CN101721410B - Solid medicinal composition of clopidogrel hydrogen sulfate - Google Patents
Solid medicinal composition of clopidogrel hydrogen sulfate Download PDFInfo
- Publication number
- CN101721410B CN101721410B CN2008101549646A CN200810154964A CN101721410B CN 101721410 B CN101721410 B CN 101721410B CN 2008101549646 A CN2008101549646 A CN 2008101549646A CN 200810154964 A CN200810154964 A CN 200810154964A CN 101721410 B CN101721410 B CN 101721410B
- Authority
- CN
- China
- Prior art keywords
- bisulfate clopidogrel
- crystal formation
- tablet
- polyethylene glycol
- silica gel
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Abstract
The invention relates to an oral medicinal composition containing I crystal-form clopidogrel hydrogen sulfate, polyethylene glycol and micro-powder silica gel, proper disintegrating agent and filling agent. The auxiliary materials of the composition are low in price and can be obtained easily; the preparation process is simple; the requirement for equipment and environment is not high; and the prepared tablet is stable in quality and good in reproducibility, and is applied to industrialized production. The prepared tablet has good stability in long-term storage and can be maintained stable after being placed for 6 months at the temperature of 40 DEG C, without appearance change and obvious degradation or crystal-form inversion phenomenon; the dissolution rate of the tablet is not reduced after the tablet is placed for a long time; and the dissolution rate of the tablet in 10 minutes can still reach more than 95 percent after the tablet is placed for 6 months at the temperature of 40 DEG C.
Description
Technical field
The present invention relates to a kind of stable combination of oral medication, concrete relating to contains the stable oral pharmaceutical composition of I crystal formation bisulfate clopidogrel.
Background technology
The chemistry of bisulfate clopidogrel is by name: S (+)-2-(2-chlorphenyl)-2-(4,5,6,7-Tetramethylene sulfide [3,2-c] and pyridine-5) methyl acetate disulfate, structure is as shown in the formula I.
Bisulfate clopidogrel is used as antithrombotic reagent clinically; It produces the effect that suppresses platelet aggregation through optionally suppressing combining and the activation of the glycoprotein GPIIIb/IIIa complex of the ADP mediation of secondary of adenosine diphosphate (ADP) (ADP) and platelet receptor.In addition, bisulfate clopidogrel can also suppress the platelet aggregation of other agonist induction through blocking-up by the platelet activation that the ADP that discharges causes.Bisulfate clopidogrel was applicable to apoplexy, the myocardial infarction of outbreak in the recent period and made a definite diagnosis the patient of peripheral arterial disease.This medicine can reduce atherosclerotic incident such as myocardium infarction, and the incidence rate that apoplexy and vascular are dead is a kind of clinical medicament active composition of great use.
Will medicament active composition be applied to clinically, just must it be prepared into a kind of stabilised pharmaceutical that is easy to use, said preparation is through still can keep stable after transportation and the storage for a long time.Because the particularity of bisulfate clopidogrel self structure, the preparation that makes it and some mixing acceptable accessories be prepared into is very unstable, and destruction easily is degraded.Such as; Point out in the U.S. Pat 5520928; Thiophene chloropyridine and can degrade rapidly down at some pharmaceutic adjuvants commonly used with the chemical compound of its analog structure is used the degraded that adjuvant such as gel, polyvinylpyrrolidone and magnesium stearate etc. can promote this compounds always.Point out in the International Application No. WO 0001364 that carboxymethyl starch sodium also can cause the degraded of bisulfate clopidogrel.In recent years, the research staff constantly makes great efforts the chemical stability problems with solution bisulfate clopidogrel preparation, and has proposed multiple solution.
The bisulfate clopidogrel (trade name:
) of drugs approved by FDA listing is oral thin membrane coated tablet, and the label composition is: bisulfate clopidogrel, castor oil hydrogenated, hydroxypropyl cellulose, mannitol, microcrystalline Cellulose and polyethylene glycol 6000.
Point out in the European patent EP 1310245; Castor oil hydrogenated can not play the effect of lubricant fully in the bisulfate clopidogrel preparation of listing; And it is fine with zinc stearate or sodium stearyl fumarate place of magnesium stearate magnesium as the lubricant effect; Adopt cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium or crospovidone (Crospovidone) as disintegrating agent simultaneously, silicon dioxide points out simultaneously that as fluidizer microcrystalline Cellulose can suppress the dissolution of bisulfate clopidogrel; Therefore without microcrystalline Cellulose, and with lactose or methylcellulose as filler and binding agent.
Castor oil hydrogenated can not play the effect of lubricant fully in the bisulfate clopidogrel preparation of the listing of in EP1310245, pointing out; The inventor finds also that in experiment the adding of castor oil hydrogenated possibly have obvious harmful effect to the disintegrate and the stripping character of oral solid formulation.The castor oil hydrogenated tack is not good, be difficult for preparation in other composition mix homogeneously, thereby in tablet skewness, further cause between the different batches tablet owing to contain hydrophobic lubricant and disintegrate, the stripping character obvious difference of inequality.The difference of dissolution will directly have influence on the infiltration rate and the degree of medicine, also will have influence on the concentration of medicine in patient's blood plasma, finally can influence the safety and the effectiveness of drug use.
As if all not too be concerned about the crystal formation of bisulfate clopidogrel in the above-mentioned open source literature; The inventor finds; The stability of the difference of crystal formation itself and mixed with excipients also is different; For example with sodium stearyl fumarate, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium and polyvinylpolypyrrolidone respectively with I crystal formation bisulfate clopidogrel mix homogeneously after, lucifuge, sealing were placed 10 days under 40 ℃ of conditions, mixture all can be become faint yellow or yellow by white; Simultaneously catabolite obviously increases, and the inventor infers and uses these excipient stable unfavorable to I crystal formation bisulfate clopidogrel.
The inventor also finds: because the compressibility of microcrystalline Cellulose own is good, have adhesive effect concurrently, the tablet of preparation is fine and close, and hardness is bigger, and its disintegration is to accomplish through the capillary tube imbibition that inside exists.And the compressibility of I crystal formation bisulfate clopidogrel powder itself is just fine, and cohesiveness is big, becomes sticky behind the chance water, can block the capillary tube that microcrystalline Cellulose forms, and makes moisture content be difficult to get into label inside.Bisulfate clopidogrel content is big in this preparation, and the adhesive effect of raw material itself is highly significant, uses microcrystalline Cellulose as if the method with routine in such tablet; Its result is exactly that label is too fine and close, and hardness is excessive, and moisture content is difficult to immerse label inside; Bisulfate clopidogrel chance water becomes sticky in addition; Further stop moisture content to infiltrate, moisture content can not fully be penetrated into tablet inside, and the adhesive effect of microcrystalline Cellulose can influence the imbibition of disintegrating agent on the contrary.Therefore, if add microcrystalline Cellulose according to the ordinary preparation method, can cause the disintegration of tablet time lengthening, stripping reduces.
The prompting Polyethylene Glycol is as lubricant in the International Application No. WO 0001364, and microcrystalline Cellulose is as filling-binding agent and disintegrating agent, and Pulvis Talci plays anti-stick effect simultaneously as lubricant, and lactose obtains stable bisulfate clopidogrel preparation as diluent.The inventor prepares the tablet that contains I crystal formation bisulfate clopidogrel according to the prescription in the International Application No. WO 0001364, obviously flavescence after lucifuge, sealing are placed 10 days under 40 ℃ of conditions, and impurity content obviously raises.And in continuous tabletting process, under the damp condition that controls environment, after the tabletting time was long slightly, the sticking phenomenon was just very serious, even normal continuous production.Simultaneously, very responsive to pressure according to the preparation of this prescription preparation, compression force has increase slightly, and the hardness of tablet just significantly increases, and the disintegration of tablet time obviously prolongs.When tablet hardness was approximately 6kg, its disintegration time surpassed 15 minutes, even longer.Even more noteworthy, the product of this prescription preparation, in batch product, disintegration time and dissolution difference are big between the tablet individuality; Disintegration time and dissolution poor reproducibility between the different batches product.This will directly have influence on the infiltration rate and the degree of medicine, also will have influence on the concentration of medicine in patient's blood plasma, finally can influence the safety and the effectiveness of medicine.Therefore, this method is not suitable for industrial amplification production.
Use hydrogenated vegetable oil place of magnesium stearate magnesium to improve the stability of clopidogrel hydrogen sulfate tablet in the International Application No. WO 2005070464; Use carboxymethyl starch sodium to solve the problem that takes place in the tabletting process simultaneously; Also use adjuvants such as lactose monohydrate, microcrystalline Cellulose and pregelatinized Starch simultaneously.
The stable pharmaceutical composition that contains pregelatinized Starch and bisulfate clopidogrel is disclosed in the International Application No. WO 2007008045.Said composition also contains diluent such as microcrystalline Cellulose, glucose, starch, sucrose, lactose, mannitol, calcium phosphate; Anhydrous silicic acid, magnesium stearate, Pulvis Talci, stearic acid, sodium stearyl fumarate, hydrogenated vegetable wet goods are as lubricant; Carboxymethyl starch sodium, starch, alginic acid and sodium salt thereof etc. are as disintegrating agent, and polyvinylpolypyrrolidone, Magnesiumaluminumsilicate, gel, methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose etc. are as binding agent.The multiple adjuvant magnesium stearate of mentioning in this prescription, Pulvis Talci, sodium stearyl fumarate etc. are stable unfavorable to I crystal formation bisulfate clopidogrel.
More than discussed the chemical stability problems of excipient to the bisulfate clopidogrel preparation, bisulfate clopidogrel can exist by multiple crystal form in addition, and the characteristics of various crystal formations self also are the factors that must consider in the exploitation preparation process.Like unformed and I type, II type, III type, IV type, V-type, VI type bisulfate clopidogrel etc., these different crystal formations have different physicochemical properties usually, like different stability, dissolubility, compressibility etc.Selecting suitable crystal formation for the stability of pharmaceutical preparation, is very important.Simultaneously, the dissolution that contains the pharmaceutical preparation of unformed or various crystal formations also is unusual important parameters.After pharmaceutical composition is applied to human body, the dissolution of active ingredient will directly have influence on the absorption of medicine, thereby finally have influence on the curative effect of medicine.
Usually, the crystal formation dissolubility that thermodynamic stability is good more is low more, and in unformed and I type commonly used, II type bisulfate clopidogrel, the thermodynamic stability of II type bisulfate clopidogrel is best, and dissolubility also is minimum certainly; The dissolubility of unformed bisulfate clopidogrel is best, but stability is the poorest, is easy to transform to the good I type of thermodynamic stability, II type; And the stability of I type bisulfate clopidogrel and dissolubility are a kind of comparatively ideal crystal forms that can be used as medicament active composition between between the two, and the present invention selects for use I type bisulfate clopidogrel as main active.
What use in the bisulfate clopidogrel preparation of FDA approval listing is crystal form II; Use I crystal formation bisulfate clopidogrel is disclosed in International Application No. WO 2008059298; Use microcrystalline Cellulose and micropowder silica gel to solve the chemical stability and the stable crystal form property problem of bisulfate clopidogrel preparation as binding agent and filler simultaneously, said preparation also contains low-substituted hydroxypropyl cellulose and castor oil hydrogenated.
The prescription of the bisulfate clopidogrel that approval is gone on the market according to FDA; Mannitol can coexist as in the same prescription with II crystal formation bisulfate clopidogrel, can't cause the instability of II crystal formation bisulfate clopidogrel, but the inventor finds in surprise; Behind I crystal formation bisulfate clopidogrel and mannitol mix homogeneously; After 40 ℃ of condition held a period of times, through dsc analysis, in the DSC of the two mixture collection of illustrative plates; The characteristic peak of I crystal formation bisulfate clopidogrel and mannitol all disappears, and a new characteristic peak (referring to accompanying drawing 3) occurs.Prompting thus; Mannitol possibly interact with I crystal formation bisulfate clopidogrel; Promote the conversion of I crystal formation bisulfate clopidogrel; Therefore the prescription of FDA and be not suitable for I crystal formation bisulfate clopidogrel, for the safety and the effectiveness that guarantee drug use, the inventor need develop suitable prescription.
The inventor unexpectedly finds through long-term experiment research, in the preparation that contains I crystal formation bisulfate clopidogrel, uses Polyethylene Glycol and micropowder silica gel can satisfy above-mentioned all expectations simultaneously, and finds to accomplish the present invention based on this.
Summary of the invention
One aspect of the present invention provides a kind of stable solid pharmaceutical composition of the I of containing crystal formation bisulfate clopidogrel, and said composition also contains Polyethylene Glycol and micropowder silica gel, and suitable disintegrants and filler.Wherein, Polyethylene Glycol is selected from mean molecule quantity at 4000-20000 normal Polyethylene Glycol, preferred polyethylene glycol 6000, Polyethylene Glycol 8000, most preferably polyethylene glycol 6000.Suitable disintegrants is selected from low-substituted hydroxypropyl cellulose.Suitable filler is selected from one or more in microcrystalline Cellulose, dextrin and the pregelatinized Starch, preferably microcrystalline cellulose.
In a specific embodiment of the present invention, solid composite medicament of the present invention comprises I crystal formation bisulfate clopidogrel, polyethylene glycol 6000, micropowder silica gel, low-substituted hydroxypropyl cellulose and microcrystalline Cellulose.
Pharmaceutical composition provided by the invention, wherein, with composition weight meter, the content of I crystal formation bisulfate clopidogrel is 10%～65%, preferred 15%～50%; The content of Polyethylene Glycol is 0.5%～50%, preferred 1%～25%; The content of micropowder silica gel is 3%～10%, preferred 3.5～5%; The content of disintegrating agent is 0.5%～7%, preferred 2%～5%; The content of filler is 25%～85%, preferred 40%～60%.
In a specific embodiment of the present invention, solid composite medicament of the present invention comprises 37.9% I crystal formation bisulfate clopidogrel, 1.16% polyethylene glycol 6000,3.87% micropowder silica gel, 4.84% low-substituted hydroxypropyl cellulose and 52.2% microcrystalline Cellulose.
Further aspect of the present invention provides the stable solid preparation of drug combination method of the above-mentioned I of containing crystal formation bisulfate clopidogrel; It comprises the steps: I crystal formation bisulfate clopidogrel, filler and disintegrating agent are sieved respectively; Mix homogeneously; Through dry granulation mechanism grain, the Polyethylene Glycol that adds recipe quantity behind the granulate that sieves again adds the micropowder silica gel mix homogeneously of recipe quantity, tabletting again.Should note controlling the content of moisture content in the tablet in the preparation process, moisture content control can be dried through adjuvant in these article tablet, master operation moisture content is monitored and reduce operating environment humidity reaches.
The stable solid pharmaceutical composition that contains I crystal formation bisulfate clopidogrel provided by the invention can also be through other method preparation; As I crystal formation bisulfate clopidogrel, filler and disintegrating agent are sieved respectively; Mix homogeneously; The Polyethylene Glycol that adds recipe quantity again adds the micropowder silica gel mix homogeneously of recipe quantity, tabletting again.Should note controlling the content of moisture content in the tablet in the preparation process, moisture content control can be dried through adjuvant in these article tablet, master operation moisture content is monitored and reduce operating environment humidity reaches.
In a specific embodiment of the present invention; The method for preparing of solid composite medicament of the present invention comprises the steps: I crystal formation bisulfate clopidogrel, microcrystalline Cellulose and low-substituted hydroxypropyl cellulose are sieved respectively; Mix homogeneously; Through dry granulation mechanism grain, the polyethylene glycol 6000 that adds recipe quantity behind the granulate that sieves again adds the micropowder silica gel mix homogeneously of recipe quantity, tabletting again.
The crystalline stable solid pharmaceutical composition of the I of containing crystal formation bisulfate clopidogrel provided by the invention can also adopt stomach dissolved film coating pre-mix dose to carry out coating.
The Polyethylene Glycol that uses among the present invention can be mean molecule quantity at 4000-20000 normal Polyethylene Glycol, preferably polyethylene glycol 6000 or Polyethylene Glycol 8000, most preferably polyethylene glycol 6000.Before using, should earlier Polyethylene Glycol be passed through comminution by gas stream to mean diameter below 50 μ m.In the solid composite medicament of the present invention, Polyethylene Glycol mainly plays the effect of stablizing I crystal formation bisulfate clopidogrel, protects it to avoid degrading or transforming to the II crystal formation, plays the effect of lubricant simultaneously.
In the present invention, micropowder silica gel can guarantee that tablet still can keep disintegrate and stripping rapidly and efficiently after long-term the placement, and the dissolution of the tablet of the different batches for preparing can both reach same level, and repeatability is better; The disintegrate of tablet provided by the invention, dissolution characteristic are very little with the compression force change, have so just avoided the tablet hardness difference that fluctuates and cause because of compression force in the tabletting process, thereby cause the problem of stripping curve notable difference; Micropowder silica gel simultaneously can keep the stable of I crystal formation bisulfate clopidogrel jointly with Polyethylene Glycol, protects it to avoid degrading or transforming to the II crystal formation; On the other hand, the effect of antiplastering aid, fluidizer is also played in micropowder silica gel in the present invention, has solved the sticking problem in the tabletting process well.For reaching above-mentioned effect, in the preparation process of preparation, micropowder silica gel should be applied between the drug particles.
Microcrystalline Cellulose plays the effect of filling, binding agent in the present invention simultaneously.According to the analysis of front,, meet water and become sticky because the cohesiveness of I crystal formation bisulfate clopidogrel powder own is big; And consumption is big; The adhesive effect of raw material itself is highly significant, if use conventional microcrystalline Cellulose, its result is exactly that stripping slows down slowly in such tablet.The present invention is through be used Polyethylene Glycol and micropowder silica gel and microcrystalline Cellulose simultaneously; Micropowder silica gel is applied between the drug particles; Overcome the adverse effect of microcrystalline Cellulose, a kind of stable combination of oral medication that comprises I crystal formation bisulfate clopidogrel is provided for I crystal formation bisulfate clopidogrel.
The advantage of the stable solid pharmaceutical composition of the I of containing crystal formation bisulfate clopidogrel provided by the invention is:
Adjuvant is cheap and easy to get, and preparation technology is simple, and is not high to equipment, environmental requirement, and the tablet quality that makes is stable, favorable reproducibility, is fit to suitability for industrialized production.
The present invention has overcome that castor oil hydrogenated possibly have obvious dysgenic problem to the disintegrate and the stripping character of oral solid formulation in the Pohle dimension preparation; Overcome I crystal formation bisulfate clopidogrel unsettled defective in the presence of some excipient; Make that tablet extended storage stability of the present invention is good, after 6 months, still keep stable 40 ℃ of condition held; Do not find that outward appearance changes, do not find that significantly degraded or crystal formation transform phenomenon yet.
Tablet provided by the invention is placed the back dissolution for a long time and can not descended.After 6 months, dissolution still can reach more than 95% in 10 minutes 40 ℃ of condition held.
Description of drawings
The DSC collection of illustrative plates of Fig. 1 mannitol
The DSC collection of illustrative plates of Fig. 2 I crystal formation bisulfate clopidogrel
Fig. 3 mannitol and I crystal formation bisulfate clopidogrel mix homogeneously are placed after 10 days the DSC collection of illustrative plates of mixture
The X ray diffracting spectrum of the I crystal formation bisulfate clopidogrel that uses among Fig. 4 the present invention
The specific embodiment
The purpose of following non-limiting example is the stable solid pharmaceutical composition of the further explain I of containing crystal formation provided by the invention bisulfate clopidogrel, and does not mean that limitation of the present invention.
1000 consumptions of supplementary material title (g)
I crystal formation bisulfate clopidogrel 97.9 (being equivalent to clopidogrel 75g)
PEG6000 3
Microcrystalline Cellulose 135
Low-substituted hydroxypropyl cellulose 12.5
Stomach dissolved film coating pre-mix dose is an amount of
1) it is subsequent use I crystal formation bisulfate clopidogrel to be crossed 40 mesh sieves.
2) 60 mesh sieves are crossed in microcrystalline Cellulose, low-substituted hydroxypropyl cellulose and micropowder silica gel respectively, 105 ℃ of oven dry 2 hours are subsequent use.
3) be that fine powder is subsequent use with the polyethylene glycol 6000 comminution by gas stream.
4) behind I crystal formation bisulfate clopidogrel, microcrystalline Cellulose and the low-substituted hydroxypropyl cellulose mix homogeneously with recipe quantity, cross the dry granulation machine, granulate with 20 mesh sieves.
5) dried granule is crossed 18 mesh sieve granulate.Detect the granule water content, water content is qualified less than 2.5%.
6) moisture content detect qualified after, add recipe quantity polyethylene glycol 6000 and micropowder silica gel, tabletting behind the mix homogeneously.
7) stomach dissolved film coating pre-mix dose is mixed with coating solution.
8) label is removed fine powder and carry out film coating.
1000 consumptions of supplementary material title (g)
I crystal formation bisulfate clopidogrel 32.6 (being equivalent to clopidogrel 25g)
Polyethylene glycol 6000 150
Pregelatinized Starch 85
Low-substituted hydroxypropyl cellulose 22
Stomach dissolved film coating pre-mix dose is an amount of
1) it is subsequent use I crystal formation bisulfate clopidogrel to be crossed 80 mesh sieves.
2) 80 mesh sieves are crossed in pregelatinized Starch, low-substituted hydroxypropyl cellulose and micropowder silica gel respectively, 105 ℃ of oven dry 2 hours are subsequent use.
3) it is subsequent use polyethylene glycol 6000 to be crossed 60 mesh sieves.
4) behind the micropowder silica gel mix homogeneously with recipe quantity I crystal formation bisulfate clopidogrel, polyethylene glycol 6000, pregelatinized Starch and low-substituted hydroxypropyl cellulose and 80% recipe quantity, cross the dry granulation machine, granulate with 20 mesh sieves.
5) dried granule is crossed 20 mesh sieve granulate.Detect the granule water content, water content is qualified less than 2.5%.
6) moisture content detects the micropowder silica gel that qualified back adds the residue recipe quantity, tabletting behind the mix homogeneously.
8) stomach dissolved film coating pre-mix dose is mixed with coating solution.
9) label is removed fine powder and carry out film coating.
1000 consumptions of supplementary material title (g)
I crystal formation bisulfate clopidogrel 97.9 (being equivalent to clopidogrel 75g)
Polyethylene glycol 6000 2
Low-substituted hydroxypropyl cellulose 4
Stomach dissolved film coating pre-mix dose is an amount of
1) it is subsequent use bisulfate clopidogrel to be crossed 40 mesh sieves.
2) 60 mesh sieves are crossed in microcrystalline Cellulose, low-substituted hydroxypropyl cellulose and micropowder silica gel respectively, 105 ℃ of oven dry 2 hours are subsequent use.
3) the polyethylene glycol 6000 comminution by gas stream is subsequent use.
4) with behind recipe quantity bisulfate clopidogrel, microcrystalline Cellulose, the low-substituted hydroxypropyl cellulose mix homogeneously, cross the dry granulation machine, granulate with 20 mesh sieves.
5) dried granule is crossed 18 mesh sieve granulate.Detect the granule water content, water content is qualified less than 2.5%.
6) moisture content detects polyethylene glycol 6000 and the micropowder silica gel that qualified back adds recipe quantity, tabletting behind the mix homogeneously.
7) stomach dissolved film coating pre-mix dose is mixed with coating solution.
8) label is removed fine powder and carry out film coating.
1000 consumptions of supplementary material title (g)
I crystal formation bisulfate clopidogrel 40 (being equivalent to clopidogrel 25g)
Polyethylene glycol 6000 62.5
Micropowder silica gel 11.2
Low-substituted hydroxypropyl cellulose 6.25
Stomach dissolved film coating pre-mix dose is an amount of
1) it is subsequent use I crystal formation bisulfate clopidogrel to be crossed 40 mesh sieves.
2) 60 mesh sieves are crossed in microcrystalline Cellulose, low-substituted hydroxypropyl cellulose and micropowder silica gel respectively, 105 ℃ of oven dry 2 hours are subsequent use.
3) the polyethylene glycol 6000 comminution by gas stream is subsequent use.
4) with behind recipe quantity bisulfate clopidogrel, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, micropowder silica gel and the polyethylene glycol 6000 mix homogeneously, detect the powder water content, water content is qualified less than 2.5%.
5) moisture content detects qualified back tabletting.
6) stomach dissolved film coating pre-mix dose is mixed with coating solution.
7) label is removed fine powder and carry out film coating.
1000 consumptions of supplementary material title (g)
I crystal formation bisulfate clopidogrel 97.9 (being equivalent to clopidogrel 75g)
Polyethylene glycol 6000 4
Low-substituted hydroxypropyl cellulose 7.5
Stomach dissolved film coating pre-mix dose is an amount of
1) it is subsequent use I crystal formation bisulfate clopidogrel to be crossed 40 mesh sieves.
2) 60 mesh sieves are crossed in pregelatinized Starch, low-substituted hydroxypropyl cellulose and micropowder silica gel respectively, 105 ℃ of oven dry 2 hours are subsequent use.
3) the polyethylene glycol 6000 comminution by gas stream is subsequent use.
4) behind I crystal formation bisulfate clopidogrel, pregelatinized Starch, low-substituted hydroxypropyl cellulose, micropowder silica gel and the polyethylene glycol 6000 mix homogeneously with recipe quantity, detect the powder water content, water content is qualified less than 2.5%.
5) moisture content detects qualified back tabletting.
6) stomach dissolved film coating pre-mix dose is mixed with coating solution.
7) label is removed fine powder and carry out film coating.
| The supplementary material title | The |
The contrast experiment 2 |
| I crystal formation bisulfate clopidogrel PEG6000 micropowder silica gel microcrystalline Cellulose low-substituted hydroxypropyl cellulose | 97.93——13512.5 | 97.9——1013512.5 |
| Stomach dissolved film coating pre-mix dose | In right amount | In right amount |
| The tabletting effect | Disintegration time prolongs, and stripping is slack-off, and disintegrate between the tablet individuality, stripping nature difference are big.It is rough simultaneously can to observe tablet surface, and the sticking tendency is arranged | The tablet side is coarse, and tablet obviously increases with punch die side friction power.Observe the sliver phenomenon. |
Can find out that from two contrast experiments Polyethylene Glycol and micropowder silica gel play an important role, and lack each composition and all are difficult to make stable compositions in I crystal formation clopidogrel bisulfate solid pharmaceutical composition.
The experiment of embodiment 7. preparation stabilities
1. sample source:
The film coating tablet that contains I crystal formation bisulfate clopidogrel that the method for embodiment 1 prepares adopts aluminum-plastic packaged.
2. investigation project:
Factors such as the character of the crystal formation of active ingredient, tablet, dissolution, enantiomer, related substance, content in the tablet.
3. detection method:
The crystal formation inspection of these article active ingredient adopts thermal analysis system (two appendix VIIIQ second methods of Chinese Pharmacopoeia version in 2005) to measure; These article dissolution test adopts dissolution method (two appendix XC second methods of Chinese Pharmacopoeia version in 2005); With pH2.0 buffer (potassium chloride 6.57g; Adding water dissolves in right amount; Add 0.1mol/L hydrochloric acid solution 119.0ml, thin up is to 1000ml again) 1000ml is dissolution medium, rotating speed is that per minute 50 changes; Enantiomer, related substance and assay all adopt HPLC (two appendix VD of Chinese Pharmacopoeia version in 2005) to measure.
4. bisulfate clopidogrel tablet stability experiment
4.1 accelerated tests
The bisulfate clopidogrel sheet is aluminum-plastic packaged, in 40 ℃ ± 2 ℃ of temperature, the condition held of relative humidity 75% ± 5% 6 months.After placement the 1st, 2,3, the detection of taking a sample respectively in June, and compare with the initial detecting result.Result of the test is seen table 1.
Table 1 bisulfate clopidogrel sheet accelerated test is investigated the result
The experiment 4.2 keep sample for a long time:
The bisulfate clopidogrel sheet is aluminum-plastic packaged, and 25 ℃ ± 2 ℃ of temperature, placement for a long time keeps sample under the condition of relative humidity 60% ± 10%.The the 3rd, 6 month some detection of taking a sample respectively after placement, and compare with the initial detecting result.Result of the test is seen table 2.
The table 2 bisulfate clopidogrel sheet investigation result that keeps sample for a long time
4.3 investigation result
The bisulfate clopidogrel sheet is (40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5%) under the accelerated tests condition, and enantiomer, its related substances only have increase slightly, and all in normal range, and character, crystal formation, dissolution and content all do not have significant change; Keep sample for a long time after (25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 10%), significant change does not all take place in each item index of sample.
Claims (4)
1. stable solid pharmaceutical composition; Contain I crystal formation bisulfate clopidogrel, polyethylene glycol 6000 and micropowder silica gel; And disintegrating agent that is selected from low-substituted hydroxypropyl cellulose and one or more the filler that is selected from microcrystalline Cellulose, dextrin and the pre-paying starch, wherein with composition weight meter, the content of I crystal formation bisulfate clopidogrel is 15%～50%; The content of Polyethylene Glycol is 1%～25%; The content of micropowder silica gel is 3.5～5%, and the content of disintegrating agent is 2%～5%, and the content of filler is 40%～60%.
2. claim 1 described stable solid pharmaceutical composition, bisulfate clopidogrel, 1.16% Polyethylene Glycol, 3.87% micropowder silica gel, 4.84% low-substituted hydroxypropyl cellulose and 52.2% microcrystalline Cellulose comprising 37.9%.
3. the described stable solid preparation of drug combination of claim 1 method; Comprise the steps: I crystal formation bisulfate clopidogrel, filler and disintegrating agent are sieved respectively; Mix homogeneously; Through dry granulation mechanism grain, the Polyethylene Glycol that adds recipe quantity behind the granulate that sieves again adds the micropowder silica gel mix homogeneously of recipe quantity, tabletting again.
4. the described stable solid preparation of drug combination of claim 1 method; Comprise the steps: I crystal formation bisulfate clopidogrel, filler and disintegrating agent are sieved respectively; Mix homogeneously, the Polyethylene Glycol that adds recipe quantity again adds recipe quantity micropowder silica gel mix homogeneously, tabletting again.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008101549646A CN101721410B (en) | 2008-10-30 | 2008-10-30 | Solid medicinal composition of clopidogrel hydrogen sulfate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008101549646A CN101721410B (en) | 2008-10-30 | 2008-10-30 | Solid medicinal composition of clopidogrel hydrogen sulfate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101721410A CN101721410A (en) | 2010-06-09 |
| CN101721410B true CN101721410B (en) | 2012-01-25 |
Family
ID=42443364
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008101549646A Active CN101721410B (en) | 2008-10-30 | 2008-10-30 | Solid medicinal composition of clopidogrel hydrogen sulfate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101721410B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101851247B (en) * | 2010-06-04 | 2013-05-29 | 浙江华海药业股份有限公司 | Composition containing clopidogrel bisulfate crystal particles |
| CN102058550B (en) * | 2010-12-30 | 2016-04-27 | 江苏亚邦强生药业有限公司 | Clopidogrel bisulfate tablet and preparation method thereof |
| CN102827184A (en) * | 2011-06-13 | 2012-12-19 | 江苏威凯尔医药科技有限公司 | Polymorph of 2-hydroxy tetrahydrothienopyridine derivatives and pharmaceutical composition |
| CN102309482B (en) * | 2011-06-20 | 2013-04-10 | 海南良方医药有限公司 | Clopidogrel hydrogensulfate composition and preparation method thereof |
| KR101324862B1 (en) * | 2011-07-12 | 2013-11-01 | (주)에이에스텍 | Spherical particle of clopidogrel bisulfate, pharmaceutical composition comprising the same and method of preparation thereof |
| CN104688694B (en) * | 2013-12-04 | 2018-09-11 | 长春海悦药业股份有限公司 | A kind of pharmaceutical composition containing bisulfate clopidogrel |
| CN104490874B (en) * | 2014-12-23 | 2017-09-29 | 北京科莱博医药开发有限责任公司 | A kind of preparation method of I type bisulfate clopidogrel particle and preparation method thereof and I type clopidogrel bisulfate solid preparation |
| CN109662948B (en) * | 2017-10-13 | 2021-04-16 | 上海上药信谊药厂有限公司 | Platelet aggregation inhibitor and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008059298A2 (en) * | 2006-11-14 | 2008-05-22 | EGIS GYÓGYSZERGYÁR Nyilvánosan Müködö Részvénytársaság | Pharmaceutical composition containing clopidogrel hydrogenesulphate of polymorph 1 form |
-
2008
- 2008-10-30 CN CN2008101549646A patent/CN101721410B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008059298A2 (en) * | 2006-11-14 | 2008-05-22 | EGIS GYÓGYSZERGYÁR Nyilvánosan Müködö Részvénytársaság | Pharmaceutical composition containing clopidogrel hydrogenesulphate of polymorph 1 form |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101721410A (en) | 2010-06-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101721410B (en) | Solid medicinal composition of clopidogrel hydrogen sulfate | |
| JP4171091B2 (en) | Tablet composition | |
| EP2292209A2 (en) | Stable pharmaceutical composition comprising a pyramidine-sulfamide | |
| AU2011316003B2 (en) | Pharmaceutical compositions containing a DGAT1 inhibitor | |
| JP5610865B2 (en) | Solid preparation | |
| KR20100015764A (en) | Stabilised pharmaceutical composition containing pregabaline | |
| US10398653B2 (en) | Solid preparations containing tofogliflozin and process of producing the same | |
| EP2635263B1 (en) | A composition comprising s-[2-([[1-(2-ethylbutyl)-cyclohexyl]-carbonyl]amino)phenyl]2-methylpropanethioate and croscarmellose sodium | |
| CN109875972B (en) | Olmesartan medoxomil and amlodipine pharmaceutical composition | |
| EP2620140A1 (en) | Crizotinib containing compositions | |
| JPWO2007123021A1 (en) | Method for producing sustained-release tablets | |
| JP2004521890A (en) | Method for producing non-hygroscopic sodium valproate composition | |
| WO2006106923A1 (en) | Disintegrating tablet in oral cavity and process for producing the same | |
| EP3362054A1 (en) | Pregabalin compositions | |
| US20180344648A1 (en) | Clobazam tablet formulation and process for its preparation | |
| JP2007145733A (en) | Sarpogrelate hydrochlolide-containing tablet | |
| JP4596586B2 (en) | Trehalose particles | |
| EP2714012A1 (en) | Cb-183,315 compositions and related methods | |
| CN115226896A (en) | Sugar sustained-release composition and preparation method thereof | |
| JP2018127417A (en) | Febuxostat-containing orally disintegrating tablet | |
| WO2024060048A1 (en) | Saccharide sustained-release composition and preparation method therefor | |
| JP2003160487A (en) | Pravastatin sodium-containing tablet and method for producing the same | |
| US20160022661A1 (en) | Dosage Form Comprising Crizotinib | |
| JP5801266B2 (en) | Method for producing tablets containing hydrophobic drugs | |
| Gangurde et al. | Metoprolol succinate sustained release tablet: A review |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| ASS | Succession or assignment of patent right |
Owner name: NANJING CHIA TAI TIANQING PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: JIANGSU ZHENGDA TIANQING PHARMACEUTICAL CO., LTD. Effective date: 20110119 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 222006 NO.8, JULONG NORTH ROAD, XINPU DISTRICT, LIANYUN GANG CITY, JIANGSU PROVINCE TO: 210038 NO.9, HUI OU ROAD, ECONOMIC AND TECHNOLOGICAL DEVELOPMENT ZONE, NANJING CITY, JIANGSU PROVINCE |
|
| TA01 | Transfer of patent application right |
Effective date of registration: 20110119 Address after: 210038 Jiangsu city of Nanjing Province Economic and Technological Development Zone No. 9 Ou Lu Hui Applicant after: Nanjing Chia Tai Tianqing Pharmaceutical Co., Ltd. Address before: 222006 Sinpo City, Lianyungang Province, North Road, No. 8, No. Applicant before: Jiangsu Chiatai Tianqing Pharmaceutical Co., Ltd. |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |