JP4124610B2 - Drug sustained-release contact lenses - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to Drug controlled release contact lenses. More particularly, good transparency, dimensional stability, it relates Drug controlled release contact lens comprising a polymer gel having a drug sustained-release effect.
[0002]
[Prior art]
Polymer gels are widely studied in the medical field as soft and wet materials. Among them, one of the fields that has been used since the oldest is an ophthalmic lens. This began with polyhydroxyethyl methacrylate gel and has been functionalized taking advantage of its water-containing properties.
[0003]
One of the functionalizations is the development of a drug release system (DDS) taking into account the in vivo kinetics of the drug. The concept of an ophthalmic lens having a DDS function has been proposed for a long time, and research has been actively conducted.
[0004]
Among ophthalmic preparations, preparations locally administered to the anterior segment include ophthalmic solutions, suspensions, eye ointments, etc., each having its own characteristics. Although the administration of eye drops is relatively easy, the eye drops are diluted with tears immediately after instillation and discharged through the lacrimal passage. That is, in order to sufficiently administer the drug, it is necessary to sufficiently increase the contact time between the cornea and the ophthalmic solution. On the other hand, suspensions and ophthalmic ointments are superior to ophthalmic solutions in that the contact time with the cornea is longer, but there are drawbacks in that the eye irritation and the visual field become cloudy.
[0005]
As a DDS device for solving these problems, there is a system in which a drug is encapsulated in a soft contact lens-shaped plastic, inserted into the eye to elute the drug in a certain amount, and the drug is absorbed from the contact site. This contains a glaucoma therapeutic drug and encapsulates pilocarpine base in ethylene vinyl acetate (product name: Ocusate). This system has the advantage that the pilocarpine base contained is released over about 7 days, thus freeing the patient from frequent eye drops and eliminating forgetting medications. However, there are also problems such as a large amount of drug released immediately after wearing, and it takes about 8 hours to reach a certain speed, and inability to wear and eye irritation symptoms associated with foreign body sensations.
[0006]
Further, an attempt to improve such problems is described in Japanese Patent Publication No. 52-32971. This is a polymer gel having a sustained drug release property in which a monomer having an electrolytic group or a polar group is grafted to a hydrated polyvinyl alcohol by actinic ray irradiation treatment, and the resulting hydrogel is impregnated with an active substance. In addition to the control by the network structure, this polymer gel efficiently and slowly releases the contained drug by the grafted electrolytic group or polar group. Examples of the electrolytic group or polar group include an anionic functional group such as a salt form carboxyl group, sulfonic acid group, and phosphoric acid group, and a quaternary ammonium base.
[0007]
On the other hand, there are those described in JP-A-6-145456 and JP-A-6-306250 as attempts to improve the problem in the same manner. That is, an object of the present invention is to hold a drug having an anionic substituent strongly inside an ophthalmic lens and to efficiently exhibit a sustained release effect. Specifically, a polymer gel having a cationic substituent such as a quaternary ammonium salt in the side chain is synthesized, and a drug having an anionic substituent is coordinated to the substituent by ion exchange. A drug coordinated by ionic bonding has a mechanism in which the coordinated drug is gradually released by an ion exchange reaction in a sustained release environment.
[0008]
[Problems to be solved by the invention]
However, the method for introducing a functional group into a polymer gel described in Japanese Patent Publication No. 52-32971 has special equipment called gamma rays, and is problematic in terms of versatility and practicality. Also, in order to obtain a network structure that is practically necessary, such as shape stability as an ophthalmic lens, it is necessary to control the irradiation amount of gamma rays. If the irradiation amount is too large, the network structure is completely formed and the polar group is formed. There is a problem that an effective drug sustained release property cannot be obtained because the interaction between the drug and the active substance is not exhibited.
[0009]
On the other hand, in JP-A-6-145456 and JP-A-6-306250, since the ophthalmic lens has a cationic functional group, it reacts very sensitively to changes in the external environment such as temperature and pH. It is difficult to obtain the shape stability that is indispensable as a lens for use. That is, there is a problem that the ability to correct vision as an ophthalmic lens is difficult to be stably expressed. In addition, since the properties of the cationic functional group are different before and after the sustained release of the drug, it similarly affects physical properties such as shape stability as an ophthalmic lens.
[0010]
Further, in the polymer gel disclosed in JP-B-52-32971, JP-A-6-145456, and JP-A-6-306250, only about 60% of the functional groups can be involved in the drug content. It is difficult to contain an amount of drug. For this reason, since a correlation between the drug content and the sustained release amount cannot be obtained at the time of designing the polymer gel, it is not practical.
[0011]
By the way, the water-containing soft contact lens composed of a monomer having a cationic functional group or an anionic functional group is ionic, so that dirt easily adheres, and it is difficult to control the water content and swelling rate of the lens. There is a problem of being.
[0012]
For example, when a monomer having an electrolytic group or polar group such as a quaternary ammonium base, an amino group, a sulfonic acid group, or a carboxyl group is used, it is necessary to devise various measures for its application.
[0013]
Accordingly, an object of the present invention, the transparency of the contact lens, in a practical ionic polymer gel having a shape stability, a drug having a cationic substituent by an ion exchange reaction, and held inside the contact lenses Te is to provide a drug controlled release contact lens that can exhibit good sustained release effect.
[0014]
In addition, since it can contain an amount of drug corresponding to the phosphate group introduced into the polymer gel, it has a controlled drug release property that can control its content according to the drug efficacy. there is provided a drug substance sustained release contact lenses ing an ionic polymer gel.
[0015]
[Means for Solving the Problems]
As a result of intensive investigations on various monomers having an electrolytic group or a polar group, the present invention has moderate ionicity and excellent transparency in the case of a polymer gel copolymerized with a monomer having a specific structure having a phosphate group. And having shape stability. Furthermore, in the case of a polymer gel having a phosphate group in the side chain, the present invention can effectively hold and slowly release a drug having a cationic substituent, and also has transparency and shape stability. It is based on the knowledge that it is excellent.
[0016]
That is, the present invention is copolymerizable with a hydrophilic monomer, at least one selected from methacrylates having a phosphate group in the side chain represented by the following structural formulas (I) and (II), and these components. in drug controlled-release contact lens comprising a copolymer of a monomer, a drug slow release of a contact lens characterized by containing a drug having a cationic substituent within the copolymer.
[0017]
[Chemical 2 ]
[0018]
DETAILED DESCRIPTION OF THE INVENTION
The present invention will be specifically described below.
[0019]
The hydrophilic monomer that is a monomer constituting the copolymer in the present invention has at least one hydrophilic group in the molecule. For example, hydroxymethyl (meth) acrylate, 2-hydroxyethyl (meth) acrylate, 2-hydroxypropyl (meth) acrylate, 2,3-dihydroxypropyl (meth) acrylate, 2-polyethylene glycol (meth) acrylate, 2-polypropylene Glycol (meth) acrylate, N, N-dimethylacrylamide, N, N-dimethylmethacrylamide, N-vinylpyrrolidone and the like can be used, but two or more of these can be used in combination (“(meth)” in this specification) “Acrylate” means both acrylate and methacrylate).
[0020]
In the present invention, the monomer having a phosphate group in the side chain, which is another monomer constituting the copolymer, has a favorable state that the phosphate group in the copolymer moderately holds the cationic drug by ionic interaction. It exhibits a sustained release effect.
[0021]
The monomer having a phosphate group in the side chain used in the present invention is a methacrylate represented by the following structural formula (I) and / or (II). n is preferably 1 to 3 in the structural formula (I). When n is 4 or more, the alkylene chain in the molecule becomes long and the interaction with the drug cannot be sufficiently achieved, the content and the release amount are affected, and a good sustained release effect cannot be obtained. Structural formula (II) is a compound containing an oxygen atom in the repeating unit, and n is preferably 1 to 4. When n is 5 or more, the molecular chain becomes long and the interaction with the drug cannot be sufficiently achieved, the content and the release amount are affected, and a good sustained release effect cannot be obtained. Although the compounds represented by the following structural formulas (I) and (II) are monoester compounds, in the present invention, the monoester compounds and diester compounds are within the range in which the diester compounds of these compounds do not interfere with the effects of the present invention. About 30% by weight or less can be contained with respect to the total amount.
[0022]
[Chemical 3 ]
[0023]
The use amount of the hydrophilic monomer and the monomer having a phosphate group in the side chain is preferably a phosphate group-containing monomer in the range of 0.1 to 40.0 wt% with respect to the hydrophilic monomer. Particularly preferably, the phosphate group-containing monomer is in the range of 5 to 20 wt%. If it is less than 0.1 wt%, the content of the drug in the gel is extremely reduced, and if it exceeds 40.0 wt%, the shape stability and mechanical strength as a polymer gel may be lowered.
[0024]
In the present invention, a crosslinkable monomer can be used in addition to the above components. The crosslinkable monomer may not be used. However, the use of the crosslinkable monomer makes it possible to form a network structure of the polymer gel and adjust the mechanical strength. Examples of the crosslinkable monomer include ethylene glycol dimethacrylate, methylene bisacrylamide, 2-hydroxy-1,3-dimethacryloxypropane, trimethylolpropane triacrylate, and the like. The amount of the crosslinkable monomer used is preferably 0.1 to 4.0 wt% with respect to the total monomer (excluding the crosslinkable monomer). Most preferably, it is 0.1-1.0 wt%.
[0025]
The present invention can further use any copolymerizable monomer. For example, if a hydrophobic monomer is used, it can be expected to adjust the water content and swelling rate of the resulting polymer gel and finely adjust the content of the drug in the polymer gel. As the hydrophobic monomer used, any monomer having compatibility with the hydrophilic monomer and the phosphate group-containing monomer can be used. For example, methyl methacrylate, isobutyl methacrylate, 2,2,2-trifluoromethacrylate, cyclohexyl methacrylate. Etc. are preferable.
[0026]
When utilized as Drug controlled release contact lenses of the present invention, a drug which can be used is a drug having a cationic substituent. The drug having a cationic substituent is preferably an organic compound selected from the group consisting of a substituent having at least one quaternary ammonium base and primary to tertiary amine base in the molecule. Examples of those that exhibit preferred pharmacological effects include neostigmine methyl sulfate, oxybuprocaine hydrochloride, naphazoline nitrate, naphazoline hydrochloride, sodium chondroitin sulfate, pilocarpine hydrochloride, distigmine bromide, ecothiopart iodide, epinephrine, epinephrine hydrogen tartrate, carteline hydrochloride Examples include orol and befnolol hydrochloride.
[0027]
The polymer gel having sustained drug release properties according to the present invention can be applied to various uses other than the above-mentioned ophthalmic attachment. Examples of such applications include various drug release systems (DDS), bactericidal sheets, antibacterial sheets, wound dressings, and poultices, and the drugs to be used can be appropriately selected according to the applications.
[0028]
In the production of the contact lens of the present invention, first, a polymerization initiator is added to the mixture of monomers, and further stirred and dissolved. As the polymerization initiator, peroxides such as lauroyl peroxide, cumene hydroperoxide, benzoyl peroxide, azobisvaleronitrile, azobisisobutyronitrile (AIBN), etc., which are general radical polymerization initiators, are used. it can. The addition amount of the polymerization initiator is preferably about 10 to 3500 ppm with respect to the total amount of monomers.
[0029]
The monomer mixture is put in a mold for contact lenses such as metal, glass, plastic, etc., sealed, heated in a range of 25 to 120 ° C. stepwise or continuously in a constant temperature bath or the like, and in 5 to 120 hours. Complete the polymerization. In the polymerization, ultraviolet rays, electron beams, gamma rays, or the like can be used. In addition, solution polymerization can be applied by adding water or an organic solvent to the monomer mixture.
[0030]
After completion of the above polymerization, the mixture is cooled to room temperature, and the resulting polymer is taken out of the mold and cut and polished as necessary. The obtained contact lens is hydrated and swollen to form a hydrous gel. Examples of the liquid (swelling liquid) used for this hydration swelling include water, physiological saline, isotonic buffer and the like. The swelling liquid is heated to 60 to 100 ° C. and dipped for a certain period of time to quickly enter a hydrated and swollen state. Moreover, it becomes possible to remove the unreactive monomer contained in the polymer by the swelling treatment.
[0031]
Next, a description will be given of the case of using the drug was sustained-release contact lens of the present invention. A drug solution in which a drug having a cationic substituent is dissolved is prepared, and the water-containing gel is immersed in the drug solution to obtain a drug sustained-release polymer gel containing the drug in the water-containing gel.
[0032]
Examples of the solvent for dissolving the drug include water, a hydrophilic solvent, a mixed solvent of water and a hydrophilic solvent, and examples of the hydrophilic solvent include alcohols such as ethanol, methanol, isopropanol, and n-butanol, and dimethyl sulfoxide. Etc.
[0033]
The drug concentration contained in the drug solution is appropriately selected depending on each drug depending on the solubility of the drug, the minimum effective concentration for exhibiting the drug effect, the maximum safe concentration, and the like. A concentration of ^{−6 to} 1.0 × 10 ⁻² mol / L is generally preferred.
[0034]
【Example】
EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited to these Examples.
[0035]
(Example 1)
2-hydroxyethyl methacrylate (HEMA) 90 wt%, phosphoric acid group-containing monomer (chemical formula I; n = 2) (PhMA) 10 wt%, ethylene glycol dimethacrylate (EDMA) 0.2 wt% (external addition), AIBN 2000 ppm are mixed. The mixture was stirred for about 1 hour with sufficient nitrogen substitution. After stirring, the monomer mixture was placed in a contact lens mold and heated in the range of 50 to 100 ° C. over 25 hours to obtain a polymer. The obtained polymer was returned to room temperature, taken out of the container, and hydrated and swollen by being immersed in physiological saline at about 80 ° C. for about 4 hours. The obtained contact lens was a colorless and transparent water-containing gel having a water content of 38%.
[0036]
Next, the contact lens made of this hydrous gel was subjected to a heat treatment at 121 ° C. for 20 minutes in physiological saline, and the size of the lens in the physiological saline before and after the heat treatment was measured at room temperature.
[0037]
Further, the water-containing gel was made to contain naphazoline nitrate by being immersed in 10 mL of a 0.5 wt% aqueous solution of naphazoline nitrate, which is a drug model prepared in advance, for a contact lens made of this hydrous gel for 48 hours. . Furthermore, the hydrogel containing naphazoline nitrate was immersed in 20 mL of distilled water at 25 ° C. for 24 hours to remove the free drug that did not ionically interact with the phosphate group.
[0038]
The naphazoline nitrate-containing gel is immersed in 10 mL of physiological saline at 25 ° C., and the immersion liquid is sampled over time for 24 hours, and the amount of naphazoline nitrate contained therein is determined by HPLC (manufactured by JASCO Corporation). And quantified. This quantification was repeated until no drug release could be confirmed in the immersion liquid, and the drug uptake amount in the hydrous gel was calculated from the cumulative elution amount of the drug.
[0039]
(Example 2)
HEMA 90 wt%, phosphate group-containing monomer (Chemical Formula I, n = 2) (PhMA) 10 wt%, and AIBN 2000 ppm were mixed, and a water-containing gel was obtained in the same manner as in Example 1. The size change of the obtained water-containing gel and the amount of drug uptake of naphazoline nitrate in the water-containing gel were quantified in the same manner as in Example 1 to examine the release behavior.
[0040]
(Comparative Example 1)
HEMA in amounts shown in Table 1, to obtain a water-containing gel in the same manner as in Example 1 using a monomer mixture consisting of methacrylic acid (MAA) and EDMA as the organic compound having a carboxyl group. The size change of the obtained hydrogel, the release behavior of naphazoline nitrate into the physiological saline, and the quantification of the amount of drug uptake in the gel were performed in the same manner as in Example 1.
[0041]
(Comparative Example 2)
A water-containing gel was obtained in the same manner as in Example 1 using a monomer mixture consisting of HEMA and a sulfonic acid group-containing styrene sulfonic acid (StSA) and EDMA in the compounding amounts shown in Table 1. The change in the size of the hydrogel, the release behavior of naphazoline nitrate into the physiological saline of the obtained hydrogel, and the quantification of the drug uptake amount in the gel were performed in the same manner as in Example 1.
[0042]
Table 2 shows the measurement results of the sizes before containing the drugs of the hydrogels of Examples 1 and 2 and Comparative Examples 1 and 2.
[0043]
From this result, the water-containing gel of Example 2 had a small size change like the water-containing gel of Example 1, and excellent shape stability was recognized. That is, it can be confirmed that the ionic polymer gel according to the present invention has excellent shape stability even when no crosslinkable monomer is used.
[0044]
The drug sustained release curves from the hydrogels of Example 1 and Comparative Examples 1 and 2 are shown in FIG. In Example 1, it has a stable sustained release property over about 15 hours, but in Comparative Examples 1 and 2, 80% or more is released in about 4 hours, and reaches a saturated release amount in about 6 hours. As a result, sustained release capability of the phosphoric acid group-containing polymer gel of the present invention can be confirmed.
[0045]
The polymer gel which does not use the crosslinkable monomer of Example 2 and the drug sustained release curve of Example 1 are shown in FIG. The drug sustained-release polymer gel according to Examples 1 and 2 showed a certain sustained-release behavior. That is, it can be confirmed that the sustained drug release property according to the present invention is not controlled by the network structure formed by the cross-linking component, but is greatly influenced by the ion exchange reaction with the phosphate substituent.
[0046]
Table 3 shows the measurement results of the size of the hydrogel before and after the sustained drug release.
[0047]
From this result, the water-containing gel of Example 2 had a small size change like the water-containing gel of Example 1, and excellent shape stability was recognized. That is, it can be confirmed that the ionic polymer gel according to the present invention has excellent shape stability even when no crosslinkable monomer is used.
[0048]
In addition, the hydrogels of Examples 1 and 2 were smaller in size change than the hydrogels of Comparative Examples 1 and 2, and excellent shape stability was observed before and after drug release. This is probably because the repulsion between the functional groups in the water-containing gel that became free after the release of the contained drug was weaker in Examples 1 and 2 than in Comparative Examples 1 and 2. The shape stability of the drug sustained-release of the contact lens of the present inventors from that which has been solved for the size change when wearing which has been a challenge, especially can be confirmed.
[0049]
(Examples 3 to 5)
HEMA, EDMA, and phosphate group-containing monomers having different side chain structures were mixed in the blending amounts shown in Table 1, and a hydrogel was obtained in the same manner as in Example 1. The obtained water-containing gel was subjected to the same operation as in Example 1, so that the water-containing gel contained naphazoline nitrate, and then the free drug in the gel was removed. The release behavior of naphazoline nitrate contained in the hydrous gel into physiological saline and the quantification of the drug uptake amount in the gel were performed in the same manner as in Example 1.
[0050]
The sustained drug release curve from the hydrous gel of this example is shown in FIG. Different sustained release curves were obtained for each of the hydrogels of Examples 1 and 3-5. This is due to the side chain length of the monomer having a phosphate group, and the slow release rate becomes slower as the degree of freedom of the side chain is smaller (the side chain length is shorter). That is, by selecting a phosphate group-containing monomer having an appropriate side chain structure depending on the drug to be used, it is possible to control the sustained release of the drug.
[0051]
Moreover, as shown in Table 4, Examples 1 and 3 to 5 give a substantially constant drug uptake amount corresponding to the content of phosphate groups in the hydrogel.
[0052]
(Example 6)
A hydrogel containing the blending amount of the phosphate group-containing monomer (PhMA) used in Example 1 at the ratio shown in Table 5 was prepared. The amount of HEMA and the amount of AIBN are the same as in Example 1. The same operation as Example 1 was performed with respect to each obtained hydrogel, and the amount of naphazoline nitrate incorporated in the hydrogel was quantified. The results are shown in Table 5.
[0053]
FIG. 4 shows the relationship between the blending amount of the phosphate group-containing monomer in the hydrogel and the drug uptake amount. This example confirms that the amount of drug uptake increases proportionally with respect to the phosphate group-containing monomer concentration. Therefore, if the polymer gel is synthesized by adjusting the amount of the phosphate group-containing monomer, the pharmacokinetics can be controlled.
[0054]
(Example 7)
The water-containing gel of Example 1 was immersed in 10 mL of a 0.5 wt% aqueous solution of vitamin B6, which was another drug model prepared in advance, at 25 ° C. for 48 hours to contain vitamin B6 in the water-containing gel. Furthermore, the hydrogel to which vitamin B6 was adsorbed was immersed in 20 mL of distilled water at 25 ° C. for 24 hours to remove the free drug that did not interact with phosphate groups in an ionic manner.
[0055]
Thereafter, the amount of vitamin B6 contained was quantified in the same manner as in Example 1.
[0056]
The sustained release curve of vitamin B6 from the hydrogel of this example is shown in FIG. From this result, it can be seen that controlled release by the presence of a cationic substituent is effective even for drugs having different molecular weights. That is, since the drug sustained-release polymer gel according to the present invention has a phosphate group that is a ligand capable of exhibiting a certain sustained-release behavior, a wide range of applications can be expected regardless of the chemical structure of the drug. Further, the amount of drug uptake was 5.97 × 10 ⁻⁵ mol / sheet as shown in Table 4, corresponding to the amount of phosphate groups in the hydrous gel.
[0057]
[Table 1]
[0058]
[Table 2]
[0059]
[Table 3]
[0060]
[Table 4]
[0061]
[Table 5]
[0062]
【The invention's effect】
ADVANTAGE OF THE INVENTION According to this invention, the ionic polymer gel which has transparency and shape stability required as a contact lens can be provided. Moreover, since it has a phosphoric acid group as a ligand inside the hydrous gel, a drug having a cationic substituent can be retained and sustainedly released by an ion exchange reaction.
[Brief description of the drawings]
FIG. 1 shows sustained drug release behavior of a polymer gel having a phosphate group, a carboxyl group, and a sulfonate group.
FIG. 2 shows sustained release behavior of a water-containing polymer gel when no crosslinkable monomer is used.
FIG. 3 shows changes in drug sustained release behavior with changes in the side chain structure of phosphate group-containing monomers.
FIG. 4 shows the relationship between the amount of a phosphate group-containing monomer and the amount of drug uptake.
FIG. 5: Sustained release behavior of vitamin B6.

Claims (2)

Copolymer of a hydrophilic monomer, at least one selected from methacrylates having a phosphate group in the side chain represented by the following structural formulas (I) and (II), and a monomer copolymerizable with these components in drug controlled-release contact lens consisting of a drug sustained-release contact lens characterized by containing a drug having a cationic substituent within the copolymer.
Drugs with cationic substituent, at least one quaternary ammonium bases, and claim 1, wherein first a primary to organic compounds selected from the substituent group consisting having a tertiary amine base in the molecule Drug sustained-release contact lenses.