KR101877031B1 - drug-loaded contact lens - Google Patents

Abstract

The present invention relates to a contact lens on which a drug is loaded, and more particularly, to a contact lens on which a drug is loaded, capable of improving a therapeutic effect of an ophthalmic disease by forming a drug layer to discharge the drug inside the lens. The contact lens on which a drug is loaded according to the present invention includes a lens part worn on an eyeball and the drug layer formed inside the lens part. The drug layer is formed by receiving a porous loading unit in which the drug is impregnated inside the lens part.

Description

[0001] The present invention relates to a drug-loaded contact lens,

BACKGROUND OF THE INVENTION Field of the Invention [0001] The present invention relates to a contact lens on which a drug is loaded, and more particularly, to a contact lens on which a medicament layer capable of releasing a drug is formed inside the lens to enhance the therapeutic effect of ophthalmic diseases.

In order to solve problems such as various eye diseases or corneal injury, it is most common to use an eye drop or an eye drop as a method of injecting a drug into the eye.

In the case of such eye drops or eyedrops, it is inconvenient to frequently administer to maintain a certain concentration to maintain the therapeutic effect, and since the drug is washed out from the eye due to blinking of the eyelid, the effective treatment concentration is maintained for a short time , The state of low concentration of the drug is continued for a long time, and the treatment effect is reduced by half.

Ophthalmic ointments, which are viscous semi-solid preparations, are often used as an alternative to these eye drops. The ointment type drug has a relatively longer time of contact with the eyeball than the eye drop, which increases the chance of absorption of the drug. However, after applying the ointment, the visibility deteriorates remarkably. As a result, .

In order to solve such a problem, development of a contact lens accommodating a drug has been advanced. Japanese Patent Application Laid-Open No. 5-11395 discloses a contact lens drug delivery device. The conventional contact lens includes a drug releasing material containing a drug. The contact lens includes a drug releasing material, And since the lens is a drug-releasing contact lens, the drug component is released from the drug releasing material to act on the eyeball.

It is an object of the present invention to provide a contact lens on which a drug is impregnated with a drug, and then a drug is continuously injected into the lens to increase the therapeutic effect of the eye disease.

To achieve the above object, the contact lens of the present invention includes a lens unit to be worn on an eyeball; And a drug layer formed inside the lens unit, wherein the drug layer is formed by receiving a drug-impregnated carrier inside the lens unit.

The support is characterized by being silica or zeolite.

Characterized in that the drug is impregnated in the carrier by supercritical fluid.

The drug is impregnated under supercritical conditions of 30 to 60 DEG C and 10 to 50 MPa.

Wherein the drug is a drug for improving dry eye.

The drug is any one selected from hyaluronic acid, diquavapol, cyclosporin, and oproxacin.

The lens unit includes a lens body coupled to the medicament layer on an inner surface formed of a spherical surface, and a coating film coupled to the inner surface of the lens body to adjust the speed and amount of drug released from the drug layer, .

0.6 parts by weight of N-vinyl-pyrrolidone, 0.6 parts by weight of glycerin, and 0.1 part by weight of ethylene glycol dimethacrylate were added to 100 parts by weight of hydroxyethyl methacrylate, 0.6 part by weight of glycerol dimethacrylate, 0.2 part by weight of glycerol methacrylate, 2,2'-azobis (2,4-dimethylvaleronitrile) ) As a polymerization initiator.

The coating film may contain 10 to 30 parts by weight of styrene, 1 to 10 parts by weight of propylene glycol, 50 to 70 parts by weight of ethoxyethanol based on 100 parts by weight of hydroxyethyl methacrylate, 0.5 to 2 parts by weight of mercaptoethanol, 1 to 5 parts by weight of methacrylic acid, 40 to 60 parts by weight of butylacetate, 2,2'-azodiisobutyronitrile (2 , 2'-azobisisobutyronitrile) in an amount of 0.1 to 0.5 parts by weight.

As described above, according to the present invention, since the drug is continuously injected into the eyeball by inserting the porous carrier into the lens after impregnating the drug into the carrier, the therapeutic effect of ophthalmic diseases can be enhanced.

1 is a perspective view of a contact lens according to an embodiment of the present invention,
Fig. 2 is a sectional view of Fig. 1,
FIG. 3 shows the result of measuring the viscosity of the coating film polymer liquid according to the temperature,
4 is a photograph showing a state of a coating film formed of S200-10, S100-10, and S100-30,
Fig. 5 is a schematic view showing a process for producing biologically-derived silica from rice hulls,
6 is a BET analysis result of the biogenic silica,
FIG. 7 shows the results of BET analysis of the specific surface area and pore size of the secondarily prepared biologically-derived silica,
Fig. 8 is a view of cutting a section of a rice husk by fixing it on a resin and observing it with EDX,
9 is a SEM analysis result obtained by photographing a section of a rice husk,
10 is a result of AFM measurement for analyzing the size of nanoparticles of the biogenic silica,
Figs. 11 and 12 are STM measurement results for analyzing the size of nano pores of the biogenic silica,
13 is a conceptual view of the impregnation process for impregnating the silica with the drug,
14 is a TGA curve of the off-rasin drug raw material,
15 is a TGA curve of the cyclosporin drug raw material,
16 is a TGA curve of hyaluronic acid drug material,
17 is a TGA curve when 1 g of silica is impregnated with 6 ml of ophlockacin,
18 is a TGA curve when 3 g of silica is impregnated with 6 ml of ophlockacin,
19 is a TGA curve when 1 g of silica is impregnated with 0.5 g of cyclosporin drug,
20 is a TGA curve when 3 g of silica is impregnated with 0.5 g of cyclosporin drug,
21 is a TGA curve when 1 g of silica is impregnated with 0.5 g of hyaluronic acid drug,
22 is a TGA curve when 3 g of silica is impregnated with 0.5 g of hyaluronic acid drug,
23 is a TGA curve when 3 g of silica is impregnated with a cyclosporin 1 g drug,
24 is a TGA curve when 3 g of silica is impregnated with a cyclosporin 3 g drug,
25 is a TGA curve when 3 g of silica is impregnated with cyclosporin 10 g drug,
26 shows the results of absorbance analysis of cyclosporin using UV-visible,
Figure 27 is a chromatogram of cyclosporin standard solution concentration,
28 is a cyclosporin standard solution calibration curve,
29 is a chromatogram showing drug elution characteristics of cyclosporin 1 g impregnated samples over time,
30 is a chromatogram showing drug elution characteristics of cyclosporin 3g impregnated sample with time,
31 is a chromatogram showing drug elution characteristics of the 10 g cyclosporin impregnated sample over time,
32 is a chromatogram showing drug elution characteristics according to cyclosporin drug impregnation at 240 min,
FIG. 33 is a graph showing drug elution characteristics according to time of cyclosporin drug impregnation,
34 is a view of a contact lens manufactured by varying the repetition times of the coating film and the drug layer,
35 is a photograph of a cross section of a contact lens observed using an optical microscope,
36 is a view of a contact lens before hydration,
37 is a water content of the contact lens formed with the drug layer over time,
38 is a graph showing the light transmittance of the optical portion of the contact lens,
Figure 39 is Eye photographs on day 1 (Experimental eye)
Figure 40 is Eye photographs on day 1 (Control eye)
Figure 41 is Eye photographs on day 7 (Experimental eye)
Figure 42 is Eye photographs on day 7 (Control eye).

Hereinafter, a contact lens bearing a drug according to a preferred embodiment of the present invention will be described in detail.

A contact lens according to an embodiment of the present invention includes a lens unit 10 to be worn on the eyeball and a drug layer 15 formed inside the lens unit 10.

The lens portion 10 is formed as a spherical surface. Typically, the central portion of the lens portion 10 is an optical region through which light is transmitted. Therefore, it is preferable that the drug layer 15 is formed in the remaining region except for the central portion of the lens portion 10, that is, around the optical region.

The lens unit 10 includes a lens body 11 having a medicinal layer bonded to an inner surface formed with a spherical surface, a lens body 11 coupled to an inner surface of the lens body 11 to contact the eyeball, And a coating film 13 for adjusting the amount.

The lens body 11 is made of a material such as hydroxyethyl methacrylate, N-vinyl-pyrrolidone, glycerin, ethylene glycol dimethacrylate, glycerol methacrylate and 0.24 parts by weight of glycerol methacrylate and azobisnitrile are polymerized to form a polymer solution. 0.6 parts by weight of N-vinyl-pyrrolidone (NVP), 0.6 parts by weight of glycerin, and 0.1 part by weight of vinylpyrrolidone were added to 100 parts by weight of 2-hydroxyethyl methacrylate (2-HEMA) 0.6 part by weight of ethylene glycol dimethacrylate (EGDMA), 0.2 part by weight of glycerol methacrylate (GMA), 0.2 part by weight of 2,2'-azobis (2,4-dimethylvaleronitrile) (2 , And 0.24 parts by weight of 2'-azobis (2,4-dimethylvaleronitrile) are polymerized to form a lens body.

The coating layer 13 may be formed of a material selected from the group consisting of hydroxyethyl methacrylate (2-HEMA), styrene, propylene glycol, ethoxyethanol, mercaptoethanol, methacrylic acid, butylacetate, and azobisisobutyronitrile (AIBN). The polymer solution is then polymerized. For example, the coating film may contain 10 to 30 parts by weight of styrene, 1 to 10 parts by weight of propylene glycol, 2 to 10 parts by weight of 2-ethoxyethanol 50 to 70 parts by weight of 2-ethoxyethanol, 0.5 to 2 parts by weight of 2-mercapto ethanol, 1 to 5 parts by weight of methacrylic acid, n-butylacetate 40 To 60 parts by weight, and 0.1 to 0.5 parts by weight of 2,2'-azobisisobutyronitrile.

The drug layer 15 is inserted between the lens body 11 and the coating film 13. Therefore, the lens portion into which the drug layer 15 is inserted has a sandwich structure.

The drug layer consists of drug-impregnated carriers. In the carrier, innumerable pores are formed. Such a carrier may be composed of an inorganic material or an organic material. An example of the carrier may be silica.

The silica may be natural or synthetic silica. Natural silica derived from natural origin can be used as the synthetic silica. For example, silica to be produced from rice hulls can be used. The silica may have a surface area of 186 m ² / g, a pore volume of 0.33 cm ² / g, and a mean pore size of 6.2 nm.

It goes without saying that zeolite can be used as another example of the support.

Drugs impregnated on the carrier can be drugs for treating various ophthalmic diseases. For example, the drug may be a drug for improving dry eye. Such a drug may be any one selected from hyaluronic acid, Diquafosol, Cyclosporine, and Ofloxacin.

Supercritical fluids can be used to impregnate the drug with the carrier.

Carbon dioxide can be used as a supercritical fluid. The carrier is injected into the chamber in which the supercritical state is maintained, and the supercritical fluid in which the drug is dissolved is injected to impregnate the carrier with the drug. The supercritical condition of the chamber may be a temperature of 30 to 60 DEG C and a pressure of 10 to 50 MPa.

As an example of the method of manufacturing the contact lens of the present invention, the polymer liquid for the lens main body is put into an arm mold, and then the male mold is bonded to the arm mold. At this time, a coating layer may be formed on the core of the male mold coupled with the arm mold by a pad printing method, and then the drug layer may be formed on the coating layer by a pad printing method.

After the male mold with the coating layer and the drug layer printed is bonded to the arm mold, the polymer liquid is cured by photocuring or thermosetting method, and then the male mold is separated from the arm mold to transfer the drug layer and the coating film to the lens body. Therefore, a contact lens in which a drug layer is formed between the lens body and the coating film can be produced.

In order to form a coating film on the male mold, the polymer solution for the coating film is thinly printed on the core of the male mold with a pad printing machine. In order to form a drug layer on the coating film, the drug-impregnated carrier is mixed with the polymer solution to prepare a mixture, and then the mixture is printed on the coating film in a predetermined pattern using a pad printing machine. To prepare the mixture, 0.1 to 10 parts by weight of the carrier impregnated with the drug may be mixed with 100 parts by weight of the polymer solution. Here, the polymer solution may be the same as the polymer solution for the coating film.

Hereinafter, the present invention will be described with reference to experimental examples.

<Development of coating film control technology>

The purpose of developing coating film control technology is to control the content of the therapeutic drug and appropriately control the drug release time.

Viscosity and process parameters were examined to control the coating film. The polymer solution for coating film (hereinafter referred to as "coating solution") was polymerized and the thickness of the coating film was controlled in the manufacturing process so as to control the drug delivery time. As a process variable, the number of repetitive coatings was examined.

1. Control of coating thickness by viscosity control

Assuming that the viscosity of the coating agent is a variable that can control the thickness of the coating film, formulation of the coating agent and reaction conditions are set as experimental factors to control the viscosity. 300 cP, 400 ~ 500 cP, 800 cP, etc. were prepared. The quality of the coating was evaluated to determine the viscosity and composition of the optimized coating.

(1) Manufacture of coatings

Styrene and 2-HEMA were mixed in the proportions shown in Table 1 below and then reacted for a predetermined time to prepare a coating agent.

Sample name Styrene (g) 2-HEMA (g) Other ^* (g) Initiator ^* (g) S100 100 960 1,032 2.12 S200 200 860 1,032 2.12 S250 250 810 1,032 2.12

-other: propylene glycol 50g, 2-ethoxyethanol 500g, 2-mercaptoethanol 10g, methacrylic acid 22g, n-butylacetate 450g

- initiator: 2,2'-azobisisobutyronitrile

The coating agent was classified into S100 polymer, S200 polymer and S250 polymer according to the styrene content. S100 polymer was reacted for 10, 30, and 60 minutes to separate three kinds of polymers (S100-10, S100-30, S100-60). S200 and S250 were prepared by reacting for 10 minutes. The polymers according to styrene content and reaction time (polymerization time) are summarized in Table 2 below.

sample name styrene content (g) Polymerization time (min) S100-10 100 10 S200-10 200 10 S250-10 250 10 S100-30 100 30 S100-60 100 60

(2) Change in viscosity characteristics with styrene and 2-HEMA content and reaction time

Viscosity was measured using a Brookfield Viscometer DV-II + Pro at 20 rpm and a temperature of 15 ° C with a # 31 spindle. The results of the viscosity measurement of each polymer according to the measurement temperature are shown in Table 3 and FIG.

Measuring temperature (캜) Viscosity (cps) S250-10 S200-10 S100-10 S100-30 S100-60 35 - - - 336 431 30 22 92 101 524 665 25 88 176 238 770 964 20 167 295 440 1158 - 15 273 467 735 - -

Referring to Table 3 and FIG. 3, as the reaction holding time becomes longer, it is possible to produce a high viscosity polymer. As the content of styrene increases, a low viscosity polymer is produced.

(3) GPC analysis according to styrene and 2-HEMA content and reaction time

The samples were analyzed by GPC (Gel Permeation Chromatography) and are summarized in Table 4 below.

Sample name Mn
(Number average molecular weight) Mw
(Weight average molecular weight) Mv
(Viscosity average molecular weight) Mw / Mn S100-10 2,132 4,568 4,568 2.143 S100-30 2,830 5,085 5,085 1.797 S100-60 2,772 4,884 4,884 1.762 S200-10 3,507 6,840 6,840 1.950 S250-10 3,279 6,669 6,669 2.034

Referring to Table 4, the polymer having the highest molecular weight was obtained at a reaction time of 30 minutes. By comparing the Mw / Mn values, a polymer with a narrow molecular weight distribution was obtained at 30 minutes and 60 minutes, compared with 10 minutes at the reaction time.

It was confirmed that higher molecular weight polymer could be obtained when the styrene content was increased from 100 to 200, 250. However, when the styrene content was 200, the higher molecular weight polymer could be obtained. The Mw / Mn values were similar, indicating that the effect of styrene content on molecular weight distribution was low.

The above GPC results showed different trends from styrene and 2-HEMA contents and viscosity characteristics (generally high molecular weight in the case of high viscosity) depending on the reaction time.

(4) Confirmation of surface quality of coating film by viscosity

Three polymers for coating films corresponding to viscosity ranges of 300 cP, 400 to 500 cP and 800 cP were selected as S200-10, S100-10 and S100-30, respectively. Then, a coating film was formed on the PBT mold using a pad printing machine, and the surface of each coating film was observed with a microscope. The atmosphere temperature was about 20 캜 when the coating film was produced.

S200-10, S100-10, and S100-30 are shown in FIG. 4 (A) is a coating film formed of S200-10 polymer, (B) is a coating film formed of S100-10 polymer, and (C) is a coating film formed of S100-30 polymer.

Referring to FIG. 4, S200-10 having a viscosity of 300 cP of the polymer formed the most stable coating film. It was concluded that S200-10 will form the most stable coating film even if the atmospheric temperature changes according to the season.

In the case of S100-10 having a viscosity of 400-500 cP, although a relatively uniform coating film was formed, a coating film on a nonuniform surface was slightly observed, and when the temperature was lowered to increase the viscosity, a coating film polymer non- A failure occurred.

In the case of S100-30 having viscosity of 800 cP or more, transition failure occurred as a whole. On the surface of the coating film, many wrinkle-like shapes were observed and it was judged that this was caused by the pressure generated in the process of transferring the coating film polymer from the pad to the mold. The wrinkles formed by the pressure of the pad seem to have not recovered the elasticity of the coating with high viscosity even when the pressure is removed.

Considering that the atmospheric temperature of the process is 20 ° C on average, the polymer S200-10 having a viscosity of 300 cP is considered to be most suitable as a coating material for forming a coating film.

2. Preparation of drug carrier

Silica and zeolite are examined as a support for impregnating the drug.

Synthetic silica (manufactured by Sigma-Aldrich) chemically synthesized with biogenic silica (self-produced) as silica was used. The zeolite was a chemically synthesized synthetic zeolite (Exxon Mobil).

(1) Production of biogenic silica

Biological silica was prepared by treating rice hulls at the Nanobio Research Center, Jeonnam Biotechnology Promotion Agency. The method described in Korean Patent No. 10-0396457 was applied. That is, the rice husk was carbonized by heating in an oxygen-free atmosphere at 200 ° C. for 6 hours, and then heated in an aerobic (or air) atmosphere at 600 ° C. for 1 hour to oxidize the rice husk. The manufacturing process is shown in Fig. 5 as a photograph.

- The above acid treatment was performed to dissolve and dissolve the organic matter contained in rice hulls and to dissolve metal ions.

- Carbonization in the anaerobic atmosphere is a process of decomposing organic matter to remove dehydration and nitrogen, and the oxidation process in the oxygen atmosphere is performed for the over-oxidation process (SiC → SiO ₂ + CO ₂ ) of the carbon covered with silica .

- The above processes of carbonization and oxidation to remove organic matters and metal ions determine the purity and pore structure of the finally produced silica.

(2) the pore size of the carrier

Table 5 shows the pore sizes and crystal form of the biologically-derived silica, synthetic silica, and synthetic zeolite.

division Biogenic silica Chemical synthetic silica Chemical synthetic zeolite Pore Size (nm) 4 to 6 nm 2 to 8 nm 3.5 nm Crystallinity Amorphous Amorphous Crystallinity Unit Price (10,000 won / kg) 1 million won 20 million won 9.6 million won Manufacturer Jeonnam Biotechnology Promotion Agency
Nanobiotechnology Research Center Sigma-Aldrich Exxonmobil

Referring to Table 5 above, all three kinds of pore sizes are similar, but the biocompatible silica produced by itself is the least expensive.

 (3) Characterization of biogenic silica

The purity of the biologically-derived silica using X-ray fluorescence (XRF) was measured and found to be 99.72% as shown in Table 6 below.

compound name conc. (%) SiO ₂ 99.72 Cl 0.08 Al ₂ O ₃ 0.08 SO ₃ 0.03 K ₂ O 0.02 Cr ₂ O ₃ 0.02 Fe ₂ O ₃ 0.02 CaO 0.01 P ₂ O ₅ 0.01

○ Measurement of specific surface area of biogenic silica

As a result of measuring the specific surface area of the first-produced biologically-derived silica (50 g) with BET (nano bio center holding equipment), the surface area was 186 m 2 / g, the pore volume was 0.33 cm 3 / g and the mean pore size was 6.2 nm Respectively. FIG. 6 shows the results of BET analysis of the first-produced silica.

The surface area and the pore volume of the silica (500g) were measured by BET (Chonnam Univ., Korea). The surface area was 167 m2 / g, the pore volume was 0.28 cm3 / g, size was measured at 6.0 nm. The measurement results are shown in Fig.

From the above results, it was found that the range of characteristics of the biogenic silica produced from rice hulls is 170 ~ 180 m2 / g in surface area, 0.3 ~ 0.3cm3 / g in pore volume and 4 ~ 6nm in mean pore size.

○ Surface image analysis of rice hulls

FIG. 8 shows a state where the rice hull was fixed to a resin, and the cross section was cut and observed with EDX. The EDX analysis of the rice husk section shows that the outer and inner parts of the rice hull have a high density of silicon and oxygen, Silica layer was present.

The SEM analysis results of the cross section of the rice hull using SEM are shown in FIG.

○ Observation of biogenic silica particles

As a result of magnification observation using an atomic force microscope (AFM), silica particles of 20 nm or less were observed (see FIG. 10). After increasing the conductivity by depositing Os atoms on the silica cross-sectional layer and analyzing the STM image, 20 nm or 60 nm particles are assembled to form 150 nm sized macroparticles, and 2 to 5 nm wide and 2 nm holes (See Figs. 11 and 12).

(4) drug impregnation

1) Overview of supercritical fluid technology

Supercritical fluid technology is a technology that selectively extracts, separates, and impregnates specific components without decomposing at a low temperature in a supercritical state using carbon dioxide as a solvent without using organic solvents (flammability, danger, toxicity, and carcinogenicity) to be.

It is suitable for the processing of food, cosmetics and pharmaceutical materials requiring high safety. It is capable of selectively extracting and supporting the desired substance by controlling temperature and pressure, and has high purity of the product and does not contain impurities.

Therefore, processing of materials by supercritical fluid technology has the advantage of increasing the value-added and product quality by upgrading existing raw materials.

Fluids in the supercritical state continuously change from a lean state close to the ideal gas to a high density state close to the liquid density, so the equilibrium properties (solubility, entrainer effect), transfer properties (viscosity, diffusion coefficient, thermal conductivity) But also solvation and molecular clustering.

These supercritical fluids can control the physical properties only by controlling the temperature and pressure. Therefore, supercritical fluids can be used as a single solvent in the reaction and separation processes to obtain solvent characteristics corresponding to various types of liquid solvents. Typical supercritical fluid solvents include carbon dioxide (Tc = 31 ° C, Pc = 73 atm). In addition, supercritical water (Tc = 374 ° C, Pc = 218 atm) has the function of an oxidation catalyst itself and can not dissolve inorganic salts. However, since it completely dissolves organic compounds, oxygen and hydrogen, It is possible to control decomposition reaction, synthesis reaction, radical reaction, and ion reaction of decomposable substance. Supercritical methanol (Tc = 239 ° C, Pc = 79atm) has a very high solubility of polar solvents and hydrocarbons and can be used for decomposition and synthesis reactions.

Supercritical carbon dioxide is used as a nonpolar solvent in the process of low polarity materials such as oils and fats, and it can induce the polarity change of the supercritical fluid by adding some substances having polarity such as alcohol.

2) Impregnation process using supercritical fluid technology

The supercritical fluid equipment at the Nanobio Research Center was used to test the impregnation of the biosilicate silica with the drug.

The supercritical carbon dioxide heated to 30 ~ 60 ℃ after pressurizing the carbon dioxide to 10 ~ 50MPa by using the high pressure pump is put into the dissolution tank injected with the drug to dissolve the drug in the supercritical carbon dioxide. Then, the supercritical carbon dioxide in which the drug is dissolved is injected into the impregnation tank in which the carrier (biologically-derived silica) is injected, and maintained for 1 hour to impregnate the carrier with the drug. When the impregnation is completed, the high pressure pump is stopped, and the supercritical carbon dioxide is discharged from the impregnation tank to recover the undiluted drug, and the supercritical carbon dioxide is decompressed.

A conceptual diagram of the above-described impregnation process is shown in Fig.

3) Drug Support Experiment 1

- Samples: Prepare 1g and 3g of biogenic silica, 0.5g of each drug substance (Cyclosporin, hyaluronic acid, and oproxacin).

- Purpose: Consideration of relative amount of drug impregnation by weight of silica carrier.

- Method: The drug was dissolved in supercritical carbon dioxide at a pressure of 15 MPa at a temperature of 50 ° C and then impregnated in an impregnation bath for 1 hour.

○ Determination of sintering temperature of drug raw materials by thermogravimetric analysis (TGA)

-. Condition: The temperature was raised to 600 ℃ at 20 ℃ / min and 40 ㎕ of Alumiun Standard was used as a sample holder.

-. Weights were measured by thermogravimetric analysis of each drug using the raw material as a control drug, and the temperature at which each drug was oxidized was used as a control for the sample.

TGA curves of each drug raw material are shown in Figs. 14 to 16, respectively, in order to examine the sintering temperature of the drug raw materials. FIG. 14 is a TGA curve of the raw material of the offroxine drug, FIG. 15 is a TGA curve of the cyclosporin drug raw material, and FIG. 16 is a TGA curve of the hyaluronic acid drug raw material.

○ thermogravimetric analysis (TGA: Thermogravimetric analysis) a silica carrier impregnated with a drug dose according to the analysis by weight

The TGA curves of the silica impregnated with each drug are shown in FIGS. 17 to 22. FIG. FIG. 17 is a TGA curve when 1 g of silica is impregnated with 6 ml drug of ophroxasin, FIG. 18 is a TGA curve when 3 g of silica is impregnated with 6 ml drug of ophroxasin, and FIG. 19 is a TGA curve of 0.5 g of cyclosporin FIG. 20 is a TGA curve when 3 g of silica is impregnated with 0.5 g of cyclosporin drug, FIG. 21 is a TGA curve of 1 g of silica impregnated with 0.5 g of hyaluronic acid drug, and FIG. Is a TGA curve obtained when 3 g of silica is impregnated with 0.5 g of hyaluronic acid.

17 and 18, in the case of oproxacin, the thermogravimetric reduction was carried out at a temperature of 150 ° C or less, and the analysis by TGA was impossible because it overlapped with the water evaporation temperature. Therefore, it seems that the off-ramasin drug needs analysis of drug impregnation using other analysis.

Referring to FIGS. 19 and 20, it was confirmed that the cyclosporin drug was impregnated into the silica as the thermogravimetric reduction was performed at 300 ° C to 450 ° C.

Referring to Figs. 21 and 22, a slight change in the thermogravimetric weight was observed in the case of hyaluronic acid. Supercritical fluids are useful for impregnating silica with nonpolar materials using supercritical CO ₂ gas, but the impregnation process seems to be poor because hyaluronic acid drugs have polar properties. It is necessary to investigate other methods such as impregnation with a co-solvent or dipping method.

(4) Drug Loading Experiment 2

- Sample: 3g of biogenic silica, Cyclosporin 1g, 3g, 10g

- Purpose: Consideration of the amount of impregnation according to the weight of drug in a certain amount of biologically derived silica carrier.

- Method: The drug was dissolved in supercritical carbon dioxide at a pressure of 15 MPa at a temperature of 50 ° C and then impregnated in an impregnation bath for 1 hour.

Analysis of drug impregnation by weight of silica carrier using thermogravimetric analysis (TGA)

-. Condition: The temperature was raised to 600 ℃ at 20 ℃ / min and 40 ㎕ of Alumiun Standard was used as a sample holder. By using supercritical fluid equipment, cyclosporin drug was impregnated and weight change was measured by thermogravimetric analysis.

23 to 25 show the analysis results of the cyclosporin drug impregnation amount according to the weight of the silica carrier using TGA.

FIG. 23 is a TGA curve when 3 g of silica is impregnated with 1 g of cyclosporin drug, FIG. 24 is a TGA curve when 3 g of silica is impregnated with 3 g of cyclosporin drug, and FIG. 25 is a TGA curve when 3 g of silica is impregnated with 10 g of cyclosporin TGA curve.

23 to 25, TGA analysis showed that the amount of drug impregnated into the silica increases as the amount of the drug increases.

5. Drug Release Sustained Release

1) Determination of the absorbance of the drug for improving dry eye through UV-vis

○ Cyclosporin was dissolved in methnol to determine the hops intensity of target drug, and it was prepared at concentrations of 100ppm and 10ppm. The absorbance at 210 nm was confirmed by UV-Visible analysis and the results are shown in Fig.

2) Drug release experiment and establishment of HPLC analysis condition

○ Drug release test using impregnation of drug in carrier

- Dissolution experiments were carried out to confirm the release characteristics of cyclosporin impregnated in silica and the elution amount according to the impregnation amount of the drug. Add 0.1 g of the cyclosporin impregnated silica drug carrier to the top of the drug elution kit and add 5 ml of methanol (HPLC grade). At this time, in order to prevent the drug carrier in the upper container from flowing into the lower container, the lower end of the upper container was closed with a 0.2 mu m membrane filter. Drug Elution Kit 20 ml of methanol (HPLC grade) was added to the lower container and eluted under conditions of a temperature of 38 ° C and a Stirring velocity of 80 rpm

-. Each 1 ml of the solution eluted through the membrane filter 0.2 탆 was taken at a predetermined time, and then the same amount (1 ml) of the dissolution test solution was added to the elution apparatus to keep the amount of the dissolution test liquid constant. The elution test solution was filtered through a 0.2 μm membrane filter and then measured by HPLC analysis. To determine the effective drug elution rate, the elution solution was taken in units of 1 minute, 3 minutes, and 5 minutes in the beginning, and then in units of 10 minutes and then in units of 120 minutes thereafter.

3) Qualitative and quantitative analysis of drug through HPLC analysis and evaluation of drug elution characteristics over time

■ Qualitative and quantitative analysis by HPLC analysis

- Samples: cyclosporin in silica impregnated sample by weight

- Purpose: Identification of impregnated drug concentration and evaluation of dissolution characteristics

- Sample Preparation

end. Cyclosporin standard substance: The cyclosporin standard substance was diluted with MeOH, and then adjusted to the following concentrations.

NO. Standard product Standard product concentration (ppm) Level 1 Level 2 Level 3 Level 4 One cyclosporin 10 50 100 250

I. HPLC measurement samples: Determination of the elution profile over time according to drug impregnation.

No. Name of sample One cyclosporin 1 g Impregnated sample: 1 min 2 cyclosporin 1 g impregnated sample: 3 min 3 cyclosporin 1 g Impregnated sample: 5 min 4 cyclosporin 1 g Impregnated sample: 10 min 5 cyclosporin 1 g Impregnated sample: 20 min 6 cyclosporin 1 g Impregnated sample: 30 min 7 cyclosporin 1 g Impregnated sample: 60 min 8 cyclosporin 1 g Impregnated sample: 120 min 9 cyclosporin 1 g Impregnated sample: 180 min 10 cyclosporin 1 g Impregnated sample: 240 min 11 cyclosporin 3g Impregnated sample: 1 min 12 cyclosporin 3 g Impregnated sample: 3 min 13 cyclosporin 3 g Impregnated sample: 5 min 14 cyclosporin 3 g Impregnated sample: 10 min 15 cyclosporin 3 g Impregnated sample: 20 min 16 cyclosporin 3 g Impregnated sample: 30 min 17 cyclosporin 3 g Impregnated sample: 60 min 18 cyclosporin 3g Impregnated sample: 120 min 19 cyclosporin 3 g Impregnated sample: 180 min 20 cyclosporin 3 g Impregnated sample: 240 min 21 cyclosporin 10 g Impregnated sample: 1 min 22 cyclosporin 10 g Impregnated sample: 3 min 23 cyclosporin 10 g Impregnated sample: 5 min 24 cyclosporin 10 g Impregnated sample: 10 min 25 cyclosporin 10 g Impregnated sample: 20 min 26 cyclosporin 10 g Impregnated sample: 30 min 27 cyclosporin 10 g Impregnated sample: 60 min 28 cyclosporin 10 g Impregnated sample: 120 min 29 cyclosporin 10 g Impregnated sample: 180 min 30 cyclosporin 10 g Impregnated sample: 240 min

All. Organic solvent

-. Mobile phase A: Methanol

la. Organic solvent preparation

-. Mobile phase A: Methanol (HPLC grade) ⇒ Used after degassing treatment

-. Analysis condition

Item Condition Column Cosmosil 5C ₁₈ -MS-II Detector PDA (UV-210nm) Gradient elution 1) A: Methanol 열 온도 65 ℃ Flow rate 1 ml / min Injection Volume 10 μl

hemp. Analysis of cyclosporin standard material

○ Method

-. Content of cyclosporin standard solution Calibration curve: STD 10, 50, 100, 250 ppm

-. Cyclosporin Elution Test Solution

&Lt; tb &gt; &lt; TABLE &gt;

-. cyclosporin standard material Result / chromatogram

       The results of the cyclosporin standard solution analysis are shown in Table 10 below.

Standard material stay
Time (Rt) division Level 1 Level 2 Level 3 Level 4 cyclosporin 3.386 Conc. (Mg / L) 10 50 100 250 Area 26140 72733 127711 306556

○ Preparation of cyclosporin calibration curve: See FIG.

○ HPLC analysis of cyclosporin drug elution samples

     -. The drug elution profiles of cyclosporin 1g impregnated samples over time are shown in FIG. 29 and Table 11.

No. Name RT Area Amount (ppm) One cyclosporin 1 g Impregnated sample: 1 min Elution test liquid 3.381 21008 1.08 2 cyclosporin 1 g Impregnated sample: 3 min Elution test solution 3.384 36944 14.56 3 cyclosporin 1 g Impregnated sample: 5 min Elution test solution 3.382 39332 16.57 4 cyclosporin 1 g Impregnated sample: 10 min Elution test liquid 3.386 43607 20.19 5 cyclosporin 1 g Impregnated sample: 20 min Dissolution test liquid 3.384 46212 22.39 6 cyclosporin 1 g Impregnated sample: 30 min Dissolution test liquid 3.384 46967 23.03 7 cyclosporin 1 g Impregnated sample: 60 min Elution test solution 3.384 51089 26.51 8 cyclosporin 1 g Impregnated sample: 120 min Dissolution test liquid 3.387 54036 29.00 9 cyclosporin 1 g Impregnated sample: 180 min Elution test solution 3.386 58557 32.83 10 cyclosporin 1 g Impregnated sample: 240 min Dissolution test liquid 3.383 62381 36.06

 -. The drug elution profiles of cyclosporin 3g impregnated samples over time are shown in FIG. 30 and Table 12.

No. Name RT Area Amount (ppm) One cyclosporin 3 g Impregnated sample: 1 min Elution test solution 3.380 20339 0.52 2 cyclosporin 3 g Impregnated sample: 3 min Elution test liquid 3.386 39826 16.99 3 cyclosporin 3 g Impregnated sample: 5 min Elution test liquid 3.384 50825 26.29 4 cyclosporin 3 g Impregnated sample: 10 min Elution test liquid 3.384 61895 35.65 5 cyclosporin 3 g Impregnated sample: 20 min Elution test solution 3.386 71629 43.88 6 cyclosporin 3 g Impregnated sample: 30 min Dissolution test liquid 3.387 71485 43.76 7 cyclosporin 3 g Impregnated sample: 60 min Elution test solution 3.385 78501 49.69 8 cyclosporin 3g Impregnated sample: 120 min Dissolution test liquid 3.386 84991 55.17 9 cyclosporin 3 g Impregnated sample: 180 min Dissolution test liquid 3.390 91789 60.92 10 cyclosporin 3 g Impregnated sample: 240 min Elution test solution 3.387 102041 69.59

 -. The drug elution profiles of cyclosporin 10 g impregnated samples over time are shown in FIG. 31 and Table 13.

No. Name RT Area Amount (ppm) One cyclosporin 10 g Impregnated sample: 1 min Elution test liquid 3.385 44782 21.18 2 cyclosporin 10 g Impregnated sample: 3 min Elution test solution 3.385 59110 33.29 3 cyclosporin 10 g Impregnated sample: 5 min Elution test liquid 3.382 65057 38.32 4 cyclosporin 10 g Impregnated sample: 10 min Dissolution test liquid 3.385 67506 40.39 5 cyclosporin 10 g Impregnated sample: 20 min Elution test solution 3.383 69482 42.06 6 cyclosporin 10 g Impregnated sample: 30 min Elution test liquid 3.381 68187 40.97 7 cyclosporin 10 g Impregnated sample: 60 min Elution test solution 3.381 69361 41.96 8 cyclosporin 10 g Impregnated sample: 120 min Dissolution test liquid 3.382 124089 88.23 9 cyclosporin 10 g Impregnated sample: 180 min Dissolution test liquid 3.380 141234 102.72 10 cyclosporin 10 g Impregnated sample: 240 min Dissolution test liquid 3.382 184712 139.48

-. The drug elution characteristics according to the drug impregnation amount at 240 min are shown in FIG. 32 and Table 14.

No. Name RT Area Amount (ppm) One cyclosporin 1 g Impregnated sample: 240 min Dissolution test liquid 3.383 32381 36.06 2 cyclosporin 3 g Impregnated sample: 240 min Elution test solution 3.387 102041 69.59 3 cyclosporin 10 g Impregnated sample: 240 min Dissolution test liquid 3.382 184712 139.48

-. FIG. 33 shows the drug elution characteristics according to the amount of the drug impregnated over time.

As a result of the above-described drug release characteristics test, it was confirmed that the drug release rate gradually increased from 5 minutes after initially showing a high release rate. This is presumably the release of the drug present on the surface of the silica, and secondarily, the drug present in the mesopores of the silica is gradually released over time. The results showed that the concentration of drug released by cyclosporin was significantly increased with increasing amount of cyclosporin impregnation. In this experiment, it was confirmed that the release rate and time of the drug impregnated into the carrier can be controlled.

6. Manufacture of contact lenses

0.6 parts by weight of NVP (N-vinyl-pyrrolidone), 0.6 parts by weight of Glycerin, 0.6 parts by weight of EGDMA (ethylene glycol dimethacrylate), and 0.1 part by weight of N-vinylpyrrolidone were added to 100 parts by weight of 2-HEMA (2-hydroxyethyl methacrylate) 0.2 part by weight of GMA (Glycerol Methacrylate), and 0.24 part by weight of 2,2'-azobis (2,4-dimethylvaleronitrile) were mixed and polymerized for 10 minutes.

The polymer solution for forming the coating film was S200-10.

Then, 5 parts by weight of the drug-impregnated silica was mixed with 100 parts by weight of the polymer solution (S200-10) as a mixture for forming the drug layer. The drug-impregnated silica was prepared by dissolving 3 g of cyclosporin in supercritical carbon dioxide at a pressure of 15 MPa and a temperature of 50 ° C., and then impregnating it in 3 g of the biosurfactant silica introduced into the impregnation tank for 1 hour.

The polymer solution for the coating film was repeatedly printed on the core of the male mold for lens molding by a pad printing machine repeatedly to form a coating film, and the mixture was printed on the coating film repeatedly 1 to 5 times by a pad printing machine to form a drug layer.

A male mold on which a coating film and a drug layer are printed is combined with an arm mold injected with a polymer solution for a lens body, and then the polymer solution is cured. Then, the male mold is separated from the arm mold to form a contact lens .

(1) Control of coating layer and drug layer according to the number of repetitive printing

The thickness of the coating layer and the drug layer is likely to increase as the number of repetitions of printing is increased when printing a coating film and a drug layer using a pad printing machine. If the thickness of the drug layer can be controlled, the content of the drug carrier in the contact lens can be controlled. Therefore, we want to check the extent to which the number of prints can be repeated within the range in which the contact lens is stably formed.

The repetition frequency of the coating film and the repetition frequency of the drug layer were used as experimental factors. The repetition frequency of the coating film was 5 levels and the repetition frequency of the drug layer was 3 levels. The number of repetition was confirmed.

The shape of the contact lens was confirmed by measuring the base curve radius (BC) and diameter (Diameter) of the contact lens. The contact lens for measurement was sufficiently impregnated in saline solution for 30 minutes or more to reach the equilibrium swelling state. Curvature radius and diameter were measured using Optic analyzer (Chiltern).

Fig. 34 shows the shape of the contact lens thus manufactured. In Fig. 34, the front number of each photograph indicates the number of repetitions of printing on the coating film, and the back number indicates the number of printing repetitions of the drug layer.

Referring to FIG. 34, the coating film and the drug layer, on which a stable contact lens is molded, are shown to have a repetition number of times of 3, respectively. Breakage and deformation occurred in the manufacturing process from the repetition frequency of the coating film 4 times or more. The radius of curvature and the diameter of the lens were not changed much by the repetition frequency.

Table 15 shows the radius of curvature and diameter of the contact lens according to the repetition times of the printing and repetition of the coating layer and the drug layer.

Coating film Drug layer B.C (mm) DIA (mm) 1 time 1 time 8.60 14.20 Episode 2 8.58 14.23 3rd time 8.60 14.27 Episode 2 1 time 8.58 14.12 Episode 2 8.58 14.12 3rd time 8.68 14.22 3rd time 1 time 8.58 14.12 Episode 2 8.52 14.18 3rd time 8.47 14.20 4 times 1 time 8.37 14.18 Episode 2 Breakage 3rd time 5 times 1 time Episode 2 3rd time

The cross section of the contact lens was observed using an optical microscope. A cross-sectional photograph of the contact lens is shown in Fig.

Referring to FIG. 35, it was confirmed that the left, right, and optical parts were well formed when the cross section of 1-3 (repetition of coating film repetition number of times, repetition number of drug layer repetition of 3 times) was observed. The change of the thickness of the drug layer which was observed according to the repetition frequency of the drug layer was difficult to be measured but it was found that the thickness of the drug layer was slightly increased on the photograph.

(2) Analysis of water content and light transmittance of contact lenses

The composition of the drug layer was prepared as shown in Table 16 below.

No. additive Drug layer composition Drug layer repetition times Sample number S1 Biogenic silica Polymer solution (s200-10): 30 g
Additive: 1 g One 1-1 2 1-2 3 1-3 S2 Hyaluronic acid Polymer solution (s200-10): 30 g
Additive: 0.166g One 2-1 2 2-2 3 2-3 S3 Bile-derived silica impregnated with hyaluronic acid (silica / hyaluronic acid) Polymer solution (s200-10): 30 g
Additive: 1 g One 3-1 2 3-2 3 3-3 S4 Biosynthetic silica impregnated with cyclosporine (silica / cyclosporin) Polymer solution (s200-10): 30 g
Additive: 1 g One 4-1 2 4-2 3 4-3 S5 Biological silica (silica / cyclosporin (aqueous solution)) impregnated with cyclosporine (aqueous solution) Polymer solution (s200-10): 30 g
Additive: 1 g One 5-1 2 5-2 3 5-3 S6 Bile-derived silica impregnated with off-rock saphenin (silica / Polymer solution (s200-10): 30 g
Additive: 1 g One 6-1 2 6-2 3 6-3

0.6 parts by weight of NVP (N-vinyl-pyrrolidone), 0.6 parts by weight of Glycerin, 0.6 parts by weight of EGDMA (ethylene glycol dimethacrylate), and 0.1 part by weight of N-vinylpyrrolidone were added to 100 parts by weight of 2-HEMA (2-hydroxyethyl methacrylate) 0.2 part by weight of GMA (Glycerol Methacrylate), and 0.24 part by weight of 2,2'-azobis (2,4-dimethylvaleronitrile) were mixed and polymerized for 10 minutes.

The polymer solution for forming the coating film was S200-10.

And the mixture for forming the drug layer was the drug layer composition shown in Table 16 above.

A polymer film for a coating film was printed once on a core of a male mold for lens molding by a pad printing machine to form a coating film, and the drug layer composition was repeatedly printed on the coating film by a pad printing machine once or three times to form a drug layer.

A male mold on which a coating film and a drug layer are printed is combined with an arm mold injected with a polymer solution for a lens body, and then the polymer solution is cured. Then, the male mold is separated from the arm mold to form a contact lens .

Based on the results of the experiment for the development of the coating film, the number of repetition of the drug layer was limited to 3 times, and the repetition number of the coating film was fixed to 1.

Thirty of the prepared contact lenses were placed in 5 ml vials and hydrated in physiological saline. Fig. 36 shows the state of the contact lens before hydration.

The water content of the contact lens according to the immersion time is shown in Table 17 and FIG. As a comparative group, C1, which is a contact lens without a drug layer, was used.

Immersion time Moisture content Formulation 2 (C1) S1 S4 0h 0% 0% 0% 2h 16% 14% 11% 3h 20% 17% 15% 6h 30% 22% 20% 9h 31% 31% 32% 12h 35% 35% 33% 24h 36% 38% 35% 30h 36% 38% 35% 36h 36% 37% 35% 48h 35% 38% 35% 54h 37% 37% 36% 60h 36% 37% 36% 70h 36% 38% 37%

As a result of the water content measurement, the water content was found to be about 35% ~ 38%. It was confirmed that there was almost no change in the water content of the contact lens due to the drug layer formation.

The light transmittance of the contact lens optic part formed with the drug layer of S4 was measured using UV-Visible, and the result is shown in FIG.

Referring to FIG. 38, the optical portion of the contact lens in which the drug layer is formed showed a light transmittance of 90% or more. This is because the drug layer is formed in a region other than the optical portion, and the drug layer is well formed into a ring-shaped structure in the contact lens.

<An irritation test>

1. INTRODUCTION

This test was performed to evaluate the potential irritation of the test material in New Zealand White male rabbits after intravenous mucosal action.

This test was conducted in accordance with "Korea Food and Drug Administration Notice 2014-155 Medical Device Standard".

1.1 Exam Schedule

- Start of experiment: November 8, 2016

- End of experiment: November 15, 2016

2. Materials and Methods

2.1 Test substance

A contact lens was prepared in the following manner.

0.6 parts by weight of NVP (N-vinyl-pyrrolidone), 0.6 parts by weight of Glycerin, 0.6 parts by weight of EGDMA (ethylene glycol dimethacrylate), and 0.1 part by weight of N-vinylpyrrolidone were added to 100 parts by weight of 2-HEMA (2-hydroxyethyl methacrylate) 0.2 part by weight of GMA (Glycerol Methacrylate), and 0.24 part by weight of 2,2'-azobis (2,4-dimethylvaleronitrile) were mixed and polymerized for 10 minutes.

The polymer solution for forming the coating film was S200-10.

And the composition for forming the drug layer was the drug layer composition shown in Table 18 below.

A polymer film for a coating film was printed once on a core of a male mold for lens molding by a pad printing machine to form a coating film, and the drug layer composition was repeatedly printed on the coating film with a pad printing machine three times to form a drug layer.

A male mold on which a coating film and a drug layer are printed is combined with an arm mold injected with a polymer solution for a lens body, and then the polymer solution is cured. Then, the male mold is separated from the arm mold to form a contact lens .

additive Drug layer composition Drug layer repetition times Sample number Biogenic silica Polymer solution (s200-10): 30 g
Additive: 1 g 3 One Hyaluronic acid Polymer solution (s200-10): 30 g
Additive: 0.166g 3 2 Bile-derived silica impregnated with hyaluronic acid (silica / hyaluronic acid) Polymer solution (s200-10): 30 g
Additive: 1 g 3 3 Biosynthetic silica impregnated with cyclosporine (silica / cyclosporin) Polymer solution (s200-10): 30 g
Additive: 1 g 3 4 Biological silica (silica / cyclosporin (aqueous solution)) impregnated with cyclosporine (aqueous solution) Polymer solution (s200-10): 30 g
Additive: 1 g 3 5 Bile-derived silica impregnated with off-rock saphenin (silica / Polymer solution (s200-10): 30 g
Additive: 1 g 3 6

2.2 Preparation of test materials

Each contact lens was dipped into a beaker at a size of 3 mm in width to prevent contamination of each contact lens, 20 ml of sterile physiological saline (Korea Pharmaceutical Industry Co., Ltd.) was sealed and then eluted at 70 ° C for 24 hours. Separately, a blank test solution was prepared by the same method using sterile physiological saline solution (Korea Pharmaceutical Industry Co., Ltd.).

2.3 Test System

1) Animal species (system)

Male, New Zealand White Rabbit

2) Source

Name: Orient Bio Co., Ltd.

Address: Gamchiro 322 (Joongwon-dong 143-1, Jungwon-gu, Seongnam-si, Gyeonggi-do)

3) Number of animals (sex), weight range and age

18 (male), 2.1-2.5 kg, each 3-4 month old

4) Reason for selecting test system

The rabbits used in this study were selected because they are commonly used for the stimulation tests and have relatively rich test data for this system, which makes it easy to interpret and evaluate the test results.

5) Purification and quarantine

After purchasing the animals, the animals were quarantined and purified in the environment of the animal breeding room of the Safety Evaluation Headquarters for 5 days, and the general health status was observed, and healthy individuals were selected for the test.

2.4 Breeding environment

1) Environmental conditions

The environment of this test is the rabbit breeding room (IV) of the researcher set to 21 ℃, 50% relative humidity, 10-15 times / hr of ventilation, 12 hours of illumination time (8:00 am to 8:00 am) ).

2) Breeding conditions

During the refinement period and the test period, rabbits were individually raised in a three-row, three row breeding box (660x500x300 mm, industrial production).

3) Breeding and drinking water

The feeds were fed with rabbit feed for experimental animals, Purina Korea (85-1, Jangdang-dong, Pyeongtaek, Gyeonggi-do), and water was freely ingested.

2.5 Configuration of Test Groups and Individual Identification

1) Configuration of test group

Eighteen rabbits weighing 2.1 kg or more were used as test animals. 0.2 ml of the test substance was added to each eye of the rabbit in 0.2 ml increments, and the other eye was instilled with 0.2 ml of a control substance (Physiological saline, Daihan Pharm Co., Ltd. Korea). The composition of the test group is shown in Table 19 below.

Test
Materials Sex Animal No. Control Test material Dose
(ml / 1 eye) Contact lens Male One 1 ^* One 0.2 2 1 ^* One 3 1 ^* One 4 1 ^* 2 5 1 ^* 2 6 1 ^* 2 7 1 ^* 3 8 1 ^* 3 9 1 ^* 3 10 1 ^* 4 11 1 ^* 4 12 1 ^* 4 13 1 ^* 5 14 1 ^* 5 15 1 ^* 5 16 1 ^* 6 17 1 ^* 6 18 1 ^* 6

2) Object Identification

Individual identification was carried out in the breeding box with the test number, the individual number, the test duration and the individual identification card with the person in charge of the test.

2.6 Test method

On the first day of testing of the test substance, a healthy New Zealnand White Rabbit was observed. Both eyes of the rabbit were visually examined. 0.2 ml of the test substance in one eye and 0.2 ml of the control substance in the other eye Respectively.

2.7 Observations

1) Observation of general symptoms

And the general symptoms, food and water intake status after the infusion period and the test substance were observed daily.

2) Weight measurement

When animals were introduced, individual weights were measured immediately before the test substance and on the 1st and 7th days after wearing.

3) Observation of the inner stimulus

The opioid mucosal response was observed on days 1, 3, 4, and 7 [Table A] after the test material treatment, in contrast to the other eye on which the control substance was instilled.

4) Evaluation of internal stimulus

The mean mucosal irritation index (MIOI, mean index of ocular irritation), acute eye irritation index (IOL) (IAOI, The Index of Acute Ocular Irritation). The degree of mucosal irritation of the test substance was determined in three steps according to the following criteria.

① 1st step judgment

As a result of examining the values of I.A.O.I appearing within 3 days after the treatment, it was confirmed that the individuals showing the observed values in the range of I.A.O.I ± 5 points were more than 40% of all animals.

② The second stage judgment

Based on the selected I.A.O.I. value according to the first stage judgment, the primary mucosa stimulation grade was determined according to [Table B].

③ Three-stage judgment (final judgment)

Based on the primary mucosal irritation grade, the final mucosal irritation grade was determined according to Table C.

5) Photographing

On days 1 and 7 after instillation of the test substance, the animals to be photographed were selected and the test number and time were recorded and photographed. Photographs are shown in Figures 39 to 42. Table 20 shows the degree of ocular lesion.

(1) cornea (A) Turbidity: the degree of dense (the most dense point observed) ○ There is no pungent or turbidity 0 ○ Although the opacity is dispersed or dense (the transparency is slightly different from the normal transparency), the end of the iris is clearly observed
One ○ Semitransparent part is easily observed, but iris end is slightly unclear 2 ○ The color of the pearl, the end of the iris is not observed, and the size of the pupil is observed to be barely observed 3 ○ The cornea is opaque and iris is not observed due to turbidity. 4 (B) Scattered corneal scopes ○ Less than 1/4 (but not 0) One ○ 1/4 or more and less than 1/2 2 ○ 1/2 or more and less than 3/4 3 ○ 3/4 to 1 4 Score = A x B x 5 Peak = 80 (2) iris (A) Reaction value ○ Normal 0 ○ Significant wrinkles, redness, swelling Moderate redness around the cornea appears alone or mixed, iris reacts to light (dull response is positive)
One ○ No response to light, bleeding and most of the damage (some or all of the above symptoms) 2 Score = A x 5 Peak = 10 (3) conjunctiva (A) Flares (only for the conjunctiva and ocular conjunctiva) ○ The blood vessels are normal 0 Some blood vessels are clearly congested One ○ Wide magenta color, each vessel is not easily observed 2 ○ Light pink 3 (B) conjunctival edema ○ Not inflated 0 ○ Slightly swollen than normal (including subcutaneous) One ○ Significant swelling with partial abduction of the lid 2 ○ Swelling of the eyelids that are about halfway down the snow 3 ○ Swelling of the eyelids about halfway over the eyes 4 (C) Emissions ○ No emissions 0 Some emissions (other than small amounts observed in the inner eye tails of normal animals) One ○ Echoes that wet eyelashes and eyelids 2 ○ Echoes around eye area and eyelashes and eyelids 3 Score = (A + B + C) x 2 peak = 20

Table 21 is based on the second stage of evaluation of mucosal irritation.

Primary mucous membrane stimulation grade Evaluation value Nonirritating (N) 0 - 0.5 Practically nonirritating (PN) 0.5 - 2.5 Minimally irritating (M ₁ ) 2.5 - 15 Mildly irritating (M ₂ ) 15 - 25 Moderately irritating (M ₃ ) 25 - 50 Severely irritating (S) 50 - 80 Extremely irritating (E) 80 - 100 Maximally irritating (Mx) 100 - 110

Table 22 is a three-level evaluation of the mucosal irritation evaluation.

Primary mucous membrane stimulation grade Judgment condition Final judgment grade Non-irritant (N) On the first day of observation, M.I.O.I. = 0 Irritant On the first day of observation, M.I.O.I. > 0 Substantial irritant Substantially irritant (PN) On the first day of observation, M.I.O.I. = 0 On the first day of observation, M.I.O.I. > 0 Minimal irritant The minimum stimulus (M ₁ ) On the second day of observation, M.I.O.I. = 0 On the second day of observation, M.I.O.I. > 0 Drug irritant Mild irritant (M ₂ ) On the third day of observation, M.I.O.I. = 0 On the third day of observation, M.I.O.I. > 0 Moderate irritant Moderate irritant (M ₃ ) (1) Observation 7 days MIOI ≤ 20
(2) On the 7th day of observation, there is no object with IIOI ≤ 10 (60% of total) or IIOI> 30 (1) Observation 7th day MIOI> 20
(2) Observations on day 7 IIOI> 10 (60% of total) or IIOI> 30 Medium-strength irritant Strongly irritant (S) (1) Observation 7 days MIOI ≤ 40
(2) Observation on day 7 IIOI ≤ 30 (60% of total) or IIOI> 60 (1) Observation day 7 MIOI> 40
(2) Observations on day 7 IIOI> 30 (60% of total) or IIOI> 60 Strength stimulant Strength stimulant (E) (1) Observation day 7 MIOI ≤ 80
(2) Observation on day 7 IIOI ≤ 60 (60% of total) or IIOI> 100 (1) Observation day 7 MIOI> 80
(2) On the 7th day of observation, there are individuals with an IIOI> 60 (60% of the total) or IIOI> 100 River stimulus Steel irritant (Mx) (1) Observation day 7 MIOI ≤ 80
(2) Observation 7 days IIOI ≤ 60 (60% of total) Strength stimulant (1) Observation day 7 MIOI> 80
(2) Observation on day 7 IIOI> 60 (60% of total) River stimulus

3. Results

3.1 Mortality and general symptoms (Table 1)

No animals with death or abnormal symptoms associated with the application of the test substance during the study period were observed.

3.2 Weight (Table 2)

Body weight measurements showed weight gain in all subjects.

3.3 Observation of treatment site (Table 3, Figure 1 - 4)

Evaluation of the treated area after the treatment of the test substance showed no mucosal irritation such as corneal opacity, iris irregularity, conjunctival redness, conjunctival edema and conjunctival effusion in the point eye group and the control group.

4. Discussion & Conclusion

To investigate the irritation of contact lenses, 18 New Zealand White male rabbits were injected with 0.2 ml of the test substance, 1 hour after instillation, 1, 2, 3, and 7 days of death, The stimulation was evaluated. During the test period, no abnormalities were observed in the dead animals and general symptoms due to the action of the test substance, and the weight change after the test substance treatment showed a normal increase in all test animals. No irritation such as corneal opacity, iris reaction, conjunctival inflammation (congestion, edema) was observed at 1 hour, 1, 2, 3, and 7 days after the test substance.

In the first step judgment, the evaluation value was calculated as 100.0%, and it was confirmed that it was more than 40% of all animals. In the two-step test, the acute intraocular stimulation index (I.A.O.I.) was calculated as "0.0", and thus the primary mucosal irritation grade was evaluated as "no irritant". Based on the primary mucosal irritation grade, the final ocular mucosal irritation grade was assessed as "no irritant" in the 3-step test.

As a result, the contact lens diluted with New Zealand rabbits did not show corneal opacity, iris reaction, conjunctival inflammation when applied to the mucosa, and the eluate of this specimen was found to be Nonirritant .

6. Tables

Table 23 shows Mortality and clinical signs.

Animal No. Times after treatment Mortality 0 1 hr 1 d 2 d 3 d 7 d One - - - - - - 0/18 ^a 2 - - - - - - 3 - - - - - - 4 - - - - - - 5 - - - - - - 6 - - - - - - 7 - - - - - - 8 - - - - - - 9 - - - - - - 10 - - - - - - 11 - - - - - - 12 - - - - - - 13 - - - - - - 14 - - - - - - 15 - - - - - - 16 - - - - - - 17 - - - - - - 18 - - - - - -

-: Normal

a: Number of dead animals / Number of total animals

 Table 24 shows the Body Weight Unit (g).

Animal No. Day (s) after application 0 One 7 One 2365.7 2405.6 2607.5 2 2311.8 2362.8 2567.4 3 2270.8 2343.5 2675.2 4 2446.3 2507.2 2805.1 5 2179.8 2205.3 2567.3 6 2190.9 2267.3 2599.3 7 2180.4 2261.7 2674.2 8 2276.4 2306.9 2706.3 9 2216.5 2351.5 2624.2 10 2315.2 2400.1 2704.2 11 2415.1 2496.2 2763.1 12 2254.2 2303.1 2576.3 13 2386.5 2454.2 2693.3 14 2296.4 2365.3 2674.2 15 2464.2 2500.2 2802.6 16 2342.2 2370.5 2675.2 17 2245.5 2285.2 2603.2 18 2352.3 2402.2 2683.1 Mean 2306.1 2366.0 2666.8 S.D. 88.0 86.7 73.9

                      S.D. : Standard deviation

Table 25 shows the evaluation of eye irritation.

Animal number One 2 3 4 5 6 7 8 9 10 Cornea
[Score A ×] Degree of opacity
(A)  Hour 1 0 0 0 0 0 0 0 0 0 0  Day 1 0 0 0 0 0 0 0 0 0 0  Day 2 0 0 0 0 0 0 0 0 0 0  Day 3 0 0 0 0 0 0 0 0 0 0  Day 7 0 0 0 0 0 0 0 0 0 0 Diffuse areas of opacity (B)  Hour 1 0 0 0 0 0 0 0 0 0 0  Day 1 0 0 0 0 0 0 0 0 0 0  Day 2 0 0 0 0 0 0 0 0 0 0  Day 3 0 0 0 0 0 0 0 0 0 0  Day 7 0 0 0 0 0 0 0 0 0 0 Iris (A)
[Score = A]  Hour 1 0 0 0 0 0 0 0 0 0 0  Day 1 0 0 0 0 0 0 0 0 0 0  Day 2 0 0 0 0 0 0 0 0 0 0  Day 3 0 0 0 0 0 0 0 0 0 0  Day 7 0 0 0 0 0 0 0 0 0 0 Conjunctivae
[Score = (A + B + C)] Redness (A)  Hour 1 0 0 0 0 0 0 0 0 0 0  Day 1 0 0 0 0 0 0 0 0 0 0  Day 2 0 0 0 0 0 0 0 0 0 0  Day 3 0 0 0 0 0 0 0 0 0 0  Day 7 0 0 0 0 0 0 0 0 0 0 Edema (B)  Hour 1 0 0 0 0 0 0 0 0 0 0  Day 1 0 0 0 0 0 0 0 0 0 0  Day 2 0 0 0 0 0 0 0 0 0 0  Day 3 0 0 0 0 0 0 0 0 0 0  Day 7 0 0 0 0 0 0 0 0 0 0 Discharge
(C)  Hour 1 0 0 0 0 0 0 0 0 0 0  Day 1 0 0 0 0 0 0 0 0 0 0  Day 2 0 0 0 0 0 0 0 0 0 0  Day 3 0 0 0 0 0 0 0 0 0 0  Day 7 0 0 0 0 0 0 0 0 0 0 IIOI ^a  Hour 1 0 0 0 0 0 0 0 0 0 0  Day 1 0 0 0 0 0 0 0 0 0 0  Day 2 0 0 0 0 0 0 0 0 0 0  Day 3 0 0 0 0 0 0 0 0 0 0  Day 7 0 0 0 0 0 0 0 0 0 0 MIOI ^b  Hour 1 0.0 ^C  Day 1 0.0  Day 2 0.0  Day 3 0.0  Day 7 0.0

a: I.I.O.I. (Individual Index of Ocular Irritation) = Score (Cornea + Iris + Conjunctivae)

b: M.I.O.I. (Mean Index of Ocular Irritation) =? I.I.O.I. / Number of animals

c: I.A.O.I. (Index of Acute Ocular Irritation) = The maximum value of M.I.O.I.

Table 26 shows the evaluation of eye irritation (continued).

Animal number 11 12 13 14 15 16 17 18 Cornea
[Score = A ×] Degree of opacity
(A)  Hour 1 0 0 0 0 0 0 0 0  Day 1 0 0 0 0 0 0 0 0  Day 2 0 0 0 0 0 0 0 0  Day 3 0 0 0 0 0 0 0 0  Day 7 0 0 0 0 0 0 0 0 Diffuse areas of opacity (B)  Hour 1 0 0 0 0 0 0 0 0  Day 1 0 0 0 0 0 0 0 0  Day 2 0 0 0 0 0 0 0 0  Day 3 0 0 0 0 0 0 0 0  Day 7 0 0 0 0 0 0 0 0 Iris (A)
[Score = A]  Hour 1 0 0 0 0 0 0 0 0  Day 1 0 0 0 0 0 0 0 0  Day 2 0 0 0 0 0 0 0 0  Day 3 0 0 0 0 0 0 0 0  Day 7 0 0 0 0 0 0 0 0 Conjunctivae
[Score = (A + B + C)] Redness (A)  Hour 1 0 0 0 0 0 0 0 0  Day 1 0 0 0 0 0 0 0 0  Day 2 0 0 0 0 0 0 0 0  Day 3 0 0 0 0 0 0 0 0  Day 7 0 0 0 0 0 0 0 0 Edema (B)  Hour 1 0 0 0 0 0 0 0 0  Day 1 0 0 0 0 0 0 0 0  Day 2 0 0 0 0 0 0 0 0  Day 3 0 0 0 0 0 0 0 0  Day 7 0 0 0 0 0 0 0 0 Discharge
(C)  Hour 1 0 0 0 0 0 0 0 0  Day 1 0 0 0 0 0 0 0 0  Day 2 0 0 0 0 0 0 0 0  Day 3 0 0 0 0 0 0 0 0  Day 7 0 0 0 0 0 0 0 0 IIOI ^a  Hour 1 0 0 0 0 0 0 0 0  Day 1 0 0 0 0 0 0 0 0  Day 2 0 0 0 0 0 0 0 0  Day 3 0 0 0 0 0 0 0 0  Day 7 0 0 0 0 0 0 0 0 MIOI ^b  Hour 1 0.0 ^C  Day 1 0.0  Day 2 0.0  Day 3 0.0  Day 7 0.0

7. Figures

Figure 39 is an eye photographs on day 1 (Experimental eye), Figure 40 is Eye photographs on day 1 (Control eye), Figure 41 is Eye photographs on day 7 (Experimental eye), Figure 42 is Eye photographs on day 7 (Control eye).

8. Results

To investigate the irritation of contact lens for dry eye improvement using supercritical fluid drug penetration technique, 0.2 ml of eluate was injected into 18 New Zealand white male rabbits for 1 hour, 1, 2, 3, and 7 The results of evaluating mortality, general symptoms and irritability during the first day are as follows.

end. During the study period, no general symptoms, no specific clinical signs and no deaths were observed.

I. The body weight was measured during the test, and all of them showed normal weight gain.

All. As a result of observing the eye irritation of the test substance, no eye irritation such as corneal opacity, iris reaction, conjunctival inflammation and congestion, edema was observed.

These results suggest that the leakage of contact lens to New Zealand White rabbits was not observed in corneal opacity, iris reaction and inflammation of conjunctiva when applied to the mucosa, and the eluate of this specimen is nonirritant Respectively.

While the invention has been shown and described with reference to certain exemplary embodiments thereof, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention as defined by the appended claims. Accordingly, the true scope of the present invention should be determined by the technical idea of the appended claims.

10: Lens 11: Body
13: coating layer 15: drug layer

Claims (9)

A lens unit to be worn on the eyeball;
And a medicament layer formed in the annular shape around the optical region, which is a central portion of the lens portion, formed by receiving a drug-impregnated carrier inside the lens portion,
Wherein the lens unit comprises a lens body having an inner surface to which the drug layer is coupled and a coating film which is coupled to an inner surface of the lens body and contacts the eyeball and controls the speed and amount of the drug released from the drug layer,
Wherein the carrier is silica, and the drug is any one selected from hyaluronic acid, cyclosporin, and oproxacin,
The lens body may include at least one member selected from the group consisting of hydroxyethyl methacrylate, N-vinyl-pyrrolidone, glycerin, ethylene glycol dimethacrylate, glycerol methacrylate, methacrylate and azobisnitrile are polymerized to form a polymer liquid,
The coating layer may be formed of a material selected from the group consisting of hydroxyethyl methacrylate, styrene, propylene glycol, ethoxyethanol, mercaptoethanol, methacrylic acid, butyl acetate butylacetate, and azobisisobutyronitrile are polymerized to form a drug-loaded contact lens. delete The drug-bearing contact lens according to claim 1, wherein the drug is impregnated into the support by supercritical fluid. 4. The drug-bearing contact lens according to claim 3, wherein the drug is impregnated in supercritical conditions of 30 to 60 DEG C and 10 to 50 MPa. delete delete delete delete Injecting a polymer liquid for a lens body into an arm mold for lens molding;
Printing a polymer liquid for a coating film on a male mold for lens molding with a pad printing machine to form a coating film;
Printing a mixture of the drug-impregnated carrier and the polymer solution on a pad printing machine to form an annular drug layer on the coating layer;
Bonding the male mold to the arm mold and curing the male mold;
And separating the male mold from the arm mold to obtain a lens part having the annular drug layer between the lens body and the coating film,
Wherein the carrier is silica, and the drug is any one selected from hyaluronic acid, cyclosporin, and oproxacin,
The polymer liquid for a lens body may be at least one selected from the group consisting of hydroxyethyl methacrylate, N-vinyl-pyrrolidone, glycerin, ethylene glycol dimethacrylate, glycerol methacrylate Glycerol methacrylate, azobisnitrile,
The polymer solution for a coating film may be at least one selected from the group consisting of hydroxyethyl methacrylate, styrene, propylene glycol, ethoxyethanol, mercaptoethanol, methacrylic acid, Butylacetate, azobisisobutyronitrile, and the like,
Wherein the polymer liquid used in the mixture is the same as the polymer liquid for the coating film.

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