CN110840836A - Benzamide compound IMB16-4 nano suspension and preparation method thereof - Google Patents
Benzamide compound IMB16-4 nano suspension and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
Abstract
The invention discloses a benzamide compound IMB16-4 nano suspension and a preparation method thereof, wherein the IMB16-4 nano suspension comprises: bulk drug IMB16-4 and stabilizer; the stabilizing agent comprises one or more of hydrophilic materials and phospholipids; the preparation method comprises the following steps: weighing bulk drug IMB16-4 and stabilizer; dissolving a bulk drug IMB16-4 in a good solvent, then dripping the solution into a water solvent containing a stabilizer, and magnetically stirring to obtain milky suspension; centrifuging the suspension, taking a precipitate, and adding the precipitate into another part of water solvent containing a stabilizing agent for dispersion; carrying out ultrasonic crushing on the dispersed solution to obtain IMB16-4 nano suspension; the IMB16-4 nanosuspension was freeze-dried. The nanosuspension can remarkably improve the solubility, dissolution rate and bioavailability of an insoluble bulk drug IMB 16-4; and the nano suspension has large drug content, so that the dosage and times of drug administration can be reduced, adverse reactions are reduced, the drug safety is improved, and the nano suspension has good drug forming property.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, and in particular relates to a benzamide compound IMB16-4 nano suspension and a preparation method thereof.
Background
Cirrhosis is a type of advanced liver fibrosis disease with chronic liver damage caused by various factors, and the liver fibrosis is an intermediate process of chronic liver disease and liver damage, and is mainly characterized in that collagen is excessively deposited in the liver, and finally, a fibrous tissue rich in collagen replaces a normal liver tissue. Because early hepatic fibrosis is a reversible pathophysiological process, the method effectively regulates the progress of hepatic fibrosis, inhibits or even reverses the progress of hepatic fibrosis, and further treats cirrhosis. The treatment difficulty of the cirrhosis, high mortality rate and high economic cost are the main reasons of the health burden of the whole family. However, cholestatic liver fibrosis is difficult to treat, and an effective therapeutic drug is in urgent need in the market, especially, no new drug of this type is developed and marketed in China, and the existing related research units are few, so that development of related drugs is urgently needed to fill the gap.
The raw material medicine benzenesulfonamide benzamide compound N- (3, 4, 5-trichlorophenyl) -2 (3-nitrobenzenesulfonamide) benzamide (IMB 16-4 for short) is a new chemical entity which is independently developed by the applicant, has a unique mechanism and a remarkable effect and can resist cholestatic liver fibrosis. However, due to minimal dissolution of IMB16-4, bioavailability is low, resulting in higher doses to be administered.
In conclusion, the new medicine IMB16-4 is prepared into the nano suspension so as to achieve the aims of small toxic and side effect, good stability and increased medicine bioavailability. At present, no report about a new medicine IMB16-4 nanosuspension and a preparation method thereof is found.
Disclosure of Invention
Aiming at the defects in the problems, the invention provides a benzamide compound IMB16-4 nano suspension and a preparation method thereof.
The invention discloses a benzamide compound IMB16-4 nano suspension, which comprises the following components in percentage by weight: bulk drug IMB16-4 and stabilizer;
the stabilizer includes one or more of a hydrophilic material and a phospholipid.
As a further improvement of the invention, the weight ratio of the bulk drug IMB16-4 to the stabilizer is 2: 1-1: 7.
As a further improvement of the invention, the weight ratio of the bulk drug IMB16-4 to the stabilizer is 1: 1-1: 2.
As a further improvement of the invention, the stabilizer comprises one or more of hydroxypropyl cellulose, soybean lecithin, poloxamer 188, polyvinylpyrrolidone, sodium carboxymethyl cellulose, a polyoxyethylene type nonionic stabilizer and sodium lauryl sulfate.
As a further improvement of the invention, the stabilizer is polyvinylpyrrolidone.
The invention also discloses a preparation method of the nano suspension, which comprises the following steps:
weighing bulk drug IMB16-4 and stabilizer;
dissolving the bulk drug IMB16-4 in a good solvent, then dropwise adding the solution into a water solvent containing the stabilizer, and magnetically stirring to obtain an emulsion suspension;
centrifuging the suspension to obtain a precipitate, and adding the precipitate to another part of water solvent containing the stabilizer for dispersion;
carrying out ultrasonic crushing on the dispersed solution to obtain IMB16-4 nano suspension;
freezing and freeze-drying the IMB16-4 nano suspension.
As a further improvement of the invention, the good solvent is DMF solvent or DMSO solvent.
As a further improvement of the invention, the volume ratio of the good solvent to the water is 1: 10-1: 300.
As a further improvement of the invention, two aqueous solvents containing the stabilizer are equal in volume.
As a further improvement of the present invention, the ultrasonic pulverization is:
and (3) crushing the dispersed solution in an ultrasonic cell crusher, and treating for 10-30 min under the condition of 180W.
Compared with the prior art, the invention has the beneficial effects that:
the invention prepares the bulk drug IMB16-4 into the nano suspension, and the nano suspension is prepared by dispersing drug particles in water under the action of a stabilizer to form a stable nano dispersion. The nano suspension can remarkably improve the solubility, dissolution rate and bioavailability of the insoluble bulk drug IMB 16-4; and the nano suspension has large drug content, so that the dosage and times of drug administration can be reduced, adverse reactions are reduced, the drug safety is improved, and the nano suspension has good drug forming property.
Drawings
FIG. 1 shows the structural formula of IMB16-4 according to one embodiment of the present invention;
FIG. 2 is a particle size diagram of a nanosuspension disclosed in one embodiment of the invention;
FIG. 3 is a DSC chart of IMB16-4 bulk drug, nanosuspension, physical mixture and adjuvant disclosed in one embodiment of the present invention;
FIG. 4 is an X-ray diffraction pattern of one embodiment of the IMB16-4 drug substance, nanosuspension, and physical mixture disclosed herein;
fig. 5 is a graph of blood concentration versus time according to an embodiment of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
The invention provides a benzamide compound IMB16-4 nanosuspension and a preparation method thereof, wherein the IMB16-4 nanosuspension comprises the following components in percentage by weight: bulk drug IMB16-4 and stabilizer; the stabilizer comprises one or more of hydrophilic materials, phospholipids and other surfactants; the preparation method comprises the following steps: weighing bulk drug IMB16-4 and stabilizer; dissolving a bulk drug IMB16-4 in a good solvent, then dripping the solution into a water solvent containing a stabilizer, and magnetically stirring to obtain milky suspension; centrifuging the suspension, taking a precipitate, and adding the precipitate into another part of water solvent containing a stabilizing agent for dispersion; carrying out ultrasonic crushing on the dispersed solution to obtain IMB16-4 nano suspension; the IMB16-4 nanosuspension was freeze-dried. The invention prepares the bulk drug IMB16-4 into the nano suspension, and the nano suspension is prepared by dispersing drug particles in water under the action of a stabilizer to form a stable nano dispersion. The nano suspension can remarkably improve the solubility, dissolution rate and bioavailability of the insoluble bulk drug IMB 16-4; and the nano suspension has large drug content, so that the dosage and times of drug administration can be reduced, adverse reactions are reduced, the drug safety is improved, and the nano suspension has good drug forming property.
The invention is described in further detail below with reference to the attached drawing figures:
the invention provides a benzamide compound IMB16-4 nanosuspension, which comprises the following components in percentage by weight: bulk drug IMB16-4 and stabilizer; wherein:
the bulk drug IMB16-4 is a benzene sulfonamide benzamide compound N- (3, 4, 5-trichlorophenyl) -2 (3-nitrobenzenesulfonamide) benzamide, and the structural formula of the compound is shown in figure 1.
The stabilizing agent comprises one or more of hydrophilic materials, phospholipids and other surfactants, and further comprises one or more of hydroxypropyl cellulose, soybean lecithin, poloxamer 188, polyvinylpyrrolidone (K15, K17, K25, K30 and the like), sodium carboxymethyl cellulose, polyoxyethylene type nonionic stabilizing agent and sodium lauryl sulfate; a preferred stabilizer is polyvinylpyrrolidone.
In the preparation process of the IMB16-4 nanosuspension, the stability of the nanosuspension is reduced on the contrary by using too much hydrophilic material or phospholipids, but the agglomeration is easy to occur among particles by using too little hydrophilic material. Therefore, the weight ratio of the bulk drug IMB16-4 to the stabilizer is 2: 1-1: 7, preferably 1: 1-1: 2, obtained through a large number of experiments.
In the preparation of the IMB16-4 nanosuspension, the bulk drug IMB16-4 dissolved in an organic phase is added into a stabilizer dissolved in an aqueous phase, and the proportion of the organic phase and the aqueous phase can also influence the size and the stability of the particle size. Therefore, the volume ratio of the organic phase to the aqueous phase is 1: 10-1: 300 through a large number of experiments.
The invention provides a preparation method of a nanosuspension, which comprises the following steps:
s1, weighing the bulk drugs IMB16-4 and the stabilizer according to the mixture ratio.
S2, dissolving the bulk drug IMB16-4 in a good solvent, then dripping the solution into a water solvent containing a stabilizer, and magnetically stirring the solution to obtain milky suspension; the good solvent can be a DMF solvent or a DMSO solvent, the volume ratio of the DMF solvent or the DMSO solvent to the water solvent is 1: 10-1: 300, the particle size of the IMB16-4 nano suspension is related to the dropping speed, and the excessively slow particle size is increased; for this purpose, the dropping rate is adjusted as required.
S3, centrifuging the suspension, taking out the precipitate, and adding the precipitate into another equal volume of water solvent containing the stabilizing agent for dispersion.
S4, carrying out ultrasonic crushing on the dispersed solution to obtain IMB16-4 nanometer suspension; the ultrasonic crushing method comprises the following steps: and (3) crushing the dispersed solution in an ultrasonic cell crusher, and treating for 10-30 min under the condition of 180W.
S5, freezing and freeze-drying the IMB16-4 nano suspension.
The benzamide compound IMB16-4 nano suspension and the preparation method thereof have the following advantages:
the stabilizer used in the IMB16-4 nano suspension is a pharmaceutic adjuvant, has high safety, no irritation, no physiological toxicity and good biocompatibility. The preparation method of the ultrasonic cell crusher has simple and convenient preparation process;
the IMB16-4 nano suspension has uniform particle size; meanwhile, the prescription is different, and the particle sizes of the medicines are distributed in the range of 70-1000 nm; the drug solubility of the nanosuspension obtained in the following specific examples is 65.9 times that of the bulk drug, and the bioavailability is improved by 76.3 times; meanwhile, the IMB16-4 nano suspension is expected to reduce the dosage and improve the drug effect, and has excellent drug forming property.
The present invention will be described in further detail with reference to examples, which should not be construed as limiting the invention thereto.
Example 1
The prescription comprises the following components: IMB 16-40.01 g as main drug, 0.02g hydroxypropyl cellulose as stabilizer.
The specific operation is as follows:
IMB 16-40.01 g was weighed out and dissolved in 1ml of DMF or DMSO solvent, then added dropwise to 10ml of 0.1% hydroxypropyl cellulose solution and stirred magnetically to give a milky suspension. The milky suspension obtained by magnetic stirring was centrifuged, and the precipitate was taken and dispersed by adding 10ml of 0.1% hydroxypropylcellulose solution. Pulverizing the dispersed solution with ultrasonic cell pulverizer under 100W for 10min, and lyophilizing the solution to powder.
Example 2
The prescription comprises the following components: IMB 16-40.01 g as main drug, 0.03g hydroxypropyl cellulose as stabilizer.
The specific operation is as follows:
IMB 16-40.01 g was weighed out, dissolved in 1ml of DMF and added dropwise to 10ml of 0.2% hydroxypropylcellulose solution, and stirred magnetically to give a milky suspension. The milky suspension obtained by magnetic stirring was centrifuged, and the precipitate was taken and dispersed by adding 10ml of 0.1% hydroxypropylcellulose solution. Pulverizing the dispersed solution with ultrasonic cell pulverizer under 100W for 10min, and lyophilizing the solution to powder.
Example 3
The prescription comprises the following components: IMB 16-40.01 g as main drug, 0.03g hydroxypropyl cellulose as stabilizer.
The specific operation is as follows:
IMB 16-40.01 g was weighed out, dissolved in 1ml of DMF and added dropwise to 10ml of 0.2% hydroxypropylcellulose solution, and stirred magnetically to give a milky suspension. The milky suspension obtained by magnetic stirring was centrifuged, and the precipitate was taken and dispersed by adding 10ml of 0.1% hydroxypropylcellulose solution. Pulverizing the dispersed solution with ultrasonic cell pulverizer under 100W for 10min, and lyophilizing the solution to powder.
Example 4
The prescription comprises the following components: IMB 16-40.01 g as main drug, 0.02g poloxamer 188 as stabilizer.
The specific operation is as follows:
IMB 16-40.01 g was weighed out, dissolved in 1ml of DMF and added dropwise to 10ml of 0.1% poloxamer 188 solution, and stirred magnetically to give a milky suspension. The milky suspension obtained by magnetic stirring was centrifuged, and the precipitate was taken and dispersed in 10ml of 0.1% poloxamer 188 solution. Pulverizing the dispersed solution with ultrasonic cell pulverizer under 100W for 10min, and lyophilizing the solution to powder.
Example 5
The prescription comprises the following components: IMB 16-40.01 g as main drug, 0.04g poloxamer 188 as stabilizer.
The specific operation is as follows:
IMB 16-40.01 g was weighed out, dissolved in 1ml of DMF and added dropwise to 10ml of 0.2% poloxamer 188 solution, and stirred magnetically to give a milky suspension. The milky suspension obtained by magnetic stirring was centrifuged, and the precipitate was taken and dispersed in 10ml of 0.2% poloxamer 188 solution. Pulverizing the dispersed solution with ultrasonic cell pulverizer under 100W for 10min, and lyophilizing the solution to powder.
Example 6
The prescription comprises the following components: IMB 16-40.01 g as main drug, 0.06g poloxamer 188 as stabilizer.
The specific operation is as follows:
IMB 16-40.01 g was weighed out, dissolved in 1ml of DMF and added dropwise to 10ml of 0.3% poloxamer 188 solution, and stirred magnetically to give a milky suspension. The milky suspension obtained by magnetic stirring was centrifuged, and the precipitate was taken and dispersed in 10ml of 0.3% poloxamer 188 solution. Pulverizing the dispersed solution with ultrasonic cell pulverizer under 100W for 10min, and lyophilizing the solution to powder.
Example 7
The prescription comprises the following components: IMB 16-40.01 g as main medicine, and sodium dodecyl sulfate 0.02g as stabilizer.
The specific operation is as follows:
IMB 16-40.01 g was weighed out, dissolved in 1ml of DMF and added dropwise to 10ml of 0.1% sodium dodecyl sulfate solution, and stirred magnetically to give a milky suspension. The milky suspension obtained by magnetic stirring was centrifuged, and the precipitate was taken and dispersed by adding 10ml of 0.1% sodium lauryl sulfate solution. Pulverizing the dispersed solution with ultrasonic cell pulverizer under 100W for 10min, and lyophilizing the solution into powder.
Example 8
The prescription comprises the following components: IMB 16-40.01 g as main medicine, and sodium dodecyl sulfate 0.04g as stabilizer.
The specific operation is as follows:
IMB 16-40.01 g was weighed out, dissolved in 1ml of DMF and added dropwise to 10ml of 0.2% sodium dodecyl sulfate solution, and stirred magnetically to give a milky suspension. The milky suspension obtained by magnetic stirring was centrifuged, and the precipitate was taken and dispersed in 10ml of 0.2% sodium lauryl sulfate solution. Pulverizing the dispersed solution with ultrasonic cell pulverizer under 100W for 10min, and lyophilizing the solution to powder.
Example 9
The prescription comprises the following components: IMB 16-40.01 g as main medicine, 0.06g sodium dodecyl sulfate as stabilizer.
The specific operation is as follows:
IMB 16-40.01 g was weighed out, dissolved in 1ml of DMF and added dropwise to 10ml of 0.3% sodium dodecyl sulfate solution, and stirred magnetically to give a milky suspension. The milky suspension obtained by magnetic stirring was centrifuged, and the precipitate was taken and dispersed in 10ml of 0.3% sodium lauryl sulfate solution. Pulverizing the dispersed solution with ultrasonic cell pulverizer under 100W for 10min, and lyophilizing the solution to powder.
Example 10
The prescription comprises the following components: IMB 16-40.01 g as main medicine and phospholipid 0.02g as stabilizer.
The specific operation is as follows:
IMB 16-40.01 g was weighed out, dissolved in 1ml of DMF and added dropwise to 10ml of 0.1% phospholipid solution, and stirred magnetically to give a milky suspension. The milky suspension obtained by magnetic stirring was centrifuged, and the precipitate was taken and dispersed in 10ml of 0.1% phospholipid solution. Pulverizing the dispersed solution with ultrasonic cell pulverizer under 100W for 10min, and lyophilizing the solution to powder.
Example 11
The prescription comprises the following components: IMB 16-40.01 g as main drug, 0.04g phospholipid as stabilizer.
The specific operation is as follows:
IMB 16-40.01 g was weighed out and dissolved in 1ml of DMF and slowly added to 10ml of 0.2% phospholipid solution and stirred magnetically to give a milky suspension. The milky suspension obtained by magnetic stirring was centrifuged, and the precipitate was taken and dispersed in 10ml of 0.2% phospholipid solution. Pulverizing the dispersed solution with ultrasonic cell pulverizer under 100W for 10min, and lyophilizing the solution to powder.
Example 12
The prescription comprises the following components: IMB 16-40.01 g as main medicine and 0.06g phospholipid as stabilizer.
The specific operation is as follows:
IMB 16-40.01 g was weighed out, dissolved in 1ml of DMF and added dropwise to 10ml of 0.3% phospholipid solution, and stirred magnetically to give a milky suspension. The milky suspension obtained by magnetic stirring was centrifuged, and the precipitate was taken and dispersed in 10ml of 0.3% phospholipid solution. Pulverizing the dispersed solution with ultrasonic cell pulverizer under 100W for 10min, and lyophilizing the solution to powder.
Example 13
The prescription comprises the following components: IMB 16-40.01 g as main drug, 0.02g polyvinylpyrrolidone K15 as stabilizer.
The specific operation is as follows:
IMB 16-40.01 g was weighed out, dissolved in 1ml of DMF and added dropwise to 10ml of 0.1% polyvinylpyrrolidone K15 solution, and stirred magnetically to give a pale blue suspension. The milky suspension obtained by magnetic stirring was centrifuged and the precipitate was taken and dispersed in 10ml of 0.1% polyvinylpyrrolidone K15. Pulverizing the dispersed solution with ultrasonic cell pulverizer under 100W for 10min, and lyophilizing the solution to powder.
Example 14
The prescription comprises the following components: IMB 16-40.01 g as main drug, 0.02g polyvinylpyrrolidone K17 as stabilizer.
The specific operation is as follows:
IMB 16-40.01 g was weighed out, dissolved in 1ml of DMF and added dropwise to 10ml of 0.1% polyvinylpyrrolidone K17 solution, and stirred magnetically to give a pale blue suspension. The milky suspension obtained by magnetic stirring was centrifuged and the precipitate was taken and dispersed in 10ml of 0.1% polyvinylpyrrolidone K17. Pulverizing the dispersed solution with ultrasonic cell pulverizer under 100W for 10min, and lyophilizing the solution to powder.
Example 15
The prescription comprises the following components: IMB 16-40.01 g as main drug, 0.02g polyvinylpyrrolidone K25 as stabilizer.
The specific operation is as follows:
IMB 16-40.01 g was weighed out, dissolved in 1ml of DMF and added dropwise to 10ml of 0.1% polyvinylpyrrolidone K25 solution, and stirred magnetically to give a pale blue suspension. The milky suspension obtained by magnetic stirring was centrifuged and the precipitate was taken and dispersed in 10ml of 0.1% polyvinylpyrrolidone K25. Pulverizing the dispersed solution with ultrasonic cell pulverizer under 100W for 10min, and lyophilizing the solution to powder.
Example 16
The prescription comprises the following components: IMB 16-40.01 g as main drug, 0.02g polyvinylpyrrolidone K30 as stabilizer.
The specific operation is as follows:
IMB 16-40.01 g was weighed out, dissolved in 1ml of DMF and added dropwise to 10ml of 0.1% polyvinylpyrrolidone K30 solution, and stirred magnetically to give a pale blue suspension. The milky suspension obtained by magnetic stirring was centrifuged and the precipitate was taken and dispersed in 10ml of 0.1% polyvinylpyrrolidone K30. Pulverizing the dispersed solution with ultrasonic cell pulverizer under 100W for 10min, and lyophilizing the solution to powder.
Example 17
The prescription comprises the following components: IMB 16-41.000 g as main medicine and polyvinyl pyrrolidone K30 0.50g as stabilizer.
The specific operation is as follows:
IMB 16-41.000 g was weighed out, dissolved in 20ml DMF and added dropwise to 100ml 0.25% polyvinylpyrrolidone K30 solution and stirred magnetically to give a light blue suspension. The milky suspension obtained by magnetic stirring was centrifuged and the precipitate was taken and dispersed in 100ml of 0.25% polyvinylpyrrolidone K30. Pulverizing the dispersed solution with ultrasonic cell pulverizer under 100W for 10min, and lyophilizing the solution to powder.
Example 18
The prescription comprises the following components: IMB 16-44.000 g as main drug, and polyvinylpyrrolidone K30 3.600g as stabilizer.
The specific operation is as follows:
IMB 16-44.000 g was weighed out, dissolved in 80ml DMF and added dropwise to 1800ml 0.1% polyvinylpyrrolidone K30 solution with magnetic stirring to give a light blue suspension. The milky suspension obtained by magnetic stirring was centrifuged and the precipitate was taken and dispersed in 1800ml of 0.1% polyvinylpyrrolidone K30. Pulverizing the dispersed solution with ultrasonic cell pulverizer under 100W for 10min, and lyophilizing the solution to powder.
Example 19
The prescription comprises the following components: IMB 16-44.000 g as main medicine, 5.800g polyvinylpyrrolidone K30 as stabilizer.
The specific operation is as follows:
IMB 16-41.000 g was weighed out, dissolved in 80ml DMF and added dropwise to 1800ml 0.1% polyvinylpyrrolidone K30 solution with magnetic stirring to give a light blue suspension. The milky suspension obtained by magnetic stirring was centrifuged and the precipitate was taken and dispersed in 1000ml of 0.4% polyvinylpyrrolidone K30. Pulverizing the dispersed solution with ultrasonic cell pulverizer under 100W for 10min, and lyophilizing the solution to powder.
Example 20
The prescription comprises the following components: IMB 16-44.000 g as main medicine, 5.800g polyvinylpyrrolidone K30 as stabilizer.
The specific operation is as follows:
IMB 16-44.000 g was weighed out, dissolved in 60ml DMF and added dropwise to 1800ml 0.1% polyvinylpyrrolidone K30 solution with magnetic stirring to give a light blue suspension. The milky suspension obtained by magnetic stirring was centrifuged and the precipitate was taken and dispersed in 1000ml of 0.4% polyvinylpyrrolidone K30. Pulverizing the dispersed solution with ultrasonic cell pulverizer under 100W for 10min, and lyophilizing the solution to powder.
Performance testing
1. The particle size distribution diagram of the nanosuspension of example 20 is shown in fig. 2, in which the particle size of the nanosuspension is 0 day, B is a particle size diagram of the nanosuspension after being placed at room temperature for 1 month, and C is a particle size diagram of the nanosuspension after being placed at room temperature for 2 months; as can be seen from FIG. 2, the IMB16-4 nanosuspension prepared in example 20 had an average particle size of 172.2nm and a PDI index of 0.183. After the nanosuspension is placed at room temperature for 1 month, the average particle size is 169nm, and the PDI index is 0.193. After the nano suspension is placed at room temperature for 2 months, the average particle size is 167.8nm, and the PDI index is 0.164. As can be seen, the stability of the IMB16-4 nanosuspension is good.
2. Differential scanning calorimetry analysis was performed on the nanosuspension and the bulk drug prepared in example 20, and it can be seen from fig. 3 that a melting peak existed at 263 ℃ in the bulk drug IMB 16-4; the nano suspension (with the content of 34.8%) with consistent drug content is weighed as DSC, and no melting peak of the raw material drug appears. After the IMB16-4 bulk drug and the PVPK30 are mixed according to the ratio of 1:2, the dosage of the same bulk drug is weighed to be used as DSC, the physical mixture is found not to have a melting peak of the bulk drug, and the influence of the melted PVPK30 (the melting point is 130 ℃) on the determination of the IMB16-4 crystal form is presumed. The results of the X-ray experiments (fig. 4) show that the drug in the nanosuspension formulation was present in an amorphous form, and remained in an amorphous form after standing at room temperature for 3 months.
3. A solubility experiment is carried out on the IMB16-4 nanosuspension prepared in example 20, wherein the solubility of the IMB16-4 nanosuspension is 15.58 mu g/ml, the solubility of the bulk drug is 0.258 mu g/ml, and the solubility of the nanosuspension is 65.9 times that of the bulk drug.
4. The nanosuspension of example 20 was subjected to a rat pharmacokinetic experiment and calculated by software gastroplus9.6 as shown in fig. 5, wherein fig. 5B is bulk drug IMB16-4 AUC (0-t) of 0.978ug-h/mL, and fig. 5 a is IMB16-4 nanosuspension AUC (0-t) of 75.63ug-h/mL of example 20. The absorption of the IMB16-4 nanosuspension prepared in example 20 was 77.3 times that of the bulk drug substance.
The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and various modifications and changes will occur to those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A benzamide compound IMB16-4 nanosuspension is characterized by comprising: bulk drug IMB16-4 and stabilizer;
the stabilizer includes one or more of a hydrophilic material and a phospholipid.
2. The nanosuspension as claimed in claim 1, wherein the weight ratio of bulk drug IMB16-4 to stabilizer is 2:1 to 1: 7.
3. The nanosuspension as claimed in claim 2, wherein the weight ratio of bulk drug IMB16-4 to stabilizer is 1:1 to 1: 2.
4. The nanosuspension of claim 1, wherein the stabilizer comprises one or more of hydroxypropyl cellulose, soy lecithin, poloxamer 188, polyvinylpyrrolidone, sodium carboxymethyl cellulose, a polyoxyethylene-type nonionic stabilizer, and sodium lauryl sulfate.
5. The nanosuspension of claim 4, wherein the stabilizing agent is polyvinylpyrrolidone.
6. A process for the preparation of a nanosuspension according to any one of claims 1 to 5, comprising:
weighing bulk drug IMB16-4 and stabilizer;
dissolving the bulk drug IMB16-4 in a good solvent, then dropwise adding the solution into a water solvent containing the stabilizer, and magnetically stirring to obtain an emulsion suspension;
centrifuging the suspension to obtain a precipitate, and adding the precipitate to another part of water solvent containing the stabilizer for dispersion;
carrying out ultrasonic crushing on the dispersed solution to obtain IMB16-4 nano suspension;
freezing and freeze-drying the IMB16-4 nano suspension.
7. The method according to claim 6, wherein the good solvent is a DMF solvent or a DMSO solvent.
8. The method according to claim 6, wherein the volume ratio of the good solvent to water is 1:10 to 1: 300.
9. The method of claim 6, wherein the stabilizer is contained in two portions in equal volumes of the aqueous solvent.
10. The method of claim 6, wherein the ultrasonic pulverization is:
and (3) crushing the dispersed solution in an ultrasonic cell crusher, and treating for 10-30 min under the condition of 180W.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112353763A (en) * | 2020-11-19 | 2021-02-12 | 河北美信医药科技有限公司 | Hot-melt extrusion preparation and preparation method thereof |
| CN114306235A (en) * | 2022-01-04 | 2022-04-12 | 中国医学科学院医药生物技术研究所 | IMB16-4 self-emulsifying mixture and preparation method and application thereof |
| CN114767658A (en) * | 2022-04-22 | 2022-07-22 | 中国医学科学院医药生物技术研究所 | Preparation method of IMB16-4 liposome nanoparticles and medicine |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006335666A (en) * | 2005-05-31 | 2006-12-14 | Ansei Seiyaku Kagi Kofun Yugenkoshi | Prevention of joint damage |
| CN101322682A (en) * | 2008-07-29 | 2008-12-17 | 沈阳药大制剂新技术有限公司 | Preparation of indissoluble medicament nano granule |
| WO2011004393A2 (en) * | 2009-07-03 | 2011-01-13 | Indian Institute Of Chemical Technology | Para amino benzoic acid based nanotubes |
| CN102772365A (en) * | 2012-06-08 | 2012-11-14 | 四川大学 | 4-(4-(3-trifluoromethyl)benzamido-phenoxy)-2-(methyl-ammonia-formoxyl)pyridine nano suspension as well as preparation method and application thereof |
| CN104173283A (en) * | 2014-08-27 | 2014-12-03 | 广州暨南生物医药研究开发基地有限公司 | Nano-suspension of Hsp90 inhibitor by using benzamide as basic skeleton and preparation method of nano-suspension |
| CN108938615A (en) * | 2017-05-22 | 2018-12-07 | 中国医学科学院医药生物技术研究所 | Benzene sulfonamido benzamide compound is used to treat the purposes of non-alcohol fatty liver |
-
2019
- 2019-11-21 CN CN201911150057.9A patent/CN110840836B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006335666A (en) * | 2005-05-31 | 2006-12-14 | Ansei Seiyaku Kagi Kofun Yugenkoshi | Prevention of joint damage |
| CN101322682A (en) * | 2008-07-29 | 2008-12-17 | 沈阳药大制剂新技术有限公司 | Preparation of indissoluble medicament nano granule |
| WO2011004393A2 (en) * | 2009-07-03 | 2011-01-13 | Indian Institute Of Chemical Technology | Para amino benzoic acid based nanotubes |
| CN102772365A (en) * | 2012-06-08 | 2012-11-14 | 四川大学 | 4-(4-(3-trifluoromethyl)benzamido-phenoxy)-2-(methyl-ammonia-formoxyl)pyridine nano suspension as well as preparation method and application thereof |
| CN104173283A (en) * | 2014-08-27 | 2014-12-03 | 广州暨南生物医药研究开发基地有限公司 | Nano-suspension of Hsp90 inhibitor by using benzamide as basic skeleton and preparation method of nano-suspension |
| CN108938615A (en) * | 2017-05-22 | 2018-12-07 | 中国医学科学院医药生物技术研究所 | Benzene sulfonamido benzamide compound is used to treat the purposes of non-alcohol fatty liver |
Non-Patent Citations (1)
| Title |
|---|
| YOUNG, DH等: "Covalent binding of the benzamide RH-4032 to tubulin in suspension-cultured tobacco cells and its application in a cell-based competitive-binding assay", 《PLANT PHYSIOLOGY》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112353763A (en) * | 2020-11-19 | 2021-02-12 | 河北美信医药科技有限公司 | Hot-melt extrusion preparation and preparation method thereof |
| CN112353763B (en) * | 2020-11-19 | 2023-03-17 | 河北美信医药科技有限公司 | Hot-melt extrusion preparation and preparation method thereof |
| CN114306235A (en) * | 2022-01-04 | 2022-04-12 | 中国医学科学院医药生物技术研究所 | IMB16-4 self-emulsifying mixture and preparation method and application thereof |
| CN114767658A (en) * | 2022-04-22 | 2022-07-22 | 中国医学科学院医药生物技术研究所 | Preparation method of IMB16-4 liposome nanoparticles and medicine |
| CN114767658B (en) * | 2022-04-22 | 2023-09-19 | 中国医学科学院医药生物技术研究所 | Preparation method of IMB16-4 liposome nanoparticle and medicine |
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