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All-trans retinoic acid injection and application

一种全反式维甲酸、注射剂的技术，应用在生物制药领域，能够解决全反式维甲酸血浆半衰期短、全反式维甲酸水溶性低、生物利用度只有30％等问题，达到抑制肿瘤细胞增值、大医疗实用性、抑制肿瘤复发的效果

Inactive Publication Date: 2018-03-06
HIGHFIELD BIOPHARM CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, the clinical application of all-trans retinoic acid is limited by the following aspects: 1. the water solubility of all-trans retinoic acid is extremely low (4.77e-03g / l); 2. the plasma half-life of all-trans retinoic acid is relatively short , and to exert its drug effect needs to maintain a certain blood drug concentration in a long period of time, and the drug effect concentration in the target organ
At present, almost all studies use oral preparations, and their bioavailability is only below 30%.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] In this example, the following three methods are used to investigate the saturation solubility of different solubilizing molecules after solubilizing ATRA.

[0074] (1) Emulsification method: Dissolve an appropriate amount of solubilizing molecules in 1ml ultrapure water as the water phase; dissolve 1mg of the drug in 1ml of an organic solvent as the organic phase; add the organic phase to the water phase under stirring, Stir overnight to evaporate the organic solvent or remove the organic solvent by rotary evaporation to obtain a drug-containing solution.

[0075] (2) Dialysis method: Dissolve the drug and solubilizing molecules in an organic solvent, then mix with 1 ml of ultrapure water, and dialyze the obtained solution in pure water to obtain a solution containing the drug.

[0076] (3) Freeze-drying method: dissolve an appropriate amount of solubilizing molecules in 1ml of pure water, add an appropriate amount of freeze-drying protective agent, as the water phase;...

Embodiment 2

[0080] EPC, HSPC and DPPC were selected as the main lipid materials respectively. Mix according to the molar ratio of PC:Chol:DSPE-PEG2000=2:1:0.125, add ATRA (the mass ratio of lipid / ATRA is 20:1, 40:1, 50:1 respectively), and add 5-7 small glass beads and hydrated by swirling for 30 minutes. Sequentially extrude through polycarbonate membranes with apertures of 400nm, 200nm, and 100nm 15 times each. The obtained all-trans retinoic acid liposomes had an average particle size in the range of 100nm±30nm and a PDI of about 0.1. Remove free all-trans retinoic acid (ATRA) by Sephadex G-50 microcolumn, within the linear range of the standard curve of all-trans retinoic acid, by removing the UV absorption peak area of ​​ATRA encapsulated into liposomes The encapsulation efficiency of the ATRA liposome obtained by the ratio of the UV absorption peak area of ​​ATRA before removal is respectively EPC liposome: 94%; HSPC liposome: 91%; DPPC liposome: 76%. The concentration of ATRA in...

Embodiment 3

[0083] Weigh 0.097 gram of hydrogenated soybean lecithin (HSPC), 0.031 gram of pegylated phospholipid 1,2-distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG2000) and 0.031 gram of cholesterol, and use 1.6 ml of Dissolve ethanol and place in a 70°C water bath to dissolve and mix. The ethanol mixture was added to 6.4 mL of calcium acetate buffer (pH 9.0). And placed in a water bath at 70 degrees Celsius for 30 minutes. The obtained liposome vesicles are sequentially extruded through polycarbonate membranes with apertures of 400nm, 200nm, 100nm, and 50nm each eight times to finally obtain liposomes with an average particle diameter of about 90nm.

[0084] Dialyze the liposomes prepared in the previous step through a dialysis membrane with a pore size of 10,000, replace the aqueous phase with a 10% mass fraction, and add a suspension of 4 mg / ml all-trans retinoic acid to a sucrose solution with a pH of 6 to 7 , and incubated at 60 degrees Celsius for 45 minute...

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Abstract

The invention belongs to the technical field of biological pharmacy, and particularly relates to an all-trans retinoic acid injection and application. The all-trans retinoic acid injection includes all-trans retinoic acid and hydrotropic molecules. According to the prepared all-trans retinoic acid injection, the apparent solubility of the all-trans retinoic acid is increased from 0.01 mg / ml in theprior art to 0.1 mg / ml or above, and at least increased by 10 times. By applying the injection, the activity of infiltrative immunosuppression cell mass in blood and tumor tissues of patients suffering from tumors can be reduced, the immune elimination effect of mechanism special for the tumors is improved, by using the injection alone or using the injection with the cooperation of other drugs for application, the growth and recurrence of the tumors can be suppressed, and therefore the all-trans retinoic acid injection has great medical practicability.

Description

technical field [0001] The invention belongs to the technical field of biopharmaceuticals, and in particular relates to an all-trans retinoic acid injection and its application. Background technique [0002] Retinoic acid is a metabolite of vitamin A in the body. All-trans retinoic acid (ATRA) is used as a drug to treat acne, and it is also an important drug for the clinical treatment of acute promyelocytic leukemia (APL). The current clinical applications are all administered through oral preparations. [0003] All-trans retinoic acid (ATRA) affects gene expression by binding to specific receptors (RARs, RXRs and RORs) in cells. In the treatment of acute promyelocytic leukemia, it can promote the differentiation of APL cells and the degradation of PML / RARαgene , to achieve therapeutic effect (Effectiveness and Pharmacokinetics of Low-Dose All-transRetinoic Acid (25mg / m2) in Acute Promyelocytic Leukemia. Blood 82,12,1993.P.3560). There are also literatures suggesting that ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/203A61K9/00A61P35/00
CPCA61K9/0019A61K31/203A61K47/24A61K47/28A61K47/44A61P35/00A61K9/1271A61K9/1075A61K9/107A61K31/19A61K9/08A61K9/10A61K9/14
Inventor 徐宇虹陈晓龙郑安杰吴烈宜
Owner HIGHFIELD BIOPHARM CORP
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