JP2006061383A - Medication sustained-release contact lens kit - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medication sustained-release contact lens kit for providing a contact lens which takes in a large amount of a medication and is constituted of a hydrogel material capable of the sustained-release of the medication while controlling a speed of releasing the medication. <P>SOLUTION: The medication sustained-release contact lens kit contains the contact lens made of the hydrogel material capable of the sustained-release of the medication and an immersion solution which contains a target medical agent of 3.3×10<SP>-3</SP>to 3.3×10 g/l. The medication sustained-release contact lens kit is constituted of a first chamber having a preservative solution containing no target medical agent and the contact lens made of the hydrogel material capable of the sustained-release of the medication without containing target medical agent and a second chamber containing the solution containing the target medical agent, and realizes to contain the target medical agent in the contact lens by opening two chambers to make the contact lens contact with the solution containing the target medical agent. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a drug sustained-release contact lens kit for providing a contact lens comprising a hydrogel material capable of sustained drug release. More specifically, the present invention is a drug for providing a contact lens that can take in a larger amount of a therapeutic agent for eye diseases (target drug) and can release the therapeutic agent over a long period of time. The present invention relates to a sustained-release contact lens kit.

  Currently, eye drops or eye ointments are used for pharmacotherapy for major diseases in the ophthalmic field such as dry eye, glaucoma, conjunctivitis, or corneal epithelial disorder. Among them, the first choice is exclusively eye drops. It is. Eye drops have the merit that they are easy to handle and minimally invasive for patients, and easy to explain to doctors, and both have great merit.

  However, it is almost impossible to keep the eye drops in the eye for a long time due to mechanical movement of eyelids and tear replacement by blinking. It is known that 99% of the drugs administered by eye drops are washed away from the punctum by the lacrimal fluid into the lacrimal tubule, and the medicinal effect is hardly expected (M. Patrick, AK mitra, Ophthalmic Drug Delivery Systems, AK Mitra (Ed.), Chapter 1, Marcel Dekker, New York (1993)).

  That is, in the case of drug administration using eye drops, the bioavailability is overwhelmingly lower than that of general internal medicines. Therefore, frequent instillation is necessary to exert the medicinal effect. This frequent instillation is not only a cumbersome task for the patient, but also reduces patient compliance (the patient taking the medicine as directed by the doctor) and forgets or supplements it. For this reason, it is difficult to cure a disease that should be cured because the drug concentration in the tissue is too low, too high, or unstable because it is administered for 2 to 3 days at a time. ing.

  Furthermore, the amount of the drug that is washed away from the keratoconjunctiva by frequent instillation and goes around the whole body increases in proportion to the number of instillations. There are many patients who repeat excessive instillation, such as eye drop dependence, and depending on the type of drug, serious systemic side effects may occur. Even within the eye, the drug concentration in the tissue fluctuates drastically due to frequent eye drops (IK Reddy, MG Ganesan, Ocular Therapeutics And Drug Delivery, IK Reddy (Ed.), Chapter 1, Technomic, Pennsylvania (1996)). The risk of side effects in the interior is very high.

  In addition, if eye drops are frequently performed in the presence of an eye disease, the original tear fluid components (mucin, lactoferrin, IgA, lysozyme, etc.) are diluted and washed away, so the disease symptoms often worsen. Furthermore, even in healthy individuals, there are even reports that new corneal epithelial disorders have occurred after frequent instillation of artificial tears (Ophthalmology New Insight 2, MEDICAL VIEW (1994)).

  Thus, eye drops are not the best drug treatment for diseases in the ophthalmic field, and there is no effective solution other than eye drops.

Based on the above, an ideal intraocular drug treatment method has the following effects. :
1. Improve the sustainability of drug efficacy and enhance the bioavailability of drugs.
2. Minimize the number of doses and improve patient compliance.
3. Reduces the loss of administered drugs and reduces side effects.
4). The patient himself can administer (not complicated work).
5. Minimally invasive

  Meanwhile, collagen shields and Ocusate (registered trademark) have been sold so far (M. Friedberg, U. Pleyer, BJ Mondino, Ophthalmol., 1991, 98, 725-732; SG Deshpande, S. Shirolkar, J Pharm. Pharmacol., 1989, 41,197-200). However, in addition to the poor wearing feeling caused by plastics, these have the disadvantage that they must be worn by a doctor because the patient's own handling was not allowed and the patient has to visit the ophthalmologist frequently. (FE Ros, JW Tiji, JA Faber, CLAO J., 1991, 17, 187-190).

  From the background as described above, it has been considered to be a drug sustained release system using a hydrogel having a high affinity with a living body and a good feeling of wearing. In fact, an attempt to instill a drug into a commercially available soft contact lens (hereinafter sometimes referred to as SCL) with the same idea and to wear it on a patient was already made in 1970 by Waltman and Kaufran et al. (SR Waltman, HE Kaufman, Inv. Ophthalmol., 1970, 9, 250-255; SM Podos, B. Becker, C. Asseff, J. Hartstein, Am. J. Ophthalmol., 1972, 73, 336 others). However, since the drug diffused in the hydrogel shows a release behavior according to diffusion rate control (M. Negishi, et al, Drug. Dev. Ind. Pharma., 1999, 25, 437-444), within 30 minutes Most drugs are released (MR Jain, Bri. Ophthalmol., 1988, 72, 150-154; JW Shell, R. Baker, Ann. Ophthalmol., 1974, 6, 1037). Although this is certainly improved compared to the time of staying on the cornea for one drop of eye drop (about 5 minutes), it is far from a “drug sustained release system”. Further, as similar to this, Patent Document 1 discloses an ophthalmic composition formed by mixing one or more of neurotrophic factors NGF and BDNF and derivatives thereof, and a glaucoma therapeutic drug using the same. Although it is described that it is blended into a contact lens, there is no description about a drug sustained release system. Further, Patent Document 2 describes a method for incorporating a hormone into a contact lens matrix, but it cannot not only secure a sufficient drug release time, but also cannot control it.

  Furthermore, the amount of drug that can be taken into one commercially available SCL is very small, and it is quite difficult to retain a sufficient amount of drug to show its efficacy (AL Weiner, Polymeric Drug delivery Systems for the Eye). , AJ Domb (Ed.), Polymeric site-specific pharmacotherapy, John Wiley & Sons, Chichester (1994), 315-346; TP Heyman, ML McDermott, et al, J. Cat. Ref. Surg., 1989, 15, 169-175). These are the biggest drawbacks of normal SCL, and for this reason, use of normal SCL as a drug carrier has been limited.

  In order to improve this point, a contact lens to which drug supply capability is added has been studied. For example, a contact lens in which a sheet-like drug is sandwiched between two hydrous soft contact lenses is disclosed (Patent Document 3). ). However, the contact lens is complicated because it requires a work to insert a sheet containing a drug into the contact lens, and a specific solution for controlling the drug concentration and the drug supply time is not shown. Absent. Patent Document 4 includes a first member that can form a lens front surface portion and a second member that can form a lens rear surface portion. In a contact lens, a gap is formed by the first member and the second member. Although a contact lens in which a drug is present in the void is described, many manufacturing processes are desired to be improved. Furthermore, Patent Document 5 describes that a detachable weight is provided on the outer peripheral edge of a hard contact lens to improve stability and wearing feeling, and to retain a drug. Is not disclosed in detail. In addition, Patent Document 6 discloses a contact lens in which a drug sustained-release agent in a fine powder form or a gel form is attached to a part of the contact lens to enhance the drug holding ability. It was complicated because it was necessary to prepare separate drug sustained-release agents separately and to attach the drugs to contact lenses before use. The contact lens as described above has a drawback in that the manufacturing process is complicated, and thus the contact lens is expensive when used for treatment.

On the other hand, as a method of incorporating a drug into the hydrogel material,
(Α) A method in which a drug is directly added to a monomer mixture and polymerization is performed in the presence of the drug. (Β) A method in which the monomer mixture is polymerized in the absence of the drug and then immersed in the drug solution to be saturated. (For example, refer to Patent Document 7 and Patent Document 8).

  However, in any of the above methods, the sustained release time of the drug is relatively short, and an effect over a long time cannot be expected. In addition, if the release rate of the drug incorporated in the hydrogel material is high, the drug concentration rapidly increases immediately after application, which increases the risk of side effects.

On the other hand, as a method for producing a material that can hold a large amount of drug in the hydrogel material,
(Γ) A method for producing an imprint gel having a molecular recognition function has been studied (see, for example, Patent Document 9).

  However, a method for providing a drug sustained-release contact lens composed of this imprint gel has not been envisaged.

  Therefore, there is a demand for a kit that can prepare and provide a contact lens capable of sustained release of a drug that can take in more drug into the gel and can release the drug over a long period of time.

JP-A-10-218787 Japanese Patent Laid-Open No. 05-093889 Japanese Patent Laid-Open No. 06-273702 JP-A-10-339857 Japanese Patent Laid-Open No. 11-024009 Japanese Patent Application Laid-Open No. 11-024010 Japanese Patent Laid-Open No. 62-103028 JP-A-62-103029 International Publication No. 03/090805 Pamphlet

  An object of the present invention is to provide a drug sustained-release contact lens kit for providing a contact lens capable of sustained release of a drug that can take in more drug into the gel and release the drug over a long period of time. Is to provide.

That is, the present invention includes, in a container, a contact lens made of a hydrogel material capable of sustained drug release and an immersion liquid, and the immersion liquid contains a target drug of 3.3 × 10 ⁻³ to 3.3 × 10 g / l. The present invention relates to a drug sustained-release contact lens kit.

  Further, the present invention comprises a first chamber having a storage solution not containing a target drug, a contact lens made of a hydrogel material capable of sustained release of a drug not containing a target drug, and a second chamber having a target drug-containing liquid. The present invention relates to a drug sustained-release contact lens kit which is opened and brought into contact with a contact lens and a target drug-containing liquid so that the target drug is contained in the contact lens.

  The contact lens preferably contains 0.1 to 1000 μg of the target drug.

The hydrogel material is
(A) a step of obtaining a monomer mixture containing a target drug, a monomer having a specific functional group capable of forming a physical cross-linking structure with the target drug, and a cross-linking agent;
(B) a step of polymerizing while maintaining a complex formed between the target drug and a monomer having a specific functional group; and (c) a step of removing unreacted monomer from the target drug from the polymer;
It is preferable that it is an imprint gel manufactured by the method of including.

  It is preferable that the water content of the hydrogel material is 10 to 80%.

  Preferably, the target drug is a glaucoma therapeutic agent and / or a lacrimal secretion enhancer, and the glaucoma therapeutic agent is timolol or pilocarpine, or a medically acceptable salt thereof, and a lacrimal secretion enhancing agent. 3-isobutyl-1-methylxanthine or bromhexine, or a medically acceptable salt thereof is more preferable.

  If the drug sustained-release contact lens kit of the present invention is used, more drug can be taken into the gel and the drug can be released over a long period of time.

The present invention includes a contact lens made of a hydrogel material capable of sustained drug release and an immersion liquid in a container, and the immersion liquid contains a target drug of 3.3 × 10 ⁻³ to 3.3 × 10 g / l. The present invention relates to a drug sustained-release contact lens kit.

  The said container is not specifically limited, For example, the case of a contact lens can be employ | adopted as it is.

  The material of the container is not particularly limited, and examples thereof include polyethylene, polyethylene terephthalate, polyvinyl chloride, polycarbonate, polypropylene, nylon, and glass.

  In the present invention, the hydrogel material is not particularly limited as long as it can take in a drug and can be sustainedly released, and is generally composed of a material used for manufacturing a contact lens.

Hydrogel materials are also
(A) a step of obtaining a monomer mixture containing a target drug, a monomer having a specific functional group capable of forming a physical cross-linking structure with the target drug, and a cross-linking agent;
(B) polymerizing while maintaining a complex formed between the target drug and the monomer having the specific functional group; and (c) removing the unreacted monomer from the target drug from the polymer. It is preferable that the imprint gel is manufactured.

  In this specification, “physical cross-linking structure” means “hydrogen bonding and / or electrostatic interaction (in addition to Coulomb force between charged particles, mutual interaction between multipoles such as dipoles and quadrupoles”). It refers to a “crosslinked structure produced by an action”.

  Specifically, as the molding material and the production method of the hydrogel material according to the present invention, those described in International Publication No. 03/09085 are suitably employed.

  Target drugs include antibiotics such as erythromycin, erythromycin lactobionate, cefmenoxime hydrochloride, chloramphenicol, sulbenicillin sodium, tobramycin, gentamicin sulfate, sisomicin sulfate, dimecacine sulfate, micronomycin sulfate, colistin, tetracycline; ofloxacin, norfloxacin Antifungal agents such as pimaricin; non-steroids such as indomethacin, diclofenac sodium, pranoprofen, azulene, dipotassium glycyrrhizinate, sodium guaiazulenesulfonate; anti-inflammatory enzymes such as lysotium chloride; anlexanox, cromoglycate Antiallergic preparations such as ketotifen fumarate; pirenoxine, sodium pentacecil sulfonate , Glutathione, catalin, cinerealialima, and other cataract treatments, epinephrine, dipivefrin hydrochloride, carteolol hydrochloride, befnolol hydrochloride, timolol maleate, pilocarpine, demepotassium bromide, iodothiothiofate, ethyl paranitroethylsulfonate Glaucoma therapeutic agents such as phenol; vitamins such as vitamin A palmitate, flavin adenine dinucleotide, pyridoxal phosphate, dianocobalamin, tocophenol acetate; corneal growth factor (KGF), nerve growth factor (NGF), epidermal growth factor (EGF) ), Fibroblast growth factor (FGF), bone-derived growth factor (BDGF), brain-derived neurotrophic factor, cell growth factors such as peptide growth factors such as interleukin; insulin, glucocorticoid, prostagland Hormones such as dexamethasone, fluorometholone, betamethasone phosphate, cortisone acetate, hydrocortisone acetate, hydrocortisone caproate, prednisolone acetate, dexamethasone sodium sulfate, dexamethasone An example is sodium metasulfobenzoate.

  Among these, it is desirable to employ the target drug shown in (I) and the monomer having the specific functional group shown in (II), and further adopt from the combination of the target drug shown in (III) and the monomer having the specific functional group. It is desirable. In addition, it is desirable to employ the crosslinking agent shown in (IV) because the flexibility of the hydrogel material can be controlled moderately, good mechanical strength can be imparted, and the effect of improving the copolymerization is great. . Further, from the viewpoints of transparency, moldability, and strength, a hydrophilic monomer or an arbitrary monomer as shown in (V) is appropriately blended. Further, additives as shown in (VI) are added as necessary.

(I) Target drugs As drugs for treating glaucoma, timolol, pilocarpine and their pharmaceutically acceptable salts, as lacrimation enhancers, 3-isobutyl-1-methylxanthine, bromhexine and their pharmaceutically acceptable drugs Salt.

(II) Monomers having a specific functional group (Meth) acrylic acid, styrene sulfonic acid, dimethylaminoethyl (meth) acrylate, diethylaminoethyl (meth) acrylate.
“(Meth) acrylate” is a general term for the two compounds “... acrylate” and “... methacrylate”.

(III) Preferred combination of a target drug and a monomer having a specific functional group When the target drug (I) is timolol, pilocarpine, 3-isobutyl-1-methylxanthine, or bromohexine, the monomer (II) having a specific functional group is (meta ) Acrylic acid and / or styrene sulfonic acid.

(IV) Crosslinking agent Ethylene glycol di (meth) acrylate, ethylene bisacrylamide.

(V) Hydrophilic monomers Hydroxyethyl (meth) acrylate, N, N-dimethylacrylamide, N, N-diethylacrylamide, N-isopropylacrylamide and N-vinylpyrrolidone.

(VI) Additives Radical polymerization initiators, photopolymerization initiators, and sensitizers.

  For the polymerization of the monomer mixed solution, any of various conventionally known methods can be employed.

  For example, the polymerization of the monomer mixed liquid proceeds by pouring the monomer mixed liquid into a resin mold and clamping the mold. As a polymerization method of the monomer mixed solution, there are a method of heating gradually or stepwise in a temperature range of room temperature to about 130 ° C., a method of irradiating electromagnetic waves such as microwaves, ultraviolet rays, or radiation (γ rays). . The polymerization may be performed by a bulk polymerization method, a solution polymerization method using a solvent or the like, or other methods.

  The polymerization of the monomer mixture is completed while maintaining the complex formed between the target drug and the monomer having a specific functional group. Therefore, the polymerization conditions may be appropriately changed so that the polymerization is completed while maintaining the complex.

  After the polymerization is completed, the polymer is removed from the mold and then washed with a large excess of washing solution to remove unreacted monomers and target drug present therein, thereby obtaining a hydrogel material.

  Cleaning solutions used to remove unreacted monomers and target drug include water, distilled water, physiological saline; dilute hydrochloric acid; sodium hydroxide aqueous solution; alcohol such as methanol, ethanol, propanol; or a mixed solution thereof Etc.

  In addition, the hydrogel material of the present invention is produced through a step of removing the unreacted monomer and the target drug, and further (d) incorporating the target drug into the polymer. The target drug to be incorporated is the same as the target drug blended in the monomer mixture. In order to incorporate the target drug, the hydrogel material may be immersed for 1 hour to several days in an aqueous solution in which the target drug is dissolved or suspended.

In a container including a contact lens made of the hydrogel material and an immersion liquid in a container, the immersion liquid contains 3.3 × 10 ⁻³ to 3.3 × 10 g / l of a target drug. The target drug concentration in the immersion liquid is more preferably 3.3 × 10 ^{−1 to} 1.65 × 10 g / l. If the concentration of the target drug in the immersion liquid is less than 3.3 × 10 ⁻³ g / l, it tends to be difficult to maintain the drug effect for a desired time, and if the concentration exceeds 3.3 × 10 g / l, excessive target The drug remains in the hydrogel material without forming a physical cross-linked structure, and the drug concentration in the ocular tissue tends to increase immediately after application.

  Further, the present invention comprises a first chamber having a storage solution not containing a target drug, a contact lens made of a hydrogel material capable of sustained release of a drug not containing a target drug, and a second chamber having a target drug-containing liquid. The present invention relates to a drug sustained-release contact lens kit which is opened and brought into contact with a contact lens and a target drug-containing liquid so that the target drug is contained in the contact lens.

  The said container can use what is divided into two or more chambers. Specific examples of the container divided into two or more chambers include the following.

1. A container that is partitioned vertically by a partition plate and that can be used as a first chamber in the upper chamber and a second chamber in the lower chamber. The partition plate is composed of two plates, each having a hole, and can be opened by rotating the upper part and / or the lower part and bringing the two holes together.
2. The container itself can be used as the first chamber, and the lid of the container is hollow, and the inside of the lid can be used as the second chamber. A hole is provided in the bottom surface of the lid, and the hole can be opened by sliding a lever provided in the upper part of the lid.
3. A container partitioned into two chambers by a partition plate. By removing the partition plate, two rooms can be made into one room.
4). A container that is partitioned into three chambers by a partition wall that can be broken, and the first chamber and the second chamber are both in contact with the third chamber. For example, the first chamber 30a and the second chamber 30b of the container shown in FIGS. 1 and 2 are made of a soft material, and the second chamber 30b is crushed so that the partition wall 36 with the third chamber 12 shown in FIG. By breaking, the second chamber 30b and the third chamber 12 can be opened by communicating the communication port 34.

  The material of the container is not particularly limited, and examples thereof include polyethylene, polyethylene terephthalate, polyvinyl chloride, polycarbonate, polypropylene, nylon, and glass.

  The hydrogel material of the present invention is preferably the hydrogel material.

  Examples of the target drug include the target drug.

  Among these, it is desirable to employ the target drug shown in (I) and the monomer having the specific functional group shown in (II), and further, the combination of the target drug shown in (III) and the monomer having the specific functional group. It is desirable to adopt from. In addition, the flexibility of the hydrogel material can be appropriately controlled, good mechanical strength can be imparted, and the effect of improving the copolymerization is great, so that the crosslinking agent shown in the above (IV) can be adopted. desirable. In addition, from the viewpoint of transparency, moldability, and strength, a hydrophilic monomer or an arbitrary monomer as shown in (V) is appropriately blended. Further, additives as shown in the above (VI) are added as necessary.

  The amount of the target drug that can be contained in one contact lens varies depending on the method of use and application, but is preferably 0.1 to 1000 μg, more preferably 10 to 500 μg. If the amount of the therapeutic agent is less than 0.1 μg, it tends to be difficult to maintain the drug effect for a desired time, and if it exceeds 1000 μg, the excess target drug does not form a physical cross-linked structure, and the hydrogel material. The drug concentration in the eye tissue tends to increase immediately after application.

  The release duration ratio of the target drug of the hydrogel material into which the target drug is re-incorporated is preferably 2 or more. If the sustained release ratio is less than 2, the incorporated drug cannot be released slowly over the desired treatment period. In addition, there is a risk of side effects due to a rapid drug concentration increase in the intraocular region after application.

The release persistence ratio is defined as M _t when the amount of target drug released from the hydrogel material at time (t) and M _{∞ as the} amount of all target drugs released at the target drug release limit. For the gel prepared without blending, the time (H _c ) when the value of M _t / M _∞ was 1 and for the gel prepared by blending the target drug, the value of M _t / M _∞ was 1. It is a value obtained from the following equation from the _remaining time (H _s ).
Release persistence ratio = H _s / H _c

  Usually, the uptake speed when taking a drug into a contact lens depends on the size of the lens network (proportional to the water content) and the concentration gradient of the drug inside and outside the lens.

  The water content of the contact lens is preferably 10 to 80%. The water content is more preferably 15 to 70%, and further preferably 20 to 60%. If the water content is less than 10%, the wearing feeling tends to be poor, and if it exceeds 80%, the drug cannot be effectively trapped in the contact lens, and the desired drug release time tends not to be obtained.

  Here, in the case of using a lens having sustained drug release for a long time, it is common to lower the water content of the lens or to form a coat layer on the surface. In these cases, the release rate of the drug from the gel is slow, but the uptake rate is also slow. This is a major drawback for practical use in the treatment of ophthalmic diseases.

  On the other hand, the hydrogel material (imprint gel, lens) has a high adsorption affinity for the target drug, so that not only the concentration gradient but also the drug uptake rate can be increased due to the affinity. Become. Also, due to the adsorption affinity between the drug and the lens, when the drug is released from the lens, the release rate is slow. Such characteristics are advantageous for application to actual disease treatment.

The drug release rate of the contact lens made of the hydrogel material is preferably 1 × 10 ⁻⁷ to 1 × 10 ⁻¹² cm ² / sec, more preferably 1 × 10 ⁻⁸ to 1 × 10 ⁻¹¹ cm ² / sec. is there. When the drug release rate is less than 1 × 10 ⁻⁷ cm ² / sec, it tends to be difficult to maintain the drug effect for a desired time, and when the drug release rate exceeds 1 × 10 ⁻¹² cm ² / sec, the drug released Since the concentration in the tissue does not reach the effective concentration, the desired effect tends not to be obtained.

  The drug release time is preferably 1 hour to 1 month, more preferably 8 hours to 14 days. If the drug release time is less than 1 hour, the number of administrations of the drug tends to increase. If the drug release time exceeds 1 month, the amount of drug taken into the contact lens increases, and there is a substance that does not form a physical cross-linked structure. Immediately after application, the drug concentration in the eye tissue tends to increase.

  The hydrogel material is transparent and flexible, exhibits excellent mechanical stability and biocompatibility, and has a large amount of drug uptake.

In addition, the hydrogel material controls the release rate of the target drug at a desired time by changing the ratio between the concentration of the monomer having a specific functional group and the concentration of the target drug in the monomer mixture used for gel preparation. can do. When the concentrations of the monomer having a specific functional group and the target drug in the monomer mixture are determined so as to satisfy the following formula (1), a hydrogel material having a higher sustained release effect can be obtained. it can.
y ≦ 0.277x−10 (1)
Here, x represents the molar concentration (mM) of the monomer having a specific functional group, and y represents the molar concentration (mM) of the target drug. In addition, in this specification, molar concentration shows the substance amount with respect to 1 L of all the polymerization components except a crosslinkable compound, a polymerization initiator, and a photosensitizer.

  Therefore, this hydrogel material can be widely used for ophthalmic lens materials such as contact lenses by applying its optical function, and can also be used for drug sustained-release capsules.

  It is preferable to modify the surface of the hydrogel material so that the hydrogel material is capable of sustained drug release with a more controlled drug release rate.

  Examples of the surface modification method include plasma irradiation, ultraviolet irradiation, graft polymerization, coating with a silicone-containing polymer, and formation of an interpenetrating network (IPN). These surface modifications may be performed singly or in combination of two or more.

  The surface modification may be performed at any time before or after the target drug is incorporated into the hydrogel material. However, in consideration of the effect of the surface modification on the drug, the drug is incorporated into the hydrogel material. It is preferable to carry out before making.

The sustained drug release of the hydrogel material is performed in the physiological saline or the like in the amount of target drug released from the hydrogel material (M _t ) at time ( _t ), and the amount of all target drugs released at the target drug release limit (M _∞ ). And the diffusion coefficient ratio (D / D ₀ ) obtained by dividing the diffusion coefficient (D) obtained by the following equation using the thickness (h) of the test sample by the diffusion coefficient (D ₀ ) of the surface unmodified hydrogel material. Indicated.
M _t / M _∞ = 4 (D · t / π) ^1/2 / h

  The diffusion coefficient ratio of the hydrogel material capable of controlled drug release capable of controlling the drug release rate is preferably less than 1, more preferably 0.9 or less, and even more preferably 0.8 or less. When the diffusion coefficient ratio is 1 or more, that is, when the diffusion coefficient is higher than that of the surface unmodified hydrogel material, the sustained release effect of the drug by the surface modification is completely lost. In addition, when the diffusion coefficient ratio is too low, although there is a drug sustained release effect, the effective concentration cannot be maintained in the ocular tissue for a long time. Therefore, when the drug duration is 1 day, 0.5 or more When it is about 10 days, it is preferably 0.01 or more.

  The immersion liquid contained in the kit of the present invention is selected from the group consisting of a preserving liquid, a cleaning preserving liquid, a target drug-containing liquid, a target drug-containing preserving liquid, and a target drug-containing cleaning preserving liquid. These preservatives and washing preservatives are not particularly limited, and one or a combination of two or more well-known various additive components used in the preparation of a normal contact lens solution may be combined with physiological saline or MPS (multiple saline). (Purpose Solution) is used. MPS is a liquid agent that can exert a cleaning effect, an rinsing effect, a sterilization effect, a storage effect, and the like on the contact lens and the inner wall of the container collectively. Examples of the additive component include preservatives, isotonic agents, buffers, and pH adjusters.

  As the preservative, commonly used ones can be adopted. Specific examples include mercury-based preservatives such as phenylmercuric nitrate, phenylmercuric acetate, and thimerosal; surfactant preservatives such as benzalkonium chloride and pyridinium bromide; chlorohexidine, polyhexamethylenebiguanide, chlorobutanol, and the like. Alcohol-based preservatives include methyl paraben, provir paraben, dimethylol dimethyl hydantoin, imidazolium urea, and the like.

  Any isotonic agent may be used as long as it can bring the osmotic pressure of the contact lens preservation solution close to the osmotic pressure of tears (280 to 300 mOsm / kg) and is ophthalmically physiologically acceptable. Inorganic salts such as potassium chloride and calcium chloride, and buffering agents listed below.

  Buffering agents include citric acid, malic acid, lactic acid, ascorbic acid, maleic acid, gluconic acid, phosphoric acid, boric acid, amino acids such as glycine and glutamic acid; acids such as tris (hydroxymethyl) aminomethane and their salts Can be given.

  Examples of the pH adjusting agent include sodium hydroxide, potassium hydroxide, hydrochloric acid and the like.

  As specific examples of the kit of the present invention, for example, the following combinations are conceivable depending on whether or not a therapeutic drug (target drug) is contained, the container, and the immersion liquid.

  In the case of (1), a moderate medicinal effect can be maintained.

  In the case of (2), it can be used as a contact lens incorporating a large amount of therapeutic agent.

  In the case of (3), when providing the kit as in (2), it can be used as a contact lens that incorporates a large amount of therapeutic agent, but it can be removed after use and immersed in a washing solution containing therapeutic agent, Again, a therapeutic agent can be included in the contact lens.

  In the case of (4), the container is divided into two chambers by a partition plate or the like, and the first chamber is filled with the contact liquid and the therapeutic agent in the second chamber, respectively. In use, this kit can open the two chambers to one chamber by removing the partition plate, etc., and bring the contact lens into contact with the therapeutic agent-containing liquid so that the therapeutic agent can be taken into the contact lens. .

By using the kit of the present invention, for example, when the therapeutic agent is a glaucoma therapeutic agent, the following usage method can be considered.
Dispose of contact lenses containing 0.1-250 μg of therapeutic agent throughout the day.
-After wearing a contact lens containing 0.1 to 250 μg of therapeutic agent throughout the day, immerse the contact lens in the therapeutic agent-containing stock solution and use the contact lens again the next day.
Using a contact lens containing 1 to 500 μg of the therapeutic agent, wear the contact lens continuously and instill the therapeutic agent at least once a day.
Using a contact lens containing 10 to 1000 μg of the therapeutic agent, wear the contact lens continuously for 2 to 30 days, and gradually release the therapeutic agent from the contact lens.

  Furthermore, the following are mentioned as an example of use of the kit of this invention.

(A) Treatment of glaucoma with continuous wear contact lenses Contact lenses prepared with the raw material monomer content of the hydrogel material as N, N-dimethylacrylamide 50 mM, methacrylic acid 400 mM, ethylene glycol dimethacrylate 600 mM, tris (trimethylsiloxy) silylpropyl methacrylate 50 mM and timolol 25 mM (Example 12 described later) A treatment kit is prepared by immersing (see) in a drug solution containing 1 mM timolol.
2. The contact lens is removed from the drug solution, washed lightly with distilled water, and then worn by the patient.
3. The patient wears the contact lens continuously for one week, and then replaces it with a new contact lens.

(B) Glaucoma treatment with daily disposable contact lenses Contact lenses (Example 3 to be described later) were prepared by blending the raw material monomer content of the hydrogel material as N, N-dimethylacrylamide 50 mM, methacrylic acid 100 mM, ethylene glycol dimethacrylate 140 mM, tris (trimethylsiloxy) silylpropyl methacrylate 50 mM, and timolol 25 mM. Prepare multiple references.
2. The patient wears the contact lens.
3. The next day, wear a new contact lens.

(C) Glaucoma treatment with contact lenses for all day wear Contact lenses (Example 3 to be described later) were prepared by blending the raw material monomer content of the hydrogel material as N, N-dimethylacrylamide 50 mM, methacrylic acid 100 mM, ethylene glycol dimethacrylate 140 mM, tris (trimethylsiloxy) silylpropyl methacrylate 50 mM, and timolol 25 mM. Prepare a preservative solution containing 1 mM timolol.
2. The patient wears a contact lens in the morning and removes the contact lens before going to bed.
3. The removed contact lens is immersed in the above preservation solution overnight.
4). The next morning, the contact lens is taken out of the cleaning stock solution, washed with tap water or a commercially available cleaning stock solution, and then the contact lens is worn.

  In the case of (A), glaucoma treatment can be continuously performed even for an elderly person who is difficult to instill. Moreover, in the usage example of (B), glaucoma treatment can be continuously performed without instilling eye drops. Moreover, in the usage example (C), glaucoma treatment can be continuously performed by exactly the same usage method as a normal vision correction contact lens.

  The kit of the present invention can be used for various treatments as needed, such as a contact lens imprinted with insulin can be used for diabetes requiring continuous treatment.

  The kit of the present invention can be used not only for humans but also for drug treatment for eye diseases of animals such as dogs.

  EXAMPLES The present invention will be described in detail below with reference to examples and comparative examples, but the present invention is not meant to be limited to these examples.

Examples 1 to 14: Production of hydrogel material As raw material monomers for the hydrogel material, N, N-dimethylacrylamide (DMAA; monomer forming a gel skeleton), methacrylic acid (MAA; monomer having a specific functional group), ethylene Glycol dimethacrylate (EDMA; crosslinker) and tris (trimethylsiloxy) silylpropyl methacrylate (SK-5001) purified by distillation were used.

  As a photopolymerization initiator, 2-hydroxy-2-methyl-1-phenylpropan-1-one (Darocur (registered trademark) 1173) purified in advance by distillation was used.

  As a target drug to be incorporated into the hydrogel material, the following timolol maleate (hereinafter referred to as timolol) was used:

  Hydrogel material raw material monomer mixture was prepared with the blending amounts of MAA, EDMA, SK-5001, timolol and DMAA shown in Table 2. 20 μL of 0.4 v / vol% Darocur 1173 is added to this mixed solution, and injected into a polypropylene mold (construction of convex and concave molds; for the production of a circular plate having a diameter of 20 mm × thickness of 0.3 mm). Was done.

Using an ultraviolet ray irradiation device (I Graphics Co., Ltd., UX0302-03; measurement wavelength 365 nm), ultraviolet rays were irradiated to the mold and the monomer mixture in the mold for 50 minutes at room temperature and an irradiation intensity of 11 mW / cm ² . Then, ultraviolet irradiation polymerization was performed.

  After completion of the polymerization, the mold was opened and a test sample was taken out.

  The obtained test sample (imprint gel) was washed with a large excess of 0.9 wt% saline for 3 days or more to remove unreacted monomers and timolol present in the gel.

  Table 3 shows the moisture content of the test materials.

  Subsequently, the obtained plate-shaped (diameter: 16 mm) dried test sample (gel) was stored in a vial containing 1 mM timolol aqueous solution at room temperature for 3 days to adsorb timolol to the test sample.

Comparative Examples 1-3: Production of Random Gel As shown in Table 2, test samples (random gels) were obtained by the same method as in Examples 1-14, except that timolol was not blended.

(Timolol concentration in the test material)
Table 3 shows the concentration of timolol contained in the test material after it was stored in a vial containing 1 mM timolol aqueous solution at room temperature for 3 days and timolol was adsorbed to the test sample.

(Diffusion coefficient)
The test sample was transferred into physiological saline, and a part (600 μL / time) of the physiological saline was periodically collected while maintaining the temperature (hereinafter referred to as the release rate measurement temperature) at 25 ° C. The amount of timolol released from the test sample (M _t ) was quantified by measuring the absorbance at a wavelength of 295 nm using (Shimadzu Corporation UV-3150).

The diffusion coefficient (D) is calculated from the following equation using the total timolol release amount (M _t ) at time (t), the total timolol release amount at the limit of timolol release (M _∞ ), and the thickness (h) of the test sample. did. The results are shown in Table 3.
M _t / M _∞ = 4 (D · t / π) ^1/2 / h

(Sustained release and sustained release ratio)
The time when the value of M _t / M _∞ was 1 was defined as the value of release duration. Furthermore, the gels made without blending timolol, M _t / M _∞ value time became 1 with (H _c), for to prepare a gel by blending timolol, the value of M _t / M _∞ The time when it became 1 (H _s ) was obtained, and the release sustainability ratio was calculated from the following equation. The results are shown in Table 3.
Release persistence ratio = H _s / H _c

(Slow release effect)
The sustained release effect of the test sample was evaluated according to the following evaluation criteria. The results are shown in Table 3.
○: Release sustainability ratio is 2 or more.
Δ: Release sustainability ratio is less than 2.

Test samples with a sustained release ratio of 2 or more were judged to be drug sustained release hydrogel materials that can preferably control the drug release rate. As a result, the molar ratio (x) of the monomer (MAA) having a specific functional group and the concentration (y) of timolol have a sustained release ratio of the hydrogel material satisfying the formula (1) of 2 or more, and the drug release rate is increased. It has been found that this is a hydrogel material capable of controlled drug release that can be controlled preferably.
y ≦ 0.277x−10 (1)

(Rabbit eyewear test using timolol-containing contact lens)
The hydrogel produced in Example 6 and Comparative Example 2 was worn on a rabbit eye, and aqueous humor was collected over time from just after wearing to 96 hours later, and a high performance liquid chromatography measuring device (Waters, 2690, manufactured by Waters). Was used to quantify the timolol concentration in the aqueous humor. An example of the result is shown in Table 4.

Comparative Example 4
0.025% Brunne ophthalmic solution (Showa Yakuhin Kagaku Kogyo Co., Ltd., 0.025% timolol solution) is instilled into the rabbit eye, and as before, the aqueous humor is collected over time, and the aqueous humor is collected by high performance liquid chromatography. The timolol concentration of was quantified. An example of the result is shown in Table 4.

  Moreover, the result of Table 5 was obtained about the timolol residence time and AUC (Area under the curve) in aqueous humor. In general, AUC is an index of bioavailability of a drug, and it is said that as the AUC increases, the drug efficacy increases.

It is an isometric view explanatory drawing which shows the container used for the contact lens kit of this invention. It is a longitudinal cross-sectional view of the container shown by FIG.

Explanation of symbols

DESCRIPTION OF SYMBOLS 10 Disposable processing case 12 Lens accommodation area | region 14 Container main body 16 Cover sheet | seat 18 Peripheral wall part 20 Bottom wall part 26 Connection holding | maintenance area | region 27 Grip part 30 Storage film | membrane 32 Process liquid storage area | region 34 Communication port 36 Bulkhead 38 Process liquid

Claims (8)

The container contains a contact lens made of a hydrogel material capable of sustained drug release and an immersion liquid, and the immersion liquid contains a target drug of 3.3 × 10 ⁻³ to 3.3 × 10 g / l. Contact lens kit. The first chamber has a storage solution that does not contain a target drug and a contact lens made of a hydrogel material capable of sustained drug release that does not contain a target drug, and a second chamber that has a target drug-containing liquid. A drug sustained-release contact lens kit in which a contact lens is brought into contact with a target drug-containing liquid, and the target drug is contained in the contact lens. The drug sustained-release contact lens kit according to claim 1 or 2, wherein the contact lens contains 0.1 to 1000 µg of a target drug. The hydrogel material is
(A) a step of obtaining a monomer mixture containing a target drug, a monomer having a specific functional group capable of forming a physical cross-linking structure with the target drug, and a cross-linking agent;
(B) a step of polymerizing while maintaining a complex formed between the target drug and a monomer having a specific functional group; and (c) a step of removing unreacted monomer from the target drug from the polymer;
The kit according to claim 1, 2 or 3, which is an imprint gel produced by a method comprising: The drug sustained-release contact lens kit according to claim 1, 2, 3, or 4, wherein the water content of the hydrogel material is 10 to 80%. 6. The drug sustained-release contact lens kit according to claim 1, wherein the target drug is a glaucoma therapeutic agent and / or a tear secretion enhancer. The sustained-release drug contact lens kit according to claim 6, wherein the therapeutic agent for glaucoma is timolol or pilocarpine, or a medically acceptable salt thereof. The drug sustained-release contact lens kit according to claim 6, wherein the tear secretion enhancer is 3-isobutyl-1-methylxanthine or bromhexine, or a medically acceptable salt thereof.

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