34 results about "Brivaracetam" patented technology

The invention relates to the technical field of medicines, in particular to a briracetam oral solution and a preparation method thereof. According to the present invention, by adjusting the formula and the preparation process of the oral solution of the briracetam, the stability of the briracetam is effectively improved, the antibacterial effect is effectively improved without adding the preservative, the taste of the oral solution is adjusted, and the medication compatibility of children patients is improved.

The present invention relates to a dual-release tri-layer tablet for brivaracetam, which is composed of three layers: an immediate-release layer, a barrier layer, and a sustained-release layer, wherein the barrier layer is drug-free and located in the center, and at least 75% of the area of ​​each of the immediate-release layer and sustained-release layer is covered by the barrier layer, and the sustained-release material in the barrier layer comprises a wax-like sustained-release material. The tablet has the following properties: after administration of the tablet, the drug substance dissolves at a rate of 25% or more within 30 minutes, 30-65% within 2 hours, 65% or more within 6 hours, and 80% or more but less than 100% within 14 hours, when measured by the paddle method at a rotation speed of 50 rpm in test solutions of pH 1.2, pH 4.5, pH 6.8, or water; and the tablet also shows zero-order release 30 minutes after administration, thereby significantly improving the release profile of the drug brivaracetam, enhancing compliance and safety, and optimizing the therapeutic effect of the drug. The present invention also relates to a dual-release tri-layer tablet for brivaracetam, and a method for preparing the same, which belong to the pharmaceutical technology.

The present application discloses a method for preparing a brivaracetam solution and the brivaracetam solution thereof, belonging to the field of medical technology. The method for preparing the brivaracetam solution comprises the following steps: (1) preparing solution 1: mixing a mixture including sodium carboxymethylcellulose and glycerol with purified water and stirring to obtain solution 1; (2) preparing solution 2: mixing purified water, methylparaben, sodium malate, malic acid, sucralose, crystalline sorbitol solution, brivaracetam, and glycerol and stirring to obtain an intermediate solution, mixing the intermediate solution with essence and stirring to obtain solution 2; (3) mixing solution 1, solution 2 and purified water, stirring, and filtering to obtain a brivaracetam solution. The method improves the clarity of the solution by controlling the order and temperature of addition of each auxiliary material, and the obtained brivaracetam solution has good stability and is free of precipitation and degradation impurities.

Disclosed is a method for enzymatic synthesis of a brivaracetam chiral intermediate, i.e., a method for synthesizing a brivaracetam chiral intermediate (R)-3-cyanohexanoic acid by catalyzing the hydrolysis of 3-cyanohexanitile using an enzyme with nitile hydrolysis activity, and the enzyme with nitrile hydrolysis activity is obtained by carrying out a single mutation or a double mutation on an amino acid at position 140 or an amino acid at position 175 in an amino acid sequence as set forth in SEQ ID NO.2. Compared with a wild type, the nitrilase mutant of the present invention has the activity increased by 10 times, an ee value increased to 300 or more from 39, a substrate conversion rate of 45%, and a product ee which can reach 98.5%, and the yield of (R)-3-aminomethyl-hexanoic acid by catalytic hydrogenation synthesis using (R)-3-cyanohexanoic acid reaches 85% or more. The present invention features a short synthesis route, mild reaction conditions, and high atom economy, and can be applied to the industrial synthesis of the brivaracetam intermediate.

The present disclosure relates to a preparation method of brivaracetam or a pharmaceutically acceptable salt thereof, which has short reaction time, good yield and high purity, and is suitable for industrial production.

A brivaracetam pharmaceutical composition contains an active pharmaceutical ingredient, a matrix forming agent, and a swelling agent. It has a sustained release effect and has a more flat release curve compared with a common gel skeleton sustained-release preparation, and thus achieves the purposes of reducing the release rate of the medicament, controlling the in vivo effective dosage of the medicament, stabilizing the blood concentration, reducing toxic and side effects and reducing the times of daily administration.

The present application relates to a kind of high stability's bexontan solution, with 0.1-10% bexontan, 20-50% high molecular material and buffer solution in bexontan solution with mass volume percentage, wherein, the high molecular material is selected from any one or combination of polymethyl methacrylate, cyclodextrin, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, the buffer solution is selected from any one of citric acid buffer solution, phosphate buffer solution, malic acid buffer solution, succinic acid buffer solution, tartaric acid buffer solution, lactic acid buffer solution, acetic acid buffer solution, bexontan solution pH4-7.5.The bexontan solution of the present application significantly delays the diffusion of drug bitter taste in oral cavity and realizes taste masking, and has excellent stability, more optimal cost, quality controllable, good taste and the like advantages.

The present application provides a polymer of a compound shown in formula I, or a copolymer of the compound shown in formula I as a monomer and a monomer containing a carbon-carbon double bond as an adhesive of a gel patch adhesive ointment layer. The gel patch adhesive ointment prepared by the present application has excellent adhesion, good compatibility with the active drug brivaracetam, and good drug release behavior, and has a wide application prospect.

The invention discloses a liquid chromatographic analysis method for isomer impurities in a briracetam intermediate, which comprises the following steps: step 1, mixing a briracetam intermediate (compound 1) sample with a diluent to prepare a sample solution; and 2, detecting the sample solution by using high performance liquid chromatography so as to determine the content of isomer impurities in the sample of the compound 1. According to the method, normal-phase high-performance liquid chromatography is adopted, and normal hexane and isopropanol are used as mobile phases, so that the elution strength is improved, and the separation capacity is improved. By adopting gradient elution, the separation capacity is improved, the peak shape is improved, and the sensitivity is increased.

To provide therapeutic approaches for treating epileptogenesis associated with a brain insult, e.g., traumatic brain injury (TBI), stroke, or brain infection.SOLUTION: Provided are liquid pharmaceutical compositions including topiramate or a pharmaceutically acceptable salt thereof, meglumine, and a pharmaceutically acceptable excipient, the liquid pharmaceutical compositions optionally further including, e.g., levetiracetam or brivaracetam and / or atorvastatin or a pharmaceutically acceptable salt thereof (e.g., atorvastatin sodium).SELECTED DRAWING: Figure 1

The invention discloses a briracetam orally disintegrating tablet and a preparation method thereof, and belongs to the technical field of biological medicines. The briracetam orally disintegrating tablet is prepared from the following components in parts by mass: 10 to 50 parts of a briracetam cyclodextrin inclusion compound, 10 to 87 parts of a filling agent, 1 to 20 parts of a disintegrating agent, 1 to 10 parts of a lubricating agent and 1 to 10 parts of a flavoring agent. According to the preparation method disclosed by the invention, the defect of poor flowability of the briracetam is effectively improved by a process of firstly preparing the cyclodextrin inclusion compound of the briracetam and then pressing the inclusion compound into the tablet; performance inspection on the tablets shows that the tablets have the characteristic of rapid disintegration accidentally, and the stability is remarkably improved.

The invention discloses an olefin reductase SeER mutant and application thereof in synthesis of chiral drugs, and provides a series of novel olefin reductase SeER mutants capable of efficiently and asymmetrically reducing beta-alkyl / aryl-beta-cyanoacrylate compounds, and the olefin reductase SeER mutants have high conversion rate (gt; 99% conversion rate), good enantioselectivity (gt; 99% ee), the substrate range is wide (gt; according to the present invention, the screened olefin reductase SeER mutant can be successfully synthesized into the chiral GABA derivative drugs such as pregabalin and brivaracetam through the chemical-enzyme coupling method, such that the overall reaction yield is improved, and the route is simple;

The application discloses a kind of brivaracetam injection pharmaceutical equipment, pharmaceutical method and its medicine, specifically related to pharmaceutical technical field, the rolling plate of the rolling assembly of the present application, the ball on the surface of rolling plate, the solid medicinal materials on the bottom of placing barrel are rolled at multiple angles, so that the drug liquid in solid medicinal materials is fully rolled out, then better complete the separation between drug liquid and solid medicinal materials.In addition, the present application also includes pharmaceutical equipment, wherein the medicine manufactured by the brivaracetam injection pharmaceutical equipment, brivaracetam is a levetiracetam analogue, and the affinity for SV2A is 13 times that of levetiracetam, the dosage is about one tenth of levetiracetam, the side effects are lower than levetiracetam, and the dosage is usually 25-100mg / day.The brivaracetam injection of the present application is stable in nature, safe and effective.

The present disclosure provides intermediates used for preparing Brivaracetam, a preparation method and a use thereof, including an intermediate compound A and an intermediate compound B and a preparation method thereof, as well as a synthetic route for using the intermediate compound B to prepare Brivaracetam. The present technical solution can obtain high-quality and high-optical purity Brivaracetam and intermediates thereof, the proportion of Brivaracetam among the four optical isomers being greater than 99.5%. In addition, neither silica gel column for separation and purification nor expensive chiral high performance liquid chromatography for resolution is required, thereby avoiding cumbersome separation and purification steps, also avoiding waste of raw materials, reducing the production cost and making it more suitable for industrial production.

The invention relates to a brivaracetam intermediate and a novel preparation method of brivaracetam, and belongs to the field of pharmaceutical chemicals. Specifically, the invention provides a novel preparation method of a brivaracetam key intermediate compound shown as a formula V-a, and R is a straight chain or branched chain alkyl group with the carbon atom number of 1-6; the method has the technical advantages of high product chiral purity, mild reaction and the like.

The invention discloses a method for preparing brivaracetam by converting an intermediate shown in # imgabs0 # into an intermediate shown in # imgabs1 #. Wherein R1 and R2 are independently selected from hydrogen, alkali metal, alkaline earth metal, alkyl or a mixture thereof.

The present invention belongs to the field of biocatalyst technology and discloses an alkene reductase mutant and its use in catalyzing the preparation of a brivaracetam synthetic intermediate. The amino acid sequence of the alkene reductase mutant of the present invention is shown in SEQ ID NO.1. The mutant, carbonyl reductase K1, and glucose dehydrogenase form a composite enzyme that can use the compound 5-hydroxy-4-n-propyl-2-furanone as a substrate, reduce double bonds and remove hydroxyl groups to obtain the compound (R)-4-propyldihydrofuran-2(3H)-one. The catalytically obtained (R)-4-propyldihydrofuran-2(3H)-one has an ee value of 93.0%, and can further obtain (R)-4-propyldihydrofuran-2(3H)-one with an ee value greater than 99.8% through diastereoisomer crystallization. The complex enzyme can be used for the efficient and green preparation of (R)-4-propyldihydrofuran-2(3H)-one, a key intermediate of brivaracetam.

The application belongs to the field of chemical medicine preparation and relates to a preparation method of brivaracetam. The brivaracetam is prepared from 3-alkenyl pyrrolidone through an asymmetric Michael addition reaction, a substitution reaction, an aminolysis reaction and the like. The method has high stereoselectivity, does not need to purchase chiral raw materials, and can obtain the brivaracetam with high yield and high purity by using common raw materials.

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a briracetam oral soluble film and a preparation method thereof. The composition provided by the invention comprises an active component, namely, the distriburacetam, a film-forming agent, a crystal inhibitor and the like, and the film-forming agent is selected from a combination of polyvinyl alcohol and hydroxypropyl cellulose. The composition provided by the invention has better in-vivo bioavailability, overcomes the defects of conventional oral solid and liquid preparations, is very suitable for administration of epilepsy patients, particularly greatly improves the compliance of the patients, and has better economic benefits and social benefits.

The present application relates to the technical field of drug synthesis, and in particular to a preparation method of brivaracetam and application thereof. By adjusting the modification group of the amide in the dihydropyrrolone intermediate I to S-tert-butylsulfinyl, the chiral induction ability of the substrate is greatly improved. The asymmetric hydrogenation of the dihydropyrrolone intermediate I can be completed by using an achiral catalyst, i.e. the pyrrolidone intermediate II can be prepared in high diastereoselectivity (diastereomer ratio dr=99.8:0.2) and high yield (yield 90%), and the method is easy to operate, the reaction condition is simple, the synthesis route is short, the total yield is high, sodium / liquid ammonia or magnesium / ultrasound is not needed, and the method is suitable for industrial production.

The invention belongs to the technical field of medicine quality detection, and particularly relates to a method for detecting the content of isomers in a briracetam oral solution. The detection method provided by the invention comprises the following steps: preparing a solution, adopting a high performance liquid chromatography, and detecting by connecting a chromatographic column 1 and a chromatographic column 2 in series and combining with a valve switching path; the chromatographic conditions of the high performance liquid chromatography comprise a chromatographic column 1 and a chromatographic column 2; a mobile phase A is an organic acid solution; a mobile phase B is acetonitrile; the elution mode is gradient elution; the valve switching setting is as follows: the chromatographic column 1 is connected into a main passage, the chromatographic column 2 and the two-way valve are respectively connected into parallel channels, the channel of the chromatographic column 2 is used at 6min and 20min, and the two channels are used at 9min and 50min. The method for detecting the content of the isomer in the Briracetam oral solution, provided by the invention, is high in sensitivity, has good specificity, system applicability and solution stability, and provides an effective prescription analysis method for drug development.

This invention discloses a briceceran sustained-release tablet and its preparation method, belonging to the field of pharmaceutical formulations. This invention aims to solve the problems of food effect, release instability, and processability issues associated with briceceran sustained-release tablets. Technical solution: A tablet-within-a-tablet structure is adopted, with the sustained-release core containing a composite hydroxypropyl methylcellulose (high / medium viscosity mixture) and micronized ethyl cellulose, and the immediate-release outer layer containing a disintegrant; the preparation includes ethanol granulation and compression steps. Technical effects: Achieves stable drug release over 24 hours, with a postprandial / fasting release difference of <3%, avoiding dose dumping, while improving flowability and hardness by 53%, suitable for industrial production.

The present invention belongs to the technical field of biocatalysts. Disclosed are an alkene reductase mutant and the use thereof in the catalytic preparation of an intermediate for the synthesis of brivaracetam. The amino acid sequence of the alkene reductase mutant of the present invention is as shown in SEQ ID NO. 1. A compound enzyme composed of the mutant, carbonyl reductase K1 and glucose dehydrogenase can, with the compound 5-hydroxy-4-n-propyl-2-furanone as a substrate, reduce double bonds and remove hydroxyl, so as to obtain the compound (R)-4-propyl dihydrofuran-2(3H)-one; and the ee value of the (R)-4-propyl dihydrofuran-2(3H)-one obtained by means of catalysis reaches 93.0%, and (R)-4-propyl dihydrofuran-2(3H)-one having an ee value of greater than 99.8% can be further obtained by means of the crystallization of diastereoisomers.

The application discloses a nitrilase mutant and application thereof in synthesis of a chiral intermediate of brivaracetam, and establishes a high-efficiency (R)-3-cyanohexanoic acid nitrilase synthesis process by constructing a nitrilase mutant with improved catalytic activity and stereoselectivity, so that the demand for industrial synthesis of a key chiral intermediate of brivaracetam is met, and a foundation is laid for industrial production of brivaracetam synthesized by a chemical-enzyme method.

The invention relates to the technical field of pharmaceutical preparations, in particular to a briracetam sustained-release micro-tablet and a preparation method thereof. Compared with the commercially available buxiracetam quick-release tablet, the buxiracetam sustained-release micro-tablet disclosed by the invention has the advantages that the size and the volume are greatly reduced, the buxiracetam sustained-release micro-tablet is easier to swallow by a patient, and the buxiracetam sustained-release micro-tablet only needs to be taken once every day, so that the medication compliance of epilepsy patients is greatly improved, and the individualized medication requirement is greatly met. According to the invention, the sustained-release coating is coated on the outer layer of the tablet core, so that a stable membrane control mechanism is realized by the briracetam sustained-release micro-tablet, a long-acting and stable release effect is achieved, factors for controlling release of the briracetam sustained-release micro-tablet are few, the release performance of the briracetam sustained-release micro-tablet and the quality of a product can be better and more stably controlled, and the briracetam sustained-release micro-tablet is suitable for industrial production. And the production process of the product is simple and controllable.

The present disclosure relates to a double-release three-layered brivaracetam tablet and a preparation method thereof, belonging to pharmaceutical technology, which is characterized in that the tablet is made of an immediate-release layer, a retarding layer and a sustained-release layer that are superposed; where the retarding layer contains no drug and is located in the middle; at least 75% of an surface area of each of the immediate-release layer and the sustained-release layer which is in contact with the retarding layer is covered by the retarding layer, and a sustained-release material in the retarding layer contains a waxy sustained-release material; and the tablet has the following characteristics: when tested using the paddle method at 50 rpm in media of pH 1.2, pH 4.5, pH 6.8, or water, not less than 25% of the API is released within 30 minutes, 30-65% within 2 hours, not less than 65% within 6 hours, and not less than 80% but less than 100% within 14 hours. After 30 minutes, the release follows a zero-order kinetic profile. This formulation significantly improves the release characteristics of brivaracetam, enhances medication compliance and safety, and optimizes its therapeutic effect.

The invention relates to the technical field of organic chemistry, in particular to a method for purifying a melogabalin besylate key intermediate, which comprises the following steps: firstly, decolorizing for 1-3 hours in a 0.5-1 mol / L organic solution at 45-65 DEG C by using 2-10% activated carbon to effectively remove colored impurities, trace isomers and unknown byproducts and remarkably improve the initial purity and appearance of the intermediate; then, for the chiral salt intermediate, carrying out temperature-controlled pulping at 15-35 DEG C by using an organic solvent of which the volume is 10-20 times that of the chiral salt intermediate, so that residual non-salified impurities and inorganic salt are dissolved in the solvent, and the target intermediate is separated out in a uniform crystal form, thereby deeply removing the residual impurities; the two-step method is mild in condition and simple and convenient to operate, the chemical and optical purity of the intermediate is synergistically improved, and the yield, quality and process stability of melogabalin besylate in subsequent synthesis are guaranteed.

This invention belongs to the field of pharmaceutical quality testing technology, specifically relating to a method for detecting isomer content in briracetam oral solution. The detection method of this invention involves preparing a solution and employing high-performance liquid chromatography (HPLC) using chromatographic columns 1 and 2 connected in series and a valve-switched flow path. The HPLC chromatographic conditions include: column 1, column 2; mobile phase A: organic acid solution; mobile phase B: acetonitrile; elution mode: gradient elution; valve switching settings: column 1 is connected to the main flow path, and column 2 and the two separate channels are connected to parallel channels. The column 2 channel is used at 6 and 20 min, and the two separate channels are used at 9 and 50 min. The method for detecting isomer content in briracetam oral solution provided by this invention has high sensitivity, good specificity, system applicability, and solution stability, providing an effective prescription analysis method for drug development.

The application provides a method for detecting impurities of brivaracetam injection by using a non-salt mobile phase system combined with reversed-phase liquid chromatography, the detection method is detected by using an HPLC method, and the mobile phase system is a mixed solution of a phosphoric acid solution and acetonitrile, wherein in the mixed solution, the volume percentage of acetonitrile is 30%-45%, and the concentration of the phosphoric acid solution is greater than or equal to 0.05%; the chromatographic column is a chiral column containing tris(4-chloro-3-methylphenyl aminomethyl ester). By using the above detection method, the related substances and isomers of brivaracetam can be separated and determined in the same analysis method, and the blank excipients do not interfere with the detection of the above components.