Ophthalmic devices and methods for making and using them

FIELD: medicine.

SUBSTANCE: invention relates to medicine, particularly to ophthalmology. An ophthalmic device comprises a polymer matrix which in turn contains a biologically active agent and a carrier. The ophthalmic device is applicable for release of the biologically active agent induced by one or more amounts of lachrymal components from the polymer matrix in contact with tears in an eye. A method for making the ophthalmic device involves mixing a matrix-forming substance, the carrier and the biologically active agent, introducing a mixture into a cast for making the device and polymerising the matrix-forming substance in the cast. A method for biologically active agent delivery to a subject involves subject's eye contact with the device wherein one or more amounts of the lachrymal components release the biologically active agent from the device.

EFFECT: invention provides the stable ophthalmic device which is effective to deliver the biologically active agents into patient's eyes for long periods of time.

19 cl, 4 dwg

 

The present invention relates to ophthalmic devices capable of delivering a biologically active substance into the body through the eyes. In particular, the present invention relates to contact lenses capable of delivering a biologically active agent into the eye.

The LEVEL of TECHNOLOGY

System controlled drug delivery or delivery delayed release are well known in the pharmaceutical industry. However, this type of technology is not well known in the industry contact lenses. Attempts to overcome this difficulty by introducing medicines into the finished product. This is carried out by conducting the swelling of the product in a suitable solvent (similar to the extraction step), followed by solubilization of the active compound/ingredient in the same solvent. Once equilibrium has been established containing the entered vehicle product removed from the solvent, let it dry to remove the solvent or solvent exchange with the solvent, which is not collateral entered active connection or not leads to swelling of the polymer matrix. This leads to dry, containing the entered tool product, which is able to highlight the desired compound or ingredient.

There are a number N. the flaws, related methods of introduction. Firstly, it requires a lot of extra steps, which can increase manufacturing costs. Secondly, the efficiency of introducing highly dependent on the parameter solubilize the compound or ingredient introduced into the lens. Thirdly, the product should be dried or subjected to exchange with the solvent. It is difcult for modern packaging systems of lenses, in which the hydrogel contact lens stored in the packaging solution (i.e. in the hydrated state). In addition, after hydration of the product is activated allocation mechanism and put the matter stands. Because hydrogel contact lenses stored in a packaging solution, most, if not all entered the connection was already allocated in the packaging solution.

Therefore, the necessary ophthalmic devices such as contact lenses capable of delivering the active compound in continuous operation for a long period of time. The device proposed in the present invention, secrete one or more biologically active agents, when the device comes into contact with one or more components of tears produced by the eyes. Thus, the components of tears initiate the secretion of biologically active products, which helps regulirovanie the rate of extraction of biologically active products from the device, especially for long periods of time.

BRIEF description of the INVENTION

In the present invention proposed a stable ophthalmic devices, which immobilized and deliver biologically active funds in the eye for long periods of time. The present invention also proposed methods of manufacture and application of ophthalmic devices. The advantages of the present invention will be partially described in the description below, and will partly be obvious from the description or can be understood when performing the embodiments described below. The benefits described below will be implemented and secured by means of the elements and combinations particularly pointed in the appended claims. It should be understood that the above General description and the following detailed description are only examples and are for explanation and not for restriction.

BRIEF DESCRIPTION of DRAWINGS

On the accompanying drawings, which are included in the present description and form part of, illustrated, some embodiments of which are described below.

Figure 1 presents the characteristics of the allocation of hyaluronan with a molecular mass of 50 kDa, 100 kDa and 1 MDA, nelfilcon matrix.

Figure 2 presents the features and advantages of the key selection hyaluronan, having a molecular weight equal to 1 MDA, nelfilcon matrix at various concentrations.

Figure 3 is characterized by thermal stability of the lens, consisting of nelfilcon with hyaluronan.

Figure 4 presents the characteristics of the allotment of Bengal rose from nelfilcon lenses placed in physiological solutions (SFF - phosphate buffered saline) and lysozyme.

DETAILED description of the INVENTION

Below are disclosed and described compounds, compositions and methods proposed in the present invention. It should be understood that embodiments of described below are not limited to specific compounds, methods of synthesis or applications and, of course, may vary. It should also be understood that the terminology used in the present invention for describing particular embodiments only and is not intended to impose restrictions.

In the present invention and in the accompanying claims is used a number of terms that have the following values.

It should be understood that when used in the description and in the accompanying claims, the terms in the singular shall include the terms in the plural, unless the context clearly requires otherwise. So, for example, reference to "a pharmaceutical carrier" includes a decree is the mixture of two or more such carriers, etc.

"Optional" or "optional" means that the subsequent described event or circumstance may or may not be implemented and that the description includes instances where the event or circumstance is and when it is not carried out. For example, the expression "optionally substituted ness. alkyl" means that NISS. the alkyl group may or may not be substituted and that the description includes both unsubstituted ness. alkyl, and substituted ness. alkyl.

If not stated otherwise, all technical and scientific terms used in the present invention, have the same values, which are usually well-known specialist with General training in the field of engineering that applies the present invention. Generally, the nomenclature used in the present invention, and laboratory procedures well known and commonly used in the art. For these procedures using conventional techniques, such as described in the art and various General literature. The nomenclature used in the present invention, and laboratory procedures described below are well known and are commonly used in the art. The present invention uses the terms, which have the following meanings, unless otherwise indicated.

"Hydrogel" means a polymer of vases is in, which can absorb at least 10 wt.% water, when it is fully gidratirovana. Hydrogel substance can be obtained by polymerization or copolymerization of at least one hydrophilic monomer in the presence or in the absence of additional monomers and/or macromeris or by stitching prepolymer.

"Silicone hydrogel" means a hydrogel obtained by copolymerization of polymerizable composition comprising at least one silicon-containing vinyl monomer or at least one silicon-containing macromer or the silicon-containing prepolymer.

"Hydrophilic" as used in the present invention means a material or part which is easier associated with water than lipids.

The term "liquid" as used in the present invention means that the material can flow like a liquid.

"Monomer" means a low molecular weight compound that can be polimerizuet actinic, thermally or chemically. Low molecular weight usually means average molecular weight equal to less than 700 Da.

When used in the present invention "actinic" in relation to the curing or polymerization of the polymerizable composition, or material, or forming a matrix substance means that the curing (for example, cross-linking and/or polymer clay is isace) conduct actinic radiation, such as, for example, ultraviolet (UV) radiation, ionizing radiation (e.g. gamma rays or x-rays, microwave radiation, and other Methods of thermal or actinic curing are well known to the person skilled in the technical field.

"Vinyl monomer" as used in the present invention means having a low molecular weight compound that contains ethylenediamino group and which can be polimerizuet actinic or thermally. Low molecular weight usually means average molecular weight equal to less than 700 Da.

The term "Ethylenediamine group" or "reinstatement group" used in the present invention in a broad sense and includes any group containing at least one group With a=C. Typical ethyleneamine groups include, without imposing restrictions acryloyl, methacryloyl, allyl, vinyl, stroll and the other containing C=C group.

"Hydrophilic vinyl monomer" as used in the present invention, means a vinyl monomer, which is capable of forming a homopolymer that can absorb at least 10 wt.% water, when it is fully gidratirovana. Suitable hydrophilic monomers are, and this list is not limiting, replacement ness. alkyl (C1-C8)-and relate and

-methacrylates, acrylamide, methacrylamide, (NISS. allyl)acrylamide and-methacrylamide, ethoxylated acrylates and methacrylates, replacement (NISS. alkyl)acrylamide and-methacrylamide, replacement ness. alkylvinyl esters, vinylsulfonate sodium, styrelseledamot sodium 2-acrylamide-2-methylpropanesulfonic acid, N-vinylpyrrole, N-vinyl-2-pyrrolidone, 2-vinylacetal, 2-vinyl-4,4'-dialkylimidazolium-5-it, 2 - and 4-vinylpyridine, vinylpyridine carboxylic acid containing only 3 to 5 carbon atoms, amino(NISS. alkyl)- (where the term "amino" also includes Quaternary ammonium), mono(NISS. alkylamino)(NISS. alkyl)and di(NISS. alkylamino)(NISS. alkyl)acrylates and methacrylates, allyl alcohol and the like,

"Hydrophobic vinyl monomer" as used in the present invention means a vinyl monomer, which is capable of forming a homopolymer that can absorb at least 10 wt.% water.

At macromer means having a molecular weight of from medium to high compound or polymer that contains functional groups capable of subsequent polymerization/crosslinking. Medium and high molecular weight usually means average molecular weight of greater than 700 Yes. In one embodiment, macromer contains Ethylenediamine group and it can be polimerizuet and cinichno or thermally.

"Prepolymer" means the original polymer, which can otvetit (for example, sewn and/or polimerizuet) actinic or thermally, or chemically to obtain a crosslinked and/or polymerized polymer having a molecular weight much higher than the original polymer. "Actinic slivaushiesia prepolymer" means the original polymer, which can be made of actinic radiation or by heating to obtain a crosslinked polymer having a molecular weight much higher than the original polymer. In the context of the present invention actinic slivaushiesia prepolymer soluble in the solvent and can be used for the manufacture of finished ophthalmic devices optical quality by casting in the form without the need for subsequent extraction.

I. Ophthalmic devices and methods for their manufacture

In the present invention proposed ophthalmic device comprising a polymer matrix and a bioactive agent, introduced in the polymer matrix, in which the biologically active substance is released from the polymer matrix with one or more components of tears. As discussed in more detail below, the biologically active agent is introduced into the polymer matrix and immobilized. The biologically active agent "are introduced in the polymer mA the matrix by modifying the characteristics of biologically active products and polymer matrix, so biologically active agent and polymer matrix interact with each other. The interaction between the bioactive agent and polymer matrix can occur in different forms. Examples of such interactions include, but are not limited to, covalent and/or non-covalent interactions (e.g. electrostatic, hydrophobic/hydrophobic, dipole-dipole, van der Vaal, the formation of hydrogen bond and the like). Each of these interactions with respect to the selection of biologically active products and polymer matrix are discussed below.

Ophthalmic device proposed in the present invention, stable in relation to the retention (i.e., immobilization) of biologically active products. The device proposed in the present invention, specifically designed for the separation of biologically active products, when they come into contact with one or more components of tears produced by the eyes. Components tears initiate the secretion of biologically active products and provide continuous secretion of biologically active funds in the eye. Thus, the ophthalmic device can be initiated by one or more components of tears for the separation of biologically active products when wearing for long life & energy saving is tion period of time. In a preferred embodiment, the ophthalmic device proposed in this invention, can be stored for long periods of time in the packaging solution without significant leaching of biologically active products from the device (i.e. leaching, which is less than about 20%, less than about 15%, less than about 10%, less than about 8%, preferably less than about 5%, more preferably less than about 2%, even more preferably less than about 1%, calculated on the total number of biologically active products, raspredelenie in the polymeric matrix, after storage for 1 year in the packing solution), placed in the packing solution (e.g. saline solution) in the package.

Caused by component tears allocation of biologically active products can be described by the following example. Contact lenses with raspredeleniya biologically active agent can be impregnated in this volume of buffered saline solution (e.g. phosphate buffered saline) and in this volume of buffered saline solution containing one or more components of tears (for example, including without restrictions lysozyme, lipids, lactoferrin, albumin and the like) for some p is the period of time (for example, 30, 60, or 120 min). Define and compare with each other the concentration of biologically active products leached from the lenses in buffered saline and buffered physiological solution containing one or more components of tears. If the concentration of leached biologically active products in buffered physiological solution containing one or more components of tears, at least 10% higher than the concentration in buffered physiological solution, it is caused by a component of tears allocation of biologically active products of the lens with raspredeleniya it biologically active agent.

The following describes the various components used for the manufacture of ophthalmic devices proposed in the present invention, and methods of making the devices. The present invention also suggested ways of using the device proposed in the present invention, for delivering one or more biologically active agents in the eye of the subject.

A. Polymer matrix

The polymer matrix used in the device proposed in the present invention, is prepared from forming a matrix substance. The term "forming a matrix substance" in the present invention is defined as any link is about, capable of polymerization by methods known in the art. Forming a matrix material may be a monomer, prepolymer, macromolecule, or any combination thereof. It is assumed that forming a matrix substance can be modified to polymerization or polymer matrix can be modified after polymerization, forming a matrix substance. Different types of modification are discussed below.

In one embodiment, forming a matrix substance (composition of prepolymer) includes prepolymer. For example, a liquid composition of prepolymer, including at least one actinic slivaushiesia prepolymer, can be used. Forming a matrix material may be a solution, solvent free liquid or melt. In one embodiment, the liquid composition of prepolymer is an aqueous solution containing at least one actinic slivaushiesia prepolymer. It should be understood that the composition of prepolymer may also include one or more vinyl monomers, one or more vinyl macromeris, and/or one or more crosslinking agents. However, the number of these components should be small, so that the finished ophthalmic device did not contain unacceptable quantities of n is polymerized monomers, macromeris and/or cross-linking reagents. The presence of objectionable quantities of unpolymerized monomers, macromeris and/or cross-linking reagents will require extraction to remove them, which will need additional stages, which are costly and inefficient.

The composition of prepolymer may further contain various components known to a person skilled in the art including, without limit, the polymerization initiators (for example, photoinitiator or thermal initiator), photosensitizers, absorbers of UV radiation, coloring tools, antimicrobial agents, inhibitors, fillers, etc. provided that the devices do not need to enter in the next stage of extraction. Examples of suitable photoinitiators include, but are not limited to, benzoylmethylene ether, 1-hydroxycyclohexyl or Darocure® or types of Irgacure®, for example, Darocure® 1173 or Irgacure® 2959. The number of photoinitiator you can choose within a wide range, you can use the amount up to 0.05 g/g prepolymer and preferably to 0.003 g/g prepolymer. Specialist in the art should know how to choose a suitable photoinitiator.

Other solvents in combination with water can be used for preparation of forming a matrix substance. In the example, an aqueous solution of prepolymer may also include, for example, alcohol such as methanol, ethanol or n - or isopropanol, or a carboxylic acid amide such as N,N-dimethylformamide or dimethylsulfoxide. In one embodiment, an aqueous solution of prepolymer does not contain another solvent. In another embodiment, an aqueous solution of prepolymer does not contain unreacted forming a matrix substance, which would need to be removed after manufacture of the device.

In one embodiment, a solution of at least one actinic slivaushiesia prepolymer can be prepared by dissolving actinic slivaushiesia prepolymer and other components in any suitable solvent known to a person skilled in the art. Examples of suitable solvents are water, alcohols (for example, NISS. the alkanols containing up to 6 carbon atoms, such as ethanol, methanol, propanol, isopropanol), amides of carboxylic acids (e.g., dimethylformamide), dipolar aprotic solvents such as dimethyl sulfoxide or methyl ethyl ketone), ketones (acetone or cyclohexanone), hydrocarbon (e.g. toluene), ethers (for example, THF, dimethoxyethane or dioxane) and halogenated hydrocarbons (e.g. dichloromethane), and any combination thereof.

In one embodiment, the image of the abuser matrix substance includes water-soluble actinic slivaushiesia prepolymer. In another embodiment, forming a matrix substance includes actinic slivaushiesia prepolymer, which is soluble in a mixture of water with organic solvents organic solvent having a melting point below about 85°C, and ophthalmologist are compatible. In various embodiments, implementation preferably actinic slivaushiesia prepolymer was mostly clean (for example, purified by ultrafiltrable to remove most of reagents from prepolymer). Thus, after polymerization, the device does not require subsequent purification, such as, for example, expensive and difficult extraction nedepoliarizutego forming a matrix substance. In addition, the stitching forming a matrix substance can hold in the absence of solvent or in an aqueous solution, does not require a subsequent exchange with the solvent or the stage of hydration.

Examples of actinic slivaushiesia prepolymers include, but are not limited to, soluble in water slivaushiesia prepolymer poly(vinyl alcohol), described in US patents No. 5583163 and 6303687 (which in its entirety is included in the present invention as a reference); soluble in water prepolymer polyurethane with terminal vinyl group as described in published patent application US No. 2004/0082680 (which is flanged in its entirety is included in the present invention as a reference); derivatives of polyvinyl alcohol, polyethylenimine or polyvinyliden, which are disclosed in US patent No. 5849841 (which in its entirety is included in the present invention as a reference);

soluble in water slivaushiesia prepolymer polyurea described in US patent No. 6479587 and in the publication of the patent application US No. 2005/0113549 (which in its entirety is included in the present invention as a reference); slivaushiesia polyacrylamide; slivaushiesia statistical copolymers vinylacetate, methyl methacrylate and co monomer as disclosed in EP 655470 and in US patent No. 5712356; slivaushiesia copolymers vinylacetate, vinyl acetate and vinyl alcohol, which are disclosed in EP 712867 and in US patent No. 5665840; copolymers simple ether-ester with schilawski side chains, which are disclosed in EP 932635 and the US patent No. 6492478; branched prepolymers polyalkyleneglycol-urethane disclosed in EP 958315 and in US patent No. 6165408; the prepolymers polyalkyleneglycol-Tetra(meth)acrylate, disclosed in EP 961941 and in US patent No. 6221303; slivaushiesia the prepolymers of the allylamine-gluconolactone disclosed in international application number WO 2000/31150 and in US patent No. 6472489; and the silicon-containing prepolymers are described in co-owned US patents No. 6039913, 7091283, 7268189 and 7238750, and in applications for US patents No. 09/525158 filed March 14, 2000 (called "Organic Compound"), 11/825961, 60/86982, submitted December 13, 2006 (entitled "PRODUCTION OF OPHTHALMIC DEVICES BASED ON PHOTO-INDUCED STEP-GROWTH POLYMERIZATION", 60/869817, filed December 13, 2006 (entitled "Actinically Curable Silicone Hydrogel Copolymers and Uses thereof"), 60/896325 filed March 22, 2007 ("Prepolymers with Dangling Polysiloxane-Containing Polymer Chains"), 60/896326 filed March 22, 2007 ("Silicone-Containing Prepolymers with Dangling Hydrophilic Polymeric Chains"), which in its entirety is included in the present invention by reference.

In one embodiment, forming a matrix substance includes water-soluble slivaushiesia prepolymer poly(vinyl alcohol), which is actinic slivaushiesia. In another embodiment, soluble in water slivaushiesia prepolymer poly(vinyl alcohol) is polyhydroxyalkane described in US patents No. 5583163 and 6303687 and having a molecular weight that is at least about 2000, and including in terms of the number of hydroxyl groups in poly(vinyl alcohol) from approximately 0.5 to approximately 80% of units of formula I-III:

In the formula I, II, and III molecular mass mean mass-average molecular weight Mw determined by gel permeation chromatography.

In the formula I, II, and III R3may denote hydrogen, C1-C6is an alkyl group or cycloalkyl group.

In f is rule I, II and III, R may denote alkylene containing up to 8 carbon atoms, or up to 12 carbon atoms and may be linear or branched. Suitable examples include octile, hexylen, pentile, butylene, propylene, ethylene, methylene, 2-propylene, 2-butylene and 3-pentile. Ness. alkylen R can contain up to 6 or up to 4 carbon atoms. In one embodiment, R is a methylene or butylene.

In the formula I R1may denote hydrogen or nits. alkyl containing up to 7, preferably up to 4 carbon atoms. In formula I, R2may designate refinancing electron slivaushiesia radical containing up to 25 carbon atoms. In one embodiment, R2may designate refinancing acyl radical of the formula R4-CO-in which R4means refinancing slivaushiesia radical containing from 2 to 24, from 2 to 8 or from 2 to 4 carbon atoms.

Refinancing slivaushiesia the radical R4can represent, for example, ethinyl, 2-propinyl, 3-propinyl, 2-butinyl, hexenyl, octenyl or dodecenyl. In one embodiment,- C(O)R4is ethinyl or 2-propenyl, so-C(O)R4represents the acyl radical of acrylic acid or methacrylic acid.

In formula II, R7may designate primary, secondary, or tertiary aminogroup the PU or Quaternary amino group of the formula N +(R')3X-in which each R' independently represents hydrogen or C1-C4alkyl radical and X represents a counterion, such as, for example HSO4-, F-, Cl-, Br-I-CH3Soo-HE-BF-or H2PO4-. In one embodiment, R7denotes the amino group, mono - or di(NISS. alkyl)amino group, mono - or diphenylamino, (NISS. alkyl)phenylaminopropyl or tertiary amino group included in a heterocyclic ring, for example-NH2, -NH-CH3, -N(CH3)2, -NH(C2H5), -N(C2H5)2, -NH(phenyl), -N(C2H5)phenyl or

In formula III, R8may refer to a radical monobasic, dibasic or trehosnovnoy saturated or unsaturated aliphatic or aromatic organic acid or sulfonic acid. In one embodiment, R8formed from Chloroacetic acid, succinic acid, glutaric acid, adipic acid, pipelinewall acid, maleic acid, fumaric acid, basis of itaconic acid, tarakanovas acid, acrylic acid, methacrylic acid, phthalic acid or trimellitic acid.

The term "ness." in connection with the radicals and compounds means, unless otherwise specified, adically or connection, containing up to 7 carbon atoms. Ness. the alkyl preferably contains up to 7 carbon atoms and includes, for example, methyl, ethyl, propyl, butyl or tert-butyl. Ness. alkoxygroup preferably contains up to 7 carbon atoms and includes, for example, a methoxy group, ethoxypropan, propoxylate, butoxypropyl or tert-butoxypropan.

In the formula N+(R')3X-, R' preferably denotes hydrogen or C1-C3-alkyl and X represents a halide, acetate or postit, for example, -N+(C2H5)3CH3COO-, -N+(C2H5)3Cl-or-N+(C2H5)3H2PO4.

In one embodiment, prepolymer is a water-soluble slivaushiesia poly(vinyl alcohol)having a molecular weight that is at least about 2000, in terms of the number of hydroxyl groups in poly(vinyl alcohol) contains from about 0.5 to about 80%, from 1 to 50%, from 1% to 25% or from 2% to 15% of units of formula I, in which R denotes ness. alkylene containing up to 6 carbon atoms, R1denotes hydrogen or nits. alkyl, R3denotes hydrogen and R2denotes a radical of the formula (IV) or (V).

where p and q independently from each other 0 or 1 and R5and R6independently on the angle from each other denote ness. alkylene containing from 2 to 8 carbon atoms, arilan containing from 6 to 12 carbon atoms, a saturated divalent cycloaliphatic group containing from 6 to 10 carbon atoms, arrenaline or alkalinuria containing from 7 to 14 carbon atoms or allenallenallen containing from 13 to 16 carbon atoms, and where R4is the same as defined above.

In one embodiment, when R, 0, R4represents C2-C8alkenyl. In another embodiment, when R is 1 and q is 1, R6stands With2-C6-alkylene and R4stands With2-C8alkenyl. In another embodiment, when p and q is 1, R5stands With2-C6-alkylene, phenylene, unsubstituted or nits. alkyl substituted cyclohexyl or cyclohexyl-ness. alkylene, unsubstituted or nits. alkyl substituted phenylene-ness. alkylen, NISS. alkaliphiles or phenylene-ness. alkaliphiles, R6stands With2-C6-alkylene and R4preferably stands With2-C8alkenyl.

Slivaushiesia poly(vinyl alcohol)containing units of formula I, I and II, I and III, or I and II and III, can be obtained by methods known in the art. For example, in US patents No. 5583163 and 6303687 disclosed methods of obtaining slivaushiesia polymers containing units of formula I,I and II, I and III, or I and II and III.

In another embodiment, actinic slivaushiesia prepolymer is slivaushiesia the polyurea described in US patent No. 6479587 or in the publication of the patent application US No. 2005/0113549 (which in its entirety is included in the present invention as a reference). In one embodiment, slivaushiesia prepolymer polyurea described by formula (I):

in which q is an integer ≥3, Q represents an organic radical, which contains at least one slivaushiesia group, CF denotes a multivalent branched copolymer fragment containing the segments a and U and optional segments and T, where And denotes a bivalent radical of formula (2):

where And denotes the divalent radical -(R11O)n-(R12O)m-(R13O)-, a linear or branched C2-C24is a divalent aliphatic radical, a C5-C24-cycloaliphatic or aliphatic-cycloaliphatic divalent radical, or a C6-C24-aromatic or arylaliphatic divalent radical, R11, R12and R13independently denote a linear or branched C2-C4-alkalinity or replacement With2-C8-alkalinity radicals,n, m and p independently represent an integer equal to from 0 to 100, provided that the sum (n+m+p) is from 5 to 1000, and RAand RA' independently represent hydrogen, unsubstituted With1-C6-alkyl, substituted C1-C6-alkyl or form a ring connection;

T denotes a bivalent radical of formula (3):

in which RTdenotes a divalent aliphatic, cycloaliphatic, aliphatic-cycloaliphatic, aromatic, arylaliphatic or aliphatic-heterocyclic radical;

U denotes a trivalent radical of the formula (4):

in which G denotes a linear or branched C3-C24-trivalent aliphatic radical, With5-C45-cycloaliphatic or aliphatic-cycloaliphatic trivalent organic radical or3-C24-aromatic or arylaliphatic trivalent radical;

In denotes the radical of the formula (5):

in which RBand RB' independently represent hydrogen, unsubstituted With1-C6-alkyl, substituted C1-C6-alkyl or form a ring connection, In1denotes a divalent aliphatic, cycloaliphatic, aliphatic-cycloaliphatic, and ematichesky or arylaliphatic hydrocarbon radical, which includes at least one amino group-NRm-, in which Rmrepresents hydrogen, the radical Q, above, or a radical of the formula (6):

in which Q is as defined above, and CF' denotes a divalent copolymer fragment containing at least two of the above segments a, b, T and U, provided that in the case of copolymer fragments of CF and CF' in each case for a segment a or b is followed by a segment T or U; provided that in the case of copolymer fragments of CF and CF' in each case for the segment T or U is followed by a segment a or b; provided that in each case the radical Q in formulas (1) and (6) associated with the segment a or b; and provided that the atom N-NRm- associated with the segment T or U, if Rmdenotes a radical of the formula (6).

In one embodiment, slivaushiesia prepolymer formula (1) is obtained by introducing ethyleneamine groups containing terminal amino groups or isocyanate groups, a polyurea, which may be a product of copolymerization of a mixture containing (a) at least one poly(oxyalkylene)diamine, (b) at least one organic polyamine, (C) optionally at least one diisocyanate, and (d) at least one polyisocyanate. In one embodiment, containing end amino groups or isocyanate groups of Polym Cavina is the product of copolymerization of a mixture, containing (a) at least one poly(oxyalkylene)diamine, (b) at least one organic di - or polyamine (preferably triamine), (C) at least one diisocyanate, and (d) at least one polyisocyanate (preferably triisocyanate).

Examples of poly(oxyalkylene)diamines, applicable in the present invention include Jeffamines®, having an average molecular weight of equal to, for example, from about 200 to 5000.

The diisocyanate may be a linear or branched C3-C24-aliphatic diisocyanate, With5-C24-cycloaliphatic or aliphatic-cycloaliphatic diisocyanate, or With6-C24-aromatic or arylaliphatic diisocyanate. Examples of diisocyanates that are applicable in the present invention include, but are not limited to, isophorondiisocyanate (IPDI), 4,4'-methylenbis(cyclohexylidene), toluylene-2,4-diisocyanate (TDI), 1,6-diisocyanato-2,2,4-trimethyl-n-hexane (HMDI), Methylenebis(cyclohexyl-4-isocyanate), Methylenebis(phenylisocyanate) and hexamethylenediisocyanate (HMDI).

The organic diamine can be a linear or branched C2-C24-aliphatic diamine With5-C24-cycloaliphatic or aliphatic-cycloaliphatic diamine or6-C24-aromatic or arylaliphatic dia is in. In one embodiment, the organic diamine is a bis(hydroxyethylene)Ethylenediamine (GDEAD).

Examples of polyamines include symmetric and asymmetric dialkylacrylamide or trialkylamine. For example, the polyamine may be Diethylenetriamine, N-2'-amino-ethyl-1,3-Propylenediamine, N,N-bis(3-aminopropyl)amine, N,N-bis(6-aminohexyl)amine or Triethylenetetramine.

The polyisocyanate may be a linear or branched C3-C24-aliphatic polyisocyanate, With5-C45-Belolipetsky or aliphatic-cycloaliphatic polyisocyanate or6-C24-aromatic or arylaliphatic the polyisocyanate. In one embodiment, the polyisocyanate is a6-C45-cycloaliphatic or alifaticheskii-cycloaliphatic compound containing 3-6 isocyanate groups and at least one heteroatom, including oxygen and nitrogen. In another embodiment, the polyisocyanate is a compound containing a group of formula (7):

in which D, D' and D" are independently denote a linear or branched bivalent1-C12is an alkyl radical, divalent5-C14-alkylcyclopentanes radical. Examples of triisocyanate include, but are not limited the tsya only them, which is the trimer of hexamethylenediisocyanate, 2,4,6-colortransparent, p,p',p"-triphenyltetrazolium and contains three functional groups of the trimer (isocyanurate) isophorondiisocyanate.

In one embodiment, containing end amino groups or isocyanate groups polyurea is a containing end amino group, a polyurea, which may allow carrying out the second stage reaction in the aquatic environment.

If forming a matrix substance contains prepolymer polyurea, prepolymer can be obtained according to methods known to experts in the art, using, for example, two-stage methodology. In the first stage containing end amino groups or isocyanate groups of the polyurea get a reaction mixture comprising (a) at least one poly(oxyalkylene)diamine, (b) at least one organic di - or polyamine, (C) at least one diisocyanate, and (d) at least one polyisocyanate. In the second stage, a polyfunctional compound containing at least one ethylenediamino group and the functional group is introduced into reaction with terminal amino groups or isocyanate groups containing terminal amino groups or isocyanate groups polyurea obtained in the first stage.

The first step of the reaction can be carried out in water elevado-organic medium or an organic solvent (for example, the ethyl acetate, THF, isopropanol and the like). In one embodiment, it is possible to use a mixture of water and water soluble organic solvent such as alkanol, such as methanol, ethanol or isopropanol, cyclic simple ether, such as tetrahydrofuran (THF), or a ketone, such as acetone. In another embodiment, the reaction medium is a mixture of water and water soluble solvent having a boiling point equal to from 50 to 85°C. or from 50 to 70°C (such as tetrahydrofuran or acetone).

The temperature of the reaction mixture in the first stage reaction method is, for example, -20 to 85°C -10 to 50°C or -5 to 30°C. the Duration of the first stage reaction method may vary within wide limits and it is shown that it is feasible to approximately 1 to 10 hours, from 2 to 8 hours, or from 2 to 3 o'clock

In one embodiment, prepolymer soluble in water at a concentration of approximately from 3 to 99 wt.%, from 3 to 90%, from 5 to 60 wt.% or from 10 to 60 wt.%, mainly in aqueous solution. In another embodiment, the concentration of prepolymer in the solution is from about 15 to about 50 wt.%, from about 15 to about 40 wt.% or from about 25 to about 40 wt.%.

In some embodiments, the implementation of the prepolymers used in the present invention, cidaut methodologies known in the art, for example by precipitation with organic solvents, such as acetone, filtration and washing, extraction in a suitable solvent, dialysis or ultrafiltration; ultrafiltration is particularly preferred. Thus, the prepolymers can be obtained in extremely pure form, for example in the form of concentrated aqueous solutions that contain no or at least mostly not contain the reaction products, such as salt, and source materials, such as, for example, polimernye components.

In one embodiment, the purification method of the prepolymers used in the present invention, is a ultrafiltration. Ultrafiltration can be performed repeatedly, for example from 2 to 10 times. Alternative ultrafiltration can be performed continuously to provide the set degree of purity. Set the degree of purity, in principle, can be as high as necessary. A suitable criterion of purity is, for example, the concentration of dissolved salts formed as by-products, the content of which can simply be determined by known methods.

In another embodiment, forming a matrix substance is a polymerizable composition comprising at m is re hydrophilic vinyl monomer, including, but not limited to, hydroxyethylmethacrylate, hydroxyethylacrylate, N-vinyl pyrrolidone. Polymerizable composition may further comprise one or more hydrophobic vinyl monomers, cross-linking reagents, radical initiators, and other components known to a person skilled in the art. For these substances usually required the extraction step.

In another embodiment, the polymer matrix is prepared from a silicon-containing prepolymers. Examples of silicon-containing prepolymers are described in the jointly owned by US patents No. 6039913, 7091283, 7268189 and 7238750, and in applications for US patents No. 09/525158 filed March 14, 2000 (entitled "Organic Compound"), 11/825961, 60/869812, filed December 13, 2006 (entitled "PRODUCTION OF OPHTHALMIC DEVICES BASED ON PHOTO-INDUCED STEP-GROWTH POLYMERIZATION"), 60/869817, filed December 13, 2006 (entitled "Actinically Curable Silicone Hydrogel Copolymers and Uses thereof"), 60/896325 filed 22 March 2007 ("Prepolymers with Dangling Polysiloxane-Containing Polymer Chains"), 60/896326 filed March 22, 2007 ("Silicone-Containing Prepolymers with Dangling Hydrophilic Polymeric Chains").

In another embodiment, forming a matrix substance is a polymerizable composition containing at least one silicon-containing vinyl monomer or macromer, or may be any composition for lenses, the purpose is to nnow for the manufacture of soft contact lenses. A typical composition for lenses include, without restrictions compositions containing lotrafilcon And, lotrafilcon In, comfilcon, balafilcon, galyfilcon, senofilcon And etc. Forming the lens material may further include other components, such as hydrophilic vinyl monomer, a crosslinking agent, a hydrophobic vinylic monomer, initiator (for example, photoinitiator or thermal initiator), a coloring agent absorbing UV-radiation agent, photosensitizers, an antimicrobial agent, etc. is Preferred if the silicone hydrogel forming lens substance used in the present invention, includes a silicon macromer. For these substances usually required the extraction step.

In the present invention can use any silicon-containing vinyl monomers. Examples of silicon-containing vinyl monomers include, without imposing restrictions methacryloyloxy, 3-methacryloxypropyltrimethoxysilane, bis(methacryloxypropyl)tetramethyldisiloxane, monomethacrylates the polydimethylsiloxane, monoacrylates a polydimethylsiloxane containing terminal mercaptopropyl the polydimethylsiloxane, N-[Tris(trimethylsiloxy)silylpropyl]acrylamide, N-[Tris(trimethylsiloxy)silylpropyl]methacrylamide and distributedtransactionprotocol the t (TRIS), N-[Tris(trimethylsiloxy)silylpropyl]methacrylamide (DMAA), N-[Tris(trimethylsiloxy)silylpropyl]acrylamide (TSAA), 2-propenylboronic acid, 2-methyl-2-hydroxy-3-[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]disiloxanyl]propoxy]propyl ester (which also can be called (3-methacrylate-2-hydroxypropoxy)propyl-bis-(trimethylsiloxy)methylsilane), (3 methacrylate-2-hydroxypropoxy)propertis(trimethylsiloxy)silane, bis-3-methacrylate-2-hydroxypropylmethylcellulose, 3 methacrylate-2-(2-hydroxyethoxy)propyloxy)propylbis(trimethylsiloxy)methylsilane, N,N,N',N'-tetrakis(3-methacrylate-2-hydroxypropyl)-alpha, omega-bis-3-aminopropyl-polydimethylsiloxane, polysiloxanes(meth)acrylic monomers, silicon-containing vinylcarbene or vinylcarbene monomers (for example, 1,3-bis[4-vinyloxycarbonyloxy)buta-1-yl]tetramethyldisiloxane; 3-(trimethylsilyl), propylenecarbonate, 3-(vinyloxycarbonyl)propyl-[Tris(trimethylsiloxy)silane], 3-[Tris(trimethylsiloxy)silyl]propylenecarbonate, 3-[Tris(trimethylsiloxy)silyl]propylethylene, 3-[Tris(trimethylsiloxy)silyl]propylenecarbonate, tert-butyldimethylchlorosilane; trimethylsilylcyanation and trimethylsilylmethylamine). Preferred elexandria monomer is TRIS, which denotes the 3-meta is eloxiertes(trimethylsiloxy)silane and has a CAS number 17096-07-0. The term "TRIS" also includes dimers 3-methacryloxypropyl(trimethylsiloxy)silane. You can use monomethacrylates or monoarylamino polydimethylsiloxane having different molecular weights. You can also use dimethacrylate or decreaserevenue polydimethylsiloxane having different molecular weights. For fototorrepisa binder polymer silicon-containing monomers used to produce the binder polymer preferably should have high hydrolytic (or nucleophilic) stability.

To obtain a silicone hydrogel material, you can use any suitable elexandria macromer with Ethylenediamine group (or groups). Especially preferred elexandria macromer selected from the group comprising Macromer And, Macromer In, Macromer With and Macromer D, described in US 5760100, which in its entirety is included in the present invention as a reference. In macromer can be included one or two acrylate, methacrylate or vinyl functional groups. Macromer that contain two or more polymerizable groups (vinyl group), can also act as cross-linking reagents. It is also possible to use di - and triblock-macromer containing politiet ciloxan and polyalkyloxy. For example, to increase the permeability for oxygen, you can use a three-block copolymer of ethylene oxide, dimethylsiloxane and ethylene oxide containing methacrylate end groups.

Forming a matrix of substances used to prepare the polymer matrix may contain one or more functional groups that are compatible with the biologically active agent. Similarly biologically active agent can be modified one or more functional groups, so that, when the biologically active substance is introduced into the polymer matrix, the biologically active substance has not been easy leaching from the matrix. In one embodiment, forming a matrix substance and the polymer matrix contains at least one ionic group, ionizable group, or a combination of both. The term "ionic group" in the present invention is defined as any group with a charge (positive, negative or both). The term "ionizable group" is defined as any group which can be converted into an ionic group. For example, the amino group (ionizable group) can be proteinopathy with the formation of positively charged ammonium group (ionic group).

Examples of anionic groups include, for example, With1-C -alkyl substituted with-SO3H, -OSO3H-ORO3H2and-COOH; phenyl substituted with-SO3H,

-COOH, -HE-CH2-SO3H; -COOH; a radical-COOY4in which Y4means

With1-C24-alkyl substituted, for example, with-COOH, -SO3H, -OSO3H-ORO3H2or a radical-NH-C(O)-O-G', where G' denotes the radical anionic carbohydrate; a radical-CONY5Y6in which Y5stands With1-C24is alkyl, substituted with

-COOH, -SO3H, -OSO3H or-ORO3H2and Y6independently has the meanings specified for Y5or denotes hydrogen or C1-C12-alkyl; or-SO3H; or its salt, such as its sodium, potassium, ammonium, etc.

Examples of cationic groups include, for example, With1-C12-alkyl, substituted by a radical NRR'R+An-in which R, R' and R'" are all independently denote hydrogen or unsubstituted or replacement C1-C6-alkyl or phenyl, and An-denotes an anion; or a radical-C(O)OY7in which Y7stands With1-C24-alkyl substituted with-NRR'R'"+An-and also denotes unsubstituted or substituted, for example, hydroxy-group, in which R, R', R'" and An-are as defined above.

Examples of zwit the er-ionic groups include the radical R 1-Zw, where R1denotes a direct bond or a functional group, for example, carbonyl, carbonate, amide, ester, dicarbonitrile, dicarboximido, urea or urethane group, and Zw denotes aliphatic fragment containing one anionic and one cationic group.

In another embodiment, forming the matrix of the substances used to prepare the polymer matrix may contain one or more hydrophobic groups to increase the hydrophobicity of the polymer matrix. For example, forming a matrix substance can be introduced into the reaction with a saturated or unsaturated liquid acid before polymerization and the preparation of the polymer matrix. Alternative molecular mass forming a matrix substance can be changed to increase or decrease the hydrophobicity of the polymer matrix. In some cases, when the biologically active agent is a hydrophobic compound, it is desirable to include a biologically active agent in a hydrophobic polymer matrix to prevent leaching funds. The choice of forming a matrix substances and biologically active products containing different types of functional groups that can be used for most improved administration of biologically active products in the polymer mA is ritsu, discussed below.

b. Media

In another embodiment, the carrier is introduced into the polymer matrix. The media can be covalently attached to the polymer matrix and/or distributed in the polymeric matrix with the formation of interpenetrating polymer grids. The media usually contains one or more functional groups (e.g., ionic, ionizable hydrophobic or any combination of them). The media can be used to improve the administration of biologically active products in the polymer matrix. Moreover, the choice of media can be used to regulate the extraction of biologically active products from the polymer matrix. If you are not limited by theoretical considerations, it can be assumed that the medium is included in a polymer matrix. This can be done by mixing the carrier to form the matrix substance and the biologically active agent to the polymerization. In one embodiment, the media contains many ionic or ionizable groups, which may give a charge-neutral hydrophobic polymeric matrix. This can be useful when introducing a biologically active agent that contains ionic groups. In one embodiment, the media includes a polycation. In another embodiment, the carrier comprises a polymer containing one or more carboxylate. Specific examples of carriers that are applicable in the present invention include, but are not limited to, polyacrylic acid, polymethacrylic acid, polystyrene, maleic acid or polyethylenimine.

C. Biologically active substance

Biologically active agent, introduced in the polymer matrix is any compound that can prevent eye disease or to reduce the symptoms of eye disease. The biologically active agent can be a drug, amino acids (e.g. taurine, glycine and the like), polypeptide, protein, nucleic acid, or any combination thereof. Examples of medicines in this invention include, but are not limited to, rebamipide, ketotifen, alptigin, cromoglicate, cyclosporine, nedocromil, levocabastine, lodoxamide, ketotifen, emedastine, nafazolina, Ketorolac or pharmaceutically acceptable salt or ester. Other examples of biologically active agents include 2-pyrrolidone-5-carboxylic acid (PAC), alpha-hydroxy acids (e.g. glycolic, lactic, malic, tartaric, almond and citric acid and their salts and the like), linoleic and gamma-linoleic acid, hyaluronan and vitamins (for example, B5, And B6, and so on).

d. Additional components

In various embodiments, implementation of the Tulane in the polymer matrix, you can enter additional components. Examples of such components include, but are not limited to, lubricants, eye ointment, thickening means or any combination of them.

Examples of lubricants include, without restrictions mezinarodni substances and hydrophilic polymers. Typical mezinarodni substances include, without restrictions polyglycolic acid, polylactide, collagen, hyaluronic acid and gelatin.

Typical hydrophilic polymers include, but are not limited to, polyvinyl alcohols (PVA), polyamides, polyimides, Polyglactin, a homopolymer of vinylacetate, a copolymer of at least one vinylacetate in the presence or absence of one or more hydrophilic vinylic comonomers, a homopolymer of acrylamide or methacrylamide, a copolymer of acrylamide or methacrylamide with one or more hydrophilic vinylic monomers and mixtures thereof.

In one embodiment, the above winlactat has the structure of formula (VI)

in which R denotes alkalinity diradical containing from 2 to 8 carbon atoms,

R1denotes hydrogen, alkyl, aryl, arylalkyl or alkylaryl, preferably hydrogen or nits. alkyl containing up to 7 and more preferably up to 4 carbon atoms, such as methyl, the Teal or propyl; aryl containing up to 10 carbon atoms, and also arylalkyl or alkylaryl containing up to 14 carbon atoms, and

R2denotes hydrogen or nits. alkyl containing up to 7 and more preferably up to 4 carbon atoms, such as, for example, methyl, ethyl or propyl.

Some N-vinylacetate corresponding to the above structural formula (V)include N-vinyl-2-pyrrolidone, N-vinyl-2-piperidone, N-vinyl-2-caprolactam, N-vinyl-3-methyl-2-pyrrolidone, N-vinyl-3-methyl-2-piperidone, N-vinyl-3-methyl-2-caprolactam, N-vinyl-4-methyl-2-pyrrolidone, N-vinyl-4-methyl-2-caprolactam, N-vinyl-5-methyl-2-pyrrolidone, N-vinyl-5-methyl-2-piperidone, N-vinyl-5,5-dimethyl-2-pyrrolidone, N-vinyl-3,3,5-trimethyl-2-pyrrolidone, N-vinyl-5-methyl-5-ethyl-2-pyrrolidone, N-vinyl-3,4,5-trimethyl-3-ethyl-2-pyrrolidone, N-vinyl-6-methyl-2-piperidone, N-vinyl-6-ethyl-2-piperidone, N-vinyl-3,5-dimethyl-2-piperidone, N-vinyl-4,4-dimethyl-2-piperidone, N-vinyl-7-methyl-2-caprolactam, N-vinyl-7-ethyl-2-caprolactam, N-vinyl-3,5-dimethyl-2-caprolactam, N-vinyl-4,6-dimethyl-2-caprolactam and N-vinyl-3,5,7-trimethyl-2-caprolactam.

Brednikova molecular mass Mnhydrophilic polymer, for example, more than 10,000 or more than 20000 exceeds the molecular weight forming a matrix substance. For example, if forming a matrix substance is a water-soluble prepolymer having an average molecular the Oh mass M nequal to from 12,000 to 25,000, the average molecular mass Mnthe hydrophilic polymer is, for example, from 25,000 to 100,000, from 30,000 to 75,000 or from 35000 to 70000.

Examples of hydrophilic polymers include, but are not limited to, polyvinyl alcohol (PVA), polyethylene oxide (i.e., the polyethylene glycol (PEG)), poly-N-vinyl pyrrolidone, poly-N-vinyl-2-piperidone, poly-N-vinyl-2-caprolactam, poly-N-vinyl-3-methyl-2-caprolactam, poly-N-vinyl-3-methyl-2-piperidone, poly-N-vinyl-4-methyl-2-piperidone, poly-N-vinyl-4-methyl-2-caprolactam, poly-N-vinyl-3-ethyl-2-pyrrolidone, and poly-N-vinyl-4,5-dimethyl-2-pyrrolidone, polyvinylimidazole, poly-N-N-dimethylacrylamide, polyacrylic acid, poly-2-ethyloxazole, heparin polysaccharides, polysaccharides, derivatives of polyoxyethylene and mixtures thereof.

Suitable derivatives of polyoxyethylene is, for example, a simple ester of n-alkylphenolethoxylate, simple ester of n-alkylpolyoxyethylene (for example, TRITON®), polyglycolic ester - surfactant (TERGITOL®), polyoxyethylenesorbitan (for example, TWEEN®), polyoxyethylene monoether glycol (e.g., BRIJ®, polyoxyethylene-9-lauric ether, polyoxyethylene-10-ether, polyoxyethylene-10-tridecylamine ether) or block copolymer of ethylene oxide and propylene oxide (for example, poloxamer or poloxamine).

In one embodiment, proizvodnymi of are polyoxyethylene block copolymers, polyethylene-polypropylene, preferably poloxamer or poloxamine, which are produced, for example, under the trade names PLURONIC®, PLURONIC-R®, TETRONIC®, TETRONIC R®or PLURADOT®. Poloxamer are triblock copolymers of the structure of PEO-PPO-PEO (PEO refers to poly(ethylene oxide) and PPO denotes poly(propylene oxide). There are a large number of poloxamers, distinguished mainly on the molecular weight and ratio of PEO/PPO. Examples of poloxamers include 101, 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 188, 212, 215, 217, 231, 234, 235, 237, 238, 282, 284, 288, 331, 333, 334, 335, 338, 401, 402, 403 and 407. The order of blocks of polyoxyethylene and polyoxypropylene you can pay and get the block copolymers of the structure of PPO-PEO-PPO, which are known as polymers PLURONIC-R®.

Poloxamine are polymers of structure (PEO-PPO)2-N-(CH2)2-N-(PPO-PEO)2that are issued in the form of products with different molecular masses and relations PEO/PPO. And in this case, the order of blocks of polyoxyethylene and polyoxypropylene you can pay and get the block copolymers of the structure (PPO-PEO)2-N-(CH2)2-N-(PEO-PPO)2that are known as polymers TETRONIC-R®.

It is also possible to obtain block copolymers of polyoxypropylene-polyoxyethylene copolymers with hydrophilic blocks containing statistical mixture repeating Venev of ethylene oxide and propylene oxide. To ensure the hydrophilic nature of the unit should prevail ethylene oxide. Similarly hydrophobic block may be a mixture of repeating units of ethylene oxide and propylene oxide. Such block copolymers are available under the trade names PLURADOT®.

that is, the Manufacture of ophthalmic devices

The present invention relates to methods for producing ophthalmic devices. Ophthalmic device is any device designed to be placed on the eye surface or implantation in eyes with surgical techniques known in the art. For example, the ophthalmic device can be a contact lens or an artificial lens. In one embodiment, the method involves the following stages:

(a) forming a mixing matrix substances and biologically active funds;

b) introducing the mixture obtained in stage (a), in the form for the manufacture of the device;

C) polymerization forming a matrix substance in the form with the formation of the device, in which the biologically active agent interacts with the polymer matrix and immobilized in the polymeric matrix formed during the polymerization forming a matrix substance.

Selection of biologically active means and forming m is trico substances may vary, in particular, depending on the individual undergoing the treatment of the disease and the required characteristics of extraction of biologically active products. For example, if the biologically active substance contains one or more anionic/ionizable groups (for example, groups COOH), forming a matrix substance may contain one or more cationic/ionizable groups (for example, groups of NH2). In this case, the electrostatic interaction between the biologically active agent and a polymer matrix formed after polymerization. For example, vifilcon, which is prepolymer comprising a copolymer of 2-hydroxyethylmethacrylate and N-vinylpyrrolidone, contains the COOH group (anionic). Thus, biologically active agents containing an ionic group or ionizable group (e.g. amino group that can be converted into positively charged ammonium) can be chosen so as to maximize the interaction between forming the matrix substance and the biologically active agent. Alternatively, if forming a matrix substance does not contain ionic/ionizable groups, the media, contains many ionic/ionizable groups can be used to provide electrostatic interaction with biologically AK is positive means. For example, nelfilcon, which is prepolymer containing functional groups of polyvinyl alcohol with N-formylmethionine, does not contain ionic or ionizable groups. Thus, a carrier, such as, for example, polyacrylic acid or polymethacrylic acid, can be used to modify the charge of the polymer matrix and reinforcing interaction between the polymer matrix and biologically active agent.

Another type of interaction considered when selecting biologically active means and forming a matrix substances are hydrophobic/hydrophobic interactions. If a particular biologically active agent is hydrophobic, at least a portion forming a matrix substances should also be relatively hydrophobic, so that the biologically active substance remained in the polymer matrix and not vasilakopoulos. One method of determining the ability of biologically active products to stand out from the polymer matrix is the study of the distribution coefficient of biologically active funds between polymers lenses and water. The increase in hydrophobicity of the polymer matrix or the use of more hydrophobic interpenetrating polymer meshes can lead to the introduction of more drugs in the lens.

Water the embodiment, the selection of biologically active means and forming a matrix substance can be based on the distribution coefficient of biologically active products in the water-octanol. The distribution coefficient in the water-octanol is expressed as logKowwhere Kowis the ratio of the amounts of biologically active products in Octanorm and water layers. The distribution coefficient in the water-octanol equal to from 0 to -1, shows that the biologically active substance has a similar solubilities in octanol and water. The distribution coefficient in this range is a reliable indicator that the biologically active substance will be released from the polymer matrix. When the reduction ratio distribution in the water-octanol (i.e. when it becomes more significant and negative) of the biologically active agent acquires a greater affinity for water. The value of pKa of biologically active products (i.e., the pH value at which 50% of the biologically active funds ionized) and the pH value of the polymer matrix (i.e. the choice of forming a matrix substance and the functional groups contained in the substance to be observed in the manufacture of ophthalmic devices. In some embodiments, the implementation of the charged ionized groups of biologically active products can be paired with the charges of the polymer matrix, or carrier, to facilitate retention of biologically active products.

By changing the hydrophobicity and/or number of the district/ionizable groups, contained in forming a matrix substance (and, ultimately, in a polymer matrix), you can select and enter a lot of different biologically active agents in the polymer matrix. In addition, you can adjust the characteristics of the extraction of biologically active products of ophthalmic devices. This is especially attractive if you want to ensure the continuous secretion of biologically active funds over long periods of time.

In another embodiment, the biologically active agent can be covalently bind to form the matrix substance to polymerization by methods known in the art. For example, if forming a matrix substance is nelfilcon, which is prepolymers polyvinyl alcohol, hydroxy-group can interact with the biologically active agent containing groups COOH, with what is happening in suitable conditions, the formation of the corresponding ether complex.

Before polymerization forming a matrix substance, a biologically active agent and other optional components (e.g., carriers) are thoroughly mixed by methods known in the art. The components can be mixed in dry form or in solution. In the case of using the solution, it is desirable to use water and to avoid is the sing of organic solvents, for which may require subsequent stages of purification to remove residual solvent. Depending on the choice of biologically active means and forming a matrix substance pH value can be changed to optimize the interaction between the components. During mixing of the biologically active agent is thoroughly combined with forming the matrix substance or dispersed therein with the formation of a homogeneous mixture. This is important as it allows the release of biologically active products at constant concentrations. Thus, the expression "introduced in a polymer matrix" means that the biologically active substance is evenly distributed throughout the polymeric matrix and are not located in separate areas of the ophthalmic device.

After forming a matrix substance, a biologically active agent and other optional components are mixed, the mixture is then poured into a spherical shape. If the ophthalmic device is a contact lens, then the lens can be manufactured by methods known in the art. For example, the contact lens can be manufactured in a conventional rotating the mould described, for example, in US patent No. 3408429, or by way of casting the model in a static form, described in US patents No. 4347198, 5508317, 5583463, 5789464 and 5849810.

p> Molds for the manufacture of contact lenses is well known in the art. For example, the form (for casting models) typically contain at least two sections (or fragment) or half of the forms, i.e. the first and the second half of the forms. The first half of the forms becomes the first former (or optical) surface and the other half forms forms the second forming (or optical) surface. The first and second half of the form is designed so that are connected to each other, so that between the first molding surface and the second molding surface formed by forming a lens cavity. Forming the surface of the half of the shape is forming the cavity surface of the mold and is in direct contact with the mixture forming a matrix substances and biologically active products.

Methods of manufacturing sections of the forms for casting contact lenses are usually well-known specialists with General training in the art. The first and second half of the forms can be manufactured by various methods, such as injection molding or machining on a lathe. Examples of suitable methods of manufacture halves forms are disclosed in US patents No. 4444711, 4460534, 5843346 and 5894002, which are also included in the present invention by reference.

To obtain forms for the manufacture of ophthalmic lenses can is about to use almost all materials known in the art. For example, you can use such polymers as polyethylene, polypropylene, polystyrene, polymethylmethacrylate, copolymers of cyclic olefins (e.g., Topas®COC produced by the company Ticona GmbH of Frankfurt, Germany and Summit, New Jersey; Zeonex®and Zeonor®produced by the company Zeon Chemicals LP, Louisville, KY), etc. you Can use other materials that allow UV radiation, such as quartz glass and sapphire.

In one embodiment, when forming a matrix substance is a liquid prepolymer in the form of a solution not containing solvent liquid or melt of one or more prepolymers, optionally in the presence of other components, can be used. Examples of forms of multiple use are disclosed in US patent No. 6627124, which in its entirety is included in the present invention as a reference. In this embodiment, the composition of the liquid prepolymer poured into a form consisting of two halves of a form, and two half forms do not touch each other, and between them there is a circular slot. The gap communicates with the cavity shape, so that the excess liquid composition prepolymer can flow through the gap. Instead of the polypropylene forms that can be used only once, you can apply forms the multiple use of quartz, glass, sapphire, because after manufacturing lenses these forms, you can quickly and effectively clean to remove unreacted materials and other residues by using water or a suitable solvent and can be dried by air. Form multiple use can be made of a copolymer of cyclic olefin, such as, for example, the brand Topas®COC 8007-S10 (clear amorphous copolymer of ethylene and norbornene), produced by the company Ticona GmbH of Frankfurt, Germany and Summit, New Jersey, Zeonex®and Zeonor®produced by the company Zeon Chemicals LP, Louisville, KY. Because of the possibility of multiple use of the half moulds for their production may require relatively large investments in order to obtain very accurate and gives reproducible results form. Because half of the form is not in contact with each other at the site of manufactured lenses, i.e. in the cavity or the surface shape eliminates the possibility of damage caused by contact. This ensures a long service life forms, which, in particular, also provides excellent reproducibility manufactured contact lenses.

After pouring the mixture into a shape forming a matrix substance is polymerized with the formation of the polymer matrix. The methodology for stage polymerization vary depending on the choice of brazowego matrix substances. In one embodiment, when forming a matrix substance contains prepolymer that includes one or more actinic slivaushiesia ethyleneamine groups for polymerization of prepolymer the form containing the mixture can be exposed to limited spatial actinic radiation.

"Spatial limited actinic radiation" means the act or process by which energy in the form of radiation, for example, through a mask or screen, or a combination of directed spatial limited way to the site, with clearly defined peripheral boundary. For example, the spatial limitation of UV radiation can be provided with a mask or screen, which contains a transparent or open area (direct station), surrounded by impervious to UV radiation area (masked area), as schematically shown in figure 1-9 in US patent No. 6627124 (which in its entirety is included in the present invention as a reference). Direct plot has a clearly defined peripheral boundary of the masked area. Energy used for knitting, represents energy radiation, preferably UV radiation, gamma radiation, electron radiation or thermal radiation, preferably, the EU and the radiation is essentially parallel beam, in order, on the one hand, properly limiting and, on the other hand, efficient use of energy.

In one embodiment, the form with the mixture is exposed to a parallel beam to provide the proper restriction and efficient use of energy. The duration of exposure energy in the mixture is relatively small, for example, less than or equal to 60 min, less than or equal to 20 min, less than or equal to 10 min, less than or equal to 5 min, from 1 to 60 s or from 1 to 30 C. After polymerization, forming a matrix substances get ready the matrix in which the biologically active agent and other components are mixed in the matrix.

In one embodiment, if the ophthalmic device made without solvent from the pre-purified prepolymer not require subsequent stages of purification such as extraction. This is because prepolymer does not contain undesirable low molecular weight impurities. Another difficulty associated with the extraction, is the fact that this procedure is by its nature deselection. Can be extracted everything that is soluble in the used solvent (e.g., a biologically active agent) and is capable of vydeliajutsia of ophthalmic devices. In addition, the extraction device to the hooting, so you can easily remove unbound fragments.

When using the methods proposed in the present invention, the ophthalmic device can be made simpler and more effective manner than in the prior art. This is due to many factors. First, you can buy cheaply or to prepare the initial substance. Secondly, if forming the matrix substances are prepolymers, the prepolymers are stable, so they can be thoroughly cleaned. So after polymerization ophthalmic devices do not require subsequent purification, such as preferably a complete extraction of unpolymerized components. Thus, when the ophthalmic device is a contact lens, ophthalmic device in the usual way by hydration directly to turn into ready to use contact lens according to the methods known in the art. In addition, the polymerization can be carried out with no solvent or in an aqueous solution and does not require subsequent exchange with the solvent or the stage of hydration. Finally, in the case of photopolymerization necessary for a short period of time and the manufacturing can be performed very cost-effective and efficient manner.

Ophthalm the logical device can be removed from the form by the techniques well known in the art. After demolding ophthalmic device can be sterilized by treatment in an autoclave according to the methods known in the art.

If the ophthalmic device is a contact lens, the contact lens can be packaged in packaging solutions known in the art. The packaging solution is an ophthalmologist acceptable, which means that the ophthalmic device in contact with a solution, usually is appropriate and safe for direct placement on the eyes or in the eyes without rinsing. Packaging solution proposed in the present invention can be any water based mud, which is used for storing ophthalmic devices. Typical solutions include, without restrictions, physiological fluids, other buffered solutions and deionized water. In one embodiment, the packaging solution is a saline solution containing salt and containing one or more of the other ingredients, including, but not limited to, a suitable buffer means, means regulating toychest, water-soluble thickeners, surfactants, antibacterial agents, Kon is ervasti and lubricants (for example, derivatives of cellulose, polyvinyl alcohol, polyvinylpyrrolidone).

The pH of the packaging solution must be maintained in the range of about from 6.0 to 8.0, preferably about 6.5 to 7.8. Examples of physiologically compatible buffer systems include, without restrictions, acetates, phosphates, borates, citrates, nitrates, sulphates, tartratami, lactates, carbonates, bicarbonates, Tris (Tris(hydroxymethylamino)aminomethan), derivatives of Tris and mixtures thereof. The amount of each buffer means is the amount needed for effective pH of the composition equal to from 6.0 to 8.0. The pH value can be adjusted depending on the biologically active products, introduced in the polymer matrix of the ophthalmic device. For example, the pH of the packaging solution can be adjusted so as not happened or almost happened undesirable leaching of biologically active products from the polymer matrix.

Aqueous solutions for packaging and storing ophthalmic devices can also be adjusted by means of regulating toychest to approximate the osmotic pressure to the value for normal tears. The solutions are generally isotonic with one saline or in combination with sterile water and make gyrotonics them. Accordingly, excess salt can lead to the formation of a hypertonic solution that will cause burning and irritation of the eyes. As in the case of pH, the concentration of the saline solution can be adjusted depending on the biologically active products, introduced in the polymer matrix of the ophthalmic device. For example, the concentration of the saline solution can be adjusted to minimize leaching of biologically active products from the polymer matrix.

Examples of suitable means of regulating toychest include, but are not limited to, sodium chloride and potassium, dextrose, glycerin, calcium chloride and magnesium. These tools are typically used individually in amounts comprising from about 0.01 to 2.5 percent (wt./about.) and preferably from about 0.2 to about 1.5% (wt./vol.). In one embodiment, the means regulating toychest, is used in an amount to provide the final value of osmotic pressure equal to from 200 to 400 milliosmoles/kg, from about 250 to about 350 milliosmoles/kg, and from about 280 to about 320 milliosmoles/kg

Examples of preservatives that are applicable in the present invention include, but are not limited to, benzylaniline and other Quaternary ammonium preservatives, salt finalstate, sorbic acid, is albuterol, dimitriades, thimerosal, methyl and propyl paraben, benzyl alcohol and phenylethanol.

Surfactants can represent almost any acceptable eye surfactants, including nonionic, anionic and amphoteric surfactants. Examples of surfactants include, without restrictions poloxamer (e.g., Pluronic®F108, F88, F68, F68LF, F127, F87, F77, R, R75, R and R), polyamine (e.g., Tetronic®707, 1107 and 1307, polietilenglikolya esters of fatty acids (e.g., Tween®20, Tween®80), polyoxyethylene or polyoxypropylene esters With12-C18-alkanes (e.g., Brij®35), polyoxyethylene (Myrj®52), polyoxyethyleneglycol (Atlas®G 2612) and amphoteric surfactants, marketed under the trade names of Mirataine® and Miranol®.

In one embodiment, the packaging solution is an aqueous salt solution having osmollnosti approximately from 200 to 450 milliosmols in 1000 ml (unit: millimol/l), approximately from 250 to 350 milliosmoles/l and about 300 milliosmols/L. In other embodiments, implementation of the packaging solution may be a mixture of water or an aqueous solution of salts with physiologically tolerable polar organic races what voditelem, such as, for example, glycerin.

Ophthalmic device used in the present invention, can be stored in any container, usually used for storage of such devices. If the ophthalmic lens is a contact lens, containers for contact lenses, applicable in the present invention include blister packs of different forms.

II. Applications

Ophthalmic device proposed in the present invention can be applied for the delivery of biologically active agents in the eye of the subject. In one embodiment, the method comprises contacting the eye of the subject with ophthalmic devices proposed in the present invention, in which one or more components of tears secretes biologically active agent from the device. As described above, the ophthalmic device can be a contact lens, which can be applied directly to the surface of the eye. Alternative ophthalmic device can be surgically inserted in the eye. Both of these options implementation are included in the definition of "contact with the eye."

When the ophthalmic device is in contact with the one or more components of tears, the biologically active agent is released from the polymer of the second matrix with the desired speed. The term "component of tears" means any biological agent contained in the eye or produced by the eye. Components tears usually are any components that are contained in human blood. Examples of components tears include, but are not limited to, lipids, phospholipids, associated with membrane proteins, proteins (e.g. albumin, lysozyme, lactoferrin) and salt.

Depending on the biologically active means and forming a matrix substance used to produce the polymer matrix, can be adjusted or set adjustable selection of biologically active products of ophthalmic devices for extended periods of time. For example, if the medicinal product containing the COOH group, which are ionizable anionic groups are introduced, or immobilized in a polymer matrix, one or more positively charged proteins contained in the eyes or produced by the eyes (e.g., lysozyme, lactoferrin) can interact with the medication and cause the selection of drug from the polymer matrix. In this case, positively charged proteins cause the selection of medicines of ophthalmic devices. Although it is possible to allocate a certain number of biologically asset is wow tools of the ophthalmic device, due to passive diffusion (i.e., for the separation of biologically active funds do not require receipt of energy) or by diffusion, activated blinking (i.e. when the blinking provides energy to facilitate diffusion of biologically active products from the polymer matrix), it is minimal, so the selection of biologically active products caused by one or more components of tears, interacting with a biologically active agent and/or polymer matrix. In the example above, the positively charged protein allocates the drug due to electrostatic or ionic interactions with the drug. However, it is assumed that may have different mechanisms of extraction of biologically active products from the polymer matrix component tears, including, but not limited to, enzymatic cleavage of biologically active products, covalently associated with a polymeric matrix, the formation of hydrogen bond between the bioactive agent and component tears and hydrophobic/hydrophobic interactions between biologically active agent and one or more components of tears.

As noted above, the characteristics of the separation of biologically active products can be a special way to adjust or fo is inform by selecting a particular biologically active agents and form the matrix substances, used to produce the polymer matrix. It is also assumed that the biologically active agent can be modified so that the modified biologically active substance specifically interacted with one or more components of tears. For example, if in the eyes of the high concentration contains one or more lipids, the biologically active agent can be modified by hydrophobic groups to enhance the interaction between the bioactive agent and lipids, which ultimately may increase the secretion of biologically active products. Characteristics of extraction of biologically active products may vary. In one embodiment, the allocations include the initial selection of biologically active products (i.e. emissions), followed by continuous secretion of biologically active funds over a long period of time. Ophthalmic device may allocate a biologically active agent within 6 h to 30 days. In another embodiment, the ophthalmic device may allocate a biologically active substance with variable speed for 24 hours of Alternative biologically active substance or its part is not highlighted, and remains in the polymer matrix until it vitalisation or more components of tears. The interaction between the bioactive agent and polymer matrix regulates the characteristics of the extraction of biologically active products. As noted above, factors such as, for example, the pH value of the polymer matrix, the value of the PKandbiologically active funds and the distribution of biologically active funds between hydrophobic and water areas of the polymer matrix, contribute regulated secretion of biologically active products.

In addition, the factors described above, can be used for controlling the amount of biologically active agent that is introduced into the polymer matrix and, ultimately, in the ophthalmological device. Number of biologically active products, which entered into ophthalmological device and is allocated may vary. The dose depends on the severity and sensitivity of pathological conditions treated. If the ophthalmic device is a contact device, it is preferable if the device contains a number of biologically active products, sufficient to ensure a continuous selection for from several hours to 30 days, preferably within 24 hours the Specialists with General training in the art can easily determine optimum dosages, methods of the dosing and frequency.

EXAMPLES

The following examples are intended to provide professionals with a common training in the art a complete disclosure and description of how implemented and evaluated and compounds, compositions and methods described and claimed in the present invention, they are only typical and not intended to limit what the authors of the present invention consider its size. An effort is made to ensure the accuracy of the values (e.g., amounts, temperature, etc), but you must consider certain errors and deviations. Unless otherwise stated, expressed in parts of the content are mass, temperature is expressed in °C or ambient temperature and pressure is atmospheric or close to atmospheric. There are certain modifications and combinations of the conditions of the reactions, for example, the concentration of the component, the necessary solvents, mixtures of solvents, temperature, pressure ranges and other parameters of reactions and conditions that can be used to optimize the purity of the product and output used for methods. To optimize such conditions techniques requires only a small volume of standard and experimental research.

I. Kromolin-sodium

A. Kromolin-sodium: Lekarstvo the e tool introduced by absorption in the matrix Dailies

Kromolin-sodium is strongly absorbed by the matrix Dailies. The amount absorbed by impregnation from a solution concentration of 4% (equivalent ophthalmic solution) was about 1 mg. to About 100 μg passively stood out during a short period of ejection, remained at about 900 μg to highlight the mechanism of initiation. After passive diffusion allocation mechanism of initiation (using the vortex model of the eye) has led to a significant selection.

b. Kromolin-sodium: the drug is introduced directly into macromer nelfilcon

A mixture of nelfilcon and kromolin-sodium polymerizable obtaining membrane and from it cut out discs with a diameter of 1.5 cm and explored the characteristics of the selection. Compared allocations directly introduced and absorbed drugs described above. To directly put funds were made much smaller (about 20 μg per lens)than 1 mg per lens absorbirowawrzayasa of the 4% solution. Directly entered the drug had the advantage that passive allocation was almost zero due to the affinity of the drug to the matrix, but in the model eye was also found significant selection is about the mechanism of initiation.

II. Ketotifen fumarate

A. Ketotifen fumarate: the drug, introduced by absorption in the matrix Dailies

Ketotifen fumarate used in much lower concentrations in ophthalmic solution (0,025%)than kromolin sodium, which was shown in experiments on the introduction. Ketotifen fumarate absorbed from 0.025% solution in the lens in the amount equal to 35 μg, and a moderate amount stood out during a short period of release, in the matrix remained about 30 micrograms. This number is very significant for daily needs. Ketotifen fumarate was characterized by increased selection on the mechanism of initiation in the vortex model of the eye compared to passive diffusion. When the selection mechanism of initiation albumin had little effect, whereas positively charged proteins, such as lysozyme, resulted in significantly enhanced effect. The number of ketotifen fumarata released by the mechanism of initiation in the vortex model of the eye from one lens, in which the tool was introduced from 0.025% solution, was sufficient for daily needs.

b. Ketotifen fumarate: the drug is introduced directly into macromer nelfilcon

A mixture of nelfilcon and ketotifen fumarata has polymerizable obtaining membrane, cut out discs with a diameter of 1.5 cm and which was sledovali allocations. Compared allocations directly introduced and absorbed drugs described above. As in the case of kromolin-sodium, distributed in the matrix, the drug is introduced directly into the polymer matrix, has characteristics highlight different characteristics of the allocation of the absorbed drug. In the end, it is established that passive diffusion quickly reaches equilibrium (within 3 h) and the drug remains bound to the matrix, but the subsequent allocation by the mechanism of initiation (using the vortex model of the eye) provides a very effective additional allocation that was reinforced positively charged protein of tears, such as lysozyme.

III. ASM981

A. Direct injection of ASM981 in macromer nelfilcon

The addition of pimecrolimus (assuming your ASM981), which is synthesized by Novartis Pharma, in the solution to form macromer of nelfilcon increased fluid content in macromer. Simple addition of ASM981 led to the dilution of macromer and photopolymerization led to wet, heterogeneous product. The membrane containing 1% ASM981, was prepared by adding 1 g of the solution ASM981 to 5 g of macromer of nelfilcon, shaking for about 5 minutes, removing the lid of the vessel for removal the Oia excess water. Mass containing ASM981 of macromer was allowed to return to the original value of 5 it is usually performed by keeping the mixture overnight in a flat-bottomed shaking the device in a nitrogen atmosphere. Then the mixture was placed in a mould for the production of membranes and polymerizable by treatment with radiation static UV lamp. The mixture was successfully polymerizable with the formation of a homogeneous membrane and the membrane was opaque. Researched passive and what is happening with stirring allocation in the water and the selection is not found.

IV. Hyaluronan (HA)

A. Direct injection of hyaluronan in macromer nelfilcon

By the above method, a mixture of nelfilcon and different amounts of hyaluronan has polymerizable with the formation of the membrane. The amount of hyaluronan entered in macromer nelfilcon, was 2, 6.5 and 40 mg hyaluronan/g nelfilcon (30 wt.% aqueous solution). Used hyaluronan with a molecular mass of approximately 50 kDa, 100 kDa and 1 MDA.

b. The study membrane with hyaluronan

The allocation of hyaluronan of the membrane was investigated by changing the number and molecular weight hyaluronan entered in the matrix. Study selection was performed by placing each lens in a solution of 5 ml of artificial tears at 35°C. figure 1 shows the allocations of hyaluronan is a (introduction of 6.5 mg hyaluronan/g nelfilcon), having different molecular masses. Figure 1 shows that high molecular weight hyaluronan (~1 MDA) is characterized by a relatively constant release rate equal to from 2 to 48 hours figure 2 shows that increasing the amount of hyaluronan significantly affects the allocation of hyaluronan from the matrix.

Also investigated thermal stability of the membranes. The lens, made with the introduction of 6.5 mg/ml 1 MDA hyaluronan, was placed in a tube containing 6.5 mg/ml hyaluronan at pH 11. The tube containing 0.8 ml) was sealed and the solution was heated at 120°C for 40 minutes figure 3 shows the amount of hyaluronan released over time. Figure 3 shows that the matrix can protect hyaluronan from decomposition, since the dependence to highlight the similar dependence for the allocation of hyaluronan from the matrix, which was not heated.

V. Vortex model of the eye

The vortex model is a model in vitro selection of the eye, described in co-ownership at the same time regarded the publication of the patent application US No. 2006/0251696 Al (which in its entirety is included in the present invention as a reference). The experiment was carried out as follows. The contact lens is first dried with blotting paper and immediately was carefully placed in 100ð¼ðºð " extraction medium in vitro (for example, in vitro for centrifuges, scintillation vial, or preferably in microprobing Eppendorf) and the contents of the microtube was stirred for 15 using, for example, vortex mixer Vibrex. 1 the contents of the microtube was stirred with, for example, vortex mixer Vibrex for another 15 canstruction medium were removed from the Eppendorf microtube and was added 100 μl of fresh extraction medium. In between stirring the extracted samples were stored at 25°C. the Concentration of the introduced substances extracted from lenses can be identified by any method known to a person skilled in the technical field.

VI. The allocation of lysozyme on the mechanism of initiation

Figure 4 shows the characteristics of the selection of the dye rose Bengal from nelfilcon lenses placed in physiological solutions (SFF) and lysozyme. Figure 4 for lenses, which was first placed in a solution of lysozyme (0 minutes), Bengal pink stands out continuously. If the lens was placed in the solution SFF without lysozyme (about 150 min), there was no allocation of Bengal pink or were allocated small number. Similar allocations were observed when storing the lens in SFF within 8 weeks. The conclusion is that the lens nelfilcon, which entered the Bengal rose is new, stable in physiological solutions over long periods of time and at the same time, after placing it in a solution of lysozyme, which is a component of tears, of the lens is allocated Bengal rose.

In this application provides links to various publications. The disclosure of these publications in their entirety are included in the present invention as a reference, is intended for a more complete description of the compounds, compositions and methods proposed in the present invention.

In the compounds, compositions and methods proposed in the present invention, it is possible to make various modifications and changes. Other embodiments of the compounds, compositions and methods proposed in the present invention, apparent from consideration of the characteristics and practical application of the compounds, compositions and methods proposed in the present invention. It is assumed that the characteristics and examples are typical.

1. Ophthalmic device comprising a polymer matrix in which the polymer matrix comprises:
(i) a biologically active substance, which is immobilized in a polymer matrix due to the electrostatic interaction, hydrophobic/hydrophobic interactions, covalent joining of the polymer matrix, or any combination thereof; and
(ii) a carrier, VK is uchumi at least one ionic group, ionizable group, or a combination of both,
in which the carrier and the biologically active agent, introduced in the polymer matrix, distributed throughout the polymeric matrix and it ophthalmological device applicable for the initiated one or more components tears of separation of biologically active products from the polymer matrix in contact with tears in her eyes.

2. The device according to claim 1 in which the polymeric matrix is obtained by polymerization liquid composition containing actinic slivaushiesia prepolymer.

3. The device according to claim 2, in which prepolymer soluble in water.

4. The device according to claim 2, in which prepolymer includes water-soluble prepolymer slivaushiesia polyvinyl alcohol; water-soluble polyurethane with terminal vinyl group; a derivative of polyvinyl alcohol, polyethylenimine or polyvinylene; soluble in water slivaushiesia prepolymer polyurea; slivaushiesia polyacrylamide; slivaushiesia statistical copolymer vinylacetate, methyl methacrylate and co monomer; slivaushiesia copolymer of vinylacetate, vinyl acetate and vinyl alcohol; copolymers of simple ether-ester with schilawski side chains; extensive prepolymer polyalkyleneglycol-urethane; prepolymer polyalkyleneglycol-Tetra(meth)acrylate; slivaushiesia prepolymer the allylamine-gluconolactone or any mixture.

5. The device according to claim 2, in which prepolymer includes a silicon prepolymer.

6. The device according to claim 2, in which prepolymer is polyhydroxyalkane having a molecular weight that is at least about 2000, and including in terms of the number of hydroxy groups in the compound is from about 0.5 to about 80% of units of formula I-III:



where R3represents hydrogen, C1-C6is an alkyl group or cycloalkyl group; R represents a linear or branched alkalinity divalently radical containing up to 12 carbon atoms; R1represents hydrogen or alkyl containing up to 7 carbon atoms; R2represents refinancing electron slivaushiesia radical containing up to 25 carbon atoms; R7represents a primary, secondary or tertiary amino group or a Quaternary amino group of the formula N+(R')3X-in which each R' independently represents hydrogen or C1-C4alkyl radical, and X is a counterion selected from the group comprising HSO4, F-, Cl-, Br, I, CH3Soo-HE-, F-or H2RHO4-; R8is particularly the radical monobasic, dibasic or trehosnovnoy saturated or unsaturated aliphatic or aromatic organic acid or sulfonic acid.

7. The device according to claim 6, in which polyhydroxyalkane has a molecular weight that is at least about 2000, and includes in terms of the number of hydroxy groups in the compound of from about 0.5 to about 80%, from 1 to 50%, from 1 to 25%, or from 2 to 15% of units of formula I in which R represents a lower alkalinity divalently radical containing up to 6 carbon atoms, R1represents hydrogen or alkyl containing up to 7 carbon atoms, R3denotes hydrogen, and R2denotes a radical of the formula (IV) or (V)


where p and q independently from each other 0 or 1, and R5and R6independently of one another represent lower alkalinity divalently radical containing from 2 to 8 carbon atoms, Allenby divalently radical containing from 6 to 12 carbon atoms, a saturated divalent cycloaliphatic group containing from 6 to 10 carbon atoms, allenallenaleen or alkalinity divalently radical containing from 7 to 14 carbon atoms or allenallenallen divalently radical containing from 13 to 16 carbon atoms, and R4represents refinancing school is developing a radical, containing from 2 to 24 carbon atoms.

8. The device according to any one of claims 1 to 7, in which the biologically active agent and the polymer matrix contains at least one ionic group, ionizable group, or a combination of both.

9. The device according to any one of claims 1 to 7, in which the biologically active substance is a drug, amino acid, polypeptide, protein, nucleic acid, or any combination thereof.

10. The device according to any one of claims 1 to 8, in which the biologically active agent comprises a drug, which is rebamipide, alptigin, cromoglicate, kromolin sodium, cyclosporine, nedocromil, levocabastine, lodoxamide, ketotifen, pimecrolimus, hyaluronan or its pharmaceutically acceptable salt or ester.

11. The device according to claim 10, in which the carrier comprises a polymer containing one or more carboxylate.

12. The device according to claim 10, in which the carrier includes polyacrylic acid, polymethacrylic acid or polyethylenimine.

13. The device according to any one of claims 1 to 12, ophthalmic device, characterized in that it can be stored in the packaging solution for a long period of time without significant leaching, where leaching is less than about 20% after storage for 1 g is Yes in the packaging solution.

14. The device according to claim 1, in which the biologically active substance is released from the polymer matrix within 6 h to 30 days.

15. The device according to any one of claims 1 to 14, which is a contact lens or an artificial lens.

16. The method of manufacturing ophthalmic device according to claim 1, which includes stages:
a. mixing forming a matrix substance, carrier and biologically active products, where the carrier includes at least one ionic group, ionizable group, or a combination;
b. introducing the mixture obtained in stage (a), in the form for the manufacture of the device;
C. polymerization forming a matrix substance in the form with the formation of the device, where the carrier and the biologically active agent, introduced in the polymer matrix, distributed throughout the polymeric matrix and where the biologically active agent immobilized in the polymeric matrix due to the electrostatic interaction, hydrophobic/hydrophobic interactions, covalent joining of the polymer matrix, or any combination thereof, in which the biologically active agent interacts with the polymer matrix and immobilized in the polymeric matrix formed during the polymerization forming a matrix substance.

17. The method according to clause 16, which forms a matrix substance includes actinic with whom Ivashina prepolymer.

18. The method according to clause 16, in which the device received a manner that is not subjected to the extraction.

19. The method of delivery of biologically active products subject, comprising contacting the eye of the subject with the device according to claim 1, in which one or more components of tears secretes biologically active agent from the device.



 

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8 cl, 5 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to an orally dispersed tablet containing: max. 15 wt % of a low-dose therapeutically active substance selected from domperidone, mequitazine, codeine (base) and loperamide hydrochloride, 55 wt % to 70 wt % of mannitol of particle size of 30 mcm to 300 mcm; min. 2 % of maltodextrine; 3.5 wt % to 8 wt % of sodium croscarmellose; 10 wt % to 20 wt % of microcrystalline cellulose; 0.5 wt % to 1.5 wt % of magnesium stearate; and 1 wt % to 5 wt % of a corrective (correctives) and sweetener (sweeteners). A tablet is presented in the form of a combination of internal and external phases. The internal phase contains said therapeutically active substance, mannitol, maltodextrine and approximately a half of sodium croscarmellose. The external phase contains approximately a half of sodium croscarmellose, microcrystalline cellulose, magnesium stearate, and also correctives and sweeteners. The tablets are applied for nausea and vomiting.

EFFECT: dispersed tablets under the invention are orally decomposed for 20-40 s, have low fragility and sufficient strength.

17 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry. A pelletised form of amison contains the active substance amison-N-methyl-4-benzylcarbamidopyridinium iodide, as an excipient - lactose, basic magnesium carbonate, or dibasic calcium phosphate, or pre-gelled starch, and also microcrystalline cellulose, as binding agents - saccharose and povidone, as an anti-cleavage agent - copolyvidone, as a desintegrant - crospovidone or sodium croscarmellose and as sliding agents - stearic acid, and/or a calcium stearate, and/or magnesium stearate. An amison pellet can be film-coated. The amison pellet is prepared by wet granulation.

EFFECT: amison pellets under the invention are characterised by high fracture and abrasion strength and have no cleavages.

6 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly a composition containing a lyophilised salt of vinflunine or vinorelbine stable at room temperature. A pharmaceutical composition containing a water-soluble salt of vinflunine or vinorelbine stable at room temperature where said salt is presented in the lyophilised form prepared in the presence at least of one carbohydrate of specific pH and relation of the water-soluble salt of vinflunine or vinorelbine and carbohydrate.

EFFECT: composition is stable.

9 cl, 2 dwg, 6 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: solid dosage form contains valsartan, amlodipine, hydrochlorothiazide and pharmaceutically acceptable additives and is presented in the form of a two-layer tablet. Quantitative proportions of valsartan, amlodipine and hydrochlorothiazide are selected from the following: 160 mg/12.5 mg/5 mg, 160 mg/12.5 mg/10 mg, 160 mg/25 mg/10 mg, 160 mg/25 mg/5 mg and 320 mg/25 mg/10 mg. Preferentially, amlodipine is used in the form of amlodipine besylate. The two-layer tablet can contain valsartan and hydrochlorothiazide in the first layer, and amlodipine in the second layer, or valsartan in the first layer, and amlodipine and hydrochlorothiazide in the second layer. Also, there are described methods for making a two-layer tablet.

EFFECT: two-layer tablet under the invention with the fixed combination of valsartan, amlodipine and hydrochlorothiazide have the biological properties equivalent to those of a free combination of said medical agents.

17 cl, 11 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: micellar composition of an amphiphilic block copolymer contains taxane, an amphiphilic block copolymer containing a hydrophilic block (A) and a hydrophobic block (B), and an agent for osmolality regulation. The amphiphilic block copolymer is a block copolymer of A-B, A-B-A or B-A-B type. The hydrophilic block (A) has number-average molecular weight 500-20000 dalton, and the hydrophobic block (B) has number-average molecular weight 500-20000 dalton. The amphiphilic block copolymer contains 40-70 wt % of the hydrophilic block (A) of weight of the copolymer. Hydroxyl terminal groups of the hydrophobic block (B) can be protected by fatty-acid groups. The agent for osmolality regulation represents an inorganic salt. What is also described is a method for preparing the given composition. The composition exhibits good stability that allows preventing fast release of a medical preparation of taxane and can improve required pharmacological action.

EFFECT: method ensures high effective preparation of the composition.

14 cl, 2 dwg, 3 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: micellar composition of an amphiphilic block copolymer contains taxane, an amphiphilic block copolymer containing a hydrophilic block (A) and a hydrophobic block (B), and an agent for osmolality regulation. The amphiphilic block copolymer is a block copolymer of A-B, A-B-A or B-A-B type. The hydrophilic block (A) has number-average molecular weight 500-20000 dalton, and the hydrophobic block (B) has number-average molecular weight 500-20000 dalton. The amphiphilic block copolymer contains 40-70 wt % of the hydrophilic block (A) of weight of the copolymer. Hydroxyl terminal groups of the hydrophobic block (B) can be protected by fatty-acid groups. The agent for osmolality regulation represents an inorganic salt. What is also described is a method for preparing the given composition. The composition exhibits good stability that allows preventing fast release of a medical preparation of taxane and can improve required pharmacological action.

EFFECT: method ensures high effective preparation of the composition.

14 cl, 2 dwg, 3 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: micellar composition of an amphiphilic block copolymer contains taxane, an amphiphilic block copolymer containing a hydrophilic block (A) and a hydrophobic block (B), and an agent for osmolality regulation. The amphiphilic block copolymer is a block copolymer of A-B, A-B-A or B-A-B type. The hydrophilic block (A) has number-average molecular weight 500-20000 dalton, and the hydrophobic block (B) has number-average molecular weight 500-20000 dalton. The amphiphilic block copolymer contains 40-70 wt % of the hydrophilic block (A) of weight of the copolymer. Hydroxyl terminal groups of the hydrophobic block (B) can be protected by fatty-acid groups. The agent for osmolality regulation represents an inorganic salt. What is also described is a method for preparing the given composition. The composition exhibits good stability that allows preventing fast release of a medical preparation of taxane and can improve required pharmacological action.

EFFECT: method ensures high effective preparation of the composition.

14 cl, 2 dwg, 3 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical and cosmetic industry, particularly an agent applied to skin. A vesicle applied to skin containing α,ε-bis(γ-N-(C10-30)acylglutamyl)lysine and/or its salt; ceramide and/or its derivative; and one or more ethers selected from glycerin ether of fatty acid, polyglycerin ether of fatty acid and glycerin ether of pyroglutamic acid taken in certain proportions. The therapeutic agent for external application to skin containing a certain amount of the vesicle.

EFFECT: vesicle and based therapeutic agent are stable, effectively encapsulates an active ingredient that allows it reaching true skin, effectively suppress transepidernal dehydration.

6 cl, 13 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, particularly to ophthalmology. An aqueous liquid ophthalmic composition contains hyaluronic acid in the concentration of 0.05-0.4% or its pharmaceutically acceptable salt, and additionally contains gluconic acid and its salt with a metal, but does not contain chlorhexidine or its salt. A method for improving the viscosity stability of the aqueous eye-drop ophthalmic composition containing hyaluronic acid is conditioned by introducing gluconic acid and its salt with the metal.

EFFECT: invention provides slowed-down viscosity reduction of the aqueous ophthalmic composition.

6 cl, 6 tbl, 6 ex

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