DRUG-LOADED EMULSION

Abstract

The present invention relates to a drug-loaded emulsion, comprising a modified hydrophobic excipient having the following formula, a hydrophobic drug and a surfactant:

##STR00001## where R is a hydrophobic natural compound or a hydrophobic synthetic compound with one to three hydroxyl groups (n=1-3); and R1 is an α-amino protecting group, and R2 is an amino acid side chain, wherein, when m=0, R is reacted 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; or when m=1, R is firstly introduced with an amino acid linking arm of different chain lengths (l=1, 2, 4, 6) via an ester group, and then introduced with an amino acid derivative with a protecting group.

Claims

1. A drug-loaded emulsion, comprising a modified hydrophobic excipient having the following formula, a hydrophobic drug and a surfactant: ##STR00023## where R is a hydrophobic natural compound or a hydrophobic synthetic compound with one to three hydroxyl groups (n=1-3); and R1 is an α-amino protecting group, and R2 is an amino acid side chain, wherein, when m=0, R is reacted 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; or when m=1, R is firstly introduced with an amino acid linking arm of different chain lengths (l=1, 2, 4, 6) via an ester group, and then introduced with an amino acid derivative with a protecting group.

2. The drug-loaded emulsion according to claim 1, wherein the modified hydrophobic excipient is protected amino acid ester of the hydrophobic excipient or protected amino acid amide of the hydrophobic excipient amino acid ester.

3. The drug-loaded emulsion according to claim 1, wherein the hydrophobic drug is a hydrophobic drug capable of having an intermolecular interaction, including aromatic ring stacking, hydrogen bond or hydrophobic interaction, with the modified hydrophobic excipients, such as paclitaxel and docetaxel.

4. The drug-loaded emulsion according to claim 1, wherein a ratio of the hydrophobic drug to the modified hydrophobic excipient is 0.01% (w/w)-99.9% (w/w) to 99.9% (w/w)-0.01(w/w), preferably 1% (w/w)-50% (w/w) to 99% (w/w)-50(w/w), and more preferably 1:1 to 1:5.

5. The drug-loaded emulsion according to claim 1, wherein the surfactant is a pharmaceutical surfactant excipient having a hydrophilic-lipophilic balance (HLB) value in the range of 0 to 40.

6. The drug-loaded emulsion according to claim 1, wherein the surfactant is a small molecule or large molecule pharmaceutical excipient with a function of solubilizing or emulsifying or wetting or foaming agent or defoaming agent or detergent.

7. The drug-loaded emulsion according to claim 1, wherein the surfactant is a small molecule or large molecule pharmaceutical excipient with a function of stabilizing a nanometer structure.

8. The drug-loaded emulsion according to claim 1, wherein the surfactant is a cationic or anionic or nonionic surfactant.

9. The drug-loaded emulsion according to claim 1, wherein the surfactant is phospholipid or cholesterol, or fatty acid with the chain length of C8-C22, or fatty acid salt with the chain length of C8-C22, sucrose fatty acid ester, sorbitan fatty acid (spans), polysorbate (Tweens) polyoxyethylene fatty acid ester (Myrij), polyoxyethylene fatty alcohol ether, or PEG-cholesterol derivative with different chain lengths, PEG-vitamin E succinate with different chain lengths, or PEG-phospholipid derivative with different chain lengths, or PEG-diglyceride derivative with different chain lengths, or any natural polymer pharmaceutical excipient or synthetic polymer pharmaceutical excipient with surface activity.

10. The drug-loaded emulsion according to claim 1, wherein the surfactant phospholipid is any one selected from a group consisting of phosphatidylcholine (PC), Phosphatidylglycerol (PG), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidic acid (PA), phosphatidylinositol (PI), eggphosphatidylcholine (EPC), egg phosphatidylglycerol (EPG), phosphatidylethanolamine (EPE), eggphosphatidylserine (EPS), egg phosphatidic acid (EPA), (egg phosphatidylinositol (EPI), soy phosphatidylcholine (SPC), soy phosphatidylglycerol (SPG), soyphosphatidylethanolamine (SPE), soy phosphatidylserine (SPS), (soy phosphatidic acid SPA), soy phosphatidylinositol (SPI), dipalmitoylphosphatidylcholine (DPPC), 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC), dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylglycerol (DPPG), dioleoylphosphatidylglycerol (DOPG), dimyristoylphosphatidylglycerol (DMPG), hexadecylphosphocholine (HEPC), hydrogenated soyphosphatidylcholine (HSPC), distearoylphosphatidylcholine (DSPC), distearoylphosphatidylglycerol (DSPG), dioleoylphosphatidylethanolamine (DSPE), palmitoylstearoylphosphatidylcholine (PSPC), palmitoylstearoylphosphatidylglycerol (PSPG), monooleoylphosphatidylethanolamine (MOPE), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC), distearoylphosphatidylethanolamine (DSPE), dipalmitoylphosphatidylserine (DPPS), 1,2-dioleoyl-sn-glycero-3-phosphatidylserine (DOPS), dimyristoylphosphatidylserine (DMPS), distearoylphosphatidylserine (DSPS), dipalmitoylphosphatidicacid (DPPA), 1,2-dioleoyl-snglycero-3-phosphatidic acid (DOPA), dimyristoylphosphatidic acid (DMPA), distearoylphosphatidic acid (DSPA), dipalmitoylphosphatidylinositol (DPPI), 1,2-dioleoylsn-glycero-3-phosphatidylinositol (DOPI), dimyristoylphosphatidylinositol (DMPI), distearoylphosphatidylinositol (DSPI), and a mixture thereof.

11. The drug-loaded emulsion according to claim 10, wherein the polyethylene glycol (PEG) with different chain lengths-the lipid derivative with the chain length of C8-C22 is a surfactant formed by connecting PEG with the chain length of 1-1000 repeating units and lipid with the chain length of C8-C22 by an ester bond or an ether bond or an amide bond.

12. The drug-loaded emulsion according to claim 11, wherein the PEG-phospholipid derivative with different chain lengths is a surfactant formed by connecting PEG with a chain length of 1-1000 repeating units and natural or synthetic phospholipid by an ester bond, an amide bond or a carbamoyl bond.

13. The drug-loaded emulsion according to claim 11, wherein, in a surfactant of the PEG-phospholipid derivative with different chain length prepared by connecting PEG with a chain length of 1-1000 repeating units with a natural or synthetic phospholipid by an ester bond or an amide bond or a carbamoyl bond, the natural or synthetic phospholipids is a natural or synthetic phospholipid with a carbon chain length of 12-22.

14. The drug-loaded emulsion according to claim 11, wherein, in a surfactant of the PEG-phospholipid derivative with different chain lengths prepared by connecting PEG with the chain length of 1-1000 repeating units with a natural or synthetic phospholipid by an ester bond or an amide bond or a carbamoyl bond, the natural or synthetic phospholipid is a natural or synthetic phospholipid having a saturated or unsaturated lipid chain with a carbon chain length of 12-22.

15. The drug-loaded emulsion according to claim 11, wherein, in a surfactant of the PEG-phospholipid derivative with different chain lengths prepared by connecting PEG with the chain length of 1-1000 repeating units with a natural or synthetic phospholipid by an ester bond or an amide bond or a carbamoyl bond, the natural or synthetic phospholipid is natural or synthetic cephalin.

16. The drug-loaded emulsion according to claim 1, wherein the natural polymer pharmaceutical excipient or synthetic polymer pharmaceutical excipient surfactant is a polysaccharide or polysaccharide derivative or polyoxyethylene-polyoxypropylene (poloxamer) or protein with surface activity.

17. The drug-loaded emulsion according to claim 1, wherein the pharmaceutical excipient surfactant is a single pharmaceutical excipient or a combination of multiple pharmaceutical excipient surfactants.

18. The drug-loaded emulsion according to claim 1, wherein the surfactant is lecithin or cholesterol or PEG-phospholipid derivative single pharmaceutical excipient or a combination of multiple pharmaceutical excipient surfactants.

19. The drug-loaded emulsion according to claim 1, wherein the surfactant is a combination of lecithin and PEG-cephalin derivative.

20. The drug-loaded emulsion according to claim 1, wherein a ratio of the hydrophobic excipient-the hydrophobic drug to the surfactant is (X+Y):Z, and Z %=100−(X+Y).

21. The drug-loaded emulsion according to claim 20, wherein a ratio of the hydrophobic excipient-the hydrophobic drug to the surfactant is (X+Y):Z=(0-50%):(100-50%).

Description

DETAILED DESCRIPTION

[0087] The present application will be described in further detail with reference to examples.

EXAMPLE 1

[0088] A preparation method of a modified hydrophobic excipient was performed as follows:

[0089] 9.34 g of castor oil (10 mmol), 29.5 g of N-fluorenylmethoxycarbonyl-N′-tert-butoxycarbonyl-L-lysine (60 mmol), 366 mg of 4-dimethylaminopyridine (DMAP) (3 mmol) were added into a 250 ml flask, then added with 12.4 g of dicyclohexylcarbodiimide (DCC) dissolved in 50 ml of anhydrous dichloromethane (60 mmol) and reacted at room temperature under dark conditions for three days. After the reaction being completed, as indicated by TLC analysis, the reaction mixture was filtered to remove the precipitate, then spin-dried, and purified by conventional purification to obtain a yellowish transparent viscous oily substance, which was cooled to obtain a glassy transparent solid as a modified hydrophobic excipient. The reaction formula was shown below. Castor oil is usually a mixture of triglycerides with different ricinoleic acid content (n=0-3), and molecular formula thereof cannot be accurately illustrated. The following reaction formula, taking n=3 as an example, is used to illustrate the method principle of the present application without limiting the present application.

##STR00008##

EXAMPLE 2

[0090] A preparation method of a hydrophobic excipient was performed as follows:

[0091] A-1, castor oil-O-glycine triester was esterified by N-tert-butoxycarbonylglycine, and then was subjected to acidification deprotection by the following synthetic route:

[0092] 9.34 g of castor oil (10 mmol), 7.2 g of N-t-butoxycarbonylglycine (45 mmol), and 366 mg of 4-dimethylaminopyridine (DMAP) (3 mmol) were added into a 250 ml flask, then added with 12.4 g of N, N′-dicyclohexylcarbodiimide (DCC) (60 mmol) dissolved in 50 ml of anhydrous dichloromethane, and reacted at room temperature under dark conditions for two days. After the reaction being completed, as indicated by TLC analysis, the reaction mixture was filtered to remove the precipitate, then spin-dried, and purified by conventional purification to obtain a colorless, transparent viscous oil, that is, the intermediate I, castor oil-O—(N-t-butoxycarbonylglycine) triester.

[0093] The intermediate I was dissolved in 40 ml of dichloromethane (DCM), then added with 40 ml of trifluoroacetic acid (TFA), and reacted at room temperature for 4 hours, to remove the protecting group. After removing excessive trifluoroacetic acid by spinning, 60 ml of dichloromethane was added to dissolve the product, then added with 10 g anhydrous sodium carbonate powder, and stirred for three days to obtain intermediate II, which was castor oil-O-glycine triester. The reaction formula was shown below. Castor oil is usually a mixture of triglycerides with different ricinoleic acid content (n=0-3), and molecular formula thereof cannot be accurately illustrated. The following reaction formula, taking n=3 as an example, is used to illustrate the method principle of the present application without limiting the present application.

##STR00009##

[0094] Or A-2, the castor oil-O-glycine triester were esterified by N-benzyloxycarbonyl glycine and then synthesized by a catalytic hydrogenation deprotection synthetic route, which included the following steps:

[0095] 9.34 g of castor oil (10 mmol), 8.6 g N-benzyloxycarbonylglycine (45 mmol), and 366 mg of 4-dimethylaminopyridine (DMAP) (3 mmol) were added to a 250 ml flask, then added with 12.4 g (60 mmol) of dicyclohexylcarbodiimide (DCC) dissolved in 50 ml of anhydrous dichloromethane, and reacted for two days at room temperature under dark conditions. After the reaction being completed, as indicated by TLC analysis, the reaction mixture was filtered to remove the precipitate, then spin-dried, and purified by conventional purification to obtain a colorless, transparent viscous oil, that is, the intermediate I, which was castor oil-O—(N-benzyloxycarbonylglycine) triester.

##STR00010##

[0096] In a catalytic hydrogenation pressure reactor, 15 g of castor oil-O—(N-benzyloxycarbonylglycine) triester was added, and then added with 40 ml of methanol and 1 ml of glacial acetic acid (HOAC). The mixture was sufficiently stirred and dissolved, added with about 600 mg of 5% palladium on carbon (Pt/C), the headspace air was replaced with hydrogen under stirring, the hydrogen pressure was increased to 5 atm, the reaction was carried out at room temperature for 4 hours, the benzyloxycarbonyl protecting group was removed, and the excess acetic acid was removed by rotary drying to obtain intermediate II, which was castor oil-O-glycine triester acetate. The reaction formula was shown below. Castor oil is usually a mixture of triglycerides with different ricinoleic acid content (n=0-3), and molecular formula thereof cannot be accurately illustrated. The following reaction formula, taking n=3 as an example, is used to illustrate the method principle of the present application without limiting the present application.

##STR00011##

[0097] B. The synthesis of N-fluorenylmethoxycarbonyl-N′-tert-butoxycarbonyl-L-lysine-N-hydroxysuccinimide ester was performed as follows:

[0098] 24 g of N-fluorenylmethoxycarbonyl-N′-tert-butoxycarbonyl-L-lysine (50 mmol) and 5.6 g (50 mmol) of N-hydroxysuccinimidein were added to a 250 ml flask, and the starting material was dissolved in 40 ml of tetrahydrofuran (THF), then added with 12.4 g (60 mmol) of dicyclohexylcarbodiimide (DCC) dissolved in 50 ml of methylene chloride, and reacted at room temperature for 1 hour. The reaction was filtered to remove the precipitate and then dried by spin-drying to obtain intermediate III, which was N-fluorenylmethoxycarbonyl-N′-tert-butylcarbonyl-L-lysine-N-hydroxysuccinimide ester. The reaction formula was shown below.

##STR00012##

[0099] C. The synthesis of the hydrophobic excipients was performed as follows:

[0100] 10.5 g of the intermediate II was dissolved in 100 ml of anhydrous dichloromethane, added with 15 ml of triethylamine (TEA), then added with 30 g of the intermediate III dissolved in 50 ml of dichloromethane, and reacted for three days under a dark condition. After the reaction being completed, as indicated by TLC analysis, the reaction mixture was filtered to remove the precipitate, then spin-dried, and purified by conventional purification to obtain a yellowish transparent viscous oily substance, which was cooled to obtain a glassy transparent solid as a modified hydrophobic excipient. The reaction formula was shown below.

##STR00013## ##STR00014##

EXAMPLE 3

[0101] A preparation method of a hydrophobic excipient was performed as follows:

[0102] A. the synthesis of hydrogenated castor oil-O-glycine triester was performed as follows:

[0103] 9.36 g of hydrogenated castor oil (10 mmol), 7.2 g of N-tert-butoxycarbonylglycine (45 mmol), 366 mg of 4-dimethylaminopyridine (DMAP) (3 mmol) were dissolved in 100 ml of anhydrous dichloromethane (DCM) in a 250 ml flask, then added with 10.3 g (50 mmol) of dicyclohexylcarbodiimide (DCC) dissolved in 50 ml of anhydrous dichloromethane, refluxed at 45° C. and reacted for two days under dark conditions. After the reaction being completed, as indicated by TLC analysis, the reaction mixture was filtered to remove the precipitate, and then spin-dried to provide a residue. The residue was recrystallized from ethyl acetate to obtain a slightly yellowish transparent oily substance, which was cooled to obtain white crystals, that is, the intermediate I, which was hydrogenated castor oil-O—(N-tert-butoxycarbonylglycine) triester.

[0104] The intermediate I was dissolved in 40 ml of dichloromethane, added with 40 ml of trifluoroacetic acid (TFA), and reacted at room temperature for 4 hours, to remove the protecting group. After removing excessive trifluoroacetic acid by spinning, 60 ml of dichloromethane was added to dissolve the product, the added with 10 g of anhydrous sodium bicarbonate powder, and stirred for three days to obtain the intermediate II, which was hydrogenated castor oil-O-glycine triester. The reaction formula was shown below. Castor oil is usually a mixture, and molecular formula thereof cannot be accurately illustrated. The following reaction formula, taking n=3 as an example, is used to illustrate the method principle of the present application without limiting the present application.

##STR00015##

[0105] B. The synthesis of N-fluorenylmethoxycarbonyl-N′-tert-butoxycarbonyl-L-lysine-N-hydroxysuccinimide ester was performed as follows:

[0106] 24 g of N-fluorenylmethoxycarbonyl-N′-tert-butoxycarbonyl-L-lysine (50 mmol) and 5.6 g (50 mmol) of N-hydroxysuccinimidein were added to a 250 ml flask, dissolved in 40 ml of anhydrous tetrahydrofuran (THF), then added with 12.4 g (60 mmol) of dicyclohexylcarbodiimide (DCC) dissolved in 50 ml of methylene chloride, reacted at room temperature for 1 hour, filtered to remove the precipitate and then dried by spin-drying to obtain the intermediate III which was N-fluorenylmethoxycarbonyl-N′-tert-butylcarbonyl-L-lysine-N-hydroxysuccinimide ester. The reaction formula was shown below.

##STR00016##

[0107] C. The synthesis of the modified hydrophobic excipient was performed as follows:

[0108] the intermediate II was dissolved in 100 ml of anhydrous dichloromethane, added with 15 ml of triethylamine (TEA), then added with the intermediate III dissolved in 50 ml of dichloromethane (DCM), refluxed at 45° C., and reacted for three days under a dark condition. After the reaction being completed, as indicated by TLC analysis, the reaction mixture was filtered to remove the precipitate, then spin-dried to obtain a residue. The residue was recrystallized from ethyl acetate, to obtain a slightly yellowish transparent oily substance, which was cooled to obtain white crystals, as the hydrophobic excipient. The reaction formula was shown below.

##STR00017##

EXAMPLE 4

[0109] A preparation method of a hydrophobic excipient was performed as follows:

[0110] A. the synthesis of the cholesterol oleamide-O-glycine triester was performed as follows:

[0111] 3.82 g of cholic acid (10 mmol) and 1.2 g of N-hydroxysuccinimide (11mmol) were added to a 250 ml flask, dissolved in 40 ml of anhydrous tetrahydrofuran (THF), then added with 2.3 g of dicyclohexylcarbodiimide (DCC) (11 mmol), and reacted at room temperature for 2 hours to form cholic acid-N-hydroxysuccinimide active ester. After the reaction being completed, as indicated by TLC analysis, the reaction was added with 2.8 g of oleylamine (10 mmol) and 1.5 ml of triethylamine (TEA) (10 mmol), and reacted overnight. After the reaction being completed, as indicated by TLC analysis, the reaction mixture was filtered to remove the precipitate, then spin-dried, and purified by conventional purification to obtain a colorless, transparent viscous oil, as the cholesterol oleamide. The reaction formula was shown below.

##STR00018##

[0112] 7.2 g N-tert-butoxycarbonylglycine (45 mmol) was added to a 100 ml flask, dissolved in 100 ml of anhydrous dichloromethane (DCM), and added with 5.4 g (25 mmol) of dicyclohexylcarbodiimide (DCC) dissolved in 50 ml of anhydrous dichloromethane, and reacted at room temperature for 0.5 h to form N-tert-butoxycarbonylglycine anhydride. The reaction formula was shown below.

##STR00019##

[0113] Cholesterol oleamide produced in the above reaction and 122 mg of 4-dimethylaminopyridine (DMAP) (1 mmol) were dissolved in 40 ml of anhydrous dichloromethane (DCM), then added with N-tert-butoxycarbonylglycine anhydride produced in the above reaction, and reacted for 48 hours. After the reaction being completed, as indicated by TLC analysis, the intermediate I was obtained, which was cholesterol oleamide-O—(N-tert-butoxycarbonylglycine) triester.

[0114] The intermediate I was dissolved in 40 ml of dichloromethane, then added with 40 ml of trifluoroacetic acid (TFA), and reacted at room temperature for 4 h, to remove protecting groups. After removing excessive trifluoroacetic acid by spinning, the obtained product was dissolved in 60 ml of dichloromethane, then added with 10 g of anhydrous sodium bicarbonate powder, and stirred for three days to obtain the intermediate II, which was cholestyryl oleylamine-O-glycine triester. The reaction formula was shown below. The reaction formula was shown below.

##STR00020##

[0115] B. The synthesis of N-fluorenylmethoxycarbonyl-N′-tert-butoxycarbonyl-L-lysine-N-hydroxysuccinimide ester was performed as follows:

[0116] 24 g of N-fluorenylmethoxycarbonyl-N′-tert-butoxycarbonyl-L-lysine (50 mmol) and 5.6 g of N-hydroxysuccinimide (50 mmol) were dissolved in 40 ml of anhydrous tetrahydrofuran (THF) in a 250 ml flask, added with 12.4 g (60 mmol) of dicyclohexylcarbodiimide (DCC) dissolved in 50 ml of dichloromethane, reacted at room temperature for 1 hour, and the mixture was filtered to remove precipitates and then dried by spin-drying to obtain the intermediate III, which was N-fluorenylmethoxycarbonyl-N′-tert-butoxycarbonyl-L-lysine-N-hydroxysuccinimide ester. The reaction formula was shown below.

##STR00021##

[0117] C. The synthesis of the hydrophobic excipients was performed as follows:

[0118] the intermediate II was dissolved in 100 ml of anhydrous dichloromethane, added with 15 ml of triethylamine (TEA), then added with the intermediate III dissolved in 50 ml of dichloromethane (DCM), and reacted for three days at room temperature under dark conditions. After the reaction being completed, as indicated by TLC analysis, the reaction mixture was filtered to remove the precipitate, then spin-dried, and purified by conventional purification to obtain a yellowish transparent viscous oily substance, which was cooled to obtain a glassy transparent solid as a modified hydrophobic excipient. The reaction formula was shown below.

##STR00022##

EXAMPLE 5

[0119] The solubility of paclitaxel in olive oil, castor oil and the hydrophobic excipients prepared in the above examples was measured.

[0120] The specific experimental method was as follows. 0.5 ml of chloroform solution of olive oil, castor oil and the hydrophobic excipients prepared in the above examples were added to a 12 ml penicillin bottle, in which the mass percentage concentration of the chloroform solution of the hydrophobic excipients was 50%. The chloroform solution was mixed with 0.5 ml of chloroform, from which 0.5 ml of diluent was taken and two-fold serial dilution was performed by using chloroform. Then 0.5 ml of a chloroform solution of paclitaxel (10 mg/ml) was added to the above-mentioned sample after the two-fold serial dilution, and then left in a hood to be naturally volatilized overnight. Crystal formation in the dried sample was observed and recorded.

[0121] Experimental data of the solubility of paclitaxel in olive oil, castor oil and the hydrophobic excipients prepared in the above examples were shown in Table 1.

TABLE-US-00001 TABLE 1 solubility of paclitaxel in olive oil, castor oil and hydrophobic excipients Hydrophobic excipient (mg) Olive oil Castor oil Example 1 Example 2 Example 4 0.98 + + + + + 1.95 + + + + + 3.90 + + + + + 7.81 + + +/− − +/− 15.65 + + − − − 31.30 + + − − − 62.50 + + − − − 125.00 + + − − − 250.00 + + − − − In Table 1, “+” indicates that crystals were precipitated, “−” indicates that no crystals was precipitated, and “+/−” indicates that the solution was slightly turbid.

[0122] The modified hydrophobic excipient obtained in example 3 was not included in the experiment because the modified hydrophobic excipient crystallized out at room temperature, and the experimental results could not be directly observed by naked eyes.

[0123] According to the data comparison in table 1, the solubility of paclitaxel in examples 1,2 and 4 is greater than that in olive oil and castor oil, which indicates that the hydrophobic excipient has π-π function by introducing the substituent group with aromatic ring fluorene, which is beneficial to the aromatic ring accumulation between the hydrophobic excipients and the drug containing aromatic group. In addition, the carbamoyl group and amide group on the hydrophobic excipient can have non-covalent physical action with the drug through hydrogen bond, and the compatibility of the hydrophobic excipient and the hydrophobic drug can be improved through the above two additional molecular effects, thereby being beneficial to increasing the solubility of the drug.

EXAMPLE 6

[0124] Blank, paclitaxel and docetaxel drug-loaded fat emulsions were prepared, and detected for the stability of the drug-loaded fat emulsion, which comprised the following steps:

[0125] Experiment 6.1

[0126] Blank fat emulsion: 1.5 mg of castor oil, 0.2 mg of egg yolk lecithin, 0.4 mg of mPEG2000-DSPE were dissolved in chloroform, blown to dry in nitrogen and dried under vacuum. Then 1 ml of phosphate buffer solution was added to adjust pH to 7.4, hydrated for 1 h, homogenized for 5 min at 20000 r/min with high speed shearing machine. The obtained blank fat emulsion was detected by Malvern ZS laser particle size analyzer, and the average particle size thereof was 200 nm.

[0127] Experiment 6.2

[0128] Paclitaxel-castor oil drug-loaded fat emulsion: 100 mg of paclitaxel, 300 mg of castor oil, 40 mg of egg yolk lecithin, and 80 mg of mPEG2000-DSPE were dissolved in chloroform, blown to dry in nitrogen and dried under vacuum. Then 20 ml of phosphate buffer solution was added to adjust pH to 7.4, hydrated for 1 h, homogenized for 5 min at 20000 r/min with high speed shearing machine. The obtained drug-loaded fat emulsion was detected by Malvern ZS laser particle size analyzer, and the average particle size thereof was 280 nm. The drug-loaded fat emulsion can be only stable for a short period of time after preparation, white precipitates began to appear after about 4 hours, and a large amount of white precipitates were formed after 12 hours.

[0129] Experiment 6.3

[0130] Docetaxel-castor oil drug-loaded fat emulsion: 100 mg of docetaxel, 300 mg of castor oil, 40 mg of egg yolk lecithin and 80 mg of mPEG2000-DSPE were taken and dissolved in chloroform, blown to dry in nitrogen and dried under vacuum. Then 20 ml of phosphate buffer solution was added to adjust pH to 7.4, hydrated for 1 h, homogenized for 5 min at 20000 r/min with high speed shearing machine. The obtained drug-loaded fat emulsion was detected by Malvern ZS laser particle size analyzer, and the average particle size thereof was 330 nm. The prepared drug-loaded emulsion had poor stability, white precipitates began to appear after about 1 hour, and a large amount of white precipitates appeared after 4 hours.

[0131] Experiment 6.4

[0132] Paclitaxel-hydrophobic excipient of example 1 drug-loaded fat emulsion: 100 mg of paclitaxel, 300 mg of hydrophobic excipient obtained in example 1, 40 mg of egg yolk lecithin, and 80 mg of mPEG2000-DSPE were dissolved in chloroform, blown to dry in nitrogen and dried under vacuum. Then 20 ml of phosphate buffer solution was added to adjust pH to 7.4, hydrated for 1 h, homogenized for 5 min at 20,000 r/min with high speed shearing machine. The obtained drug-loaded fat emulsion was detected by Malvern ZS laser particle size analyzer, and the average particle size thereof was 215 nm. And the drug-loaded fat emulsion can remain stable for about 72 h after being prepared, then a white precipitate began to appear.

[0133] Experiment 6.5

[0134] Docetaxel-hydrophobic excipient of example 1 drug-loaded fat emulsion: 100 mg of docetaxel, 320 mg of the hydrophobic excipient prepared in example 1, 40 mg of egg yolk lecithin and 80 mg of mPEG2000-DSPE were dissolved in chloroform, blown to dry in nitrogen and dried under vacuum. Then 1 ml of phosphate buffer solution was added to adjust pH to 7.4, hydrated for 1 h, homogenized for 5 min at 20,000 r/min with high speed shearing machine. The obtained drug-loaded fat emulsion was detected by Malvern ZS laser particle size analyzer, and the average particle size thereof was 225 nm. And the drug-loaded fat emulsion can remain stable for about 1 day after being prepared, then a white precipitate began to appear at about 19 h.

[0135] Experiment 6.6

[0136] Paclitaxel-hydrophobic excipient of example 2 drug loaded fat emulsion: 100 mg of paclitaxel, 300 mg of hydrophobic excipient prepared in example 2, 40 mg of egg yolk lecithin, and 80 mg of mPEG2000-DSPE were dissolved in chloroform, blown to dry in nitrogen and dried under vacuum. Then 20 ml of phosphate buffer solution was added to adjust pH to 7.4, hydrated in a 50° C. water bath for 1 h, homogenized for 5 min at 20,000 r/min with high speed shearing machine. The obtained drug-loaded fat emulsion was detected by Malvern ZS laser particle size analyzer, and the average particle size thereof was 215 nm. And the drug-loaded fat emulsion can remain stable for about 2 day after being prepared, then a white precipitate began to appear at about 76 h.

[0137] Experiment 6.7

[0138] Docetaxel-hydrophobic excipient of example 2 drug-loaded fat emulsion: 100 mg of docetaxel, 320 mg of the hydrophobic excipient prepared in example 4, 40 mg of egg yolk lecithin and 80 mg of mPEG2000-DSPE were dissolved in chloroform, blown to dry in nitrogen and dried under vacuum. Then 1 ml of phosphate buffer solution was added to adjust pH to 7.4, hydrated for 1 h, and homogenized for 5 min at 20,000 r/min with high speed shearing machine. The obtained drug-loaded fat emulsion was detected by Malvern ZS laser particle size analyzer, and the average particle size thereof was 210 nm. And the drug-loaded fat emulsion can remain stable for about 20 h after being prepared, then a white precipitate began to appear.

[0139] Experiment 6.8

[0140] Paclitaxel-hydrophobic excipient of example 3 drug loaded fat emulsion: 100 mg of paclitaxel, 300 mg of hydrophobic excipient prepared in example 3, and 40 mg of egg yolk lecithin, 80 mg of mPEG2000-DSPE were dissolved in chloroform, blown to dry in nitrogen and dried under vacuum. Then 20 ml of phosphate buffer solution was added to adjust pH to 7.4, hydrated in a 50° C. water bath for 1 h, homogenized for 5 min at 20,000 r/min with high speed shearing machine. The obtained drug-loaded fat emulsion was detected by Malvern ZS laser particle size analyzer, and the average particle size thereof was 235 nm. And the drug-loaded fat emulsion can remain stable for at least 2 day after being prepared, then a white precipitate began to appear at about 76 h.

[0141] Experiment 6.9

[0142] Docetaxel-hydrophobic excipient of example 3 drug-loaded fat emulsion: 100 mg of docetaxel, 320 mg of the hydrophobic excipient prepared in the example 3, 40 mg of egg yolk lecithin and 80 mg of mPEG2000-DSPE were dissolved in chloroform, blown to dry in nitrogen and dried under vacuum. Then 1 ml of phosphate buffer solution was added to adjust pH to 7.4, hydrated in a 50° C. water bath for 1 h, homogenized for 5 min at 20000 r/min with high speed shearing machine. The obtained drug-loaded fat emulsion was detected by Malvern ZS laser particle size analyzer, and the average particle size thereof was 220 nm. And the drug-loaded fat emulsion can remain stable for about 1 day and a half after being prepared, then a white precipitate began to appear at about 32 h.

[0143] Experiment 6.10

[0144] Docetaxel-hydrophobic excipient of example 4 drug-loaded fat emulsion: 100 mg of docetaxel, 320 mg of the hydrophobic excipient prepared in example 4, 40 mg of egg yolk lecithin and 80 mg of mPEG2000-DSPE were dissolved in chloroform, blown to dry in nitrogen and dried under vacuum. Then 1 ml of phosphate buffer solution was added to adjust pH to 7.4, hydrated for 1 h, homogenized for 5 min at 20,000 r/min with high speed shearing machine. The obtained drug-loaded fat emulsion was detected by Malvern ZS laser particle size analyzer, and the average particle size thereof was 210 nm. And the drug-loaded fat emulsion can be stable for about 22 h after being prepared, then a white precipitate began to appear.

[0145] According to the experimental result, when the castor oil is used as the oil phase, the drug-loaded fat emulsion prepared by the castor oil, the paclitaxel and the docetaxel is relatively unstable, and white precipitate is generated after about 1-4 h. When the modified hydrophobic excipient of the present application is used as an oil phase, the stability of the drug-loaded fat emulsion prepared by the modified hydrophobic excipient, paclitaxel and docetaxel generally can reach more than 20 h, which indicates that, forming the hydrophobic excipient by introducing an aromatic ring and a carbamoyl group or an amide group into a hydrophobic compound can provide the hydrophobic compound with a π-π function, thereby being beneficial for aromatic ring stacking between the hydrophobic excipient and the drug containing the aromatic group, so that they can combine with each other through non-covalent physical action. In addition, the carbamoyl group and the amide group can be combined with the drug in a non-covalent physical way through a hydrogen bond in a hydrophobic environment, so as to further improve the stability of the drug-loaded fat emulsion.

[0146] According to the experimental results, under the same conditions, the stability of the drug-loaded fat emulsion prepared from docetaxel is worse than that of the drug-loaded fat emulsion prepared from paclitaxel because docetaxel is more hydrophilic than paclitaxel.

[0147] According to the experimental result, the stability of the drug-loaded fat emulsion prepared from the modified hydrophobic excipient prepared from the hydrogenated castor oil is higher than that of the drug-loaded fat emulsion prepared from the modified hydrophobic excipient prepared from the castor oil, which indicates that adopting the hydrogenated castor oil as the raw material to prepare the hydrophobic excipient is beneficial to improve the stability of combination of hydrophobic excipient and the drug.

[0148] The examples of the specific embodiment are preferred examples of the present application, and the scope of the present application is not limited by these examples, so that all equivalent changes of the structure, shape and principle of the present application are covered by the protection scope of the present application.