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US-12616676-B2 - Preparation method and use of modified hydrophobic excipient

US12616676B2US 12616676 B2US12616676 B2US 12616676B2US-12616676-B2

Abstract

The present invention relates to a method for preparing a modified hydrophobic excipient including the following steps: Step A. obtaining intermediate I or II from a hydrophobic natural compound with one to three hydroxyl groups or a hydrophobic synthetic compound with one to three hydroxyl groups and amino acid derivatives with amino protecting groups and different chain lengths acting as raw material; Step B. obtain intermediate III from an amino acid derivative and N-hydroxysuccinimide or 1-hydroxybenzotriazole acting as raw material and a dehydrating agent; and Step C. reacting the intermediate II and the intermediate III as raw material with an acid-binding agent under a dark condition to generate a modified hydrophobic excipient.

Inventors

  • Xiang Gao

Assignees

  • ZHEJIANG ZHIDA PHARMACEUTICAL CO., LTD.

Dates

Publication Date
20260505
Application Date
20211220

Claims (8)

  1. 1 . A method for preparing a modified hydrophobic excipient, wherein the method comprises the following steps: Step A. subjecting castor oil and N-tert-butoxycarbonyl-glycine acting as raw material, a dehydrating agent and a catalyst to an esterification reaction to generate intermediate I: castor oil-O—(N-t-butoxycarbonylglycine) triester, and adding an organic acid into the intermediate I, or performing catalytic hydrogenation to remove an amino protecting group of N-tert-butyloxycarbonyl, so as to generate intermediate II: castor oil-O-glycine triester; a structural formula of intermediate I is as follows: a structural formula of intermediate II is as follows: Step B. subjecting N-fluorenylmethoxycarbonyl-N′-tert-butoxycarbonyl-L-lysine and N-hydroxysuccinimide acting as raw material and a dehydrating agent to an esterification reaction to obtain intermediate III: N-fluorenylmethoxycarbonyl-N′-tertbutylcarbonyl-L-lysine-N-hydroxysuccinimide ester; and Step C. reacting the intermediate II and the intermediate III as raw material with an acid-binding agent under a dark condition to generate a modified hydrophobic excipient, a structural formula of the modified hydrophobic excipient is as follows: wherein, the dehydrating agent is dicyclohexylcarbodiimide, the catalyst is 4-dimethylaminopyridine or pyridine, the acid-binding agent is triethylamine, and the organic acid is trifluoroacetic acid.
  2. 2 . The method according to claim 1 , wherein, in Step A, the condition of the catalytic hydrogenation reaction is H 2 (1-5 atm) and Pt/C as catalyst.
  3. 3 . The method according to claim 1 , wherein, in Step A, the intermediate I is dissolved in a solvent before adding the acid or performing hydrogenation.
  4. 4 . A stable drug-loaded fat emulsion, comprising a drug and the modified hydrophobic excipient prepared by the method according to claim 1 as an oil phase excipient.
  5. 5 . The stable drug-loaded fat emulsion according to claim 4 , wherein the drug-loaded fat emulsion is composed of the modified hydrophobic excipient, a hydrophobic drug and a surfactant, wherein the modified hydrophobic excipient, the hydrophobic drug and the surfactant are dissolved in a solvent, the solvent is removed, a buffer solution is added for hydration, and then the solution is prepared into the drug-loaded fat emulsion.
  6. 6 . The stable drug-loaded fat emulsion according to claim 5 , wherein a proportion of the modified hydrophobic excipient to the hydrophobic drug and the surfactant is 300 mg of the modified hydrophobic excipient, 0-150 mg of the hydrophobic drug, 40-450 mg of egg yolk lecithin, 0-225 mg of cholesterol and 0-300 mg of mPEG2000-DSPE.
  7. 7 . The stable drug-loaded fat emulsion according to claim 4 , wherein the drug loaded by the modified hydrophobic excipients comprises paclitaxel, and docetaxel.
  8. 8 . The stable drug-loaded fat emulsion according to claim 4 , wherein a method for preparing the drug-loaded fat emulsion comprises one or a combination of high-speed shearing, phase transition, high-pressure homogenization, micro-jet and micro-fluidic methods.

Description

CROSS-REFERENCE TO RELATED APPLICATION This application is a continuation of international PCT application serial no. PCT/CN2019/091964, filed on Jun. 19, 2019. The entirety of the above-mentioned patent application is hereby incorporated by reference herein and made a part of this specification. TECHNICAL FIELD The present application relates to the application field of preparation of pharmaceutical excipient and drug-loaded fat emulsion, in particular to a modified hydrophobic excipient, preparation method and use thereof. BACKGROUND ART Many poorly water-soluble drugs require chemical or physical methods to increase water solubility and have to be prepared as injections before use. Drugs can be solubilized by chemical coupling with hydrophilic or amphiphilic excipients, or by preparation processes such as forming a molecular inclusion with cyclodextrin, forming a micelle, nano-dispersion and liposome with a surfactant, forming emulsion with a surfactant and an oil phase, and albumin wrapping. Emulsion is a commonly used drug carrier to increase the solubility of poorly water-soluble drugs, while protecting the drugs from rapid degradation and altering the residence time of drugs in the blood and tissue distribution of drugs in the body. An emulsion is a dispersion of a liquid oil phase stabilized by a layer of hydrophilic surfactant in an aqueous phase. Solid Lipid Nanoparticles particularly refer to a dispersion of an oil phase stabilized by a layer of hydrophilic surfactant and assuming a solid state at normal temperature in an aqueous phase. A drug-loaded emulsion usually uses natural or synthetic triglyceride, fatty acid ester, cholesterol oleate or medium- and long-chain hydrocarbon as an oil phase, which have strong hydrophobicity. A drug has to be firstly well dissolved in a liquid oil phase before it can be prepared into a drug loaded emulsion is prepared. Therefore, the solubility of the drug in the oil phase is a key parameter for determining the drug loading capacity of the emulsion and the stability of the emulsion. However, many drugs have limited solubility in an oil phase having a strong hydrophobicity. Therefore, there will be very important practical significance to improve the solubility of hydrophobic drugs in an oil phase. SUMMARY In view of the defects present in existing technologies, a first purpose of the present application is to provide a modified hydrophobic excipient which has advantages of improving solubility of a drug in the hydrophobic excipient and increasing the drug loading capacity of the hydrophobic excipient. In order to achieve the above purpose, the present application provides the following technical solutions: In a first aspect, a modified hydrophobic excipient is provided, having the following molecular formula: where R is a hydrophobic natural compound or hydrophobic synthetic compound with one to three hydroxyl groups (n=1-3); R1 is an α-amino protecting group, and R2 is an amino acid side chain, wherein,when m=0, R reacts with an amino acid derivative with a protecting group by esterification to form a hydrophobic excipient carrying the amino acid derivative with a protecting group; orwhen m=1, R is first introduced with an amino acid linking arm of different chain lengths (1=1, 2, 4, 6) via an ester group, and then introduced with an amino acid derivative with a protecting group. In a further development of the first aspect of the present application, the hydrophobic natural compound or hydrophobic synthetic compound with one to three hydroxyl groups (n=1-3) includes a triglyceride with one to three hydroxyl groups or a derivative thereof or a hydrophobic derivative of a steroid, or is obtained by introducing a hydroxyl group into an unsaturated triglyceride through an epoxy reaction and an electrophilic reaction or by introducing a hydroxyl group into an unsaturated triglyceride through a Michael reaction under a photocatalytic condition. In a further development of the first aspect of the present application, the natural triglyceride with one to three hydroxyl groups is castor oil, and the derivative of the natural triglyceride with one to three hydroxyl groups is a hydrogenated derivative of castor oil. In a further development of the first aspect of the present application, the hydrophobic derivative of the steroid is any one selected from a group consisting of an ester derivative or an amide derivative of cholic acid, an ester derivative or an amide derivative of deoxycholic acid, an ester derivative or an amide derivative of lithocholic acid, and an ester derivative or an amide derivative of glycocholic acid. In a further development of the first aspect of the present application, the derivatives of the amino acids are any one selected from a group consisting of N-fluorenylmethoxy-carbonyl-N′-tert-butoxycarbonyl-L-lysine, N-fluorenylmethoxycarbonyl-N′-tert-butoxycarbonyl-D-lysine, N-benzyloxycarbonyl-N′-tert-butoxycarbonyl-L-lysine, N-benzyloxycarbonyl