CN110876750A - Sustained-release composition containing ticagrelor or pharmaceutically acceptable salt thereof - Google Patents
Sustained-release composition containing ticagrelor or pharmaceutically acceptable salt thereofDownload PDFInfo
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Abstract
Description
Technical Field
The disclosure relates to a sustained-release composition containing ticagrelor or pharmaceutically acceptable salts thereof, belonging to the field of pharmacy.
Background
Ticagrelor is a platelet aggregation inhibitor and is a novel oral antiplatelet drug of cyclopentyl triazolopyrimidine (CPTP). The chemical name is as follows: 1S,2S,3R,5S) -3- [7- { [ (1R,2S) -2- (3, 4-difluorobenzene) cyclopropyl]Amino } -5- (propylsulfanyl) -3H- [1,2,3]-triazolo [4,5-d]Pyrimidin-3-yl]-5- (2-hydroxyethoxy) cyclopentane-1, 2-diol having the molecular formula C23H28F2N6O4S, the structural formula is as follows:
ticagrelor is a member of the chemical classification Cyclopentyltriazolopyrimidine (CPTP), a selective Adenosine Diphosphate (ADP) receptor antagonist that acts on the P2Y12ADP receptor to inhibit ADP-mediated platelet activation and aggregation, similar to the mechanism of action of thienopyridines such as clopidogrel. However, in contrast, the interaction between ticagrelor and the platelet P2Y12ADP receptor is reversible, with no conformational changes and signaling, and platelet function in the blood is rapidly restored following withdrawal.
The mean platelet aggregation Inhibition (IPA) reached 41% after administration of 180mg loading dose of ticagrelor 0.5 hours and the maximum IPA effect 89% after 2-4 hours of administration, which was maintained for 2-8 hours. The pharmacokinetics of ticagrelor were linear up to 1260mg, and ticagrelor and active metabolite (AR-C124910XX) exposure was substantially proportional to dose.
The swiss medicine event monitoring system database study counted the missed-taking data of 677 coronary heart disease patients who took twice a day: 75.2% of patients are missed at least once, and 25.7% are missed at least twice in succession. If the patient misses taking the medicine for a long time, acute thrombosis is easily caused, and myocardial infarction or apoplexy is further caused. In order to reduce the number of taking times, thereby improving the medication compliance of patients and reducing the risk of myocardial infarction or stroke caused by acute thrombosis due to missed taking of ticagrelor by patients, it is necessary to prepare ticagrelor as a suitable sustained-release component. Patent CN102657629A relates to a ticagrelor sustained release tablet system and a preparation method thereof, wherein the patent uses hypromellose or hydroxypropyl cellulose as sustained release materials to prepare ticagrelor sustained release components, and the inventor tries to use cellulose polymer hydroxypropyl methyl cellulose polymer related in patent CN102657629A to prepare sustained release matrix tablets by a conventional tabletting preparation method, and as a result, incomplete release exists in the later period. Patent application CN105998026A discloses a ticagrelor composition containing two or three drug delivery systems, which does not have relevant pharmacokinetic parameters of the preparation, so the effect of the preparation in vivo is unknown; patent application CN106074357A also discloses a composition containing quick release micro-tablets, enteric quick release micro-tablets and enteric slow release micro-tablets, which attempts to achieve a sustained release effect by enteric materials. At present, no ticagrelor sustained release product is on the market.
The present disclosure provides a slow release formulation of ticagrelor, which slowly releases and absorbs the drug by staying in the upper part of the gastrointestinal tract of a human body for a long time, thereby reducing the number of times of administration, improving the compliance of the administration of patients, and reducing the risk of embolism of the patients.
Disclosure of Invention
The invention provides a slow release composition of ticagrelor or a pharmaceutically acceptable salt thereof, which controls the slow release of a medicament by increasing the retention time of the medicament in the stomach so as to reduce the taking times, achieve once-a-day administration, improve the medication compliance of a patient and reduce the embolism risk of the patient.
The slow release composition of ticagrelor or pharmaceutically acceptable salt thereof provided by the disclosure comprises a matrix forming agent and a gel forming agent.
The unit dosage form of the sustained release composition of ticagrelor or a pharmaceutically acceptable salt thereof provided by the present disclosure has a size selected from 8-22mm, preferably a size of 10-20 mm; the size of the composition can reach 9-28mm after water absorption and swelling, so that the effect of stomach retention is achieved, and the preferred size of the composition provided by the disclosure is 10-24mm after water absorption and swelling.
The matrix forming agent disclosed by the disclosure is selected from one or more of Polyoxyethylene (PEO), polyvinyl acetate, polyvinylpyrrolidone, agar, gelatin, hyaluronic acid and hydrogenated castor oil, and is preferably polyoxyethylene.
The polyoxyethylene described in the present disclosure is selected from polyoxyethylene N10, polyoxyethylene N80, polyoxyethylene N750, polyoxyethylene 205, polyoxyethylene 1105, polyoxyethylene N60K, polyoxyethylene 301, polyoxyethylene coaglunt, polyoxyethylene 303, and preferably one or more of polyoxyethylene N80, polyoxyethylene N750, polyoxyethylene 205, and polyoxyethylene 301.
The sustained release composition for ticagrelor or a pharmaceutically acceptable salt thereof according to the present disclosure comprises the matrix forming agent in an amount of 10% to 45%, preferably 15% to 40%, most preferably 20% to 35% by weight of the total composition.
In the slow release composition of ticagrelor or pharmaceutically acceptable salts thereof, the gel forming agent in the slow release part is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, polymethacrylic resin, acrylic resin, cross-linked polyvinylpyrrolidone, sodium alginate and commonly used alginate, chitosan, guar gum, stearic acid, stearyl alcohol and glyceryl monostearate, and is preferably hydroxypropyl methylcellulose. An optional range of viscosity for hydroxypropylmethylcellulose in a gel-forming agent of the present disclosure is 3-100000pa.s, optionally
The specific models comprise HPMC E3, HPMC E5, HPMC E15, HPMC E50LV, HPMC E4M, HPMC E10M, HPMC K100LV, HPMC K4M, HPMC K15M, HPMC K100M, HPMC A15LV, HPMC A4C, HPMC A15C and HPMC A4M, preferably HPMC K4M.
The sustained release composition of ticagrelor or a pharmaceutically acceptable salt thereof provided by the present disclosure comprises 10% to 45%, preferably 15% to 40%, most preferably 20% to 35% of the gel forming agent by total weight of the composition.
The sustained-release pharmaceutical composition provided by the present disclosure can expand to a size of 9mm or more after entering into the body, and can be retained in the stomach for at least 6 hours, and the release time of the active pharmaceutical ingredient ticagrelor or pharmaceutically acceptable salt thereof in the body is above 12.
The slow release composition of ticagrelor or pharmaceutically acceptable salts thereof provided by the present disclosure has the active ingredient in the form of solid dispersion, wherein the carrier material of the solid dispersion includes but is not limited to one or more of poloxamer, povidone, copovidone, polyethylene glycol, acrylic resin and the like, preferably copovidone.
The present disclosure provides a pharmaceutical composition, wherein the mass ratio of ticagrelor or a pharmaceutically acceptable salt thereof to carrier in the components is 10:1-1:10, preferably 5:1-1:5, and most preferably 3:1-1: 3.
The solid dispersion of ticagrelor or a pharmaceutically acceptable salt thereof of the present disclosure can be prepared using conventional techniques, such as solvent methods, melt methods, solid phase deposition evaporation methods, spray drying methods, ball mill milling, and the like. The present disclosure preferably employs a spray drying method to prepare the solid dispersion, i.e., the drug and the carrier are dissolved in a suitable solvent, and then the solid dispersion is prepared by spray drying. Wherein the solvent is selected from absolute ethyl alcohol, acetone, ethyl acetate, dichloromethane and the like, and the solvent is further preferred to be absolute ethyl alcohol in the disclosure.
Since ticagrelor is almost insoluble in water, the ideal effect cannot be achieved according to the conventional process, and the drug is often too slowly or incompletely dissolved. In one embodiment of the present disclosure, the immediate release component has ticagrelor particles with a size range D (90) less than 50 microns, more preferably D (90) less than 30 microns.
The slow release composition of ticagrelor or pharmaceutically acceptable salts thereof provided by the present disclosure further comprises other excipients, specifically including diluents, glidants, lubricants and the like, wherein the diluents are selected from one or more of starch, pregelatinized starch, lactose, microcrystalline cellulose (MCC), mannitol, anhydrous calcium hydrogen phosphate and calcium hydrogen phosphate dihydrate, preferably microcrystalline cellulose.
The present disclosure provides sustained release compositions wherein the diluent is present in an amount of 10% to 80%, preferably 15% to 60%, most preferably 20% to 35% by weight of the total sustained release tablet weight.
Ticagrelor or pharmaceutically acceptable salt thereof provided by the present disclosureThe glidant in the salt slow-release composition is selected from talcum powder, stearic acid and silicon dioxide (SiO)2) Preferably silicon dioxide; the lubricant is selected from one or more of Magnesium Stearate (MS), sodium fumarate stearate and hydrogenated vegetable oil, and is preferably magnesium stearate.
The content of the glidant and the lubricant in the sustained-release composition of ticagrelor or pharmaceutically acceptable salt thereof provided by the present disclosure is 0.01-10%, preferably 0.5-5%, and most preferably 1.0-2% of the total weight of the sustained-release tablet.
The slow release composition of ticagrelor or pharmaceutically acceptable salts thereof provided by the present disclosure may, in one embodiment, be added with a bioadhesive material, and the specific bioadhesive material may be selected from carbomer, chitosan, thiolated chitosan, hydroxypropylmethylcellulose, polyacrylic resin, and the like.
The sustained-release composition provided by the disclosure is characterized in that the content of ticagrelor or a pharmaceutically acceptable salt thereof in a unit preparation is 45mg to 220mg, specifically 45mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 93mg, 95mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, preferably 93mg, 120mg, 140mg, 180mg, calculated on ticagrelor.
The sustained release compositions of ticagrelor or a pharmaceutically acceptable salt thereof provided by the present disclosure can be tablets, optionally round tablets or other anisotropic tablets, such as oval, capsule, mallet, triangle, quadrilateral, pentagon, hexagon, and the like.
In one class of embodiments of the present disclosure, a sustained release composition of ticagrelor or a pharmaceutically acceptable salt thereof as described above achieves the effect of once-a-day administration.
In another class of embodiments of the present disclosure, there is provided a controlled release composition of ticagrelor or a pharmaceutically acceptable salt thereof that can comprise an immediate release component of ticagrelor or a pharmaceutically acceptable salt thereof in addition to the sustained release combination described above.
The immediate release component in the controlled release composition of ticagrelor or pharmaceutically acceptable salts thereof provided by the present disclosure optionally contains other excipients, specifically including diluents, disintegrants, glidants, lubricants and the like, wherein the diluents are selected from one or more of starch, pregelatinized starch, lactose, microcrystalline cellulose, mannitol, anhydrous calcium hydrogen phosphate and calcium hydrogen phosphate dihydrate; the glidant is selected from one or more of talcum powder, stearic acid and silicon dioxide; the lubricant is selected from one or more of magnesium stearate and sodium fumarate stearate; the disintegrating agent is selected from one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose and dry starch.
In a preferred embodiment of the controlled release composition provided by the present disclosure, the sustained release component is free of the other excipients described above.
The weight ratio of ticagrelor or salt in the quick-release component and the sustained-release component in the controlled-release composition provided by the disclosure is 5:1 to 1:10, preferably 3:1 to 1:8, most preferably 1:1 to 1: 6.
Alternative embodiments of the controlled release compositions of ticagrelor or a pharmaceutically acceptable salt thereof provided with an immediate release component of the present disclosure are pellets, microcapsules, bi-layer tablets, or core-coated tablets.
In the present disclosure, the immediate release component may be added by means of a double-layer tablet compression, a core-coated tablet, a pellet coating, a film coating, a fluidized bed coating, etc., preferably a film coating, as desired.
In the present disclosure, when the quick-release component is added by coating, the coating material may be one or more selected from hydroxypropyl methylcellulose, polyethylene glycol, acacia, absolute ethanol, polyvinyl alcohol, gastric-soluble film coating powder, etc., preferably gastric-soluble film coating powder. The coating material may also be used in combination with other pharmaceutically acceptable anti-sticking agents, plasticizers, thickeners, colorants, anti-foaming agents, opacifiers, etc.
The sustained release compositions of ticagrelor provided by the present disclosure, when further comprising an immediate release component, the introduction of the immediate release component has a negligible effect on the size of the unit dosage form after swelling.
In the controlled release composition described in the present disclosure, the ratio of ticagrelor or a pharmaceutically acceptable salt thereof to the coating material in the immediate release component is 10:1 to 1:10, preferably 5:1 to 1:5, most preferably 2:1 to 1: 2.
The present disclosure provides a method for preparing the sustained-release composition or the sustained-release component in the controlled-release composition, which is selected from a method of wet granulation tabletting, dry granulation tabletting or powder direct tabletting, preferably a method of dry granulation tabletting.
The present disclosure provides a method for preparing the immediate release component of the controlled release composition, characterized in that the method is selected from the group consisting of bi-layer tablet compression, core-coated tablet, pellet coating, film coating, fluidized bed coating, preferably film coating.
The compositions (optionally controlled release compositions or sustained release compositions) of ticagrelor or a pharmaceutically acceptable salt thereof provided by the present disclosure can be administered either on an empty stomach or after a meal, preferably after a meal.
The composition of ticagrelor or pharmaceutically acceptable salt thereof provided by the disclosure is administrated once a day, and can reach the market
The same effect was given twice daily.
Compositions of ticagrelor or a pharmaceutically acceptable salt thereof provided in the present disclosure have a delayed time to peak (Tmax) after a single administration, optionally a Tmax greater than 5h, preferably greater than 6 h.
Compositions of ticagrelor or a pharmaceutically acceptable salt thereof provided by the present disclosure, with commercially available ticagrelor
Compared with the prior art, the area under the blood concentration curve (AUC) is close, and the peak concentration of the blood concentration is stable, so that the possibility of missed administration of a patient is reduced and the risk of embolism of the patient is reduced under the condition of ensuring equivalent bioavailability.
The ticagrelor or pharmaceutical salt composition provided by the disclosure has a simple preparation process and small individual difference of drug release in vivo.
Compositions of ticagrelor or a pharmaceutically acceptable salt thereof provided by the present disclosure, with commercially available ticagrelor
CompareThe inhibition rate of platelet aggregation is equivalent.
The "dimension" referred to in this disclosure corresponds to the longest linear dimension of the cross-section of the unit dosage form having the smallest area.
Drawings
FIG. 1 is a graph of the dissolution profiles of formulations 1-5 of example 1;
FIG. 2 is a graph of the dissolution profiles of formulas 6-11 of example 2;
FIG. 3 is a graph of the dissolution profiles of formulas 12-15 of example 2.
Detailed Description
The present disclosure will be explained in more detail with reference to examples, which are merely illustrative of the technical solutions of the present disclosure, and the spirit and scope of the present disclosure is not limited thereto.
The compositions of the present disclosure are prepared as follows:
firstly, dissolving Ticagrelor (TGRL) or pharmaceutically acceptable salt and copovidone (1:1) thereof in absolute ethyl alcohol, and spray drying to prepare a ticagrelor solid dispersion (TGRL-SD); then mixing the ticagrelor solid dispersion, the matrix forming agent, the gelling agent and other necessary excipients together, and preparing the mixture into tablets through dry granulation and tabletting (the size of a stamping die is 19.2mm by 10 mm); in some embodiments, the immediate release portion is coated with an outer layer.
The method for detecting the release degree comprises the following steps: taking the product, according to a release determination method (second method of 0931 in the four parts of the Chinese pharmacopoeia 2015 edition), dissolving the product in a hydrochloric acid solution with the pH value of 1.2 and 0.2% ofTween 80, sampling, and detecting the release by using an ultraviolet-visible spectrophotometry.
In some example dissolution tests, at specific time points, the tablets were removed, the size of the tablets measured using a vernier caliper (length x width x height, mm x mm) and the rigidity of the tablets measured using a texture analyzer (maximum hardness value, N).
Example 1
After mixing the solid dispersion of ticagrelor, matrix forming agent, gelling agent and other necessary excipients together according to the prescription in table 1, the mixture is dry granulated and tabletted to prepare tablets, and in some embodiments, the immediate release portion is coated with the outer layer.
Table 1.
The prescription 1 is composed of tablet cores of the prescription 3, and the tablet cores in theprescriptions 1 and 2 contain 93mg of medicine; in the prescription 3, the tablet core contains 93mg of medicine, and the outer coating contains 27mg of medicine; the tablet core in theprescriptions 4 and 5 contains 120mg of medicine.
Example 2
After mixing the solid dispersion of ticagrelor, matrix forming agent, gelling agent and other necessary excipients according to the prescription in tables 2 and 3, the mixture is prepared into tablets through dry granulation and tabletting, and in some embodiments, the quick-release part is coated on the outer layer.
Table 2.
The prescriptions 6-8 are respectively composed of tablet cores of prescriptions 9-11, wherein tablet core in prescription 9 contains 140mg of medicine, directly contains medicine layer, and contains 40 mg; in theprescription 10, the tablet core is 140mg, the PVA isolating layer comprises a medicine layer, and the medicine layer comprises 40 mg; formula 11 comprises tablet core 140mg, HPMC isolating layer, and medicinal layer containing 40 mg.
Table 3.
Experimental example 1 dissolution experiment
The swelling and dissolution data for example 1 are shown in table 4 below.
Table 4.
As shown in the table, the prescriptions 1-5 can satisfy the requirement of slow release in vitro dissolution test, and the size of the tablet meets the requirement.
The swelling and dissolution data for formulas 6-11 of example 2 are shown in Table 5 below.
Table 5.
Formula 9 is that the outer layer in the solution is removed first, and the tablet core is swelled and then eroded;formulas 10 and 11 have the outer layer removed first in the solution, the isolation layer removed, and the core swelled first and then eroded. The initial dissolution rate of the prescriptions 9-11 is slightly higher than that of the prescriptions 6-8 due to the drug-containing layer, but the prescriptions 6-11 can meet the requirement of slow release in-vitro dissolution test, and the size of the tablet meets the requirement.
The swelling and dissolution data for formulas 12-14 in example 2 are shown in Table 6 below.
Table 6.
As shown in the table, the prescriptions 12-15 can satisfy the requirement of slow release in vitro dissolution test, and the size of the tablet meets the requirement.
Experimental example 2
The formulations in the above examples were selectively subjected to human pharmacokinetic (blood concentration) and pharmacodynamic (platelet inhibition rate) tests, and the in vitro and in vivo correlations of ticagrelor were investigated by comprehensively analyzing the relationship between in vitro release and Pharmacokinetics (PK) and Pharmacodynamics (PD).
According to the invention, different prescriptions are subjected to random, cross, single-center and contrast test studies by adopting healthy volunteer subjects, and the study evaluates the pharmacokinetics and pharmacodynamics of ticagrelor in the healthy subjects. In this study, the present formulation was administered once daily at a dose of 120mg (formulation 3), the commercial immediate release formulation was administered twice daily at a dose of 60mg, and once daily at a dose of 180mg (formulation 11), and the commercial immediate release formulation was administered twice daily at a dose of 90 mg. Plasma samples were collected for determining plasma levels and platelet inhibition of ticagrelor. Samples were analyzed by HPLC/MS/MS.
The pharmacokinetic parameters of the ticagrelor controlled release formulation are shown in tables 7 and 8.
Table 7.
Table 8.
The results of the pharmacokinetic parameters in vivo show that compared with the commercially available preparation, the Tmax of the ticagrelor controlled release preparation in the formulas 3 and 11 is obviously prolonged, the Cmax and the AUC are relatively close, and the sustained release effect can be achieved.
Claims (14)
1. A sustained release composition of ticagrelor or a pharmaceutically acceptable salt thereof comprising a matrix forming agent and a gel forming agent.
2. A sustained release composition according to claim 1, wherein the composition has a unit dosage form of a size selected from 8-22mm, preferably a size of 10-20 mm; the size after water absorption and swelling is 9-28mm, preferably 10-24 mm.
3. The sustained-release composition according to claim 1, wherein the matrix forming agent is selected from one or more of polyoxyethylene, polyvinyl acetate, polyvinylpyrrolidone, agar, gelatin, hyaluronic acid, hydrogenated castor oil, preferably polyoxyethylene; the matrix forming agent is present in an amount of 10% to 45%, preferably 15% to 40%, most preferably 20% to 35% by weight of the total composition.
4. The sustained-release composition according to claim 1, wherein the gel forming agent is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, polymethacrylic resin, acrylic resin, cross-linked polyvinylpyrrolidone, alginate, chitosan, guar gum, stearic acid, stearyl alcohol and glyceryl monostearate, preferably hydroxypropyl methylcellulose; the gel former is present in an amount of from 10% to 45%, preferably from 15% to 40%, most preferably from 20% to 35% by weight of the total composition.
5. The sustained-release composition according to any one of claims 1 to 4, wherein the ticagrelor or the pharmaceutically acceptable salt thereof is a solid dispersion, wherein the carrier material of the solid dispersion is selected from one or more of poloxamer, povidone, copovidone, polyethylene glycol, acrylic resin and the like, preferably copovidone; the mass ratio of the ticagrelor or the pharmaceutically acceptable salt thereof to the carrier is 10:1-1:10, preferably 5:1-1:5, and most preferably 3:1-1: 3.
6. The sustained release composition according to claim 5, optionally comprising one or more of a diluent, a glidant and a lubricant, wherein the content of the diluent is 8% -60%, preferably 8% -40%, and most preferably 10% -30% of the total weight of the sustained release composition; the content of the glidant and the lubricant is 0.01-10%, preferably 0.5-5%, and most preferably 1.0-2% of the total weight of the sustained-release composition.
7. A controlled release composition of ticagrelor or a pharmaceutically acceptable salt thereof, comprising the sustained release composition of any one of claims 1-6 as a sustained release component, further comprising an immediate release component comprising ticagrelor or a pharmaceutically acceptable salt thereof, said immediate release component optionally comprising one or more of a diluent, a disintegrant, a glidant, and a lubricant.
8. The controlled release composition according to any of claim 7, wherein the weight ratio of ticagrelor or salt thereof in the immediate release component to the sustained release component is 5:1 to 1:10, preferably 3:1 to 1:8, most preferably 1:1 to 1: 6.
9. The controlled release composition according to any of claims 7-8, which is a pellet, a microcapsule, a bi-layer tablet or a core-coated tablet.
10. The controlled release composition according to any of claims 7 to 9, wherein the immediate release component is added by means of a bilayer tablet compression, a core tablet, a pellet coating, a film coating, a fluid bed coating, preferably a film coating.
11. The controlled release composition according to claim 10, wherein the coating material is selected from one or more of hydroxypropyl methylcellulose, polyethylene glycol, gum arabic, absolute ethyl alcohol, polyvinyl alcohol, acrylic resin, gastric-soluble film coating powder, preferably gastric-soluble film coating powder.
12. The controlled release composition according to claim 11, wherein the mass ratio of ticagrelor or a pharmaceutically acceptable salt thereof to coating material in the immediate release component is 10:1 to 1:10, preferably 5:1 to 1:5, most preferably 2:1 to 1: 2.
13. A process for the preparation of a sustained release composition according to any one of claims 1 to 6, a sustained release component of a controlled release composition according to any one of claims 7 to 12, selected from wet granulation tableting, dry granulation tableting or powder direct tableting, preferably dry granulation tableting.
14. A process for preparing the immediate release component of the controlled release composition of any of claims 7-12, said process being selected from the group consisting of bi-layer tablet compression, core-spun tablets, pellet coating, film coating, fluid bed coating, preferably film coating.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111991362A (en)* | 2020-09-07 | 2020-11-27 | 乐普（北京）医疗器械股份有限公司 | A kind of ticagrelor sustained-release tablet and preparation method thereof |
| CN113181140A (en)* | 2021-05-07 | 2021-07-30 | 苏州康恒研新药物技术有限公司 | Ticagrelor skeleton sustained-release pellet and preparation method thereof |
| CN114533744A (en)* | 2020-11-26 | 2022-05-27 | 乐普（北京）医疗器械股份有限公司 | Ticagrelor-aspirin compound pellet preparation and preparation method thereof |
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| US11878016B2 (en)* | 2021-10-04 | 2024-01-23 | Neurim Pharmaceuticals (1991) Ltd. | Methods and products for treating subjects with autism spectrum disorders |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111991362A (en)* | 2020-09-07 | 2020-11-27 | 乐普（北京）医疗器械股份有限公司 | A kind of ticagrelor sustained-release tablet and preparation method thereof |
| CN114533744A (en)* | 2020-11-26 | 2022-05-27 | 乐普（北京）医疗器械股份有限公司 | Ticagrelor-aspirin compound pellet preparation and preparation method thereof |
| CN114533694A (en)* | 2020-11-26 | 2022-05-27 | 乐普（北京）医疗器械股份有限公司 | Compound capsule preparation containing ticagrelor and aspirin and preparation method thereof |
| CN113181140A (en)* | 2021-05-07 | 2021-07-30 | 苏州康恒研新药物技术有限公司 | Ticagrelor skeleton sustained-release pellet and preparation method thereof |
| US11878016B2 (en)* | 2021-10-04 | 2024-01-23 | Neurim Pharmaceuticals (1991) Ltd. | Methods and products for treating subjects with autism spectrum disorders |
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