Document shows that also when 10 multiple doses of antiinflammatory dosage, lornoxicam also can produce refrigeration function.
Lornoxicam has good analgesic and anti-inflammatory effects, but because the interior half-life of its body is shorter, in order to keep effective blood drug concentration, clinical oral administration lornoxicam ordinary tablet often needs medication repeatedly, and need take multi-disc at every turn, this has brought inconvenience for patient's clinical application.Simultaneously, untoward reaction takes place greatly and easily in the lornoxicam blood concentration fluctuation, and its action time is shorter.
Therefore, this area presses for the slow releasing preparation of developing lornoxicam, to reduce the number of times of taking of lornoxicam, reduces blood concentration fluctuation in its body, reduces adverse reaction rate.Develop Lomoxicam sustained release tablet and will have good clinical meaning and commercial significance.
Summary of the invention
One of purpose of the present invention is just providing a kind of Lomoxicam sustained release tablet.
Another object of the present invention is to provide the preparation method of Lomoxicam sustained release tablet.
In a first aspect of the present invention, a kind of Lomoxicam sustained release tablet is provided, described slow releasing tablet comprises the component of following weight portion:
(a) lornoxicam 2.0～60.00 weight portions;
(b) slow release retardance material 10.00～95.00 weight portions;
Wherein, described slow release retardance material comprises: (b1) hydroxypropyl methylcellulose; Or (b2) hydroxypropyl methylcellulose and other cellulosic mixture.
In an embodiment of the invention, the parts by weight of component are as follows in the described Lomoxicam sustained release tablet:
(a) lornoxicam 10.00～45.00 weight portions;
(b) slow release retardance material 20.00～80.00 weight portions.
In another embodiment of the present invention, other cellulose in the described Lomoxicam sustained release tablet is selected from: ethyl cellulose, hydroxyethyl-cellulose, methyl hydroxyethylcellulose.
In another preference, the content of hydroxypropyl methylcellulose is more than the 50wt% in the described mixture, presses the total weight of mixture.
In another preference, the content of ethyl cellulose is 5～50.00 weight portions in the described slow releasing tablet.
In another embodiment of the present invention, the hydroxypropyl methylcellulose in the described Lomoxicam sustained release tablet has following characteristic:
Viscosity is 50 centipoises～20000 centipoises; Mean diameter is 50 microns～300 microns.
In another preference, the propoxyl content in the described hydroxypropyl methylcellulose is 4.0～12.0wt%; And methoxyl content is 18.0～32.0wt%;
In another preference, the mean diameter of described hydroxypropyl methylcellulose is the 50-180 micron.
In another embodiment of the present invention, other cellulose in the described Lomoxicam sustained release tablet comprises the ethyl cellulose with following characteristic:
Viscosity is 3 centipoises～50 centipoises; Mean diameter is 50 microns～300 microns.
In another preference, the ethyoxyl content of described ethyl cellulose is 45.5～51.0wt%.
In another preference, the mean diameter of described ethyl cellulose is 50 microns～180 microns
In another embodiment of the present invention, the gross weight of described Lomoxicam sustained release tablet is 4mg～100mg/ sheet.
More preferably, the specification of described slow releasing tablet is every 8mg, 12mg, 16mg, 24mg or 48mg.
In another embodiment of the present invention, the hydroxypropyl methylcellulose in the described Lomoxicam sustained release tablet is that viscosity is the low viscosity hydroxypropyl methylcellulose of 20～400 centipoises and the mixture of the high viscosity hydroxypropyl methylcellulose that viscosity is 2000～20000 centipoises; Preferably, the weight ratio of described low viscosity hydroxypropyl methylcellulose and high viscosity hydroxypropyl methylcellulose is 1: 5 to 5: 1, more preferably 1: 2 to 2: 1.
In another embodiment of the present invention, component in the described Lomoxicam sustained release tablet (a) accounts for 10～99% of slow releasing tablet gross weight with the weight sum of component (b).
More preferably, in described slow releasing tablet, component (a) accounts for 20～95% of slow releasing tablet gross weight with the weight sum of component (b).
In another preference, component (a) accounts for 2～40% of slow releasing tablet gross weight, and more preferably 5～30%.
In another preference, component (b) accounts for 10～95% of slow releasing tablet gross weight, and more preferably 15～80%.
In another embodiment of the present invention, described Lomoxicam sustained release tablet also contains kind or the multiple pharmaceutically acceptable additive that is selected from down in the group: binding agent, filler, lubricant, fluidizer, sweeting agent or aromatic.
In a second aspect of the present invention, a kind of method for preparing Lomoxicam sustained release tablet is provided, said method comprising the steps of:
(i) with 2.0～60.00 weight portion lornoxicams, 10.00～95.00 weight portion slow release retardance material and filler mixing, add binding agent, make soft material,
Wherein, described slow release retardance material comprises: (b1) hydroxypropyl methylcellulose; Or (b2) hydroxypropyl methylcellulose and other cellulosic mixture;
(ii) to described soft material granulate, oven dry, granulate, drying and tabletting, make Lomoxicam sustained release tablet.
In another preference, described hydroxypropyl methylcellulose is that viscosity is the low viscosity hydroxypropyl methylcellulose of 20～400 centipoises and the mixture of the high viscosity hydroxypropyl methylcellulose that viscosity is 2000～20000 centipoises.
In another preference, the weight ratio of described low viscosity hydroxypropyl methylcellulose and high viscosity hydroxypropyl methylcellulose is 1: 5 to 5: 1, more preferably is 1: 2 to 2: 1.
The present invention adopts hydrophilic gel type skeleton as the slow release means, is slow release retardance material with hydroxypropyl methylcellulose or hydroxypropyl methylcellulose and other cellulosic mixture, and technology is simple, and is easy to operate, is suitable for suitability for industrialized production, the technology favorable reproducibility.Lomoxicam sustained release preparation of the present invention can reduce the number of times of taking of lornoxicam, reduces blood concentration fluctuation in its body, reduces adverse reaction rate, and only needs 12 hours or 24 hours take a slice, has improved the convenience and the compliance of patients of clinical application.
Description of drawings
Fig. 1 is release in vitro that the embodiment of the invention 1～5 prepared Lomoxicam sustained release tablet records according to the release test method line chart of writing music.Wherein, abscissa be the time (hour), vertical coordinate is the lornoxicam percent (%) of cumulative release.
Fig. 2 is that the Lomoxicam sustained release tablet (12mg/ sheet, 1) of the oral embodiment of the invention 1 (reaches the road with the lornoxicam ordinary tablet
, Zhejiang Zhenyuan Pharmaceutical Co., Ltd, lot number: 050801, specification: 4mg/ sheet, 3) after, the intravital average blood drug level-time graph of Beagles dog.Wherein, abscissa be the time (hour), vertical coordinate is the blood drug level (ng/ml) of lornoxicam.
The specific embodiment
The inventor is through groping in a large number and furtheing investigate, find to adopt hydrophilic gel type skeleton as the slow release means, with hydroxypropyl methylcellulose or hydroxypropyl methylcellulose and other cellulosic mixture is the retardance material, can make can be with the speed of design the mild Lomoxicam sustained release tablet that discharges.In addition, the present invention has also utilized the hydroxypropyl methylcellulose mixture of different viscosities or the cellulose mixtures of different viscosities in same slow-releasing system, has obtained good slow release performance and tabletting performance unexpectedly.Show that after further study Lomoxicam sustained release tablet of the present invention has tangible slow releasing function, and blood drug level is more steady.
Term
Among the present invention, term " lornoxicam ", " active medicine ", " active substance " are used interchangeably.
Among the present invention, term " contains " the various compositions of expression and can be applied to together in mixture of the present invention or the compositions.Therefore, term " mainly by ... form " and " by ... composition " be included in during term " contains ".
Among the present invention, term " pharmaceutically acceptable " composition is meant and is applicable to people and/or animal and does not have the material that excessive bad side reaction (as toxicity, stimulation and allergy) promptly has rational benefit/risk ratio.
Among the present invention, term " slow release retardance material " is meant in the intravital gastro-intestinal Fluid of aqueous solution, buffer or animal and can stops, delay the material that medicine discharges from preparation.Particularly, the retardance of the slow release among the present invention material is meant the cellulosic mixture of hydroxypropyl methylcellulose or hydroxypropyl methylcellulose and other.
Among the present invention, term " viscosity of hydroxypropyl methylcellulose " is when being meant 25 degrees centigrade, and 2 gram hydroxypropyl methylcellulose are dissolved in the viscosity of gained solution in 100 ml distilled waters.
Among the present invention, term " viscosity of ethyl cellulose " is when being meant 25 degrees centigrade, and 5 gram ethyl celluloses are dissolved in the viscosity of gained solution in 100 milliliters of toluene and the alcohol mixed solvent (toluene and alcoholic acid volume ratio are 80: 20).
Key component
Key component in the Lomoxicam sustained release preparation of the present invention is: (a) lornoxicam; (b) slow release retardance material.Wherein, described slow release retardance material comprises: (b1) hydroxypropyl methylcellulose; Or (b2) hydroxypropyl methylcellulose and other cellulosic mixture.
In the present invention, used active medicine lornoxicam can be commercially available conventional lornoxicam, and its object lesson is the lornoxicam that Zhejiang Zhenyuan Pharmaceutical Co., Ltd produces.Lornoxicam content in the slow releasing preparation of the present invention is preferably 2.0～60.00 weight portions, more preferably is 10.00～45.00 weight portions.
In the present invention, used hydroxypropyl methylcellulose can be commercially available conventional hydroxypropyl methylcellulose.Preferably, the viscosity of the used hydroxypropyl methylcellulose of the present invention is 50 centipoises～20000 centipoises, and mean diameter is 50 microns～300 microns, preferred 100 microns～180 microns.
In a preferred implementation, the propoxyl content of the used hydroxypropyl methylcellulose of the present invention is 4.0%～12.0wt%, and methoxyl content is 18.0%～32.0%.
In preferred implementation of the present invention, adopted the hydroxypropyl methylcellulose of multiple different viscosities simultaneously.In a preferred embodiment of the present invention, having adopted viscosity is the low viscosity hydroxypropyl methylcellulose of 20～400 centipoises and the mixture of the high viscosity hydroxypropyl methylcellulose that viscosity is 2000～20000 centipoises; Preferably, the weight ratio of described low viscosity hydroxypropyl methylcellulose and high viscosity hydroxypropyl methylcellulose is 1: 5 to 5: 1, more preferably 1: 2 to 2: 1.
The content of hydroxypropyl methylcellulose is preferably 2～50 weight portions in the slow releasing preparation of the present invention, more preferably is the 5-45 weight portion, more preferably the 12-40 weight portion.
In the present invention, other cellulose as slow release retardance material comprises: ethyl cellulose, hydroxyethyl-cellulose, methyl hydroxyethylcellulose.
The used ethyl cellulose of the present invention can be commercially available conventional ethyl cellulose.Preferably, the viscosity of the used ethyl cellulose of the present invention is 6 centipoises～50 centipoises, and mean diameter is 50 microns～300 microns, preferred 50 microns～180 microns.
In a preferred embodiment of the present invention, the content of ethyoxyl is 45.5%～51.0% in the described ethyl cellulose.
Ethyl cellulose cellulose content in the slow releasing preparation of the present invention is preferably 0～30 weight portion, more preferably is 0～28 weight portion, more preferably 0～25 weight portion.
Pharmaceutically acceptable additive
In compositions of the present invention, also can comprise other pharmaceutically acceptable additive.
In the present invention, used term " pharmaceutically acceptable additive " is meant the additive of pharmaceutically acceptable reinforcement preparation characteristic.Type for described additive does not have any restriction, and it can be well-known to those skilled in the art, and they include but not limited to: binding agent, filler, lubricant, fluidizer, sweeting agent or aromatic etc.
The available filler of the present invention includes but not limited to: lactose, mannitol or microcrystalline Cellulose etc.Available lubricant of the present invention and fluidizer include but not limited to: magnesium stearate or micropowder silica gel etc.The available sweeting agent of the present invention comprises but is not limited to: sweet or acesulfame potassium of A Siba etc.The available aromatic of the present invention includes but not limited to: various plant essences etc.In the time of if desired, Lomoxicam sustained release preparation of the present invention also can comprise the adjuvant of some other specific use, as bitterness masking agent etc.
In the present invention, the consumption for other additive does not have any restriction.In a preferred embodiment of the present invention, described content of additive is 2000～5000 weight portions.
In the present invention, do not have any restriction for the type of pharmaceutically acceptable filler, it can be a filler commonly used in this area.In a preferred embodiment of the present invention, described filler is selected from lactose, mannitol, microcrystalline Cellulose and their mixture.In another preferred embodiment of the present invention, described filler is the mixture that lactose, mannitol and microcrystalline Cellulose are formed.In the present invention, do not have any restriction for the consumption of filler, it can be the conventional amount used in this area.In an embodiment of the invention, the consumption of described filler is 500～5000 weight portions, is preferably 700～4000 weight portions, more preferably 1000～3500 weight portions.
In the present invention, do not have any restriction for the type of pharmaceutically acceptable fluidizer, it can be a fluidizer commonly used in this area.In a preferred embodiment of the present invention, described fluidizer is selected from one or more in magnesium stearate and the micropowder silica gel.In another preferred embodiment of the present invention, described fluidizer is a magnesium stearate.In the present invention, do not have any restriction for the consumption of fluidizer, it can be the conventional amount used in this area.In an embodiment of the invention, the consumption of described fluidizer is 10～200 weight portions, is preferably 20～150 weight portions, more preferably 37.5～100 weight portions.
In the present invention, do not have any restriction for the type of pharmaceutically acceptable sweeting agent, it can be a sweeting agent commonly used in this area.In a preferred embodiment of the present invention, described sweeting agent be selected from that A Siba is sweet, acesulfame potassium and their mixture.In another preferred embodiment of the present invention, described sweeting agent is that A Siba is sweet.In another preferred embodiment of the present invention, described sweeting agent is the mixture of the sweet and acesulfame potassium of A Siba.In the present invention, do not have any restriction for the consumption of sweeting agent, it can be the conventional amount used in this area.In an embodiment of the invention, the consumption of described sweeting agent is 35～200 weight portions, is preferably 55～150 weight portions, more preferably 75～100 weight portions.
In the present invention, do not have any restriction for the type of pharmaceutically acceptable aromatic, it can be an aromatic commonly used in this area.In a preferred embodiment of the present invention, described aromatic is selected from various plant essences or its mixture.In the present invention, for the consumption of aromatic also without any restriction, as long as it bring certain fragrance can for described compositions.In preferred implementation of the present invention, the consumption of described aromatic is 50～200 weight portions.
The Lomoxicam sustained release preparation
Lomoxicam sustained release tablet of the present invention comprises the component of following weight portion: (a) 2.0～60.00 weight portion lornoxicams; (b) 10.00～95.00 weight portion slow release retardance material; Wherein, described slow release retardance material comprises: (b1) hydroxypropyl methylcellulose; Or (b2) hydroxypropyl methylcellulose and other cellulosic mixture.Lomoxicam sustained release tablet of the present invention also can comprise aforesaid other pharmaceutically acceptable additive
The gross weight of Lomoxicam sustained release tablet of the present invention can be the tablet specification of this area routine, for example is 4mg～100mg/ sheet.In preferred implementation of the present invention, the specification of described slow releasing tablet is every 8mg, 12mg, 16mg, 24mg or 48mg.
According to drug release determination method (two appendix XD of Chinese Pharmacopoeia version in 2005), adopt drug release determination method (two appendix XC of Chinese Pharmacopoeia version in 2005) second method (slurry method) device, with 900ml phosphate buffer (pH7.4) is medium, and Lomoxicam sustained release tablet provided by the present invention can be with the steadily slowly release of speed of design.
Preparation technology
Lomoxicam sustained release preparation preferred manufacturing procedure of the present invention may further comprise the steps:
(i) with 2.0～60.00 weight portion lornoxicams, 10.00～95.00 weight portion slow release retardance material and filler mixing, add binding agent, make soft material; Wherein, described slow release retardance material comprises: hydroxypropyl methylcellulose or hydroxypropyl methylcellulose and other cellulosic mixture;
(ii) to described soft material granulate, oven dry, granulate, drying and tabletting, make Lomoxicam sustained release tablet.
Can adopt the known any method of formulation art to mix, prepare soft material and each step such as the granulation that soft material is carried out, oven dry, granulate, drying or tabletting.
Also can adopt other slow releasing tablet preparation method known in the art to prepare Lomoxicam sustained release preparation of the present invention.For example, can adopt dry granulation tablet forming technique technology or direct powder compression technology.
Major advantage of the present invention is:
1. a kind of Lomoxicam sustained release preparation that can steadily discharge is provided;
2. adopting hydrophilic gel type skeleton as the slow release means, serves as to block material with hydroxypropyl methylcellulose or hydroxypropyl methylcellulose with other cellulosic mixture, and technology is simple, and is easy to operate, is suitable for suitability for industrialized production, the technology favorable reproducibility;
3. slow releasing tablet provided by the present invention only needed 12 hours or 24 hours to take a slice, had improved the convenience and the compliance of patients of clinical application.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions among the embodiment, usually according to normal condition, or the condition of advising according to manufacturer.Unless otherwise defined, the same meaning that employed all specialties and scientific words and one skilled in the art are familiar with in the literary composition.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.
Used slow release retardance material
Hydroxypropyl methylcellulose
Viscosity 10000 centipoises: from the METHOCEL of Shanghai Colorcon Coating Technology Co., Ltd's purchase
TMK15M Premium, methoxyl content are 19-24%, and propoxyl content 7-12%, 2% solution viscosity are the 6138-9030 centipoise, 50 microns to 180 microns of particle diameters.
Viscosity 4000 centipoises: from the METHOCEL of Shanghai Colorcon Coating Technology Co., Ltd's purchase
TMK4M Premium, methoxyl content are 19-24%, and propoxyl content 7-12%, 2% solution viscosity are the 2308-4308 centipoise, 50 microns to 180 microns of particle diameters.
Ethyl cellulose
Embodiment 1
The preparation of Lomoxicam sustained release tablet 1
1000
Lornoxicam 12g
Hydroxypropyl methylcellulose (viscosity: 15g 4000 centipoises)
Hydroxypropyl methylcellulose (viscosity: 30g 100 centipoises)
Lactose 150g
Magnesium stearate 1g
Gross weight 208g
Preparation method:
4000 centipoises), hydroxypropyl methylcellulose (viscosity: 100 centipoises), lactose pulverizes, and crosses 100 mesh sieves, mechanical mixing with lornoxicam, hydroxypropyl methylcellulose (viscosity:.Add 5% polyvidone aqueous solution in the stirring and (restrain/100 milliliters, model: K30) granulate oven dry, granulate.With the dried particles behind the above-mentioned granulate, add magnesium stearate dry powder again, place and mix grain machine, mix homogeneously.With the 8mm stamping, get 1000 Lomoxicam sustained release tablets 1.
The preparation of Lomoxicam sustained release tablet 2
1000
Lornoxicam 8g
Hydroxypropyl methylcellulose (viscosity: 15g 4000 centipoises)
Hydroxypropyl methylcellulose (viscosity: 15g 50 centipoises)
Ethyl cellulose (viscosity: 15g 20 centipoises)
Lactose 150g
Magnesium stearate 1g
Gross weight 204g
Preparation method:
4000 centipoises), hydroxypropyl methylcellulose (viscosity: 50 centipoises), ethyl cellulose (viscosity: 20 centipoises), lactose pulverizes, and crosses 100 mesh sieves, mechanical mixing with lornoxicam, hydroxypropyl methylcellulose (viscosity:.(model: K30) aqueous solution is granulated, oven dry, granulate to add 5% polyvidone in the stirring.With the dried particles behind the above-mentioned granulate, add magnesium stearate dry powder again, place and mix grain machine, mix homogeneously.With the 8mm stamping, get 1000 Lomoxicam sustained release tablets 2.
Embodiment 3
The preparation of Lomoxicam sustained release tablet 3
1000
Lornoxicam 24g
Hydroxypropyl methylcellulose (viscosity: 15g 4000 centipoises)
Hydroxypropyl methylcellulose (viscosity: 15g 100 centipoises)
Hydroxypropyl methylcellulose (viscosity: 15g 50 centipoises)
Pregelatinized Starch 30g
Lactose 20g
Magnesium stearate 1g
Gross weight 120g
Preparation method:
4000 centipoises), hydroxypropyl methylcellulose (viscosity: 100 centipoises), hydroxypropyl methylcellulose (viscosity: 50 centipoises), pregelatinized Starch, lactose pulverize, and crosses 100 mesh sieves, mechanical mixing with lornoxicam, hydroxypropyl methylcellulose (viscosity:.Add 5% polyvidone (model: K30) granulate oven dry, granulate in the stirring.With the dried particles behind the above-mentioned granulate, add magnesium stearate dry powder again, place and mix grain machine, mix homogeneously.With the 8mm stamping, get 1000 Lomoxicam sustained release tablets 3.
The preparation of Lomoxicam sustained release tablet 4
1000
Lornoxicam 4g
Hydroxypropyl methylcellulose (viscosity: 15g 4000 centipoises)
Hydroxypropyl methylcellulose (viscosity: 15g 100 centipoises)
Ethyl cellulose (viscosity: 15g 20 centipoises)
Microcrystalline Cellulose (model: PH101) 20g
Magnesium stearate 1g
Gross weight 70g
Preparation method:
4000 centipoises), hydroxypropyl methylcellulose (viscosity: 100 centipoises), ethyl cellulose (viscosity: 20 centipoises), microcrystalline Cellulose (model: PH101) pulverize, cross 100 mesh sieves, mechanical mixing with lornoxicam, hydroxypropyl methylcellulose (viscosity:.Add 5% polyvidone (model: K30) granulate oven dry, granulate in the stirring.With the dried particles behind the above-mentioned granulate, add magnesium stearate dry powder again, place and mix grain machine, mix homogeneously.With the 8mm stamping, get 1000 Lomoxicam sustained release tablets 4.
Embodiment 5
The preparation of Lomoxicam sustained release tablet 5
1000
Lornoxicam 12g
Hydroxypropyl methylcellulose (viscosity: 5g 10000 centipoises)
Hydroxypropyl methylcellulose (viscosity: 10g 50 centipoises)
Lactose 172g
Pregelatinized Starch 30g
Microcrystalline Cellulose (model: PH101) 10g
Magnesium stearate 1g
Gross weight 240g
Preparation method:
10000 centipoises), hydroxypropyl methylcellulose (viscosity: 50 centipoises), lactose, microcrystalline Cellulose (model: PH101), pregelatinized Starch pulverizes, and crosses 100 mesh sieves, mechanical mixing with lornoxicam, hydroxypropyl methylcellulose (viscosity:.Add 5% polyvidone (model: K30) granulate oven dry, granulate in the stirring.With the dried particles behind the above-mentioned granulate, add magnesium stearate dry powder again, place and mix grain machine, mix homogeneously.With the 8mm stamping, get 1000 Lomoxicam sustained release tablets 5.
The composition of the slow releasing preparation of table 1 embodiment 1～5 and content (unit: g)
The release in vitro degree test of Lomoxicam sustained release tablet
Test objective:
Whether the release in vitro degree of the Lomoxicam sustained release tablet of preparation in the test implementation example 1～5 can discharge with the speed of design gently to assess slow releasing preparation of the present invention.
Test method:
A. the preparation of need testing solution:
Respectively get among the embodiment 1～5 6 of the Lomoxicam sustained release tablets of preparation, according to drug release determination method (two appendix XD of Chinese Pharmacopoeia version in 2005), adopt drug release determination method (two appendix XC of Chinese Pharmacopoeia version in 2005) second method (slurry method) device, with 900ml phosphate buffer (pH7.4) is medium, rotating speed is that per minute 50 changes, and solution 5ml was got in operation respectively in the time of 1,2,4,6,8 hour in accordance with the law, filter with 0.45 micron microporous filter membrane, subsequent filtrate suitably dilutes the back as need testing solution.
B. the preparation of reference substance solution:
Precision takes by weighing the lornoxicam reference substance, adopts the dissolving of 0.01mol/L sodium hydroxide solution, is diluted to the solution of 16 μ g/ml again with release medium.
C. sample determination:
Getting above-mentioned need testing solution and reference substance solution respectively, is blank with the release medium, measures trap A in the 378nm place, and calculates the release of each time point.
Result of the test:
See Fig. 1 according to drug release determination experimental technique gained experimental result.The result shows that Lomoxicam sustained release tablet provided by the present invention all can be with the steadily slowly release of speed of design.
Embodiment 7
Blood drug level changes relatively in the body behind oral Lomoxicam sustained release tablet and the lornoxicam ordinary tablet
Test objective:
For Lomoxicam sustained release tablet more of the present invention and lornoxicam sheet change behavior in vivo blood drug level, measured blood drug level in the body of taking the Beagles dog behind above-mentioned two kinds of preparations respectively.
Test method:
A. animal experiment:
6 Beagles dogs (male and female half and half, 8～10 kilograms of body weight) are divided into two groups, three every group at random.Respectively the single oral dose embodiment of the invention 1 prepared Lomoxicam sustained release tablet (12mg/ sheet) a slice and three of lornoxicam sheets (reach the road
, Zhejiang Zhenyuan Pharmaceutical Co., Ltd, lot number: 050801, specification: the 4mg/ sheet).In 0～24 hour, get blood 2ml from the dog front leg portions at regular intervals.
B. blood sample is handled:
Separated plasma, pipette 0.2ml blood plasma in centrifuge tube, add 3mol/L phosphoric acid,diluted 0.2ml, add mark piroxicam solution 0.1ml in the 2 μ g/ml again, vortex acidify in 2 minutes is with 3ml extractant (normal hexane: dichloromethane: isopropyl alcohol, volume ratio is 20: 10: 1) vortex extracted 3 minutes, 4000 rev/mins centrifugal 15 minutes, draw organic layer to another centrifuge tube, 35 ℃ of N
2Flow down and volatilize.Residue reuse 200 μ l mobile phases are redissolved, vortex dissolving in 2 minutes, 4000 rev/mins centrifugal 5 minutes, get 20 μ l and inject high performance liquid chromatograph and carry out peak area and measure.
C. high-efficient liquid phase chromatogram condition:
Chromatograph: Shimadzu high performance liquid chromatograph.
Chromatographic column: Hypersil ODS (150 * 4.6mm, 5 μ m);
Mobile phase: methanol: phosphate buffer (25mmol/l, pH regulator to 6.0)=1: 1;
Column temperature: 30 ℃;
Detect wavelength: 371nm;
Flow velocity: 1ml/ minute;
Result of the test:
Result of the test shows, irritate stomach and give a slice Lomoxicam sustained release tablet (12mg lornoxicam) back and in the time of about 4 hours, reach maximum plasma concentration (621ng/ml), give three lornoxicam sheets (12mg lornoxicam) back and reach maximum plasma concentration (1562ng/ml) in the time of about 2 hours and irritate stomach.
The lower area of blood concentration-time curve of lornoxicam ordinary tablet is 11362.75 ± 689.63ng*h/ml, and the lower area of blood concentration-time curve of Lomoxicam sustained release tablet is 11095.50 ± 438.56ng*h/ml, and both do not have significant difference.Compare with the lornoxicam sheet, the relative bioavailability of Lomoxicam sustained release tablet is 97.65%.
Plasma concentration curve is seen Fig. 2 in the body of two kinds of preparations, can show that from figure Lomoxicam sustained release tablet of the present invention has tangible slow releasing function, and blood drug level is more steady.
All quote in this application as a reference at all documents that the present invention mentions, just quoted as a reference separately as each piece document.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Claims (11)
1. a Lomoxicam sustained release tablet is characterized in that, described slow releasing tablet comprises the component of following weight portion:
(a) lornoxicam 2.0～60.00 weight portions;
(b) slow release retardance material 10.00～95.00 weight portions;
Wherein, described slow release retardance material comprises: (b1) hydroxypropyl methylcellulose; Or (b2) mixture of hydroxypropyl methylcellulose and other cellulose derivative,
Wherein, described hydroxypropyl methylcellulose is that viscosity is the low viscosity hydroxypropyl methylcellulose of 20～400 centipoises and the mixture of the high viscosity hydroxypropyl methylcellulose that viscosity is 2000～20000 centipoises.
2. Lomoxicam sustained release tablet as claimed in claim 1 is characterized in that, the parts by weight of described component are as follows:
(a) lornoxicam 10.00～45.00 weight portions;
(b) slow release retardance material 20.00～80.00 weight portions.
3. Lomoxicam sustained release tablet as claimed in claim 1 is characterized in that, described other cellulose derivative is selected from: ethyl cellulose, hydroxyethyl-cellulose, methyl hydroxyethylcellulose.
4. Lomoxicam sustained release tablet as claimed in claim 1 is characterized in that, the mean diameter of described hydroxypropyl methylcellulose is the 50-180 micron.
5. Lomoxicam sustained release tablet as claimed in claim 1 is characterized in that, described other cellulose derivative comprises the ethyl cellulose with following characteristic:
Viscosity is 3 centipoises～50 centipoises; With
Mean diameter is 50 microns～300 microns.
6. Lomoxicam sustained release tablet as claimed in claim 1 is characterized in that, the gross weight of described slow releasing tablet is 4mg～100mg/ sheet.
7. Lomoxicam sustained release tablet as claimed in claim 1 is characterized in that, the weight ratio of described low viscosity hydroxypropyl methylcellulose and high viscosity hydroxypropyl methylcellulose is 1: 5 to 5: 1.
8. Lomoxicam sustained release tablet as claimed in claim 7 is characterized in that, the weight ratio of described low viscosity hydroxypropyl methylcellulose and high viscosity hydroxypropyl methylcellulose is 1: 2 to 2: 1.
9. Lomoxicam sustained release tablet as claimed in claim 1 is characterized in that, component in the described slow releasing tablet (a) accounts for 10～99% of slow releasing tablet gross weight with the weight sum of component (b).
10. as each described Lomoxicam sustained release tablet in the claim 1～9, it is characterized in that described slow releasing tablet also contains one or more pharmaceutically acceptable additives that are selected from down in the group: binding agent, filler, lubricant, fluidizer, sweeting agent or aromatic.
11. a method for preparing Lomoxicam sustained release tablet is characterized in that, said method comprising the steps of:
(i) with 2.0～60.00 weight portion lornoxicams, 10.00～95.00 weight portion slow release retardance material and filler mixing, add binding agent, make soft material,
Wherein, described slow release retardance material comprises: (b1) hydroxypropyl methylcellulose; Or (b2) mixture of hydroxypropyl methylcellulose and other cellulose derivative,
And wherein, described hydroxypropyl methylcellulose is that viscosity is the low viscosity hydroxypropyl methylcellulose of 20～400 centipoises and the mixture of the high viscosity hydroxypropyl methylcellulose that viscosity is 2000～20000 centipoises;
(ii) to described soft material granulate, oven dry, granulate, drying and tabletting, make Lomoxicam sustained release tablet.
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| Title |
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| JP特开2001-172183A 2001.06.26 |
| 张建军等.高效液相色谱法测定氯诺昔康薄膜衣片的溶出度.《中国医院药学杂志》.2005,第25卷(第5期),447-448. * |
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