DRUG-LOADED COMPOSITE NANOFIBER MEMBRANE SYSTEM, METHOD FOR PREPARING THE SAME, AND APPLICATION THEREOF

Abstract

A drug-loaded composite nanofiber membrane system, the system including a first nanofiber layer, a second nanofiber layer, and a third nanofiber layer. The first nanofiber layer includes a poly(lactic-co-glycolic acid) copolymer, poly(p-dioxanone) and a drug. The second nanofiber layer includes the poly(lactic-co-glycolic acid) copolymer, polyglycolic acid and the drug. The third nanofiber layer includes the poly(lactic-co-glycolic acid) copolymer, polyethylene glycol and the drug.

Claims

1. A drug-loaded composite nanofiber membrane system, the system comprising: a first nanofiber layer, the first nanofiber layer comprising a poly(lactic-co-glycolic acid) copolymer, poly(p-dioxanone), and a drug; a second nanofiber layer, the second nanofiber layer comprising the poly(lactic-co-glycolic acid) copolymer, polyglycolic acid, and the drug; and a third nanofiber layer, the third nanofiber layer comprising the poly(lactic-co-glycolic acid) copolymer, polyethylene glycol, and the drug.

2. The system of claim 1, wherein the poly(lactic-co-glycolic acid) copolymer has a viscosity average molecular weight of 40,000-250,000 Da; the poly(p-dioxanone) has an intrinsic viscosity of 1-10 dL/g; the polyglycolic acid has an intrinsic viscosity of 0.5-10 dL/g; and polyethylene glycol has a viscosity average molecular weight of 1000-20000 Da.

3. The system of claim 1, wherein the poly(lactic-co-glycolic acid) copolymer has a viscosity average molecular weight of 40,000-120,000 Da; the poly(p-dioxanone) has an intrinsic viscosity of 1-5 dL/g; the polyglycolic acid has an intrinsic viscosity of 0.5-5 dL/g; and polyethylene glycol has a viscosity average molecular weight of 2000-10000 Da.

4. The system of claim 1, wherein a mass ratio of the poly(lactic-co-glycolic acid) copolymer to poly(p-dioxanone) in the first nanofiber layer is between 70:30 and 97:3; and a molar ratio of lactic acid unit to hydroxyacetic acid unit in the poly(lactic-co-glycolic acid) copolymer in the first nanofiber layer is greater than or equal to 1:1.

5. The system of claim 2, wherein a mass ratio of the poly(lactic-co-glycolic acid) copolymer to poly(p-dioxanone) in the first nanofiber layer is between 70:30 and 97:3; and a molar ratio of lactic acid unit to hydroxyacetic acid unit in the poly(lactic-co-glycolic acid) copolymer in the first nanofiber layer is greater than or equal to 1:1.

6. The system of claim 3, wherein a mass ratio of the poly(lactic-co-glycolic acid) copolymer to poly(p-dioxanone) in the first nanofiber layer is between 70:30 and 97:3; and a molar ratio of lactic acid unit to hydroxyacetic acid unit in the poly(lactic-co-glycolic acid) copolymer in the first nanofiber layer is greater than or equal to 1:1.

7. The system of claim 1, wherein the drug in the first nanofiber layer is taxol, doxorubicin, cis-platinum, carboplatin, 5-fluorouracil, or a combination thereof.

8. The system of claim 1, wherein a mass ratio of the poly(lactic-co-glycolic acid) copolymer to polyglycolic acid in the second nanofiber layer is between 60:40 and 99:1; and a molar ratio of lactic acid unit to hydroxyacetic acid unit in the poly(lactic-co-glycolic acid) copolymer in the second nanofiber layer is greater than or equal to 1:1.

9. The system of claim 7, wherein a mass ratio of the poly(lactic-co-glycolic acid) copolymer to polyglycolic acid in the second nanofiber layer is between 60:40 and 99:1; and a molar ratio of lactic acid unit to hydroxyacetic acid unit in the poly(lactic-co-glycolic acid) copolymer in the second nanofiber layer is greater than or equal to 1:1.

10. The system of claim 1, wherein the drug in the second nanofiber layer is taxol, doxorubicin, cis-platinum, carboplatin, 5-fluorouracil, or a combination thereof.

11. The system of claim 1, wherein a mass ratio of the poly(lactic-co-glycolic acid) copolymer to polyethylene glycol in the third nanofiber layer is between 70:30 and 97:3; and a molar ratio of the lactic acid to the hydroxyacetic acid in the poly(lactic-co-glycolic acid) copolymer in the third nanofiber layer is greater than or equal to 1:1.

12. The system of claim 10, wherein a mass ratio of the poly(lactic-co-glycolic acid) copolymer to polyethylene glycol in the third nanofiber layer is between 70:30 and 97:3; and a molar ratio of the lactic acid to the hydroxyacetic acid in the poly(lactic-co-glycolic acid) copolymer in the third nanofiber layer is greater than or equal to 1:1.

13. The system of claim 1, wherein the drug in the third nanofiber layer is taxol, doxorubicin, cis-platinum, carboplatin, 5-fluorouracil, or a combination thereof.

14. The system of claim 1, wherein in the first nanofiber layer, a mass ratio of the drug to polymers is between 1:4 and 1:10; in the second nanofiber layer, a mass ratio of the drug to polymers is between 1:4 and 1:10; and in the third nanofiber layer, a mass ratio of the drug to polymers is between 1:4 and 1:10.

15. A method for preparing the drug-loaded composite nanofiber membrane system of claim 1, the method comprising: 1) respectively dissolving and mixing polymers and the drug according to raw materials of three nanofiber layers to obtain three mixed solutions; and 2) sequentially introducing the three mixed solutions in 1) for electrostatic spinning to obtain the drug-loaded composite nanofiber membrane system.

16. The method of claim 15, wherein 1) is performed as follows: dissolving the drug for each nanofiber layer in a solvent, and adding polymers for each nanofiber layer in a mixture of the drug and solvent, stirring and mixing, thereby obtaining the three mixed solutions; the solvent is N,N-dimethylformamide, acetone, hexafluoroisopropanol, or a combination thereof; an inner diameter of a spinneret is 0.4 mm during electrostatic spinning; a voltage during electrostatic spinning is 10-25 kV; a spinning distance during the electrostatic spinning is 5-15 cm; a temperature for electrostatic spinning is 20-30° C.; an advancing speed of each mixed solution during the electrostatic spinning is 4-10 mL/L; a receiving device during the electrostatic spinning is a metal drum with a diameter of 5 cm, and a rotation speed is 600-900 rpm; and after 2), the drug-loaded composite nanofiber membrane system is vacuum-dried at 20-30° C. for 24-72 h.

17. The method of claim 16, wherein: the voltage during electrostatic spinning is 10-25 kV; the spinning distance during the electrostatic spinning is 8-15 cm; the advancing speed of each mixed solution during the electrostatic spinning is 6-10 mL/L; and the receiving device during the electrostatic spinning is the metal drum with the diameter of 5 cm, and the rotation speed is 800 rpm.

18. The method of claim 15, comprising: dissolving the drug for each nanofiber layer in a solvent, and adding polymers for each nanofiber layer in a mixture of the drug and solvent, stirring and mixing, thereby obtaining the three mixed solutions; respectively loading the three mixed solutions into a 22G flat-head dispensing syringe for electrostatic spinning at 20-30° C., where an inner diameter of a spinneret is 0.4 mm; an advancing speed of each mixed solution is 4-10 mL/L, a spinning voltage is 10-25 kV, a spinning distance is 5-15 cm, a receiving device is a metal drum with a diameter of 5 cm; a rotation speed of the metal drum is 600-900 rpm, thus yielding a drug-loaded composite nanofiber membrane system; and vacuum-drying the drug-loaded composite nanofiber membrane system at 20-30° C. for 24-72 h.

19. The method of claim 16, comprising: dissolving the drug for each nanofiber layer in a solvent, and adding polymers for each nanofiber layer in a mixture of the drug and solvent, stirring and mixing, thereby obtaining the three mixed solutions; respectively loading the three mixed solutions into a 22G flat-head dispensing syringe for electrostatic spinning at 20-30° C., where an inner diameter of a spinneret is 0.4 mm; an advancing speed of each mixed solution is 4-10 mL/L, a spinning voltage is 10-25 kV, a spinning distance is 5-15 cm, a receiving device is a metal drum with a diameter of 5 cm; a rotation speed of the metal drum is 600-900 rpm, thus yielding a drug-loaded composite nanofiber membrane system; and vacuum-drying the drug-loaded composite nanofiber membrane system at 20-30° C. for 24-72 h.

20. A method for preparing an antitumor drug, the method comprising applying the drug-loaded composite nanofiber membrane system of claim 1.

Description

BRIEF DESCRIPTION OF THE DIAGRAMS

[0059] FIG. 1 is a first drug release curve of a drug-loaded composite nanofiber membrane system prepared in Example 1;

[0060] FIG. 2 is a second drug release curve of a drug-loaded composite nanofiber membrane system prepared in Example 1;

[0061] FIG. 3 is a third drug release curve of a drug-loaded composite nanofiber membrane system prepared in Example 1; and

[0062] FIG. 4 is a fourth drug release curve of a drug-loaded composite nanofiber membrane system prepared in Example 1.

DESCRIPTION OF THE INVENTION

[0063] To further illustrate, embodiments detailing a drug release curve of a drug-loaded composite nanofiber membrane system are described below. It should be noted that the following embodiments are intended to describe and not to limit the disclosure.

Example 1

[0064] This example provided a drug-loaded composite nanofiber membrane system, comprising a first nanofiber layer, a second nanofiber layer, and a third nanofiber layer.

[0065] The first nanofiber layer comprised poly(lactic-co-glycolic acid) (PLGA) copolymer (molecular weight of 60000), poly(p-dioxanone) (PDO) (intrinsic viscosity of 1.2-2.4 dL/g) and taxol. A mass ratio of PLGA to PDO was 9:1. Taxol accounted for 15% of the total mass of PLGA and PDO, and a molar ratio of lactic acid (LA) to GA in PLGA was 1:1.

[0066] The second nanofiber layer comprised poly(lactic-co-glycolic acid) (PLGA) copolymer (molecular weight of 80,000), polyglycolic acid (PGA) (intrinsic viscosity of 0.5-1.8 dL/g) and taxol. A mass ratio of PLGA to PGA was 93:7. Taxol accounted for 10% of the total mass of PLGA and PGA, and the molar ratio of LA to GA in PLGA was 3:1.

[0067] The third nanofiber layer comprised poly(lactic-co-glycolic acid) (PLGA) copolymer (molecular weight of 80,000), polyethylene glycol (PEG) (molecular weight of 2000) and taxol. A mass ratio of PLGA to PEG was 95:5. Taxol accounted for 20% of the total mass of PLGA and PEG, and the molar ratio of LA to GA in PLGA was 3:1.

[0068] The method for preparing the drug-loaded composite nanofiber membrane system was as follows:

[0069] (1) dissolving taxol for the first, second, and third nanofiber layers in hexafluoroisopropanol, acetone, and N,N-dimethylformamide, respectively, adding the polymers for each nanofiber to the three drug solutions, stirring and mixing the solutions to obtain three mixed solutions;

[0070] (2) loading the three mixed solutions in (1) into a 22G flat-head dispensing syringe for electrostatic spinning at 25° C., where the spinneret had an inner diameter of 0.4 mm; the advancing speed of each mixed solution was 4 mL/L, the spinning voltage was 25 kV, the spinning distance was 15 cm, the receiving device was a metal drum with the diameter of 5 cm; the rotation speed was 600 rpm, to yield the drug-loaded composite nanofiber membrane system; and

[0071] (3) vacuum-drying the drug-loaded composite nanofiber membrane system in (2) at 25° C. for 24 h.

[0072] The drug-loaded composite nanofiber membrane system was tested for drug release, and the drug release curve was drawn as follows: the dried drug-loaded composite nanofiber membrane system was cut into 10 mg samples, and the samples were put into a centrifuge tube with 10 mL of a fresh phosphate buffered saline (PBS) solution. Then the samples were put in an air bath constant temperature shaker, with the temperature of 37° C., and the speed of the shaker of 100 rpm. At designated time intervals, 1 mL of release solution was taken out, and an equal amount of the fresh PBS solution was added. Then, a standard curve of the drug′ concentration was measured with an ultraviolet-visible spectrophotometer, and the amount of drug released by the drug-loaded composite nanofiber membrane system was determined according to the standard curve. All experimental groups were in five copies, and the measured drug release amount was expressed as mean±standard deviation. The experimental results were shown in FIG. 1. The drug release system presented a typical three-stage release feature, with a release cycle of nearly 600 h. In the initial stage, the drug release was sustained but slow, and began to accelerate in an intermediate stage. At 420 h, the drug release rate was greatly accelerated until the drug was completely released.

Example 2

[0073] This example provided a drug-loaded composite nanofiber membrane system, comprising a first nanofiber layer, a second nanofiber layer, and a third nanofiber layer.

[0074] The first nanofiber layer comprised poly(lactic-co-glycolic acid) (PLGA) copolymer (molecular weight of 120000), poly(p-dioxanone) (PDO) (intrinsic viscosity of 2.4-4.8 dL/g) and doxorubicin. A mass ratio of PLGA to PDO was 8:1. Doxorubicin accounted for 15% of the total mass of PLGA and PDO, and a molar ratio of LA to GA in PLGA was 1:1.

[0075] The second nanofiber layer comprised poly(lactic-co-glycolic acid) (PLGA) copolymer (molecular weight of 40000), polyglycolic acid (PGA) (intrinsic viscosity of 2.5-4.0 dL/g) and doxorubicin. A mass ratio of PLGA to PGA was 6:4. Doxorubicin accounted for 10% of the total mass of PLGA and PGA, and the molar ratio of LA to GA in PLGA was 3:1.

[0076] The third nanofiber layer comprised poly(lactic-co-glycolic acid) (PLGA) copolymer (molecular weight of 150,000), polyethylene glycol (PEG) (molecular weight of 5000) and doxorubicin. The mass ratio of PLGA to PEG was 95:5. Doxorubicin accounted for 25% of the total mass of PLGA and PEG, and contained three poly(lactic-co-glycolic acid) copolymers with different LA/GA molar ratios. The molar ratio of LA to GA and a relative mass fraction of the poly(lactic-co-glycolic acid) copolymers to the nanofiber layer were 85:15 (50%), 75:2 (25%), and 65:35 (25%), respectively.

[0077] The method for preparing the drug-loaded composite nanofiber membrane system was as follows:

[0078] (1) dissolving adriamycin in the first, second, and third nanofiber layers in hexafluoroisopropanol, acetone, and N,N-dimethylformamide, respectively, adding the polymers for each nanofiber to the three drug solutions, stirring and mixing the solutions to obtain three mixed solutions;

[0079] (2) loading the three mixed solutions in (1) into a 22G flat-head dispensing syringe for electrostatic spinning at 25° C., where the spinneret had an inner diameter of 0.4 mm; the advancing speed of each mixed solution was 6 mL/L, the spinning voltage was 20 kV, the spinning distance was 10 cm, the receiving device was a metal drum with the diameter of 5 cm; the rotation speed was 700 rpm, to yield the drug-loaded composite nanofiber membrane system; and

[0080] (3) vacuum-drying the drug-loaded composite nanofiber membrane system in (2) at 25° C. for 48 h.

[0081] The drug-loaded composite nanofiber membrane system was tested for drug release, and the drug release curve was drawn using the same method as in Example 1. The experimental results were shown in FIG. 2. The drug release system presented a typical three-stage release feature, with a release cycle of nearly 1800 h.

Example 3

[0082] This example provided a drug-loaded composite nanofiber membrane system, comprising a first nanofiber layer, a second nanofiber layer, and a third nanofiber layer.

[0083] The first nanofiber layer comprised poly(lactic-co-glycolic acid) (PLGA) copolymer (molecular weight of 40000), poly(p-dioxanone) (PDO) (intrinsic viscosity of 2.4-4.8 dL/g) and 5-fluorouracil. A mass ratio of PLGA to PDO was 7:1. Fluorouracil accounted for 15% of the total mass of PLGA and PDO, and a molar ratio of LA to GA in PLGA was 1:1.

[0084] The second nanofiber layer comprised poly(lactic-co-glycolic acid) (PLGA) copolymer (molecular weight of 200000), polyglycolic acid (PGA) (intrinsic viscosity of 8.0-9.0 dL/g) and 5-fluorouracil. A mass ratio of PLGA to PGA was 7:3. 5-fluorouracil accounted for 10% of the total mass of PLGA and PGA, and the molar ratio of LA to GA in PLGA was 3:1.

[0085] The third nanofiber layer comprised poly(lactic-co-glycolic acid) (PLGA) copolymer (molecular weight of 150000), polyethylene glycol (PEG) (molecular weight of 10000) and 5-fluorouracil. A mass ratio of PLGA to PEG was 95:5. 5-fluorouracil accounted for 25% of the total mass of PLGA and PEG, and the molar ratio of LA to GA in PLGA was 5:1.

[0086] The method for preparing the drug-loaded composite nanofiber membrane system was as follows:

[0087] (1) dissolving 5-fluorouracil in the first, second, and third nanofiber layers in hexafluoroisopropanol, acetone, and N,N-dimethylformamide, respectively, adding the polymers for each nanofiber to the three drug solutions, stirring and mixing the solutions to obtain three mixed solutions;

[0088] (2) loading the three mixed solutions in (1) into a 22G flat-head dispensing syringe for electrostatic spinning at 25° C., where the spinneret had an inner diameter of 0.4 mm; the advancing speed of each mixed solution was 10 mL/L, the spinning voltage was 10 kV, the spinning distance was 5 cm, the receiving device was a metal drum with the diameter of 5 cm; the rotation speed was 900 rpm, to yield the drug-loaded composite nanofiber membrane system; and

[0089] (3) vacuum-drying the drug-loaded composite nanofiber membrane system in (2) at 25° C. for 72 h.

[0090] The drug-loaded composite nanofiber membrane system was tested for drug release, and the drug release curve was drawn using the same method as in Example 1. The experimental results were shown in FIG. 3. The drug release system presented a typical three-stage release feature, with a release cycle of nearly 1000 h. The drug release was fast in the initial stage, and began to slow down at 150 h, but a large amount of drug was still released. The drug was completely released in the third stage.

Example 4

[0091] This example provided a drug-loaded composite nanofiber membrane system, comprising a first nanofiber layer, a second nanofiber layer, and a third nanofiber layer.

[0092] The first nanofiber layer comprised poly(lactic-co-glycolic acid) (PLGA) copolymer (molecular weight of 40000), poly(p-dioxanone) (PDO) (intrinsic viscosity of 2.4-4.8 dL/g) and cis-platinum. A mass ratio of PLGA to PDO was 7:3. Cis-platinum accounted for 15% of the total mass of PLGA and PDO, and a molar ratio of LA to GA in PLGA was 1:1.

[0093] The second nanofiber layer comprised poly(lactic-co-glycolic acid) (PLGA) copolymer (molecular weight of 200000), polyglycolic acid (PGA) (intrinsic viscosity of 8.0-9.0 dL/g) and cis-platinum. A mass ratio of PLGA to PGA was 6:4. Cis-platinum accounted for 10% of the total mass of PLGA and PGA, and the molar ratio of LA to GA in PLGA was 2:1.

[0094] The third nanofiber layer comprised poly(lactic-co-glycolic acid) (PLGA) copolymer (molecular weight of 150000), polyethylene glycol (PEG) (molecular weight of 10000) and cis-platinum. A mass ratio of PLGA to PEG was 7:3. Cis-platinum accounted for 25% of the total mass of PLGA and PEG, and the molar ratio of LA to GA in PLGA was 4:1.

[0095] The method for preparing the drug-loaded composite nanofiber membrane system was as follows:

[0096] (1) dissolving cisplatin in the first, second, and third nanofiber layers in hexafluoroisopropanol, acetone, and N,N-dimethylformamide, respectively, adding the polymers for each nanofiber to the three drug solutions, stirring and mixing the solutions to obtain three mixed solutions;

[0097] (2) loading the three mixed solutions in (1) into a 22G flat-head dispensing syringe for electrostatic spinning at 25° C., where the spinneret had an inner diameter of 0.4 mm; the advancing speed of each mixed solution was 10 mL/L, the spinning voltage was 25 kV, the spinning distance was 15 cm, the receiving device was a metal drum with the diameter of 5 cm; the rotation speed was 900 rpm, to yield the drug-loaded composite nanofiber membrane system; and

[0098] (3) vacuum-drying the drug-loaded composite nanofiber membrane system in (2) at 25° C. for 72 h.

[0099] The drug-loaded composite nanofiber membrane system was tested for drug release, and the drug release curve was drawn using the same method as in Example 1. The experimental results were shown in FIG. 1. The drug release system presented a typical three-stage release feature, with a release cycle of nearly 360 h. The drug release was fast in the initial stage, and began to slow down at 60 h, but a large amount of drug was still released. The drug was completely released in the third stage.

[0100] It will be obvious to those skilled in the art that changes and modifications may be made, and therefore, the aim in the appended claims is to cover all such changes and modifications.