CN114533703B - Tripterine composite film and preparation method and application thereof - Google Patents
Tripterine composite film and preparation method and application thereof Download PDFInfo
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- CN114533703B CN114533703B CN202210218854.1A CN202210218854A CN114533703B CN 114533703 B CN114533703 B CN 114533703B CN 202210218854 A CN202210218854 A CN 202210218854A CN 114533703 B CN114533703 B CN 114533703B
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Abstract
The invention belongs to the crossing field of biomedical materials and medicine, and discloses a tripterine composite membrane, a preparation method and application thereof. The composite membrane comprises a membrane substrate formed by polyester fibers, wherein the surface of the polyester fibers is provided with a porous structure, tripterine is loaded in the porous structure of the polyester fibers, and chitosan is coated on the surface of the polyester fibers. The preparation method comprises the following steps: (1) Soaking the polyester fiber in a tripterine ethanol solution, taking out, and naturally drying in air to obtain the medicine-carrying polyester fiber; (2) And immersing the drug-loaded polyester fiber in chitosan aqueous solution or hyaluronic acid aqueous solution, taking out and drying to obtain the tripterine composite membrane. The application of the tripterine composite film in preparing the subconjunctival fibrosis resistant pharmaceutical preparation. The tripterine composite membrane prepared by the invention can obviously reduce subconjunctival fibrosis degree, has good subconjunctival fibrosis inhibiting effect and has eye medicine safety.
Description
Technical Field
The invention belongs to the crossing field of biomedical materials and medicine, and particularly relates to a tripterine composite membrane, a preparation method and application thereof.
Background
Pterygium and pseudopterygium secondary to ocular trauma and inflammation are common and frequently encountered diseases of the eye, affecting the visual function and appearance of the patient. Pterygium can be treated by surgery, but due to postoperative myofibroblast activation, a large amount of extracellular matrix is secreted to cause subconjunctival fibrosis, recurrence after pterygium resection is caused, the recurrence rate of pterygium after simple resection is up to 100%, and blepharocollosis adhesion caused after recurrence can seriously threaten the eyesight of patients and affect the appearance. 5-fluorouracil (5-FU) is one of the common clinical medicines for inhibiting subconjunctival fibrosis, but the 5-FU still has the defects of rapid metabolism, poor dosage controllability and the like in clinical application, so that the subconjunctival fibrosis resisting effect is poor in clinical application. Mitomycin C used in surgery, while inhibiting subconjunctival fibroblast proliferation to some extent, is prone to corneal epithelial toxicity and scleral lysis. The bioavailability of the administration mode of local point medicine is less than 5 percent, which causes poor curative effect of the medicine. How to overcome the ocular drug administration barrier, improve the drug concentration of ocular target tissues, provide a substitute drug formulation for continuous drug administration while reducing the drug administration frequency, is always a hotspot and difficulty of pharmaceutical research, and is also a key problem to be solved by ophthalmology.
Tripterine (Celastrol) is bioactive monomer extracted from radix Tripterygii Wilfordii, and has molecular formula of C 29H38O4 and molecular weight of 450.61. Tripterine has various biological activities such as anti-inflammatory, anti-tumor, and inhibiting new blood vessel, and has strong biological functions. Studies show that tripterine can inhibit pulmonary fibrosis and systemic sclerosis of rats induced by bleomycin, and can effectively inhibit kidney and liver fibrosis. Tripterine exhibits potent anti-inflammatory and anti-fibrotic activity. No study report of the inhibition of subconjunctival fibrosis by tripterine is seen in the study of subconjunctival fibrosis. Although tripterine has a strong biological activity and potential anti-tissue fibrosis drugs, its extremely poor water solubility limits its further application. How to enhance the water solubility and the bioavailability is the first difficult problem to be solved by researchers. There is no report of the application of its pharmaceutical formulation to the surgery to inhibit subconjunctival fibrosis.
Disclosure of Invention
The invention aims to provide a tripterine composite membrane and a preparation method and application thereof.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
The tripterine composite membrane comprises a membrane substrate composed of polyester fibers, wherein the surface of the polyester fibers is provided with a porous structure, the inside of the porous structure of the polyester fibers is loaded with tripterine, and the surface of the polyester fibers is coated with chitosan.
Preferably, the polyester fiber is polylactic acid fiber, polylactic acid-glycolic acid copolymer fiber, lactide-glycolide copolymer fiber or poly-3-hydroxybutyrate fiber.
The preparation method comprises the following steps:
(1) Soaking the polyester fiber in a tripterine ethanol solution, taking out, and naturally drying in air to obtain the medicine-carrying polyester fiber;
(2) And immersing the drug-loaded polyester fiber in chitosan aqueous solution or hyaluronic acid aqueous solution, taking out and drying to obtain the tripterine composite membrane.
Preferably, in the step (1), the concentration of the tripterine ethanol solution is 1-10mg/mL, and the purity of the ethanol is more than 95 v%.
Preferably, in the step (2), the concentration of the chitosan aqueous solution is 1-5g/mL, and the concentration of the hyaluronic acid aqueous solution is 0.5-1.5g/mL.
Preferably, in step (2), the drying temperature is 30-45 ℃.
The invention mainly uses the porous structure of the polyester fiber for carrying medicine, and the polyester fiber can be prepared and obtained according to the prior art, so long as the surface of the polyester fiber is ensured to have the porous structure. Preferably, the polyester fiber is prepared by the following steps: dissolving a polyester material in a mixed solvent consisting of dichloromethane and dimethylformamide to obtain a spinning solution; then carrying out electrostatic spinning on the obtained spinning solution to obtain the spinning solution; wherein, the polyester material and the mixed solvent are = (0.05-0.15) g to 1mL; in the mixed solvent, the volume ratio of dichloromethane to dimethyl formyl is (5-9) to (1-5) and the sum of the dichloromethane and the dimethyl formyl is 10; the electrostatic spinning conditions are as follows: the voltage is 10 KV to 15KV, and the propelling speed is 0.2 mL/h to 1.0mL/h; the polyester material is polylactic acid, polylactic acid-glycolic acid copolymer, lactide-glycolide copolymer or poly-3-hydroxybutyrate.
The application of the tripterine composite film in preparing the subconjunctival fibrosis resistant pharmaceutical preparation.
The beneficial effects are that: the invention adopts an electrostatic spinning process, firstly prepares the polyester fiber loaded with the tripterine, coats chitosan on the surface to strengthen the apparent solubility of the polyester fiber, and implants the polyester fiber into subconjunctival injury model under the conjunctiva in the operation, thereby obviously reducing the subconjunctival fibrosis degree, having better subconjunctival fibrosis inhibiting effect and ophthalmic drug safety.
Drawings
Fig. 1: SEM image (a), diameter (C) and pore size distribution (D) of polylactic acid fiber, SEM image (B) of tripterine composite membrane.
Fig. 2: 8 weeks after surgery, slit lamp photographs (A), subconjunctival HE pictures (B), masson staining pictures (C) and Masson staining statistical pictures (D) of Normal (Normal), control (Control), blank carrier membrane (ONFM), tripterine complex membrane treatment (ONFM-CSR).
Fig. 3: 8 weeks after surgery, eye tissue HE pictures of Normal (Normal), control (Control), blank carrier membrane (ONFM), and tripterine complex membrane treatment (ONFM-CSR).
Detailed Description
The present invention will be described in further detail below for the purpose of making the present invention clearer and more specific. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
Example 1
A preparation method of a tripterine composite film comprises the following steps:
(1) Dissolving 0.24 g polylactic acid (PLLA) in a mixed solvent consisting of 2: 2 mL methylene dichloride and dimethylformamide according to a volume ratio of 8:2 to obtain a spinning solution; then carrying out electrostatic spinning on the obtained spinning solution to obtain polylactic acid fibers; wherein, the electrostatic spinning condition is: the voltage is 12KV, and the propulsion speed is 0.5mL/h;
(2) Immersing the polylactic acid fiber prepared in the step (1) in a tripterine-absolute ethanol solution with the concentration of 5 mg/mL for 30s, taking out the polylactic acid fiber and naturally drying the polylactic acid fiber in air to obtain the drug-loaded polylactic acid fiber;
(3) Immersing the drug-loaded polylactic acid fiber in chitosan water solution with the concentration of 1g/mL for 3min, taking out and drying at 30 ℃ to obtain the tripterine composite membrane, and marking as ONFM-CSR.
The SEM image, diameter and pore size distribution of the polylactic acid fiber obtained in the step (1) are shown in the figures 1 (A), 1 (C) and 1 (D), respectively, and the SEM image of the tripterine composite membrane obtained in the step (3) is shown in the figure 1 (B). As can be seen from fig. 1: the diameter distribution range of the polylactic acid fiber is 500-1000 nm (figure 1C), a large number of surface pores can be clearly observed from the polylactic acid fiber (figure 1A), the pore size is distributed between 20-70 and nm, and the majority is concentrated between 30-40 and nm (figure 1D); the morphology and structure of the polylactic acid fiber remained good after drug loading and chitosan coating, the surface of the porous fiber changed, the pores completely disappeared, and a smooth surface was shown on the fiber (fig. 1B).
Comparative example 1
A preparation method of a blank carrier film comprises the following steps:
(1) Step (1) is the same as in example 1;
(2) Naturally drying the polylactic acid fiber prepared in the step (1) in air to obtain blank drug-loaded polylactic acid fiber;
(3) And immersing the blank drug-loaded polylactic acid fiber in a chitosan water solution with the concentration of 1g/mL for 3min, taking out the fiber and drying the fiber at the temperature of 30 ℃ to prepare a blank carrier film, and marking the blank carrier film as ONFM.
Animal test
The inventors evaluated the anti-subconjunctival fibrosis effect of the tripterine composite film prepared in example 1 (ONFM-CSR) and the blank carrier film prepared in comparative example 1 (ONFM) by using SD rat subconjunctival injury animal model, and detailed steps are as follows:
SD rats were intraperitoneally injected with 10% (W/V) chloral hydrate solution, 0.4mL/100g. Periocular disinfection by iodophor, sterile normal saline after disinfection washes the conjunctival sac of the eye, and 0.5% (15 mL: 75 mg) of procaine hydrochloride eye drops are used for local anesthesia of the ocular surface. Subconjunctival lesions of 5mm x 8mm limbal incisions on the temporal side were made under a microscope, subconjunctival was implanted with celastrol composite membrane (ONFM-CSR) or blank carrier membrane (ONFM) 1mm x 5mm, and the wounds were self-closing. The eye gel of Bi Jiati is coated in conjunctival sac to prevent infection. The surgery was performed on the right eye of the animal. The eye drops of tobramycin are applied to the conjunctival sac of the experimental animal after operation for three times a day, one drop at a time, and seven days to prevent infection. Experimental animals were divided into three groups: a group of subconjunctival implants without operation are used as blank Control (Control), a group of subconjunctival implants are used as blank carrier films (ONFM), and a group of subconjunctival implants are used as tripterine composite films (ONFM-CSR); normal SD rats (no conjunctival injury, no implant under conjunctiva) were used as Normal controls (Normal) at the same time as the experiment. The animal was observed under the postoperative slit lamp for the surgical eye and conjunctiva, cornea, anterior chamber and eye conditions were recorded. The observation period was 8 weeks. After the end of the experiment, euthanasia was induced using intraperitoneal injection of excess anesthesia, and animal eye specimens were left fixed for HE and Masson staining.
The animal experiment results show that:
8 weeks after surgery, the slit lamp photograph (A), the subconjunctival HE photograph (B), the Masson staining photograph (C) and the Masson staining statistical photograph (D) of the blank control group, the blank carrier membrane group (ONFM) and the tripterine composite membrane treatment group (ONFM-CSR) are shown in FIG. 2. During the experiment, all groups have no postoperative infection, all groups have no obvious inflammation in the anterior chamber, and the crystalline lens is transparent; three groups of bleeding conjunctiva congestion after 1 week of operation have no obvious difference; congestion gradually lessens 2 weeks after surgery; at 8 weeks post-surgery, congestion was not evident in each group (fig. 2A). For each group of rows HE and Masson staining, HE showed that the blank and ONFM groups of subconjunctival fiber alignment disorders, ONFM-CSR group subconjunctival matrix alignment rules (fig. 2B), further rows Masson staining for subconjunctival collagen formation, ONFM-CSR group significantly inhibited subconjunctival collagen synthesis, the differences being statistically significant compared to the blank and ONFM groups (fig. 2C, D, P < 0.05). The results show that: subconjunctival implantation of the celastrol composite membrane (ONFM-CSR) can obviously inhibit subconjunctival fibrosis. And HE evaluation was performed on each tissue of the eye, see fig. 3 for results: no obvious local toxicity is found, which indicates that the tripterine composite film has eye medicine safety.
In conclusion, tripterine is a hydrophobic drug, and an electrostatic spinning process is adopted to prepare a polylactic acid degradable film loaded with tripterine, and sugar is coated on the surface of the polylactic acid degradable film so as to improve the apparent solubility of the polylactic acid degradable film; the administration mode of direct subconjunctival placement in the operation can be adopted, so that the tripterine continuously and slowly acts on target tissues, and the bioavailability of the tripterine is improved. Animal experiments show that: the implantation of the tripterine composite membrane (ONFM-CSR) can obviously reduce the subconjunctival fibrosis degree, and has better subconjunctival fibrosis inhibition effect.
Claims (7)
1. A tripterine composite film is characterized in that: the composite membrane comprises a membrane substrate formed by polyester fibers, wherein the surface of the polyester fibers is provided with a porous structure, tripterine is loaded in the porous structure of the polyester fibers, and chitosan is coated on the surface of the polyester fibers; wherein the polyester fiber is polylactic acid fiber, polylactic acid-glycolic acid copolymer fiber or poly 3-hydroxybutyrate fiber.
2. A method for preparing a tripterine composite film according to claim 1, which is characterized by comprising the following steps:
(1) Soaking the polyester fiber in a tripterine ethanol solution, taking out, and naturally drying in air to obtain the medicine-carrying polyester fiber;
(2) And immersing the drug-loaded polyester fiber in the chitosan aqueous solution, taking out and drying to obtain the tripterine composite membrane.
3. The method for preparing the tripterine composite film according to claim 2, which is characterized in that: in the step (1), the concentration of the tripterine ethanol solution is 1-10mg/mL, and the purity of the ethanol is more than 95 v%.
4. The method for preparing the tripterine composite film according to claim 2, which is characterized in that: in the step (2), the concentration of the chitosan aqueous solution is 1-5g/mL.
5. The method for preparing the tripterine composite film according to claim 2, which is characterized in that: in the step (2), the drying temperature is 30-45 ℃.
6. The method for preparing the tripterine composite film according to claim 2, wherein the polyester fiber is prepared according to the following process: dissolving a polyester material in a mixed solvent consisting of dichloromethane and dimethylformamide to obtain a spinning solution; then carrying out electrostatic spinning on the obtained spinning solution to obtain the spinning solution; wherein, the polyester material and the mixed solvent are = (0.05-0.15) g to 1mL; in the mixed solvent, the volume ratio of dichloromethane to dimethyl formyl is (5-9) to (1-5) and the sum of the dichloromethane and the dimethyl formyl is 10; the electrostatic spinning conditions are as follows: the voltage is 10 KV to 15KV, and the propelling speed is 0.2 mL/h to 1.0mL/h; the polyester material is polylactic acid, polylactic acid-glycolic acid copolymer or poly 3-hydroxybutyrate.
7. Use of a celastrol composite membrane according to claim 1 for the preparation of a pharmaceutical formulation against subconjunctival fibrosis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210218854.1A CN114533703B (en) | 2022-03-08 | Tripterine composite film and preparation method and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210218854.1A CN114533703B (en) | 2022-03-08 | Tripterine composite film and preparation method and application thereof |
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| CN114533703A CN114533703A (en) | 2022-05-27 |
| CN114533703B true CN114533703B (en) | 2024-05-31 |
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Citations (10)
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