102 results about "Clevidipine" patented technology

The invention discloses a method for preparing butyrate clevidipine. The method comprises that 2, 3-dichlorobenzaldehyde, acetoacetate propionitrile ester and 3-amino-2-methyl crotonate are mixed and one-pot Hantzsch reaction is conducted, base catalyst is added to remove 2-cyanoethyl to obtain key intermediate, the key intermediate reacts with n-butyric acid chloromethyl ester to obtain butyrate clevidipine crude product, and the crude product is recrystallized to obtain high-purity butyrate clevidipine. Raw material 3-amino-2-methyl crotonate can be prepared by using low-price methyl acetoacetate. Raw material acetoacetate propionitrile ester can be prepared by using diketene. The synthesis of all raw materials requires no chromatographic separation for purification. The intermediate is synthesized through one-pot Hantzsch reaction, the reaction speed is fast, the condition is mild, the technological reliability is high and the purity of the intermediate is high. The conditions for the reaction of the key intermediate and the n-butyric acid chloromethyl ester can be easily controlled, the operation is simple and convenient, the cost is low, the post treatment requires no chromatographic separation for purification, the purity of the obtained butyrate clevidipine is above 99.5 percent and the mass production can be realized.

The invention relates to a preparation method of 4-(2, 3-dichlorophenyl)-2, 6-dimethyl-1, 4-dihydro-5-methoxylcarbonyl-3-pyridinecarboxylic acid (I). The method is characterized in that methyl acetoacetate, stronger ammonia water and 2, 3-dichlorobenzaldehyde are used as raw materials for direct cyclic condensation to obtain 4-(2, 3-dichlorophenyl)-2, 6-dimethyl-1, 4-dihydro-3, 5-pyridinedicarboxylic acid methyl ester (II); part of the compound II is hydrolyzed under alkaline condition to obtain the product 4-(2, 3-dichlorophenyl)-2, 6-dimethyl-1, 4-dihydro-5-methoxylcarbonyl-3-pyridinecarboxylic acid (I). The method has the advantages that the starting materials are cheap and easy to obtain, the production cost is lowered, the reaction is easy to operate and industrialization is easy to realize.

Pharmaceutical formulations comprising clevidipine and an antimicrobial agent exhibit a reduced propensity for microbial growth and provide increased convenience to health care workers administering clevidipine-containing formulations to patients.

The invention discloses to an emulsion containing clevidipine and a preparation process and application thereof, relating to the emulsion utilizing the clevidipine and pharmaceutically acceptable salt or hydrate as active ingredients and the preparation process and the application thereof. The emulsion used for vein injection, which utilizes the clevidipine and the pharmaceutically acceptable salt or hydrate as the active ingredients, is formed by carrying out a certain preparation process on the active ingredients and pharmaceutically acceptable auxiliary materials, and can be used for rapid depressurization during and after a surgery. In the invention, the clevidipine and the pharmaceutically acceptable salt are taken as the active ingredients and some auxiliary materials with specific varieties and ratios are added, thus the emulsion for vein injection is developed according to the preparation process explained by the patent.

The invention discloses a lipid nanosuspension containing clevidipine butyrate, and a freeze-drying preparation of the lipid nanosuspension. A preparation method comprises the following steps that (1) a surfactant is dispersed in an aqueous solution to form a solution A; (2) the clevidipine butyrate is dispersed in the solution A obtained in Step (1) to form a suspension solution B; (3) the suspension solution B is cut for 1-5min at a high speed to form a first emulsion C; (4) the first emulsion C is subjected to high-pressure homogenization treatment, and the clevidipine butyrate lipid nanosuspension is obtained; (5) a freeze-drying protective agent is added to the nanosuspension, and filtration and sterilization are performed; (6) freeze-drying is performed, moisture is removed, and the freeze-drying preparation of the clevidipine butyrate lipid nanosuspension is obtained. The lipid nanosuspension and the freeze-drying preparation are free of any organic solvent and long chain triglyceride or medium chain triglyceride, high in safety, low in toxic and side effects, high in drug loading capacity, good in stability and free from drug leakage; and meanwhile, a preparation technology is simple, and the repeatability is good, and the industrial production can be realized.

A composition having clevidipine as an active ingredient is described. The composition includes clevidipine as an active ingredient and an amount of the impurity H168/79 that is no greater than about 1.5%, or where the ratio between clevidipine and H168/79 is equal or above 60 to 1.

The invention relates to a therapeutic emulsion of clevidipine butyrate. The emulsion comprises clevidipine butyrate, a lipid phase, an emulsifier, and water or a buffer. The invention also relates to a purpose and a preparation method of the emulsion.

Pharmaceutical compositions, and a method of stabilizing pharmaceutical compositions having clevidipine, or any pharmaceutically acceptable salt thereof, as the active ingredient is described. The method includes the slowing down or inhibiting of the oxidation pathway of clevidipine. This can be accomplished by reducing the amount the pharmaceutical composition is exposed to oxygen and/or light during the manufacturing and storing processes. According to this method, oxygen must be removed or replaced, or light must be sufficiently blocked such that light energy cannot reach the active ingredient of the composition, or is reduced to a level that the light-induced oxidation reaction converting clevidipine to H324/78 is minimized, such that the total detectable level of H324/78 in a given composition sample does not exceed about 0.2% on a weight-by-weight basis, or the ratio of clevidipine to H324/78 is equal to or greater than about 450 to 1 on a weight-to-weight basis.

The invention relates to a clevidipine butyrate structured lipid emulsion which comprises clevidipine butyrate, structured triglyceride, an emulsifier, an isotonic agent, a pH regulator, and injection water, wherein the weight volume percentage of clevidipine butyrate is 0.05-0.1% (w/v); the weight volume percentage of structured triglyceride is 5-30% (w/v); the weight volume percentage of the emulsifier is 1.0-2.0% (w/v); and the weight volume percentage of the isotonic agent is 1.0-5.0% (w/v).

The invention discloses a method for detecting clevidipine butyrate and related substances in preparations of the clevidipine butyrate. The method is characterized in that gradient elution is carried out by virtue of a C18 chromatographic column by taking methanol-acetonitrile-phosphate buffer salt solution as a mobile phase according to a reversed-phase high-performance liquid chromatography and an ultraviolet detector is used. By means of the method, effective separation of the clevidipine butyrate from all known impurities can be realized; interference of various impurities generated in the synthesis and preparation production processes to the purity of products can be avoided; the quantity of the clevidipine butyrate or preparations can be controlled comprehensively and effectively; the method is simple to operate and high in specificity and sensitivity and is capable of well detecting the clevidipine butyrate and related substances in the preparations; and an effective and reliable analysis method is provided for quality control of research, development and production processes.

The invention discloses a clevidipine butyrate emulsion and a preparation method thereof. The clevidipine butyrate emulsion includes an oil phase and a water phase. The oil phase comprises clevidipine butyrate, long-chain oil and a stabilizer. The water phase comprises an emulsifier and water. A mass ratio of the oil phase and the water phase is 1:11-1:1. The clevidipine butyrate accounts for 0.05-0.5% of the total mass of the clevidipine butyrate emulsion; the long-chain oil accounts for 10-50% of the total mass of the clevidipine butyrate emulsion; the stabilizer accounts for 0.01-0.5% of the total mass of the clevidipine butyrate emulsion; and the emulsifier accounts for 0.5-5.0% of the total mass of the clevidipine butyrate emulsion. The water phase can also include a metal ion chelating agent and/or an isotonic agent. The emulsion can also include a pH adjusting agent. The clevidipine butyrate emulsion is safe and effective, is less in adverse reactions, is high in drug encapsulation efficiency, is good in storage stability, is controllable in preparation processes and is low in contents of impurities. The method is easy to industrially control.

The invention discloses a clevidipine butyrate freeze-dried emulsion, and belongs to the field of a pharmaceutical preparation. The freeze-dried emulsion is prepared from clevidipine butyrate, glycerol, an acidity regulator, a stabilizing agent, a freeze-drying protecting agent, injection oil, a water-phase surfactant and an oil-phase surfactant. The clevidipine butyrate freeze-dried emulsion disclosed by the invention is free from high-temperature sterilization, and is under a dry state in the storage process; compared with other clevidipine butyrate dosage forms, the clevidipine butyrate freeze-dried emulsion has characteristics of good stability, low toxic and side effects, good curative effect, and the like, and is better applicable to critical injection; and the emulsion has great popularization and application values.

The invention relates to a method and compounds for the preparation of clevidipine butyrate, a very short acting hypertensive calcium antagonist, as well as the synthesis of these compounds useful for the preparation of clevidipine (also known as clevidipine butyrate). Moreover the invention also discloses polymorphic forms of clevidipine butyrate, useful for the preparation of pharmaceutical compositions, and processes to prepare them.

The invention relates to a method for preparing clevidipine butyrate and also relates to a method for preparing 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-methoxycarbonyl-3-picolinic acid methyl ester (an intermediate I) and 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-methoxycarbonyl-3-pyridine carboxylic acid (an intermediate II) which are used as intermediates of the clevidipine butyrate. The intermediate I is prepared by using 2,3-dichlorobenzaldehyde, ammonium acetate and methyl acetoacetate as raw materials and performing a reaction by using ultrasound. The intermediate II is prepared by carrying out enzyme hydrolysis on the intermediate I. When the clevidipine butyrate is prepared by using the method disclosed by the invention, ammonia water is not used as the raw material, so that no irritant gas is generated. Moreover, the cyclizative condensation is carried out by using ultrasonic waves and the hydrolysis is carried out by using carboxy lesterase, so that the reaction time can be shortened and the reaction yield is increased.

The invention belongs to the field of a pharmaceutical preparation, and in particular relates to a clevidipine butyrate injection. The injection comprises 0.01-10% of clevidipine butyrate, 0.1-10% of oil phase, 5-50% of phospholipid and 40-90% of organic solvent in percentage by weight. According to the invention, the clevidipine butyrate injection with good stability can be obtained, and the clevidipine butyrate can be used for lowering blood pressure during a surgery and after the surgery and when an oral therapy is not feasible or desirable. In comparison with the prior art, the clevidipine butyrate injection is always an anhydrous system in a storage process of the injection, the injection can be prepared on spot during use, thereby being capable of preventing an oxidation reaction of phospholipids and a degradation reaction of medicines, prolonging the preservation time of the preparation and improving the stability of the injection provided by the invention.

The invention discloses a clevidipine butyrate intralipid and a preparation method thereof. The intralipid comprises clevidipine butyrate active components, injection oil, an emulsifier, an isoosmotic adjusting agent, a pH adjusting agent and injection water, and also comprises a stabilizer, and the stabilizer is an electronegative phosphatide compound. The preparation method of the intralipid comprises the following steps: preparing an oil phase, preparing a water phase, mixing the prepared oil phase with the prepared water phase, shearing to form an crude intralipid, adding water to a constant volume, carrying out high pressure homogenization to obtain a finished intralipid, adjusting the pH value, filtering, carrying out nitrogen loading, and disinfecting. The addition of the electronegative phosphatide compound as the stabilizer in the invention improves the stability of the clevidipine butyrate intralipid, reduces the toxic side effects, ensures the use safety of the clevidipine butyrate intralipid, and has practical values.

The invention provides a preparation method of a sample used for HPLC detection of disodium edetate in a clevidipine butyrate injection emulsion. The preparation method comprises the following steps: adding an isopropanol and n-hexane mixed liquid into the clevidipine butyrate injection emulsion, shaking the mixed liquid and the emulsion, centrifuging the obtained solution, taking obtained water phase, and adding a metal ion salt solution able to complex edetic acid to form a complex in order to form a sample solution. The invention also provides a method for detecting disodium edetate in the clevidipine butyrate injection emulsion. The detection method is an HPLC method. An oil phase and a water phase in the clevidipine butyrate injection emulsion are effectively separated to make disodium edetate dissolved in the water phase be accurately detected. The detection method has the advantages of high detection sensitivity, good precision and high specificity, and is an effective method for strictly controlling the content of disodium edetate in the clevidipine butyrate injection emulsion.

The invention discloses an antihypertensive drug fat milk injection and a preparation method thereof. The antihypertensive drug fat milk injection is a clevidipine butyrate fat milk injection and contains clevidipine butyrate and a pharmacologically acceptable medical excipient; the medical excipient comprises an oil-phase medium, an emulsifier, an osmotic pressure regulator, a stabilizer, a metalcheating agent, a pH value regulator and injection water. The antihypertensive drug fat milk injection has stable quality and high safety and is not irritant to blood vessels.

The invention discloses a clevidipine butyrate liposome preparation and a preparation method thereof. The preparation includes 0.05wt%(wt%)-0.1%(wt%) of clevidipine butyrate, 40%(wt%) -70%(wt%) of phosphatidylcholine, 10%(wt%)-40%(wt%) of phosphatidyl glycerol, 10%(wt%)-30%(wt%) of sterol, and 0.55%(wt%)-3.3%(wt%) of stabilizer. The stabilizer contains a component A and a component B, wherein the component A is selected from one or more of oleic acid, sodium oleate, linoleic acid and sodium linoleate; and the component B is selected from one or more of vitamin E, coenzyme Q10, propyl gallate and ascorbyl palmitate. The liposome prepared by the method is in the form of liquid, and can be stored for a long time, therefore not only the potential safety hazard due to use of middle-chain and long-chain triglyceride in the traditional clevidipine butyrate emulsion is thoroughly solved, but also the freeze-drying operation in the traditional liposome preparation is omitted and the production cost is reduced; moreover, the liposome preparation is convenient for clinical application, overcomes the defect of uneven quality of redissolved freeze-drying liposome preparation and is beneficial to increase of the compliance and the medication safety of a patient.

The invention discloses a purification method of clevidipine butyrate The purification method comprises following steps: step A, an ethanol solution of clevidipine butyrate is prepared, and organic impurities are removed by crystallization purification; step B, crystals purified by ethanol are dissolved in acetonitrile, and then are precipitated by adding water so as to remove a large amount of inorganic impurities; and step C, the crystals purified by acetonitrile are dissolved in an ethanol solution with a concentration of 50 to 90% so as to remove a small amount of inorganic impurities. The products are dissolved completely by mixing the poor solvent with the good solvent so as to realize complete purification; the purity of clevidipine butyrate reaches 99.5%; and arsenic, lead and chloride indexes are all much lower than that of standards.