CN115737578A - Clopidogrel hydrogen sulfate and aspirin compound tablet and preparation method thereof - Google Patents
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Abstract
The invention relates to the technical field of medicines, in particular to a clopidogrel hydrogen sulfate and aspirin compound tablet and a preparation method thereof. The compound tablet consists of clopidogrel bisulfate particles, aspirin enteric-coated particles and a lubricant; the raw materials of the clopidogrel bisulfate particles comprise clopidogrel bisulfate, an adhesive, a disintegrating agent and a filling agent. The compound tablet has the advantages that the viscosity of clopidogrel bisulfate particles is reduced, the adhesion among the clopidogrel bisulfate particles is avoided, the clopidogrel bisulfate particles are prevented from being adhered to tabletting equipment, the drug loss is low, the smooth tabletting is facilitated, meanwhile, the adhesion between the clopidogrel bisulfate particles and aspirin enteric-coated particles can be avoided, and the clopidogrel bisulfate particles and the aspirin enteric-coated particles are uniformly distributed in the compound tablet.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a clopidogrel hydrogen sulfate and aspirin compound tablet and a preparation method thereof.
Background
Clopidogrel hydrogen sulfate aspirin compound tablets serving as antiplatelet drugs are marketed in the European Union in 2010. The compound tablet
Is a double-layer tablet, however, the aspirin in the tablet is not enteric-coated, and the effect which is biologically equivalent to that of the aspirin enteric-coated tablet can not be achieved.
In the prior art, a scheme for preparing the compound tablet by using a solvent-melting method is provided. The method for preparing the clopidogrel hydrogen sulfate particles by the solvent-melting method comprises the following steps: (1) Heating a high molecular polymer with the melting point of 40-90 ℃ to be molten, adding a solvent, and keeping the solution state; (2) Mixing the main medicine and the auxiliary materials, and adding the mixture into the solution obtained in the step (1). Rotary evaporation removed most of the solvent to give the wrap. (3) drying the wrappage in vacuum to remove residual solvent; and sieving to obtain clopidogrel wrapped by high molecular polymer. Wherein the solvent is methanol, ethanol, isopropanol, acetone or water. In the solvent-melting method, organic solvents (methanol, ethanol and acetone) or water are used, so that clopidogrel hydrogen sulfate as a main drug is easy to dissolve, so that clopidogrel hydrogen sulfate particles are adhered, and tabletting cannot be normally performed.
Therefore, the compound tablet must reduce the viscosity of clopidogrel bisulfate particles to realize smooth production.
Disclosure of Invention
Aiming at the technical problems, the invention provides a clopidogrel hydrogen sulfate aspirin compound tablet and a preparation method thereof. The compound tablet has the advantages that the viscosity of clopidogrel bisulfate particles is reduced, the adhesion of the clopidogrel bisulfate particles is avoided, and the smooth tabletting is favorably realized; meanwhile, the adhesion between the clopidogrel bisulfate particles and the aspirin enteric-coated particles can be avoided, so that the clopidogrel bisulfate particles and the aspirin enteric-coated particles are uniformly distributed in the compound tablet.
In order to solve the technical problems, the invention adopts the following technical scheme:
in a first aspect, the invention provides a clopidogrel hydrogen sulfate aspirin compound tablet, which consists of clopidogrel hydrogen sulfate particles, aspirin enteric-coated particles and a lubricant; the raw materials of the clopidogrel bisulfate particles comprise clopidogrel bisulfate, an adhesive, a disintegrating agent and a filling agent.
The compound tablet not only maintains the quick-acting release of clopidogrel hydrogen sulfate, but also prepares aspirin into aspirin enteric-coated particles, so that aspirin is not released in gastric acid and is released in intestines. The clopidogrel bisulfate particles of the compound tablet do not use organic solvents or water, so that clopidogrel bisulfate as a main drug does not generate dissolution property, the viscosity of the clopidogrel bisulfate particles is reduced, and the adhesion among the clopidogrel bisulfate particles is avoided; meanwhile, the adhesion between the clopidogrel bisulfate particles and the aspirin enteric-coated particles can be avoided, so that the clopidogrel bisulfate particles and the aspirin enteric-coated particles are uniformly distributed in the compound tablet. The clopidogrel bisulfate and aspirin enteric-coated particles can effectively isolate the contact between the main medicines, avoid the mutual action of the clopidogrel bisulfate and the aspirin to cause respective degradation and the generation of new impurities, and remarkably improve the stability of the clopidogrel bisulfate and aspirin compound tablets.
Preferably, the binder in the clopidogrel bisulfate particles is polyethylene glycol; the filler is microcrystalline cellulose and mannitol; the disintegrant is low-substituted hydroxypropyl cellulose.
The invention reduces the viscosity of clopidogrel hydrogen sulfate particles through the synergistic effect of the preferable polyethylene glycol, microcrystalline cellulose, mannitol and low-substituted hydroxypropyl fiber; meanwhile, no organic solvent or water is used, so that the clopidogrel hydrogen sulfate is prevented from being dissolved, and the clopidogrel hydrogen sulfate particles are not adhered.
The polyethylene glycol can coat the surface of clopidogrel hydrogen sulfate, so that the clopidogrel hydrogen sulfate is isolated from contacting with the external environment, and the clopidogrel hydrogen sulfate is prevented from being adhered; hydroxypropyl cellulose is used as a disintegrating agent, microcrystalline cellulose and mannitol are used as fillers, and under the synergistic effect of the hydroxypropyl cellulose and the microcrystalline cellulose, the viscosity of clopidogrel hydrogen sulfate particles is reduced 。
Preferably, the clopidogrel bisulfate particles comprise the following components in parts by weight: 75-100 parts of clopidogrel hydrogen sulfate, 30-35 parts of polyethylene glycol, 30-35 parts of microcrystalline cellulose, 65-67 parts of mannitol and 10-13 parts of low-substituted hydroxypropyl cellulose.
Preferably, the polyethylene glycol is polyethylene glycol 6000 or polyethylene glycol 4000.
Under the condition of adopting the auxiliary materials, the preparation method of the clopidogrel bisulfate particles comprises the following steps: mixing clopidogrel hydrogen sulfate and polyethylene glycol, heating and melting at 60-70 deg.C, cooling, adding the rest adjuvants, mixing, and granulating.
Preferably, the aspirin enteric-coated particles are aspirin enteric-coated skeleton particles prepared from aspirin, an enteric material, a filler and a glidant, or aspirin enteric-coated particles prepared by coating enteric-coated pellets with aspirin.
Preferably, the enteric material is triethyl citrate and methacrylic acid-ethyl acrylate copolymer; the filler is at least one of corn starch and microcrystalline cellulose; the glidant is at least one of talcum powder and hydrogenated castor oil.
According to the invention, the components are mixed with aspirin to prepare aspirin enteric-coated particles by taking methacrylic acid-ethyl acrylate copolymer and triethyl citrate as enteric-coated materials, taking microcrystalline cellulose and/or corn starch as fillers and taking talcum powder and/or hydrogenated castor oil as glidants, so that the aspirin enteric-coated particles can be released in the intestines efficiently and stably without being released in the stomach, and thus the enteric-coated effect of aspirin is achieved.
The methacrylic acid-ethyl acrylate copolymer can be quickly released in duodenum and the parts below, and can wrap aspirin to form an enteric coating, so that the aspirin is prevented from being released in stomach.
Preferably, the raw materials of the aspirin enteric-coated skeleton particle at least comprise the following components in parts by weight: 90-100 parts of aspirin, 10-12 parts of methacrylic acid-ethyl acrylate copolymer, 8-10 parts of triethyl citrate, 18-20 parts of microcrystalline cellulose, 30-35 parts of corn starch and 1-3 parts of talcum powder; or
90-100 parts of aspirin, 10-12 parts of methacrylic acid-ethyl acrylate copolymer, 8-10 parts of triethyl citrate, 18-20 parts of microcrystalline cellulose, 30-35 parts of corn starch, 1-3 parts of talcum powder and 3-3.3 parts of hydrogenated castor oil;
the raw materials of the aspirin enteric-coated granule comprise the following components in parts by weight:
90-100 parts of aspirin, 10-12 parts of methacrylic acid-ethyl acrylate copolymer, 8-10 parts of triethyl citrate and 18-20 parts of microcrystalline cellulose blank pill core.
The preparation method of the aspirin enteric-coated skeleton granules comprises the following steps: mixing 5-8 wt% of triethyl citrate ethanol solution with methacrylic acid-ethyl acrylate copolymer, heating and dissolving at 40-50 deg.C, adding aspirin, mixing, adding other adjuvants, mixing, and granulating; or mixing aspirin and filler, adding 5-8 wt% of triethyl citrate ethanol solution, mixing to obtain soft material granule, volatilizing, spraying 5-8 wt% of water dispersion of methacrylic acid-ethyl acrylate copolymer, oven drying at 60-65 deg.C, and sequentially adding glidant;
the preparation method of the aspirin enteric-coated granule comprises the following steps: adding aspirin to an ethanol solution of triethyl citrate at 5-8% by weight to obtain a mixed solution; spraying the mixed solution on a microcrystalline cellulose blank pellet core, coating a barrier coating with an ethanol solution accounting for 5-8% by weight of triethyl citrate, and then coating an enteric coating with an aqueous dispersion accounting for 30-35% by weight of methacrylic acid-ethyl acrylate copolymer.
Preferably, the lubricant comprises sodium lauryl sulfate and magnesium stearate.
Magnesium stearate is used as a lubricant and has good lubricating and flow aiding effects. The sodium dodecyl sulfate is used as solubilizer and can promote the absorption of the medicine by human body.
Preferably, the addition amount of the sodium lauryl sulfate in the lubricant is 3wt% -5wt%, and the addition amount of the magnesium stearate is 0.5wt% -1wt%.
In a second aspect, the invention also provides a preparation method of the clopidogrel bisulfate aspirin compound tablet, which at least comprises the following steps:
and uniformly mixing the clopidogrel hydrogen sulfate particles with the aspirin enteric-coated particles, adding a lubricant, uniformly mixing, tabletting and coating to obtain the clopidogrel hydrogen sulfate aspirin compound tablets.
The clopidogrel bisulfate particles obtained by the preparation method do not use organic solvents or water, so that clopidogrel bisulfate which is one of main medicines does not generate dissolution property, the viscosity of the clopidogrel bisulfate particles is reduced, the adhesion among the clopidogrel bisulfate particles is avoided, the clopidogrel bisulfate particles are prevented from being adhered to tabletting equipment, the medicine loss is low, and the smooth tabletting of the compound tablet is facilitated. The aspirin enteric-coated granule realizes the enteric-coated effect of the aspirin. And the clopidogrel bisulfate particles are mixed with the aspirin enteric-coated particles, and the viscosity of the clopidogrel bisulfate particles is reduced, so that the clopidogrel bisulfate particles and the aspirin enteric-coated particles are prevented from being adhered to each other, and the clopidogrel bisulfate particles and the aspirin enteric-coated particles are uniformly distributed in the compound tablet. The preparation method is simple and easy to implement, does not need complex production equipment, has the characteristics of environmental protection and strong economic feasibility.
Drawings
Fig. 1 is a dissolution profile of clopidogrel bisulfate aspirin compound tablets of examples 1 to 4 of the present invention and a commercially available enteric coated tablet of byalrin.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and do not delimit the invention.
Example 1
Step 1: putting 100 parts of clopidogrel bisulfate and 30 parts of polyethylene glycol 6000 into a heatable mixing device, heating and dissolving at 60 ℃ until the polyethylene glycol 6000 is melted, cooling, then sequentially adding 30 parts of microcrystalline cellulose, 65 parts of mannitol and 10 parts of hydroxypropyl cellulose, mixing and granulating, and sieving by a 16-mesh sieve to obtain clopidogrel bisulfate particles;
step 2: mixing 8 parts of 5wt% triethyl citrate ethanol solution and 10 parts of methacrylic acid copolymer LD, heating and dissolving at 40 ℃, then adding 100 parts of aspirin, uniformly mixing, cooling, then sequentially adding 30 parts of corn starch, 18 parts of microcrystalline cellulose and 1 part of talcum powder, granulating, and sieving by a 16-mesh sieve to obtain aspirin enteric-coated granules;
and step 3: uniformly mixing the clopidogrel bisulfate particles with the aspirin enteric-coated particles, adding 5wt% of sodium dodecyl sulfate and 1wt% of magnesium stearate, uniformly mixing, sieving with a 12-mesh sieve, and tabletting;
and 4, step 4: and (3) coating the compressed tablets obtained in the step (3) by using 10 parts of 20wt% of Opadry 32K14834 to obtain the clopidogrel hydrogen sulfate aspirin compound tablets.
Example 2
Step 1: putting 85 parts of clopidogrel bisulfate and 33 parts of polyethylene glycol 6000 into heatable mixing equipment, heating and dissolving at 65 ℃ until the polyethylene glycol is melted, cooling, then sequentially adding 33 parts of microcrystalline cellulose, 66 parts of mannitol and 13 parts of hydroxypropyl cellulose, mixing, granulating, and sieving by a 18-mesh sieve to obtain clopidogrel bisulfate particles;
step 2: mixing 95 parts of aspirin, 33 parts of corn starch and 19 parts of microcrystalline cellulose, adding 9 parts of 7wt% triethyl citrate ethanol solution, uniformly mixing to prepare soft material particles, volatilizing, spraying 11 parts of 33wt% aqueous dispersion of methacrylic acid-ethyl acrylate copolymer (L30D-55), drying at 60 ℃, sequentially adding 3.2 parts of hydrogenated castor oil and 2 parts of talcum powder, mixing, granulating, and sieving with a 18-mesh sieve to obtain aspirin enteric-coated particles;
and 3, step 3: mixing the clopidogrel hydrogen sulfate particles and aspirin enteric-coated particles uniformly, adding 4wt% of sodium dodecyl sulfate and 0.8wt% of magnesium stearate, sieving with a 16-mesh sieve, and tabletting
And 4, step 4: and (4) coating the pressed tablet obtained in the step (3) with 10 parts by weight of 15wt% of Opadry 32K14834 to obtain the clopidogrel hydrogen sulfate aspirin compound tablet.
Example 3
Step 1: putting 75 parts of clopidogrel hydrogen sulfate and 35 parts of polyethylene glycol 4000 into heatable mixing equipment, heating and dissolving at 70 ℃, cooling after the polyethylene glycol is melted, then sequentially adding 35 parts of microcrystalline cellulose, 67 parts of mannitol and 13 parts of hydroxypropyl cellulose, mixing, granulating, and sieving by a 18-mesh sieve to obtain clopidogrel hydrogen sulfate particles;
step 2: adding 90 parts of aspirin to 4 parts of an ethanol solution of 5wt% triethyl citrate to obtain a mixed solution; spraying the mixed solution on 18 parts of microcrystalline cellulose pellets by using a fluidized bed for bottom spraying, then coating and isolating by using 4 parts of 8wt% triethyl citrate ethanol solution, and finally coating the enteric coating by using 10 parts of 35wt% L30D-55 aqueous dispersion to obtain aspirin enteric-coated particles;
and step 3: uniformly mixing the clopidogrel bisulfate particles with the aspirin enteric-coated particles, adding 3wt% of sodium dodecyl sulfate and 0.5wt% of magnesium stearate, uniformly mixing, sieving with a 16-mesh sieve, and tabletting;
and 4, step 4: and (3) coating the compressed tablets obtained in the step (3) by using 10 parts of 25wt% of Opadry 32K14834 to obtain the clopidogrel hydrogen sulfate aspirin compound tablets.
Example 4
Step 1: putting 100 parts of clopidogrel hydrogen sulfate and 30 parts of polyethylene glycol 4000 into a heatable mixing device, heating and dissolving at 65 ℃ until the polyethylene glycol 4000 is melted, cooling, then sequentially adding 30 parts of microcrystalline cellulose, 65 parts of mannitol and 10 parts of hydroxypropyl cellulose, mixing, granulating, and sieving by a 16-mesh sieve to obtain clopidogrel hydrogen sulfate particles;
step 2: mixing 8 parts of 5wt% triethyl citrate ethanol solution and 10 parts of methacrylic acid copolymer LD, heating and dissolving at 50 ℃, then adding 100 parts of aspirin, uniformly mixing, cooling, then sequentially adding 30 parts of corn starch, 18 parts of microcrystalline cellulose and 1 part of talcum powder, granulating, and sieving by a 16-mesh sieve to obtain aspirin enteric-coated granules;
and step 3: uniformly mixing the clopidogrel bisulfate particles with the aspirin enteric-coated particles, adding 5wt% of sodium dodecyl sulfate and 1wt% of magnesium stearate, uniformly mixing, sieving with a 12-mesh sieve, and tabletting;
and 4, step 4: and (4) coating the pressed tablet obtained in the step (3) by using 10 parts of 20wt% of Opadry 32K14834 to obtain the clopidogrel hydrogen sulfate aspirin compound tablet.
Example 5
Step 1: putting 85 parts of clopidogrel bisulfate and 33 parts of polyethylene glycol 6000 into heatable mixing equipment, heating and dissolving at 70 ℃ until the polyethylene glycol is melted, cooling, then sequentially adding 33 parts of microcrystalline cellulose, 66 parts of mannitol and 13 parts of hydroxypropyl cellulose, mixing, granulating, and sieving by a 18-mesh sieve to obtain clopidogrel bisulfate particles;
step 2: mixing 95 parts of aspirin, 33 parts of corn starch and 19 parts of microcrystalline cellulose, adding 9 parts of 5wt% triethyl citrate ethanol solution, uniformly mixing to prepare soft material particles, volatilizing, spraying 11 parts of 30wt% aqueous dispersion of methacrylic acid-ethyl acrylate copolymer (L30D-55), drying at 65 ℃, then sequentially adding 3.2 parts of hydrogenated castor oil and 2 parts of talcum powder, mixing, granulating, and sieving with a 18-mesh sieve to obtain aspirin enteric-coated particles;
and step 3: uniformly mixing the clopidogrel bisulfate particles with the aspirin enteric-coated particles, adding 5wt% of sodium dodecyl sulfate and 1wt% of magnesium stearate, sieving with a 16-mesh sieve, and tabletting;
and 4, step 4: and (4) coating the pressed tablet obtained in the step (3) with 10 parts by weight of 15wt% of Opadry 32K14834 to obtain the clopidogrel hydrogen sulfate aspirin compound tablet.
Example 6
Step 1: putting 85 parts of clopidogrel bisulfate and 33 parts of polyethylene glycol 6000 into heatable mixing equipment, heating and dissolving at 70 ℃ until the polyethylene glycol is melted, cooling, then sequentially adding 33 parts of microcrystalline cellulose, 66 parts of mannitol and 13 parts of hydroxypropyl cellulose, mixing, granulating, and sieving by a 18-mesh sieve to obtain clopidogrel bisulfate particles;
step 2: adding 95 parts of aspirin to 5 parts of an ethanol solution of 5wt% triethyl citrate to obtain a mixed solution; spraying the mixed solution on 19 parts of microcrystalline cellulose pellets by using a fluidized bed for bottom spraying, then coating and isolating by using 5 parts of 5wt% triethyl citrate ethanol solution, and finally coating the enteric coating by using 11 parts of 30wt% L30D-55 aqueous dispersion to obtain aspirin enteric-coated particles;
and step 3: uniformly mixing the clopidogrel bisulfate particles with the aspirin enteric-coated particles, adding 5wt% of sodium dodecyl sulfate and 1wt% of magnesium stearate, uniformly mixing, sieving with a 16-mesh sieve, and tabletting;
and 4, step 4: and (3) coating the compressed tablets obtained in the step (3) by using 10 parts of 25wt% of Opadry 32K14834 to obtain the clopidogrel hydrogen sulfate aspirin compound tablets.
Verification example 1
(1) Dissolution and Release test
The clopidogrel bisulfate aspirin compound tablets obtained in examples 1 to 3 and commercially available aspirin bailey enteric-coated tablets (100 mg/30 tablets, lot number: BJ 24849) were measured by a dissolution and release rate measuring method (second method, supplement XD of second division of second edition, chinese pharmacopoeia 2000).
The method comprises the following steps: taking the clopidogrel bisulfate aspirin compound tablet obtained in the example 1-3 and a commercial aspirin Bayer enteric-coated tablet, taking 600ml of 0.1mol/L hydrochloric acid solution as a solvent according to a dissolution rate and release rate measurement method, operating according to the method at the rotating speed of 100r/min, taking 10ml of the solution after 120 minutes, and filtering the solution to be used as a test solution (1).
Then, 200ml of 0.2mol/L sodium phosphate solution at 37 ℃ is added, the mixture is uniformly mixed, 2mol/L hydrochloric acid solution or 2mol/L sodium hydroxide solution is used for adjusting the pH value of the solution to be 6.8 +/-0.05, the solution is continuously dissolved for 60min, 10ml of the solution is taken and filtered at 15min, 20min, 30min, 45min and 60min respectively, and the solution is used as a test solution (2).
The sample solution (1) was blanked with a 0.1mol/L hydrochloric acid solution, and the absorbance was measured at a wavelength of 280 nm. The absorption value should not be greater than 0.05.
Taking aspirin reference substance, adding 0.05mol/L sodium phosphate buffer solution (preparation method of 0.05mol/L sodium phosphate buffer solution, measuring 250ml of 0.2mol/L sodium phosphate solution and 750ml of 0.1mol/L hydrochloric acid solution, mixing, and making pH value be 6.8 +/-0.05), dissolving, and quantitatively diluting to obtain solution containing 50mg aspirin in every 1ml, and using the solution as reference substance solution.
Taking the test solution (2) and the reference solution, measuring the absorbance at the wavelength of 265 +/-2 nm by taking 0.05mol/L sodium phosphate buffer solution as a blank, and calculating the dissolution amount of each tablet. The limit is 70% of the indicated amount, which is in compliance with the regulations.
The release results are shown in table 1.
TABLE 1 Release degree results
As can be seen from table 1, the degrees of release of the clopidogrel bisulfate aspirin complex tablet obtained in examples 1 to 4 of the present invention and the commercially available aspirin bailey enteric tablet in a 0.1mol/L hydrochloric acid solution are both less than 1%, which indicates that the degrees of release of the clopidogrel bisulfate aspirin complex tablet prepared in the present invention and the commercially available aspirin bailey enteric tablet in a 0.1mol/L hydrochloric acid solution both meet the requirements, thereby proving that aspirin in the clopidogrel bisulfate aspirin complex tablet of the present invention is not released in the stomach.
In the dissolution medium with the pH value of 6.8 +/-0.05, the clopidogrel bisulfate aspirin compound tablets obtained in the embodiments 1 to 4 have the release degrees of 88.6 percent, 95.9 percent, 94.1 percent and 96.2 percent in 60min, and the release degree of the commercially available aspirin baiye enteric-coated tablets is 92.1 percent in 60 min.
Fig. 1 is a dissolution profile of clopidogrel bisulfate aspirin compound tablets of examples 1 to 4 of the present invention and a commercially available enteric coated tablet of byalrin.
As can be seen from figure 1, the clopidogrel bisulfate aspirin compound tablets of examples 1 to 4 and the commercially available aspirin byae tablet enteric-coated tablets both show good enteric-coated effects, and the dissolution curves are basically consistent, wherein f1 is more than or equal to 65.
(2) Stability study
An accelerated test and a long-term stability test are carried out by taking the clopidogrel bisulfate aspirin compound tablet prepared in the embodiment 2 of the invention as a research object. The stability investigation test conditions and the method refer to related tests in appendix of 'Chinese pharmacopoeia' of 2020 edition, the test is accelerated for 6 months, and the long-term stability is investigated to 12 months, and the results are shown in table 2.
TABLE 2 accelerated test (temperature 40 ℃ C. + -. 2 ℃ C., relative humidity 75%. + -. 5%)
TABLE 3 Long-term stability test (temperature 25. + -. 2 ℃ C., relative humidity 60%. + -. 10%)
As can be seen from tables 2 and 3, when the clopidogrel bisulfate aspirin compound tablet obtained in example 2 of the present invention is examined for 6 months under the acceleration conditions of the temperature of 40 ℃ ± 2 ℃ and the relative humidity of 75% ± 5%, and when the temperature of 25 ± 2 ℃ and the relative humidity of 60% ± 10% are examined for 12 months, no significant change in the main drug index occurs, which indicates that the clopidogrel bisulfate aspirin compound tablet obtained in example 2 of the present invention has good quality stability.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. A clopidogrel bisulfate aspirin compound tablet is characterized in that the compound tablet consists of clopidogrel bisulfate particles, aspirin enteric-coated particles and a lubricant; wherein, the raw materials of the clopidogrel bisulfate particles comprise clopidogrel bisulfate, an adhesive, a disintegrating agent and a filling agent.
2. The clopidogrel bisulfate aspirin complex tablet according to claim 1, wherein the binder in the clopidogrel bisulfate particles is polyethylene glycol; and/or
The filler is microcrystalline cellulose and mannitol; and/or
The disintegrating agent is low-substituted hydroxypropyl cellulose.
3. The clopidogrel bisulfate aspirin compound tablet according to claim 2, wherein the clopidogrel bisulfate particles include the following components in parts by weight: 75-100 parts of clopidogrel hydrogen sulfate, 30-35 parts of polyethylene glycol, 30-35 parts of microcrystalline cellulose, 65-67 parts of mannitol and 10-13 parts of low-substituted hydroxypropyl cellulose; and/or
The polyethylene glycol is polyethylene glycol 6000 or polyethylene glycol 4000.
4. The clopidogrel bisulfate aspirin complex tablet according to claim 2 or 3, characterized in that the preparation method of the clopidogrel bisulfate particles includes: mixing clopidogrel hydrogen sulfate and polyethylene glycol, heating and melting at 60-70 deg.C, cooling, adding other adjuvants, mixing, and granulating.
5. The clopidogrel bisulfate aspirin compound tablet according to claim 1, wherein the aspirin enteric-coated particles are aspirin enteric-coated skeleton particles prepared from aspirin, an enteric material, a filler and a glidant, or aspirin enteric-coated particles prepared by coating an enteric coating on aspirin-loaded pellets.
6. The clopidogrel bisulfate aspirin complex tablet according to claim 5, wherein the enteric material is triethyl citrate and a methacrylic acid-ethyl acrylate copolymer;
the filler is selected from at least one of corn starch and microcrystalline cellulose; and/or
The glidant is at least one of talcum powder and hydrogenated castor oil.
7. The clopidogrel bisulfate aspirin compound tablet according to claim 6, wherein the raw materials of the aspirin enteric-coated skeleton particles comprise the following components in parts by weight: 90-100 parts of aspirin, 10-12 parts of methacrylic acid-ethyl acrylate copolymer, 8-10 parts of triethyl citrate, 18-20 parts of microcrystalline cellulose, 30-35 parts of corn starch and 1-3 parts of talcum powder; or
90-100 parts of aspirin, 10-12 parts of methacrylic acid-ethyl acrylate copolymer, 8-10 parts of triethyl citrate, 18-20 parts of microcrystalline cellulose, 30-35 parts of corn starch, 1-3 parts of talcum powder and 3-3.3 parts of hydrogenated castor oil;
the raw materials of the aspirin enteric-coated granule comprise the following components in parts by weight: 90-100 parts of aspirin, 10-12 parts of methacrylic acid-ethyl acrylate copolymer, 8-10 parts of triethyl citrate and 18-20 parts of microcrystalline cellulose blank pill core.
8. The clopidogrel bisulfate aspirin compound tablet according to claim 6 or 7, wherein the preparation method of the aspirin enteric framework particles comprises: mixing 5-8 wt% of triethyl citrate ethanol solution with methacrylic acid-ethyl acrylate copolymer, heating and dissolving at 40-50 deg.C, adding aspirin, mixing, adding other adjuvants, mixing, and granulating; or
Mixing aspirin and bulking agent, adding 5-8 wt% triethyl citrate ethanol solution, mixing to obtain soft material granule, volatilizing, spraying 30-35 wt% aqueous dispersion of methacrylic acid-ethyl acrylate copolymer, oven drying at 60-65 deg.C, and adding glidant;
the preparation method of the aspirin enteric-coated granule comprises the following steps: adding aspirin to an ethanol solution of 5-8% by weight triethyl citrate to obtain a mixed solution; spraying the mixed solution on a microcrystalline cellulose blank pellet core, coating a barrier coating with an ethanol solution accounting for 5-8% by weight of triethyl citrate, and then coating an enteric coating with an aqueous dispersion accounting for 30-35% by weight of methacrylic acid-ethyl acrylate copolymer.
9. The clopidogrel bisulfate aspirin complex tablet according to claim 1, wherein the lubricant comprises sodium lauryl sulfate and magnesium stearate 。
10. The process for producing clopidogrel bisulfate aspirin complex tablets according to any one of claims 1 to 9, characterized by comprising at least the steps of: and uniformly mixing the clopidogrel hydrogen sulfate particles with the aspirin enteric-coated particles, adding the lubricant, uniformly mixing, tabletting and coating to obtain the clopidogrel hydrogen sulfate aspirin compound tablets.
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| CN116617174A (en) * | 2023-05-12 | 2023-08-22 | 石家庄四药有限公司 | Tablet containing clopidogrel hydrogen sulfate and aspirin and preparation method thereof |
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Cited By (2)
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| CN116617174A (en) * | 2023-05-12 | 2023-08-22 | 石家庄四药有限公司 | Tablet containing clopidogrel hydrogen sulfate and aspirin and preparation method thereof |
| CN116617174B (en) * | 2023-05-12 | 2024-03-08 | 石家庄四药有限公司 | Tablet containing clopidogrel hydrogen sulfate and aspirin and preparation method thereof |
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