DRUG-IODINATED OIL DISPERSION, METHOD FOR PREPARING SAME AND ITS APPLICATION IN EMBOLIZATION TREATMENT FOR LIVER CANCER

Abstract

Disclosed is a method of preparing a drug-iodinated oil dispersion by high-pressure dissolution. In the invention, drug molecules are dissolved in and thoroughly mixed with iodinated oil under high pressure and rapid stirring. After the depressurization, the drug molecules are dispersed in the iodinated oil to prepare a uniformly-mixed drug-iodinated oil dispersion. The drug-iodinated oil dispersion prepared herein, compared to the drug-iodinated oil suspension and emulsion, has advantages of controllable morphology, long-term stability and slow drug-releasing rate, moreover, the drug molecules do not negatively affect the iodinated oil in physicochemical properties such as viscosity. In the liver cancer treatment, the prepared drug-iodinated oil dispersion is firstly injected through the hepatic arteries to perform the embolization, and the drug molecules are slowly released for a sustained treatment. The invention provides a good reference for the therapy combined with iodinated oil embolization.

Claims

1. A drug-iodinated oil dispersion, comprising a drug molecule and an iodinated oil injection; wherein the drug molecule has a concentration of 0.05-5 mg/mL in the drug-iodinated oil dispersion; the drug-iodinated oil dispersion is prepared through the following steps: 1) dispersing the drug molecule in a first solvent to obtain a solution A; 2) adding the iodinated oil injection and the solution A to a high-pressure reactor; 3) boosting a pressure of the high-pressure reactor to 10-20 Mpa and controlling a temperature of the high-pressure reactor at 30-50 C.; and stirring the reaction mixture for 0.5-2 h after the pressure and the temperature are stable; and 4) depressurizing the high-pressure reactor; and collecting the drug-iodinated oil dispersion from the high-pressure reactor.

2. The drug-iodinated oil dispersion of claim 1, wherein the iodinated oil injection comprises 37.0%-41.0% by weight of iodine.

3. The drug-iodinated oil dispersion of claim 1, wherein the first solvent is ethanol.

4. The drug-iodinated oil dispersion of claim 3, wherein the drug molecule has a concentration of 0.5-10 mg/mL in the solution A, and a volume ratio of the solution A to the iodinated oil injection is 0.01-0.5:1-10.

5. The drug-iodinated oil dispersion of claim 1, wherein the drug molecule is selected from a chemotherapeutic drug molecule, a radiotherapeutic drug molecule, a radiotherapy-sensitized chemotherapeutic drug molecule, a photosensitive drug molecule, or a combination thereof.

6. The drug-iodinated oil dispersion of claim 5, wherein the chemotherapeutic drug molecule comprises at least one of epirubicin, 5-fluorouridine, pirarubicin, pingyangmycin, gemcitabine, camptothecin and paclitaxel.

7. The drug-iodinated oil dispersion of claim 5, wherein the radiotherapeutic drug molecule comprises at least one of .sup.131I-, .sup.177Lu- and .sup.64Cu-labeled radiotherapeutic molecules.

8. The drug-iodinated oil dispersion of claim 5, wherein the radiotherapy-sensitized chemotherapeutic drug molecule comprises at least one of docetaxel, curcumin, tirapazamine, cisplatin, doxorubicin and mitomycin C.

9. The drug-iodinated oil dispersion of claim 5, wherein the photosensitive drug molecule comprises at least one of indocyanine green, new indocyanine green IR-820, 5-aminolevulinic acid and porphyrin dye.

10. A use method of the drug-iodinated oil dispersion of claim 1, comprising: applying the drug-iodinated oil dispersion in the preparation of a tumor-treating drug or an embolic agent.

11. A method for preparing a drug-iodinated oil dispersion, comprising: 1) dispersing a drug molecule in ethanol to obtain a solution A; 2) adding an iodinated oil injection and the solution A to a high-pressure reactor; 3) boosting a pressure of the high-pressure reactor to 10-20 Mpa and controlling a temperature of the high-pressure reactor at 30-50 C.; and stirring the reaction mixture for 0.5-2 h after the pressure and the temperature are stable; and 4) depressurizing the high-pressure reactor; and collecting the drug-iodinated oil dispersion from the high-pressure reactor.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0037] FIG. 1A shows absorption curves of iodinated oil (IO), indocyanine green (ICG), doxorubicin (Dox), doxorubicin-iodinated oil dispersion (IO@ICG) and indocyanine green/doxorubicin-iodinated oil dispersion (IO@ICG/Dox).

[0038] FIG. 1B shows pictures of IO@ICG and the IO@ICG/Dox after stored at body temperature for two weeks.

[0039] FIG. 2 shows fluorescence imaging and intensity of ICG and IO@ICG.

[0040] FIG. 3 shows changes of the fluorescence intensity of the ICG and the IO@ICG over time.

DETAILED DESCRIPTION OF EMBODIMENTS

[0041] The application will be more clearly illustrated with reference to the following embodiments.

[0042] 1) A doxorubicin-iodinated oil dispersion of the application is prepared as follows.

[0043] (a) 5-10 mg of doxorubicin is weighed and added to 2 mL of ethanol, then the reaction mixture is mixed uniformly under ultrasonication in an ultrasonic cleaner for 5 min to produce a doxorubicin-ethanol solution.

[0044] (b) 2-5 mL of an iodinated oil injection is added to a high-pressure reactor.

[0045] (c) 100-200 L of the doxorubicin-ethanol solution is added to the high-pressure reactor.

[0046] (d) The high-pressure reactor is sealed, and then pressurized to 10-20 Mpa and controlled at 30-50 C. by a system. After the pressure and temperature are stable, the reaction mixture is stirred by a stirring paddle at 8,000-12,000 rpm for 0.5-2 h.

[0047] (e) The high-pressure reactor is slowly depressurized by discharging air, and the doxorubicin-iodinated oil dispersion is collected.

[0048] 2) An indocyanine green-iodinated oil dispersion of the application is prepared as follows.

[0049] (a) 0.5-1 mg of indocyanine green is weighed and added to 2 mL of ethanol, then the reaction mixture is mixed uniformly under ultrasonication in an ultrasonic cleaner for 5 min to produce an indocyanine green-ethanol solution.

[0050] (b) 2-5 mL of the iodinated oil injection is added to a high-pressure reactor.

[0051] (c) 100-200 L of the indocyanine green-ethanol solution is added to the high-pressure reactor.

[0052] (d) The high-pressure reactor is sealed, and then pressurized to 10-20 Mpa and controlled at 30-50 C. by the system. After the pressure and temperature are stable, the reaction mixture is stirred by a stirring paddle at 8,000-12,000 rpm for 0.5-2 h.

[0053] (e) The high-pressure reactor is slowly depressurized by discharging air, and the indocyanine green-iodinated oil dispersion is collected.

[0054] 3) An indocyanine green/doxorubicin-iodinated oil dispersion of the application is prepared as follows.

[0055] (a) 0.5-1 mg of indocyanine green and 0.5-1 mg of doxorubicin are added to 2 mL of ethanol, and then the reaction mixture is mixed uniformly under ultrasonication in an ultrasonic cleaner for 5 min to produce an indocyanine green/doxorubicin-ethanol solution.

[0056] (b) 2-5 mL of an iodinated oil injection is added to a high-pressure reactor.

[0057] (c) 100-200 L of the indocyanine green/doxorubicin-ethanol solution is added to the high-pressure reactor.

[0058] (d) The high-pressure reactor is sealed, and then pressurized to 10-20 Mpa and controlled at 30-50 C. by the system. After the pressure and temperature are stable, the reaction mixture is stirred by a stirring paddle at 8,000-12,000 rpm for 0.5-2 h.

[0059] (e) The high-pressure reactor is slowly depressurized by discharging air, and the indocyanine green/doxorubicin-iodinated oil dispersion is collected.

[0060] In the preparation of above drug-iodinated oil dispersions, no significant variation is observed in the viscosity, solubility and diffusibility of the iodinated oil.

[0061] 4) A use method of a drug-iodinated oil dispersion in the co-therapy involving embolization for liver cancer includes the following steps.

[0062] (a) A doxorubicin-iodinated oil dispersion is injected in the hepatic feeding artery to perform embolization, so that the doxorubicin-iodinated oil dispersion can be held in large quantities in the liver cancer area for a long time to slowly release chemotherapeutic drug molecules, thereby realizing a long-term co-treatment of embolization and chemotherapy.

[0063] (b) An indocyanine green-iodinated oil dispersion or an indocyanine green/doxorubicin-iodinated oil dispersion is injected in the hepatic feeding artery to perform embolization. Meanwhile, the tumor area is monitored using magnetic resonance imaging. After the embolization is performed for 2-4 weeks, the tumor area is significantly reduced, and at this time, the surgical resection navigated by holographic molecular imaging can be performed to the tumor area through the indocyanine green fluorescence imaging.

EXAMPLE 1

[0064] A doxorubicin-iodinated oil dispersion was prepared through the following steps.

[0065] (a) 5 mg of doxorubicin was weighed and added to 2 mL of ethanol, then the reaction mixture was mixed uniformly under ultrasonication in an ultrasonic cleaner for 5 min to produce a doxorubicin-ethanol solution.

[0066] (b) 2 mL of an iodinated oil injection was added to a high-pressure reactor.

[0067] (c) 200 L of the doxorubicin-ethanol solution was added to the high-pressure reactor.

[0068] (d) The high-pressure reactor was sealed, and then pressurized to 10 Mpa and controlled at 30 C. by a system. After the pressure and temperature were stable, the reaction mixture was stirred by a stirring paddle at 9,000 rpm for 1 h.

[0069] (e) The high-pressure reactor was slowly depressurized by discharging air, and the doxorubicin-iodinated oil dispersion was collected.

EXAMPLE 2

[0070] An indocyanine green-iodinated oil dispersion was prepared through the following steps.

[0071] (a) 1 mg of indocyanine green was added to 2 mL of ethanol, then the reaction mixture was mixed uniformly under ultrasonication in an ultrasonic cleaner for 5 min to produce an indocyanine green-ethanol solution.

[0072] (b) 5 mL of an iodinated oil injection was added to a high-pressure reactor.

[0073] (c) 150 L of the indocyanine green-ethanol solution was added to the high-pressure reactor.

[0074] (d) The high-pressure reactor was sealed, and then pressurized to 20 Mpa and controlled at 40 C. by a system. After the pressure and temperature were stable, the reaction mixture was stirred by a stirring paddle at 8,000 rpm for 2 h.

[0075] (e) The high-pressure reactor was slowly depressurized by discharging air, and the indocyanine green-iodinated oil dispersion was collected.

EXAMPLE 3

[0076] An indocyanine green/doxorubicin-iodinated oil dispersion was prepared through the following steps.

[0077] (a) 0.75 mg of indocyanine green and 0.75 mg of doxorubicin were added to 2 mL of ethanol, then the reaction mixture was mixed uniformly under ultrasonication in an ultrasonic cleaner for 5 min to produce an indocyanine green/doxorubicin-ethanol solution.

[0078] (b) 2.5 mL of an iodinated oil injection was added to a high-pressure reactor.

[0079] (c) 150 L of the indocyanine green/doxorubicin-ethanol solution was added to the high-pressure reactor.

[0080] (d) The high-pressure reactor was sealed, then pressurized to 15 Mpa and controlled at 50 C. by a system. After the pressure and temperature were stable, the reaction mixture was stirred by a stirring paddle at 12,000 rpm for 0.5 h.

[0081] (e) The high-pressure reactor was slowly depressurized by discharging air, and the indocyanine green/doxorubicin-iodinated oil dispersion was collected.

[0082] As shown in FIG. 1A, compared to the pure ICG molecule, the ICG molecule in IO@ICG has a different absorption curve, however, an ICG characteristic peak was still observed. Compared to the pure ICG molecule and pure Dox molecule, ICG and Dox molecules in IO@ICG/Dox have different absorption curves, however, ICG and Dox characteristic peaks can still be observed. Moreover, in the IO@ICG and the IO@ICG/Dox, the ICG characteristic peak becomes narrower, which was similar to the ICG characteristic peak shown in the absorption curve of the nanostructure constructed by pure ICG.

[0083] As shown in FIG. 1B, the IO@ICG and the IO@ICG/Dox dispersions were respectively allowed to stand for two weeks at ambient temperature, and no significant sedimentation appeared, showing good stability of the IO@ICG and IO@ICG/Dox dispersions.

[0084] As shown in FIG. 2, IO@ICG was found to have obvious fluorescence emission when excited at 650 nm. Moreover, by comparing the fluorescence intensities of the IO@ICG and ICG under the excitation, IO@ICG had a significantly increased fluorescence intensity at this wavelength than ICG.

[0085] As shown in FIG. 3, the ICG had a gradually decreased fluorescence intensity over time, and a fluorescence half-life of the ICG was about three days. Though the prepared IO@ICG also had a gradually decreased fluorescence intensity over time, it can maintain a higher fluorescence intensity for a longer time. After placed for 12 days, the fluorescence intensity of the IO@ICG was still maintained at 3/4 or more of the initial value. These results fully demonstrated that the IO@ICG prepared in the application has excellent stability over time.

[0086] In the application, a drug-iodinated oil dispersion is prepared through the SHIFT. Compared to drug-iodinated oil suspensions or emulsions, the drug-iodinated oil dispersion has controllable concentration and dispersibility, better stability and predictable release performance. In addition, the drug will not significantly affect the physical properties of the iodinated oil, enabling the application of the drug-iodinated oil dispersion in the embolization treatment for liver cancer. Therefore, the drug-iodinated oil dispersion of the invention can be applied in the co-therapy of embolization and drug for liver cancer.