KR20190118254A - A method for manufacturing a hydrogel drug contact lens containing a drug (lidocaine, vitamin E) manufactured by a phase separation method - Google Patents

Abstract

The present invention relates to a method for manufacturing a drug delivery contact lens polymerized with a drug (lidocaine, vitamin E) manufactured by HEMA and a phase separation method. The method for manufacturing the drug delivery contact lens polymerized with the drug (vitamin E) manufactured by HEMA and the phase separation method has excellent biosynthesis and biodegradability, thereby being applied to a drug delivery media to manufacture contact lenses for preventing and treating eye diseases by varying a polymerization ratio of drug particles manufactured by the phase separation method. Therefore, there is a remarkable effect that a drug delivery effect can be increased by applying different contact lenses to each person.

Description

A method for manufacturing a hydrogel drug contact lens containing a drug (lidocaine, vitamin E) manufactured by a phase separation method}

The present invention relates to a method for producing a contact lens polymerized with a drug (lidocaine, vitamin E) in HEMA, and more particularly to a method for manufacturing a drug contact lens by polymerizing a drug (lidocaine, vitamin E) phase-separated from HEMA will be.

     Ointments and eye drops used in the eye have advantages in terms of convenience and cost, and various types are commercially available. Recently, a new emulsion-type eye drops have been studied, such as lipid film thickness, symptom improvement, and tear film formation time. However, it is reported that repeated dosages are required for the optimal therapeutic effect due to the low absorption capacity of only 5% or less, even though the use of the eye drops is higher than 90%. In addition, for the treatment of chronic eye diseases, the problem of increasing the bioavailability in which the efficacy of the drug is continuously and targeted at the appropriate place and the release rate is controlled has emerged. Sensitive hydrogels, called smart hydrogels, store and release drugs depending on light, chemicals, pressure, temperature, pH and electrical sensitivity, and can be delivered to specific locations where drugs are requested. Hydrogels of hydroxyethyl methacrylate are expanded by interaction with hydroxy groups at high concentrations of hydrogen ions.

Due to the morphological change of the hydrogel network binding structure in response to external pH, drug particles in the gel are affected by release, stability, affinity and diffusion rate. The more fixed charge, the lower the ionic strength, the higher the swelling ability at high pH concentrations. Improved performance can be expected in various devices such as micro actuators, micro valves, chemical sensors, microfluidic flow, filtration separation, and biological tissues to which biocompatible hydrogel component polymers are applied. 50 years ago, with the convenience, long-wearing and the possibility of continuous drug release was found in the biomaterials of contact lenses used by more than 140 million people worldwide, and hyaluronic acid immersed in combination with drugs Contact lenses have been reported. Drug delivery contact lenses have increased interest in the treatment and prevention of drug lenses as a convenience that can be extended from a short term to a long term, and a commercially superior alternative to the existing dosage forms. However, the bioavailability increased compared to the conventional eye drops, but due to the shortcomings such as short drug release time and long drug loading time, eye drops still occupy a high market share.

The use of fewer drugs improves efficiency and improves the therapeutic effect, and the treatment system of drugs and contact lenses that can be used conveniently and safely at the same time as the vision correction is being developed as an alternative to control the disease. Because of the nature of the contact lens matrix and drug nature such as hydrophilicity and hydrophobicity, the drug particles can be continuously delivered to the surface and tissue of the eye, which is advantageous as a system for maximizing treatment and improving patient adaptability. Hydrogel contact lens is a material that can deliver oxygen to corneal epithelial cells, tear evaporation and suppression of tear layer and low cost production and is one of the most important polymers that can effectively control drug delivery. Structural changes occur that allow drug control in a variety of ways.

Therefore, the drug release control hydrogel network design has the effect of polymer compound and crosslinking density on performance, and requires matching of the drug molecule composition to be released with specific size, and the hydrogel itself determines the diffusion and adsorption or permeation of the solute. do.

 Among the various places in the human body, the therapeutic contact lens suitable for the eye focuses on the present invention how the relationship between the drug release pattern, the release amount and the release mechanism according to the properties of the drug and the polymerized hydrogel.

 Drug delivery lenses using conventional contact lenses have been studied in which the therapeutic effects of closed-angle glaucoma, infectious diseases, and inflammation are combined with contact lenses, and are interested in drug storage and release efficiency, lens thickness, moisture content, and drug release rate. Followed.

 Recently, the scope of research has been expanded to a method in which a drug is fixed through an unstable bond, a colloidal dispersion system, a chemically modified lens manufacturing method, and a method of imprinting drug molecules on a lens.

 The invention of HPMC drug molecules imprinted on commercial silicone hydrogel lenses reported a slow release but prolonged release time of up to 60 days, and a study that increased the sustainability of the drug by 30 days by coating the drug on contact lenses. It became.

 On the other hand, the lens body having a spherical surface to be worn on the eye in the prior art Patent No. 10-1427392 as a prior art to solve the problems of the conventional drug delivery contact lens; An accommodating part formed in an inlet groove shape toward the outside of the lens body in contact with the eye; A therapeutic contact lens is described, which includes; a medicine part accommodated in the accommodating part and formed of an ointment or a gel-type drug so as to deliver a medicine component to the eye when the lens body is worn.

 Furthermore, as described in Korean Patent Publication No. 10-1572973, i) 2-hydroxyethyl methacrylate (HEMA), ii) methyl methacrylate (MMA), and iii) N-vinyl- as monomers. 2-pyrrolidone (NVP); A bifunctional crosslinker compound of formula (1) as claimed in claim 1; A first step of stirring the raw material containing azobisisobutyronitrile (AIBN) as an initiator; The stirred raw material is poured into a mold for soft contact lens molding, the mold into which the raw material is injected is placed in an oven, the oven temperature is maintained at 35 to 50 ° C. for 20 to 40 minutes, and then the temperature is set to 100 to 140 ° C., 80 to A second step of preparing a hydrogel soft contact lens by polymerization by maintaining for 100 minutes; And a third step of supporting a drug in the hydrogel soft contact lens. The method of manufacturing a hydrogel soft contact lens for drug release is disclosed.

However, the conventional drug delivery contact lenses as described above are not suitable for the treatment of chronic eye disease with a short drug release time, and the drug loading time is long because the drug must be immersed or immersed for a long time.

      In order to solve the above problems, the present invention provides a drug carrier through a method for producing a contact lens polymerized with HEMA (lidocaine, vitamin E) produced by the phase separation method.

      The present invention provides a vitamin E drug carrier that is effective in treating and preventing diseases of lidocaine and glaucoma and cataracts used in eye surgery.

      In another aspect, the present invention is to provide a method for producing a drug delivery contact lens that can increase the duration of drug delivery by applying a contact lens according to eye diseases through poorly soluble and fat-soluble drugs.

The hydrogel drug carrier polymerized with the drug prepared by the phase separation method according to the embodiments of the present invention includes a polymer structure including a hydrogel polymer and drug particles bonded to the hydrogel polymer, The drug is stored in the polymer structure, and the drug is released from an external solvent of the polymer structure.

The hydrogel polymer may include hydroxyethyl methacrylate.

The polymer structure may include 99% by weight of the hydrogel polymer.

The hydrogel drug carrier containing the drug prepared by the phase separation method may be a contact lens.

The hydrogel drug carrier containing a drug prepared by the phase separation method according to the embodiments of the present invention is stored in a polymer structure to which a hydrogel polymer and the drug (lidocaine, vitamin E) are combined, and an external solvent of the polymer structure. The change is controlled by the release of the drug.

In the method for preparing a hydrogel drug carrier containing a drug prepared by a phase separation method according to embodiments of the present invention, combining the drug with a surfactant to form a drug stability, adding to the aqueous solution of maltodextrin and stirring And heat-reacting the mixed solution at a high temperature of 80 degrees such that phase separation occurs.

The method for preparing a hydrogel drug carrier containing a drug prepared by the phase separation method according to the present invention is applied to a drug delivery medium with excellent biosynthesis and biodegradability, and by varying the polymerization ratio of the drug prepared by the phase separation method. Since the contact lens can be manufactured according to the treatment cycle change, there is a remarkable effect such that the drug delivery effect can be increased by applying a contact lens suitable for different eye conditions for each person.

Table 1 shows the water content of drug delivery contact lenses according to Comparative Examples and Examples of the present invention.
Table 2 shows the expansion index and diffusion coefficient of the drug (lidocaine, vitamin E) delivery contact lens prepared by the phase separation method and when the drug (lidocaine, vitamin E) was directly injected into the hydrogel as a comparative example and the embodiment of the present invention. Indicated.
1 is a diagram showing the state of the solution according to the time change of the static state by mixing the drug (lidokane (a)) with P 124, matodextrin and heated at a high temperature of 80 degrees for 30 minutes.
Figure 2 is a comparative example of the drug (vitamin E (b)), P 124, matodextrin is mixed and heated for 30 minutes at a high temperature of 80 degrees is a diagram showing the state of the solution according to the time change of the static state.
3 is a graph measuring drug particles using a particle size analyzer of a drug (lidocaine (a)) prepared by a phase separation method according to an embodiment of the present invention.
4 is a graph measuring drug particles using a particle size analyzer of a drug (vitamin E (b)) prepared by a phase separation method according to an embodiment of the present invention.
5 is a view showing the surface of the drug particles and drug delivery contact lens photographed with an optical microscope to confirm the stable state of the drug (lidocaine) prepared by the phase separation method according to an embodiment of the present invention.
6 is a view showing the surface of the drug particles and drug delivery contact lens taken by optical microscope to confirm the stable state of the drug (vitamin E) prepared by the phase separation method according to an embodiment of the present invention.
7 is a graph showing a drug release pattern in a PBS pH 7.4 environment of a hydrogel drug delivery contact lens according to another embodiment and comparative example of the present invention.

The contact lenses containing p-HEMA 100 wt% contact lens and coacervation drug (Lidocaine, Vitamin E) were manufactured to a thickness of 90 μm, and the results of the lens being immersed in PBS and hydrated are shown below. Lidocaine drug lens was 41.71 ± 2.82% and Vitamin E drug lens was 41.23 ± 0.97%, which was 10.90% and 9.62% higher than that of p-HEMA 100 wt% contact lens without drug.

Moisture content (%) = s-d / s * 100

Where s is the weight of the swollen lens and d is the weight of the dried lens. When drugs (lidocaine, Vitamin E) were prepared by coacervation and polymerized with HEMA polymers, the water content of contact lenses increased. This is because some of the surfactants used for the coacervation capture during the monomer polymerization is shown to increase the binding strength of the hydroxy group (-OH) and water molecules at the terminal of the HEMA polymer.

After stirring a solution of a drug (lidocaine, Vitamin E) with P 124, which is a surfactant, and an aqueous solution of maltodextrin, at 80 ° C. for 30 minutes, phase separation of the solution is shown with time. (FIGS. 1 and 2). ) After stirring the aqueous solution containing the drug and maltodextrin, after a certain period of time in a static environment, a phase separation of the coacervate phase in which P 124 is present in a large amount and the dilution phase in which a small amount is present. Immediately after stirring, maltodextrin and P 124 were dissolved to form a transparent liquid. The lidocaine test tube was slightly faint due to the solubility of the drug, and yellow light was observed in the Vitamin E test tube. Up to 3 hours under static conditions appeared opaque, and after 8 hours it was formed into three layers including the translucent lower layer and the opaque upper layer. The coacervation drug layer was about 43% and about 36% of the total volume, respectively, and no precipitation of the drug was observed.

3 and 4 show the mean size distribution of coacervation (Lidocaine, Vitamin E) drug particles. The coacervation lidocaine particles were found to be 19.77 ± 3.48 μm and the vitamin E coacervation particle size was 14.50 ± 3.51 μm. The size of coacervation lidocaine particles was larger due to the difference in the molecular size of Lidocaine and Vitamin E (0.25 ~ 0.85 ㎛, 0.20 ~ 1.46 ㎛).

The stability of the coacervation drug contained in the prepared drug contact lens was observed. (FIG. 5, FIG. 6) Both kinds of coacervation drug particles at a constant temperature before polymerization were freely formed as spherical stable microcapsules. I could see the flow. Coacervation drug was stable at both room temperature and high temperature, and did not transform into spherical shape. Compared with lidocaine, vitamin E particles were relatively small and widely distributed. After polymerization of the coacervation drug particles with the HEMA polymer, the surface of the dried lens was analyzed and spherical particles were retained.

Contact lenses were prepared by mixing drugs (lidocaine, Vitamin E) with HEMA polymers or with coacervated drugs. After the photopolymerization of the mixed polymer solution, the amount of drug released was immersed in PBS solution (pH 7.4). (Figure 5) The p-HEMA contact lenses containing Lidocaine and Vitamin E were 2 days and 5 days, respectively. The drug was released for days. The lens containing the lipophilic Vitamin E drug had 25.35% more cumulative release compared to poorly soluble Lidocaine lens, and the release time lasted for 3 more days. The diffusion coefficient of the Vitamin E lens was 1.38 times larger than that of the Lidocaine lens (Table 2). On the other hand, the rate of drug release during the day was approximately 85% and 67%, respectively, based on the total release rate. The release of each drug was concentrated. Drug model of polymerized drug in solution state is difficult to effectively collect poorly soluble drugs and needs to be supplemented to be used as stable sustained release drug system.

The drug delivery lens using coacervation was released for 17 days with lidocaine and 17 days with Vitamin E. Compared with the cumulative release of the drug in the solution state and the polymerized lens, the cumulative release of the coacervation drug lens (lidocaine, Vitamin E) increased by 10% and 43%, respectively, and the release period also increased by 9.5 times and 3.4 times. . Analysis of drug diffusion coefficient (D) (Table 2) Lidocaine was released at an average of 0.04 mg per day, about 1.67 μg per hour, and Vitamin E was released at 0.07 mg per day, 2.92 μg per hour. The cumulative release of lidocaine for 10 days and vitamin E for 6 days was released at a rate of 50% or less of the total drug release, and it was confirmed that stable drug delivery was possible without excessive initial release. The stable drug structure prepared by coacervation (phase separation) and the polymerization of HEMA polymers seem to play a structural role in releasing the drug at a constant rate.

Contact lenses polymerized with p-HEMA and drug (lidocaine, Vitamin E) in solution showed that the drug was released by diffusion of Fick according to Korsmeyer-Peppas (Table 2). Vitamin E) The contact index has a diffusion index (n) between 0.5 and 1.0, and the drug release mechanism is anomalous diffusion due to the diffusion of drug particles stored in the lens and the expansion of the lens material itself. Prolonged and increased release.

Claims (1)

Method for manufacturing drug contact lenses that increases the duration of drug delivery to the outside of a drug delivery contact lens prepared by polymerizing drugs (lidocaine, vitamin E) prepared by HEMA and phase separation method

Images