CN117942311A - Preparation method of ticagrelor sustained release tablets - Google Patents
Preparation method of ticagrelor sustained release tablets Download PDFInfo
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- CN117942311A CN117942311A CN202211288407.XA CN202211288407A CN117942311A CN 117942311 A CN117942311 A CN 117942311A CN 202211288407 A CN202211288407 A CN 202211288407A CN 117942311 A CN117942311 A CN 117942311A
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- 229960002528 ticagrelor Drugs 0.000 title claims abstract description 67
- OEKWJQXRCDYSHL-FNOIDJSQSA-N ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 title claims abstract description 67
- 239000007939 sustained release tablet Substances 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
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- 238000000034 method Methods 0.000 claims abstract description 27
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- 238000000576 coating method Methods 0.000 claims description 32
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
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- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
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- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims 1
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- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
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- NJDNDJPFOPBMTJ-UHFFFAOYSA-N 5-cyclopentyl-2h-triazolo[4,5-d]pyrimidine Chemical class C1CCCC1C1=NC=C(NN=N2)C2=N1 NJDNDJPFOPBMTJ-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention provides a ticagrelor sustained release tablet dispersed in an amorphous form and a preparation method thereof. Specifically, the ticagrelor is an amorphous solid dispersion, the solid dispersion takes a high molecular polymer as a carrier, and the composition further comprises a slow-release framework material, a filler, a disintegrating agent and a lubricant. According to the invention, a hot-melt extrusion dispersion technology is adopted, and a specific drug carrier is adopted, so that the drug is in a highly dispersed state, the problem of indissolvable of ticagrelor is solved, meanwhile, the ticagrelor does not need micronization, the synthesized raw materials can be directly used, the material loss is reduced, the process steps are reduced, and the prepared ticagrelor sustained release tablet has high bioavailability and good safety.
Description
Technical Field
The invention belongs to the field of preparation of pharmaceutical preparations, and particularly relates to a preparation method of ticagrelor sustained release tablets.
Background
Ticagrelor belongs to cyclopentyl triazolopyrimidine compounds, is a first reversible P2Y12 platelet inhibitor, is a novel anti-platelet aggregation drug, does not need liver activated active drugs, and has quick action initiation; moreover, its binding to platelet receptors is reversible, which is beneficial for reducing the risk of bleeding in patients with acute coronary syndromes.
In 2010, ticagrelor (Ticagrelor) was first approved in the european union. 7 months 2011, was marketed in the united states. The medicine is now marketed in more than 40 countries worldwide. The medicine has the advantages of quick response, obvious clinical curative effect and good safety, and is one of medicines with obvious clinical curative effect and good market prospect in oral anticoagulation medicines.
Ticagrelor is a white or off-white to pale pink powder, and the log P (n-octanol/water) is about 4.5 at pH 7.4. The solubility in physiological pH environment between pH1.0 and pH7.4 is not affected by pH, and is about 10 mug/ml, belonging to insoluble medicine; meanwhile, the permeability is about 51%, and the medicine belongs to low-permeability medicines. Ticagrelor belongs to class IV (i.e., low solubility and low permeability) as classified by biopharmaceutical BCS. Because ticagrelor belongs to a low-solubility and low-permeability drug, the dissolution and the permeability of the preparation are key speed limiting processes for influencing the absorption of the ticagrelor in vivo. The bioavailability of the ticagrelor tablet in human body is about 36%, which indicates that the bioavailability of the drug is lower.
Several documents have disclosed pharmaceutical compositions of ticagrelor solid dispersion and methods for preparing the same, such as solid dispersions prepared by solvent evaporation and spray drying of CN104434805A, CN109718218a and CN110876732 a; raw materials and carriers are required to be dissolved in a large amount of organic solvents, pollution is easy to generate to the environment, a solvent recovery device is required to be additionally arranged, the organic solvents are easy to volatilize, and toxic solvents in the production process can cause damage to human bodies. In addition, the organic solvent needs to be subjected to explosion-proof treatment of equipment and workshops in the production process, so that the solvent is prevented from being stored, and fire explosion accidents are avoided in the production process. The methods can improve the dissolution rate of the medicine, but have complex process and high energy consumption, and are not suitable for industrial commercial production.
CN104971070a discloses that ticagrelor and other pharmaceutical excipients are combined to prepare an oral nano-composition, and further a ticagrelor nano-composition suspension is prepared; however, the improvement in solubility and bioavailability achieved by the above method is very little.
Swiss drug event monitoring system database study counted the missed data for 677 patients with coronary heart disease who took twice a day: 75.2% of patients were missed at least once and 25.7% of patients were missed at least twice consecutively. If patients take the medicine for a long time, acute thrombosis is very easy to be caused, and myocardial infarction or apoplexy is caused. In order to reduce the number of administrations, improve the compliance of patients taking medicine, reduce the risk of myocardial infarction or stroke due to acute thrombosis caused by patients missing ticagrelor, it is necessary to prepare the ticagrelor into suitable sustained release components.
At present, some documents disclose pharmaceutical compositions of ticagrelor sustained release preparations and preparation methods thereof, such as patent CN102657629B, patent CN103860504A and patent CN103520164B. Through analysis of the above patent technologies, patent CN102657629B and patent CN103860504A, although capable of prolonging in vivo duration of action, could not achieve rapid onset of action. Although the patent CN103520164B can achieve a rapid onset of action, 1 day 1 administration cannot be sustained for 24 hours. According to the research, the pharmaceutical composition provided by the invention has higher bioavailability, the sustained release effect of taking the sesquiterpene up to 180mg (90 mg x2 tablets) can be achieved by smaller 120mg, the sustained release preparation is prepared by adopting a hot-melt extrusion solid dispersion technology, the quick effect can be achieved after 1-day 1-time administration, the continuous effect can be ensured within 24 hours, and simultaneously, the Cmax can be reduced on the basis of ensuring the effective blood concentration, so that the problems of improving the patient compliance and reducing the medication safety on the premise of not reducing the curative effect are solved.
Disclosure of Invention
In order to solve the problems in the prior art, the inventor provides a method for preparing a ticagrelor sustained release tablet by using a hot-melt extrusion technology through long-term research, and the ticagrelor sustained release tablet obtained by the method remarkably improves the solubility of the drug, can quickly reach the effective blood concentration of the drug, has quicker onset of action, and improves the bioavailability of the drug absorbed in vivo. In addition, the safety risk brought by high-dose administration can be reduced on the premise of ensuring the effectiveness of the medicine. The inventor finds that under the condition of high humidity of original research, dissolution is reduced due to water absorption failure of sodium carboxymethyl starch, and the stability of the medicine is obviously improved by using crospovidone or croscarmellose sodium as a disintegrating agent.
The sustained release tablet is prepared from skeleton materials such as hypromellose, and the low dosage of 120mg can be administered once a day for 24 hours, thereby reducing the administration times, improving the compliance of patients in administration, and reducing the risk of myocardial infarction or apoplexy caused by acute thrombosis due to missed administration of the patients.
The technical scheme is as follows: a preparation method of ticagrelor sustained release tablets comprises the following steps:
step (1), uniformly mixing a ticagrelor bulk drug, a polymer and silicon dioxide;
Extruding the mixture obtained in the step (1) through a double-screw hot-melt extruder, wherein the extrusion temperature of the double-screw hot-melt extruder is set to be 1 zone 20-30 ℃,2 zone 50-100 ℃,3-6 zone 120-130 ℃,7-9 zone 100-110 ℃, the screw rotating speed is 300+/-50 rpm, and the feeding speed is 25+/-5 rpm;
Step (3), cooling the extrudate obtained in the step (2), crushing the extrudate by using a cone-type granulator, and crushing the crushed extrudate by using a hammer crusher;
step (4), uniformly mixing the crushed material obtained in the step (3) with a filler, a slow-release material, a disintegrating agent and a lubricant, and tabletting to obtain a ticagrelor tablet;
And (5) dissolving the film coating premix in water to prepare coating liquid, putting the ticagrelor tablet obtained in the step (4) into a coating pot, adding the coating liquid by a spray gun, controlling the temperature of a tablet bed to be 40-45 ℃ and coating weight gain to be 3-6%.
Wherein, the ratio of the bulk drugs is 15-30%, the ratio of the polymer is 20-40%, the ratio of the silicon dioxide is 0.8-1.2%, the ratio of the slow release material is 20-25%, the ratio of the disintegrating agent is 2-5%, the ratio of the lubricant is 0.5-1.5%, and the ratio of the filling agent is the rest ratio.
Wherein the polymer in the step (1) is selected from the group consisting of copovidone, polyvinylpyrrolidone-polyvinyl acetate copolymer, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose titanate, hydroxypropyl methylcellulose phthalate and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, preferably copovidone VA64.
Wherein the silicon dioxide in the step (1) is colloidal silicon dioxide.
The ratio of the raw materials is 15-30%, preferably 20%.
The polymer content is 20-40%, preferably 20%.
The double-screw extruder in the step (2) is a co-rotating meshed double-screw extruder.
In the step (3), the extrudate is generally subjected to two or more crushing treatments, and the extrudate is generally subjected to multiple treatments in a hammer crushing manner in a conventional crushing process. Compared with a repeated hammer type crushing mode, the crushing mode has the advantages that the feeding speed is controllable, the crushed particles are more uniform, the crushing process is stable, and the large-scale production is easy.
The disintegrating agent in the step (4) may be crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium and sodium carboxymethyl starch, preferably crospovidone or croscarmellose sodium.
The lubricant in the step (4) is one or more selected from magnesium stearate, stearic acid and sodium stearyl fumarate, preferably magnesium stearate.
The filler in the step (4) comprises one or two of a water-soluble filler and a water-insoluble filler. The water-soluble filler is selected from one or more of lactose and mannitol, and more preferably lactose. The water insoluble filler is selected from one or more of starch, microcrystalline cellulose, and calcium hydrogen phosphate, and more preferably microcrystalline cellulose.
The slow release material in the step (4) is selected from cellulose derivatives such as methyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methylcellulose, hydroxymethyl cellulose, sodium hydroxymethyl cellulose and the like, preferably hydroxypropyl methylcellulose.
The proportion of disintegrant is 2-5%, preferably 3%. The proportion of lubricant is 0.5-1.5%, preferably 1%. The filler is used in the remaining proportion of the preparation.
The term "ratio" of each component in the present invention refers to the mass ratio.
The total proportion of the raw materials, the polymer, the silicon dioxide, the slow-release material, the disintegrating agent, the lubricant and the filler is 100 percent.
The film coating premix in the step (5) consists of hypromellose, titanium dioxide, talcum powder, PEG400 and yellow ferric oxide, such as03B32376. The solid content of the coating liquid is 12%, and the coating weight is increased by 3-6%, preferably 5%.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages:
(1) The synthesized raw material medicine and the polymer can be directly mixed to prepare the solid dispersion without micronization of the raw material medicine. The medicine loss is reduced, the problems of electrostatic adsorption, dust flying and the like are avoided, and the labor protection of production personnel is higher.
(2) The ticagrelor is dispersed in a polymer carrier, so that the solubility of the drug is obviously improved, the effective blood concentration of the drug can be quickly reached, the effect is quicker, and the bioavailability of the drug absorbed in vivo is improved.
(3) A large amount of organic solvents are not needed, so that the damage to human bodies caused by toxic solvents in the production process is avoided. In addition, the organic solvent needs to be subjected to explosion-proof treatment of equipment and workshops in the production process, so that the solvent is prevented from being stored, fire explosion accidents are generated in the production process, and the applicability to factories is wider.
(4) The hot melt extrusion technology is a continuous manufacturing process, has larger batch, simpler factory amplification and easier realization of commercial production.
(5) The slow-release ticagrelor tablet is prepared from the hypromellose, and the low dosage of 120mg can be taken once a day for 24 hours effectively, so that the taking times are reduced, the compliance of patients in taking medicine is improved, and the risk of myocardial infarction or apoplexy caused by acute thrombosis due to missed taking medicine of the patients is reduced. On the premise of ensuring the effectiveness of the medicine, the safety risk brought by high-dose administration is also reduced.
Detailed description of the preferred embodiments
The following examples are provided for a better understanding of the present invention and are not limited to the preferred embodiments.
Example 1
Mixing ticagrelor raw material with polymer and colloidal silica in proportion, extruding the mixture in a twin screw extruder, and extruding process parameters: the feeding speed is 20rpm, the screw rotating speed is 250rpm, the temperature is 1 zone 20-30 ℃,2 zone 50-100 ℃,3-6 zone 120-130 ℃, and 7-9 zone 100-110 ℃. The extrudate is cooled and then crushed into suitable granules using a cone granulator and hammer mill. Mixing the obtained crushed particles with filler, slow release material, disintegrating agent and lubricant uniformly, and tabletting to obtain ticagrelor tablet. Dissolving the film coating premix in water to prepare coating liquid, putting the obtained plain tablets into a coating pot, adding the coating liquid by a spray gun, controlling the temperature of a tablet bed to be 40-45 ℃ and the coating weight to be increased by 5%, thus obtaining the ticagrelor sustained release tablet formulas 1-3 as shown in table 1.
The dissolution behavior investigation method of prescriptions 1-3 comprises the following steps: the dissolution profile was measured using 900ml dissolution medium, 75rpm slurry method, 0.1M HCL dissolution medium was examined for 2 hours, then transferred to dissolution medium with pH 6.8 for 24 hours, and the data are shown in Table 2.
Table 1 composition of prescriptions 1-3
TABLE 2 dissolution results for prescriptions 1-3
According to the dissolution results, the ticagrelor sustained release tablets prepared by the formulas 1-3 can be quickly dissolved to reach the effective concentration, the medicine can be continuously and stably released within 24 hours, a patient can achieve the required curative effect by taking one tablet every day, the risk of acute thrombosis of the patient is greatly reduced, the taste is excellent, and the medicine taking compliance of the patient is remarkably improved.
Example 2
Mixing ticagrelor raw material with polymer and colloidal silica in proportion, extruding the mixture in a twin screw extruder, and extruding process parameters: the feeding speed is 25rpm, the screw rotating speed is 300rpm, the temperature is 1 zone 20-30 ℃,2 zone 50-100 ℃,3-6 zone 120-130 ℃, and 7-9 zone 100-110 ℃. The extrudate is cooled and then crushed into suitable granules using a cone granulator and hammer mill. Mixing the obtained crushed particles with filler, slow release material, disintegrating agent and lubricant uniformly, and tabletting to obtain ticagrelor tablet. The film coating premix is dissolved in water to prepare coating liquid, the obtained plain tablets are placed in a coating pot, the coating liquid is added by a spray gun, the temperature of a tablet bed is controlled between 40 ℃ and 45 ℃, the coating weight is increased by 5%, and the ticagrelor sustained release tablet formulas 4 and 5 are obtained as shown in table 3. Dissolution behavior investigation method for prescriptions 4 and 5: the dissolution profile was measured using 900ml dissolution medium, 75rpm slurry method, 0.1M HCL dissolution medium was examined for 2 hours, then transferred to dissolution medium with pH 6.8 for 24 hours, and the data are shown in Table 4.
Table 3 composition of prescriptions 4 and 5
Table 4 dissolution results for prescriptions 4 and 5
From the elution results, it can be seen that the type of filler has little effect on elution.
Example 3
Mixing ticagrelor raw material with polymer and colloidal silica in proportion, extruding the mixture in a twin screw extruder, and extruding process parameters: the feeding speed is 30rpm, the screw rotating speed is 350rpm, the temperature is 1 zone 20-30 ℃,2 zone 50-100 ℃,3-6 zone 120-130 ℃, and 7-9 zone 100-110 ℃. The extrudate is cooled and then crushed into suitable granules using a cone granulator and hammer mill. Mixing the obtained crushed particles with filler, slow release material, disintegrating agent and lubricant uniformly, and tabletting to obtain ticagrelor tablet. The film coating premix is dissolved in water to prepare coating liquid, the obtained plain tablets are placed in a coating pot, the coating liquid is added by a spray gun, the temperature of a tablet bed is controlled between 40 ℃ and 45 ℃, the coating weight is increased by 5%, and the ticagrelor sustained release tablet prescription 6-9 is obtained, as shown in table 5. Dissolution behavior investigation method of prescriptions 6-9: the dissolution profile was measured using 900ml dissolution medium, 75rpm slurry method, 0.1M HCL dissolution medium was examined for 2 hours, then transferred to dissolution medium with pH 6.8 for 24 hours, and the data are shown in Table 6.
Table 5 composition of prescriptions 6-9
TABLE 6 dissolution results for prescriptions 6-9
As can be seen from the dissolution results, the preparation of the ticagrelor sustained release tablets according to the prescriptions 6-9 can achieve quick release and continuous and stable release for 24 hours, a patient can achieve the required curative effect by taking one tablet every day, and compared with the dissolution results according to the prescriptions 1, the prescriptions 6-9 have the phenomena of too slow release and too fast release in the earlier stage than the prescriptions 1, and the prescriptions 6, 7 and 9 have the problem of incomplete end release, compared with the preferential copovidone VA64..
Example 4
Mixing ticagrelor raw material with polymer and colloidal silica in proportion, extruding the mixture in a twin screw extruder, and extruding process parameters: the feeding speed is 30rpm, the screw rotating speed is 350rpm, the temperature is 1 zone 20-30 ℃,2 zone 50-100 ℃,3-6 zone 120-130 ℃, and 7-9 zone 100-110 ℃. The extrudate is cooled and then crushed into suitable granules using a cone granulator and hammer mill. Mixing the obtained crushed particles with filler, slow release material, disintegrating agent and lubricant uniformly, and tabletting to obtain ticagrelor tablet. The film coating premix is dissolved in water to prepare coating liquid, the obtained plain tablets are placed in a coating pot, the coating liquid is added by a spray gun, the temperature of a tablet bed is controlled between 40 ℃ and 45 ℃, the coating weight is increased by 5%, and the ticagrelor sustained release tablet formulas 10 and 11 are obtained as shown in table 7. Dissolution behavior investigation method for prescriptions 10 and 11: the dissolution profile was measured using 900ml dissolution medium, 75rpm slurry method, 0.1M HCL dissolution medium was examined for 2 hours, then transferred to dissolution medium with pH 6.8 for 24 hours, and the data are shown in Table 8.
Table 7 composition of prescriptions 10 and 11
Table 8 dissolution results for prescriptions 10 and 11
As can be seen from the dissolution results, the drug release is obviously slowed down along with the increase of the proportion of the hydroxypropyl cellulose, so that 20% -25% of hydroxypropyl methylcellulose is preferably used as a slow release material, and the most preferably 20% of slow release material is used for preparing the ticagrelor slow release tablet.
Example 5
Mixing ticagrelor raw material with polymer and colloidal silica in proportion, extruding the mixture in a twin screw extruder, and extruding process parameters: the feeding speed is 30rpm, the screw rotating speed is 350rpm, the temperature is 1 zone 20-30 ℃,2 zone 50-100 ℃,3-6 zone 120-130 ℃, and 7-9 zone 100-110 ℃. The extrudate is cooled and then crushed into suitable granules using a cone granulator and hammer mill. Mixing the obtained crushed particles with filler, slow release material, disintegrating agent and lubricant uniformly, and tabletting to obtain ticagrelor tablet. The film coating premix is dissolved in water to prepare coating liquid, the obtained plain tablets are placed in a coating pot, the coating liquid is added by a spray gun, the temperature of a tablet bed is controlled between 40 ℃ and 45 ℃, the coating weight is increased by 5%, and the ticagrelor sustained release tablet formulas 12 and 13 are obtained as shown in table 9. Dissolution behavior investigation method of prescriptions 12 and 13: the dissolution profile was measured using 900ml dissolution medium, 75rpm slurry method, 0.1M HCL dissolution medium was examined for 2 hours, then transferred to dissolution medium with pH 6.8 for 24 hours, and the data are shown in Table 10.
Table 9 composition of prescriptions 12 and 13
Table 10 dissolution results for prescriptions 12 and 13
From the dissolution results, it can be seen that the dissolution results of crospovidone, croscarmellose sodium and sodium carboxymethyl starch are substantially consistent.
EXAMPLE 6 stability Studies
Stability studies were performed on formulations 1, 12 and 13 in examples 1 to 5, respectively, and the change in dissolution profile was examined after 30 days of standing under high humidity (rh=92.5%) conditions, and the results are shown in table 11.
Table 11 stability dissolution study data for 30 days of standing
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Comparing the dissolution curves of 0 day and 30 days, the release of the prescription 13 taking sodium carboxymethyl starch as the disintegrant is obviously slowed down after being placed for 30 days under the high humidity condition (RH=92.5%) and the release of the prescription 1 and the prescription 12 are not obviously changed, so that the preparation of the ticagrelor sustained release tablet by taking crosslinked povidone and sodium carboxymethyl cellulose instead of taking sodium carboxymethyl starch which is ground as the disintegrant is preferentially considered, and the release of the sodium carboxymethyl starch is obviously slowed down after being placed for 30 days under the high humidity condition, so that the invention is more stable than the release of the sodium carboxymethyl starch which is ground.
EXAMPLE 7 solubility study
The solubility of the ticagrelor drug substance and ticagrelor in formulation 1 was measured in water and a series of pH buffered solutions representing physiological pH ranges, and the solubility data are shown in table 12.
TABLE 12 solubility study data (Unit: ug/ml)
| Medium (D) | Ticagrelor | Ticagrelor in formula 1 |
| PH1.0 hydrochloric acid | 16.3 | 1526 |
| Phosphate at pH4.5 | 7.3 | 784 |
| Phosphate at pH6.8 | 6.2 | 686 |
| Water and its preparation method | 7.6 | 793 |
As can be seen from the above table data, the solubility of ticagrelor in water and in the buffer solution having ph=1.0 to 6.8 is greatly increased in formula 1 as compared to the drug substance of ticagrelor.
Example 8 evaluation of bioavailability
The formulations in the above examples were optionally subjected to animal pharmacokinetic (plasma) tests.
The experimental method comprises the following steps: six male beagle dogs with an average body weight of (12.0±2.0) kg were selected as test animals. The ticagrelor sustained release tablets 1 tablet of the present invention (each tablet contains 120mg of ticagrelor, the tested preparation, prescription 1); ticagrelor immediate release tablet 2 tablets (each containing 90mg of Ticagrelor, reference formulation) were administered in two doses. Fasting for 12h before administration, and taking blank blood before administration at 8 o' clock in the morning. The tested and reference preparation groups are respectively in the ranges of 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24 and 36 hours, 6ml of upper limb venous blood is taken and placed in a heparin anticoagulation tube, centrifugation is carried out at 3500rpm for 10 minutes, upper plasma is taken, and the upper plasma is frozen and stored at the temperature of minus 20 ℃ for standby.
Plasma sample treatment: 200 mu L of plasma containing medicine is taken in a plastic centrifuge tube, 50 mu L of internal standard solution is added, vortex 30s is adopted for uniform mixing, 600 mu L of acetonitrile is added, vortex 1min is adopted for centrifugation at 12000rpm for 10min, 10 mu L of supernatant is taken for sample injection, LC-MS/MS is adopted for measuring the content of the sample, and the results are shown in Table 13.
The following pharmacokinetic parameters were measured:
cmax (ng/mL): corresponding to the maximum plasma concentration observed,
Tmax (h): corresponding to the observation time for obtaining the maximum concentration,
AUC 0-t: the time corresponding to the final quantifiable concentration is calculated by the trapezoidal method corresponding to the area under the curve or integral of the plasma concentration as a function of time t.
AUC 0-∞: corresponding to the area under the curve or integral of plasma concentration as a function of time extrapolated to infinity.
Table 13 pharmacokinetic data for formulation 1 and reference formulation
According to the in vivo pharmacokinetics and in vitro release data analysis of animals combined with the drug, compared with a commercial reference preparation, the ticagrelor sustained release tablet provided by the invention has the advantages that the Tmax is obviously prolonged, the Cmax and the AUC are relatively close, and the sustained release effect can be achieved.
The preparation is dissolved out in vitro in the early stage to release a certain medicine, and has a certain blood concentration (C 2h) in the animal body, so that the medicine effect of the medicine in 2 hours is ensured, and the quick effect of the medicine is ensured; the blood concentration of the medicine after 12 hours is ensured to be at a certain level, and the medicine effect can be maintained for 24 hours; the maximum blood concentration (C max) of the medicine is equal to or slightly lower than that of the ticagrelor quick release tablet, so as to avoid side effects caused by overhigh medicine effect in 12 hours.
Claims (9)
1. The preparation method of the ticagrelor sustained release tablet comprises the following steps:
step (1), uniformly mixing a ticagrelor bulk drug, a polymer and silicon dioxide;
Extruding the mixture obtained in the step (1) through a double-screw hot-melt extruder, wherein the extrusion temperature of the double-screw hot-melt extruder is set to be 1 zone 20-30 ℃,2 zone 50-100 ℃,3-6 zone 120-130 ℃,7-9 zone 100-110 ℃, the screw rotating speed is 300+/-50 rpm, and the feeding speed is 25+/-5 rpm;
Step (3), cooling the extrudate obtained in the step (2), crushing the extrudate by using a cone-type granulator, and crushing the crushed extrudate by using a hammer crusher;
step (4), uniformly mixing the crushed material obtained in the step (3) with a filler, a slow-release material, a disintegrating agent and a lubricant, and tabletting to obtain a ticagrelor tablet;
step (5), dissolving the film coating premix in water to prepare coating liquid, putting the ticagrelor tablet obtained in the step (4) into a coating pot, adding the coating liquid by a spray gun, controlling the temperature of a tablet bed to be 40-45 ℃ and the weight gain of the coating to be 3-6%;
Wherein, the ticagrelor bulk drug accounts for 15-30%, the polymer accounts for 20-40%, the silicon dioxide accounts for 0.8-1.2%, the slow release material accounts for 20-25%, the disintegrating agent accounts for 2-5%, the lubricant accounts for 0.5-1.5%, and the filler accounts for the rest.
2. The method of claim 1, wherein the polymer of step (1) is selected from the group consisting of copovidone, polyvinylpyrrolidone-polyvinyl acetate copolymer, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose titanate, hydroxypropyl methylcellulose phthalate, and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.
3. The method of claim 2, wherein the polymer of step (1) is copovidone VA64.
4. The method of claim 1, wherein the silica of step (1) is colloidal silica.
5. The preparation method according to claim 1, wherein the filler in the step (4) is one or more selected from lactose, calcium hydrogen phosphate, mannitol, and microcrystalline cellulose; the slow release material is a cellulose derivative selected from methylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hypromellose, hydroxymethyl cellulose or sodium hydroxymethyl cellulose; the disintegrating agent is selected from one of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium and sodium carboxymethyl starch; the lubricant is one or more selected from magnesium stearate, stearic acid, silicon dioxide and sodium stearyl fumarate.
6. The method according to claim 4, wherein the filler in step (4) is lactose or microcrystalline cellulose, the slow-release material is hypromellose, the disintegrant is crospovidone or croscarmellose sodium, and the lubricant is magnesium stearate.
7. The method of claim 1, wherein the coating solution obtained in step (5) has a solids content of 12%.
8. The method of claim 1, wherein the coating weight in step (5) is increased by 5%.
9. The preparation method of claim 1, wherein the ticagrelor sustained release tablet comprises 20% of active ingredients, 20% of polymers, 20% of sustained release materials, 3% of disintegrating agents and 1% of lubricants.
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