CN103772378A - Meloxicam compound and tablet thereof - Google Patents
Meloxicam compound and tablet thereof Download PDFInfo
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- CN103772378A CN103772378A CN201410037599.6A CN201410037599A CN103772378A CN 103772378 A CN103772378 A CN 103772378A CN 201410037599 A CN201410037599 A CN 201410037599A CN 103772378 A CN103772378 A CN 103772378A
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention relates to a meloxicam compound and a tablet thereof. The meloxicam has a chemical structural formula shown in a formula , the compound is a crystal compound, and an X-ray powder diffraction pattern obtained by Cu-K alpha ray measurement is shown in figure 1;every 1000 tablets of the tablet are prepared by taking meloxicam as an active ingredient and various auxiliary materials in parts by weight as follows: 5-10 parts of meloxicam, 50-70 parts of microcrystalline cellulose, 20-40 parts of pregelatinized starch, 10-30 parts of low-substituted hydroxypropyl cellulose, 3-5 parts of poloxamer, 10-20 parts of carboxymethyl starch sodium and 3% of PVP K30An appropriate amount of the aqueous solution and 0.5-1 part by weight of magnesium stearate. The meloxicam compound has good dissolubility, and the prepared tablet has excellent dissolution, good stability and good bioavailability.
Description
Technical field
The invention belongs to medical technical field, specifically, relate to a kind of meloxicam compound and tablet thereof.
Background technology
Meloxicam (meloxicam, MLX) is novel NSAID (non-steroidal anti-inflammatory drug) (NSAIDs), within 1996, is gone on the market first by German Boehringer Ingelheim company in South Africa.Studies have reported that, MLX is (lower than 15mg every day) under low dosage, is cyclooxygenase-2(COX-2) preferential selective depressant.Compared with the MLX NSAIDs traditional with Naproxen Base, Ibuprofen BP/EP, piroxicam etc., anti-inflammatory pain-stopping effect is similar, and gi tract tolerance significantly improves, and during patient's medication, almost there is no gastric-intestinal perforation, hemorrhage, ulcer situation, feels sick, vomiting phenomenon is few.
CN103054872A discloses a kind of meloxicam pharmaceutical composition and preparation method thereof.Meloxicam pharmaceutical composition by weight percentage composition meter comprises following component: 2%～10% effective constituent meloxicam, 70%～80% weighting agent, 7%～11% disintegrating agent, 2%～5% tackiness agent, 0.2%～0.8% solubilizing agent, 0.2%～5% lubricant, and appropriate solvent.The rational auxiliary material of pharmaceutical composition of meloxicam provided by the present invention is chosen and proportional distribution, make the prepared meloxicam tablet of the present invention in vitro in stripping tool be significantly improved.In this pharmaceutical composition, be insoluble in the feature of water for meloxicam, added solubilizing agent to increase the stripping of tablet.Described solubilizing agent is one or more the composition in poloxamer, Tween-80, sodium lauryl sulphate.
CN103099791A relates to a kind of meloxicam oral preparations that increases dissolution rate and preparation method thereof.It is characterized in that mainly containing: meloxicam: 1, solubilizing agent: 0.02～0.047, tackiness agent: 0.20～0.40, weighting agent: 3.33～4.67, lubricant: 0.013～0.08, disintegrating agent: 0.33～1.33.Said preparation has improved drug dissolution, has improved clinical efficacy.Because meloxicam belongs to insoluble drug, be the rate-limiting factor that affects main ingredient absorption and even bioavailability at GI process in leaching, in this oral preparations, in prescription, increasing solubilizing agent (Labraso) is a kind of effectively short suction means.
CN101618026A discloses a kind of meloxicam tablet and production technique and purposes, and product is made up of with pregelatinized Starch, micropowder silica gel, Magnesium Stearate, ethanol, gastric solubility film coating pre-mix dose meloxicam, lactose, pregelatinized Starch, low-substituted hydroxypropyl cellulose, Tween-80,12% concentration punching slurry.Production method comprises steps such as making label, dressing.
" technical study of meloxicam tablet and quality control " [Gao Xiurui, hide Hengchang, Deng. the technical study of meloxicam tablet and quality control, Shandong medicine thing, 2008,27(9): 555-558] adopt orthogonal experiment, using dissolution rate as index, basifier, tamanori and disintegrating agent in prescription are screened, adopt content and the dissolution rate of Determination of Meloxicam by Ultraviolet Spectrophotometry sheet.The best prescription that draws meloxicam tablet is every and contains Trisodium Citrate 20mg, 30 POVIDONE K 30 BP/USP
3018mg, polyvinylpolypyrrolidone 12mg.In this prescription, be insoluble in the feature of water for meloxicam, added basifier to increase the stripping of tablet.
The Dissolution of Tablet of pharmacopeia regulation is speed and the degree of main ingredient stripping in the solvent of regulation in tablet.Within the regular hour, the number of main ingredient stripping, will directly have influence on the curative effect of medicine.In prior art, be insoluble in the feature of water for meloxicam, mostly in the preparation process of tablet, increase solubilizing agent or basifier to promote the stripping of tablet.But, in prolonged application, find that the stability of the tablet take meloxicam as main effective constituent is bad, affect the performance of pharmaceutical effectiveness.
The inventor starts with from effective constituent meloxicam, after a large amount of research, make a kind of new crystal compound of meloxicam, this compound is compared and is had good solvability compared with the meloxicam of prior art, thereby guarantee the speed of this medicine stripping from preparation, and pleasantly surprised find that the tablet that adopts this new crystal meloxicam to make not only has good stability, also there is the bioavailability significantly improving, thereby completed the present invention.
Summary of the invention
The object of the present invention is to provide a kind of meloxicam compound, described meloxicam is a kind of meloxicam new crystal compound that is different from prior art, and this compound has good solvability.
For realizing object of the present invention, the present invention adopts following technical scheme:
A kind of meloxicam compound, wherein, described meloxicam has the chemical structural formula shown in formula (I), and this compound is crystalline compounds, and the X-ray powder diffraction pattern that use Cu-K alpha-ray measures is as shown in Figure 1;
The crystalline powder that meloxicam is micro-yellow to faint yellow or yellowish green to pistac, almost insoluble in water.And the solvability of medicine directly affects the dissolution rate of medicine from preparation, for insoluble or the very slow medicine of dissolution rate, its dissolving from preparation discharges the speed limit process that just becomes drug absorption, the solvability that is medicine becomes the principal element that affects drug absorption, thereby directly affects onset time, efficacy strength and the time length of medicine.Therefore, develop a kind of meloxicam having improved solubility and just seem particularly important.For same compound, because crystallization condition as the difference of solvent, anti-solvent, temperature, speed of cooling etc., can obtain the crystallization that different crystalline lattice is arranged, i.e. polymorphic.The same medicine of different crystal forms may have significant difference at aspects such as solubleness, fusing point, density, stability.The present invention has obtained a kind of meloxicam new crystal having improved solubility by a large amount of research.
Meloxicam crystalline compounds of the present invention is adopted with the following method and is prepared:
(1) get meloxicam bulk drug, under 0～5 ℃ of condition, add sodium hydroxide solution appropriate, stir meloxicam is dissolved, then add the mixed solvent of dimethyl formamide and methyl alcohol, stir and obtain settled solution;
(2) in the settled solution of step (1) gained, add activated carbon decolorizing, stir, filter, obtain filtrate;
(3) filtrate step (2) being obtained is warming up to 20～30 ℃, adds while stirring salt acid for adjusting pH value to slightly acidic;
(4) finish, continue under agitation condition, to drip the acetone of 20～30 ℃, after dripping, be cooled to 0～5 ℃, leave standstill, filter, washing, vacuum-drying obtains described meloxicam compound.
Wherein, in step (1), the amount ratio of described meloxicam bulk drug and the mixed solvent of dimethyl formamide and methyl alcohol is 1g:5～10ml; The concentration of described sodium hydroxide solution is 10～15%, and the percentage ratio here refers to mass percent concentration.
In described dimethyl formamide and the mixed solvent of methyl alcohol, the volume ratio of dimethyl formamide and methyl alcohol is 1:0.2～0.5.
In step (2), the consumption of gac is 0.01～0.02%(g/ml of settled solution total amount), the time of described stirring is 0.5～1.5 hour.
In step (3), the stirring velocity while adding hydrochloric acid is 90～120r/min.
In step (4), the volume ratio of the mixed solvent of described acetone and dimethyl formamide and methyl alcohol is 3～5:1.
In step (4), the stirring velocity while adding acetone is 20～30r/min.
Same compound, different crystalline structures causes inner solid-state structure difference, causes its lattice energy difference, thereby causes its physicals also different, so different crystal formations can have different apparent solubilities and dissolution rate.According in this, the inventor attempts the crystalline structure by changing meloxicam compound, thereby improves the solvability of meloxicam, to obtaining the good meloxicam of a kind of solvability.
The inventor is through a large amount of tests repeatedly, constantly change crystallization method and comprise the crystallization conditions such as solvent, anti-solvent, temperature, finally obtained a kind of new crystal of meloxicam, the meloxicam of this new crystal has solvability in the water of improvement compared with the meloxicam of prior art.
The present invention also provides a kind of meloxicam tablet, and wherein, every 1000 meloxicams by following weight part of described tablet are that activeconstituents and various auxiliary material are prepared from:
Preferably, every 1000 meloxicams by following weight part of described tablet are that activeconstituents and various auxiliary material are prepared from:
In the present invention, use low-substituted hydroxypropyl cellulose as disintegrating agent, can obviously shorten the disintegration of meloxicam, thereby improve drug dissolution.
In the time that raw material itself has certain viscosity, thereby the viscosity that adds wetting agent can soak and bring out raw material is made softwood and is made the particle that hardness is suitable.If viscosity is excessive, the tablet of making is really up to the mark, is unfavorable for medicine stripping from solid preparation.By adjusting kind and the consumption of wetting agent, the stripping that can improve solid preparation Chinese traditional medicine.In the present invention, adopt poloxamer and 3%PVP K
30the aqueous solution as wetting agent, the dissolution rate of tablet is significantly improved.Wherein 3%PVP K
30the consumption of the aqueous solution be appropriate, consumption, as long as can meet and can dissolve poloxamer, makes supplementary material can reach the amount of softwood processed, this point is that those skilled in the art are thinkable.The 3%PVP K used according to the concrete prescription of Meloxicam Tablets of the present invention
30the consumption of the aqueous solution be about 80ml.
The present invention tests by Plasma Concentration, show under the prescription condition identical with preparation method, adopt compared with the meloxicam tablet that meloxicam tablet that meloxicam compound provided by the present invention makes makes with commercially available meloxicam bulk drug, the meloxicam tablet that adopts meloxicam compound provided by the present invention to make has better plasma concentration curve.
In the present invention, described low-substituted hydroxypropyl cellulose adopts inside and outside addition.
Low-substituted hydroxypropyl cellulose in the present invention adopts inside and outside addition, has more accelerated the disintegration of meloxicam tablet, thereby has shortened the disintegration time of meloxicam tablet.
In the present invention, described meloxicam tablet also comprises coating material.
In the present invention, described coating material is the coating liquid that Opadry and ethanol are made.
The preparation method that described meloxicam tablet is also further provided of the present invention, the method comprises the steps:
1) screening
Take meloxicam, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, pregelatinized Starch and carboxymethylstach sodium by described consumption respectively, cross respectively 100 mesh sieves;
2) mix
The order of pressing the low-substituted hydroxypropyl cellulose → pregelatinized Starch → Microcrystalline Cellulose of consumption described in meloxicam → carboxymethylstach sodium → 1/2, equivalent incremental method carries out pre-mixing, then puts and in mixing tank, mix to obtain powder mix;
3) granulate
The PVP K of preparation 3%
30the aqueous solution is appropriate, adds the poloxamer of described consumption, is stirred to dissolve, and makes wetting agent; In above-mentioned powder mix, add prepared wetting agent, make softwood, 20 mesh sieves are granulated, and are dried to pellet moisture <4%, and the whole grain of 18 mesh sieves, obtains dry particle;
4) always mixed
In above-mentioned dry particle, add the low-substituted hydroxypropyl cellulose of consumption described in the Magnesium Stearate of described consumption and residue 1/2, always mix, obtain mixture;
5) compressing tablet
Said mixture is carried out to compressing tablet, obtain meloxicam tablet.
The quality of mobility will directly affect tablet weight variation, the content homogeneity of preparation.Have the filling that good mobility is beneficial to tabletting machine nib, this meaning in high speed tablet press is even more important.The mobility tool of main ingredient different mixing time ordered pair gained powder mix in mixing process has a certain impact.The present invention has investigated the impact of the mobility of different mixing time ordered pair powder mix by the slope of repose of working sample, thereby has determined the mixing order of main ingredient.
In preparation method of the present invention, after main ingredient is sieved according to the good fluidity of above-mentioned ordered pair main ingredient mixing gained powder mix.
Meanwhile, in the present invention, adopt the aqueous solution of poloxamer and 3%PVP K30 as wetting agent, the dissolution rate of tablet to be significantly improved.
In above-mentioned preparation method, being dried described in step 3) is 70 ℃ of forced air dryings.
In the present invention, described preparation method also comprises further the meloxicam tablet of gained is carried out to dressing.
In the present invention, described dressing is that the coating liquid that adopts Opadry and ethanol to make carries out dressing.
Compared with prior art, tool of the present invention has the following advantages:
(1) meloxicam compound provided by the present invention has good solvability;
(2) meloxicam tablet provided by the present invention not only has good result of extraction, and has good stability;
(3) meloxicam tablet provided by the present invention has good bioavailability.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction pattern of meloxicam crystalline compounds of the present invention;
Fig. 2 is 18 routine healthy male subjects single oral meloxicam reference sheets 1, reference sheet 2, the average Plasma Concentration-time curve of test film 15mg.
Embodiment
Providing embodiment is below further described the present invention; it is important to point out that following examples can not be interpreted as limiting the scope of the present invention, some nonessential improvement that the person skilled in the art in this field makes the present invention according to foregoing invention content and adjustment still belong to protection scope of the present invention.
The preparation of embodiment 1, meloxicam compound
(1) get meloxicam bulk drug 50g, under 0 ℃ of condition, adding mass percent concentration is that 10% NaOH solution is appropriate, stirring is dissolved meloxicam, adding the volume ratio of dimethyl formamide and methyl alcohol in the mixed solvent 250ml(mixed solvent of dimethyl formamide and methyl alcohol is 1:0.2 again), stir and obtain settled solution;
(2) in the settled solution of step (1) gained, add 0.01%(g/ml) activated carbon decolorizing, stir 0.5 hour, filter, obtain filtrate;
(3) filtrate step (2) being obtained is warming up to 20 ℃, adds while stirring salt acid for adjusting pH value to 6, and wherein stirring velocity is 90r/min;
(4) finish, under the condition that continuation low whipping speed is 20r/min, drip the acetone of 20 ℃, the volume ratio of the mixed solvent of acetone and dimethyl formamide and methyl alcohol is 3:1; After dripping, be cooled to 0 ℃, leave standstill 3 hours, filter, washing, vacuum-drying obtains described meloxicam compound.
The X-ray powder diffraction pattern that the meloxicam crystalline compounds use Cu-K alpha-ray of gained is measured as shown in Figure 1.
The preparation of embodiment 2, meloxicam compound
(1) get meloxicam bulk drug 50g, under 5 ℃ of conditions, adding mass percent concentration is that 15% NaOH solution is appropriate, stirring is dissolved meloxicam, adding the volume ratio of dimethyl formamide and methyl alcohol in the mixed solvent 500ml(mixed solvent of dimethyl formamide and methyl alcohol is 1:0.5 again), stir and obtain settled solution;
(2) in the settled solution of step (1) gained, add 0.02%(g/ml) activated carbon decolorizing, stir 0.5～1.5 hour, filter, obtain filtrate;
(3) filtrate step (2) being obtained is warming up to 30 ℃, adds while stirring salt acid for adjusting pH value to 5, and wherein stirring velocity is 120r/min;
(4) finish, under the condition that continuation low whipping speed is 30r/min, drip the acetone of 30 ℃, the volume ratio of the mixed solvent of acetone and dimethyl formamide and methyl alcohol is 5:1; After dripping, be cooled to 5 ℃, leave standstill 3 hours, filter, washing, vacuum-drying obtains described meloxicam compound.
The X-ray powder diffraction pattern and the embodiment 1 that use Cu-K alpha-ray to measure the meloxicam crystalline compounds of gained match.
The preparation of embodiment 3, meloxicam compound
(1) get meloxicam bulk drug 50g, under 3 ℃ of conditions, adding mass percent concentration is that 12% NaOH solution is appropriate, stirring is dissolved meloxicam, adding the volume ratio of dimethyl formamide and methyl alcohol in the mixed solvent 350ml(mixed solvent of dimethyl formamide and methyl alcohol is 1:0.3 again), stir and obtain settled solution;
(2) in the settled solution of step (1) gained, add 0.015%(g/ml) activated carbon decolorizing, stir 1 hour, filter, obtain filtrate;
(3) filtrate step (2) being obtained is warming up to 25 ℃, adds while stirring salt acid for adjusting pH value to 6, and wherein stirring velocity is 110r/min;
(4) finish, under the condition that continuation low whipping speed is 25r/min, drip the acetone of 25 ℃, the volume ratio of the mixed solvent of acetone and dimethyl formamide and methyl alcohol is 4:1; After dripping, be cooled to 3 ℃, leave standstill 3 hours, filter, washing, vacuum-drying obtains described meloxicam compound.
The X-ray powder diffraction pattern and the embodiment 1 that use Cu-K alpha-ray to measure the meloxicam crystalline compounds of gained match.
The preparation of embodiment 4, meloxicam compound
(1) get meloxicam bulk drug 50g, under 2 ℃ of conditions, adding mass percent concentration is that 14% NaOH solution is appropriate, stirring is dissolved meloxicam, adding the volume ratio of dimethyl formamide and methyl alcohol in the mixed solvent 400ml(mixed solvent of dimethyl formamide and methyl alcohol is 1:0.4 again), stir and obtain settled solution;
(2) in the settled solution of step (1) gained, add 0.02%(g/ml) activated carbon decolorizing, stir 0.8 hour, filter, obtain filtrate;
(3) filtrate step (2) being obtained is warming up to 28 ℃, adds while stirring salt acid for adjusting pH value to 6, and wherein stirring velocity is 100r/min;
(4) finish, under the condition that continuation low whipping speed is 28r/min, drip the acetone of 28 ℃, the volume ratio of the mixed solvent of acetone and dimethyl formamide and methyl alcohol is 3.5:1; After dripping, be cooled to 2 ℃, leave standstill 3 hours, filter, washing, vacuum-drying obtains described meloxicam compound.
The X-ray powder diffraction pattern and the embodiment 1 that use Cu-K alpha-ray to measure the meloxicam crystalline compounds of gained match.
FORMULATION EXAMPLE 1, meloxicam tablet
1, prescription:
2, preparation method:
(1) screening
According to prescription, get respectively meloxicam, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, pregelatinized Starch and the carboxymethylstach sodium of embodiment 1, cross respectively 100 mesh sieves;
(2) mix
The order of pressing meloxicam → carboxymethylstach sodium → low-substituted hydroxypropyl cellulose (1/2 recipe quantity) → pregelatinized Starch → Microcrystalline Cellulose, equivalent incremental method carries out pre-mixing, then puts in mixing tank and mix and make to mix, and obtains powder mix;
(3) granulate
The PVP K of preparation 3%
30the about 80ml of the aqueous solution, adds the poloxamer of recipe quantity, is stirred to dissolve, and makes wetting agent; Above-mentioned powder mix is made to softwood, and 20 mesh sieves are granulated, and are dried to pellet moisture <4%; The whole grain of 18 mesh sieves, obtains dry particle;
(4) always mixed
In above-mentioned dry particle, add the Magnesium Stearate of recipe quantity and the low-substituted hydroxypropyl cellulose of residue 1/2 recipe quantity, always mix, obtain mixture;
(5) compressing tablet
Said mixture is carried out to compressing tablet and obtain meloxicam tablet.
FORMULATION EXAMPLE 2, meloxicam tablet
Prescription:
(1) Core formulation:
(2) coating fluid prescription:
Opadry (OY-C-7000A) 6.0g
80% ethanol 100.00ml
Preparation method:
(1) screening
According to prescription, get respectively meloxicam, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, pregelatinized Starch and the carboxymethylstach sodium of embodiment 2, cross respectively 100 mesh sieves;
(2) mix
The order of pressing meloxicam → carboxymethylstach sodium → low-substituted hydroxypropyl cellulose (1/2 recipe quantity) → pregelatinized Starch → Microcrystalline Cellulose, equivalent incremental method carries out pre-mixing, then puts in mixing tank and mix approximately 30 minutes, makes to mix, and obtains powder mix;
(3) granulate
The PVP K of preparation 3%
30the about 80ml of the aqueous solution, adds the poloxamer of recipe quantity, is stirred to dissolve, and makes wetting agent; Above-mentioned powder mix is made to softwood, and 20 mesh sieves are granulated, and 70 ℃ of forced air dryings, to pellet moisture <4%; The whole grain of 18 mesh sieves, obtains dry particle;
(4) always mixed
In above-mentioned dry particle, add the Magnesium Stearate of recipe quantity and the low-substituted hydroxypropyl cellulose of residue 1/2 recipe quantity, always mix, obtain mixture;
(5) compressing tablet
Said mixture is carried out to compressing tablet and obtain meloxicam label;
(6) dressing
(6.1) preparation of coating liquid
Get 80% ethanolic soln 100ml, under agitator, at the uniform velocity stir; Take Opadry (OY-C-7000A) by recipe quantity, slowly add in above-mentioned 80% ethanolic soln by amount, stir and make to be uniformly dispersed, and maintain whipped state at least 45 minutes, obtain coating liquid.
(6.2) dressing
Get label, blow away unilateral fine powder, be placed in coating pan, regulate suitable coating pan rotating speed, drum hot blast (approximately 55 ℃ of air outlet temperatures), makes label temperature maintain 40～50 ℃; Spray coating liquid carries out dressing, and synchronous blowing hot-air is dry, makes final dressing weightening finish be about 3.0%, obtains meloxicam coating tablet.
FORMULATION EXAMPLE 3, meloxicam tablet
Prescription:
Preparation method: with FORMULATION EXAMPLE 1.
FORMULATION EXAMPLE 4, meloxicam tablet
Prescription:
Preparation method: with FORMULATION EXAMPLE 1.
FORMULATION EXAMPLE 5, meloxicam tablet
Prescription:
(1) Core formulation:
(2) coating fluid prescription:
Opadry (OY-C-7000A) 6.0g
80% ethanol 100.00ml
Preparation method: with FORMULATION EXAMPLE 2.
FORMULATION EXAMPLE 6, meloxicam tablet
Prescription:
(1) Core formulation:
(2) coating fluid prescription:
Opadry (OY-C-7000A) 6.0g
80% ethanol 100.00ml
Preparation method: with FORMULATION EXAMPLE 2.
FORMULATION EXAMPLE 7, meloxicam tablet
Prescription:
(2) coating fluid prescription:
Opadry (OY-C-7000A) 6.0g
80% ethanol 100.00ml
Preparation method: with FORMULATION EXAMPLE 2.
Comparative example 1, meloxicam tablet
1, prescription:
2, preparation method: with FORMULATION EXAMPLE 1, difference is that step (3) is: add 40% appropriate amount of ethanol to make softwood in above-mentioned powder mix, 20 mesh sieves are granulated, and are dried to pellet moisture <4%; The whole grain of 18 mesh sieves, obtains dry particle; Other step is with FORMULATION EXAMPLE 1.
Comparative example 2, meloxicam tablet
1, prescription:
2, preparation method: with FORMULATION EXAMPLE 1, difference is that step (3) is: add 6% starch slurry to make in right amount softwood in above-mentioned powder mix, 20 mesh sieves are granulated, and are dried to pellet moisture <4%; The whole grain of 18 mesh sieves, obtains dry particle; Other step is with FORMULATION EXAMPLE 1.
Test example 1, solubility test
1, sample
Meloxicam reference substance 1: commercially available meloxicam (Ningbo City Medicine Technology Research Co., Ltd);
Meloxicam reference substance 2: the meloxicam making according to the method for CN102775401A embodiment 1;
Meloxicam trial target 1: the meloxicam compound that the embodiment of the present invention 1 makes;
Meloxicam trial target 2: the meloxicam compound that the embodiment of the present invention 2 makes.
2, test method
By abundant meloxicam reference substance 1 porphyrize, be dried to constant weight, take 50mg, add distilled water 250ml, be placed in constant temperature oscillation instrument, in 25 ± 0.2 ℃, under 100r/min condition, vibrate, respectively at different point in time sampling, 0.45 μ m filtering with microporous membrane, measures optical density, calculating concentration.From experimental result, meloxicam is a kind of hydrophobic insoluble medicine, within the scope of 0～12h, the increase in time of its concentration is linear to be increased, within the scope of 12～24h, and the concentration reduction of advancing the speed, tend to gradually saturated, meloxicam dissolves and reaches balance about 48h, and now gained concentration is equilibrium solubility, is 4.5 μ g/ml.Can record the equilibrium solubility of meloxicam reference substance 15 ℃ time with method is 3.5 μ g/ml.
Be measured in the same method meloxicam reference substance 2, meloxicam trial target 1 and meloxicam trial target 2 equilibrium solubility in the time of 25 ℃ and 5 ℃.Result is as shown in table 1 below:
Table 1, solubility test result
| ? | Reference substance 1 | Reference substance 2 | Trial target 1 | Trial target 2 |
| Equilibrium solubility 25 ℃ time | 4.5μg/ml | 4.5μg/ml | 17.2μg/ml | 17.3μg/ml |
| Equilibrium solubility 5 ℃ time | 3.5μg/ml | 3.6μg/ml | 16.1μg/ml | 16.3μg/ml |
From above-mentioned test-results, more commercially available meloxicam is compared, the solubleness that meloxicam compound tool of the present invention has clear improvement.
The prepared meloxicam compound of other embodiment of the present invention has also been carried out to above-mentioned test, and the result of its acquisition is similar.
The impact of test example 2, order by merging flow
In the preparation process of tablet, the impact of the mobility of the order by merging of main ingredient on powder mix is larger.This test example is investigated the impact of the mobility of different order by merging on powder mix by the slope of repose of working sample.
Sample 1: press the order of the low-substituted hydroxypropyl cellulose → pregelatinized Starch → Microcrystalline Cellulose of consumption described in meloxicam → carboxymethylstach sodium → 1/2, equivalent incremental method carries out pre-mixing, then put and in mixing tank, mix to obtain powder mix; (the each consumption of main ingredient and screening are with FORMULATION EXAMPLE 1)
Sample 2: press the order of the low-substituted hydroxypropyl cellulose → carboxymethylstach sodium → pregelatinized Starch → Microcrystalline Cellulose of consumption described in meloxicam → 1/2, equivalent incremental method carries out pre-mixing, then put and in mixing tank, mix to obtain powder mix; (the each consumption of main ingredient and screening are with FORMULATION EXAMPLE 1)
Sample 3: press the order of the low-substituted hydroxypropyl cellulose → Microcrystalline Cellulose of consumption described in meloxicam → pregelatinized Starch → carboxymethylstach sodium → 1/2, equivalent incremental method carries out pre-mixing, then put and in mixing tank, mix to obtain powder mix; (the each consumption of main ingredient and screening are with FORMULATION EXAMPLE 1)
Sample 4: press the order of the low-substituted hydroxypropyl cellulose → pregelatinized Starch of consumption described in meloxicam → Microcrystalline Cellulose → carboxymethylstach sodium → 1/2, equivalent incremental method carries out pre-mixing, then put and in mixing tank, mix to obtain powder mix.(the each consumption of main ingredient and screening are with FORMULATION EXAMPLE 1)
The measuring method at slope of repose: accept the particle being flowed down by funnel with the disk of known radius (R), by particle from the continuous injection of funnel, until obtain the highest cone.The height (H) that records cone, calculates slope of repose α by Tan α=H/R, replication 5 times, averaged.
Measurement result is in table 2.
Table 2
| ? | Sample 1 | Sample 2 | Sample 3 | Sample 4 |
| Slope of repose α | 33° | 45° | 48° | 52° |
Can find out from the above results, adopt the powder mix of order by merging gained of the present invention to there is good mobility.
Test example 3, quality product are investigated
1, quality inspection method
According to dissolution method (" two appendix X C first methods of Chinese Pharmacopoeia 2005 version), take phosphate buffered saline buffer (pH7.4) 900mL as solvent, rotating speed: 75rmin
-1, operation, in the time of 45min, gets solution 10mL in accordance with the law, filters, and gets subsequent filtrate as need testing solution; Separately be taken at 105 ℃ of about 20mg of meloxicam reference substance that are dried to constant weight, accurately weighed, put in 200mL measuring bottle, add 0.1molL
-1sodium hydroxide solution 75mL, ultrasonic making dissolved, and adds 0.1molL
-1potassium dihydrogen phosphate 100mL, is diluted with water to scale, shakes up, and precision measures 5mL, puts in 50mL measuring bottle, adds phosphate buffered saline buffer (pH7.4) to scale, shakes up, in contrast product solution; Get above-mentioned two kinds of solution, according to spectrophotometry (" two appendix IV A of Chinese Pharmacopoeia 2005 version), at 362nm wavelength, place measures respectively optical density, calculates every stripping quantity, and limit is labelled amount 75%, should conform with the regulations.
2, through production test and the parallel check experiment of more than 20 batches of time more than a year, not only profile is bright and clean attractive in appearance to adopt prescription of the present invention to produce meloxicam tablet, and unilateral writing is clear, and hardness (friability) is good, stable content, and every quality index such as dissolution rate is good.The comparison of the prescription parallel check experiment main project detected result of the prescription that table 3 is FORMULATION EXAMPLE 1 of the present invention and comparative example 1, comparative example 2.
The meloxicam tablet parallel check experiment main project detected result of table 3, the present invention and comparative example
As can be seen from Table 3, compare with comparative example 2 compared with comparative example 1, the present invention adopts poloxamer and 3%PVP K
30the aqueous solution replaces 40% ethanol or 6% starch slurry to granulate as wetting agent, and the meloxicam tablet making not only profile is bright and clean attractive in appearance, and unilateral writing is clear, and hardness (friability) is good, stable content, and also every quality index such as dissolution rate is good.
3, in order to verify the stability of meloxicam tablet quality (dissolution rate index) of the present invention and comparative example explained hereafter, the present invention has carried out following the tracks of investigation, the meloxicam tablet that produced in January, 2012 according to FORMULATION EXAMPLE 1 of the present invention, comparative example 1 and comparative example 2 carries out reserved sample observing comparison, the results are shown in Table 4.
Its dissolution rate situation reserved sample observing result of the meloxicam tablet of table 4, the present invention and comparative example
As can be seen from Table 4, compare with comparative example 2 with comparative example 1, adopt prescription of the present invention to produce, not only product dissolution rate index increases substantially, and by the reserved sample observing result of two years, its quality is reliable and stable, prove that the present invention's prescription is feasible.To improving the quality of products, guarantee that pharmaceutical effectiveness has positive effect.
The meloxicam tablet prepared to other FORMULATION EXAMPLE of the present invention also carried out above-mentioned test, and the result of its acquisition is similar.
Test example 4, Dissolution Rate Testing
1, sample
Meloxicam comparison film 1(Mobic, German Boehringer Ingelheim company, every 7.5mg);
The meloxicam tablet that meloxicam comparison film 2(makes according to CN103054872A embodiment 1, every 7.5g);
The meloxicam tablet that meloxicam comparison film 3(makes according to the prescription of FORMULATION EXAMPLE 1 of the present invention and method, every 7.5mg, difference is that meloxicam used is commercially available meloxicam bulk drug, is provided by Ningbo City Medicine Technology Research Co., Ltd);
Meloxicam test film (meloxicam tablet that FORMULATION EXAMPLE 1 of the present invention makes, every 7.5mg).
2, method: dissolution determination is with test example 1.
Dissolution rate comparison: test film of the present invention and above-mentioned three kinds of comparison films are carried out to dissolution test Data Comparison, and method, with under 3 of tests, the results are shown in Table 5.
The dissolution rate comparison (n=6) of table 5, meloxicam tablet of the present invention and comparison film
Result shows, test film of the present invention can very fast disintegration, and medicine reaches more than 90% in 30min, and the dissolution rate that tool is significantly improved compared with comparison film 1, has close dissolution rate with comparison film 2 and comparison film 3.
3, in order to verify the stability of meloxicam tablet quality (dissolution rate index) of the present invention and prior art, the present invention has carried out following the tracks of investigation, comparison film 1, comparison film 2, comparison film 3 and test film of the present invention to prior art carry out reserved sample observing comparison, the results are shown in Table 6.
Its dissolution rate situation reserved sample observing result of the meloxicam tablet of table 6, the present invention and comparative example
By the reserved sample observing result of 9 months, quality product of the present invention was reliable and stable, to improving the quality of products, guaranteed that pharmaceutical effectiveness has positive effect.
The meloxicam tablet prepared to other FORMULATION EXAMPLE of the present invention also carried out above-mentioned test, and the result of its acquisition is similar.
Test example 5, Plasma Concentration test
1, medicine, reagent and instrument
Meloxicam tablet (test film, the meloxicam tablet that FORMULATION EXAMPLE 1 of the present invention makes, every 7.5mg); Meloxicam tablet (reference sheet 1, the meloxicam tablet making according to the prescription of FORMULATION EXAMPLE 1 of the present invention and method, every 7.5mg, difference is that meloxicam used is commercially available meloxicam bulk drug, by Ningbo City Medicine Technology Research Co., Ltd); Import meloxicam tablet (reference sheet 2, every 7.5mg, the large pharmaceutical factory of the vigorous woods Yin lattice writing brush of Germany).Methyl alcohol, top grade is pure, Beijing Chemical Plant; All the other reagent are analytical pure.Test water is the deionization Asia redistilled water that boils.
High performance liquid chromatograph: Merek Hitaehi L-6000 pump, Waters484 ultraviolet, Waters7454B totalizing instrument, G ilosn231 automatic sampler.
2, method
2.1 experimenter
18 routine men's health volunteers, year at age (20.1 ± 1.0), height (170.9 ± 5.5) cm, body weight (61.7 ± 4.6) kg.Experimenter is not in the mood for, liver, kidney and metabolic disturbance medical history, medicine-less allergy history, and through health check-up comprehensively, blood, routine urinalysis, liver, renal function, X-ray chest-fluoroscopy, blood pressure and electrocardiogram(ECG are all normal.Experimenter does not take any medicine in 2 weeks, fasting 12h before taking medicine, in 7:30-8:00 in morning next day empty stomach oral test sheet, reference sheet 1 and the each 15mg of reference sheet 2 respectively, uses 150mL warm water delivery service.The laggard unified recipe diet of the 4h that takes medicine.Duration of test regulation drinking-water time and amount of drinking water, quit smoking, wine, tea, coffee and avoid strenuous exercise.
2.2 test design and blood specimen collection
18 routine experimenters adopt three preparations, three cycle trial design, are divided at random 3 groups, every group of 6 examples, and according to random sequence oral meloxicam test film, reference sheet 1 or reference sheet 2 respectively, between medicine, the cleaning phase is 2 weeks.Before taking medicine (0h) and take medicine after 0.5,1,2,3,5,7,9,12,24,48,72,96,120h ulnar vein blood sampling 4mL, centrifugal separation plasma, blood plasma is to be measured in-40 ℃ of storages.
The preparation of 2.3 sample preparation and typical curve
Draw 0.5mL blood plasma, add people lmolL
-1hydrochloric acid 75 μ L, after mixing, the 3.5mL that adds diethyl ether, jolting 10min, centrifugal 10min(3500rmin
-1), get organic phase 3mL, dry up in 37 ℃ of water-baths, with methyl alcohol 0.2mL redissolution, get 20 μ L sample introductions.
Precision takes meloxicam standard substance, and compound concentration is respectively 0.05,0.1,0.5,1,2,3 μ gL
-1standard blood sample solution, by operating under sample preparation and carrying out HPLC analysis, record its peak area, ask the mean value of 3 peak areas (A), with A and concentration (C, μ gL
-1) linear regression, obtain regression equation: C=-0.002945+6.142 × 10
6a, r=0.9978(n=5).At 0.05～3.0 μ gL
-1concentration range internal linear relation is good, and minimal detectable concentration is 0.05 μ gL
-1.
2.4 chromatographic condition
Stationary phase is Supelco C
18chromatographic column (250mm × 4.6mm, 10 μ m), moving phase: methyl alcohol-phosphate buffered saline buffer (l:1, pH7.4), flow velocity 1mLmin
-1.Detection wavelength is 362nm.
2.5 data processing
Adopt 3P97 pharmacokinetics supervisor to carry out calculation of parameter.
3, result
Average Plasma Concentration-time curve as shown in Figure 2.
As can be seen from Figure 2, adopt meloxicam tablet of the present invention (test film) to compare and there is good plasma concentration curve with reference sheet 2 compared with reference sheet 1, and under the prescription condition identical with preparation method, adopt compared with the meloxicam tablet (reference sheet 1) that meloxicam tablet (test film) that meloxicam compound provided by the present invention makes makes with commercially available meloxicam bulk drug, adopt the meloxicam tablet (test film) that meloxicam compound provided by the present invention makes to there is better plasma concentration curve.
The prepared meloxicam tablet of other embodiment of the present invention has also been carried out to above-mentioned test, and the result of its acquisition is similar.
Claims (10)
1. a meloxicam compound, is characterized in that, described meloxicam has the chemical structural formula shown in formula (I), and this compound is crystalline compounds, and the X-ray powder diffraction pattern that use Cu-K alpha-ray measures as shown in Figure 1;
2. a tablet that contains meloxicam compound claimed in claim 1, is characterized in that, every 1000 meloxicams by following weight part of described tablet are that activeconstituents and various auxiliary material are prepared from:
3. meloxicam tablet according to claim 2, is characterized in that, every 1000 meloxicams by following weight part of described tablet are that activeconstituents and various auxiliary material are prepared from:
4. according to the meloxicam tablet described in claim 2 or 3, it is characterized in that, described low-substituted hydroxypropyl cellulose adopts inside and outside addition.
5. meloxicam tablet according to claim 4, is characterized in that, described meloxicam tablet also comprises coating material.
6. meloxicam tablet according to claim 5, is characterized in that, described coating material is the coating liquid that Opadry and ethanol are made.
7. a preparation method for the tablet described in claim 2-4 any one, is characterized in that, described preparation method comprises the steps:
1) screening
Take meloxicam, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, pregelatinized Starch and carboxymethylstach sodium by described consumption respectively, cross respectively 100 mesh sieves;
2) mix
The order of pressing the low-substituted hydroxypropyl cellulose → pregelatinized Starch → Microcrystalline Cellulose of consumption described in meloxicam → carboxymethylstach sodium → 1/2, equivalent incremental method carries out pre-mixing, then puts and in mixing tank, mix to obtain powder mix;
3) granulate
The PVP K of preparation 3%
30the aqueous solution is appropriate, adds the poloxamer of described consumption, is stirred to dissolve, and makes wetting agent; In above-mentioned powder mix, add prepared wetting agent, make softwood, 20 mesh sieves are granulated, and are dried to pellet moisture <4%, and the whole grain of 18 mesh sieves, obtains dry particle;
4) always mixed
In above-mentioned dry particle, add the low-substituted hydroxypropyl cellulose of consumption described in the Magnesium Stearate of described consumption and residue 1/2, always mix, obtain mixture;
5) compressing tablet
Said mixture is carried out to compressing tablet, obtain meloxicam tablet.
8. preparation method according to claim 7, is characterized in that, being dried described in step 3) is 70 ℃ of forced air dryings.
9. according to the preparation method described in claim 7 or 8, it is characterized in that, described preparation method also comprises further the meloxicam tablet of gained is carried out to dressing.
10. preparation method according to claim 9, is characterized in that, described dressing is that the coating liquid that adopts Opadry and ethanol to make carries out dressing.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106619547A (en) * | 2016-11-18 | 2017-05-10 | 江苏飞马药业有限公司 | Low-specification meloxicam tablet composition and preparation method thereof |
| CN116251067A (en) * | 2023-04-23 | 2023-06-13 | 淄博市中心医院 | Fluconazole tablet, preparation method and application |
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| CN106619547A (en) * | 2016-11-18 | 2017-05-10 | 江苏飞马药业有限公司 | Low-specification meloxicam tablet composition and preparation method thereof |
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|---|---|
| CN103772378B (en) | 2016-02-24 |
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