23 results about "Ticagrelor" patented technology

The present disclosure provides a method of reversing ticagrelor-associated bleeding in a patient by administering an antibody or fragment thereof that binds to ticagrelor.

The invention discloses a method for detecting the impurity content of ticagrelor, the impurity is N-nitrosoticagrelor, and the detection method comprises the following steps: diluting an initial sample, and preparing to obtain a detection sample; a detection sample enters a mobile phase through a sample injector, a chromatographic column with phenyl-hexyl bonded silica gel particles as a filler is adopted to carry out gradient elution treatment on the detection sample to obtain an eluted sample, the mobile phase comprises an organic phase and a water phase, and the gradient elution conditions comprise that in the first stage, the ratio of the organic phase to the water phase is in direct proportion to the duration; in the second stage, the ratio of the organic phase to the water phase is the ratio at the end of the first stage; in the third stage, in the mobile phase, the ratio of the organic phase to the water phase is inversely proportional to the duration; a fourth stage, in the mobile phase, the ratio of the organic phase to the water phase is the ratio at the end of the third stage, and the ratio of the organic phase to the water phase in the fourth stage is smaller than the ratio of the organic phase to the water phase in the second stage; and performing mass spectrometry analysis on the eluted sample to determine the components of the eluted sample.

The invention provides an isoquinoline derivative with a novel structure, a pharmaceutically acceptable salt thereof, a preparation method of the isoquinoline derivative, a pharmaceutical composition containing the isoquinoline derivative and pharmaceutical application of the isoquinoline derivative, and belongs to the technical field of medicines. In-vitro experiments show that the isoquinoline derivative has significant inhibitory activity on arachidonic acid-induced platelet aggregation, and the antiplatelet activity of part of compounds is superior to that of aspirin. In a rat carotid artery thrombosis model induced by FeCl3, the isoquinoline derivative remarkably prolongs thrombosis time and reduces thrombus weight, and the in-vivo antithrombotic curative effect of the isoquinoline derivative is equivalent to that of aspirin and ticagrelor. A mouse tail bleeding model shows that the side effects of bleeding amount and bleeding time of the isoquinoline derivative are obviously lower than those of aspirin and ticagrelor. Therefore, the series of isoquinoline derivatives have the advantages of efficient antithrombotic effect and low bleeding risk, and have good application prospects in preparation of drugs for preventing and treating thrombotic diseases. In addition, the preparation method provided by the invention has the advantages of easily available raw materials, simple steps and strong operability, and the obtained target product has high quality and good efficiency.

The present invention discloses engineered platelets carrying platelet activation inhibitor nanoparticles, a preparation method and application thereof, which belongs to the field of pharmaceutical technology and relates to a preparation method of engineered platelets carrying ticagrelor nanoparticles and its therapeutic use in malignant solid tumors. The preparation of the engineered platelets described in the present invention includes the steps of extracting and purifying platelets, preparing gelatin nanoparticles loaded with platelet activation inhibitors, anchoring the nanoparticles to the outer surface of platelets, etc. The engineered platelets of the present invention are targeted to reach the tumor site by recruiting tumor-associated platelets in the body, and specifically respond to matrix metalloproteinases to release the carried platelet activation inhibitor, thereby inhibiting the activation of platelets in the tumor microenvironment, enhancing tumor vascular leakage, alleviating the immunosuppressive microenvironment, and effectively enhancing the effects of chemotherapy and immunotherapy.

The present invention relates to aqueous ticagrelor solutions provided for intravenous administration for use in the treatment of a Gram-positive bacterial infection in the blood stream of a patient in need thereof. The invention is advantageous to further improve the effectiveness of bacteremia treatments, especially for MSSA and MRSA bacteremia and bacteremia-associated thrombocytopenia.

The present invention provides a pharmaceutical composition comprising ticagrelor at a dose of 90 mg, acetylsalicylic acid at a dose of from 75 to 100 mg, at least one of a diluent, a binder, a wetting agent, a glidant, and a lubricant. The pharmaceutical composition of the present invention solves a set of significant technological challenges due to the physicochemical properties and difference in dosage of each drug. Said pharmaceutical composition is stable, such that the composition is safe and effective in the treatment and prevention of cardiovascular diseases. The invention is further directed to a process for manufacturing a pharmaceutical composition.

The application belongs to the field of pharmaceutical chemical industry, and particularly relates to a preparation method of a ticagrelor intermediate (1R, 2S)-2-(3, 4-difluorophenyl)cyclopropylamine, which comprises the following steps: taking compound II as raw material, and reacting with N-bromosuccinimide and sodium acetate to prepare target intermediate compound I. Compared with the prior art, the reaction has the advantages of mild reaction condition, simple operation, high safety, simple post-treatment, and safety and environmental protection. It is determined that the yield of the product prepared by the technical scheme disclosed in the application can reach more than 88%, and the purity is more than 99%.

The application discloses a detection method of the impurity content of ticagrelor, the impurity is N-nitroso-ticagrelor, and the detection method comprises the following steps: diluting an initial sample to prepare a detection sample; feeding the detection sample into a mobile phase through a sample injector; performing gradient elution treatment on the detection sample by using a chromatographic column with phenyl-hexyl bonded silica gel particles as filler to obtain an elution sample, the mobile phase comprises an organic phase and an aqueous phase, and the gradient elution conditions comprise the following steps: in the first stage, the ratio of the organic phase to the aqueous phase is directly proportional to the time length; in the second stage, the ratio of the organic phase to the aqueous phase is the ratio at the end of the first stage; in the third stage, the ratio of the organic phase to the aqueous phase in the mobile phase is inversely proportional to the time length; in the fourth stage, the ratio of the organic phase to the aqueous phase in the mobile phase is the ratio at the end of the third stage, and the ratio of the organic phase to the aqueous phase in the fourth stage is smaller than that in the second stage; and performing mass spectrometric analysis on the elution sample to determine the composition of the elution sample.

The present application provides a kind of ticagrelor pharmaceutical composition, the composition includes ticagrelor and pharmaceutically acceptable carrier, the weight percentage of the ticagrelor is 10%-20%, the pharmaceutically acceptable carrier is selected from any one or combination of binder, disintegrant, diluent, lubricant, glidant, the weight percentage of the disintegrant is 10%-30%.The present application significantly reduces the dynamic disintegration time and static disintegration time of tablet by scientific screening and optimization of the formulation of solid pharmaceutical composition, facilitate the rapid absorption of drug in patients, avoid intubation simplify clinical medication regimen, in addition, it is convenient for patients with dysphagia to take medicine, significantly improve the compliance of patients to take medicine, optimize the particle size and particle powder properties of ticagrelor, solve the problem of large tablet weight difference and poor content uniformity caused by poor flowability of ticagrelor after tabletting, improve the uniformity, effectiveness and safety of the drug, realize the controllable quality of drug.

The present invention provides a pharmaceutical composition comprising ticagrelor for use in the treatment, reduction, or prevention of ischemic events in a patient who has undergone percutaneous coronary intervention (PCI), comprising the step of administering an effective amount of ticagrelor to the patient to initiate or maintain P2Y12 inhibition during percutaneous coronary intervention (PCI); wherein the pharmaceutical composition is an aqueous ticagrelor solution comprising a solubilizing agent in an effective amount for solubilizing ticagrelor; wherein the pharmaceutical composition is provided by intravenous administration, and the effective amount of ticagrelor is administered intravenously.

The present invention provides a pharmaceutical composition comprising ticagrelor for treating, reducing, or preventing ischemic events in patients undergoing percutaneous coronary intervention (PCI), comprising administering an effective amount of ticagrelor to the patient to initiate or maintain P2Y12 inhibition during PCI, characterized in that the pharmaceutical composition is an aqueous solution of ticagrelor comprising an effective amount of a solubilizer for solubilizing ticagrelor, and the pharmaceutical composition is provided for intravenous administration; wherein the effective amount of ticagrelor is administered intravenously.

Herein is provided a method of reversing ticagrelor-enhanced bleeding in a patient comprising administering to said patient during surgery, in a perioperative setting, or during an invasive procedure an antibody or antigen-binding fragment thereof that binds to ticagrelor. Also provided is a method of reversing ticagrelor-enhanced bleeding in a patient comprising administering an antibody or antigen-binding fragment thereof that binds to ticagrelor, wherein the patient is elderly, has underlying cardiac or pulmonary or metabolic disease, optionally wherein the patient has a minimum percent inhibition of P2Y 12 reaction units (PRU) over 4 hours after starting administration of the antibody or antigen-binding fragment thereof that is less than the percent inhibition of PRU before administration.

The invention provides a preparation method of a ticagrelor intermediate, and relates to the technical field of medicine synthesis. The invention provides a ticagrelor intermediate preparation method, which comprises: mixing a compound I, L-tartaric acid and an anhydrous solvent, and carrying out a salt forming reaction to obtain a ticagrelor intermediate having a structure represented by a formula II. The anhydrous solvent is adopted, the ticagrelor intermediate is prevented from being decomposed into impurities under the acidic condition in the reaction process, meanwhile, the temperature of the salt forming reaction is controlled to be 75 DEG C or below, the ring-opening side reaction of the compound I can be avoided, the impurity content is low, and the yield and purity of the ticagrelor intermediate are high. Moreover, the preparation method provided by the invention is simple to operate, low in production cost, green, environment-friendly and suitable for industrial production. The test result of the embodiment shows that the yield of the ticagrelor intermediate is 87.8-96.8% according to the preparation method provided by the invention.

A method of treating acute myocardial infarction in a patient by administering to the patient a combination of r-SAK and an antiplatelet agent such as ticagrelor. The acute myocardial infarction can be ST-elevation myocardial infarction. The patient can be one who is expected to receive percutaneous coronary intervention within 120 minutes from his or her first medical contact, e.g., one who is expected to receive percutaneous coronary intervention within 120 minutes from his or her first medical contact but more than 30 minutes from his or her first medical contact. A pharmaceutical composition for use in treating acute myocardial infarction in a patient is also provided which include r-SAK and an antiplatelet agent.

The invention discloses a ticagrelor solid dispersion with high bioavailability as well as a preparation, a preparation method and application thereof, the solid dispersion is prepared from ticagrelor and a specific ternary carrier system through a hot melt extrusion process, and the ternary carrier system consists of Soluplus, copovidone and hydroxypropyl methylcellulose. The solid dispersion further forms a pharmaceutical composition with a disintegrating agent, a filler and a lubricant. Through the synergistic effect of the ternary carrier and the hot melt extrusion technology, ticagrelor stably exists in an amorphous state, and the dissolution rate and oral bioavailability of the medicine are remarkably improved. Experiments show that the 30-min dissolution rate of the preparation in a phosphate buffer solution with the pH being 6.8 is larger than or equal to 85%, the relative bioavailability of the preparation in beagle reaches 150%-250% of that of commercially available tablets, the stability is excellent, the crystallization phenomenon is avoided in a 6-month accelerated test, and the preparation has great clinical value and market prospects.

Herein is provided a method of reversing ticagrelor-enhanced bleeding in a patient comprising administering to said patient during surgery, in a perioperative setting, or during an invasive procedure an antibody or antigen-binding fragment thereof that binds to ticagrelor. Also provided is a method of reversing ticagrelor-enhanced bleeding in a patient comprising administering an antibody or antigen-binding fragment thereof that binds to ticagrelor, wherein the patient is elderly, has underlying cardiac or pulmonary or metabolic disease, optionally wherein the patient has a minimum percent inhibition of P2Y12 reaction units (PRU) over 4 hours after starting administration of the antibody or antigen-binding fragment thereof that is less than the percent inhibition of PRU before administration.

The invention discloses an immobilized enzyme for preparing a ticagrelor intermediate and a preparation method of the immobilized enzyme. The immobilized enzyme comprises a carbonyl reductase mutant and an immobilized carrier, and the amino acid sequence of the carbonyl reductase mutant is as shown in SEQ ID NO: 1; the immobilized carrier is selected from the group consisting of LX1000EA, LX1000IDA, LX1000HA and LX1000ME, and the immobilized carrier is selected from the group consisting of LX1000EA, LX1000IDA and LX1000ME. The immobilized enzyme provided by the invention is used as a biocatalyst for biocatalytic preparation of a ticagrelor intermediate (S)-2-chloro-1-(3, 4-difluorophenyl) ethanol, the product yield and purity are high, the repeated utilization rate of the enzyme is high, and the separation and purification process is simple.

This invention discloses a highly bioavailable ticagrelor solid dispersion, its formulation, preparation method, and application. The solid dispersion is prepared by hot melt extrusion of ticagrelor and a specific ternary carrier system, wherein the ternary carrier system is from Soluplus. ® The formulation consists of copovidone and hydroxypropyl methylcellulose. This solid dispersion is further combined with disintegrants, fillers, and lubricants to form a pharmaceutical composition. This invention utilizes the synergistic effect of a ternary carrier and hot-melt extrusion technology to ensure ticagrelor exists stably in an amorphous form, significantly improving drug dissolution and oral bioavailability. Experiments show that the formulation exhibits a dissolution rate ≥85% in pH 6.8 phosphate buffer after 30 min, and a relative bioavailability in beagle dogs reaching 150%–250% of commercially available tablets. It also demonstrates excellent stability, with no crystallization observed in a 6-month accelerated assay, indicating significant clinical value and market potential.

The present disclosure provides a method of reversing ticagrelor-associated bleeding in a patient by administering an antibody or fragment thereof that binds to ticagrelor.

The application provides a dioxolane compound and a preparation method and application thereof, and a preparation method of a ticagrelor intermediate, relates to the technical field of drug synthesis. The dioxolane compound provided by the application can be used to prepare the ticagrelor intermediate with the structure of formula B by carrying out a hydrolysis reaction under alkaline conditions and then adding a reducing agent to carry out a reduction reaction, the process is simple, the palladium-carbon hydrogenation reduction is not needed, the preparation process is mild, atomic economy is strong, production safety is high, the product yield is high, the product purity is high, the production cost is low, post-treatment is simple, three wastes are few, and the application is suitable for industrialized production.

The present invention relates to providing an aqueous ticagrelor solution for intravenous administration for use in the treatment of Gram-positive bacterial infections in the bloodstream of a patient in need thereof. The pharmaceutical composition is beneficial to further improving the effectiveness of bacteremia treatment, especially the effectiveness of MSSA and MRSA bacteremia and thrombocytopenia related to bacteremia.

The present invention provides a pharmaceutical composition containing ticagrelor for use in reducing or preventing thromboembolic events before and / or during and / or after neurovascular arterial procedures in a patient requiring the use of the pharmaceutical composition containing ticagrelor, comprising administering an effective amount of the pharmaceutical composition containing ticagrelor to a patient, wherein the pharmaceutical composition is an aqueous solution containing a solubilizing agent for ticagrelor and the pharmaceutical composition is administered intravenously; wherein the patient suffers from a cerebral aneurysm, cerebral arteriosclerosis, cervical arteriosclerosis, neurovascular carotid dissection or carotid dissection.

The invention relates to the technical field of ticagrelor, in particular to a ticagrelor clathrate compound and a preparation method and application thereof. The ticagrelor clathrate compound comprises ticagrelor and a macrocyclic compound for clathrating the ticagrelor, and the macrocyclic compound is at least one of cucurbit [7] uril, beta-cyclodextrin and hydroxypropyl beta-cyclodextrin. According to the invention, the macrocyclic compound and the ticagrelor are clathrated to form a stable drug clathrate, the solubility and pharmacological action of the ticagrelor are enhanced, and a preparation with excellent chemical stability, low biotoxicity and good drug release performance is provided. Meanwhile, the novel application of the ticagrelor clathrate compound in preparation of the medicine for treating systemic lupus erythematosus is defined.