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

Abstract

A drug-loaded nanofiber membrane includes a first fiber, a second fiber, and a drug. The drug is dispersed into the first fiber. The first fiber includes poly(lactic-co-glycolic acid) copolymer (PLGA copolymer), and the second fiber includes poly(p-dioxanone) (PDO).

Claims

1. A drug-loaded nanofiber membrane comprising a first fiber, a second fiber, and a drug dispersed into the first fiber; the first fiber comprising poly(lactic-co-glycolic acid) copolymer (PLGA copolymer), and the second fiber comprising poly(p-dioxanone) (PDO); wherein: the PLGA copolymer is a mixture of a high-molecular weight PLGA copolymer and a low-molecular weight PLGA copolymer; the high-molecular weight refers to a viscosity-average molecular weight of 100,000 to 150,000 Da, and the low-molecular weight refers to a viscosity-average molecular weight of 40,000 to 80,000 Da; a mass ratio of the high-molecular weight PLGA copolymer to the low-molecular weight PLGA copolymer is between 25:75 and 3:97; and a total mass of the second fiber accounts for 1%-25% of a total mass of the first fiber.

2. The membrane of claim 1, wherein the total mass of the second fiber accounts for 1%-15% of a total mass of the first fiber.

3. The membrane of claim 1, wherein a molar ratio of lactic acid unit to hydroxyacetic acid unit in the PLGA copolymer is between 1:1 and 9:1.

4. The membrane of claim 1, wherein a molecular weight of PDO is 60000-250,000 Da.

5. The membrane of claim 1, wherein the drug comprises an antibiotic drug, an anti-tumor drug, an anti-inflammatory drug, or a combination thereof.

6. The membrane of claim 5, wherein the drug comprises ciprofloxacin, ciprofloxacin hydrochloride, moxifloxacin, levofloxacin, cefradine, tinidazole, 5-fluorouracil, adriamycin, cisplatin, paclitaxel, gemcitabine, capecitabine, aspirin, indomethacin, or a combination thereof.

7. The membrane of claim 1, wherein a total mass of the drug accounts for 1%-35% of a total mass of the first fiber and the second fiber.

8. A method of preparing the membrane of claim 1, the method comprising: 1) mixing the drug and the PLGA copolymer in a first solvent to yield a first mixed solution; and mixing PDO in a second solvent to yield a second mixed solution; and 2) separately taking a part of the first mixed solution and the second mixed solutions in 1), and introducing the part of the first and the second mixed solutions to a multi-nozzle electrostatic spinning apparatus for electrostatic spinning, thereby obtaining the drug-loaded nanofiber membrane.

9. The method of claim 8, wherein in 1), the solvent is selected from the group consisting of N, N-dimethylformamide, acetone, hexafluoroisopropanol, and a combination thereof.

10. The method of claim 8, wherein in 1), the drug and the PLGA copolymer are stirred in the first solvent at 40-50° C. for mixing.

11. The method of claim 8, wherein an inner diameter of a nozzle for the multi-nozzle electrostatic spinning apparatus is 0.4 mm during electrostatic spinning.

12. The method of claim 8, wherein a voltage for the electrostatic spinning is 10-25 kV.

13. The method of claim 12, wherein the voltage for the electrostatic spinning is 20-25 kV.

14. The method of claim 8, wherein a spinning distance for the electrostatic spinning is 5-15 cm.

15. The method of claim 14, wherein the spinning distance for the electrostatic spinning is 5-15 cm.

16. The method of claim 8, wherein a temperature for the electrostatic spinning is 20-30° C.

17. The method of claim 8, wherein an advancing speed of each mixed solution for the electrostatic spinning is 4-10 mL/L.

18. The method of claim 17, wherein the advancing speed of each mixed solution for the electrostatic spinning is 6-10 mL/L.

19. The method of claim 8, wherein a receiving device during the electrostatic spinning is a metal drum with a diameter of 5-15 cm, and a rotation speed thereof is 600-900 rpm.

20. The method of claim 19, wherein the receiving device during the electrostatic spinning is a metal drum with a diameter of 5-15 cm, and the rotation speed thereof is 800 rpm.

21. The method of claim 8, further comprising vacuum drying the drug-loaded nanofiber membrane obtained in 2) at 20-30° C. for 24-72 h.

22. The method of claim 8, comprising: 1) mixing the drug and the PLGA copolymer in a first solvent to yield a first mixed solution; and mixing PDO in a second solvent to yield a second mixed solution; 2) respectively loading the first mixed solution and the second mixed solution in 1) into a 22G flat-head dispensing syringe, introducing the first mixed solution and the second mixed solution to a multi-nozzle electrostatic spinning apparatus for electrostatic spinning at 20-30° C. to obtain a drug-loaded nanofiber membrane, where a nozzle of the multi-nozzle electrostatic spinning apparatus has an inner diameter of 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 5-15 cm; a rotation speed of the metal drum is 600-900 rpm; and 3) vacuum-drying the drug-loaded nanofiber membrane in 2) at 20-30° C. for 24-72 h.

23. A method for preparing a drug delivery system, the method comprising applying the drug-loaded nanofiber membrane of claim 1.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0043] FIG. 1 is a drug release curve of a drug-loaded nanofiber membrane prepared in Example 1;

[0044] FIG. 2 is a drug release curve of a drug-loaded nanofiber membrane prepared in Example 2;

[0045] FIG. 3 is a drug release curve of a drug-loaded nanofiber membrane prepared in Example 3;

[0046] FIG. 4 is a drug release curve of a drug-loaded nanofiber membrane prepared in Example 4;

[0047] FIG. 5 is a drug release curve of a drug-loaded nanofiber membrane prepared in Example 5;

[0048] FIG. 6 is a drug release curve of a drug-loaded nanofiber membrane prepared in Example 6;

[0049] FIG. 7 is a scanning electron micrograph showing a cross-sectional view of a drug-loaded nanofiber membrane prepared in Example 1;

[0050] FIG. 8 is a scanning electron micrograph showing a cross-sectional view of a drug-loaded nanofiber membrane prepared in Example 2;

[0051] FIG. 9 is a scanning electron micrograph showing a cross-sectional view of a drug-loaded nanofiber membrane prepared in Example 3;

[0052] FIG. 10 is a scanning electron micrograph showing a cross-sectional view of a drug-loaded nanofiber membrane prepared in Example 4;

[0053] FIG. 11 is a scanning electron micrograph showing a cross-sectional view of a drug-loaded nanofiber membrane prepared in Example 5; and

[0054] FIG. 12 is a scanning electron micrograph showing a cross-sectional view of a drug-loaded nanofiber membrane prepared in Example 6.

DETAILED DESCRIPTION

[0055] To further illustrate, embodiments detailing a drug-loaded nanofiber membrane, a method for preparing the same, and application thereof are described below. It should be noted that the following embodiments are intended to describe and not to limit the disclosure.

Example 1

[0056] A drug-loaded nanofiber membrane comprises a first fiber, a second fiber, and paclitaxel; a PLGA copolymer and PDO are extruded separately to form the first fiber and the second fiber; paclitaxel is dispersed into the first fiber; a mass ratio of a high-molecular weight PLGA copolymer (MW=150000) to a low-molecular weight PLGA copolymer (MW=80000) is 25:75; a total mass of the second fiber accounts for 10% of a total mass of the first fiber; and a total mass of paclitaxel accounts for 10% of a total mass of the two fibers.

[0057] A method for preparing the drug-loaded nanofiber membrane comprises:

[0058] 1. mixing paclitaxel, the PLGA copolymer in acetone to obtain a first mixed solution; and mixing PDO in hexafluoroisopropanol to obtain a second mixed solution; and

[0059] 2. respectively loading the first mixed solution and the second mixed solution in 1) into a 22G flat-head dispensing syringe, introducing the first mixed solution and the second mixed solution to a multi-nozzle electrostatic spinning apparatus for electrostatic spinning at 25° C. to obtain a drug-loaded nanofiber membrane, where the nozzle of the multi-nozzle electrostatic spinning apparatus has an inner diameter of 0.4 mm; the advancing speed of each mixed solution is 5 mL/L, the spinning voltage is 15 kV, the spinning distance is 5 cm, the receiving device is the metal drum with the diameter of 5 cm; the rotation speed of the metal drum is 600 rpm; and

[0060] 3. vacuum-drying the drug-loaded nanofiber membrane in 2) at 25° C. for 24 h.

[0061] The drug-loaded nanofiber membrane was tested for drug release, and the drug release curve was drawn as follows: the dried drug-loaded nanofiber membrane was cut into 10 mg samples, put into a centrifuge tube with 10 mL of a fresh phosphate buffered saline (PBS) solution, and then put in an air bath constant temperature shaker at a temperature of 37° C. and a shaking speed 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 nanofiber membrane 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 release cycle of nearly 11 days. At 24 h, the drug release rate was greatly accelerated until the drug was completely released.

[0062] The drug-loaded nanofiber membrane was scanned with an electron microscope. Specifically, the drug-loaded nanofiber membrane was soaked in PBS for 7 days, rinsed with deionized water several times, and dried in a vacuum-drying oven for 48 h. Prior to observation of cross-sectional morphology, the dried sample was immersed into liquid nitrogen, broken, attached to a sample stage, and coated with a layer of platinum by a vacuum sputtering system. The experimental results were shown in FIG. 7. When the drug-loaded nanofiber membrane was soaked in PBS for 7 days, the drug-loaded nanofiber membrane continued to swell, which decreased the gap between the fibers, causing a small part of the fibers to bond together.

Example 2

[0063] A drug-loaded nanofiber membrane comprises a first fiber, a second fiber, and fluorouracil; a PLGA copolymer and PDO are extruded separately to form the first fiber and the second fiber; fluorouracil is dispersed into the first fiber; a mass ratio of a high-molecular weight PLGA copolymer (MW=100000) to a low-molecular weight PLGA copolymer (MW=40000) is 15:85; a total mass of the second fiber accounts for 15% of a total mass of the first fiber; and a total mass of fluorouracil accounts for 20% of a total mass of the two fibers.

[0064] A method for preparing the drug-loaded nanofiber membrane comprises:

[0065] 1. mixing fluorouracil, the PLGA copolymer in acetone to obtain a first mixed solution; and mixing PDO in hexafluoroisopropanol to obtain a second mixed solution; and

[0066] 2. respectively loading the first mixed solution and the second mixed solution in 1) into a 22G flat-head dispensing syringe, introducing the first mixed solution and the second mixed solution to a multi-nozzle electrostatic spinning apparatus for electrostatic spinning at 25° C. to obtain a drug-loaded nanofiber membrane, where the nozzle of the multi-nozzle electrostatic spinning apparatus has an inner diameter of 0.4 mm; the advancing speed of each mixed solution is 10 mL/L, the spinning voltage is 25 kV, the spinning distance is 10 cm, the receiving device is the metal drum with the diameter of 5 cm; the rotation speed of the metal drum is 800 rpm; and

[0067] 3. vacuum-drying the drug-loaded nanofiber membrane in 2) at 25° C. for 48 h.

[0068] The drug-loaded nanofiber membrane was tested for drug release, and the drug release curve was drawn following the method of Example 1. The experimental results were shown in FIG. 2. The drug release system presented a release cycle of nearly 7 days, without a sudden release of the drug. At 18 h, the drug release rate was greatly accelerated and most of the drug had been released on the 5.sup.th day.

[0069] Following the method of Example 1, the drug-loaded nanofiber membrane was scanned with an electron microscope. The experimental results were shown in FIG. 8. When the drug-loaded nanofiber membrane was soaked in PBS for 7 days, the drug-loaded nanofiber membrane continued to swell, causing a part of the fibers to bond together.

Example 3

[0070] A drug-loaded nanofiber membrane comprises a first fiber, a second fiber, and capecitabine; a PLGA copolymer and PDO are extruded separately to form the first fiber and the second fiber; capecitabine is dispersed into the first fiber; a mass ratio of a high-molecular weight PLGA copolymer (MW=120000) to a low-molecular weight PLGA copolymer (MW=60000) is 5:95; a total mass of the second fiber accounts for 1% of a total mass of the first fiber; and a total mass of capecitabine accounts for 15% of a total mass of the two fibers.

[0071] A method for preparing the drug-loaded nanofiber membrane comprises:

[0072] 1. mixing capecitabine, the PLGA copolymer in acetone to obtain a first mixed solution; and mixing PDO in hexafluoroisopropanol to obtain a second mixed solution; and

[0073] 2. respectively loading the first mixed solution and the second mixed solution in 1) into a 22G flat-head dispensing syringe, introducing the first mixed solution and the second mixed solution to a multi-nozzle electrostatic spinning apparatus for electrostatic spinning at 25° C. to obtain a drug-loaded nanofiber membrane, where the nozzle of the multi-nozzle electrostatic spinning apparatus has an inner diameter of 0.4 mm; the advancing speed of each mixed solution is 8 mL/L, the spinning voltage is 10 kV, the spinning distance is 15 cm, the receiving device is the metal drum with the diameter of 5 cm; the rotation speed of the metal drum is 900 rpm; and

[0074] 3. vacuum-drying the drug-loaded nanofiber membrane in 2) at 25° C. for 72 h.

[0075] The drug-loaded nanofiber membrane was tested for drug release, and the drug release curve was drawn following the method of Example 1. The experimental results were shown in FIG. 3. The drug release system presented a release cycle of nearly 26 days, without a sudden release of the drug. The drug release curve was similar to that of a fibrous membrane only comprising PLGA. On the 7.sup.th day, the drug release rate was greatly accelerated until the drug was completely released.

[0076] Following the method of Example 1, the drug-loaded nanofiber membrane was scanned with an electron microscope. The experimental results were shown in FIG. 9. When the drug-loaded nanofiber membrane was soaked in PBS for 7 days, the drug-loaded nanofiber membrane continued to swell, which further decreased the gap between the fibers, causing most of the fibers to bond together.

Example 4

[0077] A drug-loaded nanofiber membrane comprises a first fiber, a second fiber, and ciprofloxacin; a PLGA copolymer and PDO are extruded separately to form the first fiber and the second fiber; ciprofloxacin is dispersed into the first fiber; a mass ratio of a high-molecular weight PLGA copolymer (MW=150000) to a low-molecular weight PLGA copolymer (MW=60000) is 3:97; a total mass of the second fiber accounts for 5% of a total mass of the first fiber; and a total mass of ciprofloxacin accounts for 10% of a total mass of the two fibers.

[0078] A method for preparing the drug-loaded nanofiber membrane comprises:

[0079] 1. mixing ciprofloxacin, the PLGA copolymer in acetone to obtain a first mixed solution; and mixing PDO in hexafluoroisopropanol to obtain a second mixed solution; and

[0080] 2. respectively loading the first mixed solution and the second mixed solution in 1) into a 22G flat-head dispensing syringe, introducing the first mixed solution and the second mixed solution to a multi-nozzle electrostatic spinning apparatus for electrostatic spinning at 25° C. to obtain a drug-loaded nanofiber membrane, where the nozzle of the multi-nozzle electrostatic spinning apparatus has an inner diameter of 0.4 mm; the advancing speed of each mixed solution is 6 mL/L, the spinning voltage is 15 kV, the spinning distance is 15 cm, the receiving device is a metal drum with the diameter of 5 cm; the rotation speed of the metal drum is 600 rpm; and

[0081] 3. vacuum-drying the drug-loaded nanofiber membrane in 2) at 25° C. for 72 h.

[0082] The drug-loaded nanofiber membrane was tested for drug release, and the drug release curve was drawn following the method of Example 1. The experimental results were shown in FIG. 4. The drug release system presented a release cycle of nearly 25 days, without a sudden release of the drug. On the 5.sup.th day, the drug release rate was greatly accelerated until the drug was completely released.

[0083] Following the method of Example 1, the drug-loaded nanofiber membrane was scanned with an electron microscope. The experimental results were shown in FIG. 10. When the drug-loaded nanofiber membrane was soaked in PBS for 7 days, the drug-loaded nanofiber membrane continued to swell, which further decreased the gap between the fibers, causing most of the fibers to bond together.

Example 5

[0084] A drug-loaded nanofiber membrane comprises a first fiber, a second fiber, and cefradine; a PLGA copolymer and PDO are extruded separately to form the first fiber and the second fiber; cefradine is dispersed into the first fiber; a mass ratio of a high-molecular weight PLGA copolymer (MW=150000) to a low-molecular weight PLGA copolymer (MW=60000) is 10:90; a total mass of the second fiber accounts for 7% of a total mass of the first fiber; and a total mass of cefradine accounts for 10% of a total mass of the two fibers.

[0085] A method for preparing the drug-loaded nanofiber membrane comprises:

[0086] 1. mixing cefradine, the PLGA copolymer in acetone to obtain a first mixed solution; and mixing PDO in hexafluoroisopropanol to obtain a second mixed solution; and

[0087] 2. respectively loading the first mixed solution and the second mixed solution in 1) into a 22G flat-head dispensing syringe, introducing the first mixed solution and the second mixed solution to a multi-nozzle electrostatic spinning apparatus for electrostatic spinning at 25° C. to obtain a drug-loaded nanofiber membrane, where the nozzle of the multi-nozzle electrostatic spinning apparatus has an inner diameter of 0.4 mm; the advancing speed of each mixed solution is 6 mL/L, the spinning voltage is 15 kV, the spinning distance is 15 cm, the receiving device is the metal drum with the diameter of 5 cm; the rotation speed of the metal drum is 600 rpm; and

[0088] 3. vacuum-drying the drug-loaded nanofiber membrane in 2) at 25° C. for 24 h.

[0089] The drug-loaded nanofiber membrane was tested for drug release, and the drug release curve was drawn following the method of Example 1. The experimental results were shown in FIG. 5. The drug release system presented a release cycle of nearly 15 days, without a sudden release of the drug. On the 4.sup.th day, the drug release rate was greatly accelerated until the drug was completely released.

[0090] Following the method of Example 1, the drug-loaded nanofiber membrane was scanned with an electron microscope. The experimental results were shown in FIG. 11. When the drug-loaded nanofiber membrane was soaked in PBS for 7 days, the drug-loaded nanofiber membrane continued to swell, which further decreased the gap between the fibers, causing a part of the fibers to bond together.

Example 6

[0091] A drug-loaded nanofiber membrane comprises a first fiber, a second fiber, and levofloxacin; a PLGA copolymer and PDO are extruded separately to form the first fiber and the second fiber; levofloxacin is dispersed into the first fiber; a mass ratio of a high-molecular weight PLGA copolymer (MW=150000) to a low-molecular weight PLGA copolymer (MW=60000) is 10:90; a total mass of the second fiber accounts for 25% of a total mass of the first fiber; and a total mass of levofloxacin accounts for 10% of a total mass of the two fibers.

[0092] A method for preparing the drug-loaded nanofiber membrane comprises:

[0093] 1. mixing levofloxacin, the PLGA copolymer in acetone to obtain a first mixed solution; and mixing PDO in hexafluoroisopropanol to obtain a second mixed solution; and

[0094] 2. respectively loading the first mixed solution and the second mixed solution in 1) into a 22G flat-head dispensing syringe, introducing the first mixed solution and the second mixed solution to a multi-nozzle electrostatic spinning apparatus for electrostatic spinning at 25° C. to obtain a drug-loaded nanofiber membrane, where the nozzle of the multi-nozzle electrostatic spinning apparatus has an inner diameter of 0.4 mm; the advancing speed of each mixed solution is 6 mL/L, the spinning voltage is 15 kV, the spinning distance is 15 cm, the receiving device is the metal drum with the diameter of 5 cm; the rotation speed of the metal drum is 600 rpm; and

[0095] 3. vacuum-drying the drug-loaded nanofiber membrane in 2) at 25° C. for 24 h.

[0096] The drug-loaded nanofiber membrane was tested for drug release, and the drug release curve was drawn following the method of Example 1. The experimental results were shown in FIG. 6. The drug release system presented a release cycle of nearly 1 days, without a sudden release of the drug.

[0097] Following the method of Example 1, the drug-loaded nanofiber membrane was scanned with an electron microscope. The experimental results were shown in FIG. 12. When the drug-loaded nanofiber membrane was soaked in PBS for 7 days, an increased gap between the fibers of the drug-loaded nanofiber membrane causes only a few fibers to bond together.

[0098] 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.