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    • 专利摘要:
    Hydrogels for drug administration. The invention relates to a hydrogel suitable to be incorporated into optical devices. More specifically, it relates to a soft contact lens that allows the controlled release of drugs at the ocular level. More particularly, the drug is an aldose reductase inhibitor. The invention also relates to the process of preparation of the hydrogels, and of the delivery systems incorporating an active principle inhibitor of aldose reductase. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2604196A1
    申请号:ES201730074
    申请日:2017-01-23
    公开日:2017-03-03
    发明作者:Fernando ALVAREZ RIVERA；Angel Concheiro Nine；Carmen Alvarez Lorenzo
    申请人:De Santiago, University of；Universidade De Santiago；
    IPC主号:
    专利说明:

    DESCRIPTION

    Hydrogels for administration of aldose reductase inhibitor drugs
    image 1
    image2
    image3

    Technical sector 5
    The invention relates to a hydrogel suitable for incorporation into optical devices. More specifically, it refers to a hydrogel that allows the controlled release of drugs at the ocular level. More particularly, the drug is an aldose reductase inhibitor. The invention also relates to the process of preparing the hydrogels, and their use.
     10
    Background
    Approximately 415 million people worldwide suffer from diabetes mellitus and this number is expected to increase in the coming years. Lack of glycemic control can also lead to a variety of complications in the anterior segment of the eye, including diabetic keratopathy, dry eye syndrome, glaucoma and 15 cataracts. It is known that aldose reductase inhibitors are useful for the prevention or treatment of diabetic eye complications. Most treatments of diabetes over the eye consist of oral and intravitreal administration.
    On the other hand, in the field of ophthalmology it has been proposed the use of contact lenses as a vehicle for sustained transfer of drugs, which results in a prolonged permanence of the drug in the post-lens tear fluid and, therefore, on the cornea, so that the ocular absorption is favored and the side effects diminish. Although this approach has been investigated for decades, there are still difficulties in the technique to implement it efficiently due to the low affinity of the contact lens components for a large majority of drugs, which results in incorporation. of subtherapeutic doses and poor transfer control (C. Gonzalez-Chomón, A. Concheiro, C. Alvarez-Lorenzo. Soft contact lenses for controlled ocular delivery: 50 years in the making. Therapeutic Delivery 4: 1141-1161, 2013 ).
    To date, there is no contact lens that acts as a platform for the release of aldose reductase inhibitors. 30
    Thus there is still a demand for ocular dosage forms of aldose reductase inhibitors that can be comfortably applied, for example, from contact lenses.

    Description of the invention
    The authors of the present invention have developed a hydrogel for the controlled administration of drugs. In particular, said hydrogel comprises functional groups that can interact with an aldose reductase inhibitor. More particularly, the interaction between the hydrogel functional groups and the aldose reductase inhibitor is reversible. In this way, the hydrogels of the invention act as platforms for the controlled transfer of said substances. The load of the aldose reductase inhibitors can be modulated according to the formulation of the hydrogels of the invention, and a high incorporation thereof is achieved. In addition, the assignment profiles were sustained for a week and at concentrations suitable for therapeutic application. 10
    In addition, the hydrogels of the invention have suitable characteristics for preparing contact lenses, eye inserts, intraocular lenses and ocular bandages. The hydrogels of the invention are useful for the treatment or prevention of ocular pathologies, especially those that are related to diabetes.
     fifteen
    In one aspect, the invention relates to a hydrogel comprising a methacrylic monomer, a dimethacrylic monomer and a silane monomer of formula I

    I
    where R1, R2, R3 and R4 may be the same or different and are C1-C4-alkyl,
    R5 can be hydrogen or hydroxyl,
    n has the value 1, 2 or 3,
    m has a value between 1 and 10.
    In a particular embodiment, the hydrogel further comprises an aldose reductase inhibitor.
    In a particular embodiment, the aldose reductase inhibitor is selected from epalrestat, alrestatin, ponalrestat, tolrestat, zenarestat, zopolrestat, fidarestat, imirestat, lidorestat, minalrestat, ranirestat, sorbinyl and salfedrin B11. 5
    In a particular embodiment, the hydrogel further comprises a monomer with at least one amino group.
    In another aspect the invention relates to a process for obtaining the hydrogel described above comprising the polymerization of a mixture of monomers, said mixture of monomers comprises a methacrylic monomer, a dimethacrylic monomer and a silane monomer of formula I

    I
    where R1, R2, R3 and R4 may be the same or different and are C1-C4-alkyl,
    R5 can be hydrogen or hydroxyl,
    n has the value 1, 2 or 3,
    m has a value between 1 and 10,
    and optionally an aldose reductase inhibitor may be present.
    The hydrogels of the invention are suitable for the preparation of contact lenses, eye inserts, intraocular lenses or ocular bandages. Thus, in another aspect the invention relates to a contact lens, ocular insert, intraocular lens or ocular bandage comprising a hydrogel as described above.
    In another aspect the invention relates to the use of the hydrogel, of the contact lens, of the eye insert, of the intraocular lens or of the bandage for the preparation of a medicament. In a particular embodiment, the medicament is used for the treatment of ocular pathologies related to diabetes. In a particular embodiment, the eye pathologies related to diabetes are selected from keratopathy, dry eye syndrome, glaucoma, cataracts, retinopathy.

    Description of the figures
    Figure 1. Light transmission (%) of hydrogels prepared in the absence (5ni) and presence (5Ai) of epalrestat after washing in boiling water and swelling in 10 SLF.
    Figure 2. HET-CAM test photos showing the choriolantoic membranes after 5 minutes of incubation with an aqueous solution of epalrestat (6.36 μg / mL) or hydrogel disks (swollen in 0.9% NaCl). The effects of negative (C-; 0.9% NaCl) and positive (C +; 0.1N NaOH) controls are also shown. fifteen
    Figure 3. Epalrestat release profiles from discs prepared in the presence of epalrestat (imprinted) a) without APMA and b) with APMA in 0.9% NaCl (45 mL, magnetic stirring 200 rpm, room temperature, protected from light). The disks evaluated were boiled in water (15 min) after polymerization and then dried at constant weight. twenty
    Figure 4. Loading of epalrestat in hydrogels a) imprinted with APMA, b) prepared in the absence of epalrestat (non-imprinted) with APMA, c) non-imprinted without APMA d) imprinted without APMA immersed in 50 mL of active ingredient solution 5.43μg / mL.
    Figure 5. Epalrestat ceded in 0.9% NaCl (50 mL) from (a) hydrogels loaded with non-imprinted epalrestat and (b) hydrogels loaded with imprinted epalrestat. All 25 hydrogels comprise APMA.
    Figure 6. Quantities of epalrestat in the donor card and accumulated in cornea after 6 hours of contact with a solution of epalrestat or epalrestat discs loaded 3Ani and 6Ani. The experiment was carried out at 35 ° C using a carbonate buffer at pH 7.2 as the receptor medium. 30



    Detailed description of the invention
    The hydrogels of the invention allow the loading and controlled transfer of aldose reductase inhibitors. Said load and transfer can be modulated by varying the composition of the hydrogels.
    In a particular embodiment, the invention relates to a hydrogel comprising a methacrylic monomer, a dimethacrylic monomer, a silane monomer of formula I and an aldose reductase inhibitor.
    In a particular embodiment, the invention relates to a hydrogel comprising a methacrylic monomer, a dimethacrylic monomer, a silane monomer of formula I and a monomer with at least one amino group. 10
    In a more particular embodiment, the invention relates to a hydrogel comprising a methacrylic monomer, a dimethacrylic monomer, a silane monomer of formula I, a monomer with at least one amino group and an aldose reductase inhibitor.

    Monomers 15
    The monomers of which the hydrogels of the present invention are composed play a fundamental role in their functionality. In order for these hydrogels to be suitable for preparing contact lenses, eye insert, intraocular lens or ocular bandage, the monomers that compose them must be selected so that after polymerization the product has acceptable physical-chemical and optical characteristics.
    Thus, as structural monomers of the hydrogels of the invention, methacrylic monomers and silane monomers of formula I are used. The methacrylic monomer is a monomer commonly used in contact lenses. In a particular embodiment, the methacrylic monomer is selected from 2-hydroxyethyl methacrylate, 2-25 hydroxypropyl methacrylate, 1- (tristrimethylsiloxysilylpropyl) methacrylate, methyl methacrylate, methacrylic acid, aminopropyl methacrylate, cyclohexyl methacrylate, butyl methacrylate, butyl methacrylate, butyl methacrylate, butyl methacrylate, butyl methacrylate aminoethyl methacrylate. In a more particular embodiment, the methacrylic monomer is 2-hydroxyethyl methacrylate.
    In another particular embodiment, the methacrylic monomer is in a proportion between 5 and 95% in the hydrogel. In another particular embodiment, the methacrylic monomer is in a proportion of between 50 and 95% in the hydrogel. In another particular embodiment, the methacrylic monomer is in a proportion of between 60 and 95% in the hydrogel.
    The silane of formula I is a third generation silicone that allows to reach a level of oxygen permeability higher than that achieved with other materials. Oxygen permeability is a fundamental parameter in contact lenses and prevents corneal hypoxia.
    In addition, the silane of formula I can form hydrophobic interactions with the active principle aldose reductase inhibitor.
    In a particular embodiment, in the silane monomer of formula I, R1, R2, R3 and R4 are the same and are selected from methyl and ethyl.
    In a preferred embodiment, the silane of formula I corresponds to the following formula
     10
    In another particular embodiment, the silane monomer is in a proportion of between 5 and 95% in the hydrogel. In another particular embodiment, the silane monomer is in a proportion of between 50 and 95% in the hydrogel. In another particular embodiment, the silane monomer is in a proportion of between 5 and 50% in the hydrogel.
    In addition, the hydrogel is composed of dimethacrylic monomers that act as crosslinkers. In a particular embodiment, the dimethacrylic monomer is selected from ethylene glycol dimethacrylate, 1,3-butanediol diacrylate, 1,4-butanediol diacrylate, 1,6-hexanediol diacrylate, ethylene glycol diacrylate, fluorescein O, O'-diacrylate, glycerol 1 , 3-diglycerolate diacrylate, pentaerythritol diacrylate monostearate, 1,6-hexanediol ethoxylate diacrylate, 3-hydroxy-2,2-dimethylpropyl 3-hydroxy-2,2-dimethylpropionate diacrylate, bisphenol 20 A ethoxylate diacrylate, di (ethylene glycol , neopentyl glycol diacrylate, poly (ethylene glycol) diacrylate, poly (propylene glycol) diacrylate, propylene glycol glycol diacrylate, tetra (ethylene glycol) diacrylate, 1,3-butanediol dimethacrylate, 1,4-butanediol dimethacrylate, 1,6 dimethacrylate, bisphenol A dimethacrylate, diurethane dimethacrylate, ethylene
    glycol dimethacrylate, fluorescein O, O'-dimethacrylate, glycerol dimethacrylate, bisphenol A ethoxylate dimethacrylate, bisphenol A glycerolate dimethacrylate, di (ethylene glycol) dimethacrylate, poly (ethylene glycol) dimethacrylate, poly (dimethylene acrylate, tetraethylene glycol (ethylene glycol) dimethacrylate, triethylene glycol dimethacrylate, poly (lauryl methacrylate-co-ethylene glycol dimethacrylate) and poly (methyl methacrylate-co-ethylene glycol 5 dimethacrylate). In a more particular embodiment, the dimethacrylic monomer is ethylene glycol dimethacrylate.
    In another particular embodiment, the dimethacrylic monomer is in a proportion of 0.01 and 5% in the hydrogel.
    Optionally, a monomer with at least one amino group may be employed in the hydrogels of the present invention. In a preferred embodiment, when the aldose reductase inhibitor contains a carboxylic group, the hydrogels of the invention further comprise a monomer with at least one amino group. The amino group allows ionic interactions to be established with a carboxylic acid group present in the aldose reductase inhibitor. In a particular embodiment, the monomer with an amino group is selected from N- (3-aminopropyl) methacrylamide, N- (2- aminoethyl) methacrylamide, 2-aminoethyl methacrylate, methacrylamidopropyltrimethylammonium chloride, 3-dimethylaminoneopentyl acrylate, N, N-diethylaminoethyl acrylate, N, N-diethylaminoethyl methacrylate, N, N-diethylaminomethyl acrylate, N, N-diethylaminomethyl methacrylate, N, N-diethylaminopropyl acrylate, N, N-diethylaminopropyl methacrylate, N, N-20 dimethylaminopropyl. In a preferred embodiment, the monomer with at least one amino group is N- (3-aminopropyl) methacrylamide.
    It has been observed that the hydrogels of the invention comprising N- (3-aminopropyl) methacrylamide are capable of loading a greater amount of active ingredient than when said monomer is not present. This could be because said monomer in addition to establishing ionic interactions with the aldose reductase inhibitor, forms a cavity that mimics the binding cavity to the aldose reductase inhibitor.
    In another particular embodiment, the monomer with at least one amino group is in a proportion of between 0.1 and 10% in the hydrogel. 30


    Aldose reductase inhibitor
    In a particular embodiment, the aldose reductase inhibitor is selected from epalrestat, alrestatin, ponalrestat, tolrestat, zenarestat, zopolrestat, fidarestat, imirestat, lidorestat, minalrestat, ranirestat, sorbinyl and salfedrin B11.
    Preferably, the aldose 5 reductase inhibitors containing a carboxyl group are selected in the present invention. Said carboxyl group can establish ionic interactions with the monomer with at least one amino group. In a preferred embodiment the aldose reductase inhibitor is selected from epalrestat, alrestatin, ponalrestat, tolrestat and zenarestat.
    In a particular embodiment, the hydrogel of the invention comprises a methacrylic monomer, a dimethacrylic monomer, a silane monomer of formula I as described above, and a monomer with at least one amino group. In a more particular embodiment, the hydrogel of the invention comprises a methacrylic monomer, a dimethacrylic monomer, a silane monomer of formula I as described above, a monomer with at least one amino group and an aldose reductase inhibitor selected from epalrestat, alrestatin, ponalrestat, tolrestat and zenarestat.

    Preparation Procedure
    The hydrogels are prepared by a polymerization process of the selected monomers. During the polymerization the active ingredient aldose reductase inhibitor 20 may be present.
    In one aspect, the invention is directed to a process for obtaining the hydrogels described above, which comprises the polymerization of a mixture of monomers, said mixture of monomers comprises a methacrylic monomer, a dimethacrylic monomer and a silane monomer of formula I as described above, and optionally an aldose reductase inhibitor may be present.
    In a particular embodiment, the volume ratio of methacrylic monomer is between 5 and 95%.
    In another particular embodiment, the volume ratio of the dimethacrylic monomer is between 0.01 and 5%. 30
    In another particular embodiment, the volume ratio of the silane monomer is between 5 and 95%.
    In a particular embodiment, the monomer mixture further comprises a monomer with at least one amino group.
    In a particular embodiment, the polymerization is carried out by heating the mixture or by exposing it to ultraviolet-visible radiation.
    In a particular embodiment, the process for obtaining the hydrogels of the invention comprises the polymerization of a mixture of monomers, said mixture of monomers comprises a methacrylic monomer, a dimethacrylic monomer and a silane monomer of formula I, and an inhibitor Aldose reductase is present during polymerization.
    In a more particular embodiment, the process for obtaining the hydrogels of the invention comprises the polymerization of a mixture of monomers, said mixture of monomers comprises a methacrylic monomer, a dimethacrylic monomer, a silane monomer of formula I and a monomer with at least one amino group, and an aldose reductase inhibitor is present during polymerization.
    The following are examples that illustrate the invention and should not be considered as a limitation thereof.

    Examples
    Example 1. Process for obtaining hydrogels with hydroxyethyl methacrylate, ethylene glycol dimethacrylate and monomethacryloxypropyl-sim-polydimethylsiloxane hydroxypropyl 20.
    Hydrogels were prepared by mixing hydroxyethyl methacrylate (HEMA), ethylene glycol dimethacrylate (EGDMA) and finished monomethacryloxypropyl-sim-polydimethylsiloxane hydroxypropyl (MCS-MC12) by mixing the monomers in the proportions indicated in Table 1, also incorporating azoisobutyronitrile initiator , and optionally 25 N- (3-aminopropyl) methacrylamide hydrochloride (APMA) and / or epalrestat, injecting the mixture into molds consisting of glass plates previously treated with dichlorodimethylsilane and separated by a 0.5 mm thick silicone frame, and heating at 50 ° C for 12 hours and at 70 ° C for another 24 hours. The hydrogel sheets were immersed in boiling water for 15 minutes to remove the 30 non-reactive monomers and facilitate the cutting of 10 mm diameter discs. The discs were dried in a 70 ° C oven and the degree of swelling was evaluated, in duplicate, at room temperature by immersion and water by applying the equation:
    ℎ ℎ (%) = - 0 0 100
    In which Wo represents the initial weight of the dry disk and Wt the weight after reaching the swelling balance.
    Hydrogels with higher silicone monomer content showed a lower degree of swelling. 5

    Table 1. Composition of mixtures of monomers used to synthesize hydrogels, degree of swelling of hydrogels in water and partition coefficient of epalrestat between hydrogel and water (KN / W).
     Code  HEMA (mL) MCS-MC12 (mL) EGDMA (μL) AIBN (mg) APMA (mg) Epalrestat (mg) Swelling (%) KN / W
     1ni  0 3 45.2 4.93 0 0 1.3 (1.0) 66 (28)
     1i  0 3 45.2 4.93 0 19.2 0.9 (0.7) 37 (23)
     2ni  0.5 2.5 45.2 4.93 0 0 3.8 (1.1) 80 (2)
     2i  0.5 2.5 45.2 4.93 0 19.2 1.7 (0.8) 27 (36)
     2Ani  0.5 2.5 45.2 4.93 21.45 0 2.6 (0.5) 188 (12)
     2Ai  0.5 2.5 45.2 4.93 21.45 19.2 3.5 (1.5) 141 (18)
     3ni  1.5 1.5 45.2 4.93 0 0 14.2 (0.7) 62 (3)
     3i  1.5 1.5 45.2 4.93 0 19.2 13.9 (1.1) 12 (10)
     3Ani  1.5 1.5 45.2 4.93 21.45 0 15.7 (0.6) 982 (17)
     3Ai  1.5 1.5 45.2 4.93 21.45 19.2 14.4 (0.7) 966 (24)
     4ni  2.5 0.5 45.2 4.93 0 0 32.3 (0.8) 39 (2)
     4i  2.5 0.5 45.2 4.93 0 19.2 34.2 (1.6) 10 (6)
     4Ani  2.5 0.5 45.2 4.93 21.45 0 37.2 (0.1) 1031 (23)
     4Ai  2.5 0.5 45.2 4.93 21.45 19.2 37.5 (0.4) 1020 (18)
     5ni  2.75 0.25 45.2 4.93 0 0 41.5 (3.8) 36 (2)
     5i  2.75 0.25 45.2 4.93 0 19.2 41.7 (0.5) 29 (34)
     5Ani  2.75 0.25 45.2 4.93 21.45 0 44.5 (1.0) 1070 (28)
     5Ai  2.75 0.25 45.2 4.93 21.45 19.2 45.2 (0.5) 1083 (32)
     6ni  3 0 45.2 4.93 0 0 49.8 (2.5) 42 (12)
     6i  3 0 45.2 4.93 0 19.2 48.3 (0.5) 28 (20)
     6Ani  3 0 45.2 4.93 21.45 0 56.0 (0.9) 1071 (24)
     6Ai  3 0 45.2 4.93 21.45 19.2 52.5 (0.3) 1105 (43)
    Example 2. Evaluation of the optical transparency and ocular compatibility of the hydrogels prepared according to the composition shown in Table 1.
    The transmittance between 190 and 700 nm of hydrogel disks previously hydrated in artificial tear fluid was recorded. The results corresponding to the 5ni and 5Ai disks are shown in Figure 1. All hydrogels showed a transmittance of greater than 90% at a wavelength of 600 nm.
    The ocular compatibility was evaluated in a subrogated model that uses fertilized chicken chorioallantoid membrane (HET-CAM). Discs of each hydrogel prepared according to the composition shown in Table 1 were hydrated in 0.9% NaCl medium and then placed on the chorioallantoid membrane. The possible changes in the vasculature of the membrane were observed for five to 10 minutes, recording lysis, bleeding and coagulation times. The 0.9% NaCl solution was used as a negative control and a 0.1N NaOH solution as a positive control. Photographs of chorioallantoid membranes with a disc of each hydrogel formulation are shown in Figure 2. All discs passed the compatibility test, not causing lysis, bleeding or coagulation.

    Example 3. Method of obtaining hydrogels with hydroxyethyl methacrylate, ethylene glycol dimethacrylate and monomethacryloxypropyl-sim-polydimethylsiloxane hydroxypropyl terminated incorporating epalrestat during synthesis and yielding the drug in a sustained manner.
    Hydrogels were prepared by mixing hydroxyethyl methacrylate (HEMA), ethylene glycol dimethacrylate (EGDMA) and finished monomethacryloxypropyl-sim-polydimethylsiloxane hydroxypropyl (MCS-MC12) by mixing the monomers in the proportions indicated in Table 1, also incorporating azoisobutyronitrile initiator , N- (3-aminopropyl) 25 methacrylamide hydrochloride (APMA) and epalrestat (codes ending in letter i), injecting the mixture into molds consisting of glass plates previously treated with dichlorodimethylsilane and separated by a 0.5 mm thick silicone frame , and heating at 50 ° C for 12 hours and at 70 ° C for an additional 24 hours. The hydrogel sheets were immersed in boiling water for 15 minutes to remove the 30 non-reactive monomers and facilitate the cutting of 10 mm diameter discs. The disks were transferred separately to vials containing 0.9% NaCl (45 mL) and kept under magnetic stirring at 200 rpm at room temperature and protected from
    the light. At pre-set times, samples of 3 mL of medium were removed and the absorbance at 400 nm was measured. After measurement, the samples were immediately returned to the corresponding vial. The results obtained are shown in Figure 3.
    All hydrogels provided sustained assignment profiles for one week.
     5
    Example 4. Procedure for incorporating epalrestat in hydrogels with hydroxyethyl methacrylate, ethylene glycol dimethacrylate and monomethacryloxypropyl-sim-polydimethylsiloxane hydroxypropyl terminated.
    Hydrogels prepared according to the composition shown in Table 1 were immersed in boiling water for 15 minutes to remove non-reactive monomers and facilitate the cutting of 10 mm diameter discs. Then, they underwent a thorough washing process by immersion in ethanol: water (10:90 v / v, 100 mL) for 48 h, replacing the medium every 24 h. Washing continued in 0.9% NaCl medium for 24 h, 24 h artificial tear fluid, 72 h water, 24 h artificial tear fluid, 48 h water, 0.9% NaCl 8 days, and finally water 3 more days, under magnetic stirring (200 rpm) at 15 room temperature and protected from light. During washing, the removal of epalrestat used during the synthesis was monitored spectrophotometrically at 400 nm. Finally the discs were dried at constant weight.

    The dried discs were placed individually in 50 mL of 20 epalrestat aqueous solution (6.14 micrograms / mL) protected from light (in triplicate) and kept under magnetic stirring at room temperature. At pre-established time periods, the absorbance of the loading solutions was measured spectrophotometrically at 400 nm and the amount of drug loaded was estimated from the difference between the initial and final amount of drug in the solution. The incorporation profiles 25 of epalrestat are shown in Figure 4.
    The distribution coefficient of epalrestat between the hydrogel and the aqueous medium, KN / W, was calculated using the following equation:
    Built-in drug = [(Vs + KN / W · Vp) / Wp] · C0
    In this equation, Vs is the volume of water absorbed by the hydrogel, Vp the volume of dry polymer, Wp the weight of dry hydrogel and C0 the concentration of epalrestat in the loading solution.
    The KN / W values, shown in Table 1, show that hydrogels containing the APMA monomer have a very high affinity for the drug, approximately two orders of magnitude higher than hydrogels prepared without APMA.
    The hydrogels loaded with the drug by the described procedure were taken to 50 mL 5 of 0.9% NaCl to assess their ability to regulate the transfer of epalrestat. The profiles obtained, which are shown in Figure 5, show that the hydrogels sustain the assignment for several days.

    Example 5. Corneal permeability test of epalrestat assigned from hydrogels 10 with hydroxyethyl methacrylate, ethylene glycol dimethacrylate and finished hydroxypropyl monomethacryloxypropyl-sim-polydimethylsiloxane.
    A corneal permeability test was carried out using bovine eyes from a municipal slaughterhouse. The corneas were placed in diffusion cells, separating the receptor compartment (carbonate buffer pH 7.2; 6.5 mL) from the donor compartment. In each donor compartment a disc loaded with epalrestat (6Ani and 3Ani formulations; Codes as in Table 1) or an epalrestat control solution was placed. At pre-established times, samples were taken from the receiving medium and the amount of epalrestat was quantified. Each experiment was carried out in triplicate. After 6 hours of the test, the corneas were removed and the amount accumulated in them was quantified by extracting with ethanol: water 50; 50 v / v for 12 hours and assessing the epalrestat content by HPLC.
    The amounts of epalrestat remaining in the donor compartment and those accumulated in the cornea are shown in Figure 6. Hydrogels transferred amounts of epalrestat to the corneas in the range that gives rise to therapeutic effects. 25

    权利要求:
    Claims (17)
    [1]
    image 1
    image2
    1. Hydrogel comprising a methacrylic monomer, a dimethacrylic monomer and a silane monomer of formula I
    I
     5
    where R1, R2, R3 and R4 may be the same or different and are C1-C4-alkyl,
    R5 can be hydrogen or hydroxyl,
    n has the value 1, 2 or 3,
    m has the value between 1 and 10.
    [2]
    2. Hydrogel, according to claim 1, further comprising an aldose 10 reductase inhibitor.
    [3]
    3. Hydrogel, according to claim 2, wherein the aldose reductase inhibitor is selected from epalrestat, alrestatin, ponalrestat, tolrestat, zenarestat, zopolrestat, fidarestat, imirestat, lidorestat, minalrestat, ranirestat, sorbinyl and salfedrin B11.
    [4]
    4. Hydrogel, according to claim 3, wherein the aldose reductase inhibitor is epalrestat.
    [5]
    5. Hydrogel, according to any of the preceding claims, further comprising a monomer with at least one amino group.
    [6]
    6. Hydrogel, according to any of the preceding claims wherein the methacrylic monomer is selected from 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, 1-20 (tristrimethylsiloxysilylpropyl) -methacrylate, methylmethacrylate, methacrylic acid, aminopropyl methacrylate, cyclohexyl methacrylate, cyclohexyl methacrylate, butyl methacrylate, glycerol methacrylate and 2-aminoethyl methacrylate.
    [7]
    7. Hydrogel, according to any of the preceding claims wherein R1, R2, R3 and R4 in the silane monomer of formula I are the same and are selected from methyl and ethyl.
    [8]
    8. Hydrogel, according to any of the preceding claims wherein the silane monomer is
     5
    [9]
    9. Hydrogel, according to any of the preceding claims wherein the dimethacrylic monomer is selected from ethylene glycol dimethacrylate, 1,3-butanediol diacrylate, 1,4-butanediol diacrylate, 1,6-hexanediol diacrylate, ethylene glycol diacrylate, fluorescein O, O'-diacrylate, glycerol 1,3-diglycerolate diacrylate, pentaerythritol diacrylate monostearate, 1,6-hexanediol ethoxylate diacrylate, 3-hydroxy-2,2-dimethylpropyl 3-hydroxy-10 2,2-dimethylpropionate diacrylate, bisphenol A ethoxylate diacrylate , di (ethylene glycol) diacrylate, neopentyl glycol diacrylate, poly (ethylene glycol) diacrylate, poly (propylene glycol) diacrylate, propylene glycol glycerol diacrylate, tetra (ethylene glycol) diacrylate, 1,3-butanediol dimethacrylate, 1,4-butanediol dimethacrylate dimethacrylate, 1,6-hexanediol dimethacrylate, bisphenol A dimethacrylate, diurethane dimethacrylate, ethylene glycol dimethacrylate, fluorescein O, O'-15 dimethacrylate, glycerol dimethacrylate, bisphenol A ethoxylate dimethacrylate, bisphenol A glycerolate imetacrylate, di (ethylene glycol) dimethacrylate, poly (ethylene glycol) dimethacrylate, poly (propylene glycol) dimethacrylate, tetraethylene glycol dimethacrylate, tri (ethylene glycol) dimethacrylate, triethylene glycol dimethacrylate, poly (lacyl dimethyl acrylate) poly (methyl methacrylate-co-ethylene glycol dimethacrylate). twenty
    [10]
    10. Hydrogel according to any of claims 5 to 9, wherein the monomer with an amino group is selected from N- (3-aminopropyl) methacrylamide, N- (2- aminoethyl) methacrylamide, 2-aminoethyl methacrylate, chloride methacrylamidopropyltrimethylammonium, 3-dimethylaminoneopentyl acrylate, N, N-diethylaminoethyl acrylate, N, N-diethylaminoethyl methacrylate, N, N-diethylaminomethyl acrylate, N, N-diethylaminomethyl methacrylate, N, N-25
    diethylaminopropyl acrylate, N, N-diethylaminopropyl methacrylate, N, N-dimethylaminopropylacrylamide.
    [11]
    11. Hydrogel according to any of the preceding claims comprising a methacrylic monomer, a dimethacrylic monomer, a silane monomer of formula I as described in claim 1, and a monomer with at least one amino group. 5
    [12]
    12. Hydrogel according to any of the preceding claims comprising a methacrylic monomer, a dimethacrylic monomer, a silane monomer of formula I as described in claim 1, a monomer with at least one amino group and an aldose reductase inhibitor selected from between epalrestat, alrestatin, ponalrestat, tolrestat and zenarestat. 10
    [13]
    13. Contact lens, ocular insert, intraocular lens or ocular bandage comprising a hydrogel according to any of claims 1-12.
    [14]
    14. Method for obtaining the hydrogel according to any of claims 1-12, which comprises the polymerization of a mixture of monomers, said mixture of monomers comprises a methacrylic monomer, a dimethacrylic monomer and a silane monomer of formula I as described described in claim 1, and optionally an aldose reductase inhibitor may be present.
    [15]
    15. Use of the hydrogel according to any of claims 1-12, of the contact lens, of the eye insert, of the intraocular lens or of the bandage according to claim 13, for the preparation of a medicament. twenty
    [16]
    16. Use of the hydrogel according to any of claims 1-12, of the contact lens, of the eye insert, of the intraocular lens or of the bandage according to claim 13, for the preparation of a medicament for the treatment of related ocular pathologies with diabetes
    [17]
    17. Use of the hydrogel according to claim 16, wherein the ocular pathologies related to diabetes are selected from keratopathy, dry eye syndrome, glaucoma, cataracts and retinopathy.
    类似技术:
    公开号 | 公开日 | 专利标题
    TWI476022B|2015-03-11|Contact lenses and methods of making and using thereof
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    KR19980703301A|1998-10-15|Sterile ophthalmic gel preparation and production process applicable as eye drops
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    同族专利:
    公开号 | 公开日
    WO2018134467A1|2018-07-26|
    ES2604196B2|2017-09-11|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    EP0231572A2|1986-02-06|1987-08-12|Progressive Optical Research Ltd.|Silicone-sulfone and silicone-fluorocarbon-sulfone gas permeable contact lenses and compositions thereof|
    WO2011005839A1|2009-07-07|2011-01-13|Convatec Technologies Inc.|Pressure sensitive silicone adhesives with amphiphilic copolymers|
    WO2011037893A2|2009-09-22|2011-03-31|Coopervision International Holding Company, Lp|Wettable hydrogel materials for use in ophthalmic applications and methods|
    WO2013033553A1|2011-09-01|2013-03-07|Vertellus Specialties Inc.|Methods for producing biocompatible materials|
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    PCT/ES2018/070051| WO2018134467A1|2017-01-23|2018-01-23|Hydrogels for administering drugs that are aldose reductase inhibitors|
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