CN115475230B - Carfilzomib nanoemulsion suspension freeze-dried preparation and preparation method thereof - Google Patents
Carfilzomib nanoemulsion suspension freeze-dried preparation and preparation method thereof Download PDFInfo
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Abstract
The invention provides a carfilzomib nanoemulsion suspension freeze-dried preparation, which comprises a compound prepared from carfilzomib and hydroxypropyl cellulose-L, a surfactant, an antioxidant, a pH regulator and a freeze-drying protective agent, wherein the obtained nanoemulsion suspension freeze-dried preparation has good re-solubility, can be quickly reconstituted into colloidal dispersion after being diluted by water for injection, has uniform particle size, good stability and low impurity content. In addition, the nanoemulsion suspension freeze-dried preparation has higher drug content, and effectively solves the problems of poor water solubility and low drug content of carfilzomib.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a carfilzomib nanoemulsion suspension freeze-dried preparation for injection and a preparation method thereof.
Background
Kyprolis (carfilzomib) for injection is an antitumor drug which is only used for veins, is an analogue of a cyclooxygenase tetrapeptide proteasome inhibitor, and is suitable for treating patients with multiple myeloma.
Carfilzomib (carfilzomib) was approved by the FDA as a second proteasome inhibitor following bortezomib for use in patients with multiple myeloma who received at least 2 drugs prior to treatment, including bortezomib and immunomodulator treatment. Carfilzomib is a specific, irreversible targeted inhibitor, originally developed by Proteolix, produced by the company aonyx (Onyx) pharmaceutical, and approved by the FDA for marketing in 7/20 of 2012.
Although carfilzomib has good anti-tumor effect, the carfilzomib has poor water solubility, poor stability in water and easy generation of impurities, so that the lyophilized preparation is a more ideal dosage form. And under the condition of contacting with oxygen, carfilzomib N-oxide is easy to generate, so that oxygen is required to be isolated in the preparation process. The prescription of Kyprolis on the market contains 60mg of carfilzomib, 3000mg of sulfobutyl betacyclodextrin sodium, 57.7mg of citric acid and a proper amount of sodium hydroxide, but the drug loading rate is less than 2%, a large amount of cyclodextrin is used, the load of kidneys can be increased after the cyclodextrin enters the blood circulation system of a human body, meanwhile, the cyclodextrin can act on cell membranes on the inner walls of blood vessels to cause cell injury, vein spasm and phlebitis can be caused after long-term use, potential safety hazards exist, and dexamethasone needs to be given before each administration to prevent infusion reaction.
Aiming at the problems of poor water solubility and poor stability of carfilzomib, various researches on carfilzomib for injection are carried out at present. CN106310221a reports a carfilzomib composition, which adopts human serum albumin and carfilzomib to form intravenous carfilzomib protein nanoparticles, and the protein plays roles of dispersing and stabilizing particles in the nanoparticles. However, in this method, a large amount of an organic solvent such as chloroform, methylene chloride, etc. is required. In addition, the method adopts human serum albumin as a stabilizer, has high price, greatly increases the cost of the preparation and increases the burden of patients.
CN105919972a provides a nano granule preparation of entrapped carfilzomib, which is prepared by selecting specific polyethylene glycol block copolymer and lecithin as surfactant, and has water solubility superior to cyclodextrin inclusion carfilzomib of entrapped carfilzomib Mi Na granule, and has lower impurity content. However, this method still uses a large amount of organic solvents, such as methylene chloride, during the preparation process, which also increases the toxicity of the formulation. Moreover, the preparation method is complex, has harsh conditions, is only a small-scale production process, and is difficult to realize in scale-up production.
CN105497871a provides a liposome freeze-dried composition of carfilzomib drug and its preparation method, cholesterol and phospholipid are selected as inclusion agents, and one or two of vitamin C and vitamin E are added as antioxidants to improve the stability of phospholipid and prevent phospholipid from being oxidized and deteriorated when exposed in air. Similar to the previous method, the method also uses organic solvent such as chloroform or anhydrous diethyl ether as solvent in the preparation process, which increases the toxicity of the preparation, and has complicated preparation process and higher requirements on production conditions.
W02016116882A2 discloses a carfilzomib freeze-dried composition for parenteral administration comprising carfilzomib or a pharmaceutically acceptable salt, hydrate, etc., one or more sugars, an acidulant, one or more solvents, optionally other pharmaceutically acceptable excipients, said composition not comprising cyclodextrin. Wherein the sugar is selected from mannitol, sucrose, glucose, etc., the solvent is selected from acetonitrile, tert-butanol, DMSO, DMA.PG, tween, water, etc., and the acidulant is selected from tartaric acid, citric acid, aspartic acid, etc. Although the problem of insoluble carfilzomib is solved by adopting solvents such as tween and the like, the toxicity of the preparation is increased.
CN107802606a discloses a freeze-dried powder of carfilzomib for injection, which comprises carfilzomib, lactose, an antioxidant, a surfactant and auxiliary materials. The surfactant is polyethylene glycol-12-hydroxystearate, and a cyclodextrin inclusion technology is not used, so that potential safety hazards caused by cyclodextrin are avoided, however, the problem of solubility of carfilzomib is not effectively solved, and the effective concentration still cannot meet clinical requirements.
Disclosure of Invention
The invention mainly aims to provide a carfilzomib nanoemulsion suspension freeze-dried preparation, which effectively solves the problems of poor water solubility, poor stability and lower content of active ingredients of the existing preparation existing in carfilzomib.
The invention adopts the following technical scheme:
A carfilzomib nanoemulsion suspension lyophilized formulation comprising: the composite is prepared from carfilzomib and hydroxypropyl cellulose-L, a surfactant, an antioxidant, a pH regulator and a freeze-drying protective agent.
Preferably, the carfilzomib nanoemulsion suspension freeze-dried preparation comprises: 1 part of carfilzomib, 1-20 parts of hydroxypropyl cellulose-L, 1-10 parts of surfactant, 1-5 parts of antioxidant, pH regulator and freeze-drying protective agent.
Preferably, the carfilzomib nanoemulsion suspension freeze-dried preparation comprises 1 part of carfilzomib, 1-10 parts of hydroxypropyl cellulose L, 1-5 parts of surfactant, 1-3 parts of antioxidant, pH regulator and freeze-drying protective agent.
Preferably, the surfactant is selected from one or two of sodium dodecyl sulfate and dioctyl sodium succinate sulfonate; further preferred is dioctyl sodium sulfosuccinate.
Preferably, the antioxidant is selected from one or more of vitamin E, ethylenediamine tetraacetic acid, derivatives of ethylenediamine tetraacetic acid, and deferoxamine mesylate, cysteine hydrochloride, vitamin C and sulfite; further preferred is vitamin C.
Preferably, the pH regulator is selected from one or more of hydrochloric acid, phosphoric acid, acetic acid or citric acid; hydrochloric acid is more preferred.
Preferably, the pH adjustment range is 3.4 to 3.6.
Preferably, the lyoprotectant is selected from one or more of sucrose, lactose, glucose, maltose, mannitol and sorbitol; mannitol is further preferred.
Preferably, the weight ratio of the lyoprotectant to the active ingredient carfilzomib is 1:0.5 to 10.
The invention also provides a preparation method of the carfilzomib nanoemulsion suspension freeze-dried preparation, which comprises the following steps:
(1) Dissolving carfilzomib and hydroxypropyl cellulose-L in an organic solvent, hermetically stirring for 25-35 hours at a temperature lower than 35 ℃, and removing the organic solvent by rotary evaporation to form a uniform complex of carfilzomib and hydroxypropyl cellulose-L;
(2) Dissolving the compound in the step (1) in an organic solvent to obtain an organic phase; dissolving a surfactant, an antioxidant and a freeze-drying protective agent in water, and regulating the pH value to 3.4-3.6 by using a pH regulator to obtain a water phase; mixing and stirring the organic phase and the water phase to form colostrum;
(3) Shearing the colostrum obtained in the step (2) at a high speed, transferring the mixture into a high-pressure homogenizer for nanoemulsifying, and performing ultrasonic treatment to obtain a nanoemulsion suspension;
(4) Removing the organic solvent by rotary evaporation, adding water for injection to a certain volume, sterilizing with a 0.22 μm filter membrane, packaging, lyophilizing, filling nitrogen for protection, and capping after tamponade to obtain the carfilzomib nanoemulsion suspension lyophilized preparation.
Preferably, the organic solvent in the step (1) and the step (2) is methanol or dichloromethane.
Preferably, the concentration of carfilzomib in the step (1) in the organic solvent is 40-80 mg/mL.
Preferably, the concentration of surfactant in the aqueous phase of step (2) is from 0.13 to 1.35g/mL, more preferably from 0.13 to 0.67mg/mL; the concentration of the antioxidant is 0.13-0.67 g/mL, more preferably 0.13-0.40 mg/mL; the concentration of the freeze-drying protective agent is 0.066-1.35 g/mL.
Preferably, the volume ratio of the aqueous phase to the organic phase in step (2) is 1:1.
Preferably, in the step (3), the high-speed shearing rotating speed is 11000-20000 rpm, and the high-speed shearing time is 10min.
Preferably, the temperature in the high-pressure homogenizing process of the step (3) is 30-45 ℃, the mixture is homogenized for 2-5 times under 5000psi pressure, and then homogenized for 5-10 times under 9000-21000 psi pressure.
Preferably, the ultrasonic process in the step (3) is to ultrasonically process the nanoemulsion for 10-15 times under the power of 500-1000W, and the ultrasonic time is 5-10 seconds/time.
Preferably, the average particle size of the nanoemulsion suspension prepared in the step (3) ranges from 450 nm to 550nm.
Preferably, the lyophilization process described in step (4) is as follows:
Pre-freezing: the semi-finished product which is filled and half-plugged is placed on a baffle plate in a freeze-drying machine box for pre-freezing, and the semi-finished product reaches the pre-freezing temperature in the shortest time possible, wherein the pre-freezing temperature is between-30 ℃ and-40 ℃ for 8-12 h;
Sublimation drying stage: when the vacuum degree in the drying box reaches 150mbar to 200mbar, the preferable vacuum degree is 170mbar; raising the main drying temperature to-20 to-15 ℃, using for 10-15 hours, and preserving heat for 10-20 hours after raising the temperature;
And (3) a re-drying stage: raising the re-drying temperature to 10-15 ℃; when in use, the time is 1 to 3 hours; and pumping the vacuum degree in the drying box to limit vacuum, and preserving the heat for 4-7 h.
The preparation method of the carfilzomib nanometer suspension freeze-dried powder comprises the steps of preparing the nanometer emulsion suspension with the particle size of 450-550 nm by utilizing high shearing and cavitation of a high-pressure emulsion machine and an ultrasonic pulverizer under the action of a surfactant, preparing the stable solid powder injection by freeze-drying, and diluting the obtained freeze-dried powder with proper amount of water for injection to quickly reconstruct into colloidal dispersion.
Compared with the prior art, the invention has the technical effects that:
(1) The nanoemulsion suspension freeze-dried preparation has the advantages of good re-solubility, uniform particle size, good stability and low impurity content.
(2) The nanoemulsion suspension freeze-dried preparation has higher drug content, and effectively solves the problems of poor water solubility and low drug content of carfilzomib.
Detailed Description
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not limiting thereof, so that simple modifications of the invention based on the method of the invention are within the scope of the invention as claimed.
Example 1
Prescription:
The preparation method comprises the following steps:
(1) 4.0g of carfilzomib and 4.0g of hydroxypropyl cellulose-L are completely dissolved in 50mL of dichloromethane, the mixed solution is stirred in a closed way for 25h, the reaction temperature is controlled to be 30 ℃, the mixed solution is introduced into a flask of a vacuum rotary evaporator, and the dichloromethane is removed by rotary evaporation to form a uniform complex of the carfilzomib and the hydroxypropyl cellulose-L;
(2) Dissolving 4.0g of vitamin C, 4.0g of dioctyl sodium sulfosuccinate and 2.0g of mannitol in 30mL of water for injection, regulating the pH to 3.4 by using 0.1mol/L hydrochloric acid to obtain a water phase, dissolving the compound of carfilzomib and hydroxypropyl cellulose-L prepared in the step (1) by using 30mL of dichloromethane, and mixing and stirring an organic phase and the water phase to form colostrum;
(3) Shearing the formed colostrum at high speed at 11000rpm for 10min, transferring the mixture into a high-pressure homogenizer, homogenizing at 5000psi for 3 times, homogenizing at 9000psi at 30deg.C for 10 times, and performing nanoemulsification; ultrasonic treatment is carried out on the prepared primary suspension agent for 10 times under the power of 500W, and the ultrasonic treatment time is 10 seconds/time, so as to prepare a nanoemulsion suspension agent;
(4) The methylene dichloride is removed by rotary evaporation in vacuum for 10 hours on a vacuum rotary evaporator at the temperature lower than 50 ℃, the obtained mixture is added with water for injection to a volume of 100mL, the mixture is filtered by a 0.22 mu m membrane, sterilized, filled and freeze-dried, nitrogen protection is filled after the freeze-drying is finished, and capping is carried out after the capping is carried out, so that the carfilzomib nanoemulsion suspension freeze-dried preparation is obtained, and the freeze-drying process is as follows:
pre-freezing: placing the half-finished product which is filled and half-plugged on a partition board in a freeze-drying machine box for pre-freezing, wherein the temperature is-30 ℃ and the heat preservation time is 8 hours;
sublimation drying stage: when the vacuum degree in the drying oven reaches 150mbar, the main drying temperature is raised to-15 ℃ for 10 hours, and the heat preservation time is 15 hours after the temperature is raised;
and (3) a re-drying stage: raising the temperature to 10 ℃ for 1 hour; and pumping the vacuum degree in the drying box to limit vacuum, and preserving the heat for 4 hours.
Example 2
Prescription:
The preparation method comprises the following steps:
(1) 4.0g of carfilzomib and 40.0g of hydroxypropyl cellulose-L are completely dissolved in 50mL of dichloromethane, the mixed solution is stirred for 30 hours in a sealing way, the reaction temperature is controlled to be 30 ℃, the mixed solution is introduced into a flask of a vacuum rotary evaporator, and dichloromethane is removed by rotary evaporation to form a uniform complex of carfilzomib and hydroxypropyl cellulose-L;
(2) Dissolving 12.0g of vitamin C, 20.0g of dioctyl sodium sulfosuccinate and 20.0g of mannitol in 30mL of water for injection, regulating the pH to 3.4 by using 0.1mol/L hydrochloric acid to obtain a water phase, dissolving the compound of carfilzomib and hydroxypropyl cellulose-L prepared in the step (1) by using 30mL of dichloromethane, and mixing and stirring an organic phase and the water phase to form colostrum;
(3) Shearing the formed colostrum at a high speed of 15000rpm for 10min, transferring the mixture into a high-pressure homogenizer, homogenizing for 3 times at 5000psi, homogenizing for 5 times at 12000psi under controlled temperature of 35 ℃, and performing nanoemulsification; ultrasonic treatment is carried out on the prepared primary suspension agent for 15 times under the power of 500W, the ultrasonic treatment time is 5 seconds/time, and the nanoemulsion suspension agent is prepared;
(4) The methylene dichloride is removed by rotary evaporation in vacuum for 10 hours on a vacuum rotary evaporator at the temperature lower than 50 ℃, the obtained mixture is added with water for injection to a volume of 100mL, the mixture is filtered by a 0.22 mu m membrane, sterilized, filled and freeze-dried, nitrogen protection is filled after the freeze-drying is finished, and capping is carried out after the capping is carried out, so that the carfilzomib nanoemulsion suspension freeze-dried preparation is obtained, and the freeze-drying process is as follows:
Pre-freezing: placing the half-finished product which is filled and half-plugged on a partition board in a freeze-drying machine box for pre-freezing, wherein the temperature is minus 35 ℃ and the heat preservation time is 10 hours;
Sublimation drying stage: when the vacuum degree in the drying oven reaches 170mbar, the main drying temperature is raised to-20 ℃ for 12 hours, and the heat preservation time is 20 hours after the temperature is raised;
And (3) a re-drying stage: raising the temperature to 15 ℃ and taking 2 hours; and pumping the vacuum degree in the drying box to limit vacuum, and preserving the heat for 5 hours.
Example 3
Prescription:
The preparation method comprises the following steps:
(1) 4.0g of carfilzomib and 40.0g of hydroxypropyl cellulose-L are completely dissolved in 50mL of dichloromethane, the mixed solution is stirred for 30 hours in a sealing way, the reaction temperature is controlled to be 30 ℃, the mixed solution is introduced into a flask of a vacuum rotary evaporator, and dichloromethane is removed by rotary evaporation to form a uniform complex of carfilzomib and hydroxypropyl cellulose-L;
(2) 12.0g of ethylenediamine tetraacetic acid, 20.0g of sodium dodecyl sulfate and 20.0g of sorbitol were dissolved in 30mL of water for injection, and pH was adjusted to 3.4 with 0.1mol/L hydrochloric acid to obtain an aqueous phase. Dissolving the compound of carfilzomib and hydroxypropyl cellulose-L prepared in the step (1) by 30mL of dichloromethane, and mixing and stirring an organic phase and an aqueous phase to form colostrum;
(3) Shearing the formed colostrum at a high speed of 15000rpm for 10min, transferring the mixture into a high-pressure homogenizer, homogenizing at 5000psi for 3 times, homogenizing at 12000psi at 35 ℃ for 2 times, and performing nanoemulsification; ultrasonic treatment is carried out on the prepared primary suspension agent for 15 times under the power of 500W, the ultrasonic treatment time is 5 seconds/time, and the nanoemulsion suspension agent is prepared;
(4) The methylene dichloride is removed by rotary evaporation in vacuum for 10 hours on a vacuum rotary evaporator at the temperature lower than 50 ℃, the obtained mixture is added with water for injection to a volume of 100mL, the mixture is filtered by a 0.22 mu m membrane, sterilized, filled and freeze-dried, nitrogen protection is filled after the freeze-drying is finished, and capping is carried out after the capping is carried out, so that the carfilzomib nanoemulsion suspension freeze-dried preparation is obtained, and the freeze-drying process is as follows:
Pre-freezing: placing the half-finished product which is filled and half-plugged on a partition board in a freeze-drying machine box for pre-freezing, wherein the temperature is minus 35 ℃ and the heat preservation time is 10 hours;
Sublimation drying stage: when the vacuum degree in the drying oven reaches 170mbar, the main drying temperature is raised to-20 ℃ for 12 hours, and the heat preservation time is 20 hours after the temperature is raised;
And (3) a re-drying stage: raising the temperature to 15 ℃ and taking 2 hours; and pumping the vacuum degree in the drying box to limit vacuum, and preserving the heat for 5 hours.
Example 4
Prescription:
The preparation method comprises the following steps:
(1) 4.0g of carfilzomib and 80.0g of hydroxypropyl cellulose-L are completely dissolved in 100mL of dichloromethane, the mixed solution is stirred in a closed way for 35h, the reaction temperature is controlled to be 30 ℃, the mixed solution is introduced into a flask of a vacuum rotary evaporator, and the dichloromethane is removed by rotary evaporation to form a uniform complex of the carfilzomib and the hydroxypropyl cellulose-L;
(2) 20.0g of vitamin C, 40.0g of dioctyl sodium sulfosuccinate and 40.0g of mannitol are dissolved in 30mL of water for injection, and the pH is adjusted to 3.6 by 0.1mol/L hydrochloric acid to obtain an aqueous phase. Dissolving the compound of carfilzomib and hydroxypropyl cellulose-L prepared in the step (1) by 30mL of dichloromethane, and mixing and stirring an organic phase and an aqueous phase to form colostrum;
(3) Shearing the formed colostrum at high speed with the rotation speed of 20000rpm for 10min, transferring the mixture into a high-pressure homogenizer, homogenizing at 5000psi for 5 times, homogenizing at 21000psi at 40 ℃ for 10 times, and performing nanoemulsification; ultrasonic treatment is carried out on the prepared primary suspension agent for 10 times under the power of 1000W, and the ultrasonic treatment time is 10 seconds/time, so as to prepare a nanoemulsion suspension agent;
(4) The methylene dichloride is removed by rotary evaporation in vacuum for 10 hours on a vacuum rotary evaporator at the temperature lower than 50 ℃, the obtained mixture is added with water for injection to a volume of 100mL, the mixture is filtered by a 0.22 mu m membrane, sterilized, filled and freeze-dried, nitrogen protection is filled after the freeze-drying is finished, and capping is carried out after the capping is carried out, so that the carfilzomib nanoemulsion suspension freeze-dried preparation is obtained, and the freeze-drying process is as follows:
pre-freezing: placing the half-finished product which is filled and half-plugged on a partition board in a freeze-drying machine box for pre-freezing, wherein the temperature is-40 ℃ and the heat preservation time is 8 hours;
Sublimation drying stage: when the vacuum degree in the drying oven reaches 200mbar, the main drying temperature is raised to-20 ℃ for 15 hours, and the heat preservation time is 20 hours after the temperature is raised;
and (3) a re-drying stage: raising the temperature to 15 ℃ and taking 3 hours; and pumping the vacuum degree in the drying box to limit vacuum, and preserving the heat for 7h.
Example 5
Prescription:
The preparation method comprises the following steps:
(1) 4.0g of carfilzomib and 80.0g of hydroxypropyl cellulose-L are completely dissolved in 100mL of methanol, the mixture is sealed and stirred for 35h, the reaction temperature is controlled to be 30 ℃, the mixture is introduced into a flask of a vacuum rotary evaporator, and the methanol is removed by rotary evaporation to form a uniform complex of carfilzomib and hydroxypropyl cellulose-L;
(2) 20.0g of cysteine hydrochloride, 40.0g of sodium dodecyl sulfate and 40.0g of lactose were dissolved in 30mL of water for injection, and pH was adjusted to 3.6 with 0.1mol/L hydrochloric acid to obtain an aqueous phase. Dissolving the compound of carfilzomib and hydroxypropyl cellulose-L prepared in the step (1) with 30mL of methanol, and mixing and stirring an organic phase and an aqueous phase to form colostrum;
(3) Shearing the formed colostrum at high speed with the rotation speed of 20000rpm for 10min, transferring the mixture into a high-pressure homogenizer, homogenizing at 5000psi for 5 times, homogenizing at 21000psi at 30 ℃ for 10 times, and performing nanoemulsification; ultrasonic treatment is carried out on the prepared primary suspension agent for 10 times under the power of 1000W, and the ultrasonic treatment time is 10 seconds/time, so as to prepare a nanoemulsion suspension agent;
(4) The method comprises the steps of removing methanol by rotary evaporation in vacuum for 10 hours at a temperature lower than 50 ℃ on a vacuum rotary evaporator, adding water for injection into the obtained mixture to a volume of 100mL, filtering by a 0.22 mu m membrane, sterilizing, filling, freeze-drying, filling nitrogen for protection after freeze-drying is finished, and capping after tamponade to obtain the carfilzomib nanoemulsion suspension freeze-dried preparation, wherein the freeze-drying process comprises the following steps:
pre-freezing: placing the half-finished product which is filled and half-plugged on a partition board in a freeze-drying machine box for pre-freezing, wherein the temperature is-40 ℃ and the heat preservation time is 8 hours;
Sublimation drying stage: when the vacuum degree in the drying oven reaches 200mbar, the main drying temperature is raised to-20 ℃ for 15 hours, and the heat preservation time is 20 hours after the temperature is raised;
and (3) a re-drying stage: raising the temperature to 15 ℃ and taking 3 hours; and pumping the vacuum degree in the drying box to limit vacuum, and preserving the heat for 7h.
Example 6
Prescription:
The preparation method comprises the following steps:
(1) 4.0g of carfilzomib and 40.0g of hydroxypropyl cellulose-L are completely dissolved in 50mL of dichloromethane, the mixed solution is stirred for 30 hours in a sealing way, the reaction temperature is controlled to be 30 ℃, the mixed solution is introduced into a flask of a vacuum rotary evaporator, and dichloromethane is removed by rotary evaporation to form a uniform complex of carfilzomib and hydroxypropyl cellulose-L;
(2) 12.0g of vitamin E, 80.0g of poloxamer and 20.0g of lactose are dissolved in 30mL of water for injection, and the pH is adjusted to 4.0 by 0.1mol/L hydrochloric acid to obtain an aqueous phase. Dissolving the compound of carfilzomib and hydroxypropyl cellulose-L prepared in the step (1) by 30mL of dichloromethane, and mixing and stirring an organic phase and an aqueous phase to form colostrum;
(3) Shearing the formed colostrum at a high speed of 15000rpm for 10min, transferring the mixture into a high-pressure homogenizer, homogenizing for 3 times at 5000psi, homogenizing for 5 times at 12000psi under controlled temperature of 35 ℃, and performing nanoemulsification; ultrasonic treatment is carried out on the prepared primary suspension agent for 15 times under the power of 500W, and the ultrasonic treatment time is 5 seconds/time, so that the nano suspension agent is prepared;
(4) The methylene dichloride is removed by rotary evaporation in vacuum for 10 hours on a vacuum rotary evaporator at the temperature lower than 50 ℃, the obtained mixture is added with water for injection to a volume of 100mL, the mixture is filtered by a 0.22 mu m membrane, sterilized, filled and freeze-dried, nitrogen protection is filled after the freeze-drying is finished, and capping is carried out after the capping is carried out, so that the carfilzomib nanoemulsion suspension freeze-dried preparation is obtained, and the freeze-drying process is as follows:
Pre-freezing: placing the half-finished product which is filled and half-plugged on a partition board in a freeze-drying machine box for pre-freezing, wherein the temperature is minus 35 ℃ and the heat preservation time is 10 hours;
Sublimation drying stage: when the vacuum degree in the drying oven reaches 170mbar, the main drying temperature is raised to-20 ℃ for 12 hours, and the heat preservation time is 20 hours after the temperature is raised;
and (3) a re-drying stage: raising the temperature to 15 ℃; when in use, the time is 2 hours; and pumping the vacuum degree in the drying box to limit vacuum, and preserving the heat for 5 hours.
Example 7
Prescription:
The preparation method comprises the following steps:
(1) 4.0g of carfilzomib and 40.0g of hydroxypropyl cellulose-L are completely dissolved in 50mL of dichloromethane, the mixed solution is stirred for 30 hours in a sealing way, the reaction temperature is controlled to be 30 ℃, the mixed solution is introduced into a flask of a vacuum rotary evaporator, and dichloromethane is removed by rotary evaporation to form a uniform complex of carfilzomib and hydroxypropyl cellulose-L;
(2) 2.0g of sodium metabisulfite, 2.0g of dioctyl sodium sulfosuccinate and 20.0g of lactose were dissolved in30 mL of water for injection, and pH was adjusted to 3.0 with 0.1mol/L hydrochloric acid to obtain an aqueous phase. Dissolving the compound of carfilzomib and hydroxypropyl cellulose-L prepared in the step (1) by 30mL of dichloromethane, and mixing and stirring an organic phase and an aqueous phase to form colostrum;
(3) Shearing the formed colostrum at a high speed of 15000rpm for 10min, transferring the mixture into a high-pressure homogenizer, homogenizing for 3 times at 5000psi, homogenizing for 5 times at 12000psi under controlled temperature of 35 ℃, and performing nanoemulsification; ultrasonic treatment is carried out on the prepared primary suspension agent for 15 times under the power of 500W, the ultrasonic treatment time is 5 seconds/time, and the nanoemulsion suspension agent is prepared;
(4) The methylene dichloride is removed by rotary evaporation in vacuum for 10 hours on a vacuum rotary evaporator at the temperature lower than 50 ℃, the obtained mixture is added with water for injection to a volume of 100mL, the mixture is filtered by a 0.22 mu m membrane, sterilized, filled and freeze-dried, nitrogen protection is filled after the freeze-drying is finished, and capping is carried out after the capping is carried out, so that the carfilzomib nanoemulsion suspension freeze-dried preparation is obtained, and the freeze-drying process is as follows:
Pre-freezing: placing the half-finished product which is filled and half-plugged on a partition board in a freeze-drying machine box for pre-freezing, wherein the temperature is minus 35 ℃ and the heat preservation time is 10 hours;
Sublimation drying stage: when the vacuum degree in the drying oven reaches 170mbar, the main drying temperature is raised to-20 ℃ for 12 hours, and the heat preservation time is 20 hours after the temperature is raised;
And (3) a re-drying stage: raising the temperature to 10 ℃; when in use, the time is 2 hours; and pumping the vacuum degree in the drying box to limit vacuum, and preserving the heat for 5 hours.
Example 8
Prescription:
The preparation method comprises the following steps:
(1) 4.0g of carfilzomib and 40.0g of hydroxypropyl cellulose-L are completely dissolved in 50mL of dichloromethane, the mixed solution is stirred for 30 hours in a sealing way, the reaction temperature is controlled to be 30 ℃, the mixed solution is introduced into a flask of a vacuum rotary evaporator, and dichloromethane is removed by rotary evaporation to form a uniform complex of carfilzomib and hydroxypropyl cellulose-L;
(2) Dissolving 12.0g of vitamin C, 20.0g of dioctyl sodium sulfosuccinate and 20.0g of mannitol in 30mL of water for injection, regulating the pH to 3.4 by using 0.1mol/L hydrochloric acid to obtain a water phase, dissolving the compound of carfilzomib and hydroxypropyl cellulose-L prepared in the step (1) by using 30mL of dichloromethane, and mixing and stirring an organic phase and the water phase to form colostrum;
(3) Shearing the formed colostrum at a high speed of 15000rpm for 5min, transferring the mixture into a high-pressure homogenizer, homogenizing for 3 times at 5000psi, homogenizing for 5 times at 12000psi under a controlled temperature of 50 ℃, and performing nanoemulsification; and (3) carrying out ultrasonic treatment on the prepared primary suspension for 15 times under the power of 500W for 5 seconds/time to prepare the nanoemulsion suspension.
(4) The methylene dichloride is removed by rotary evaporation in vacuum for 10 hours on a vacuum rotary evaporator at the temperature lower than 50 ℃, the obtained mixture is added with water for injection to a volume of 100mL, the mixture is filtered by a 0.22 mu m membrane, sterilized, filled and freeze-dried, nitrogen protection is filled after the freeze-drying is finished, and capping is carried out after the capping is carried out, so that the carfilzomib nanoemulsion suspension freeze-dried preparation is obtained, and the freeze-drying process is as follows:
Pre-freezing: placing the half-finished product which is filled and half-plugged on a partition board in a freeze-drying machine box for pre-freezing, wherein the temperature is-45 ℃ and the heat preservation time is 4 hours;
sublimation drying stage: when the vacuum degree in the drying oven reaches 170mbar, the main drying temperature is raised to-25 ℃ for 10 hours, and the heat preservation time is 30 hours after the temperature is raised;
and (3) a re-drying stage: raising the temperature to 20 ℃; when in use, the time is 4 hours; and pumping the vacuum degree in the drying box to limit vacuum, and preserving the heat for 4 hours.
Comparative example 1
The sodium carboxymethyl cellulose was used instead of hydroxypropyl cellulose-L in the recipe, and the other recipes and processes were the same as in example 1.
Comparative example 2
The sodium alginate was used instead of hydroxypropyl cellulose-L in the formulation, and the other formulation and process were the same as in example 1.
Comparative example 3
The recipe is as in example 1, and the preparation method is as follows:
(1) Dissolving 4.0g of vitamin C, 4.0g of dioctyl sodium sulfosuccinate and 2.0g of mannitol in 30mL of water for injection, regulating the pH to 3.4 by using 0.1mol/L hydrochloric acid to obtain a water phase, dissolving a compound of 4.0g of carfilzomib and 4.0g of hydroxypropyl cellulose-L in 30mL of dichloromethane, mixing and stirring an organic phase and the water phase to form colostrum;
(3) Shearing the formed colostrum at high speed at 11000rpm for 10min, transferring the mixture into a high-pressure homogenizer, homogenizing at 5000psi for 3 times, homogenizing at 9000psi at 30deg.C for 10 times, and performing nanoemulsification; ultrasonic treatment is carried out on the prepared primary suspension agent for 10 times under the power of 500W, and the ultrasonic treatment time is 10 seconds/time, so as to prepare a nanoemulsion suspension agent;
(4) The methylene dichloride is removed by rotary evaporation in vacuum for 10 hours on a vacuum rotary evaporator at the temperature lower than 50 ℃, the obtained mixture is added with water for injection to a volume of 100mL, the mixture is filtered by a 0.22 mu m membrane, sterilized, filled and freeze-dried, nitrogen protection is filled after the freeze-drying is finished, and capping is carried out after the capping is carried out, so that the carfilzomib nanoemulsion suspension freeze-dried preparation is obtained, and the freeze-drying process is as follows:
pre-freezing: placing the half-finished product which is filled and half-plugged on a partition board in a freeze-drying machine box for pre-freezing, wherein the temperature is-30 ℃ and the heat preservation time is 8 hours;
sublimation drying stage: when the vacuum degree in the drying oven reaches 150mbar, the main drying temperature is raised to-15 ℃ for 10 hours, and the heat preservation time is 15 hours after the temperature is raised;
and (3) a re-drying stage: raising the temperature to 10 ℃ for 1 hour; and pumping the vacuum degree in the drying box to limit vacuum, and preserving the heat for 4 hours.
Verification embodiment
1. Quality evaluation of nanoemulsion suspension lyophilized preparation
Taking the carfilzomib nanoemulsion suspension freeze-dried preparation products prepared in examples 1-8 and comparative examples 1-3, re-dissolving the products by adopting a 5% glucose solution at 25 ℃, and examining the appearance properties before and after re-dissolving, the pH value of the solution after re-dissolving, the moisture content of the product before re-dissolving and the particle size of the nanoemulsion suspension after re-dissolving, wherein the particle size is measured by using a laser scattering particle size analyzer. The results are shown in Table 1.
TABLE 1
Remarks: ■ White to off-white loose nuggets or powders; ● A suspension;
Experimental results show that the carfilzomib nanoemulsion suspension freeze-dried preparation prepared by the method has the appearance of white to white loose blocks or powder, low moisture content, small and uniform particle size after re-dissolution, and is superior to the preparation products prepared by comparative examples 1-3.
2. Stability investigation
Samples of the carfilzomib nanoemulsion suspension lyophilized formulations prepared in examples 1-8 and comparative examples 1-3 were taken and subjected to solution stability studies at 25 ℃ after reconstitution with a 5% glucose solution. The results are shown in Table 2.
TABLE 2
The experimental results show that the solution of the nanoemulsion suspension freeze-dried preparation prepared by the invention can be stored for at least 8 hours at the temperature of 25 ℃, the content of related substances is less than 1.0%, the content of the related substances is higher than 98%, the content of the related substances is lower than that in the prior art, the content of active ingredients is high, and the stability is good.
Claims (2)
1. A carfilzomib nanoemulsion suspension lyophilized formulation comprising: the composite is prepared from carfilzomib and hydroxypropyl cellulose-L, a surfactant, an antioxidant, a pH regulator and a freeze-drying protective agent; wherein, 1 part of carfilzomib, 1-20 parts of hydroxypropyl cellulose-L, 1-10 parts of surfactant and 1-5 parts of antioxidant; the surfactant is one or two selected from sodium dodecyl sulfate and dioctyl sodium sulfosuccinate; the antioxidant is selected from one or more of vitamin E, ethylenediamine tetraacetic acid, derivatives of ethylenediamine tetraacetic acid, deferoxamine mesylate, cysteine hydrochloride, vitamin C and sulfite; the pH regulator is selected from one or more of hydrochloric acid, phosphoric acid, acetic acid or citric acid; the pH adjusting range is 3.4-3.6; the freeze-drying protective agent is one or more selected from sucrose, lactose, glucose, maltose, mannitol and sorbitol; the nanoemulsion suspension freeze-dried preparation is prepared by the following method:
(1) Dissolving carfilzomib and hydroxypropyl cellulose-L in dichloromethane, hermetically stirring for 25-35 h at a temperature lower than 35 ℃, and removing the dichloromethane by rotary evaporation to form a uniform complex of carfilzomib and hydroxypropyl cellulose-L;
(2) Dissolving the compound in the step (1) in dichloromethane to obtain an organic phase; dissolving a surfactant, an antioxidant and a freeze-drying protective agent in water, regulating the pH value to be 3.4-3.6 by using a pH regulator, and obtaining a water phase; mixing and stirring the organic phase and the water phase to form colostrum;
(3) Shearing the colostrum obtained in the step (2) at a high speed, transferring the mixture into a high-pressure homogenizer for nanoemulsifying, and performing ultrasonic treatment to obtain a nanoemulsion suspension;
(4) Removing dichloromethane by rotary evaporation, adding water for injection into the obtained mixture to fix volume, filtering and sterilizing with a 0.22 mu m filter membrane, sub-packaging, freeze-drying, filling nitrogen for protection after freeze-drying, and capping after tamponade to obtain a carfilzomib nanoemulsion suspension freeze-drying preparation;
the freeze-drying process in the step (4) is as follows:
pre-freezing: the semi-finished product which is filled and half-plugged is placed on a baffle plate in a freeze-drying machine box to be pre-frozen, wherein the pre-freezing temperature is between minus 30 ℃ and minus 40 ℃ for 8 to 12 hours;
Sublimation drying stage: when the vacuum degree in the drying box reaches 150mbar to 200mbar, the main drying temperature is increased to minus 20 ℃ to minus 15 ℃ for 10 to 15 hours, and the heat preservation time is 10 to 20 hours after the temperature is increased;
And (3) a re-drying stage: raising the re-drying temperature to 10-15 ℃; when in use, the time is 1 to 3 hours; and pumping the vacuum degree in the drying box to limit vacuum, and preserving the heat for 4-7 h.
2. The nanoemulsion suspension lyophilized formulation according to claim 1, comprising: 1 part of carfilzomib, 1-10 parts of hydroxypropyl cellulose L, 1-5 parts of surfactant, 1-3 parts of antioxidant, pH regulator and freeze-drying protective agent.
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| CN101612131A (en) * | 2009-07-17 | 2009-12-30 | 郑州大学 | 2-methoxyestradiol nanosuspension frozen powder and preparation method thereof |
| CN102133177A (en) * | 2011-03-22 | 2011-07-27 | 山东大学 | Plagiochin nanocrystal preparation and preparation method thereof |
| CN107802606A (en) * | 2017-12-11 | 2018-03-16 | 齐鲁制药(海南)有限公司 | A kind of injection Carfilzomib and preparation method thereof |
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| US10301353B2 (en) * | 2014-12-31 | 2019-05-28 | Dr. Reddy's Laboratories Limited | Co-crystal of carfilzomib with maleic acid and process for the preparation of pure carfilzomib |
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| CN102133177A (en) * | 2011-03-22 | 2011-07-27 | 山东大学 | Plagiochin nanocrystal preparation and preparation method thereof |
| CN107802606A (en) * | 2017-12-11 | 2018-03-16 | 齐鲁制药(海南)有限公司 | A kind of injection Carfilzomib and preparation method thereof |
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