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    • 专利摘要:
    Contact lenses for allergic conjunctivitis. The present invention relates to hydrogels, delivery systems and optical devices suitable for the treatment or prevention of allergic conjunctivitis, in particular, seasonal allergic conjunctivitis. The hydrogels of the invention are useful in soft contact lenses, and for loading antihistamine active ingredients such as olopatadine, ketotifen or azelastine in an amount sufficient to elicit a response of adequate efficacy. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2550105A1
    申请号:ES201530906
    申请日:2015-06-25
    公开日:2015-11-04
    发明作者:Carmen ÁLVAREZ LORENZO；Clara GONZÁLEZ CHOMON；Ángel CONCHEIRO NINE
    申请人:Universidade de Santiago de Compostela；
    IPC主号:
    专利说明:

    image 1
    Contact lenses for allergic conjunctivitis Technical sector
    The invention relates to a hydrogel and a drug delivery system comprising it, and which are suitable for incorporation into optical devices. Plus
    5 Specifically, it refers to a soft contact lens that allows the controlled release of drugs at the ocular level. More particularly, the drug is an antihistamine. The invention also relates to the process of preparing hydrogels, and release systems incorporating an antihistamine active ingredient. 10 Background
    Eye allergy is a common problem that can vary over a wide range in terms of severity, from mild forms such as seasonal allergic conjunctivitis, to more severe forms such as vernal keratoconjunctivitis or giant papillary conjunctivitis that can lead to vision loss. The most common ocular allergy is seasonal allergic conjunctivitis, which is an IgE-mediated hypersensitivity reaction where allergens, mainly pollen, interact with IgE antibodies bound to sensitized mast cells inducing their activation and causing the release of histamine, tryptase, prostaglandins , leukotrienes and proinflammatory cytokines (PS Bilkhu, JS Wolffsohn, SA Naroo. A review of non-pharmacological and
    20 pharmacological management of seasonal and perennial allergic conjunctivitis. Contact lens & Anterior Eye 35: 9-16, 2012).
    Among the drugs used in the treatment of seasonal allergic conjunctivitis are olopatadine, ketotifen and azelastine, which in addition to having an antihistamine effect are mast cell membrane stabilizers. Olopatadine, in particular, also has anti-inflammatory properties. Olopatadine is sold in an aqueous ophthalmic solution in the form of hydrochloride at concentrations of 0.1% or 0.2% and is more effective than other drugs, such as ketotifen fumarate, for its greater affinity and selectivity towards H1 receptor (McGill JI. A review of the use of olopatadine in allergic conjunctivitis. Int Ophthalmol. 30 25: 171-9, 2004). However, eye administration of drugs in the form of eye drops has important limitations: only 5% of the dose of drug administered
    image2
    penetrates the cornea, bioavailability at the ocular level is low and significant systemic absorption can occur that may cause side effects (Kompella UB, Kadam RS, Lee VHL. Recent advances in ophthalmic drug delivery. Ther. Deliv. 1, 435– 456, 2010). The limited duration of the effect of the drug requires frequent applications, which causes concentration peaks in the eye structures.
    In the field of ophthalmology it has been proposed the use of contact lenses as a vehicle for sustained cession of drugs, which results in a prolonged permanence of the drug in the post-lens tear fluid and, therefore, on the cornea, of 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 leads to the 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) .
    Biomimetic hydrogels, which have the appropriate optical and mechanical properties as contact lenses, have been described for charging ketotifen and yielding it over time (Venkatesh S, Sizemore SP, Byrne ME. Biomimetic hydrogels for enhanced loading and extended release of ocular Therapeutics, Biomaterials 28, 717-724, 2007). However, these optical hydrogels are only capable of loading a maximum of 0.050 mmol / g, which is equivalent to 15.5 mg / g (section
    3.1 and Figure 2b, pages 720-721), the release of up to 80% of the active substance occurs in the first 4 days (page 723) and the release is completed in 8 days.
    Therefore, there is still a need to provide a drug release vehicle for the treatment or prevention of eye allergies, which allows a high drug load so that it is sufficient to obtain an acceptable efficacy response, which provides a high bioavailability. eyepiece, that does not require repeated applications at short intervals of time, that does not lead to marked peaks of drug concentration in the eye structures and that minimizes side effects.
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    Brief Description of the Invention
    The authors of the present invention have developed a delivery system for the administration of ocular drugs, in particular antihistamine active ingredients, such as olopatadine, ketotifen and azelastine, and more particularly olopatadine, which allows the drug to be loaded efficiently and in sufficient quantity. and yield it in a controlled manner over time to achieve a therapeutic effect. This release system comprises a hydrogel that has suitable optical and biocompatibility properties, so that the release system and / or the hydrogel can be employed in ophthalmology, in particular as a contact lens, eye insert, intraocular lens or ocular bandage.
    Thus, in a first aspect, the invention relates to a hydrogel comprising at least one methacrylic monomer, at least one acrylic monomer, a crosslinking agent, and at least one functional monomer selected from those in the group consisting of a monomer with at least one aryl group, a monomer with at least one amido group and a monomer with at least one acidic group with a pKa of less than 4, with the proviso that if a functional monomer in the hydrogel is a monomer with at least one group aryl then the hydrogel further comprises at least one of the other functional monomers.
    In a particular embodiment, the methacrylic monomers are selected from 2-hydroxyethyl methacrylate, 1- (tristrimethylsiloxysilylpropyl) -methacrylate, methylmethacrylate, methacrylic acid, aminopropyl methacrylate and cyclohexyl methacrylate. In a more particular embodiment, the methacrylic monomer is 2-hydroxyethyl methacrylate.
    In a particular embodiment, the acrylic monomers are selected from acrylic acid and fluoro-siloxane acrylate. In a more particular embodiment, the acrylic monomer is acrylic acid.
    In a particular embodiment, the crosslinking agent 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 A ethoxylate diacrylate, di (ethylene glycol) diacryl glycol diacrylopene diacrylate diacrylate, poly (ethylene glycol) diacrylate, poly (propylene glycol) diacrylate, propylene glycol glycollate diacrylate, tetra (ethylene glycol) diacrylate, 1,3-butanediol dimethacrylate, 1,4-butanediol dimethacrylate, 1,6-hexanediol dimethacrylate dimethyl biscrylic acid To 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 ilen glycol) dimethacrylate, poly (propylene glycol) dimethacrylate, tetraethylene glycol dimethacrylate, tri (ethylene glycol) dimethacrylate, triethylene glycol dimethacrylate, poly (lauryl methacrylate-co-ethylene glycol dimethacrylate) and poly (methyl methacrylate) ethylene glycol dimethyl acrylate . In a more particular embodiment, the crosslinking agent is ethylene glycol dimethacrylate.
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    In a particular embodiment, in the functional monomer having at least one acidic group with a pKa of less than 4, said acidic group is selected from sulfonate, sulfonic, phosphate, phosphonate and carboxylic present in an alpha or beta amino acid.
    In a particular embodiment, in the above-described hydrogel the selected functional monomer is a monomer with at least one acidic group with a pKa lower than 4. In a particular embodiment, in the above-described hydrogel the selected functional monomers are a monomer with at least an aryl group and a monomer with at least one acidic group with a pKa lower than 4. More particularly, in the hydrogel described above the selected functional monomers are a monomer with at least one aryl group and a monomer with at least one sulfonate group . In another particular embodiment, in the hydrogel described above the selected functional monomer is a monomer with at least one amido group. In another particular embodiment, in the hydrogel described above the selected functional monomers are a monomer with at least one aryl group, a monomer with at least one amido group and a monomer with at least one sulfonate group. In another particular embodiment, in the hydrogel described above the selected functional monomer is a monomer with at least one sulfonate group.
    In a particular embodiment, the invention relates to a hydrogel as described above, comprising at least one methacrylic monomer, at least one acrylic monomer, a crosslinking agent, benzylmethacrylate and 2-acrylamido-2-methyl-1-propanesulfonic acid.
    image5
    In another particular embodiment, the invention relates to a hydrogel as described above, comprising at least one methacrylic monomer, at least one acrylic monomer, a crosslinking agent and acrylamide.
    In a particular embodiment, in the hydrogel of the invention the functional monomer possessing at least one aryl group is selected from benzyl methacrylate, benzylacrylate, o-nitrobenzylmethacrylate, vinylbenzoic acid, benzydryl methacrylate, N-benzylmethacrylamido, phenyl acrylate, phenyl methacrylate, 4 acrylate, 2-naphthyl acrylate, 2fenoxietilmetacrilato, 2-phenylethyl, 2-phenylethyl methacrylate, perfluorophenyl pentafluorofenilacrilato, pentafluorofenilmetacrilato, 2-naftilmetacrilato, pentabromofenilacrilato, pentabromofenilmetacrilato, pentafluorofenilacrilato, pentafluorofenilmetacrilato. In a particular embodiment the functional monomer possessing at least one aryl group is the benzylmethacrylate monomer.
    In a more particular embodiment, the aryl group of the functional monomer described above is a benzyl group. In a more particular embodiment, in the hydrogel of the invention the functional monomer with an aryl group is selected from benzyl methacrylate, benzyl acrylate, o-nitrobenzyl methacrylate, benzidyl methacrylate and Nbenzylmethacrylamide.
    In a particular embodiment, in the hydrogel of the invention the functional monomer possessing at least one amido group is selected from acrylamido, methacrylamide, N- (noctadecyl) acrylamide, N-benzylmethacrylamide, N, N-diethylacrylamide, N, N-dimethyl acrylamide, N, N-dimethylmethacrylamido, N, N-diphenyl N-ethylmethacrylamido, N- (tertoctyl) acrylamido, N-iso-propylacrylamido, N, N'-cystamine bisacrylamido, N, N'diallylacrylamide and N- (2-hydroxypropyl) methacrylamido In a particular embodiment the functional monomer possessing at least one amido group is the acrylamide monomer. In a more particular embodiment, the monomer having at least one acidic group with a pKa of less than 4 is 2-acrylamido-2-methyl-1-propanesulfonic acid.
    A second aspect of the invention relates to a process for obtaining the hydrogel of the invention as described above, which comprises the polymerization of a mixture of monomers, said mixture comprises at least one methacrylic monomer, at least one acrylic monomer, a crosslinking agent, and at least one functional monomer selected from those of the group consisting of a monomer with at least one aryl group, a monomer with at least one amido group and a monomer with at least one acid group with a pKa less than 4, and optionally an active antihistamine principle is present during polymerization.
    image6
    A third aspect of the invention relates to the hydrogel obtainable by the process described above.
    A fourth aspect of the invention relates to a release system comprising a hydrogel, as described above, and an antihistamine active ingredient.
    In a particular embodiment, in the release system of the invention the antihistamine active ingredient is selected from olopatadine, ketotifen and azelastine.
    In a particular embodiment, in the release system of the invention the active ingredient is olopatadine.
    A fifth aspect of the invention relates to a contact lens, ocular insert, intraocular lens or ocular bandage comprising a release system or a hydrogel as described above.
    In a particular embodiment, the contact lens, eye insert, intraocular lens or ocular bandage consists of a release system or a hydrogel as described above.
    A sixth aspect of the invention relates to the use of the release system, contact lens, eye insert, intraocular lens or ocular bandage as described above for the preparation of a medicament.
    A particular embodiment refers to the use of the release system, contact lens, eye insert, intraocular lens or ocular bandage as described above for the preparation of a medicament for the treatment or prevention of allergic conjunctivitis.
    Another particular embodiment relates to the release system, contact lens, eye insert, intraocular lens or ocular bandage as described above for use as a medicine.
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    ocular, intraocular lens or ocular bandage as described above for use in the treatment or prevention of allergic conjunctivitis. 5 Description of the figures
    Figure 1 shows the degree of swelling of the hydrogels prepared in example 1, when they come in contact with water (dark bars) and when they come in contact with artificial tear fluid (light colored bars).
    Figure 2 shows the result of the HET-CAM test described in example 2, where
    10 the figure on the left is the negative control, the figure on the center is the result with hydrogel 1, and the figure on the right is the positive control.
    Figure 3 shows the load of olopatadine, the influence of functional monomers and the influence of the imprinting process.
    Figure 4 shows the olopatadine assignment profiles, as described in the
    Example 4, where profiles for hydrogels synthesized in the absence of drug (non-imprinted) are indicated by dashed lines, and profiles for hydrogels synthesized in the presence of drug (imprinted) are indicated with continuous strokes.
    Figure 5 shows the histamine levels (left Y axis) recorded in a mast cell culture after preincubation with a olopatadine solution
    20 followed by exposure to anti-IgE. The rhombuses indicate the amount of olopatadine released (Y axis on the right) from the hydrogels (X axis) at 4 hours. Statistically significant differences: "a" denotes differences with respect to the negative control (unstimulated mast cells) and "b" denotes differences with respect to the positive control (stimulated mast cells pre-incubated with artificial lacrimal fluid without olopatadine).
    Figure 6 shows the olopatadine release profiles, as described in example 4, during the first 8 hours where the profiles for hydrogels synthesized in the absence of drug (non-imprinted) are indicated by dashed lines, and the profiles for hydrogels synthesized in the presence of drug (imprinted) they are indicated with continuous strokes.
    image8 Detailed description of the invention
    The term "aryl" in the present invention refers to an aromatic hydrocarbon group with 6 to 10 carbon atoms, such as phenyl, naphthyl, optionally substituted with one or more substituents selected from the group consisting of a halogen atom, a group alkyl, an alkoxy group, an alkene group, or a nitro group.
    The term "benzyl" in the present invention refers to an aromatic hydrocarbon group of 6 carbon atoms that is attached to the rest of the molecule by a methylene group (-CH2-).
    In the present invention the term "olopatadine", the term "azelastine" and the term "ketotifen" refer to said compounds in their free base form, in the form of salt, hydrate, solvate and any of its geometric isomers, enantiomers or diastereomers, interchangeably. In particular they refer to the compounds as a free base, or to the compounds in the form of hydrochloride, hydrobromide, sulfate, nitrate, and also include organic salts such as acetate, maleate, oxalate, fumarate, hydrogen fumarate, succinate, etc. In particular, "olopatadine" refers to the free base, hydrochloride and any of its geometric isomers Z, E and mixtures, interchangeably. In particular, the term "azelastine" refers to the free base and hydrochloride, interchangeably. In particular, the term "ketotifen" refers to the free base and fumarate, interchangeably.
    The present invention provides a hydrogel that is useful in the preparation of optical devices such as contact lenses, eye inserts, intraocular lenses or ocular bandages, due to the optical and physical-chemical properties it possesses, such as oxygen permeability, optical transmittance and water swelling, as described in example 2 and figure 1. These features are especially suitable for application as soft contact lenses.
    A necessary property for the hydrogels of the invention to be useful in its application as soft contact lenses is the degree of swelling, which is studied in example 1 with water and with artificial tear fluid. In said example, hydrogels 17 and 18 of Table 1, which have as a single functional monomer a monomer with a benzyl group, have a swelling degree of less than 40%; while if the functional monomer with a benzyl group is polymerized with one or a functional one, it has an amido group as in the case of hydrogels 23 and 24, the degree of swelling exceeds 40%.
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    The release systems of the invention are specially designed to be useful in optical devices. Thus, the hydrogels of the invention comprise methacrylic and acrylic monomers, which are widely used in contact lenses. However, these polymerized monomers charge active ingredients but in an amount insufficient to have therapeutic effect (see example 5.3, hydrogel 1).
    The authors of the present invention have designed release systems that in addition to being suitable for optical devices, are capable of loading antihistamine active ingredients efficiently, in particular active ingredients indicated for the prevention or treatment of allergic conjunctivitis such as olopatadine, ketotifen or azelastine, in particular olopatadine. Said antihistamine active ingredients bind to active sites of the H1 receptor, which belongs to the family of G-protein coupled receptors (GPCR). In addition, in the ligand there is a phosphate ion that acts as a binding site for anions at the receptor entrance and is not displaced by these interactions (Shimamura T. Structure of the human histamine H1 receptor complex with doxepin. Nature 475: 65 -70, 2011).
    Thus, the authors of the present invention have selected functional monomers that once polymerized form a hydrogel that mimics the H1 receptor and has efficient binding points for antihistamine active ingredients. The selection of functional monomers is such that the resulting hydrogels, in addition, must have the appropriate optical characteristics to be present in optical devices as set forth above. In particular, the release systems of the invention are suitable for loading olopatadine, which is characterized by having a carboxylic acid group that extends its binding with the receptor into the extracellular space and interacts with lysine 191 and tyrosine 108.
    Thus, in a first aspect, the invention relates to a hydrogel comprising at least one methacrylic monomer, at least one acrylic monomer, a crosslinking agent, and at least one functional monomer selected from those in the group consisting of a monomer with at least one aryl group, a monomer with at least one amido group and a monomer with at least one acidic group with a pKa of less than 4, with the proviso that if the selected functional monomer has at least one aryl group then the hydrogel comprises in addition at least one of the other functional monomers.
    image10
    The highest degree of swelling in artificial tear fluid is achieved when the hydrogel of the invention has a single functional monomer, said functional monomer is a monomer with at least one amido group, such as acrylamide (hydrogels 3, 4, 23 and 24, figure one); or when functional monomers are selected from which at least one functional monomer has an aryl group, such as benzylmethacrylate, and at least one monomer has an acidic group with a pKa of less than 4, such as 2-acrylamido-2-methyl-1-propanesulfonic acid (hydrogels 25, 26A and 26B, figure 1).
    Thus, in a particular embodiment, the functional monomer in the hydrogel of the invention is a functional monomer with at least one amido group. In another particular embodiment, the functional monomers in the hydrogel of the invention are a functional monomer with at least one aryl group and a functional monomer with at least one acidic group with a pKa of less than 4.
    The release system of the invention makes it possible to load antihistamine active ingredients, such as olopatadine, ketotifen or azelastine, in an amount sufficient so that, when transferred, it induces an antihistamine effect. As can be seen in Figure 3, the amount of olopatadine loaded in the hydrogels of the invention is greater than 20 mg per gram of dry hydrogel after 5 days of incubation; and is greater than 40 mg / g of dry hydrogel after 20 days of incubation. The highest olopatadine load was achieved when a functional monomer with at least one acidic group with a pKa of less than 4 was present in the hydrogel. In particular, when the three types of functional monomers selected in the invention were present in the hydrogel.
    Thus, in a particular embodiment the functional monomer in the hydrogel of the invention is a monomer with at least one acidic group with a pKa of less than 4. In another particular embodiment, the functional monomers in the hydrogel of the invention are a monomer with at least one acid group with a pKa less than 4.
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    In a particular embodiment the functional monomer possessing at least one aryl group is the benzylmethacrylate monomer. In a particular embodiment the functional monomer possessing at least one amido group is the acrylamide monomer. In a particular embodiment, in the functional monomer having at least one acidic group with a pKa of less than 4, said acidic group is selected from sulfonic, sulphonate, phosphate, phosphonate and carboxylic acid present in a monomer that is an alpha or beta amino acid. . In a more particular embodiment, the monomer having at least one acidic group with a pKa of less than 4 is 2-acrylamido-2-methyl-1-propanesulfonic acid.
    A second aspect of the invention relates to a process for obtaining the hydrogel of the invention as described above, which comprises the polymerization of a mixture of monomers, said mixture of monomers comprises at least one methacrylic monomer, at least one monomer acrylic, a crosslinking agent, and at least one functional monomer selected from those in the group consisting of a monomer with at least one aryl group, a monomer with at least one amido group and a monomer with at least one acid group with a pKa less than 4, and optionally an active ingredient selected from olopatadine, ketotifen and azelastine is present during polymerization.
    In a particular embodiment, the invention relates to a process for obtaining the hydrogel of the invention as described above, which comprises the polymerization of a mixture of monomers, said mixture of monomers comprises at least one methacrylic monomer, at least one Acrylic monomer, a crosslinking agent, a monomer with at least one aryl group and a monomer with at least one acidic group with a pKa of less than 4, and optionally an antihistamine active ingredient is present during polymerization.
    In a particular embodiment, the invention relates to a process for obtaining the hydrogel of the invention as described above, which comprises the polymerization of a mixture of monomers, said mixture of monomers comprises at least one methacrylic monomer, at least one Acrylic monomer, a crosslinking agent, and a monomer with at least one acidic group with a pKa of less than 4, and optionally an antihistamine active ingredient is present during polymerization.
    image12
    In a more particular embodiment, the invention relates to a process for obtaining the hydrogel of the invention as described above, which comprises the polymerization of a mixture of monomers, said mixture of monomers comprises at least one methacrylic monomer, at least an acrylic monomer, a crosslinking agent, benzylmethacrylate and 2-acrylamido-2-methyl-1-propane sulfonic acid, and optionally an antihistamine active ingredient is present during polymerization.
    In a more particular embodiment, the invention relates to a process for obtaining the hydrogel of the invention as described above, which comprises the polymerization of a mixture of monomers, said mixture of monomers comprises 2-hydroxyethyl methacrylate, acrylic acid, a crosslinking agent, benzylmethacrylate and 2-acrylamido-2-methyl-1-propanesulfonic acid, and optionally an antihistamine active ingredient is present during polymerization.
    In a particular embodiment, the invention relates to a process for obtaining the release systems of the invention comprising
    a) the polymerization of a mixture of monomers, said mixture of monomers comprises at least one methacrylic monomer, at least one acrylic monomer, a crosslinking agent, and at least one functional monomer selected from those in the group consisting of a monomer with at minus an aryl group, a monomer with at least one amido group and a monomer with at least one acidic group with a pKa of less than 4,
    b) incubation of a hydrogel obtained in step a) in a solution of an active ingredient selected from olopatadine, ketotifen and azelastine.
    When an active ingredient selected from olopatadine, ketotifen and azelastine is present in step a), then the method comprises an additional intermediate stage between stages a) and b) comprising washing the hydrogels obtained in step a).
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    In a particular embodiment, the invention relates to a process for obtaining the release systems of the invention comprising
    a ') polymerization of a monomer mixture, said monomer mixture comprises at least one methacrylic monomer, at least one acrylic monomer, a crosslinking agent, and at least one functional monomer selected from those in the group consisting of a monomer with at less an aryl group, a monomer with at least one amido group and a monomer with at least one acidic group with a pKa of less than 4, in the presence of an active ingredient selected from olopatadine, ketotifen and azelastine,
    b ’) washing of the hydrogel resulting from stage a’),
    c ’) incubation of the hydrogel resulting from stage b’) in a solution of an active substance selected from olopatadine, ketotifen and azelastine.
    A further aspect of the invention relates to the release system obtainable by the method described above.
    In a particular embodiment, the methacrylic monomers are selected from 2-hydroxyethyl methacrylate, 1- (tristrimethylsiloxysilylpropyl) -methacrylate, methylmethacrylate, methacrylic acid, aminopropyl methacrylate and cyclohexyl methacrylate. In a more particular embodiment, the methacrylic monomer is 2-hydroxyethyl methacrylate.
    In a particular embodiment, the acrylic monomers are selected from acrylic acid and fluoro-siloxane acrylate. In a more particular embodiment, the acrylic monomer is acrylic acid.
    In a particular embodiment, the crosslinking agent 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 A ethoxylate diacrylate, Di (ethylene glycol, diacrylate Neopentyl glycol diacrylate, Poly (ethylene glycol) diacrylate, Poly (propylene glycol) diacrylate, Propylene glycol glycollate diacrylate, Tetra (ethylene glycol) diacrylate, 1,3-Butanediol dimethacrylate, 1,4-Butanediol dimethacrylate dimethacrylate dimethyl acrylate , 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 tilen glycol) dimethacrylate, Poly (propylene glycol) dimethacrylate, Tetraethylene glycol dimethacrylate, Tri (ethylene glycol) dimethacrylate, Triethylene glycol dimethacrylate, Poly (lauryl methacrylate-co-ethylene glycol dimethacrylate-dimethyl methacrylate) . In a more particular embodiment, the crosslinking agent is ethylene glycol dimethacrylate.
    image14
    In a particular embodiment, in the functional monomer having at least one acidic group with a pKa of less than 4, said acidic group is selected from sulfonate, sulfonic, phosphate, phosphonate and carboxylic present in an alpha or beta amino acid.
    In a particular embodiment, in the hydrogel of the invention the functional monomer possessing at least one aryl group is selected from benzyl methacrylate, benzyl acrylate, o-nitrobenzyl methacrylate, benzidyl methacrylate, N-benzylmethacrylamide and phenyl acrylate. In a particular embodiment the functional monomer possessing at least one aryl group is the benzylmethacrylate monomer.
    In a particular embodiment, in the hydrogel of the invention the functional monomer possessing at least one amido group is selected from acrylamido, methacrylamide, N- (noctadecyl) acrylamide, N-benzylmethacrylamide, N, N-diethylacrylamide, N, N-dimethyl acrylamide, N, N-dimethylmethacrylamido, N, N-diphenyl N-ethylmethacrylamido, N- (tertoctyl) acrylamido, N-iso-propylacrylamido, N, N'-Cystaminebisacrylamido, N, N'diallylacrylamide and N- (2-hydroxypropyl) methacrylamido In a particular embodiment the functional monomer possessing at least one amido group is the acrylamide monomer. In a more particular embodiment, the monomer having at least one acidic group with a pKa of less than 4 is 2-acrylamido-2-methyl-1-propanesulfonic acid.
    In a particular embodiment, the polymerization takes place in the presence of a radical initiator. In a particular embodiment, the radical initiator is selected from 2,2'-azobis (2-methylpropionitrile), 2,2'-azobis (2-methylpropionamidine) dihydrochloride, 1,1'-azobis (cyclohexanecarbonitrile), 4, 4'-azobis (4-cyanovaleric acid), 2-azidoethyl 2-bromoisobutyrate, bis [2- (2'bromoisobutyryloxy) ethyl] disulfide, 2-bromoisobutyric anhydride, dodeci 2bromoisobutyrate, polyethylene glycol bi (2-bromoisobutyrate), propargylbutyrate Bromoisobutyrate, 1- [4- (2-hydroxyethoxy) -phenyl] -2-hydroxy-2-methyl-1-propane-1-one, 2-methylbenzophenone, 3-methylbenzophenone, and 4-methylbenzophenone.
    image15
    In a particular embodiment, the polymerization takes place by application of heat or application of light.
    In a particular embodiment, methacrylic monomers are present in the polymerization mixture in a proportion of between 81% and 97 mol% with respect to the total monomers in the mixture.
    In a particular embodiment, the acrylic monomers are present in the polymerization mixture in a proportion of between 2.5% and 5.3 mol% with respect to the total of the
    10 monomers in the mixture.
    In a particular embodiment, the functional monomers with at least one aryl group are present in the polymerization mixture in a proportion between 0% and 5.7 mol% with respect to the total monomers in the mixture.
    In a particular embodiment, the functional monomers with at least one amido group
    15 are present in the polymerization mixture in a proportion between 0% and 5.7 mol% with respect to the total monomers in the mixture.
    In a particular embodiment, the functional monomers with at least one acidic group with a pKa of less than 4 are present in the polymerization mixture in a proportion of between 0% and 2.8 mol% with respect to the total monomers in the
    20 mix
    Another aspect of the invention relates to the hydrogel obtainable by the process described above.
    In a particular embodiment, the invention relates to a hydrogel as described above, obtainable by a process comprising polymerization.
    25 of a mixture of monomers, said mixture of monomers comprises at least one methacrylic monomer, at least one acrylic monomer, a crosslinking agent, and a monomer with at least one acidic group with a pKa of less than 4, and optionally an antihistamine active ingredient It is present during polymerization.
    image16
    above, obtainable by a process comprising the polymerization of a mixture of monomers, said mixture of monomers comprises at least one methacrylic monomer, at least one acrylic monomer, a crosslinking agent, a monomer with at least one aryl group and a monomer with at less an acid group with a pKa of less than 4, and optionally an antihistamine active ingredient is present during polymerization.
    In a more particular embodiment, the invention relates to a hydrogel as described above, obtainable by a process comprising the polymerization of a mixture of monomers, said mixture of monomers comprises at least one methacrylic monomer, at least one acrylic monomer, a crosslinking agent, benzylmethacrylate and 2-acrylamido-2-methyl-1-propanesulfonic acid, and optionally an antihistamine active ingredient is present during polymerization.
    In a more particular embodiment, the invention relates to a hydrogel as described above, obtainable by a process comprising the polymerization of a mixture of monomers, said mixture of monomers comprises 2-hydroxyethyl methacrylate, acrylic acid, a crosslinking agent, Benzylmethacrylate and 2-acrylamido-2-methyl-1-propanesulfonic acid, and optionally an antihistamine active ingredient is present during polymerization.
    A fourth aspect of the invention relates to a release system comprising a hydrogel, as described above, and an antihistamine active ingredient.
    In a particular embodiment, the antihistamine active ingredient is selected from olopatadine, ketotifen and azelastine.
    The release system of the invention allows an antihistamine active ingredient to be loaded efficiently and released in a controlled manner causing a therapeutic effect. Figure 4 shows that hydrogels prepared only with a methacrylic monomer, such as hydrogel 1 or 2, release 10% olopatadine within the first 24 hours, which is insufficient in terms of efficacy. Hydrogels in which the only functional monomer is a monomer with at least one benzyl group (hydrogels 17 and 18, figure 4) have a behavior similar to that of the greatest amount and with an almost constant velocity during the first 8 hours, avoiding a peak Initial assignment (burst) (example 4, figure 6). The best results for the transfer of olopatadine are obtained when the hydrogels of the invention comprise a monomer with at least one acidic group with a pKa lower than 4. The hydrogel 25 yields up to 150 mg of olopatadine / g of hydrogel in 48 hours.
    image17
    In a particular embodiment, the release system of the invention comprises a hydrogel as defined above, wherein the only functional monomer of said hydrogel is a monomer with at least one acidic group with a pKa of less than 4.
    In a particular embodiment, the release system of the invention comprises a hydrogel as defined above, wherein the functional monomers of said hydrogel are a monomer with at least one aryl group and a monomer with at least one acidic group with a lower pKa to 4. In a more particular embodiment, the release system of the invention comprises a hydrogel as defined above, wherein the functional monomers of said hydrogel are benzylmethacrylate and 2-acrylamido-2-methyl-1-propanesulfonic acid.
    In another particular embodiment, the release system of the invention comprises a hydrogel as defined above, wherein the functional monomers of said hydrogel are a functional monomer with at least one aryl group, a functional monomer with at least one amido group and a functional monomer with at least one acidic group with a pKa of less than 4.
    A fifth aspect of the invention relates to a contact lens, ocular insert, intraocular lens or ocular bandage comprising a release system or a hydrogel as described above.
    In particular, the contact lenses of the invention are soft contact lenses. The contact lenses of the invention provide advantages over the traditional application of antihistamine active ingredients in the form of drops (eye drops). In comparison, conventional olopatadine drops provide between 0.02 and 0.04 milligrams in the eye at each application, and administration should be repeated every 6 or 12 hours; while soft contact lenses prepared from the release systems of the present invention (approximate weight of 30 mg) can cover a means that each lens contains a sufficient amount of olopatadine for at least one week of treatment, which is the minimum time for allergic conjunctivitis symptoms to revert in a patient (M. Brodsky, Allergic conjunctivitis and contact lenses: experience with olopatadine hydrochloride 0.1%, Therapy Acta Ophthalmol. Scand., 2000: 78: 56-59).
    image18
    In a particular embodiment, the invention relates to a soft contact lens comprising a hydrogel or a release system as described above. In a more particular embodiment, the active ingredient in the release system of the invention is olopatadine. In a particular embodiment, the soft contact lenses of the invention comprise olopatadine.
    In a particular embodiment, the invention relates to a contact lens, eye insert, intraocular lens or ocular bandage comprising a release system for administration of olopatadine comprising a hydrogel, said hydrogel comprises at least one methacrylic monomer, at least an acrylic monomer, a crosslinking agent, and a monomer with at least one amido group.
    In a particular embodiment, the invention relates to a contact lens, eye insert, intraocular lens or ocular bandage comprising a release system for administration of olopatadine comprising a hydrogel, said hydrogel comprises at least one methacrylic monomer, at least an acrylic monomer, a crosslinking agent, a monomer with an aryl group and a monomer with an acid group with a pKa of less than 4. In a more particular embodiment, the invention relates to a contact lens, eye insert, intraocular lens or Eye dressing comprising a release system for administration of olopatadine comprising a hydrogel, said hydrogel comprises at least one methacrylic monomer, at least one acrylic monomer, a crosslinking agent, benzyl methacrylate and 2-acrylamido-2-methyl-1-propane sulfonic acid.
    In a particular embodiment, the invention relates to a contact lens, eye insert, intraocular lens or ocular bandage comprising a release system for administration of olopatadine comprising a hydrogel, said hydrogel comprises at least one methacrylic monomer, at least an acrylic monomer, a crosslinking agent, a monomer with at least one aryl group, a monomer with at least one amido group and a monomer with at least one acidic group with a pKa less than 4. In a more particular embodiment, the invention is refers to a contact lens, eye insert or ocular bandage comprising a release system for administration of olopatadine comprising a hydrogel, said hydrogel comprises at least one methacrylic monomer, at least one acrylic monomer, a crosslinking agent, benzylmethacrylate, acrylamide and 2-acrylamido-2-methyl-1-propanesulfonic acid.
    image19
    The contact lens, eye insert, intraocular lens or ocular bandage of the invention is useful in a method for preventing or treating allergic conjunctivitis, more particularly seasonal allergic conjunctivitis.
    Thus, a sixth aspect of the invention relates to the use of the release system, contact lens, eye insert, intraocular lens or ocular bandage as described above for the preparation of a medicament.
    A particular embodiment refers to the use of the release system, contact lens, eye insert, intraocular lens or ocular bandage as described above for the preparation of a medicament for the treatment or prevention of allergic conjunctivitis.
    Another particular embodiment relates to the release system, contact lens, eye insert, intraocular lens or ocular bandage as described above for use as a medicine.
    A particular embodiment relates to the release system, contact lens, eye insert, intraocular lens or ocular bandage as described above for use in the treatment or prevention of allergic conjunctivitis.
    In a particular embodiment, the invention relates to the use of the release system described above, comprising olopatadine, for the preparation of a medicament for the prevention or treatment of allergic conjunctivitis.
    In a particular embodiment, the hydrogel of the invention as described above for use to prevent or treat allergic conjunctivitis, more particularly seasonal allergic conjunctivitis.
    image20
    The following are examples that illustrate the invention and should not be considered as a limitation thereof. Examples
    5 1. Synthesis of hydrogels 1.1. materials
    2-Hydroxyethyl methacrylate (HEMA) ophthalmic grade, acrylic acid (AAc) and acrylamide (AAm) from Merck (Germany). 2-Acrylamido-2-methyl-1-propane sulfonic acid (AMPSA), dimethyl sulfoxide (DMSO), ethylene glycol dimethacrylate 10 (EGDMA) and dichlorodimethylsilane from Sigma-Aldrich (St. Louis MO, USA). 2,2’azobis (2-methylpropionitrile) (AIBN) from Acros Organics (Thermo Fisher Scientific, Geel, Belgium). Benzylmethacrylate (BzMA) from Polysciences (Germany) and olopatadine hydrochloride from Ragactives (Spain) (Figure 1). Purified water obtained by reverse osmosis (resistivity> 18.2 MΩ cm; MilliQ®, Millipore, Spain). Tear fluid
    15 artificial prepared with 6.78 g / L NaCl, 2.18 g / L NaHCO3, 1.38 g / L KCl, 0.084 g / L CaCl2 · 2H2O (pH adjusted to 8). PH 5 acetate buffer prepared with 0.2 M sodium acetate and 0.2 M acetic acid. All other reagents were analytical grade. 1.2. Method of preparation of the hydrogels
    20 AAc (200 or 400 mM), AAm (200 or 400 mM), AMPSA (200 mM) and / or BzMA (400 mM), DMSO (1 mL) and the EGDMA crosslinking agent (200 or 400 mM) were mixed with HEMA (4 mL), as indicated in Table 1. AIBN (10 mM) was incorporated as a polymerization initiator. Each monomer mixture was injected into a mold consisting of two glass plates (previously treated with dichlorodimethylsilane)
    25 separated by a silicone frame (0.4 mm thick). The polymerization was carried out at 50 ° C for 12 hours and was completed at 70 ° C for 24 hours. Imprinted hydrogels were similarly prepared by adding olopatadine hydrochloride (50 or 100 mM) to the monomer mixtures. The hydrogels were removed from the molds, washed in boiling water for 5 minutes and cut into 10 mm diameter discs. The
    30 discs were kept in water for 5 days, in 0.9% NaCl for 24 hours and in water for another 3 days. Next, the discs were immersed in acetate buffer. Table 1. Composition of imprinted hydrogels (hydrogels with even numbers) and unprinted hydrogels (hydrogels with odd numbers). 1 mL of DMSO and 0.00821 g of AIBN were incorporated into all monomer mixtures.
    image21
    Hydrogel HEMA (mL)Drug (g)AAc (µL)BzMA (µL)AAm (g)AMPSA (g)EGDMA (µL)
    one 400000188.6
    3 4068.600.0720188.6
    17 4068.6338.900188.6
    2. 3 40137.200.1440188.6
    25 4068.6338.900.207188.6
    29 4068.6338.90.0720.207377.2
    2 40.18690000188.6
    44 0.186968.600.0720188.6
    18 40.186968.6338.900188.6
    24 40.1869137.200.1440188.6
    26A 40.186968.6338.900.207188.6
    26B 40.093568.6338.900.207188.6
    30A 40.186968.6338.90.0720.207377.2
    30B 40.093568.6338.90.0720.207377.2
    10 2. Characterization of the hydrogels The methods used in the characterization of the prepared hydrogels and the results are shown below. 2.1 Differential scanning calorimetry (DSC)
    15 DSC analyzes were performed on a DSC Q-100 (TA Instruments, USA) equipped with a cooling system. Fragments of dry discs (4-6 mg) were placed in aluminum capsules and subjected to heating to 150 ° C, 5 heating was maintained up to 300 ° C at a rate of 10 ° C / min. Nitrogen (50 mL / min) was used as the purge gas.
    image22
    5 2.2 Transparency
    Hydrated discs were placed on the inner wall of a quartz cuvette filled with water and the transmittance between 190 and 700 nm was recorded on a UV-Vis spectrophotometer (Agilent 8453, Germany). The 600 nm transmittance of all prepared and swollen hydrogels was superior
    10 to 97% indicating its excellent optical transparency (table 2).
    2.3. Oxygen permeability
    The oxygen permeability of hydrogel disks previously hydrated in 0.9% NaCl was measured using a Createch model 210T perimeter (Rehder Development 15 Co., Castro Valley, CA, USA) at room temperature and 100% relative humidity.
    Table 2. This table shows the results obtained by using the described methods of differential scanning calorimetry, transparency and oxygen permeability.
    Hydrogel Tg (ºC)Transmittance (%)O2 permeability (cm2 / s) (mL O2 / mm Hg) x1011
    one 122.299.69.23
    3 122.198.910.20
    17 119.298.87.50
    2. 3 122.597.97.73
    25 123.897.411.40
    29 134.999.17.14
    2 120.299.913.70
    4 121.099.714.40
    18 118.898.64.32
    24 122.297.411.90
    image23
    2.4. Swelling Pre-weighed dry discs (Ws) were immersed in water or tear fluid and the weight gain (Wd) was monitored. The degree of swelling was calculated as
    5 continues: Sw = (Ws - Wd) x 100 / Wd Ec. (1) All hydrogels swelled rapidly in the first three hours and approached equilibrium after 8 hours, both when swollen with water and with tear fluid artificial.
    10 The swelling results of the hydrogels prepared in example 1 are shown in Figure 1. The lowest values were obtained with hydrogels 17 and 18 prepared with BzMA as the only functional monomer; while the highest swelling values were obtained for hydrogels 23 and 25, particularly when artificial tear fluid was used.
    fifteen 2.5 HET-CAM test
    The biocompatibility of hydrogels was evaluated using the HET-CAM [US National Toxicoloy Program, Evaluation of In Vitro Ocular Test Methods. http://ntp.niehs.nih.gov/pubhealth/evalatm/test-method-evaluations/ocular/in-vitro-test
    20 methods / index.html, May 2015]. Fertilized chicken eggs (Avirojo, Pontevedra, Spain) were incubated at 37 ° C and 60% relative humidity for 9 days. Next, the air chamber of the upper part of the egg was cut with the aid of a circular blade, the inner membrane was hydrated with 0.9% NaCl for 30 min and then removed to expose the chorioallantoid membrane. Hydrogel discs previously hydrated in
    25 0.9% NaCl were kept in contact with the chorioallantoid membrane for 5 min and the appearance of hemorrhage (H), lysis (L) or coagulation (C) was monitored. As negative and positive controls, 0.9% NaCl and 0.1N NaOH solutions were used, respectively. The degree of irritation was calculated using the equation:
    image24

    
     image25 
     image26 

    

    
     image27 
     image28 

    
    ·
     image29 

     image30 
    

    9
    Ec. (2)
    300
    7

    300

    300
    IS
    As a result of this test it was concluded that no hydrogel prepared in example 1 induced bleeding, lysis or coagulation and all behaved as the
    5 negative control (0.9% NaCl). Thus, IS is equal to 0. On the other hand, the positive control (0.1 N NaOH) had an IS value of 20. Figure 2 shows the behavior of hydrogel 1 and the other hydrogels behaved in the same way.
    3. Incorporation of olopatadine
    10 Dry discs were immersed in drug solutions (0.2 or 10 mg / mL; 20 mL) at room temperature. At pre-established times, samples (500 µL) were removed from the drug solution and the olopatadine concentration was determined by HPLC (717 plus Autosampler and 600 Controller, Waters, USA) equipped with a diode network detector and an Agilent column ZORBAX SB-C18 (3.5 µm, 4.6x150 mm). Mobile phase
    15 was water: 30:70 acetonitrile at a flow of 1 mL / min. 20 µL aliquots were injected and the absorbance at 236 nm was recorded. The retention time was 2.3 min. Functional monomer factor (FMF) was calculated by dividing the total amount of olopatadine charged by gels prepared with functional monomer by the amount of drug charged by the HEMA hydrogel without functional monomers (Hydrogel 1).
    The imprinting factor (IF) was calculated as the ratio between the amount of drug charged by each imprinted hydrogel and the amount of drug charged by the corresponding non-imprinted hydrogel. The partition coefficient of olopatadine between the polymer network and water, KN / W, was estimated for each hydrogel from the total amount of olopatadine incorporated
    25 using the expression (Kim SW, Bae YH, Okano T. Hydrogels: swelling, drug loading, and release. Pharm. Res. 9: 283-290, 1992): Loaded Olopatadine (total) = [(Vs + KN / W · Vp) / Wp] · C0 Ec. (3) where Vs is the volume of water in the hydrogel, Vp is the volume of the dry hydrogel, Wp is the weight of the dry hydrogel and C0 the concentration of drug in the loading solution.
    30 When the discs were immersed in the 0.2 mg / mL concentration olopatadine solution, all discs quickly captured olopatadine during the first 24 hours, followed by sustained incorporation in the time that lasted for
    image31
    2) were able to incorporate 30 mg / g in the first 5 days and up to 38 mg / g when they reached equilibrium. The amount of olopatadine that these HEMA discs were able to accommodate in the aqueous phase was 0.1 mg / g, which means that the coefficient of olopatadine distribution between the polymer network and water is 188 (table 3). The amount of olopatadine charged by hydrogel 1 is in accordance with the published data for Acuvue (J&J) submerged in Patanol (0.1% ophthalmic solution olopatadine hydrochloride) (NL Dassanayake, TC Carey, GR Owen. A Laboratory Model to Determine the Uptake and Release of Olopatadine by Soft Contact Lenses.
    10 Ophthalmol. Scand. 2000: 78: 16–17). Hydrogels that combine AAc, BzMA and AMPSA (hydrogel 25) load olopatadine faster and in an amount twice as large as hydrogels prepared only with HEMA (Figure 3). Table 3. Load data of olopatadine and partition coefficient of olopatadine between
    15 polymer network and water.
    Hydrogel Olopatadine incorporated (mg / g)KN / W
    one 38.51188
    3 39.34192
    17 52.05255
    2. 3 52.27255
    25 79.42389
    29 87.22427
    2 37.25182
    4 46.39227
    18 41.87205
    24 50.64248
    26A 59.51291
    26B 69.15339
    30A 56.70277
    30B 85.64420
    image32
    4. Assignment of olopatadine
    The discs loaded with drug by immersion in solutions of concentration 0.2 mg / mL were immersed in 20 mL of artificial tear fluid at 37 ° C and kept under gentle agitation (25 rpm). The discs loaded with drug by immersion in solutions of 10 mg / mL concentration were immersed in 2 mL of artificial tear fluid at 37 ° C and kept under gentle agitation (25 rpm). At different time intervals, samples (500 µL) of the transfer medium were taken and the drug concentration was assessed by HPLC, as indicated in the previous section. Samples were replenished with fresh medium. The transfer data of olopatadine from the hydrogels prepared in example 1, are collected in Figure 4 in which the time intervals in which the samples were taken are indicated.
    5. Cytocompatibility and evaluation of antihistamine activity
    5.1. Cells
    MC / 9 cells (murine liver mast cells, ATCC® CRL-8306TM) were maintained in Dulbecco's Modified Eagle medium (DMEM, Sigma-Aldrich, USA) supplemented with 10% fetal bovine serum (FBS, Sigma-Aldrich, USA ), 10% T-STIM with concanavalin A (BD Biosciences, Bedford, USA), 1% antibiotic (104 units / mL penicillin and 104 µg / mL streptomycin; HyClone Laboratories, Thermo Scientific, USA), 0.05 mM 2mercaptoethanol (Sigma- Aldrich, USA) and 2 mM L-glutamine (200 mM; Sigma-Aldrich, USA) at 37 ° C in an environment with 5% CO2 and 90% relative humidity. 5.2. Cytotoxicity
    Cytotoxicity was evaluated using a lactate dehydrogenase kit (Cytotoxicity detection kit (LDH) v. 10, Roche, Germany). The discs were immersed in artificial tear fluid and autoclaved (121 ° C for 20 min). Then, they were placed in 24-well plates containing 105 cells in 1 mL of medium in each well, and incubated for 24 and 48 hours at 37 ° C in an environment with 5% CO2 and 90% relative humidity. The protocol described in the kit instructions was followed to measure LDH. Cells not exposed to the discs were used as a negative control, while cells lysed with Triton X-100 solution were used as a positive control. Blank samples were used as medium
    image33
    culture. The tests were carried out in duplicate and the cytotoxicity was calculated using the following equation: Cytotoxicity (%) = [(Absolute - Negative Abscontrol) / (Absolute Positive - Negative Abscontrol)] x100
    5 Ec. (4) The results obtained showed that the hydrogels of the invention are cytocompatible, with a cytotoxicity level of less than 1% after 24 hours and 48 hours in direct contact.
    10 5.3. Histamine release
    Cells grown in 24-well plates (103 cells / 500 µL) were incubated with IgE (4 µg / mL; BioPorto Diagnostics, Gentofte, Denmark) at 37 ° C and 5% CO2 for 12 h. Next, 500 µL of olopatadine standard solutions (0.25-5 mg / mL in artificial tear fluid) or of transfer medium samples taken at 15 at 4 and 48 hours after the start of the hydrogel assay were added to the cells which had been loaded with the drug by immersion in olopatadine solution of 10 mg / mL concentration (the transfer assays are described in example 4). Positive controls prepared by adding tear fluid without olopatadine to the cells and negative controls prepared with cells that were neither exposed to IgE nor to anti were also tested.
    20 IgE. The cells were incubated for 2 hours. Next, anti-IgE (5 µL / mL; Serotec, BioRad, USA) was incorporated into the cells (minus the negative control) and the plates were incubated for 1 hour. The concentration of histamine in the supernatants (previously diluted 1: 3) was quantified following the instructions of the Histamine EIA kit (SPIbio, bertin pharma, France).
    25 The results obtained are shown in Figure 5, where the inefficiency of hydrogel 1 is observed and it is shown that hydrogels 25 and 26 are the most effective.
    权利要求:
    Claims (21)
    [1]
    image 1
    1. Hydrogel comprising at least one methacrylic monomer, at least one acrylic monomer, a crosslinking agent, and at least one functional monomer selected from those in the group consisting of a monomer with at least one phenyl group, a monomer with at at least one amido group and a monomer with at least one acidic group with a pKa less than 4, with the proviso that if a functional monomer in the hydrogel has at least one phenyl group then the hydrogel further comprises at least one of the other monomers functional.
    [2]
    2. The hydrogel according to claim 1, wherein the functional monomer in the hydrogel is the monomer with at least one acidic group with a pKa of less than 4.
    [3]
    3. The hydrogel according to claim 1, wherein the functional monomers in the hydrogel are a monomer with at least one phenyl group and a monomer with at least one acidic group with a pKa of less than 4.
    4-The hydrogel according to claim 1, wherein the functional monomer in the hydrogel is a functional monomer with at least one amido group.
    [5]
    5. The hydrogel according to claim 1, wherein the functional monomers in the hydrogel are a monomer with at least one phenyl group, a monomer with at least one amido group and a monomer with at least one acid group with a pKa of less than 4 .
    [6]
    6. The hydrogel according to claim 1, wherein the functional monomer in the hydrogel is a monomer with at least one acidic group with a pKa of less than 4.
    [7]
    7. The hydrogel according to claims 1, 3 or 5 wherein the functional monomer possessing at least one phenyl group is the benzyl methacrylate monomer.
    [8]
    8. The hydrogel according to claims 1, 4 or 5, wherein the functional monomer possessing at least one amido group is the acrylamide monomer.
    [9]
    9. The hydrogel according to claims 1, 2, 3, 5 or 6, wherein the acid group with a pKa of less than 4 is selected from sulfonate, sulphonic, phosphate, phosphonate and carboxylic acid present in an alpha or beta amino acid.
    image2
    [10]
    10. The hydrogel according to claim 1, 2, 3, 5 or 6, wherein the monomer having at least one acidic group with a pKa of less than 4 is 2-acrylamido-2-methyl-1-propane sulfonic acid.
    [11]
    11. Method for obtaining the hydrogel according to claims 1-10, which comprises the polymerization of a mixture of monomers, said mixture of monomers comprises at least one methacrylic monomer, at least one acrylic monomer, a crosslinking agent, and at least a functional monomer selected from those of the group consisting of a monomer with at least one phenyl group, a monomer with at least one amido group and a monomer with at least one acidic group with a pKa of less than 4, and optionally an active ingredient Antihistamine is present during polymerization.
    [12]
    12. Method according to claim 11, wherein the polymerization takes place in the presence of a radical initiator.
    [13]
    13. Process according to claim 11, wherein the methacrylic monomers are present in the polymerization mixture in a proportion of between 81% and 97 mol% with respect to the total monomers in the mixture.
    [14]
    14. Process according to claim 11, wherein the acrylic monomers are present in the polymerization mixture in a proportion between 2.5% and 5.3 mol% with respect to the total monomers in the mixture.
    [15]
    15. Process according to claim 11, wherein the functional monomers with at least one phenyl group are present in the polymerization mixture in a proportion of between 0% and 5.7 mol% with respect to the total monomers in the mixture.
    [16]
    16. Process according to claim 11, wherein the functional monomers with at least one amido group are present in the polymerization mixture in a proportion between 0% and 5.7 mol% with respect to the total monomers in the mixture.
    [17]
    17. Process according to claim 11, wherein the functional monomers with at least one acidic group with a pKa of less than 4 are present in the polymerization mixture in a proportion between 0% and 2.8 mol% with respect to the total monomers in the mix.
    image3
    [18]
    18. Hydrogel obtainable by the method as described in claims 11-17.
    19. Release system comprising a hydrogel, according to any of the preceding claims, and an antihistamine active ingredient.
    [20]
    20.-Release system according to claim 19, wherein the active ingredient is olopatadine.
    [21]
    21.-Contact lens, eye insert, intraocular lens or ocular bandage comprising
    10 a release system according to any of claims 19-20 or a hydrogel according to any of claims 1-10 and 18.
    [22]
    22. Soft contact lens comprising a release system according to any of claims 19-20 or a hydrogel according to any of claims 110 and 18.
    23. Use of the release system, according to claims 19-20, of the contact lens, eye insert, intraocular lens or ocular bandage according to claim 21, or of the soft contact lens according to claim 22, for Preparation of a medicine.
    [24]
    24. Use of the release system, according to claims 19-20, of the lens of
    Contact, ocular insert, intraocular lens or ocular bandage according to claim 21, or of the soft contact lens according to claim 22, for the preparation of a medicament for the treatment or prevention of allergic conjunctivitis.
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    同族专利:
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    ES2550105B2|2016-10-07|
    WO2016207460A1|2016-12-29|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US4123407A|1976-11-26|1978-10-31|American Optical Corporation|Hydrophilic contact lens|
    US20120087971A1|2005-02-04|2012-04-12|Auburn University|Contact drug delivery system|
    US20140034519A1|2013-08-02|2014-02-06|Bausch & Lomb Incorporated|Hydrogel monomer mix containing added water|CN106084116A|2016-06-17|2016-11-09|宁波国际材料基因工程研究院有限公司|Hydrogel and preparation method thereof, the application of hydrogel|
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