CN115167005A

CN115167005A - Preparation method of drug-loaded contact lens based on graphene oxide

Info

Publication number: CN115167005A
Application number: CN202210980529.9A
Authority: CN
Inventors: 王鹏; 戴燕; 辛剑宇; 刘爱平; 潘光云; 陶雄; 杨媛
Original assignee: Sichuan Xingtai Pule Medical Technology Co ltd
Current assignee: Sichuan Xingtai Pule Medical Technology Co ltd
Priority date: 2022-08-16
Filing date: 2022-08-16
Publication date: 2022-10-11

Abstract

The invention relates to a medical material, and provides a preparation method of a medicine-carrying type contact lens based on graphene oxide in order to improve the medicine release condition of the contact lens, which comprises the following preparation steps: preparing a graphene oxide dispersion liquid; (2) preparing a monomer mixed solution; (3) Dissolving a medicine in the graphene oxide dispersion liquid obtained in the step (1), adding the monomer mixed liquid obtained in the step (2), stirring, pouring into a mold, pouring and curing, and demolding to obtain the graphene oxide-based medicine-carrying contact lens. The preparation method of the medicine-carrying contact lens based on the graphene oxide does not influence the optical performance of the contact lens, and can effectively improve the release condition of the medicine.

Description

Preparation method of drug-loaded contact lens based on graphene oxide

Technical Field

The invention relates to the technical field of medical materials, in particular to a preparation method of a medicine-carrying contact lens based on graphene oxide.

Background

Glaucoma is a degenerative disease that damages the optic nerve due to elevated intraocular pressure and requires immediate treatment, otherwise it leads to vision loss and ultimately blindness. The primary principle in the glaucoma treatment regimen to slow or prevent deterioration is to reduce the intraocular pressure to a level that does not continue to damage the optic nerve.

At present, the ophthalmic administration mode is mainly to carry out local eye drop dropping on eyes, but due to the defects of frequent administration, too fast medicine loss speed, extremely low bioavailability and the like, researchers begin to search for a new administration mode. The contact lens is also called cornea contact lens, which is a lens directly worn on the cornea of eyeball and plays the role of correcting vision and preventing ophthalmic diseases. Materials for contact lenses can be classified into rigid gas impermeable, rigid gas permeable, soft non-hydrophilic materials and soft hydrophilic materials according to their preparation. The main component for preparing the soft hydrophilic material is poly-beta-hydroxyethyl methacrylate (HEMA), and the soft hydrophilic material has good optical and mechanical properties and excellent biocompatibility.

Contact lenses can provide higher drug bioavailability and fewer side effects by maintaining a more stable, controlled concentration of drug in the tear film than eye drops. Drug-loaded contact lenses are the most focused new means of replacing the traditional eye drug delivery mode at present. When the contact lens is worn on the eye, the majority of the loaded drug will diffuse from the lens into the post-lens tear film, with the released drug having an extended pre-corneal residence time and a more direct diffusion path to the ocular surface due to the lens' immunity to the blink reflex and tear fluid exchange.

However, the incorporation of hydrophobic drugs (such as bimatoprost) into contact lenses can be challenging because they can alter key lens properties such as swelling and light transmittance. In addition, hydrophobic drug-loaded contact lenses can cause ocular surface congestion due to lens dehydration at the end of the day.

Disclosure of Invention

The invention aims to provide a preparation method of a medicine-carrying contact lens based on graphene oxide, which does not affect the optical performance of the contact lens and can effectively improve the release condition of a medicine.

The embodiment of the invention is realized by the following technical scheme: the preparation method of the medicine-carrying contact lens based on the graphene oxide comprises the following preparation steps:

(1) Preparing a graphene oxide dispersion liquid: graphene oxide was synthesized from graphite by a modified Hummer method using sodium nitrate, potassium permanganate and concentrated sulfuric acid. Graphite flakes are added to an Erlenmeyer flask containing sodium nitrate and concentrated sulfuric acid. The solution was stirred at 15 ℃ to form a graphite layer. To effect oxidation, potassium permanganate was gradually added to the above solution, and stirring was continued. The resulting solution was stirred at room temperature for 7 days, then hydrogen peroxide was added to neutralize excess potassium permanganate. The dark brown slurry was washed several times with deionized water until a neutral pH was obtained. And (4) pouring out the supernatant, and drying to obtain graphene oxide powder.

Dispersing the obtained graphene oxide powder in a 1-vinyl-2-pyrrolidone (PVP-K90) aqueous solution for keeping the stability of the graphene oxide dispersion; the preparation process can also be directly omitted, and a graphene oxide finished product is purchased.

(2) Preparing a monomer mixed solution: mixing the monomer a and the monomer b, an initiator, a cross-linking agent and a solvent, performing ultrasonic dispersion, and performing magnetic stirring uniformly to obtain a monomer mixed solution;

wherein the monomer a is beta-hydroxyethyl methacrylate (HEMA), the monomer b comprises but is not limited to one or two or three of dimethyl acrylic acid (MMA), acrylic Acid (AA), N-vinyl pyrrolidone (NVP), siloxane, propyl methacrylate and 2- (4-benzoyl-3-hydroxyphenoxy) ethyl 2-acrylate;

such initiators include, but are not limited to, thermal initiators such as azodiisopropylnitrile, dibenzoyl peroxide, azobisisobutyronitrile (AIBN), t-butyl peroxyneodecanoate; examples of the photoinitiator include 2-hydroxy-2-methyl-1-phenylacetone, 1-hydroxycyclohexyl phenyl ketone and the like;

the cross-linking agent includes but is not limited to one or two of Ethylene Glycol Dimethacrylate (EGDMA), tetraethylene glycol diacrylate, diethylene glycol dimethacrylate, ethylene glycol diacrylate, diethylene glycol diacrylate and the like;

the solvent can be water or ethanol, acetonitrile and the like;

(3) Preparing a graphene oxide drug-loaded contact lens: dissolving a medicine in a graphene oxide dispersion solution, incubating for 24 hours, adding a monomer mixed solution for preparing a contact lens, stirring for 24 hours at 50rpm, pouring into a contact lens mold for casting, wherein the thermal polymerization reaction needs to be cured for 0.5-2 hours at 105-120 ℃; curing for 10-30 minutes is needed for ultraviolet light initiated polymerization; and demolding the mold to obtain the graphene oxide supported contact lens.

The medicine is mainly hydrophobic ophthalmic medicine, including but not limited to bimatoprost, travoprost, latanoprost, tafluprost and other medicines for treating glaucoma.

The technical scheme of the embodiment of the invention at least has the following advantages and beneficial effects: according to the preparation method of the medicine-carrying contact lens based on the graphene oxide, after the graphene oxide is added, the loss of ophthalmic medicines in the extraction and sterilization processes is obviously reduced. With increasing amounts of graphene oxide, the lenses showed a significant reduction in burst and cumulative release of the drug. The presence of graphene oxide improves the swelling properties of the lens due to its water retention properties. Also, the transmittance is improved due to the molecular dispersion of the drug on the surface of the graphene oxide. Compared with eye drops, the relative bioavailability of the drug is obviously improved when the graphene oxide is used for loading the lens.

Drawings

FIG. 1 shows the cumulative release of bimatoprost from contact lenses obtained by three different methods as provided in Experimental example 1 of the present invention.

Detailed Description

Example 1

Graphene oxide-loaded bimatoprost contact lenses.

Graphite flake (1 g) was charged to an Erlenmeyer flask (250 mL) containing 0.5g sodium nitrate and 50mL 98% concentrated sulfuric acid. The solution was stirred at a speed of 150rpm for 20 minutes at 15 ℃ to form a graphite layer. To carry out the oxidation, 3g of potassium permanganate are gradually added to the above solution and stirred at 150rpm below 15 ℃ (20 min). The resulting solution (greenish) was stirred at room temperature (30-35 ℃) for 7 days, then 30% v/v hydrogen peroxide (10 mL) was added to neutralize excess potassium permanganate. The dark brown slurry was washed several times with deionized water until a neutral pH was obtained. And (4) pouring out the supernatant, and drying the slurry to obtain graphene oxide powder.

Step 2: and (3) preparing a contact lens monomer mixed solution.

Hydroxyethyl methacrylate (HEMA, 1 mL) as the base contact lens material, dimethylacrylic acid (DMA, 310 μ L) as comonomer, ethylene glycol dimethacrylate (EGDMA, 10 μ L) as a cross-linking agent to increase dimensional stability agent, N-vinyl pyrrolidone (NVP, 10 μ L) as a plasticizer to provide the required flexibility, methacryloxypropyl tris (trimethylsiloxy) silane (2.5 μ L) for increasing oxygen permeability, irgacure (20 mg) as photoinitiator. Mix and sonicate to dissolve, magnetically stir for 30 minutes, centrifuge for 5 minutes at 12000rpm using a high speed centrifuge, and pour off the supernatant.

And step 3: preparation of graphene oxide loaded bimatoprost contact lenses

The graphene oxide powder was first dispersed in 1.6% w/v PVP-K90 solution, bimatoprost (5 mg) was weighed and incubated with 100. Mu.L of the graphene oxide dispersion for 24 hours, then 1mL of the contact lens monomer mixture solution was added. The dispersion of bimatoprost-graphene oxide in the monomer mixture was stirred at 50rpm for 24 hours before casting.

80 μ L of the mixture was cast in a mold and the mold was exposed to 365-370nm radiation in a UV transilluminator (curing/polymerization) for 12 minutes. Unreacted monomer was removed from the lenses by boiling (100 ℃) the individual lenses in water for 1 hour. Followed by autoclaving.

Comparative example 1

No graphene oxide load is used to synthesize bimatoprost contact lenses.

Hydroxyethyl methacrylate (HEMA, 1 mL), dimethylacrylic acid (DMA, 310. Mu.L), ethylene glycol dimethyl acrylate (EGDMA, 10. Mu.L), N-vinyl pyrrolidone (NVP, 10. Mu.L), methacryloxypropyl tris (trimethylsiloxy) silane (2.5. Mu.L), irgacure (20 mg) were weighed, mixed and sonicated to dissolve, magnetically stirred for 30 minutes, centrifuged for 5 minutes at 12000rpm using a high speed centrifuge, and the supernatant decanted. Bimatoprost-loaded contact lenses were made by adding 16mg PVP-K90 to 1mL of the monomer mixture containing bimatoprost (5 mg). An excess of the monomer mixture solution was added to the female mold and the male mold was locked into place. After this, the mold was exposed to 365-370nm radiation in an ultraviolet transilluminator (curing/polymerization) for 12 minutes. And finally, carrying out high-pressure sterilization.

Comparative example 2

No graphene oxide loading, bimatoprost soaked contact lenses.

Hydroxyethyl methacrylate (HEMA, 1 mL), dimethylacrylic acid (DMA, 310. Mu.L), ethylene glycol dimethyl acrylate (EGDMA, 10. Mu.L), N-vinyl pyrrolidone (NVP, 10. Mu.L), methacryloxypropyl tris (trimethylsiloxy) silane (2.5. Mu.L), irgacure (20 mg) were weighed, mixed and sonicated to dissolve, magnetically stirred for 30 minutes, centrifuged for 5 minutes at 12000rpm using a high speed centrifuge, and the supernatant decanted. PVP-K90 was added to the monomer mixture solution before shaping and polymerization. The monomer mixture solution is added to the female mold and the male mold is locked into place. After this, the mold was exposed to 365-370nm radiation in an ultraviolet transilluminator (curing/polymerization) for 12 minutes.

Bimatoprost is loaded by soaking the contact lenses in a bimatoprost solution for 10 days, followed by autoclaving. Wherein the content of bimatoprost in deionized water is 0.015% w/v NaHCO3 and 0.9% w/vNaCl, and the bimatoprost is dissolved at a certain concentration to form a bimatoprost soaking solution.

Experimental example 1

The samples obtained in the above example 1 and comparative examples 1 to 2 were weighed to calculate the swelling degree, and the transmittance of the contact lens was measured using an ultraviolet-visible spectrophotometer; the results are shown in table 1 below. As can be seen from the results of swelling ratio and transmittance, the contact lenses prepared by using bimatoprost loaded with graphene oxide are superior to the group without graphene oxide in both swelling ratio and transmittance, so that the use of graphene oxide loaded with a drug also improves the swelling property of the lenses due to the water retention property of graphene oxide, and also improves the transmittance due to the molecular dispersion of the drug on the surface of graphene oxide.

TABLE 1 swelling and Transmission of different contact lenses

/	% degree of swelling	% transmittance
			GO-loaded bimatoprost contact lenses	96.5	98.8
No GO load, synthetic bimatoprost contact lenses	91.7	97.5
			No GO loading, soaking bimatoprost contact lenses	92.1	96.3

Experimental example 2

Analysis of bimatoprost amount released from contact lenses in vitro release experiments were performed by placing individual lenses at 34 ℃ into glass vials containing 2mL 0.9% w/v NaCl in addition to 0.015% w/v NaHCO3 in deionized water, placing the vials in a 37 ℃,80rpm thermostated shaking chamber for drug release testing, and withdrawing 2mL of release medium at a predetermined time point while replenishing the same volume of solution until bimatoprost was detected. The amount of bimatoprost released was quantified using HPLC at 210 nm. Drug release rate profiles were obtained for bimatoprost cumulative release and soaking time (as shown in figure 1).

In example 1, the GO containing contact lenses showed some improvement in drug burst release with the drug release rate profile (within 24 hours) because there was a strong interaction of the drug with GO (pi-pi interaction) generated during lens processing, thereby preventing loss and release of the drug from the contact lens matrix. The amount of drug released is also less. The bimatoprost synthetic contact lenses without GO showed higher burst release with increasing amount of bimatoprost in comparative example 1. In comparative example 2, without GO, the cumulative release time and burst behavior of soaking bimatoprost contact lenses was shorter and more pronounced. The result shows that the graphene oxide is used for loading bimatoprost, so that the burst release of bimatoprost can be effectively reduced, the release rate of bimatoprost is reduced, and the release time is prolonged.

The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and various modifications and changes will occur to those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A preparation method of a medicine-carrying contact lens based on graphene oxide is characterized by comprising the following preparation steps:

(1) Preparing a graphene oxide dispersion liquid;

(2) Preparing a monomer mixed solution;

(3) Dissolving a medicine in the graphene oxide dispersion liquid obtained in the step (1), adding the monomer mixed liquid obtained in the step (2), stirring, pouring into a mold, pouring and curing, and demolding to obtain the graphene oxide-based medicine-carrying contact lens.

2. The method for preparing a drug-loaded contact lens based on graphene oxide according to claim 1, wherein in the step (1), the graphite flake, sodium nitrate and concentrated sulfuric acid are mixed and stirred, the oxidant is added and then stirring is continued, then the excess oxidant is neutralized, and the graphene oxide powder is obtained after washing and drying.

3. The method for preparing a drug-loaded contact lens based on graphene oxide according to claim 2, wherein the graphene oxide powder obtained in step (1) is dispersed in an aqueous solution of 1-vinyl-2-pyrrolidone to obtain a graphene oxide dispersion.

4. The method for preparing a graphene oxide-based drug-loaded contact lens according to claim 1, wherein in the step (2), the monomer a, the monomer b, the initiator, the cross-linking agent and the solvent are mixed, dispersed and uniformly stirred to obtain a monomer mixture.

5. The method for preparing a graphene oxide-based drug-loaded contact lens according to claim 4, wherein the monomer a in the step (2) is beta-hydroxyethyl methacrylate;

the monomer b is one or more of dimethylacrylic acid, acrylic acid, N-vinyl pyrrolidone, siloxane, propyl methacrylate and 2-acrylic acid 2- (4-benzoyl-3-hydroxyphenoxy) ethyl ester.

6. The method for preparing a graphene oxide based drug-loaded contact lens according to claim 4, wherein the cross-linking agent in the step (2) is one or two of ethylene glycol dimethacrylate, tetraethylene glycol diacrylate, diethylene glycol dimethacrylate, ethylene glycol diacrylate, diethylene glycol diacrylate, etc.;

the initiator is one or more of azodiisopropanonitrile, dibenzoyl peroxide, azodiisobutyronitrile, tert-butyl peroxyneodecanoate, 2-hydroxy-2-methyl-1-phenyl acetone and 1-hydroxycyclohexyl phenyl ketone.

7. The method for preparing a graphene oxide-based drug-loaded contact lens according to claim 1, wherein in the step (3), the curing condition is 105-120 ℃ and 0.5-2h.

8. The method for preparing graphene oxide-based drug-loaded contact lenses according to claim 1, wherein in the step (3), the drug is a hydrophobic ophthalmic drug.

9. The method for preparing the graphene oxide-based drug-loaded contact lens according to claim 8, wherein in the step (3), the drug is one or more of bimatoprost, travoprost, latanoprost and tafluprost.