CN101851247A - Composition containing clopidogrel bisulfate crystal particles - Google Patents
Composition containing clopidogrel bisulfate crystal particles Download PDFInfo
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- CN101851247A CN101851247A CN 201010198134 CN201010198134A CN101851247A CN 101851247 A CN101851247 A CN 101851247A CN 201010198134 CN201010198134 CN 201010198134 CN 201010198134 A CN201010198134 A CN 201010198134A CN 101851247 A CN101851247 A CN 101851247A
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Abstract
The invention discloses clopidogrel bisulfate crystal particles with the median particle diameter of at least 120 microns. The invention also discloses a method for preparing the crystal particles, a pharmaceutical composition containing the crystal particles and a preparation method of the pharmaceutical composition.
Description
Technical field
The present invention relates to crystal grain of antiplatelet drug bisulfate clopidogrel and preparation method thereof, and contain preparation of this clopidogrel bisulfate crystal particles and preparation method thereof.
Technical background
Clopidogrel is the well-known a kind of platelet suppressant drug with following structure.
Report suppresses hematoblastic gathering by clopidogrel among the US4847265, can reduce the chance of arterial thrombosis, effectively prevents and treat diseases such as atherosclerosis and heart trouble.Clopidogrel is a kind of heavy-gravity oily matter, and in order to be more suitable for preparation, clopidogrel is to use in preparation with salifiable form, as SR-25990C, at Chinese called after bisulfate clopidogrel and clopidogrel benzene sulfonate etc.
Bisulfate clopidogrel has following structural formula:
At present, the bisulfate clopidogrel sheet of making the SR-25990C form administration in the whole world with trade(brand)name
Sell.Every sulfur acid clopidogrel hydrogen of this medicine 98mg, convert for the activeconstituents clopidogrel be 75mg.The dextrorotatory isomer of clopidogrel is its activity form, have the effect of anticoagulant, and the clopidogrel levoisomer does not have the effect of anticoagulant, even has certain toxicity.Clopidogrel dextrorotatory isomer instability, transform easily and generate clopidogrel levoisomer (being that USP describes the impurity C:(R in the clopidogrel sheet item)-(the 2-chloro-phenyl)-(6 that does not have pharmaceutical active, 7-dihydro-4H-thieno-[3,2-C] pyridine-5-yl)-methyl acetate), it (is that USP describes the impurity A in the clopidogrel sheet item: (+)-(2-chloro-phenyl)-(6 that the also easy hydrolysis of clopidogrel simultaneously generates clopidogrel acid, 7-dihydro-4H-thieno-[3,2-C] pyridine-5-yl) acetate).Clopidogrel is pale brown look thick liquid, though be crystal powder as bisulfate clopidogrel behind its salify, but still very strong static is arranged, this causes being easy to sticking and causes producing and can not carry out smoothly when the solid preparation compressing tablet.The effective means that solves sticking is exactly to add the good Magnesium Stearate of oilness, and alkaline lubricant such as sodium stearyl fumarate, but in medicine stored, this type of alkaline lubricant can promote the generation of impurity A and impurity C rapidly is especially in high temperature and moist environment.In addition, can add antisticking agent micropowder silica gel or silicon-dioxide, but micropowder silica gel and silicon-dioxide have very strong water absorbability, under the condition that moisture exists, the degraded product impurity A can roll up.Therefore, for the preparation of bisulfate clopidogrel, suppress the generation of impurity A and impurity C simultaneously but also to realize smoothly industrialization be very the difficulty.
Constantly there is the investigator to attempt to address this problem for many years.
EP1310245 discloses a kind of clopidogrel hydrogen sulfate salt tablets, is lubricant with Zinic stearas, stearic acid or sodium stearyl fumarate.
It is the stable SR-25990C preparation of lubricant with the Glyceryl Behenate that WO2007/091279A1 discloses a kind of.
It is the stable SR-25990C preparation of lubricant that CN200610063151.7 discloses palmitic acid stearic acid ester of glycerol, and the method that adds the micropowder silica gel of 3.3-4.8% ratio and adopt grinding equivalent to increase progressively improves the producibility of preparation.
CN200710129305.2 discloses the particle that adopts the melt pelletization method to prepare bisulfate clopidogrel and preparation to improve stability of formulation and producibility.
CN200810305453.X discloses with beta-cyclodextrin the bisulfate clopidogrel inclusion has been improved preparation stability.
US2010/0086590 discloses with hydrophilic polymer bisulfate clopidogrel to be wrapped up and has improved stability of formulation, suppresses the degraded of clopidogrel, guarantees the dissolution rate of medicine simultaneously.
The degradation impurity of clopidogrel is that the selection and the preparation method of the generation of clopidogrel acid and isomer and auxiliary material is closely related.The preparation method of the bisulfate clopidogrel sheet of patent disclosure has melt pelletization method, fluidized bed coating to prepare the method for compressing tablet behind the particle, and this kind preparation method need consume big energy, and needs complicated production unit; And bulk drug and auxiliary material mix the method for back non-slurry pelletizing, because very strong static and the viscosity of bisulfate clopidogrel still can not be avoided the sticking problem in compressing tablet.Therefore, for the very strong medicine of this static of bisulfate clopidogrel, reduce its static and realize that the direct compression of preparation has important practical to be worth to suitability for industrialized production.The median particle diameter D50 of the bisulfate clopidogrel bulk drug that direct crystallization obtains has very strong static at 50-100 μ m, prepares with the method for solvent direct crystallization that static is few, median particle diameter D50 is to be difficult for realizing greater than the bisulfate clopidogrel of 120 μ m.
The contriver is through laboratory and plant-scale research widely, found the new and creative roll-in preparation method of the few and median particle diameter D50 of preparation static greater than the clopidogrel bisulfate crystal particles of 120 μ m, use D50 can solve the problem of compressing tablet sticking greater than the clopidogrel bisulfate crystal particles of 120 μ m in the solid preparation, do not use antisticking agent micropowder silica gel or silicon-dioxide, thereby solved the problem that clopidogrel is degraded and generated clopidogrel acid or be converted into left-handed clopidogrel.The clopidogrel bisulfate crystal particles for preparing with this method is more or less the same with the bulk density and the particle diameter of preferred weighting agent, this clopidogrel bisulfate crystal particles can be used for direct compression and prepares tablet, owing to use the bisulfate clopidogrel particle that this static is few, particle diameter is big, also can realize the filling and the packing of the exact dosage desired of hard capsule and granule.
Goal of the invention
First purpose of the present invention provides the clopidogrel bisulfate crystal particles that median particle diameter D50 is 120 μ m at least.
It is the method for the clopidogrel bisulfate crystal particles of 120 μ m at least that second purpose of the present invention provides preparation median particle diameter D50.
The 3rd purpose of the present invention provides and includes the oral solid formulation that median particle diameter D50 is the clopidogrel bisulfate crystal particles of 120 μ m at least, wherein said oral solid formulation can be tablet, capsule or granule, the tablet that makes by direct compression preferably, said preparation has good medicine stability, and its dissolution rate is subjected to the influence of temperature and humidity little.
The 4th purpose of the present invention provides and includes the preparation method of oral solid formulation that median particle diameter D50 is the clopidogrel bisulfate crystal particles of 120 μ m at least.
Summary of the invention
The present invention is particularly including alone or in combination following aspect:
At first, the invention provides the clopidogrel bisulfate crystal particles of median particle diameter at least 120 μ m.
According to the present invention, the median particle diameter of clopidogrel bisulfate crystal particles is preferably 120-1000 μ m, more preferably 150-500 μ m.
" crystal grain " used herein is meant any combination of monocrystalline, aggregate and constrictor.
" size distribution " used herein is meant the cumulative volume size distribution as the equal spherical diameter of determining by laser diffraction in the Mastersizer2000 device." median particle diameter D50 " is meant the intermediate value of described size distribution.
Secondly, the present invention also provides the method for preparation median particle diameter for the clopidogrel bisulfate crystal particles of at least 120 μ m, described method comprises the bisulfate clopidogrel fine powder with certain speed feeding, be pressed into sheet or block through running roller, this flap or block cut into little flap or block through the cutters of certain speed afterwards, through the whole grain of whole grain cutter, obtain clopidogrel bisulfate crystal particles after the screen cloth screening by certain hole more afterwards.
According to the present invention; it is the method for the clopidogrel bisulfate crystal particles of 120-1000 μ m that the preparation median particle diameter is provided; adopt the conventional VectorFreund non-slurry pelletizing machine that uses of pharmacy industry; Alexanderwerk non-slurry pelletizing machine or other brand can realize roll-in and cutting; whole grain; the equipment of the function of sieving; the concrete feed worm rotating speed with 10-100rpm is sent to the bisulfate clopidogrel fine powder between the running roller; running roller is pressed into flap with 3-20rpm with the bisulfate clopidogrel fine powder; running roller pressure is 10-150bar; the running roller gap is 0.5-4.0mm; flap is through cutters; after whole grain cutter is pulverized; screen cloth screening by the 0.25-3.5mm aperture obtains the clopidogrel bisulfate crystal particles that median particle diameter is 120-1000 μ m.
According to the present invention, median particle diameter is the preparation method of the clopidogrel bisulfate crystal particles of 120-1000 μ m, and wherein the feed worm rotating speed is preferably 20-80rpm.
According to the present invention, median particle diameter is the preparation method of the clopidogrel bisulfate crystal particles of 120-1000 μ m, and roller speed is preferably 5-10rpm, and running roller pressure is preferably 20-100bar, 20-60bar more preferably, and the running roller gap is preferably 1-2.5mm.
According to the present invention, median particle diameter is the preparation method of the clopidogrel bisulfate crystal particles of 120-1000 μ m, and whole grain swivel speed is preferably 50-150rpm, more preferably 95-105rpm.
According to the present invention, median particle diameter is the preparation method of the clopidogrel bisulfate crystal particles of 120-1000 μ m, and mesh size is preferably 0.5-3mm, can be one or more layers screen cloth.
According to the present invention, median particle diameter is the preparation method of the clopidogrel bisulfate crystal particles of 120-1000 μ m, it is screen cloth circular, square, equilateral triangle that whole grain screen cloth is preferably the sieve aperture shape, if square or equilateral triangle sieve aperture, then mesh size is meant the length of side of sieve aperture.
According to the present invention, median particle diameter is the preparation method of the clopidogrel bisulfate crystal particles of 120-1000 μ m, preferably can use vibrating feed device, vacuum degasser, refrigerating unit.
The present invention also provides a kind of bisulfate clopidogrel oral solid formulation, include the clopidogrel bisulfate crystal particles that median particle diameter is 120 μ m at least, preferably include the clopidogrel bisulfate crystal particles that median particle diameter is 120-1000 μ m, preferredly include the clopidogrel bisulfate crystal particles that median particle diameter is 150-500 μ m.
According to bisulfate clopidogrel oral solid formulation of the present invention, include acceptable weighting agent, disintegrating agent, dry adhesives, lubricant on the clopidogrel bisulfate crystal particles that accounts for total formulation weight amount 5%-95% and the pharmaceutics.
According to bisulfate clopidogrel oral solid formulation of the present invention, preferably include the clopidogrel bisulfate crystal particles that accounts for total formulation weight amount 8%-80%.
According to bisulfate clopidogrel oral solid formulation of the present invention, the preferred clopidogrel bisulfate crystal particles that accounts for total formulation weight amount 10%-65% that includes.
Be at least the clopidogrel bisulfate crystal particles of 120 μ m for median particle diameter, the auxiliary material that must select bulk density and particle diameter to be complementary with it could guarantee crystal grain and auxiliary material blended homogeneity, and guarantee in the process that is prepared into solid preparation (as be pressed into tablet or can becomes capsule), demixing phenomenon not to take place, could guarantee that content of medicines is even.
Therefore, according to bisulfate clopidogrel oral solid formulation of the present invention, contain and be selected from following auxiliary material, but be not limited in the weighting agent of following auxiliary material one or more: lactose, sorbyl alcohol, N.F,USP MANNITOL, glucose, sucrose, starch, pregelatinized Starch, Microcrystalline Cellulose, optimize Microcrystalline Cellulose, and the mixture of above-mentioned auxiliary material such as starch milk saccharide complex, cellulose milk sugar mixture etc.
Starch milk saccharide complex and cellulose milk sugar mixture are that starch and lactose and Mierocrystalline cellulose and lactose are prepared from by special process, though contain this two kinds of materials on the composition, but not the simple addition of two kinds of materials on the function, but have better compressibility and better mobile, as the starch milk saccharide complex STARLAC and the cellulose milk sugar mixture CELLACTOSE of the happy company of U.S. agent.In the present invention, find surprisingly, starch milk saccharide complex and cellulose milk sugar mixture have with median particle diameter D50 and are at least bulk density and the size distribution that the clopidogrel bisulfate crystal particles of 120 μ m is complementary, in high speed compressing tablet process, can better guarantee the content of medicines homogeneity, and have better compressibility.
Therefore, according to bisulfate clopidogrel oral solid formulation of the present invention, weighting agent is preferably from the starch milk saccharide complex, the cellulose milk sugar mixture.
According to bisulfate clopidogrel oral solid formulation of the present invention, filler loading preferably accounts for the 3%-65% of total formulation weight amount.
According to bisulfate clopidogrel oral solid formulation of the present invention, contain and be selected from following auxiliary material, but be not limited in the disintegrating agent of following auxiliary material one or more: low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, Xylo-Mucine, calcium carboxymethylcellulose, crosslinked starch sodium, pregelatinized Starch.
According to bisulfate clopidogrel oral solid formulation of the present invention, the disintegrating agent consumption preferably accounts for the 0.5%-10% of total formulation weight amount.
According to bisulfate clopidogrel oral solid formulation of the present invention, contain in the dry adhesives that is selected from following auxiliary material but is not limited to following auxiliary material one or more: hypromellose, methylcellulose gum, polyvidone, copolyvidone, hydroxypropylcellulose, Star Dri 5.
According to bisulfate clopidogrel oral solid formulation of the present invention, the dry adhesives consumption preferably accounts for the 1%-15% of total formulation weight amount.
According to bisulfate clopidogrel oral solid formulation of the present invention, contain a kind of lubricant that is selected from following auxiliary material but is not limited only to following auxiliary material or the mixture of multiple lubricant: the hydrogenated vegetable oil that comprises hydrogenated cottonseed oil, hydrogenated castor oil, hydrogenated soybean wet goods, stearic acid, polyoxyethylene glycol, sucrose ester.
According to bisulfate clopidogrel oral solid formulation of the present invention, lubricant quantity preferably accounts for the 0.5%-10% of gross weight, more preferably accounts for the 1%-8% of total formulation weight amount.
Common solid preparation contains silicon-dioxide or micropowder silica gel usually as glidant and antisticking agent, improving the flowability of medicinal mixture, and avoids sticking to take place, and is beneficial to follow-up compressing tablet or capsule and fills.But silicon-dioxide or micropowder silica gel all are the extremely light materials of quality, and the dust of kicking up easily in operation pollutes the production space, and is not easy to clean.A large amount of dust is full of the production space, can bring disadvantageous effect to production operation personnel's health.
In addition, silicon-dioxide and micropowder silica gel have very strong water absorbability, under the condition that moisture exists, can promote rolling up of bisulfate clopidogrel degraded product impurity A.Therefore, for bisulfate clopidogrel solid preparation, use silicon-dioxide and micropowder silica gel to be unfavorable for guaranteeing the stability of product.
The present invention uses clopidogrel bisulfate crystal particles, because particle diameter is big, static is few, has avoided the dosage of compressing tablet sticking and filled capsules inaccurate, has improved the flowability of mixture simultaneously, thereby has avoided using silicon-dioxide or micropowder silica gel.
Therefore, according to clopidogrel bisulfate solid preparation of the present invention, preferably do not contain silicon-dioxide or micropowder silica gel.
According to clopidogrel bisulfate solid preparation of the present invention, formulation can be a tablet, capsule, or granule.
According to clopidogrel bisulfate solid preparation of the present invention, formulation is preferably tablet, more preferably thin membrane coated tablet.
The present invention also provides the preparation method of described clopidogrel bisulfate solid preparation, may further comprise the steps:
(1) be the clopidogrel bisulfate crystal particles of 120-1000 μ m with median particle diameter and sieve after weighting agent, disintegrating agent, dry adhesives mix, remix is even, and it is even to add mix lubricant then;
(2) mixture of step (1) is made solid preparation.
According to the preparation method of clopidogrel bisulfate solid preparation of the present invention, optionally be prepared into tablet, may further comprise the steps:
(1) be the clopidogrel bisulfate crystal particles of 120-1000 μ m with median particle diameter and sieve after weighting agent, disintegrating agent, dry adhesives mix, remix is even, and it is even to add mix lubricant then;
(2) mixture with step (1) is pressed into plain sheet;
(3) optionally, the plain coating tablets with step (2) obtains coating tablet.
After clopidogrel bisulfate crystal particles and weighting agent, disintegrating agent, dry adhesives, mix lubricant, directly be pressed into the method for tablet, having does not need this very big advantage of drying step, has increased the stability of product.
Simultaneously; use the method for clopidogrel bisulfate crystal particles mixed pressuring plate to solve the bisulfate clopidogrel powder of fine grain size and the sticking problem of pharmaceutical excipient direct compression used; owing to use the bisulfate clopidogrel particle compressing tablet that static is few, particle diameter is big to solve the sticking problem; therefore do not need to add antisticking agent silicon-dioxide or micropowder silica gel again, thereby avoided a large amount of generations of acid of degraded product clopidogrel and isomer.
According to the preparation method of clopidogrel bisulfate solid preparation of the present invention, optionally be prepared into capsule, may further comprise the steps:
(1) be the clopidogrel bisulfate crystal particles of 120-1000 μ m with median particle diameter and sieve after weighting agent, disintegrating agent, dry adhesives mix, remix is even, and it is even to add mix lubricant then;
(2) the mixture can with step (1) becomes capsule.
According to the preparation method of clopidogrel bisulfate solid preparation of the present invention, optionally be prepared into granule, may further comprise the steps:
(1) be the clopidogrel bisulfate crystal particles of 120-1000 μ m with median particle diameter and sieve after weighting agent, disintegrating agent, dry adhesives mix, remix is even, and it is even to add mix lubricant then;
(2) mixture of step (1) is distributed into the granule of single dose.
According to one embodiment of the invention, described clopidogrel bisulfate solid preparation is the coating tablet form, concrete preparation by the following method:
(1) is used in the method granulating equipment, under the feed worm rotating speed of 10-60rpm, the bisulfate clopidogrel fine powder is sent between the running roller, running roller is pressed into flap with 5-10rpm with the bisulfate clopidogrel fine powder, running roller pressure is 20-60bar, the running roller gap is 1.0-3.5mm, flap is after cutters, whole grain cutter are pulverized, and circular hole or square-mesh screen screening by the 0.5-3.0mm aperture obtain the clopidogrel bisulfate crystal particles that foregoing median particle diameter is 150-500 μ m;
(2) with the clopidogrel bisulfate crystal particles of step (1), with weighting agent, disintegrating agent, dry adhesives in tempering tank with 5-15rpm mixing 5-30min;
(3) mixture of step (2) is sieved processing, mesh size is 1.5-3.0mm;
(4) material that sieves of step (3) is put in the tempering tank, continues with 5-15rpm mixing 10-30min;
(5) add lubricant in the mixture of step (4), with 5-15rpm mixing 3-15min;
(6) mixture with step (5) adopts suitable compression mold to be pressed into tablet;
(7) tablet coating with step (6) makes coating tablet.
In the preparation method of this tablet, the particle diameter of clopidogrel bisulfate crystal particles is 150-500 μ m, starch milk saccharide complex that the clopidogrel bisulfate crystal particles of this particle size range and particle diameter are suitable or cellulose milk sugar mixture and other pharmaceutical excipients can mix, in the high speed compressing tablet, layering can be do not caused, the uniform tablet of content can be obtained.Tablet of the present invention can pass through ordinary method, uses the tabletting machine with positive feed to make.Dressing suitably is based on the conventional dressing mixture coating powder produced of Colorcon for example.
Wonderful, the contriver finds clopidogrel bisulfate solid preparation prepared in accordance with the present invention, has than prior art products (at China listing Bo Liwei
The bisulfate clopidogrel sheet) better stable, quicken or the standing storage condition under, increases slowly according to the related substance of clopidogrel bisulfate solid preparation of the present invention, stripping changes less, longer keeping life is arranged, can better guarantee the security that the patient takes medicine.
Embodiment
By specific embodiment the present invention is described below.Yet these embodiment only are in order to demonstrate the invention, rather than restriction the present invention.
Embodiment 1
Open Alexanderwerk non-slurry pelletizing machine; the setting feeding speed is 20rpm; the pinch roller rotating speed is 5rpm; pinch roller pressure is 30bar; the pinch roller gap is 2.5mm; the bisulfate clopidogrel fine powder is added in the loading hopper of Alexanderwerk non-slurry pelletizing machine; roll-in through pinch roller forms sheet or block; this flap or block cut into small pieces or fritter through cutters afterwards; pass through the whole grain of whole grain cutter afterwards; whole grain swivel speed is 100rpm, obtains the clopidogrel bisulfate crystal particles that particle diameter is 120-1000 μ m after the lower screen cloth of upper screen cloth by 2.0mm and 0.63mm sieves again.
The particle properties contrast of table 1 clopidogrel bisulfate crystal particles and starch lactose
| Particle properties | The clopidogrel bisulfate crystal particles that embodiment 1 obtains | The starch lactose |
| Median particle diameter D50 | ??215.3μm | ??180.2μm |
| Particle properties | The clopidogrel bisulfate crystal particles that embodiment 1 obtains | The starch lactose |
| Bulk density | ??0.63g/ml | ??0.66g/ml |
The median particle diameter D50 that measures the clopidogrel bisulfate crystal particles that embodiment 1 obtains with Ma Erwen laser particle analyzer (Mastersizer2000) is 215.3 μ m, and the median particle diameter D50 of filler starch lactose is 180.2 μ m, the bulk density of the clopidogrel bisulfate crystal particles that embodiment 1 obtains is 0.63g/ml, and the bulk density of starch milk saccharide complex STARLAC is 0.66g/ml.The clopidogrel bisulfate crystal particles that embodiment 1 obtains has similar bulk density and size distribution to the starch milk saccharide complex, can guarantee that in the high speed compressing tablet material is not stratified, obtains the uniform tablet of content.
Embodiment 2
By with median particle diameter D50 being the direct tablet that makes that compresses of clopidogrel bisulfate crystal particles of 150-500 μ m.
Tablet ingredients:
Is that the screen cloth of 1.2mm sieves with the clopidogrel bisulfate crystal particles that derives from embodiment 1 with the aperture, and in the always mixed tube of HBD-100, mixed 10 minutes with the 10rpm rotating speed, add low-substituted hydroxypropyl cellulose, hypromellose, starch lactose, continue to mix and cross the 1.2mm screen cloth after 15 minutes, hydrogenated cottonseed oil is crossed 250 μ m screen clothes, add, and continue to mix discharging after 5 minutes.
The circle of loading onto diameter 8.0 on the FETTE tabletting machine dashes, with 20kg gained mixture with 100,000/speed at one hour rating compressing tablet, the 200mg of plate core weight, 100,000 in batches.The high speed compressing tablet, unilateral not sticking.Finished product bisulfate clopidogrel coating tablet will be obtained behind the plain coating tablets.
Bo Liwei with the Chinese market sale
As the contrast medicine, with grind medicine certainly 60 ℃ of conditions, 92.5% relative humidity (RH) condition, and 60 ℃/75% relative humidity combination condition lower open mouth was placed 10 days according to embodiment 2 preparation, investigate the changing conditions of proterties, label and the impurity of slice, thin piece, the result is as follows:
| Sequence number | The sample title | Proterties | Impurity A % | Impurity C% | Single maximum unknown impuritie % | Total impurities % |
| 1 | Bo Liwei lot number: 2,294 0 days samples | The pink disk, label white. | 0.03 | 0.5 | 0.11 | 0.95 |
| 2 | Bo Liwei lot number: placed 10 days for 2,294 60 ℃ | The pink disk, label white. | 0.05 | 0.52 | 0.13 | 0.96 |
| 3 | The Bo Liwei lot number: 2294 92.5%RH placed 10 days | The pink disk, slice, thin piece moisture absorption deliquescing, weightening finish 18%, label white. | 0.69 | 0.72 | 0.52 | 2.36 |
| 4 | The Bo Liwei lot number: 2,294 60 ℃/75%RH placed 10 days | Disk, but coating powder fades into off-white color, the label overstrike. | 11.62 | 6.10 | 1.38 | 19.96 |
| 5 | 20 days samples of embodiment | The pink disk, label white. | 0.01 | 0.19 | 0.09 | 0.51 |
| 6 | Embodiment placed 10 days for 2 60 ℃ | The pink disk, label white. | 0.05 | 0.26 | 0.08 | 0.58 |
| 7 | Embodiment 2 92.5%RH placed 10 days | The pink disk, not deliquescing of slice, thin piece moisture absorption, weightening finish 4.0%, label white. | 0.16 | 0.24 | 0.11 | 0.69 |
| 8 | 2 60 ℃/75%RH of embodiment placed 10 days | The pink disk, coating powder does not fade, label white. | ??1.74 | ??0.5 | ??0.12 | ??3.06 |
By last table data as can be known, with the former medicine Bo Liwei that grinds
Compare, the bisulfate clopidogrel crystal formulations that embodiment 2 provides is subjected to the influence of temperature and humidity littler, the proterties of slice, thin piece does not have obvious variation under high temperature and super-humid conditions, and clopidogrel acid (impurity A) and levoisomer (impurity C) and total impurities also to grind medicine than former under the equal investigation condition much lower, especially under hot and humid 60 ℃/75%RH condition, show that bisulfate clopidogrel crystal formulations of the present invention has better stability.
Medicine in vivo from preparation stripping just can be absorbed, thereby play therapeutic action, therefore, the stripping of medicine is most important to the performance of drug effect.And some medicines in long-term storage because the influence of temperature and humidity can cause the stripping of medicine to descend.The Bo Liwei of the original hard pair of aluminium packing that Chinese market is sold
Placed 10 days under hot and humid 60 ℃/75%RH combination condition simultaneously with the medicine that grinds certainly of embodiment 2 preparations of hard two aluminium packing, investigate the stripping curve of slice, thin piece, the curve that is depicted as dissolution rate and time as shown in Figure 1.
As can be seen from the figure, the former medicine Bo Liwei that grinds
After placing 10 days under the hot and humid 60 ℃/75%RH combination condition, the dissolution rate of 30min is 54%, compares with 0 day and has reduced by 42.6%; And the bisulfate clopidogrel sheet of embodiment 2 is after placing 10 days under the hot and humid 60 ℃/75%RH combination condition, the dissolution rate of 30min is 81%, compared with 0 day and to have reduced by 18.2%, the bisulfate clopidogrel crystal formulations that shows embodiment 2 preparations is compared with the former sheet that grinds, be subjected to the influence of temperature and humidity littler, in long-term storage, dissolution rate is subjected to the influence of temperature and humidity less, longer validity period is arranged, can better guarantee the safety that the patient takes medicine.
Description of drawings
Accompanying drawing 1: according to the product of embodiment 2 and the stripping curve stability contrast of prior art products.
Claims (12)
1. clopidogrel bisulfate crystal particles is characterized in that, described crystalline median particle diameter D50 is 120-1000 μ m.
2. the clopidogrel bisulfate crystal particles of claim 1 is characterized in that, described crystalline median particle diameter D50 is 150-500 μ m.
3. each the method for clopidogrel bisulfate crystal particles of preparation claim 1-2 is characterized in that, said method comprising the steps of:
(1) the bisulfate clopidogrel powder is pressed into bisulfate clopidogrel sheet or block with the speed feeding of 10-100rpm through running roller, and roller speed 3-20rpm, pinch roller pressure are 10-150bar, and the pinch roller gap is 0.5-4.0mm;
(2) the bisulfate clopidogrel flap of step (1) gained or block obtain little bisulfate clopidogrel flap or block through the cutters cutting of certain speed;
(3) the little bisulfate clopidogrel flap that obtains of step (2) or block are through the whole grain of whole grain cutter, whole grain swivel speed is 20-150rpm, after being the screen cloth screening of 0.25-3.5mm by the aperture again, obtain the clopidogrel bisulfate crystal particles that median particle diameter D50 is 120-1000 μ m.
4. clopidogrel bisulfate solid preparation, wherein comprise each clopidogrel bisulfate crystal particles of claim 1-2, with acceptable weighting agent, disintegrating agent, dry adhesives, lubricant on the pharmaceutics, described solid preparation can be tablet, capsule, granule.
5. clopidogrel bisulfate solid preparation as claimed in claim 4, it is characterized in that containing the clopidogrel bisulfate crystal particles that accounts for total formulation weight amount 5%-95%, preferably contain the clopidogrel bisulfate crystal particles that accounts for total formulation weight amount 8%-80%, more preferably contain the clopidogrel bisulfate crystal particles that accounts for total formulation weight amount 10%-65%.
6. clopidogrel bisulfate solid preparation as claimed in claim 4 is characterized in that weighting agent is selected from: lactose, sorbyl alcohol, N.F,USP MANNITOL, glucose, sucrose, starch, pregelatinized Starch, Microcrystalline Cellulose is optimized Microcrystalline Cellulose, and the mixture of above-mentioned auxiliary material such as starch milk saccharide complex, the cellulose milk sugar mixture, preferred starch lactose mixture or cellulose milk sugar mixture, the consumption of weighting agent accounts for the 3%-65% of total formulation weight amount.
7. clopidogrel bisulfate solid preparation as claimed in claim 4, it is characterized in that disintegrating agent is selected from: low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, croscarmellose sodium, calcium carboxymethylcellulose, Xylo-Mucine, carboxymethylstach sodium, preferred low-substituted hydroxypropyl cellulose, the consumption of disintegrating agent accounts for the 0.5%-10% of total formulation weight amount.
8. clopidogrel bisulfate solid preparation as claimed in claim 4 is characterized in that dry adhesives is selected from: hypromellose, methylcellulose gum, polyvidone, copolyvidone, hydroxypropylcellulose, Star Dri 5, the consumption of dry adhesives accounts for the 1%-15% of total formulation weight amount.
9. clopidogrel bisulfate solid preparation as claimed in claim 4, it is characterized in that lubricant is selected from: hydrogenated cottonseed oil, hydrogenated castor oil, hydrogenated soybean oil, polyoxyethylene glycol, stearic acid, sucrose ester, the consumption of lubricant accounts for the 0.5%-10% of total formulation weight amount, preferably accounts for the 1%-8% of total formulation weight amount.
10. clopidogrel bisulfate solid preparation as claimed in claim 4 is characterized in that, does not contain micropowder silica gel or silicon-dioxide in the described solid preparation.
11. prepare the method for clopidogrel bisulfate solid preparation as claimed in claim 4, comprise following steps:
(1) with claim 1-2 each clopidogrel bisulfate crystal particles with sieve after weighting agent, disintegrating agent, dry adhesives mix, remix is even, it is even to add mix lubricant then;
(2) mixture of step (1) is made solid preparation.
12. the preparation method of clopidogrel bisulfate solid preparation as claimed in claim 11 comprises following steps:
(1) each clopidogrel bisulfate crystal particles and starch milk saccharide complex or cellulose milk sugar mixture, disintegrating agent, dry adhesives of claim 1-2 sieved after mixing, remix is even, and it is even to add mix lubricant then;
(2) the uniform mixture that step (1) is obtained directly compresses and obtains plain sheet;
(3) the plain coating tablets that step (2) is obtained obtains coating tablet.
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