114 results about "Bivalirudin" patented technology

The present invention relates to compounds for treatment that protects the endothelium, prevents pathologic thrombus formation in the microcirculation and preserves platelet number and function and thus may be related to treatment or prevention of ischemic events in patients with cardiovascular disease. The present invention is particularly useful for patients having or being at increased risk of development of an ischemic event such as an acute myocardial infarction and / or no-reflow phenomena and / or ischemia-reperfusion injury by administration of agent(s) modulating and / or preserving endothelial integrity. The compounds may be administered in combination with standard treatment of acute cardiovascular ischemic events such as Platelet inhibitors such as aspirin (ASA), Thienopyridins, GPIIb / IIIa inhibitors), Parenteral anticoagulants such as unfractioned heparin (UFH), bivalirudin, enoxaparin, and fondaparinux, Verapamil, Adenosine, Sodium nitroprusside, Nitroglycerin, Epinephrine, Beta-blockers and surgical methods such as percutaneous coronary intervention (PCI), PCI with thrombus aspiration, PCI with stents.

The invention belongs to the technical field of polypeptide medicament preparation methods, and in particular relates to a preparation method for bivalirudin. The preparation method for the bivalirudin comprises solid phase polypeptide synthesis for preparing bivalirudin resin, acid hydrolysis of the bivalirudin resin to obtain a crude bivalirudin product, and purification of the crude bivalirudin product to obtain a purified bivalirudin product, wherein the solid phase polypeptide synthesis for preparing the bivalirudin resin comprises the following steps of: sequentially connecting corresponding Fmoc- protected amino acids in the following sequences to Fmoc-Leu-carrier resin by a solid phase coupling synthesis method: R1-D-Phe-Pro-Arg(Pbf)-Pro-X-Asn(R2)-Gly-Asp(OtBu)-, Phe-Glu(OtBu)-Glu(OtBu)-Ile-Pro-Glu(OtBu)-Glu(OtBu)- and Tyr(tBu)-Leu-resin, and thus obtaining the bivalirudin resin; and when the X fragment is connected, only one times of solid phase coupling synthesis reaction is used, and the corresponding Fmoc- protected amino acid is Fmoc-Gly-Gly-Gly-Gly-OH. The purity of the bivalirudin is more than 99.5 percent, and the single impurity is less than 0.2 percent.

The present application provides an improved process for the preparation of Bivalirudin and its pharmaceutical compositions.The present application also provides an improved process for the purification of Bivalirudin.

The invention provides a liquid phase synthesis method for bivalirudin. Firstly, three all-protected fragments, namely 6 peptide with an all-protected N-terminal, 6 peptide with an all-protected middle segment and 8 peptide with an all-protected C-terminal are gradually synthesized, then all-protected bivalirudin is obtained by orderly condensing the three fragments, finally all protective genes are removed to obtain a crude product of the bivalirudin, and then a pure product of the bivalirudin is obtained through high-efficiency liquid chromatography purification. The method does not need a resin, excessive protected amino acid and a condensing agent, is easy to realize mass production, and has relatively lower production cost.

This invention discloses a preparation method of solid-phase peptide synthesizing bivalirudin. It includes the following steps: taking any one of triphenyl methyl chloride resin, 4-methyl-triphenyl methyl chloride resin, 4-methoxy-triphenyl methyl chloride resin, 2-chlorine-triphenyl methyl chloride resin, or Wang resin as the starting raw materials, connecting amino acids in turn according to the method of solid-phase synthesis, to get a protective 28-peptide resin, removing Fmoc-protective group in turn, side-chain protecting group and cutting the peptide to get a crude, then purifying the crude through C18 (or C8) high-pressure column to get bivalirudin exquisite article. In this invention, the peptide yield of every step is more than 99%, and the total yield is 14%.

The present invention is directed to the following: methods of treating or preventing stent thrombosis using pharmaceutical compositions comprising cangrelor and optionally bivalirudin; methods of reducing mortality in a subject undergoing stent implantation using pharmaceutical compositions comprising cangrelor and optionally bivalirudin; medicaments comprising cangrelor and optionally bivalirudin useful for treating or preventing stent thrombosis, or useful for reducing mortality in a subject undergoing stent implantation; pharmaceutical compositions comprising cangrelor and bivalirudin; and methods of preparing a medicament comprising cangrelor and optionally bivalirudin useful for treating or preventing stent thrombosis, or useful for reducing mortality in a subject undergoing stent implantation.

The invention discloses a preparation method of polypeptide solid-phase synthesis bivalirudin crude product. The preparation method comprises the following steps of: (1) mixing Fmoc-amino-acid resin or Fmoc-polypeptide resin and an unprotecting agent and removing Fmoc protecting group; (2) in the existence of a condensing agent, leading amino acid with Fmoc or Boc and amino acid or polypeptide onthe resin to carry out condensation; (3) repeating the step (1) and step (2) and obtaining polypeptide resin shown as formula II; and (4) in the existence of a cutting agent, leading the polypeptide and the resin on the polypeptide resin to be separated, and obtaining bivalirudin shown as formula I. The unprotecting agent contains 3 to 20 percent of piperidine and 0.5 to 10 percent of bicyclic amidine by total volume.

The present invention relates to a process for the production of bivalirudin, a 20-mer peptide of formula H-D-Phe1-Pro-Arg-Pro-Gly5-Gly-Gly-Gly-Asn-Gly10-Asp-Phe-Glu-Glu-lle15-Pro-Glu-Glu-Tyr-Leu20-OH (I) via a convergent five-fragment synthesis, and to several peptide intermediates thereof.

The invention discloses a preparation method of polypeptide solid-phase synthesis Bivalirudin, comprising the following steps of: (1) condensing Fmoc-Asn(Trt)-Gly-OH with a polypeptide resin shown as the formula V in the presence of a condensing agent to obtain a polypeptide resin shown as the formula III; (2) mixing the polypeptide resin shown as the formula III with a deprotection agent to remove a Fmoc protective group; (3) condensing Fmoc-Gly-Gly-Gly-Gly-OH with a polypeptide resin shown as the formula VI in the presence of the condensing agent to obtain a polypeptide resin shown as the formula IV; (4) sequentially condensing polypeptide of the polypeptide resin shown as the formula IV with amino acids from the end C to the end N according to the sequence from Pro to Arg, Pro and to D-Phe by a method of solid-phase synthesis so as to prepare a polypeptide resin shown as the formula II; and (5) separating polypeptide and resin on the polypeptide resin shown as the formula II in thepresence of a separating agent to obtain Bivalirudin shown as the formula I.

Ready-to-use bivalirudin compositions, methods of using the ready-to-use bivalirudin compositions, and methods of preparing the ready-to-use bivalirudin compositions. The ready-to-use bivalirudin compositions comprise bivalirudin and one or more stabilizing agents. The one or more stabilizing agents may be buffering agents having a pKa of about 2.5 to about 6.5, pH-adjusting agents, polymers, preservatives, antioxidants, sugars or polyols, or a combination thereof. The ready-to-use bivalirudin compositions may also comprise [9-10]-cycloimido bivalirudin, [11-12]-cycloimido bivalirudin, or a combination thereof. The method of using the ready-to-use bivalirudin compositions comprises administering the ready-to-use compositions to a patient in need thereof. Further, the method of preparing the ready-to-use bivalirudin compositions comprises mixing bivalirudin with one or more stabilizing agents.

The present invention relates to compositions and methods for cell transplantation. In particular, the present invention provides a composition comprising procoagulant cells and at least one factor Xa inhibitor, preferably rivaroxaban, as well as at least one thrombin inhibitor, preferably bivalirudin.

Pharmaceutical batch(es) or pharmaceutical formulation(s) comprising bivalirudin as the active ingredient, and a method of preparing the pharmaceutical batch(es) or pharmaceutical formulation(s). The pharmaceutical batch(es) or pharmaceutical formulation(s) may have a maximum impurity level of Asp9-bivalirudin that does not exceed about 0.6%. Also, the pharmaceutical batch(es) or pharmaceutical formulation(s) may have a reconstitution time that does not exceed about 42 seconds. The method of preparing the pharmaceutical batch(es) or pharmaceutical formulation(s) may comprise dissolving bivalirudin in a solvent to form a first solution, efficiently mixing a pH-adjusting solution with the first solution to form a second solution in which the pH-adjusting solution may comprise a pH-adjusting solution solvent, and removing the solvent and the pH-adjusting solution solvent from the second solution.

A method for preventing the formation of a bivalirudin precipitate during preparation of a pharmaceutical drug product comprising about 250 mg of bivalirudin, a dried bivalirudin drug product, and a concentrated liquid bivalirudin drug product. The method for preventing the formation of a bivalirudin precipitate comprises (i) preparing an aqueous solution comprising a buffer and a pH greater than the isoelectric point of bivalirudin; (ii) adding bivalirudin salt to the aqueous solution to form a bulk solution; (iii) transferring the bulk solution to one or more vessels; and (iv) drying the bulk solution. The buffer may have a pKa of about 4 to less than 7, and a pH greater than the isoelectric point of bivalirudin. The pH of the bulk solution may be maintained at a level greater than the isoelectric point of bivalirudin. Further, the bulk solution may have a final pH of about 4 to about 7.

The present invention is directed to the following: methods of treating or preventing stent thrombosis using pharmaceutical compositions comprising cangrelor and optionally bivalirudin; methods of reducing mortality in a subject undergoing stent implantation using pharmaceutical compositions comprising cangrelor and optionally bivalirudin; medicaments comprising cangrelor and optionally bivalirudin useful for treating or preventing stent thrombosis, or useful for reducing mortality in a subject undergoing stent implantation; pharmaceutical compositions comprising cangrelor and bivalirudin; and methods of preparing a medicament comprising cangrelor and optionally bivalirudin useful for treating or preventing stent thrombosis, or useful for reducing mortality in a subject undergoing stent implantation.

The invention discloses an anticoagulant polypeptide, belonging to the field of biomedicine. The primary structure of the anticoagulant polypeptide is shown as the general formula: (D)-FPRP-X1-X2-X3-X4-X5-QGDFEPIPEDAYDE-NH2. The invention has the advantages that the invention designs and synthesizes one type of anticoagulant polypeptide according to the structure characteristics and action mode of thrombin and Bivalirudin which is anticoagulant drug, and the polypeptide can inhibit the activity of the thrombin efficiently and specifically; furthermore, the number of amino acid in the anticoagulant polypeptide is equal to that of the Bivalirudin, thus synthesis is easy, and the activity of anticoagulation is stronger.

A method for producing bivalirudin using solid phase peptide synthesis by the following steps: a) mixing a Fmoc-amino acid resin or a Fmoc-peptide resin with a de-protective agent so as to remove Fmoc-; b) in the presence of a condensing agent, condensing a Fmoc- or Boc-amino acid with the amino acid or the peptide bound to the resin; c) repeating the steps a) and b) to yield a peptide resin represented by Formula I,(SEQ ID NO. 1)Boc-D-Phe1-Pro2-Arg(Pbf)3-Pro4-Gly5-Gly6-Gly7-Gly8-Asn(Trt)9-Gly10-Asp(OtBu)11-Phe12-Glu(OtBu)13-Glu(OtBu)14-Ile15-Pro16-Glu(OtBu)17-Glu(OtBu)18-Tyr(tBu)19-Leu20-Resin (I)and d) in the presence of a cleavage agent, separating the peptide from the resin to yield bivalirudin represented by Formula II (SEQ ID NO. 2).D-Phe-Pro-Arg-Pro-Gly-Gly-Gly-Gly-Asn-Gly-Asp-Phe-Glu-Glu-Ile-Pro-Glu-Glu-Tyr-Leu (II)Based on its total volume, the de-protective agent is composed of between 3 and 20% of piperidine and between 0.5 and 10% of bicyclic amidine. The method is low in cost and the resultant bivalirudin has high purity.