JP5238115B2 - Drug sustained-release polymer gel and ophthalmic lens comprising the same - Google Patents

Description

  The present invention relates to a drug sustained-release polymer gel having drug sustained-release performance and an ophthalmic lens comprising the same. Specifically, the present invention relates to a drug sustained-release polymer gel that controls drug release by the action of a hydrophobic polymer layer formed on the surface of the polymer gel and an ophthalmic lens comprising the same.

  In the drug treatment of various eye diseases, the instilled drug needs to be well absorbed by the target tissue to exert its effect. However, ophthalmic solution is generally washed away quickly by tears, and the medicinal effect lasts only for a short time. Therefore, it is very inefficient from the viewpoint of drug treatment of eyeball tissue. In addition, if a sufficient effective concentration is to be maintained, frequent and large doses are required, and naturally the side effects become a problem.

  Accordingly, drug delivery systems aimed at efficiently allowing a drug to reach a target tissue and acting from around 1970 have been studied. In particular, since polymer gels can contain a drug together with water, research and development are being conducted as a useful drug sustained-release device.

  In general, a drug in a polymer gel is dissolved or dispersed in water present in the polymer network, and is released by diffusing in the water. Therefore, the drug release amount and release behavior are affected by the water content of the polymer gel and the external environment surrounding the gel. For example, when a polymer gel in a drug saturated state is poured into water, the drug in the polymer gel quickly diffuses into water, and it is difficult to control drug release.

  By the way, sustained drug release systems using polymer gels are roughly classified into the following types.

1. 1. Stimulus response type system Monolithic system 2. Reservoir type system A stimulus response type system requires an external stimulus such as a chemical substance, an electric field, a magnetic field, an ultrasonic wave, and heat, and this may cause some influence on the living body, which is not preferable.

  The monolithic system is a method in which a drug is dispersed or dissolved in a polymer gel to release the drug slowly, and it is easy to produce a device, and even if the device is broken, there is no outflow of a high concentration drug solution and it is safe. However, since the amount of drug release up to about 60% in the polymer gel is proportional to the square root of time, the concentration gradient decreases with time, and the release rate decreases. Therefore, in order to control the release of the drug, a device for keeping the drug strongly in the polymer gel by various intermolecular forces such as electrostatic interaction and keeping the concentration gradient constant has been studied.

  For example, Patent Document 1 controls drug release by impregnating a polyvinyl alcohol (PVA) hydrogel obtained by graft polymerization with a radical polymerizable monomer having a functional group such as an electrolytic group or a polar group by actinic radiation treatment. The technology to do is disclosed.

  However, since this method uses gamma rays as a means for introducing a functional group into the PVA water-containing gel, control of the amount of irradiation is required, and the equipment is special and has not been put into practical use.

  In Patent Document 2 and Patent Document 3, a drug having an anionic group is held in a polymer gel having a quaternary ammonium salt in the side chain, and electrostatic interaction between the quaternary ammonium group and the anionic group is performed. Disclosed is a technique for controlling drug release by forming a bond.

  However, since the cationic polymer gel expresses an electrostatic interaction only with a drug having an anionic group, the types of drugs that can be used are limited.

  A reservoir type system basically consists of a drug reservoir and a controlled release membrane, and controls the release of the drug by the controlled release membrane. For example, when the drug inside the controlled release membrane is present at a saturation concentration or more, The reduced amount of drug released to the outside of the gel is supplied by dissolving the drug remaining in the gel, so that the drug concentration inside the release control film is kept constant. Therefore, if the concentration of the external liquid is zero, the release rate is constant regardless of time from Fick's first law, and it can be the most effective sustained drug release device.

  For example, in Patent Document 4, a contact lens is manufactured by adhering a lens front surface portion and a rear surface portion with an adhesive, and has a chamber therein, and a drug is contained in the chamber. A reservoir-type drug sustained-release contact lens that is supplied to the eye is disclosed. However, there are concerns about the safety of the adhesive with respect to the eye tissue, and there is a disadvantage that the feeling of wearing on the eye is poor.

  Further, as a disadvantage of the reservoir type system, there is a risk that a high concentration drug solution flows out from the inside when the release control membrane is broken.

  JP-A-52-56148   JP-A-6-145456   JP-A-6-306250   Japanese National Patent Publication No. 7-5000026

Problems to be solved by the invention

  The object of the present invention is not limited to the type of drug to be included in the polymer gel, is safe for the eye tissue and has a good feeling on the eye, and controls the release of the drug for effective sustained release. The object is to provide a sustained-release polymer gel capable of exhibiting performance and an ophthalmic lens comprising the same.

Means for solving the problem

[Means for Solving the Problems]
The present invention is a sustained-release drug gel characterized in that the surface of a polymer gel is coated with an acrylic ester-based hydrophobic polymer layer by a graft polymerization method .

  Further, the present invention provides the sustained-release drug as described above, wherein the acrylic ester-based hydrophobic polymer layer is formed by polymerizing at least one compound represented by the following general formula (1): Polymer gel.

(R ₁ is at least one selected from the group consisting of an alkyl group having 1 to 10 carbon atoms, an alkyl group having a siloxane bond having 1 to 10 silicon atoms, and a fluoroalkyl group having 3 to 18 fluorine atoms. And R ₂ is a hydrogen atom or a methyl group.)

  Furthermore, the present invention is a drug sustained-release ophthalmic lens comprising the above-mentioned drug sustained-release polymer gel and having an ophthalmic lens shape.

  As a result of examining the conventional monolithic type and reservoir type system, the present invention has found that a hydrophobic layer having a poor affinity with water can be formed on the surface of the polymer gel to thereby continuously release the drug in water. Is due to. That is, in the present invention, as a drug release control layer, a hydrophobic polymer layer having almost no water as a drug transport medium is formed on the surface of the polymer gel, and its action controls the diffusion of the drug to the outside. ing. In addition, since the polymer gel having its own sustained release ability is used as the drug reservoir, it is possible to avoid outflow of the drug solution when the release control membrane is broken.

As the hydrophobic monomer forming the hydrophobic polymer layer, there are various monomers such as a styrene monomer, a vinyl monomer, and a (meth) acrylate monomer. In the present invention, a (meth) acrylate monomer is used. The hydrophobic polymer layer can control drug release, but when used as an ophthalmic lens, excessive hydrophobization of the surface of the polymer gel makes the wearing feeling as an ophthalmic lens poor. A guideline that does not make the wearing feeling inferior is about 120 degrees or less in terms of the water contact angle measured by the droplet method as the wettability of the ophthalmic lens surface. In order to obtain a lens surface with a contact angle of 120 degrees or less, R ₁ is an alkyl group having 1 to 10 carbon atoms, an alkyl group having a siloxane bond having 1 to 10 silicon atoms, and a fluoroalkyl having 3 to 18 fluorine atoms. At least one group selected from the group consisting of groups, and various (meth) acrylates in which R ₂ is a hydrogen atom or a methyl group are preferred.

  As the (meth) acrylate monomer in the present invention, methyl (meth) acrylate, ethyl (meth) acrylate, n-butyl (meth) acrylate, t-butyl (meth) acrylate, pentyl (meth) acrylate, hexyl (meth) Acrylate, cyclohexyl (meth) acrylate, octyl (meth) acrylate, nonyl (meth) acrylate, trimethylsilyl (meth) acrylate, pentamethyldisiloxanylmethyl (meth) acrylate, pentamethyldisiloxanylpropyl (meth) acrylate, Tris (trimethylsiloxy) silylpropyl (meth) acrylate, methylbis (trimethylsiloxy) silylpropyl (meth) acrylate, isobutylhexamethyltrisiloxanylmethyl (meth) acrylate , Trimethylsilylmethyl (meth) acrylate, trimethylsilylpropyl (meth) acrylate, tris (trimethylsiloxy) silylpropylglycerol (meth) acrylate, methylbis (trimethylsiloxy) silylpropylglycerol (meth) acrylate, trifluoroethyl (meth) acrylate , Tetrafluoropropyl (meth) acrylate, tetrafluoropentyl (meth) acrylate, hexafluoroisopropyl (meth) acrylate, heptafluorobutyl (meth) acrylate, octafluorooctyl (meth) acrylate, nonafluoropentyl (meth) acrylate, dodeca Fluorooctyl (meth) acrylate, tridecafluorooctyl (meth) acrylate, tridecafluorohe Chill (meth) acrylate, heptadecafluorodecyl (meth) acrylate, octadecanol fluoro undecyl (meth) acrylate. The acrylic ester-based hydrophobic polymer layer in the present invention is formed by polymerizing at least one of these compounds. A polyfunctional hydrophobic monomer can also be used in order to improve the mechanical strength and oil resistance of the hydrophobic polymer layer. Examples of the polyfunctional hydrophobic monomer include ethylene glycol di (meth) acrylate, diethylene glycol di (meth) acrylate, trimethylolpropane tri (meth) acrylate, and pentaerythritol tri (meth) acrylate.

  The drug sustained-release polymer gel of the present invention forms a hydrophobic polymer layer on the gel surface by graft polymerization. In this method, the polymer gel is immersed in a hydrophobic monomer or a hydrophobic monomer solution diluted with various solvents and irradiated with ultraviolet rays. Hydrophobic monomers activated by ultraviolet irradiation are bonded to the polymer gel surface to form a hydrophobic polymer layer.

  As the polymer gel in the present invention, any synthetic polymer can be used. Examples of the synthetic polymer include polyhydroxyethyl methacrylate, polyvinyl alcohol, polyvinyl pyrrolidone, polymethacrylic acid, polyacrylic acid, and the like, which can be used regardless of the ionicity or nonionicity of the polymer gel. Further, the water content of the polymer gel is preferably about 20 to 80% in order to maintain good drug sustained release.

  Surface graft polymerization can be carried out in various solvents, and nonpolar solvents such as hexane and toluene, polar solvents such as acetone and tetrahydrofuran, and mixtures thereof can be used.

  The ultraviolet irradiation time is usually 3 minutes to 90 minutes, and preferably 5 to 60 minutes in consideration of optical transparency and deterioration of the polymer gel. In less than 3 minutes, it is difficult to form a hydrophobic polymer layer capable of controlled drug release on the surface. When ultraviolet rays are irradiated for longer than 90 minutes, the polymer gel tends to become cloudy.

  Since the drug sustained-release polymer gel of the present invention performs drug release by controlling drug diffusion in the hydrophobic polymer layer, the type of drug is not limited. Examples of the drug that can be used in the present invention include general ophthalmic drugs such as prophylactic and healing agents for eye diseases such as inflammation and wounds, diagnostic agents, and immunosuppressants, and can also be used as eye drops. And only the active ingredient can also be used. Specific examples of such drugs include, for example, tear increasing agents, cell promoters, corneal thickness increase inhibitors, mydriatics, miotic agents, antibiotic preparations, antibacterial agents, antihistamines, anti-inflammatory agents, and anticholinergic agents. , Antiglaucoma compounds, antiviral agents, carbonic anhydrase control, antifungal agents, anesthetics and the like.

  The drug sustained-release polymer gel of the present invention can also be used in drug-release devices for various uses other than ophthalmic lenses. For example, a sterilization sheet, an insecticidal sheet, a poultice, etc. are mentioned. Moreover, the drug to be used can also be suitably selected according to each use.

  Hereinafter, a preferred embodiment of the present invention will be described taking an ophthalmic lens as an example. However, this embodiment is provided for understanding of the present invention, and the scope of the present invention is not limited to the embodiment described later.

  In this example, in order to explain the diffusion control of the drug by the hydrophobic polymer layer, naphazoline nitrate (molecular weight 273, cationic), cromoglycate sodium (molecular weight 512, anionic) and lysozyme chloride (molecular weight about 10,000, Three drugs with different (cationic) molecular weight and charge were used. Each of them is a drug contained in commercially available allergic conjunctivitis eye drops.

(Preparation of ophthalmic lens treated with hydrophobic polymer layer)
The taking lens subjected to the treatment with the hydrophobic polymer layer is prepared by pouring a monomer solution having the composition shown in Table 1 into a contact lens mold, and the taking lenses 1 to 5 are thermally polymerized using azobisisobutyronitrile as an initiator. The ophthalmic lens 6 was obtained by UV polymerization in the absence of a catalyst. The dosing lens 6 was subjected to alkali hydrolysis after polymerization. The water content of the ophthalmic lens was calculated by the following formula using a weight method.

  (Weight at swelling−weight at drying) ÷ weight at swelling × 100

(Method for preparing drug sustained-release ophthalmic lens and method for measuring drug content)
The ophthalmic lens treated with the hydrophobic polymer layer was placed in 5 mL of an aqueous drug solution (0.3% by weight) and immersed at 25 ° C. for 48 hours to obtain a drug sustained-release ophthalmic lens containing the drug. . The amount of drug contained in the aqueous solution of the drug aqueous solution after 48 hours of immersion is quantified by HPLC, and the difference from the amount of drug in 5 mL of the drug aqueous solution is calculated to determine the amount of drug contained in the sustained-release ophthalmic lens. It was. The HPLC used was JASCO Corporation.

(Change over time in the cumulative drug release amount of the sustained-release ophthalmic lens)
After immersing the drug sustained-release ophthalmic lens in 2 mL of physiological saline at 37 ° C., the immersion solution was changed over time (1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours). Then, after 7 hours, 8 hours, 9 hours, 10 hours, and 24 hours, the drug concentration was measured and the cumulative drug release amount of the sustained-release ophthalmic lens was determined. Furthermore, the percentage with respect to the drug inclusion amount was defined as the drug release rate released from the drug sustained-release ophthalmic lens.

(Light transmittance measurement method)
The light transmittance (380 to 780 nm) was measured using UV-2200 manufactured by Shimadzu Corporation.

(Contact angle measurement method)
The ophthalmic lens that has been subjected to the hydrophobic polymer layer treatment is immersed in physiological saline. After confirming that the equilibrium swelling state was reached, water on the surface of the ophthalmic lens was quickly wiped off with a cloth, and measurement was performed by a droplet method using a contact angle meter CA-D type manufactured by Kyowa Interface Science Co., Ltd.

Example 1
Hexane was used as a solvent, the methyl methacrylate was adjusted to 0.5% by weight, and the mixture was placed in a sample bottle to perform nitrogen gas replacement. The ophthalmic lens 1 was immersed in the hexane solution and irradiated with ultraviolet rays for 15 minutes using an ultraviolet irradiation device (manufactured by Mitsubishi Rayon Engineering Co., Ltd.). After removing unreacted substances, a drug sustained-release ophthalmic lens was produced based on the method for preparing a drug sustained-release ophthalmic lens. The above measurement was performed on the obtained drug sustained-release ophthalmic lens. The drug used was naphazoline nitrate.

(Examples 2 to 6)
Similar to Example 1 using a hexane solution of ethyl methacrylate, n-butyl methacrylate, tris (trimethylsiloxy) silylpropyl methacrylate, hexafluoroisopropyl methacrylate, 1: 1 mixture of methyl methacrylate and hexafluoroisopropyl methacrylate as the hydrophobic monomer The drug sustained-release ophthalmic lens was prepared by the method. The drug inclusion amount was measured for the obtained drug sustained-release ophthalmic lens. The drug used was naphazoline nitrate.

(Examples 7 and 8)
With the same composition as in Example 1, a UV-irradiation time was changed from 30 minutes to 45 minutes to produce a drug sustained-release ophthalmic lens. The above measurement was performed on the obtained drug sustained-release ophthalmic lens. The drug used was naphazoline nitrate.

(Examples 9 and 10)
The above-mentioned measurement was performed on a drug sustained-release ophthalmic lens obtained in the same manner as in Example 1 using sodium cromoglycate and lysozyme chloride as drugs.

(Examples 11 and 12)
A drug sustained-release ophthalmic lens was produced from ophthalmic lenses 2 and 3 in the same manner as in Example 1. The above measurement was performed on the obtained drug sustained-release ophthalmic lens. The drug used was naphazoline nitrate.

(Examples 13 to 15)
A drug sustained-release ophthalmic lens was prepared from ophthalmic lenses 4, 5 and 6 in the same manner as in Example 1. The above measurement was performed on the obtained drug sustained-release ophthalmic lens. The drug used was naphazoline nitrate.

(Comparative Example 1)
The above measurement was performed on the ophthalmic lens 1 in which the hydrophobic polymer layer was not formed. The drug used was naphazoline nitrate.

  The treatment conditions and physical properties of Examples 1 to 15 and Comparative Example 1 are shown in Table 2, and Table 3 shows the drug release results of Examples and Comparative Examples. In Examples 1 to 15, the visible light transmittance was 90% or more and the contact angle was 120 degrees or less.

  From FIG. 1, almost 90% of naphazoline nitrate was released in about 2 hours from the ophthalmic lens of Comparative Example 1 in which the hydrophobic polymer layer was not formed. In Example 1, naphazoline nitrate was released even after 24 hours. The release rate is approximately 70%, and a sustained release can be confirmed. In addition, comparing Examples 1, 7 and 8 from FIG. 2, it can be confirmed that the drug release is more controlled because the thickness of the hydrophobic polymer layer increases as the surface graft polymerization time increases.

  In addition, in the drugs used in Examples 1, 9 and 10, naphazoline nitrate and lysozyme chloride are cationic, and cromoglycate sodium is anionic, but it is not affected by these charges, but rather has a large molecular weight. Is influenced by. In Examples 1, 11 and 12, the water content of the ophthalmic lens is different. In addition to the diffusion control by the hydrophobic polymer layer, the gap of the network structure of the polymer gel forming the ophthalmic lens is reduced to reduce the water content. When the drug is lowered, the diffusibility of the drug is lowered. Further, from Examples 12 to 15, drug release can be controlled without depending on the type of ophthalmic lens used.

Effect of the invention

  In the drug sustained-release polymer gel of the present invention, the diffusion and release of the drug inside the gel is controlled by the hydrophobic polymer layer formed on the gel surface. Therefore, when used in a taking lens, it is possible to continuously release any drug with a good eye feeling.

  The time-dependent change figure of the drug release rate of a drug sustained release ophthalmic lens.   The time-dependent change figure of the drug release rate in each layer thickness of the hydrophobic polymer layer of a drug sustained release ophthalmic lens.

Claims (3)

A hydrophobic polymer layer is formed on the surface of a polymer gel excluding silk protein and animal-derived keratin, collagen and gelatin by graft polymerization of an acrylic ester-based hydrophobic polymer by graft polymerization in a solvent. Then, a polymer gel for sustained drug release, which is used by being immersed in an aqueous drug solution and including the drug.
2. The sustained-release drug according to claim 1, wherein the acrylic ester-based hydrophobic polymer is formed by polymerizing at least one compound represented by the following general formula (1). Polymer gel.
[Chemical 1]
(R ₁ is at least one selected from the group consisting of an alkyl group having 1 to 10 carbon atoms, an alkyl group having a siloxane bond having 1 to 10 silicon atoms, and a fluoroalkyl group having 3 to 18 fluorine atoms. And R ₂ is a hydrogen atom or a methyl group.)
An ophthalmic lens for sustained drug release comprising the polymer gel for sustained drug release according to claim 1 or 2 and having an ophthalmic lens shape.