JP2018140969A - Annular device for treatment of posterior eye diseases - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a drug-containing medical device capable of long-term treatment of a disease of posterior ocular tissue as compared with the prior art. The above object is to (1) an anionic drug; and (2) a condensate of an alkyl quaternary ammonium compound having a substituted or unsubstituted aralkyl group and a (meth) acrylic acid as a constituent, or a salt thereof. Solved by anionic drug-containing medical cyclic devices that contain a cationic monomer containing and a copolymer containing a copolymerizable monomer thereof and are hollow cyclic for treating diseases of the posterior ocular tissue. Will be done. [Selection diagram] Fig. 2

Description

The present invention relates to an annular device for treating posterior eye diseases.

Drug delivery type soft contact lenses (DDSCL) have been developed as devices that enable drug treatment of eye diseases, in which a drug is held in a contact lens and the drug is gradually released in the eye tissue after wearing. According to this device, since DDSCL can be coated on the entire ocular surface, it is possible to deliver a therapeutically effective concentration of drug to anterior ocular tissues such as cornea and aqueous humor and external ocular tissues such as tears and conjunctiva. Yes (see Patent Document 1 and Patent Document 2).

On the other hand, Patent Document 3 discloses a hollow annular (ring-shaped) device having an opening at the center.

International Publication No. 2010/095478 International Publication No. 2015/159942 International Publication No. 2010/092735

The DDSCL described in Patent Documents 1 and 2 has a point to be improved in selectively delivering a drug from the lens to the posterior eye tissue such as the posterior retina, choroid, sclera, and vitreous.

In general, the drug in the polymer gel is dissolved or dispersed in water present in the polymer network, and is diffused and released from the water toward the eye tissue. 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 immersed in water, the drug in the polymer gel quickly diffuses into water, and it is difficult to control the behavior of drug release.

Since the annular device described in Patent Document 3 is a polymer gel, when the annular device is attached to the sclera surface, most of the included drug is released in a short time. Therefore, according to the annular device described in Patent Document 3, it is possible to efficiently deliver the drug to the posterior ocular tissue, but there is a problem to be improved that long-term treatment is difficult. .

Therefore, compared with the annular device described in Patent Document 3, the present invention intends to provide a drug-containing medical device capable of treating a disease of the posterior segment tissue in the long term. Let it be an issue.

The present inventors examined a circular device that can be used for treatment of retinal diseases such as posterior eye diseases, particularly retinal edema, retinal degeneration, retinopathy, retinal vascular occlusion, macular edema, macular degeneration, etc. .

He focused on the fact that dexamethasone sodium phosphate (dexamethasone phosphate), a drug used to treat diabetic macular edema and retinal vein occlusion, is an anionic drug. Then, by selecting at least one cationic compound as one of the components of the cyclic device that is the drug carrier, dexamethasone phosphate can be ionically included in the cyclic device. I thought it would be possible to extend the retention time. Based on this idea, the inventors have succeeded in creating a cyclic device including an anionic drug and a copolymer containing a predetermined cationic monomer and a monomer copolymerizable therewith. The present invention is an invention completed based on such knowledge and successful examples.

Therefore, according to one aspect of the present invention, (1) an anionic drug; and (2) as a constituent, the following general formula (I)
(I)
(Where
R ₁ represents a hydrogen atom or CH ₃ ;
1 to 3 of R _{2 to} R ₄ are each independently represented by the following general formula (II)
(II)
(Wherein x represents an integer of 1 to 3; and R _{5 to} R ₉ each independently represents a hydrogen atom or a C _{1 to} C ₆ linear or branched hydrocarbon group)
And the remaining 2 to 0 of them represent a C _{1 to} C ₃ linear or branched hydrocarbon group; and
n represents an integer of 1 to 4)
An anionic drug-containing medical annular device comprising a cationic monomer represented by the formula (1) and a copolymer comprising a monomer copolymerizable therewith, and having a hollow ring shape for treating diseases of posterior ocular tissue Is provided.

Preferably, the copolymer (2) further contains a hydrophilic monomer as a constituent component, and the anionic drug-containing medical annular device is a hydrogel.

Preferably, the cationic monomer is methacryloxyethyldimethylbenzylammonium chloride (MOEBAC).

Preferably, the anionic agent is dexamethasone phosphate.

Preferably, the anionic drug-containing medical annular device is an annular device having two concentric grooves on the sclera contact surface side.

According to the anionic drug-containing medical annular device of one embodiment of the present invention, it is possible to treat posterior ocular tissue diseases such as diabetic macular edema and retinal vein occlusion. The anionic drug-containing medical annular device of one embodiment of the present invention includes a therapeutic drug ionically bonded to the annular device substrate, and thus has excellent retention of the therapeutic drug, resulting in a long-term result. It is possible to perform cross-therapy.

FIG. 1 is a cross-sectional view and a top view of an anionic drug-containing medical annular device of one embodiment of the present invention. FIG. 2 is a graph showing the relationship between the amount of cationic monomers and the amount of drug uptake in Examples (2), (5) and (7) and Comparative Examples (2) to (4). FIG. 3 is a graph showing an anionic drug release amount at a predetermined time for Example (1) and Comparative Example (1).

Hereinafter, the details of the anionic drug-containing medical annular device of the present invention will be described. However, the technical scope of the present invention is not limited only to the matters of this item, and the present invention achieves its purpose. Various aspects can be taken.

The anionic drug-containing medical annular device of one embodiment of the present invention includes at least a copolymer including (1) an anionic drug and (2) a predetermined cationic monomer and a monomer copolymerizable therewith.

Since the copolymer (2) is an anionic drug carrier, the following general formula (I) is used as a constituent:
(I)
(Where
R ₁ represents a hydrogen atom or CH ₃ ;
1 to 3 of R _{2 to} R ₄ are each independently represented by the following general formula (II)
(II)
(Wherein x represents an integer of 1 to 3; and R _{5 to} R ₉ each independently represents a hydrogen atom or a C _{1 to} C ₆ linear or branched hydrocarbon group)
And the remaining 2 to 0 of them represent a C _{1 to} C ₃ linear or branched hydrocarbon group; and
n represents an integer of 1 to 4)
It has the characteristics in mix | blending the cationic monomer shown by these.

Since the cationic monomer represented by the general formula (I) has a hydrophobic effect, even when it is blended in a high ratio as a polymerization component, the water content of the anionic drug-containing medical cyclic device is significantly increased. Absent. That is, the technical scope of the present invention is not limited to any speculation, but the anionic drug-containing medical annular device has a high proportion of the cationic monomer, so that the amount of drug to be included increases. Nevertheless, since the increase in the moisture content can be reduced, it is possible to suppress the decrease in strength of the device itself and the release of the contained drug at a high concentration in the initial stage.

In addition, even if the cationic monomer represented by the general formula (I) is blended at a high ratio, it does not cause a shape defect after the drug is released. Therefore, the anionic drug-containing medical cyclic device contains a drug encapsulated at a high concentration. Even after release, almost no change in shape is seen, and excellent shape stability can be exhibited.

The cationic monomer represented by the general formula (I) is not particularly limited as long as it has a structure represented by the general formula (I). For example, methacryloxyethyldimethylbenzyl represented by the following general formula (III) Ammonium chloride (MOEBAC) is mentioned.

(III)

For example, MOEBAC represented by the general formula (III) is available from MRC Unitech, and can be produced with reference to JP-A-2001-106732.

The blending amount of the cationic monomer represented by the general formula (I) is not particularly limited as long as the device can maintain a certain shape. For example, the blending amount of the hydrophilic monomer that is the second polymerization component described later is used. On the other hand, it can be several mol% to several tens mol%. The specific blending amount of the cationic monomer is preferably in a range not exceeding 30 mol% with respect to 1 mol of the hydrophilic monomer, for example, 0.5 to 20 mol% (0.005 to 0.2 mol). ) Is more preferable, and a range of 0.5 to 10 mol% (0.005 to 0.1 mol) is more preferable. When the blending amount of the cationic monomer is less than 0.5 mol%, the amount of the anionic drug that can be encapsulated decreases, and an anionic drug-containing medical device having a therapeutic effect may not be constructed. Moreover, when the compounding amount of the cationic monomer exceeds 30 mol%, the water content of the obtained cyclic device is increased, the shape is not stable, and furthermore, sufficient strength when used as a cyclic device cannot be maintained, Wearing feeling may be impaired.

An anionic drug-containing medical annular device can be made into a hydrogel by blending a hydrophilic monomer as a second polymerization component in addition to a cationic monomer. The hydrophilic monomer is not particularly limited as long as it is a polymerizable compound having at least one hydrophilic group and (meth) acryloyl group or vinyl group in the molecule. For example, hydroxymethyl (meth) acrylate, 2-hydroxy Ethyl (meth) acrylate, 2-hydroxypropyl (meth) acrylate, 2,3-dihydroxypropyl (meth) acrylate and 2-polyethylene glycol mono (meth) acrylate, 2-polypropylene glycol (meth) acrylate, N, N-dimethyl (Meth) acrylamide, N, N-diethyl (meth) acrylamide, N-vinylpyrrolidone and the like can be mentioned. As the hydrophilic monomer, one of these can be used alone, or two or more can be mixed and blended.

The blending amount of the hydrophilic monomer is not particularly limited as long as the polymer obtained by copolymerization can form a hydrogel, but is, for example, 50 to 90 wt% in the total polymerization components, preferably 60-80 wt%. When the compounding quantity of a hydrophilic monomer is less than 50 wt%, the softness | flexibility of the cyclic device obtained may fall and a wearing feeling may be impaired. Moreover, when the compounding quantity of a hydrophilic monomer exceeds 90 wt%, there exists a possibility that a sufficient quantity of a cationic monomer cannot be mix | blended.

In order to control the outflow rate of the anionic drug to the tear fluid as a polymerization component of the anionic drug-containing medical annular device, a hydrophobic monomer can be blended. The hydrophobic monomer is not particularly limited as long as it is a polymerizable compound having no hydrophilic group in the molecule and having one or more (meth) acryloyl groups or vinyl groups, for example, trifluoroethyl methacrylate. (Meth) acrylic monomers such as methacrylamide, siloxanyl methacrylate, methyl methacrylate, n-butyl methacrylate, tert-butyl methacrylate, benzyl methacrylate, ethylhexyl methacrylate, lauryl (meth) acrylate; and α-mono (methacryloyl) Oxymethyl) polydimethylsiloxane, α, ω-di (methacryloxymethyl) polydimethylsiloxane, α-mono (3-methacryloyloxypropyl) polydimethylsiloxane, α, ω-di (3-methacryloyloxypropyl) polydi Methylsiloxane, α-mono (3-methacryloyloxybutyl) polydimethylsiloxane, α, ω-di (3-methacryloyloxybutyl) polydimethylsiloxane, α-monovinylpolydimethylsiloxane, α, ω-divinylpolydimethylsiloxane, 3-tris (trimethylsiloxy) silylmethyl (meth) acrylate, 3-tris (trimethylsiloxy) silylpropyl (meth) acrylate, 3-methylbis (trimethylsiloxy) silylmethyl (meth) acrylate, 3-methylbis (trimethylsiloxy) silylpropyl ( (Meth) acrylate, 3-trimethylsiloxydimethylsilylmethyl (meth) acrylate, 3-trimethylsiloxydimethylsilylpropyl (meth) acrylate, 3-methyldimethoxysilylpropyl ( Silicone-containing monomers such as data) acrylate. As the hydrophobic monomer, one of these can be used alone, or two or more can be mixed and blended.

The blending amount of the hydrophobic monomer in the anionic drug-containing medical cyclic device is not particularly limited, and is, for example, 0 to 30 wt%, preferably 0 to 20 wt% in all the polymerization components. When the blending amount of the hydrophobic monomer exceeds 30 wt%, it is not preferable because the softness of the obtained circular device is lowered and the wearing feeling may be impaired.

In addition to the above components, a crosslinkable monomer can be blended as a component of the anionic drug-containing medical cyclic device in order to adjust the formation of the network structure of the polymer gel and the mechanical strength. The crosslinkable monomer is not particularly limited as long as it is a compound having two or more (meth) acryl groups or vinyl groups in the molecule. For example, ethylene glycol di (meth) acrylate, methylene bis (meth) acrylamide, 2-hydroxy Examples include -1,3-di (meth) acryloxypropane and trimethylolpropane tri (meth) acrylate. As the crosslinkable monomer, one of these can be used alone, or two or more can be mixed and blended.

Although the compounding quantity of a crosslinkable monomer is not specifically limited, For example, it is 0.3-10 mol% with respect to the total mol of a polymerization component, Preferably it is 0.7-3 mol%. When the blending amount of the crosslinkable monomer exceeds 10 mol%, it is not preferable because the softness as the obtained anionic drug-containing medical cyclic device is deteriorated and the wearing feeling may be impaired.

An anionic drug-containing medical annular device can be manufactured by combining steps known by those skilled in the art, and the manufacturing method is not particularly limited, and can include, for example, the following steps:
A step of adding a polymerization initiator to a mixture of monomers constituting an anionic drug-containing medical cyclic device, and stirring and dissolving to obtain a monomer mixture; putting the obtained monomer mixture in a desired mold, A step of obtaining a copolymer by a polymerization reaction; a step of cooling and peeling the copolymer from a mold, cutting and polishing as necessary, and then hydrating and swelling the molded copolymer to obtain a hydrogel; and The step of obtaining an anionic drug-containing medical annular device in which the obtained hydrogel is immersed in a solution in which the drug is dissolved to hold the drug inside the hydrogel.

As polymerization initiators, peroxide polymerization initiators such as lauroyl peroxide, cumene hydroperoxide, and benzoyl peroxide, which are general radical polymerization initiators; azobisdimethylvaleronitrile, azobisisobutyronitrile, etc. These azo polymerization initiators can be used alone or in combination of two or more. The addition amount of the polymerization initiator is not particularly limited as long as it is a sufficient amount for accelerating the copolymerization reaction of the monomer. For example, 10 to 7000 ppm is preferable with respect to the total monomer weight of the polymerization component.

In the step of obtaining a copolymer, the monomer mixture is placed in a metal, glass, plastic or other mold, sealed, heated in a stepwise or continuous manner in a thermostatic bath or the like in the range of 25 to 120 ° C., This can be done by completing the polymerization in 120 hours. For polymerization, ultraviolet rays, electron beams, gamma rays, and the like can be used. Moreover, solution polymerization can be adapted by adding water or an organic solvent to the monomer mixture.

In the step of obtaining a hydrogel, after completion of the polymerization, the mixture is cooled to room temperature, and the obtained polymer is peeled from the mold, cut and polished as necessary, and then hydrated and swollen to obtain a hydrogel. Examples of the liquid (swelling liquid) to be used include water, physiological saline, isotonic buffer and the like. The swelling liquid is heated to 60 to 100 ° C. and immersed for a certain time to obtain a swollen state. Further, it is preferable to remove unpolymerized monomers contained in the polymer during the swelling treatment.

The step of obtaining an anionic drug-containing medical annular device is carried out by immersing the hydrogel obtained through the above process in a solution in which the anionic drug is dissolved, and subjecting it to steam sterilization at high temperature and high pressure. . The anionic drug is retained in the hydrogel by ionic bonding with a cationic group imparted by a cationic monomer that is a constituent of the hydrogel. By performing this process under high temperature and high pressure conditions, it can also serve as a high-pressure steam sterilization treatment. As a result, it becomes possible to safely and soundly wear an anionic drug-containing medical annular device, The effect is that one can be omitted.

An anionic drug will not be specifically limited if it is a drug which has anionic groups, such as a sulfo group, a carboxyl group, and a phosphate group. Preferred examples of the drug having a sulfo group include sodium azulene sulfonate, sodium dexamethasone metasulfobenzoate, and sodium chondroitin sulfate. The drug having a carboxyl group is preferably sodium cromoglycate, potassium cromoglycate, bromofenac sodium, diclofenac sodium, valsartan, dexamethasone phosphate sodium, betamethasone phosphate sodium, moxifloxacin, amlexanox, pranoprofen , Norfloxacin, ofloxacin, sodium hyaluronate, sodium chondroitin sulfate and the like. Preferred examples of the drug having a phosphate group include dexamethasone phosphate sodium and betamethasone phosphate sodium. In the present invention, one or more of these anionic drugs can be used.

Examples of the solvent for dissolving the drug include water, a hydrophilic solvent, a mixed solvent of water and a hydrophilic solvent, and the like. Examples of the hydrophilic solvent include alcohols such as ethanol, methanol, isopropanol, and n-butanol, dimethyl sulfoxide, and a buffer solution.

The concentration of the drug contained in the drug solution is not particularly limited, and can be appropriately set depending on each drug, for example, the solubility of the drug, the minimum effective concentration for exhibiting a therapeutic effect, and the maximum safe concentration.

An anionic drug-containing medical annular device can be used for various applications by processing its shape. Specifically, an ophthalmic lens such as a contact lens can be obtained by providing a curvature. Moreover, if it is made into the shape of the ring which covers a sclera part, a drug can be efficiently delivered from the sclera surface to a posterior ocular tissue. Furthermore, if it is in sheet form, it can be used as a wound dressing or poultice.

Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples, and the present invention can take various modes as long as the problems of the present invention can be solved. .

[Preparation of Examples (1) to (8)]
In a mixture containing 2-hydroxyethyl methacrylate (HEMA) and methacryloxyethyldimethylbenzylammonium chloride (MOEBAC) in a ratio shown in Table 1 to be described later with respect to 1 mol of HEMA, 1 mol% of polyethylene glycol diester with respect to the total moles of monomers. 3000 ppm (external) azobisisobutyronitrile (AIBN) with respect to the total weight of acrylate (A-200) and monomer was added and mixed by stirring to obtain a monomer mixture. The obtained monomer mixed solution was put in a molding die for a ring device, and the temperature was raised over a period of 17 hours in the range of 30 to 110 ° C. to be subjected to a copolymerization reaction, thereby obtaining a polymer. The obtained polymer is returned to room temperature and taken out of the mold, and then immersed in an ethanol-containing phosphate buffer solution at 60 ° C. and then in a phosphate buffer solution for 1 hour, respectively, and further immersed in pure water at room temperature for 2 hours or more. By soaking, hydrohydrated and swollen hydrogel was obtained. The obtained hydrogels of Examples (1) to (8) were immersed in a 0.2 wt% aqueous solution of dexamethasone sodium phosphate (DSP) and then subjected to autoclaving at 121 ° C. for 30 minutes. The annular devices of Examples (1) to (8) were obtained.

[Preparation of Comparative Examples (1) to (4)]
Examples (1) to (8) except that a cationic monomer was not used as a constituent component, or methacrylamidopropyltrimethylammonium chloride (MAPTAC) was used in the proportion shown in Table 1 instead of MOEBAC. Similarly, a hydrogel swollen by hydration was obtained. The obtained hydrogels of Comparative Examples (1) to (4) were immersed in a 0.2 wt% DSP aqueous solution, and then subjected to high-pressure steam sterilization at 121 ° C. for 30 minutes, thereby causing Comparative Examples (1) to (4). ) Annular device was obtained.

[Method for evaluating anionic drug sustained-release medical device]
(1) Measurement of moisture content The cyclic devices of Examples (1) to (8) and Comparative Examples (1) to (4) after taking in an anionic drug were taken out from the chemical solution, and after wiping off excess water, The mass (W ₁ ) of the device in the state was measured. Thereafter, 60 ° C. Weight of the device after drying for 24 hours in a drier of a (W ₂₎ was measured in accordance with the following equation from each weight was calculated water content.
Water content (% by weight) = [(W ₁ −W ₂ ) / W ₁ ] × 100

(2) Measurement of uptake amount of anionic drug The annular devices of Examples (1) to (8) and Comparative Examples (1) to (4) after uptake of the anionic drug were immersed in physiological saline, It was allowed to stand at room temperature for 72 hours, and the encapsulated anionic drug was gradually released into physiological saline. Quantitative determination of anionic drugs in physiological saline after sustained release using high performance liquid chromatography (HPLC, manufactured by JASCO Corporation) according to a conventional method, and incorporation of anionic drugs per unit device from the obtained values Amount (μg / g).

(3) Retention of anionic drug After immersing the fixed devices of Examples (1) to (8) and Comparative Examples (1) to (4) in physiological saline at room temperature, 1 hour later, 2 hours After 4 hours and 8 hours later, the amount of drug released at each time was measured by the same method as (2). From the release amount and the uptake amount at each time, a 50 wt% release time of the total uptake amount of the drug was calculated.

(4) Shape stability After the sustained release of drugs, the shapes of the fixed devices of Examples (1) to (8) and Comparative Examples (1) to (4) were visually confirmed using a dimension analyzer.
A: A perfect circle and no irregularities on the surface.
X: Not a perfect circle or uneven on the surface.

The meanings of the abbreviations in the table are as follows:
MOEBAC: methacryloxyethyldimethylbenzylammonium chloride MAPTAC: methacrylamidopropyltrimethylammonium chloride DSP: dexamethasone sodium phosphate

In Examples (1) to (8), even if the blending amount of the cationic monomer was increased from 0.5 to 20 mol%, the increase rate of the water content was small as 23.8% as a whole. It was possible to introduce a cationic group without affecting the rate.

On the other hand, in Comparative Examples (2) to (4), although the cationic monomer is blended at the same molar ratio as in the Examples, the cationic monomer used does not have a benzene ring in the molecule. Since the increase rate of the moisture content was as large as 47.2% compared to the Examples, the moisture content increased with the increase in the amount of the cationic monomer, and the stability of the lens shape tended to decrease. .

Furthermore, when a cationic monomer was contained at the same molar ratio, a cationic monomer having a benzene ring in the molecule was used compared to a comparative example using a cationic monomer having no benzene ring in the molecule. The amount of anionic drug taken up was higher in Examples. This is clear from FIG. 2 which is a graph showing the relationship between the monomer amount of the cationic monomer and the drug uptake amount. From FIG. 2, the example could significantly increase the amount of drug uptake by the amount of monomer as compared with the comparative example.

Moreover, FIG. 3 is a figure showing the release rate for every fixed time of the anionic drug taken in the annular device of Example (1) and Comparative Example (1). In Comparative Example (1), since a cationic monomer is not blended as a constituent component, it can be seen that drug retention was low and the included drug was released in a short time.

From the above, according to the anionic drug-containing medical cyclic device of one embodiment of the present invention, by using a cationic monomer having a benzene ring in the molecule as a constituent of the drug carrier, Because it can increase the amount of drug contained without causing a decrease in strength and can be released over a long period of time, it has a combination of shape stability after drug release and a high therapeutic effect. Device could be provided.

The anionic drug-containing medical annular device of one embodiment of the present invention is a medical device that can be controlled to a desired amount of drug uptake and has excellent gel strength and shape stability after drug release. It can contribute to the health and welfare of mankind, which can provide safe and excellent therapeutic effects.

Claims (5)

(1) an anionic drug; and (2) as a constituent, the following general formula (I)
(I)
(Where
R ₁ represents a hydrogen atom or CH ₃ ;
1 to 3 of R _{2 to} R ₄ are each independently represented by the following general formula (II)
(II)
(Wherein x represents an integer of 1 to 3; and R _{5 to} R ₉ each independently represents a hydrogen atom or a C _{1 to} C ₆ linear or branched hydrocarbon group)
And the remaining 2 to 0 of them represent a C _{1 to} C ₃ linear or branched hydrocarbon group; and
n represents an integer of 1 to 4)
An anionic drug-containing medical annular device comprising a cationic monomer represented by the formula (1) and a copolymer comprising a monomer copolymerizable therewith, and having a hollow ring shape for treating diseases of posterior ocular tissue . The anionic drug-containing medical annular device according to claim 1, wherein the copolymer of (2) further comprises a hydrophilic monomer as a constituent component, and the anionic drug-containing medical device is a hydrogel. . The anionic drug-containing medical cyclic device according to claim 1 or 2, wherein the cationic monomer is methacryloxyethyldimethylbenzylammonium chloride (MOEBAC). The anionic drug-containing medical cyclic device according to any one of claims 1 to 3, wherein the anionic drug is dexamethasone sodium phosphate ester. The anionic drug-containing medical device according to any one of claims 1 to 4, wherein the anionic drug-containing medical annular device is an annular device having two concentric grooves on the sclera contact surface side. For annular devices.