CN101342177A - Lornoxicam double-layer sustained release tablets - Google Patents
Lornoxicam double-layer sustained release tablets Download PDFInfo
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- CN101342177A CN101342177A CNA2007100436881A CN200710043688A CN101342177A CN 101342177 A CN101342177 A CN 101342177A CN A2007100436881 A CNA2007100436881 A CN A2007100436881A CN 200710043688 A CN200710043688 A CN 200710043688A CN 101342177 A CN101342177 A CN 101342177A
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Abstract
The invention relates to a double-layer sustained release lornoxicam tablet which comprises (a) a quick release layer and (b) a sustained release layer, wherein, the quick release layer comprises (a1) the lornoxicam, (a2) alkaline matter and (a3) an other optional carrier or pharmaceutically acceptable excipient and the sustained release layer comprises the (b1) lornoxicam, (b2) sustained release substance and (b3) the other optional carrier or the pharmaceutically acceptable excipient. The weight proportion of (a1) and (b1) is 1:50 to 50:1. The invention also provides a preparation method of the double-layer sustained release lornoxicam tablet. The double-layer sustained release preparation of the invention has the advantages of the quick effect of the quick release preparation and the sustained effect of sustained release preparation. In addition, the double-layer sustained release preparation can maintain the effect of effective blood concentration continuously and stably after the effective blood concentration is reached rapidly.
Description
Technical field
The invention belongs to technical field of medicine, be specifically related to double-layer sustained release tablets of a kind of nonsteroidal antiinflammatory drug lornoxicam and preparation method thereof.
Background technology
Lornoxicam (Lornoxicam) is an oxygen former times health non-steroid antiphlogistic, and chemistry 6-chloro-4-hydroxy-2-methyl-3-N-(2-pyridine radicals) by name-2H-fen thiophene is [2,3-e]-1,2-thiazines-3-Methanamide-1 also, the 1-dioxide.Lornoxicam has good analgesic and anti-inflammatory effects, and the dosage form of going on the market at present has thin membrane coated tablet and lyophilized injectable powder.
Because the half-life is shorter in the lornoxicam body, for keeping effective blood drug concentration, clinical oral administration lornoxicam Film coated tablets needs medication repeatedly, and need take multi-disc at every turn, this makes troubles for patient's clinical application, and because blood concentration fluctuation causes the adverse reaction rate height greatly.
In addition, lornoxicam still is a kind of insoluble drug, water insoluble and acid solution.Therefore, if lornoxicam is made common slow releasing tablet carries out oral administration, because medicine release in gastric juice is very low, blood drug level reaches treatment concentration rapidly after taking certain difficulty, it is slow to play a role, and it is slow to prove effective, and is unfavorable for rapid amelioration of inflammation or pain.
At present, do not see the report of Lornoxicam double-layer sustained release tablets exploitation and research both at home and abroad.
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 novel Lomoxicam sustained release tablet and will have good clinical meaning and commercial significance.
Summary of the invention
Purpose of the present invention can reach effective blood drug concentration after just providing a kind of using fast, and continues to keep the Lornoxicam double-layer sustained release tablets of stable effective blood drug concentration subsequently.
A first aspect of the present invention provides a kind of Lornoxicam double-layer sustained release tablets, and it comprises (a) release layer and (b) slow release layer, wherein:
Described release layer comprises:
(a1) lornoxicam;
(a2) alkaline matter;
(a3) Ren Xuan pharmaceutically acceptable other carrier or excipient;
Described slow release layer comprises:
(b1) lornoxicam;
(b2) slow-release material;
(b3) Ren Xuan pharmaceutically acceptable other carrier or excipient;
Wherein, be 1 (a1): 50-50 with (b1) weight ratio: 1, and
Described alkaline matter makes lornoxicam in the described double-layer sustained release tablets according to Chinese Pharmacopoeia drug release determination method, with 750ml 0.1mol/L hydrochloric acid is release medium, and the release in the 1st hour reaches the 10-50wt% of lornoxicam gross weight in the described double-layer sustained release tablets.
In a preference of the present invention, be 1 (a1): 25-25: 1, preferred 1: 10-10: 1, more preferably 1: 5-5: 1 with (b1) weight ratio.
In another preference of the present invention, (a1) account for the 0.1-50wt% of described double-layer sustained release tablets gross weight, preferred 0.5-45wt%, more preferably 1-40wt%.
In another preference of the present invention, (b1) account for the 0.1-50wt% of described double-layer sustained release tablets gross weight, preferred 0.5-45wt%, more preferably 1-40wt%.
In another preference of the present invention, described alkaline matter makes lornoxicam in the described double-layer sustained release tablets according to Chinese Pharmacopoeia drug release determination method, with 750ml 0.1mol/L hydrochloric acid is release medium, release in the 1st hour reaches more than the 10wt% of described double-layer sustained release tablets gross weight, preferred 10-45wt%, more preferably 15-40wt%, most preferably 20-40wt%.
In another preference of the present invention, the gross weight of described slow releasing tablet is 50～1000mg/ sheet, preferred 100～500mg/ sheet.
In preferred implementation of the present invention, (a2) alkaline matter in the described Lornoxicam double-layer sustained release tablets is selected from: arginine, sodium bicarbonate, sodium carbonate, lysine, trometamol, meglumine, sodium hydroxide or their combination.
In a preference of the present invention, described alkaline matter is preferably arginine, trometamol, sodium bicarbonate or their combination.
In another preferred implementation of the present invention, (a2) alkaline matter in the described Lornoxicam double-layer sustained release tablets is 1 with (a1) weight ratio of lornoxicam: 100-100: 1.
In a preference of the present invention, described (a2) alkaline matter is 1 with (a1) weight ratio of lornoxicam: 50-50: 1, preferred 1: 25-25: 1, more preferably 1: 15-15: 1.
In another preference of the present invention, (a2) alkaline matter accounts for the 0.1-25wt% of described double-layer sustained release tablets gross weight, preferred 0.5-20wt%, more preferably 1-10wt%.
In another preferred implementation of the present invention, (a) release layer accounts for the 10-90wt% of described double-layer sustained release tablets gross weight in the described Lornoxicam double-layer sustained release tablets, (b) slow release layer accounts for the 10-90wt% of described double-layer sustained release tablets gross weight, is 100wt% with (b) weight sum (a).
In preference of the present invention, (a) release layer accounts for the 20-80wt% of described double-layer sustained release tablets gross weight, preferred 30-50wt%; (b) slow release layer accounts for the 20-80wt% of described double-layer sustained release tablets gross weight, preferred 50-70wt%.
In another preference of the present invention, (a) release layer is 1 with (b) weight ratio of slow release layer: 25-25: 1, preferred 1: 10-10: 1, more preferably 1: 5-5: 1.
In another preferred implementation of the present invention, (b2) slow-release material in the described Lornoxicam double-layer sustained release tablets is selected from: cellulose derivative, CBP, sodium alginate, glyceryl monostearate or their combination.
In a preference of the present invention, described cellulose derivative is selected from one or more the combination in hypromellose, methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, the sodium carboxymethyl cellulose.
In another preference of the present invention, 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; Preferably, the weight ratio of described low viscosity hydroxypropyl methylcellulose and high viscosity hydroxypropyl methylcellulose is 1: 10 to 10: 1, more preferably is 1: 5 to 5: 1.
In another preferred implementation of the present invention, (b2) slow-release material is 1 with (b1) weight ratio of lornoxicam in the described Lornoxicam double-layer sustained release tablets: 100-100: 1.
In a preference of the present invention, described (b2) slow-release material is 1 with (b1) weight ratio of lornoxicam: 50-50: 1, preferred 1: 25-25: 1, more preferably 1: 15-15: 1.
In another preference of the present invention, (b2) slow-release material accounts for the 0.1-25wt% of described double-layer sustained release tablets gross weight, preferred 0.5-20wt%, more preferably 1-10wt%.
In another preferred implementation of the present invention, pharmaceutically acceptable other carrier that (a3) in the described Lornoxicam double-layer sustained release tablets is optional or excipient be selected from down the group in one or more: filler, binding agent, disintegrating agent or lubricant; (b3) Ren Xuan pharmaceutically acceptable other carrier or excipient be selected from down the group in one or more: filler, binding agent or lubricant.
In a preference of the present invention, (a3) filler in is selected from: microcrystalline Cellulose, lactose, pregelatinized Starch, mannitol; Binding agent is selected from: hypromellose solution, povidone solution; Disintegrating agent is selected from: cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose; Lubricant is selected from: magnesium stearate, Pulvis Talci, micropowder silica gel, Polyethylene Glycol.
In another preference of the present invention, (a3) account for the 1-90wt% of (a) slow release layer gross weight, preferred 5-80wt%, more preferably 10-70wt%.
In another preference of the present invention, (b3) filler in is selected from: microcrystalline Cellulose, lactose, mannitol, Icing Sugar; Binding agent is selected from: hypromellose solution, povidone solution, ethyl cellulose alcoholic solution; Lubricant is selected from: magnesium stearate, Pulvis Talci, micropowder silica gel, Polyethylene Glycol.
In another preference of the present invention, (b3) account for the 1-90wt% of (b) slow release layer gross weight, preferred 5-80wt%, more preferably 10-70wt%.
In another preferred implementation of the present invention, each component has content as follows in the described Lornoxicam double-layer sustained release tablets:
(a) release layer
(a1) lornoxicam 0.1-100 weight portion
(a2) alkaline matter 1-100 weight portion
(a3) Ren Xuan pharmaceutically acceptable other carrier or excipient 1-1000 weight portion
(b) slow release layer
(b1) lornoxicam 0.1-100 weight portion
(b2) slow-release material 20-500 weight portion
(b3) Ren Xuan pharmaceutically acceptable other carrier or excipient 20-1500 weight portion.
In a preference of the present invention, each component has content as follows in the described double-layer sustained release tablets:
(a) release layer
(a1) lornoxicam 1-80 weight portion
(a2) alkaline matter 5-80 weight portion
(a3) Ren Xuan pharmaceutically acceptable other carrier or excipient 10-800 weight portion
(b) slow release layer
(b1) lornoxicam 1-80 weight portion
(b2) slow-release material 20-300 weight portion
(b3) Ren Xuan pharmaceutically acceptable other carrier or excipient 50-1000 weight portion.
In another preferred implementation of the present invention, described Lornoxicam double-layer sustained release tablets also randomly comprises other antalgic and inflammation relieving active component, or randomly comprises one or more other additional layers.
In a preference of the present invention, described other antalgic and inflammation relieving active component is selected from: tramadol hydrochloride, acetaminophen, aspirin.
In another preference of the present invention, described one or more additional layers are selected from: rapid release or slow release layer, adhesive layer and/or the coatings of the common layer of lornoxicam, other antalgic and inflammation relieving active component.
A second aspect of the present invention provides a kind of method for preparing each described Lornoxicam double-layer sustained release tablets among the claim 1-8, and described method comprises step:
(i) provide release layer material and slow release layer material, wherein
Described release layer material comprises: (a1) lornoxicam; (a2) alkaline matter; (a3) Ren Xuan pharmaceutically acceptable other carrier or excipient;
Described slow release layer material comprises: (b1) lornoxicam; (b2) slow-release material; (b3) Ren Xuan pharmaceutically acceptable other carrier or excipient; With
(ii) described release layer material and described slow release layer material are pressed into double-layer sustained release tablets.
In a preference of the present invention, described Lornoxicam double-layer sheet is to adopt wet granulation pressed disc method, dry granule tabletting method or direct powder compression preparation.
Description of drawings
Fig. 1 is Lornoxicam double-layer sustained release tablets 1 provided by the present invention (embodiment 1), Lornoxicam double-layer sustained release tablets 2 (embodiment 2), Lornoxicam double-layer sustained release tablets 3 (embodiment 3) and the lornoxicam monolayer slow releasing tablet 4 that does not contain release layer, according to the release in vitro of the drug release determination experimental technique gained line chart of writing music.
Wherein, abscissa be the time (hour), vertical coordinate is total release percentage (%).Described release is meant that in the medicine total amount in the whole double-layer tablet be benchmark, the medicine percent that discharges in the whole double-layer tablet.
The specific embodiment
The inventor is through groping in a large number and furtheing investigate, find that the dissolubility of lornoxicam in alkaline medium improves greatly, utilize the release layer that contains the preferred proportion alkaline matter to make lornoxicam dissolve release rapidly in the gastric juice in vivo thus, thereby reach effective blood drug concentration fast, and utilize slow release method to make active constituents of medicine slowly continue to discharge subsequently, to keep effective blood drug concentration stably.Finished the present invention on this basis.
Particularly, the inventor has invented the double-layer sustained release tablets of lornoxicam, and it contains a release layer and a slow release layer simultaneously.Wherein, described release layer comprises lornoxicam and pharmaceutically acceptable alkaline matter.Although lornoxicam is dissolving hardly in pure water and acid medium, it has wonderful solubility property in high pH value medium.Therefore, for lornoxicam after making administration can be dissolved in rapidly in the acid medium, the inventor adds the alkaline matter of preferred amounts in release layer, making it is enough to make the lornoxicam in the release layer to dissolve rapidly, described alkaline matter is for for example: arginine, sodium bicarbonate, sodium carbonate, lysine, trometamol, meglumine, sodium hydroxide, or its combination.Simultaneously, the inventor adopts the slow release means, adopts the retardance material to make the Lomoxicam sustained release layer that can discharge gently with the speed of design, has reached to make blood drug level effect more stably.
Both can reach required blood drug level rapidly after Lornoxicam double-layer sustained release tablets of the present invention is taken, the blood drug level of can remaining valid has in a long time again greatly improved the effectiveness of medicine and patient's compliance.
Lornoxicam and term explanation
Among the present invention, term " lornoxicam ", " active medicine ", " active substance " are used interchangeably.This term also comprises lornoxicam and pharmaceutically acceptable salt thereof, hydrate.
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.
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 excessive bad side reaction (as toxicity, stimulation and allergy) that the material of rational benefit/risk ratio is promptly arranged.
Among the present invention, term " effective dose " refers to the therapeutic agent treatment, alleviates or prevent the amount of target disease or situation, or shows the amount of detectable treatment or preventive effect.Depend on the nature and extent of the build of this object and health status, disease and the therapeutic agent selecting to give and/or the combination of therapeutic agent for the accurate effective dose of a certain object.Therefore, specifying accurately in advance, effective dose is useless.Yet, for certain given situation, can determine this effective dose with normal experiment, the clinicist can judge.
Among the present invention, term " pharmaceutically acceptable carrier " refers to be used for the treatment of the carrier of agent administration, itself does not induce generation to accepting the individual deleterious antibody of said composition, and after the administration or give do not have undue toxicity after the health product." Lei Mingdun pharmaceutical science " (Remington ' s Pharmaceutical Sciences, Mack Pub.Co. can find discussing fully about pharmaceutically acceptable carrier in N.J.1991).
Release layer
Among the present invention, term " release layer " is meant the drug release layer that contains alkaline matter, and it can discharge lornoxicam rapidly in gastric juice, thereby reaches effective blood drug concentration fast.
Lornoxicam has wonderful solubility property in high pH value medium.Therefore, for lornoxicam after making administration can be dissolved in rapidly in the acid medium, the inventor adds a certain amount of alkaline matter in release layer makes it to be enough to make the lornoxicam in the release layer to dissolve rapidly.
Described alkaline matter for example includes but not limited to: arginine, sodium bicarbonate, sodium carbonate, lysine, trometamol, meglumine, sodium hydroxide, or its combination.Preferred arginine, trometamol, sodium bicarbonate or their combination.
In embodiment of the present invention, alkaline matter accounts for the 0.1-25wt% of described double-layer sustained release tablets gross weight, preferred 0.5-20wt%, more preferably 1-10wt%.The content of described alkaline matter is the 1-100 weight portion, is preferably the 5-80 weight portion, more preferably the 10-60 weight portion.
Lornoxicam content in the described release layer is the 0.1-100 weight portion, is preferably the 1-80 weight portion, more preferably the 10-60 weight portion.Lornoxicam accounts for the 0.1-25wt% of described double-layer sustained release tablets gross weight, preferred 0.5-20wt%, more preferably 1-10wt%.
In preferred implementation of the present invention, the weight ratio of described alkaline matter and lornoxicam is 1: 100-100: 1, preferred 1: 50-50: 1, more preferably 1: 25-25: 1, most preferably 1: 15-15: 1.
Except that above-mentioned material, also randomly comprise pharmaceutically acceptable other carrier or excipient, for example filler, disintegrating agent, binding agent and lubricant in the release layer prescription of Lornoxicam double-layer sustained release tablets of the present invention.Wherein, filler is such as but not limited to microcrystalline Cellulose, lactose, pregelatinized Starch, mannitol.Binding agent is such as but not limited to hypromellose solution, povidone solution.Disintegrating agent is such as but not limited to cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose.Lubricant is such as but not limited to magnesium stearate, Pulvis Talci, micropowder silica gel, Polyethylene Glycol.
The content of described other carrier or excipient is the 1-1000 weight portion, is preferably the 10-800 weight portion, more preferably the 20-600 weight portion.They account for the 1-90wt% of slow release layer gross weight, preferred 5-80wt%, more preferably 10-70wt%.
In gastric juice, described release layer preferably discharged the lornoxicam of 30%-100% in the release layer in 5 minutes-60 minutes, more preferably in 10 minutes-60 minutes, discharge the lornoxicam of 40%-95% in the release layer, most preferably discharge the lornoxicam of 50%-90% in the release layer in 15 minutes-45 minutes.
Slow release layer
Among the present invention, term " slow release layer " is meant the drug release layer that contains slow release retardance material and lornoxicam, and it can slowly and enduringly discharge in vivo, thereby keeps effective blood drug concentration stably.Term " slow release retardance material " and " slow-release material " are used interchangeably, and refer to can stop in the intravital gastro-intestinal Fluid of aqueous solution, buffer or animal, delay the material that medicine discharges from preparation.
Slow-release material in the double-layer sustained release tablets slow release layer of the present invention can be selected from such as but not limited to cellulose derivative, CBP, sodium alginate, glyceryl monostearate, preferred CBP or cellulose derivative, wherein cellulose derivative can be one or more the combination in hypromellose, methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, the sodium carboxymethyl cellulose.
In a preferred embodiment of the present invention, 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; Preferably, the weight ratio of described low viscosity hydroxypropyl methylcellulose and high viscosity hydroxypropyl methylcellulose is 1: 10 to 10: 1, preferred 1: 5 to 5: 1, and more preferably 1: 2 to 2: 1.
The content of described slow-release material is the 10-500 weight portion, is preferably the 20-400 weight portion, more preferably the 50-300 weight portion.Described slow-release material accounts for the 0.1-25wt% of described double-layer sustained release tablets gross weight, preferred 0.5-20wt%, more preferably 1-10wt%.
Lornoxicam content in the described release layer is the 0.1-100 weight portion, is preferably the 1-80 weight portion, more preferably the 10-60 weight portion.Lornoxicam accounts for the 0.1-25wt% of double-layer sustained release tablets gross weight, preferred 0.5-20wt%, more preferably 1-10wt%.
The weight ratio of slow-release material described in the slow release layer and lornoxicam is 1: 100-100: 1, preferred 1: 50-50: 1, more preferably 1: 25-25: 1, most preferably 1: 15-15: 1.
Except that above-mentioned material, also can comprise other pharmaceutically acceptable carrier or excipient, in the slow release layer prescription of Lornoxicam double-layer sustained release tablets of the present invention as filler, binding agent and lubricant.Filler can be such as but not limited to microcrystalline Cellulose, lactose, mannitol, Icing Sugar.Binding agent can be such as but not limited to hypromellose solution, povidone solution, ethyl cellulose alcoholic solution.Lubricant can be such as but not limited to magnesium stearate, Pulvis Talci, micropowder silica gel, Polyethylene Glycol.
The content of described other carrier or excipient is the 20-1500 weight portion, is preferably the 50-1000 weight portion, more preferably the 80-800 weight portion.They preferably account for the 1-90wt% of slow release layer gross weight, preferred 5-80wt%, more preferably 10-70wt%.
Described slow release layer preferably slowly steadily discharged the lornoxicam of 10%-99% in vivo in 2-24 hour, more preferably discharged the lornoxicam of 15%-95% in 2-24 hour, most preferably the lornoxicam of release 20%-90% in 2-24 hour.Described double-layer sustained release tablets preferably can be in 24 hours, more preferably in 18 hours, and the blood drug level of most preferably in 12 hours, remaining valid.
Double-layer sustained release tablets
Term " double-layer sustained release tablets ", " double-layer sustained release tablets of the present invention " or " Lornoxicam double-layer sustained release tablets " are used interchangeably, all refer to comprise the lornoxicam preparation of release layer of the present invention and slow release layer, it has in vivo in the gastric juice rapidly, and dissolving discharges, thereby reach effective blood drug concentration fast, and slowly continue to discharge the slow releasing pharmaceutical active component subsequently in vivo, to keep the effect of effective blood drug concentration stably.In addition, this term has also comprised and has randomly comprised other antalgic and inflammation relieving active component, or randomly comprised Lornoxicam double-layer sustained release preparations of one or more other additional layers.
In the described double-layer sustained release tablets, release layer can stack up and down with slow release layer, or places the outside of slow release layer, preferably release layer and slow release layer is stacked up and down.
The gross weight of Lornoxicam double-layer sustained release tablets of the present invention is 50～1000mg/ sheet, preferred 100～500mg/ sheet.
The lornoxicam total content is the 0.1-99wt% of tablet total weight in the Lornoxicam double-layer sustained release tablets of the present invention, preferred 0.5-90wt%, more preferably 1-80wt%.
Wherein, the weight ratio of lornoxicam is 1 in lornoxicam in the release layer and the slow release layer: 25-25: 1, preferred 1: 10-10: 1, more preferably 1: 5-5: 1.
(a) release layer accounts for the 10-90wt% of described double-layer sustained release tablets gross weight, and (b) slow release layer accounts for the 10-90wt% of described double-layer sustained release tablets gross weight, is 100wt% with (b) weight sum (a).
In an embodiment of the invention, release layer accounts for the 20-80wt% of described double-layer sustained release tablets gross weight, preferred 30-50wt%; Slow release layer accounts for the 20-80wt% of described double-layer sustained release tablets gross weight, preferred 50-70wt%.In an embodiment of the invention, the weight ratio of release layer and slow release layer is 1: 25-25: 1, preferred 1: 10-10: 1, more preferably 1: 5-5: 1.
In an embodiment of the invention, alkaline matter accounts for the 0.1-25wt% of described double-layer sustained release tablets gross weight, preferred 0.5-20wt%, more preferably 1-10wt%.
According to drug release determination method (two appendix XD of Chinese Pharmacopoeia version in 2005), adopt dissolution method (two appendix XC of Chinese Pharmacopoeia version in 2005) second method (slurry method) device, with 750ml 0.1mol/L hydrochloric acid is release medium, in the medicine total amount in the whole double-layer sustained release tablets is benchmark, described alkaline matter makes the lornoxicam in the double-layer sustained release tablets reach more than 10% the 1st hour release, 10-50wt% for example, preferred 10-45wt%, more preferably 15-40wt%, most preferably 20-40wt%.
For example, in preferred implementation of the present invention, the optimization formula of Lornoxicam double-layer sustained release tablets is:
The component of lornoxicam and adjuvant and content are in the release layer:
Lornoxicam 1-12 weight portion
Alkaline matter 5-80 weight portion
Cross-linking sodium carboxymethyl cellulose 5-40 weight portion
Pregelatinized Starch 20-300 weight portion
5% povidone solution 10-100 weight portion
Magnesium stearate 0.2-5 weight portion
The component of lornoxicam and adjuvant and content are in the slow release layer: (every consumption)
Lornoxicam 4-36 weight portion
Hypromellose 20-300 weight portion
Lactose 30-300 weight portion
5% povidone solution 40-200 weight portion
Magnesium stearate 0.2-7 weight portion
The most preferred prescription of Lornoxicam double-layer sustained release tablets of the present invention is:
The component of lornoxicam and adjuvant and content are in the release layer: (every consumption)
Lornoxicam 1-12 weight portion
Alkaline matter 10-40 weight portion
Cross-linking sodium carboxymethyl cellulose 5-15 weight portion
Pregelatinized Starch 50-120 weight portion
5% povidone solution 40-80 weight portion
Magnesium stearate 0.5-2 weight portion
The component of lornoxicam and adjuvant and content are in the slow release layer: (every consumption)
Lornoxicam 4-36 weight portion
Hypromellose 30-80 weight portion
Lactose 80-200 weight portion
5% povidone solution 60-100 weight portion
Magnesium stearate 0.5-3 weight portion
In addition, Lornoxicam double-layer sustained release tablets also can randomly comprise other antalgic and inflammation relieving active component.Described other antalgic and inflammation relieving active component for example can be selected from: tramadol hydrochloride, acetaminophen, aspirin etc.
In addition, randomly also comprising one or more other Lornoxicam double-layer sustained release tablets of additional layer is also contained in the scope of the present invention.Described one or more additional layer is selected from: rapid release or slow release layer, adhesive layer and/or the coatings of the common layer of lornoxicam, other antalgic and inflammation relieving active component.
In addition, Lornoxicam double-layer sustained release tablets of the present invention also can with two or more medication combined administration, and generally have and be better than the individually dosed respectively effects of two kinds of medicines.Preferably, co-administered medicine or other preparation therapeutic activity of not disturbing lornoxicam of the present invention.
Preparation technology
Lornoxicam double-layer sustained release tablets of the present invention can adopt the conventional method preparation of this area.For example can adopt wet granulation pressed disc method, dry granule tabletting, direct powder compression preparation.
Described preparation method comprises the steps:
(i) provide release layer material and slow release layer material, wherein
Described release layer material comprises: (a1) lornoxicam; (a2) alkaline matter; (a3) Ren Xuan pharmaceutically acceptable other carrier or excipient;
Described slow release layer material comprises: (b1) lornoxicam; (b2) slow-release material; (b3) Ren Xuan pharmaceutically acceptable other carrier or excipient; With
(ii) described release layer material and described slow release layer material are pressed into double-layer sustained release tablets.
Wherein the content of each material component and ratio are as hereinbefore defined.
For example, in a preferred embodiment of the present invention, adopted the wet granulation pressed disc method, its concrete technological process is:
A. the pre-treatment of supplementary material
Lornoxicam, magnesium stearate are crossed 100 mesh sieves, standby.Other adjuvant is crossed 80 mesh sieves, and is standby.Getting polyvidone adds water and makes clear and bright solution for standby.
B. the particulate preparation of release layer
1. lornoxicam, alkaline matter, cross-linking sodium carboxymethyl cellulose, pregelatinized Starch are mixed, cross three mixings of 60 sieves;
2. add povidone solution and make soft material;
3. crossing 30 order nylon mesh granulates;
4. 50 ± 2 ℃ of dryings 60 minutes;
5. dried granule is crossed 30 order nylon mesh granulate, added the abundant mix homogeneously of magnesium stearate, obtain the release layer granule.
C. the particulate preparation of slow release layer
1. lornoxicam, hypromellose, lactose are mixed, cross three mixings of 60 sieves;
2. add povidone solution and make soft material;
3. crossing 30 order nylon mesh granulates;
4. 50 ± 2 ℃ of dryings 60 minutes;
5. dried granule is crossed 30 order nylon mesh granulate, added the abundant mix homogeneously of magnesium stearate, obtain the slow release layer granule.
D. the compacting of double-layer sustained release tablets
Release layer granule and slow release layer granule are placed container respectively, use the bi-layer tablet press tabletting.
The advantage of Lornoxicam double-layer sustained release tablets of the present invention is:
1. the double-layer sustained release preparation that has prepared lornoxicam first;
2. described double-layer sustained release preparation utilizes the alkaline matter in the release layer, the patient is taken medicine after, release layer part can rapid disintegrate in acidic gastric juice, dissolving discharges lornoxicam, makes blood drug level reach treatment concentration rapidly; And slow-released part is kept effective blood drug concentration with the slow release of given pace, reduces blood concentration fluctuation, reduces Cmax, to reduce patient's medicining times, reduces adverse reaction rate.
2. the method for preparing described Lornoxicam double-layer sustained release tablets is easy, and raw material is easy to obtain, and cost is lower, is suitable for large-scale production.
Embodiment
By the following examples the present invention is further described.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 in the following example is usually according to normal condition or according to preparing the condition that manufacturer advises.Unless otherwise indicated, otherwise percentage ratio and umber calculate by weight.
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 among the present invention.The usefulness that preferable implementation method described in the literary composition and material only present a demonstration.
Embodiment 1 Lornoxicam double-layer sustained release tablets 1
Prescription
Release layer part (every consumption)
4 milligrams of lornoxicams
16 milligrams of L-arginine
10 milligrams of cross-linking sodium carboxymethyl celluloses
84 milligrams of pregelatinized Starch
30 milligrams of 5% polyvidones
1 milligram of magnesium stearate
Slow release layer part (every consumption)
8 milligrams of lornoxicams
Hypromellose (viscosity: 4000 centipoises) 15 milligrams
Hypromellose (viscosity: 100 centipoises) 30 milligrams
122 milligrams of lactose
(model: K30) solution is 80 milligrams for 5% polyvidone
1.8 milligrams of magnesium stearate
Preparation method
(1) preparation of immediate-release granules:
Lornoxicam, pregelatinized Starch, L-arginine, cross-linking sodium carboxymethyl cellulose are crossed 60 mesh sieve mixings.Add in the stirring 5% polyvidone (restrain/100 milliliters, model: K30) solution system soft material, cross the granulation of 30 mesh sieves, 50 ℃ of dryings 1 hour, dried granule is crossed 30 mesh sieve granulate, the abundant mix homogeneously of adding magnesium stearate promptly gets immediate-release granules.
(2) preparation of slow-releasing granules:
4000 centipoises), hypromellose (viscosity: 100 centipoises), lactose crosses 60 mesh sieve mixings with lornoxicam 8g, hypromellose (viscosity:.Add in the stirring 5% polyvidone (restrain/100 milliliters, model: K30) solution system soft material, cross the granulation of 30 mesh sieves, 50 ℃ of dryings 1 hour, dried granule is crossed 30 mesh sieve granulate, the adding magnesium stearate, mix homogeneously promptly gets slow-releasing granules.
(3) making of double-layer sustained release tablets 1:
Slow-releasing granules and immediate-release granules are made double-layer sustained release tablets with the punching press of 8mm scrobicula.Every lornoxicam 12mg.
Prescription
Release layer part (every consumption)
6 milligrams of lornoxicams
2 milligrams of L-arginase 12s
15 milligrams of cross-linking sodium carboxymethyl celluloses
105 milligrams of pregelatinized Starch
40 milligrams of 5% polyvidones
1.5 milligrams of magnesium stearate
Slow release layer part (every consumption)
12 milligrams of lornoxicams
Hypromellose (viscosity: 4000 centipoises) 20 milligrams
Hypromellose (viscosity: 100 centipoises) 50 milligrams
105 milligrams of lactose
(model: K30) solution is 80 milligrams for 5% polyvidone
2.3 milligrams of magnesium stearate
Preparation method
(1) preparation of immediate-release granules:
Lornoxicam, pregelatinized Starch, L-arginine, cross-linking sodium carboxymethyl cellulose are crossed 60 mesh sieve mixings.Add in the stirring 5% polyvidone ((restrain/100 milliliters, model: K30) solution system soft material, cross the granulation of 30 mesh sieves, 50 ℃ of dryings 1 hour, dried granule is crossed 30 mesh sieve granulate, the abundant mix homogeneously of adding magnesium stearate promptly gets immediate-release granules.
(2) preparation of slow-releasing granules:
4000 centipoises), hypromellose (viscosity: 100 centipoises), lactose crosses 60 mesh sieve mixings with lornoxicam, hypromellose (viscosity:.Add in the stirring 5% polyvidone (restrain/100 milliliters, model: K30) solution system soft material, cross the granulation of 30 mesh sieves, 50 ℃ of dryings 1 hour, dried granule is crossed 30 mesh sieve granulate, the adding magnesium stearate, mix homogeneously promptly gets slow-releasing granules.
(3) making of double-layer sustained release tablets 2:
Slow-releasing granules and immediate-release granules are made double-layer sustained release tablets with the punching press of 8mm scrobicula.Every lornoxicam 24mg.
Embodiment 3 Lornoxicam double-layer sustained release tablets 3
Prescription
Release layer part (every consumption)
3 milligrams of lornoxicams
42 milligrams of sodium bicarbonate
20 milligrams of carboxymethyl starch sodium
85 milligrams of pregelatinized Starch
40 milligrams of 5% polyvidones
1.5 milligrams of magnesium stearate
Slow release layer part (every consumption)
9 milligrams of lornoxicams
Hypromellose (viscosity: 4000 centipoises) 18 milligrams
Hypromellose (viscosity: 50 centipoises) 65 milligrams
80 milligrams of lactose
(model: K30) solution is 60 milligrams for 5% polyvidone
2.3 milligrams of magnesium stearate
Preparation method
(1) preparation of immediate-release granules:
Lornoxicam, pregelatinized Starch, sodium bicarbonate, carboxymethyl starch sodium are crossed 60 mesh sieve mixings.Add in the stirring 5% polyvidone ((restrain/100 milliliters, model: K30) solution system soft material, cross the granulation of 30 mesh sieves, 50 ℃ of dryings 1 hour, dried granule is crossed 30 mesh sieve granulate, the abundant mix homogeneously of adding magnesium stearate promptly gets immediate-release granules.
(2) preparation of slow-releasing granules:
4000 centipoises), hypromellose (viscosity: 50 centipoises), lactose crosses 60 mesh sieve mixings with lornoxicam, hypromellose (viscosity:.Add in the stirring 5% polyvidone (restrain/100 milliliters, model: K30) solution system soft material, cross the granulation of 30 mesh sieves, 50 ℃ of dryings 1 hour, dried granule is crossed 30 mesh sieve granulate, the adding magnesium stearate, mix homogeneously promptly gets slow-releasing granules.
(3) making of double-layer sustained release tablets 3:
Slow-releasing granules and immediate-release granules are made double-layer sustained release tablets with the punching press of 8mm scrobicula.Every lornoxicam 24mg.
Prescription
Every consumption
12 milligrams of lornoxicams
16 milligrams of L-arginine
Hypromellose (viscosity: 4000 centipoises) 15 milligrams
Hypromellose (viscosity: 100 centipoises) 30 milligrams
260 milligrams of lactose
(model: K30) solution is 80 milligrams for 5% polyvidone
2 milligrams of magnesium stearate
Preparation method
4000 centipoises), hydroxypropyl methylcellulose (viscosity: 100 centipoises), L-arginine, lactose pulverize, 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 the magnesium stearate mix homogeneously again.Make sheet with the punching press of 8mm scrobicula, get lornoxicam monolayer slow releasing tablet 4.
The lornoxicam monolayer slow releasing tablet 4 among embodiment 5 embodiment 4 and the release of the double-layer sustained release tablets among the embodiment 1-3 are relatively
Test objective
For the release characteristic with the Lornoxicam double-layer sustained release tablets that contains release layer and slow release layer simultaneously compares, as described in embodiment 4, prepared the lornoxicam monolayer slow releasing tablet 4 that does not contain release layer and only contain slow release layer.
The main purpose of preparation monolayer slow releasing tablet 4 is to compare with double-layer sustained release tablets 1-3 of the present invention, whether can in the acid solution of simulation human gastric juice environment, discharge lornoxicam to assess double-layer sustained release preparation of the present invention, and can discharge active medicine gently with the speed of design.
Assay method
The test determination of release in vitro degree is as follows:
(1) preparation of need testing solution:
Respectively get among the embodiment 1～4 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 dissolution method (two appendix XC of Chinese Pharmacopoeia version in 2005) second method (slurry method) device, the 1st hour is release medium with 750ml 0.1mol/L hydrochloric acid, pouring the 250ml sodium phosphate buffer after 1 hour into (takes by weighing the 73.6g sodium phosphate dodecahydrate and adds suitable quantity of water dissolving back adding 0.1mol/L sodium hydroxide 31.8ml, be diluted to 1000ml, shake up) be release medium, rotating speed is that per minute 50 changes, operation in accordance with the law, 1,2,4,6, got solution 5ml in 8 hours respectively, filter with 0.45 micron microporous filter membrane, subsequent filtrate suitably dilutes the back as need testing solution.
(2) 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.
(3) 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 Lornoxicam double-layer sustained release tablets 1,2,3 provided by the present invention rapid (1 hour) in acid solution discharges about 25% lornoxicam.And the lornoxicam monolayer slow releasing tablet that does not contain release layer only discharges in 1 hour in acid medium and is lower than 5% lornoxicam, significantly is lower than the burst size of double-layer sustained release tablets in acid solution.
Simultaneously, can obviously find out Lornoxicam double-layer sustained release tablets of the present invention all steadily releases lentamente behind rapid release by release profiles.
This result shows that Lornoxicam double-layer sustained release tablets of the present invention has that quick releasing formulation proves effective soon, the advantage of slow releasing preparation lasting medicine, after it can play and reach effective blood drug concentration fast, continues to keep the effect of stable effective blood drug concentration.
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 (10)
1. Lornoxicam double-layer sustained release tablets, it comprises (a) release layer and (b) slow release layer, wherein:
Described release layer comprises:
(a1) lornoxicam;
(a2) alkaline matter;
(a3) Ren Xuan pharmaceutically acceptable other carrier or excipient;
Described slow release layer comprises:
(b1) lornoxicam;
(b2) slow-release material;
(b3) Ren Xuan pharmaceutically acceptable other carrier or excipient;
Wherein, be 1 (a1): 50-50 with (b1) weight ratio: 1, and
Described alkaline matter makes lornoxicam in the described double-layer sustained release tablets according to Chinese Pharmacopoeia drug release determination method, with 750ml 0.1mol/L hydrochloric acid is release medium, and the release in the 1st hour reaches the 10-50wt% of lornoxicam gross weight in the described double-layer sustained release tablets.
2. Lornoxicam double-layer sustained release tablets as claimed in claim 1 is characterized in that, described (a2) alkaline matter is selected from: arginine, sodium bicarbonate, sodium carbonate, lysine, trometamol, meglumine, sodium hydroxide or their combination.
3. Lornoxicam double-layer sustained release tablets as claimed in claim 1 is characterized in that, described (a2) alkaline matter is 1 with (a1) weight ratio of lornoxicam: 100-100: 1.
4. Lornoxicam double-layer sustained release tablets as claimed in claim 1, it is characterized in that, (a) release layer accounts for the 10-90wt% of described double-layer sustained release tablets gross weight, and (b) slow release layer accounts for the 10-90wt% of described double-layer sustained release tablets gross weight, is 100wt% with (b) weight sum (a).
5. Lornoxicam double-layer sustained release tablets as claimed in claim 1 is characterized in that, described (b2) slow-release material is selected from: cellulose derivative, CBP, sodium alginate, glyceryl monostearate or their combination.
6. Lornoxicam double-layer sustained release tablets as claimed in claim 1 is characterized in that, (b2) slow-release material is 1: 1 00-100 with (b1) weight ratio of lornoxicam: 1.
7. Lornoxicam double-layer sustained release tablets as claimed in claim 1 is characterized in that, (a3) optional pharmaceutically acceptable other carrier or excipient are to be selected from down in the group one or more: filler, binding agent, disintegrating agent or lubricant; (b3) Ren Xuan pharmaceutically acceptable other carrier or excipient be selected from down the group in one or more: filler, binding agent or lubricant.
8. Lornoxicam double-layer sustained release tablets as claimed in claim 1 is characterized in that, each component has content as follows in the described double-layer sustained release tablets:
(a) release layer
(a1) lornoxicam 0.1-100 weight portion
(a2) alkaline matter 1-100 weight portion
(a3) Ren Xuan pharmaceutically acceptable other carrier or excipient 1-1000 weight portion
(b) slow release layer
(b1) lornoxicam 0.1-100 weight portion
(b2) slow-release material 20-500 weight portion
(b3) Ren Xuan pharmaceutically acceptable other carrier or excipient 20-1500 weight portion.
9. Lornoxicam double-layer sustained release tablets as claimed in claim 1 is characterized in that, it also randomly comprises other antalgic and inflammation relieving active component, or randomly comprises one or more other additional layers.
10. the method for preparing each described Lornoxicam double-layer sustained release tablets among the claim 1-8, described method comprises step:
(i) provide release layer material and slow release layer material, wherein
Described release layer material comprises: (a1) lornoxicam; (a2) alkaline matter; (a3) Ren Xuan pharmaceutically acceptable other carrier or excipient;
Described slow release layer material comprises: (b1) lornoxicam; (b2) slow-release material; (b3) Ren Xuan pharmaceutically acceptable other carrier or excipient; With
(ii) described release layer material and described slow release layer material are pressed into double-layer sustained release tablets.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100436881A CN101342177B (en) | 2007-07-12 | 2007-07-12 | Lornoxicam double-layer sustained release tablets |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100436881A CN101342177B (en) | 2007-07-12 | 2007-07-12 | Lornoxicam double-layer sustained release tablets |
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| CN101342177B CN101342177B (en) | 2011-10-26 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102917696A (en) * | 2010-06-01 | 2013-02-06 | 韩国联合制药株式会社 | Aceclofenac slow-release preparation providing an optimum pharmacological clinical effect when administered once a day |
| CN104224860A (en) * | 2014-10-13 | 2014-12-24 | 北京人福军威医药技术开发有限公司 | Ginkgo leaf sustained-release tablet with stable release performance |
| CN109111469A (en) * | 2018-10-09 | 2019-01-01 | 中国药科大学 | A kind of amorphous compound altogether of lornoxicam |
| CN114533690A (en) * | 2022-03-22 | 2022-05-27 | 许昌市中心医院 | Novel preparation containing anticoagulant cilostazol and preparation method thereof |
-
2007
- 2007-07-12 CN CN2007100436881A patent/CN101342177B/en active Active
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102917696A (en) * | 2010-06-01 | 2013-02-06 | 韩国联合制药株式会社 | Aceclofenac slow-release preparation providing an optimum pharmacological clinical effect when administered once a day |
| CN102917696B (en) * | 2010-06-01 | 2015-04-01 | 韩国联合制药株式会社 | Aceclofenac slow-release preparation providing an optimum pharmacological clinical effect when administered once a day |
| CN104224860A (en) * | 2014-10-13 | 2014-12-24 | 北京人福军威医药技术开发有限公司 | Ginkgo leaf sustained-release tablet with stable release performance |
| CN109111469A (en) * | 2018-10-09 | 2019-01-01 | 中国药科大学 | A kind of amorphous compound altogether of lornoxicam |
| CN114533690A (en) * | 2022-03-22 | 2022-05-27 | 许昌市中心医院 | Novel preparation containing anticoagulant cilostazol and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101342177B (en) | 2011-10-26 |
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