CN114533703A - Tripterine composite membrane and preparation method and application thereof - Google Patents
Tripterine composite membrane and preparation method and application thereof Download PDFInfo
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- CN114533703A CN114533703A CN202210218854.1A CN202210218854A CN114533703A CN 114533703 A CN114533703 A CN 114533703A CN 202210218854 A CN202210218854 A CN 202210218854A CN 114533703 A CN114533703 A CN 114533703A
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- 239000012528 membrane Substances 0.000 title claims abstract description 53
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- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 239000000835 fiber Substances 0.000 claims abstract description 53
- 229920000728 polyester Polymers 0.000 claims abstract description 35
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- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 description 1
- BFUUJUGQJUTPAF-UHFFFAOYSA-N 2-(3-amino-4-propoxybenzoyl)oxyethyl-diethylazanium;chloride Chemical compound [Cl-].CCCOC1=CC=C(C(=O)OCC[NH+](CC)CC)C=C1N BFUUJUGQJUTPAF-UHFFFAOYSA-N 0.000 description 1
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- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
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- 206010037147 pseudopterygium Diseases 0.000 description 1
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- 201000003086 pulmonary systemic sclerosis Diseases 0.000 description 1
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- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 1
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Images
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
- A61K9/0051—Ocular inserts, ocular implants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7015—Drug-containing film-forming compositions, e.g. spray-on
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Ophthalmology & Optometry (AREA)
- Inorganic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the crossing field of biomedical materials and medicine, and discloses a tripterine composite membrane, and 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 the surface of the polyester fibers is coated with chitosan. The preparation method comprises the following steps: (1) soaking the polyester fiber in tripterine ethanol solution, taking out and naturally drying in the air to obtain drug-loaded polyester fiber; (2) and soaking the drug-loaded polyester fiber in a chitosan aqueous solution or a hyaluronic acid aqueous solution, taking out and drying to prepare the tripterine composite membrane. Application of tripterine composite membrane in preparing medicinal preparation for resisting subconjunctival fibrosis is provided. The tripterine composite membrane prepared by the invention can obviously reduce the degree of subconjunctival fibrosis, has better effect of inhibiting subconjunctival fibrosis and has the safety of eye medicines.
Description
Technical Field
The invention belongs to the crossing field of biomedical materials and medicine, and particularly relates to a tripterine composite membrane, and a preparation method and application thereof.
Background
Pterygium and pseudopterygium following ocular trauma and inflammation are common, frequently encountered diseases in the eye, affecting the visual function and appearance of the patient. The pterygium can be treated by operation, but due to the activation of myofibroblasts after the operation, a large amount of extracellular matrix is secreted to cause the fibrosis under the conjunctiva, so that the recurrence after the pterygium resection is caused, the recurrence rate of the pterygium in 1 year after the simple resection reaches 100 percent, and the adhesion of the meibomian ball caused after the recurrence can seriously threaten the vision of a patient and influence the appearance. 5-fluorouracil (5-FU) is one of common clinical drugs for inhibiting subconjunctival fibrosis, but 5-FU still has the defects of rapid metabolism, poor dose controllability and the like in clinical application, so that the subconjunctival fibrosis resistant effect of the clinical application is poor. Mitomycin C, although it inhibits the proliferation of sub-conjunctival fibroblasts to some extent during surgery, is liable to cause corneal epithelial toxicity and scleral lysis. The bioavailability of the local dotting drug in the administration mode is less than 5 percent, so that the therapeutic effect of the drug is poor. How to overcome the ocular administration barrier, improve the drug concentration of the ocular target tissue and provide a substitute drug formula for continuous administration and reducing the administration frequency is always a hotspot and a difficulty of pharmaceutical research and is a key problem to be solved urgently in ophthalmology.
Tripterine (Celastrol) is a bioactive monomer extracted from radix Tripterygii Wilfordii, and has molecular formula of C29H38O4And the molecular weight is 450.61. Tripterine has antiinflammatory, antitumor, and angiogenesis inhibiting effects, and has strong biological function. Research shows that the tripterine can inhibit pulmonary fibrosis and systemic sclerosis of rats induced by bleomycin and can effectively inhibit renal and liver fibrosis. Tripterine exhibits potent anti-inflammatory and anti-fibrotic activity. No report on the inhibition of subconjunctival fibrosis by tripterine is found in the subconjunctival fibrosis research. Although tripterine has strong biological activity and potential drugs for resisting tissue fibrosis, the extremely poor water solubility limits the further application of the tripterine. How to enhance the water solubility and improve the bioavailability is the research of researchersThe first difficult problem to solve. No report has been found on the application of the pharmaceutical preparation to 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 purpose, the technical scheme adopted by the invention is as follows:
a composite membrane of tripterine comprises a membrane substrate composed of 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.
Preferably, the polyester fiber is a polylactic acid fiber, a polylactic acid-glycolic acid copolymer fiber, a lactide-glycolide copolymer fiber or a poly-3-hydroxybutyrate fiber.
The preparation method comprises the following steps:
(1) soaking the polyester fiber in tripterine ethanol solution, taking out and naturally drying in the air to obtain drug-loaded polyester fiber;
(2) and soaking the drug-loaded polyester fiber in a chitosan aqueous solution or a hyaluronic acid aqueous solution, taking out and drying to prepare 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 step (2), the concentration of the aqueous chitosan solution is 1-5g/mL, and the concentration of the aqueous hyaluronic acid solution is 0.5-1.5 g/mL.
Preferably, in the step (2), the drying temperature is 30 to 45 ℃.
The invention mainly utilizes the porous structure of the polyester fiber to carry out drug loading, and the polyester fiber can be prepared according to the prior art as long as the surface of the polyester fiber is ensured to have the porous structure. Preferably, the polyester fiber is prepared by 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 = (0.05-0.15) g: 1 mL; in the mixed solvent, the volume ratio of the dichloromethane to the dimethylformyl is (5-9) to (1-5), and the sum of the two is 10; the electrostatic spinning conditions were: the voltage is 10-15KV, and the propelling speed is 0.2-1.0 mL/h; the polyester material is polylactic acid, polylactic acid-glycolic acid copolymer, lactide-glycolide copolymer or poly 3-hydroxybutyrate.
Application of tripterine composite membrane in preparing medicinal preparation for resisting subconjunctival fibrosis is provided.
Has the advantages that: the tripterine water solubility is very poor, the solubility in water at 37 ℃ is only 3.8 micrograms per milliliter, the invention adopts the electrostatic spinning process, firstly the polyester fiber loaded with the tripterine is prepared, the surface is coated with chitosan to enhance the apparent solubility, and in a subconjunctival injury model, the tripterine composite membrane is implanted under the conjunctiva in an operation, so that the subconjunctival fibrosis degree can be obviously lightened, and the tripterine composite membrane has better subconjunctival fibrosis inhibiting effect and eye drug safety.
Drawings
FIG. 1: SEM picture (A), diameter (C) and pore size distribution (D) of polylactic acid fiber, and SEM picture (B) of tripterine composite membrane.
FIG. 2: after 8 weeks, slit lamp photographs (a), subconjunctival HE pictures (B), Masson stain pictures (C), and Masson stain statistical pictures (D) of the Normal group (Normal), the blank Control group (Control), the blank carrier membrane group (ONFM), and the tripterine composite membrane treatment group (ONFM-CSR).
FIG. 3: after 8 weeks, HE pictures of eye tissues of a Normal group (Normal), a blank Control group (Control), a blank carrier membrane group (ONFM) and a tripterine composite membrane treatment group (ONFM-CSR) are obtained.
Detailed Description
In order to make the invention clearer and clearer, the invention is further described in detail below. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
A preparation method of a tripterine composite membrane comprises the following steps:
(1) dissolving 0.24 g of polylactic acid (PLLA) in 2 mL of mixed solvent consisting of dichloromethane and dimethylformamide according to the volume ratio of 8: 2 to obtain spinning solution; then carrying out electrostatic spinning on the obtained spinning solution to prepare polylactic acid fibers; wherein the electrostatic spinning conditions are as follows: the voltage is 12KV, and the propelling speed is 0.5 mL/h;
(2) soaking the polylactic acid fiber prepared in the step (1) in a tripterine-absolute ethyl alcohol solution with the concentration of 5 mg/mL for 30s, taking out and naturally drying in the air to obtain drug-loaded polylactic acid fiber;
(3) soaking the drug-loaded polylactic acid fiber in a chitosan water solution with the degree of 1g/mL for 3min, taking out the chitosan water solution and drying the chitosan water solution at the temperature of 30 ℃ to obtain the tripterine composite membrane which is marked as ONFM-CSR.
The SEM picture, diameter and pore size distribution of the polylactic acid fiber obtained in the step (1) are respectively shown in a figure 1 (A), a figure 1 (C) and a figure 1 (D), and the SEM picture of the tripterine composite membrane obtained in the step (3) is shown in a 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), from which a large number of surface pores can be clearly observed (figure 1A), the pore size distribution is between 20-70 nm, and the majority is concentrated at 30-40 nm (figure 1D); after the polylactic acid fiber is subjected to drug loading and chitosan coating, the appearance and the structure are still kept good, the surface of the porous fiber is changed, pores are completely disappeared, and a smooth surface is shown on the fiber (fig. 1B).
Comparative example 1
A method for preparing a blank carrier film comprises the following steps:
(1) the same procedure as in (1) of example 1;
(2) naturally drying the polylactic acid fiber prepared in the step (1) in the air to obtain blank drug-loaded polylactic acid fiber;
(3) and soaking the blank drug-loaded polylactic acid fiber in a chitosan aqueous solution with the degree of 1g/mL for 3min, taking out the blank drug-loaded polylactic acid fiber and drying the blank drug-loaded polylactic acid fiber at 30 ℃ to obtain a blank carrier membrane marked as ONFM.
Animal testing
The inventors used the tripterine composite membrane (ONFM-CSR) prepared in example 1 and the blank carrier membrane (ONFM) prepared in comparative example 1 to evaluate the anti-subconjunctival fibrosis effect of the tripterine composite membrane in an 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/100 g. The iodophor is used for disinfecting the eye periphery, sterile normal saline is used for washing the eye conjunctival sac after disinfection, and 0.5 percent (15 mL: 75 mg) of proparacaine hydrochloride eye drops are used for local anesthesia of the eye surface. Making subconjunctival injury of corneal limbus incision with 5mm × 8mm on temporal side under microscope, implanting tripterine composite membrane (ONFM-CSR) or blank carrier membrane (ONFM) 1mm × 5mm under conjunctiva, and closing the wound. The gatifloxacin ophthalmic gel is smeared in a conjunctival sac to prevent infection. The surgery was performed on the right eye of the animals. The postoperative experimental animal drops for local eye drop of tobramycin of conjunctival sac three times a day, one drop at a time, for seven days, so as to prevent infection. The experimental animals were divided into three groups: one group of intraoperative subconjunctival non-implant as blank Control (Control), one group of subconjunctival implant blank carrier membrane (ONFM), and one group of subconjunctival implant tripterine composite membrane (ONFM-CSR); normal SD rats (without conjunctival damage, without subconjunctival implant) were used as Normal controls (Normal) simultaneously with the experiment. The animals were observed under a postoperative slit lamp for operative eyes and conjunctival, corneal, anterior chamber and ocular conditions were recorded. The observation period was 8 weeks. After the experiment, the animal was euthanized by using an abdominal cavity injection for inducing excessive anesthesia, and the animal eye specimen was left for fixation and HE and Masson staining was performed.
The results of animal experiments show that:
after 8 weeks of operation, slit lamp photographs (A), subconjunctival HE photographs (B), Masson staining photographs (C) and Masson staining statistical photographs (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. Postoperative infection does not occur in each group during the experiment, obvious inflammation does not occur in each anterior chamber, and the lens is transparent; conjunctival congestion bleeding occurred in 1 week after the operation of the three groups, and no obvious difference exists among the groups; gradual relief of hyperemia 2 weeks post-surgery; congestion was not evident in each group 8 weeks post-surgery (fig. 2A). HE and Masson staining was performed on each group, HE showed that the blank control and ONFM group had disordered subconjunctival fiber arrangement, ONFM-CSR group had regular subconjunctival matrix arrangement (fig. 2B), and Masson staining was further performed on subconjunctival collagen formation, showing that ONFM-CSR group significantly inhibited subconjunctival collagen synthesis, with differences statistically significant compared to the blank control and ONFM groups (fig. 2C, D, P < 0.05). The results show that: the implantation of the tripterine composite membrane (ONFM-CSR) under conjunctiva can obviously inhibit the fibrosis under conjunctiva. And HE evaluation was performed on each tissue of the eye, the results are shown in fig. 3: no obvious local toxicity is found, which indicates that the tripterine composite membrane has the safety of eye drugs.
In conclusion, the tripterine is a hydrophobic drug, the invention firstly adopts an electrostatic spinning process to prepare the tripterine-loaded polylactic acid degradable membrane, and sugar is coated on the surface of the tripterine-loaded polylactic acid degradable membrane to improve the apparent solubility of the tripterine-loaded polylactic acid degradable membrane; can be directly placed under conjunctiva in operation to make tripterine continuously and slowly act on target tissue, thereby improving the bioavailability of tripterine. Animal experiments show that: the celastrol composite membrane (ONFM-CSR) is implanted, so that the subconjunctival fibrosis degree can be obviously reduced, and the subconjunctival fibrosis inhibiting effect is better.
Claims (8)
1. A celastrol complex film which 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 the surface of the polyester fibers is coated with chitosan.
2. The celastrol composite membrane according to claim 1, wherein: the polyester fiber is polylactic acid fiber, polylactic acid-glycolic acid copolymer fiber, lactide-glycolide copolymer fiber or poly 3-hydroxybutyrate fiber.
3. A method for preparing the tripterine composite membrane according to claim 1 or 2, which comprises the following steps:
(1) soaking the polyester fiber in tripterine ethanol solution, taking out and naturally drying in the air to obtain drug-loaded polyester fiber;
(2) and soaking the drug-loaded polyester fiber in a chitosan aqueous solution or a hyaluronic acid aqueous solution, taking out and drying to prepare the tripterine composite membrane.
4. The method for preparing a tripterine composite membrane according to claim 3, wherein the tripterine composite membrane comprises: 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%.
5. The method for preparing a tripterine composite membrane according to claim 3, wherein the tripterine composite membrane comprises: 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 0.5-1.5 g/mL.
6. The method for preparing a tripterine composite membrane according to claim 3, wherein the tripterine composite membrane comprises: in the step (2), the drying temperature is 30-45 ℃.
7. The method for preparing a tripterine composite membrane according to claim 3, wherein 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: 1 mL; in the mixed solvent, the volume ratio of the dichloromethane to the dimethylformyl is (5-9) to (1-5), and the sum of the two is 10; the electrostatic spinning conditions were: the voltage is 10-15KV, and the propelling speed is 0.2-1.0 mL/h; the polyester material is polylactic acid, polylactic acid-glycolic acid copolymer, lactide-glycolide copolymer or poly 3-hydroxybutyrate.
8. Use of the tripterine composite membrane of claim 1 or 2 in the preparation of a pharmaceutical formulation against sub-conjunctival fibrosis.
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