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CN-121978240-A - Encapsulation rate determination method of sulfobutyl betacyclodextrin inclusion drug

CN121978240ACN 121978240 ACN121978240 ACN 121978240ACN-121978240-A

Abstract

The invention discloses a method for measuring the encapsulation rate of a sulfobutyl betacyclodextrin inclusion drug, and relates to the field of quality control of sulfobutyl betacyclodextrin inclusion materials. The method comprises the steps of (1) adding a solvent 1 into a freeze-dried product of the sulfobutyl betacyclodextrin inclusion drug, extracting, taking supernatant or subsequent filtrate, measuring the free drug amount by liquid chromatography, (2) taking the freeze-dried product of the sulfobutyl betacyclodextrin inclusion drug to be dissolved by the solvent 2, measuring the total drug amount by liquid chromatography, and (3) calculating the encapsulation rate of the inclusion drug according to the free drug amount and the total drug amount. The determination method is simpler and more convenient, good in repeatability and high in accuracy.

Inventors

  • WANG JUN
  • JIANG SHUQIN
  • LIU LIN
  • ZHANG BO
  • CHU HONGXING
  • CHENG KAISHENG
  • ZENG QINGYUAN

Assignees

  • 合肥亿帆生物制药有限公司

Dates

Publication Date
20260505
Application Date
20260211

Claims (10)

  1. 1. The method for measuring the encapsulation efficiency of the sulfobutyl betacyclodextrin inclusion drug is characterized by comprising the following steps of: (1) Adding solvent 1 into freeze-dried product of sulfobutyl betacyclodextrin inclusion medicine, extracting dissolved free medicine which is not included by sulfobutyl betacyclodextrin, taking supernatant or subsequent filtrate, and adopting a proper method to measure the free medicine amount; (2) In addition, the freeze-dried product of the sulfobutyl betacyclodextrin inclusion medicine is taken, added with a solvent 2 to be completely dissolved, and the total medicine amount is measured by adopting a proper method; (3) The encapsulation efficiency of the inclusion drug was calculated according to the following formula: 。
  2. 2. the method according to claim 1, wherein the content of the sulfobutyl betacyclodextrin inclusion drug comprises at least one of voriconazole, ziprasidone mesylate, aripiprazole, amiodarone hydrochloride, carfilzomib, posaconazole, melphalan hydrochloride, carbamazepine, delafloxacin, allopregnanolone, adefovir, fosphenytoin sodium, levothyroxine sodium, docetaxel, fosaprepitant.
  3. 3. The method according to claim 1, wherein the solvent 1 is one or a combination of acetonitrile, absolute ethanol, isopropanol, acetone, N-propanol, tetrahydrofuran, N-butanol, isobutanol, t-butanol, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, polyethylene glycol 400, tween 80, dioxane.
  4. 4. The method according to claim 1, wherein in the step (1), the mass-to-volume ratio of the sulfobutyl betacyclodextrin inclusion drug to the solvent 1 is 1:5-15, g: ml.
  5. 5. The method according to claim 4, wherein in the step (1), the mass-to-volume ratio of the sulfobutylbetacyclodextrin inclusion drug to the solvent 1 is 1:10, g:mL.
  6. 6. The assay method of claim 1, wherein in step (1), the extraction is ultrasonic extraction or shaking extraction.
  7. 7. The method according to claim 6, wherein in the step (1), the extraction is shaking extraction, and further wherein the time of shaking extraction is 1 to 10 minutes.
  8. 8. The method according to claim 1, wherein in the step (2), the solvent 2 is one or a combination of water, formamide, ethylene glycol, dimethyl sulfoxide, and glycerol.
  9. 9. The method according to claim 8, wherein in the step (2), the solvent 2 is water.
  10. 10. The method according to claim 1, wherein in step (1) or step (2), the suitable method for measuring the amount of free drug or total amount of drug is liquid chromatography.

Description

Encapsulation rate determination method of sulfobutyl betacyclodextrin inclusion drug Technical Field The invention relates to the field of quality control of sulfobutyl betacyclodextrin inclusion compounds, in particular to a method for measuring the encapsulation rate of sulfobutyl betacyclodextrin inclusion drugs. Background The difficulty of developing new drugs is increased remarkably due to the low solubility and absorptivity of the poorly soluble drugs, and in the development of new drugs, the ratio of the poorly soluble candidate drugs of BCS II and BCS IV is more than 90%, so that the solution of the solubility problem is important for improving the bioavailability and the curative effect of the drugs. The medicine solubilization means are divided into chemical modification and physical modification according to the physicochemical process, wherein the chemical modification comprises salification and prodrug design, and the physical modification comprises micronization, solid dispersion, emulsification, cyclodextrin inclusion and the like. Cyclodextrins are cyclic oligosaccharides produced from starch, the most commonly used natural cyclodextrins being alpha-cyclodextrin, beta-cyclodextrin and gamma-cyclodextrin, consisting of 6, 7 and 8 glucopyranose units, respectively. The ring opening of α -cyclodextrin is too small for many drugs, while γ -cyclodextrin, although having a large molecular hole, is costly to produce and cannot be mass produced industrially, so β -cyclodextrin is one of the best known inclusion materials. Natural beta-cyclodextrin has strong nephrotoxicity, and poor water solubility caused by intramolecular hydrogen bond formation, and has limited application in drug solubilization. To solve the problems of water solubility and nephrotoxicity, scientists chemically modified the primary secondary hydroxyl groups (especially the 2,3 and 6 hydroxyl groups) on the beta-cyclodextrin molecules to form representative beta-cyclodextrin derivatives, such as methyl betacyclodextrin, carboxymethyl betacyclodextrin, hydroxypropyl betacyclodextrin, sulfobutyl betacyclodextrin and the like. Among them, sulfobutyl betacyclodextrin is most used in marketed drugs. In order to evaluate the inclusion effect of the betacyclodextrin inclusion compound, the encapsulation efficiency thereof needs to be measured. Chinese patent CN116474119A sets the methyl betadine clathrate of solid tetrazine dicarboxamide in a sealed container filled with 20mL diethyl ether, shakes for 10min by using a vortex mixer, washes out the free tetrazine dicarboxamide, pours the diethyl ether mixed with the free tetrazine dicarboxamide, and naturally volatilizes diethyl ether in a ventilation place until no diethyl ether taste exists, thus obtaining the free tetrazine dicarboxamide. And measuring the peak area of the obtained free tetrazine dicarboxamide by using a high performance liquid chromatograph, calculating the content of the free tetrazine dicarboxamide, and comparing the content with the input tetrazine dicarboxamide to calculate the inclusion rate of the medicine. For the sulfobutyl betacyclodextrin inclusion drug, the molecular weight difference between the sulfobutyl betacyclodextrin inclusion drug and the free drug molecule is small, the permeation of solute is considered to be also dependent on the molecular shape, hydration degree, ionic charge and polarity, in order to enable the free drug to rapidly permeate through the membrane, the molecular weight cut-off of the dialysis membrane is selected to be 100 times the allowable molecular weight and not higher than 50% -80% of the molecular weight to be cut-off, and the molecular weight ratio of two substances to be separated is at least 25, so that a ultrafiltration tube or a dialysis bag with proper molecular weight cut-off cannot be found for separation. Gel chromatography is often used for separation of substances of different sizes, but after injection of a trace amount of sample solution into the chromatography, the inclusion compound is dissociated by dilution with a large amount of mobile phase, resulting in final elution of the inclusion compound without drug molecules. Therefore, the method for determining the encapsulation efficiency of the sulfobutyl betacyclodextrin inclusion medicine, which is simple and convenient, good in repeatability and high in accuracy, is developed and has important significance. Disclosure of Invention Aiming at the limitations of the existing means for separating the sulfobutyl betacyclodextrin inclusion drugs from free drug molecules, the invention utilizes the solubility difference (the sulfobutyl betacyclodextrin inclusion drug freeze-dried product is indissolvable in specific organic solvents, and trace free drug molecules can be completely dissolved in the specific organic solvents) to ensure that the sulfobutyl betacyclodextrin inclusion drug freeze-dried product is extracted by the organic solvents and then centrifuged