Eye device, capable of delivering therapeutic preparation and method of obtaining thereof
SUBSTANCE: group of inventions relates to ophthalmology and is intended for delivery of a therapeutic preparation into an eye. An eye device contains a non-biodegradable mass of material, which includes a hydrophobic component, represented in an amount, sufficient for contact angle of the material to be larger than 50° and formed of at least 80% by weight of acryl material. The device also contains the therapeutic preparation, located on the peripheral surface of the material mass. The therapeutic preparation is hydrophobic and has a coefficient of distribution in the system octane/water PC Log P, equal at least to 1.0. The material mass is formed for introduction into the human eye. Attraction of the therapeutic agent to the hydrophobic part controls a delayed release of the therapeutic preparation in such a way that less than 50 wt % of the therapeutic preparation is released from the eye device into the basic salt solution (BSS) within at least three days. The method of the eye device obtaining includes submergence of the material mass into the solution, which contains a solvent and the therapeutic preparation.
EFFECT: application of the group of inventions ensures delivery of the therapeutic preparation into the eye within long period of time.
19 cl, 12 dwg, 1 tbl, 12 ex
Cross-reference to related applications
This application claims the priority of provisional patent application U.S. No. 61/082352, filed July 21, 2008, under 35 U.S.C. §119 full contents of which are incorporated into this description by reference.
The technical field of the invention
The present invention relates to an ophthalmic device, which is loaded with a therapeutic agent. In particular, the present invention relates to ophthalmic device (e.g., intraocular lens (IOL)), which is loaded with a therapeutic agent (e.g., anti-inflammatory, antiproliferative agent, an immunosuppressant, or any combination thereof), so that the device is able to deliver a therapeutic agent to the eye for a long period of time after the device is introduced into the eye.
Prior art inventions
In recent years, steadfastly increasing number of eye operations, such as for cataract surgery where an intraocular lens (IOL) (IOL)) is injected into the patient's eye. IOL design and set in different areas of the eye, and they can be used to Supplement or correction, provide natural lens of the eye, or can replace the natural lens of the eye. Lenses that complement or cor is antiroot vision without replacing the natural lens of the eye, usually called phakic lenses, while lenses that replace the natural lens, usually called aphaktic lenses. These lenses can be positioned in the anterior chamber (PC (AC)) eye (phakic lens PC) or the rear camera (LC (PC)) eye (phakic lens gear).
While IOLs provide millions of patients improved vision, IOL can also have disadvantages. In particular, the IOL can be causes of eye diseases, such as secondary cataract or posterior capsule opacification (FCL (PCO)).
To help prevent PPC is a therapeutic agent, such as anti-inflammatory agents or anti-proliferative tools that can be entered in eyes after introducing IOL. Such a therapeutic agent is usually injected through the methods of local delivery, such as ointments and eye drops. Such methods, however, have at least two significant drawbacks. First, for such locally injected therapeutic agents may be difficult to achieve the target areas of the eyes, because the eyes can behave as an essential physiological barriers that inhibit the penetration of therapeutic agents into the back of the eye. Secondly, the effectiveness of such local delivery methods usually depends on the commitment of the patient to the treatment prescribed in the scheme of applying the eye ointment and and drops.
In light of these shortcomings, it is desirable to provide an ophthalmic device that is inserted into the eye and which delivers the desired amount of therapeutic agent over a period of time after surgery for cataract. Such a device can be used to deliver tools that help to avoid PPC. Moreover, the introduction of such a device in the eye after the operation or at another time may additionally or alternatively be used to deliver therapeutic agents that inhibit other eye diseases or disorders, such as glaucoma, macular edema, retinopathy, macular degeneration, chronic inflammation, infection or similar.
For the effective design of such devices requires a mechanism by which a therapeutic agent is continuously or periodically released from the device over a desired period of time. However, during long periods of release control the release of therapeutic agents can be extremely difficult. Mainly, have found an Association between certain ophthalmic materials and release of therapeutic agents from such materials, and such connection may be used to provide the desired periods of release.
The essence of the image is possible
The present invention is directed to an ocular device that is at least partially made of ophthalmic material. Ophthalmic material is usually acrylic, hydrophobic, or both. The ocular device is usually loaded with therapeutic agent. In preferred variants of the invention, therapeutic agent and ophthalmic material are hydrophobic to facilitate the filling material means or to aid in lengthening the release of another therapeutic agent of the ophthalmic material.
The ocular device may be appropriate for the location in the eye or location on the outer surface of the eye. In a preferred variant of the invention, the ocular device that is partially or completely formed from the ophthalmic material is an IOL or device suitable for location in the eye with IOL.
Brief description of figures
The features and inventive aspects of the present invention will be more apparent upon reading the following detailed description, claims and figures, for which the following is a brief description:
Figure 1 is a graph showing the approximate release drugs over time the La ocular device in accordance with one aspect of the present invention.
Figure 2 is another graph of the approximate release drugs over time for ophthalmic device in accordance with one aspect of the present invention.
Figure 3 is another graph of the approximate release drugs over time for ophthalmic device in accordance with one aspect of the present invention.
Figure 4 is a graph showing the approximate release drugs over time for a variety of ophthalmic devices in accordance with one aspect of the present invention.
Figure 5 is another graph of the approximate release drugs over time for a variety of ophthalmic devices in accordance with one aspect of the present invention.
6 is a graph showing fluorescence intensity over time, as the rate of release of the medicinal product in accordance with one aspect of the present invention.
7 is a comparative graph of the release of drugs various drugs in accordance with one aspect of the present invention.
Fig is a representation of an exemplary ophthalmic device in accordance with one aspect of the present invention.
Fig.9 represents the FDS is the first image of another exemplary ophthalmic device in accordance with one aspect of the present invention.
Figure 10 is a view of another exemplary ophthalmic device in accordance with one aspect of the present invention.
11 and 12 are graphs of the approximate release drugs over time for the coated ophthalmic device in accordance with one aspect of the present invention.
Detailed description of the invention
The present invention is based on the provision of eye device that is at least partially formed of ophthalmic material that is appropriate for the position, but more preferably within a patient's eye. The device may also be located on or inside the human body, however, the device is particularly desirable for ophthalmic use.
Ophthalmic material device suitable for loading therapeutic agent being delivered into the eye. Ophthalmic material may also be suitable for use in intraocular lens (IOL), although, as discussed further below, the material can be presented in the form of an IOL or other configuration. Material or one or more components of the material is, as a rule, relatively hydrophobic and preferably a therapeutic tool also Prowse is some degree of hydrophobicity. In one preferred embodiment, the invention provide material in the form of aphaktic IOL, and a therapeutic tool includes a significant amount of anti-inflammatory drugs to reduce inflammation that can occur after surgery for cataract.
Ophthalmic material is preferably a polymeric material, which consists of a hydrophobic component, a hydrophilic component, or both. Ophthalmic material is, as a rule, acrylic, that, as used in the present description, means that the material includes at least one acrylate. Ophthalmic material may also include other ingredients, as further explained below.
The hydrophobic component may consist of a single monomer or a variety of different monomers, such monomers can form polymers, which may be homopolymers or copolymers. Each of the monomers included in the hydrophobic component may be hydrophobic or provide hydrophobicity eye material during formation. Preferably a significant portion (e.g., at least 60, 80, or 95 wt.% or all of the hydrophobic component is formed from acrylate. Suitable monomers for the hydrophobic component include, but are not limited to: 2-ethylphenols the methacrylate; 2-ethylenemethacrylic; 2-ethylthiomethyl; 2-ethyldiethanolamine; 2-ethylenevinylacetate; 2-ethylenevinylacetate; fenilsalicilat; phenylacrylate; bezelmaterial; benzoylacrylate; 2-fenilatilmalonamid; 2-phenylethylamine; 3-phenylpropionitrile; 3-phenylpropylamine; 4-phenylbutyrate; 4-phenylbutyramide; 4-methylphenylethyl; 4-methylphenylacetic; 4-methylbenzonitrile; 4-methylbenzylamine; 2-2-methylphenylacetonitrile; 2-2-methylphenylethylamine; 2-3-methylphenylacetonitrile; 2-3-methylphenylethylamine; 2-4-methylphenylethylamine; 2-4-methylphenylethylamine; 2-(4-propylphenyl)ethyl methacrylate; 2-(4-propylphenyl)acrylate; 2-(4-(1-methylethyl)phenyl)ethyl methacrylate; 2-(4-(1-methylethyl)phenyl)acrylate; 2-(4-methoxyphenyl)ethyl methacrylate; 2-(4-methoxyphenyl)acrylate; 2-(4-cyclohexylphenol)ethyl methacrylate; 2-(4-cyclohexylphenol)acrylate; 2-(2-chlorophenyl)ethyl methacrylate; 2-(2-chlorophenyl)acrylate; 2-(3-chlorphenyl)ethyl methacrylate; 2-(3-chlorophenyl)acrylate; 2-(4-chlorophenyl)ethyl methacrylate; 2-(4-chlorophenyl)acrylate; 2-(4-bromophenyl)ethyl methacrylate; 2-(4-bromophenyl)acrylate; 2-(3-phenylphenyl)ethyl methacrylate; 2-(3-phenylphenyl)acrylate; 2-(4-phenylphenyl)ethyl methacrylate; 2-(4-phenylphenyl)acrylate; 2-(4-benzoylphenyl)ethyl methacrylate; 2-(4-benzoylphenyl)acrylate; combinations thereof, or the like. In preferred embodiments implement the program of the invention the hydrophobic component comprises or essentially fully formed from (i.e. at least 90 wt.%) one or more materials that are phenylacrylate or methacrylates, especially those selected from the group consisting of 2-generatesecret (PEA), 2-generatesecret (PEMA).
The hydrophobicity of the hydrophobic component can usually be measured in accordance with the methodology supine drops. To measure the hydrophobicity of the hydrophobic ingredients component and only the hydrophobic component can be converted in accordance with the Protocol cure for ocular device for producing solid flat substrate. Of course, for this treatment, the amount of curing means may, if desired, be adjusted. In particular, the hydrophobic component is usually a percentage of all curable material in ophthalmic device and the amount of curing agent may be adjusted to the same percentage of the total curing agent that forms an ocular device. Then, in accordance with the methodology supine drop, drop of water is placed (or allow to fall from a certain distance) on the surface of the substrate. When the liquid is deposited, using a goniometer to measure the angle of contact. For the purposes of the present invention the ingredients, especially the monomers that contribute to the receipt of such a contact angle greater than 50° regarded part of the hydrophobic component, and preferably, so the contact angle measured in this way was more than 50°, typically more than 55°, and more likely more than 60°.
The hydrophilic component, when included, may comprise a single monomer or a variety of different monomers, such monomers can form polymers, which may be homopolymers or copolymers. Each of the monomers of the hydrophilic component must be hydrophilic or to ensure the hydrophilicity of the ocular material during its formation. As the hydrophobic component, for a significant part (e.g., at least 60, 80, or 95% by mass or fully) a hydrophilic component preferably comprises acrylate. Suitable hydrophilic monomers for component include, but are not limited to: 2-hydroxyethylmethacrylate; 2-hydroxyethylacrylate; N-vinylpyrrolidone; glycomimetic; glycerinated; mono - and dimethacrylate of polyethylene oxide; and mono - and diacrylates of polyethylene oxide. In preferred variants of the invention, the hydrophilic component comprises or essentially fully formed from (i.e. at least 90 wt.%) one or more monomers, which are hydroxyethylacrylate or methacrylates, such as hydroxyethylmethacrylate (HEMA).
The hydrophilicity of the hydrophilic component can be measured in the same way, the cat is who described hydrophobic component. For the purposes of the present invention the ingredients, especially the monomers that contribute to advancing contact angle of the hydrophilic substances to below 40°, are considered part of the hydrophobic component and it is preferable that the contact angle measured in this way was less than 40°, typically less than 35 and probably less than 30°.
Ocular device according to the present invention may additionally include a variety of additional ingredients, which may or may not be hydrophobic or hydrophilic ingredients, as further described below. Such ingredients may include, without limitation, plasticizers, UV absorbers, polymerizable tools, curing and/or crosslinking means, combinations thereof and the like.
It is envisaged that many different compounds can be used as polimerizuet, curing and/or crosslinking means for polymerization and crosslinking of the ocular device as necessary to obtain the polymer matrix. As examples, a peroxide such as hydrogen peroxide benzophenone or peroxocarbonate (for example, bis-(4-tert-butylcyclohexyl)PEROXYDICARBONATE) or azonitrile, such as azobisisobutyronitrile and the like, can be used to initiate polymerization and/or crosslinking hydrophobic component, a hydrophilic component Il is both. Suitable crosslinking agents can also include, for example of ethylene glycol dimethacrylate, diethylene glycol dimethacrylate, alismataceae, dimethacrylate 1,3-propane diol, alismataceae, dimethacrylate 1,6-hexandiol, dimethacrylate of 1,4-butanediol and the like. Preferred cross-linking means are of ethylene glycol dimethacrylate (EGDMA) and diacrylate 1,4-butanediol (BDDA). In General, the amount of any of the used polymerization initiators, cross-linking means or both will be about 10% (mass/mass) or less of ophthalmic material of the present invention.
Any material that absorbs ultraviolet light included in the ophthalmic material is usually a compound that absorbs ultraviolet light (i.e. light having a wavelength shorter than about 400 nm), but does not absorb substantial amounts of visible light. Compound that absorbs ultraviolet light, may be included in the mixture of monomers and captured in the polymer matrix, when the mixture of monomers is polymerized. Suitable connections, ultraviolet absorbent include substituted benzophenone such as 2-hydroxybenzophenone and 2-(2-hydroxyphenyl)benzotriazole and tin compounds, such as O-methyl, tinuvin R. the UV Absorber can be captured in the polymer matrix only through physical capture or can also re herawati with the matrix.
In addition to the material that absorbs ultraviolet light, ophthalmic devices, made of ophthalmic material of the present invention, can include colored dyes, such as yellow dyes described in U.S. patent No. 5470932, which is included in the present description for any purpose.
The ocular device is usually formed by polymerization and/or crosslinking. In particular, the ingredients ophthalmic material is combined, and the components that make up the polymer, particularly a hydrophobic component, a hydrophilic component, or both, are polymerized and preferably stitched together to produce the polymer matrix. Preferably, although not necessary, during the process of polymerization and/or crosslinking is heated. While usually it is envisaged that the ophthalmic material of the present invention may be a thermoplastic, it is generally preferable that such a material has been thermoset.
Additional ingredients may or may not be part of the hydrophobic component or the hydrophilic component of the ophthalmic material. For clarity, these ingredients, especially ultraviolet absorbers, and means for polymerization and/or crosslinking should be regarded only as part of a hydrophobic or hydrophilic components, if they come in the reaction (i.e. react x is mikeski) in the polymer matrix with the components and they are required hydrophobic or hydrophilic characteristics in the formation of the ocular device. Therefore, for example, a crosslinking agent diacrylate 1,4-butanediol will be treated as part of a hydrophobic component, as it usually responds in a polymer matrix and takes the necessary hydrophobic characteristics. On the contrary, the UV absorber based on tin, which only physically captured (not responding) polymer matrix, will not be considered part of, or any hydrophobic or hydrophilic components.
At some point before and/or during the polymerization and crosslinking, ophthalmic material is usually located in the casting form for molding material in ocular device. Usually it is envisaged that the ophthalmic material can be shaped in any desired configuration that is appropriate for a local location on the eye or location in the vitreous body or depot injections into the vitreous body in the eye. Eye device and/or ophthalmic material may be located partially in the eye (for example, as a tube) or essentially completely in the eye (for example, intraocular lenses or component associated with the lens). In the most preferred embodiment of the invention the ophthalmic material molded in the IOL, which has one or more convex surfaces and refractive index, suitable for promotion, or both the cookies of view of the human eye. IOL may be the PC IOL, the IOL gear or aphaktic. Also envisaged that the device may be molded as an IOL scleral buckling. For purposes of illustration Fig shown intraocular lens device 10 having the intraocular lens 12 and scleral 14, each or both of which can be eye devices that are made up of ophthalmic material of the present invention. It is envisaged that the ocular device according to the present invention can be part of the IOL or scleral lenses or can be mass (e.g., disk) of material that is separate from the IOL, which can be inserted in the eye with or without IOL. Also for illustration purposes, figure 9 shows the disk 18 in the form of a ring, which can be located in the eye with IOL.
In one preferred embodiment of the invention, which is illustrated in figure 10, the ophthalmic material can be shaped as a capsular tension ring 24. In this embodiment of the invention the tension ring 24 is located in the capsular bag 26 of the eye to maintain tension on the and/or space in the capsular bag 26. This ring 24 can essentially cover IOL 28, which is located in the capsular bag 26 and, mostly, usually has no obstruction of view through the IOL 28.
You must understand that the ophthalmic material on astasia invention may be biodegradable or nonbiodegradable in the eye. However, it is generally preferable to ophthalmic material was part of the structure, which is durable in the eye and is, therefore, usually nonbiodegradable in the eye.
When the ocular device create therapeutic agent is associated with ocular device, so that when applying the device to the eye it can ensure the release of therapeutic agent over an extended period of time. Mostly it was found that the hydrophobic component of the present invention, especially when the component is acrylic, provides affinity for hydrophobic therapeutic agents, where the agents have a tendency to the dissociation of the hydrophobic component in an aqueous environment at a speed substantially slower than the funds dissociable from other materials. As such, the hydrophobic component can be used to deliver therapeutic agents into the eye or other water environment for a long period of time.
Hydrophobic therapeutic agent determines in the present description as any tool that is moderately soluble in water (for example, not fully soluble in the medium in a concentration in which it is introduced into the aqueous composition), especially when immersed in this aqueous environment without the means to facilitate restorani the funds. Usually it is envisaged that therapeutic agent can include one or more funds. A preferred class of therapeutic agents include eye medicines, especially hydrophobic and/or nizkorazmernye eye medications. Non-limiting examples include funds from glaucoma; antiangiogenic tools; anti-infective tools; anti-inflammatory agents; antiproliferative funds; growth factors and inhibitors of growth factors; immunosuppressants; and anti-allergic drugs. Funds from glaucoma include beta-blockers, such as timolol, betaxolol, levobetaxolol and carteolol; miotti, such as pilocarpine; carbonic anhydrase inhibitors such as brinzolamide and dorzolamide; prostaglandins, such as travoprost, bimatoprost and latanoprost; serotonergic means; muscarinic means; dopaminergic agonists; adrenergic agonists, such as apraclonidine, brimonidine. Antiangiogenic drugs include acetate anecortave (RETAANE.TM., Alcon.TM Laboratories, Inc. Of Fort Worth, Tex.) and inhibitors of the receptor tyrosinekinase. Anti-infective tools include quinolones, such as ciprofloxacin, moxifloxacin and Gatifloxacin, and aminoglycosides such as tobramycin and gentamicin. Anti-inflammatory agents include non-steroid and steroid is s anti-inflammatory drugs, such as suprofen, diclofenac, bromfenac, Ketorolac, nepafenac, rimexolone and tetrahydrocortisol. Antiproliferative tools include, without limitation, colchicine, mitomycin, methotrexate, daunomycin, daunorubicin and 5-fluorouracil. Growth factors include, without limitation, epidermal growth factor (EGF), fibroblast growth factor (FGF), growth factor hepatocyte (HGF), nerve growth factor (NGF), platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF-β). Immunosuppressants include, without limitation, the calcineurin inhibitors (eg, cyclosporine) and inhibitors of the target of rapamycin in mammalian cells (MTOR) (e.g., sirolimus, zotarolimus, everolimus, temsirolimus); anti-allergic drugs include loratadin, epinasty. Ocular drug may be present in the form of pharmaceutically acceptable salts, such as timolol maleate, tartrate of brimonidine or diclofenac sodium. As understood by the specialist in the field of engineering, non-steroidal anti-inflammatory drugs (NSAIDs), such as nepafenac, are particularly desirable to facilitate the prevention of secondary cataract.
A therapeutic agent can be applied to ophthalmic material and/or device in particle form or another. If a therapeutic tool or part is in the form of particles, in one of the variations is the embodiment of the invention it may be, preferably milled or particles otherwise treated to a very small size. It may even be desirable to process the particles to submicron size or even to nanoparticles.
Usually it is preferable that a therapeutic tool showed the degree of hydrophobicity, such that a therapeutic tool had a relatively high log P of the distribution coefficient (PC Log P), which can be determined in accordance with Sangster, James (1997) Octanol-Water Partition Coefficients, Fundamentals and Physical Chemistry, vol.2 of Wiley Series in Solution Chemistry, Chichester, John Wiley &Son Ltd. [ISBN 978-0471973973]. Usually, therapeutic agent has a PC Log P of, at least, 1,0, usually, at least, of 1.6, still more typically at least 2.0 or even probably at least a 2.5. For a therapeutic agent comprising two or more hydrophobic substances, it is preferable that both tools had a PC Log P greater than these values.
Many different protocols can be used for applying a therapeutic agent to an ocular device. Usually it is envisaged that therapeutic agent can react with the formation of the connection with ophthalmic material of the ocular device. Alternative or additional therapeutic agent can be associated with ophthalmic material other forces have tendentsiy.ozhidat therapeutic agent in contact with or near ophthalmic material. Without communication with theory believe that such forces are hydrophobic interactions, forces van der Waals forces, physical capture, hydrogen bonds, forces of electric charges, or any combination thereof.
In one preferred variant of the invention, therapeutic agent is dissolved in a solvent such as acetone, methanol, benzene, toluene, alcohol, combination or similar with obtaining a solution of a therapeutic agent. Ophthalmic material, ophthalmic device, or both dipping and impregnating solution for a period of time. After that, ophthalmic material, ophthalmic device, or both are removed from the solution and dried, e.g., heat and/or vacuum, so that some amount of a therapeutic agent remains on the ophthalmic material. Means for applying to the device is usually looking at the outside peripheral surfaces formed of ophthalmic material, although the tool may be located on the inside.
The amount of therapeutic agent, located on the ophthalmic material can vary widely depending on therapeutic agent and the desired dosage means. Usually the total mass of a therapeutic agent that is located on ophthalmicus the m material is at least about 0.01 micrograms and is typically less than about 1 milligram. In a particularly preferred embodiment of the invention, where therapeutic agent is completely or essentially completely NSAIDs, such as nepafenac, ophthalmic device is an intraocular lens (for example, aphaktic IOL) or a ring for placement in the capsular bag (e.g., capsular tension ring), the amount of therapeutic agent is typically at least about 5 nanograms and usually at least about 10 micrograms and is usually less than about 10 milligrams, and more often less than about 500 micrograms.
While the hydrophobic component of the ophthalmic material tends to attract a hydrophobic therapeutic agent, a hydrophilic component, when included, can not provide the same attraction. Essentially, it was found that the inclusion of the hydrophilic component has a tendency to accelerate the release of a therapeutic agent ophthalmic material and/or device. Therefore, in a preferred embodiment of the invention ocular ophthalmic device or material can include a balance of hydrophobic and hydrophilic acrylate to achieve the desired output or release profile of therapeutic is the means. By incorporating large quantities of the hydrophilic component, the release of a therapeutic agent can be accelerated.
The rate of release of a therapeutic agent can vary widely depending on therapeutic agent and the properties of the ophthalmic material. Moreover, the rate of release of a therapeutic agent can, at least to some extent, vary depending on the patient, which apply eye device. However, a constant measure of the rate of release can be developed by immersing the ocular device in a balanced salt solution (BSS) and measuring the release at different time intervals. The specificity of this measurement are discussed in the examples and the comparative data below. For the present invention BSS is a sterile physiological balanced salt solution of sodium chloride (NaCl), potassium chloride (KCl), calcium chloride (CaCl2-H2O), magnesium chloride (MgCl2-OH2O), sodium acetate (C2H3NaO2-3H2O) and sodium citrate (C6H5Na3O7-2H2O). BSS is isotonic to the eye tissues. Each ml contains: sodium chloride of 0.64%, potassium chloride of 0.075%, calcium chloride 0,048%, magnesium chloride 0.03%, sodium acetate 0,39%, citrate N. the Tria 0,17%, sodium hydroxide and/or hydrochloric acid (for pH regulation) and the rest is water.
Usually for the present invention preferably less than 80% or even less than 50 wt.% a therapeutic agent released from the ocular device in the BSS during the period, which is at least three days, usually at least one week, more typical, at least two weeks, probably at least 30 days and even possibly at least 90 or 180 days and preferably more than 50% or even more than 80 wt.% a therapeutic agent would be released in BSS during the period of time that is less than 730 days, usually less than 365 days, more often less than 180 days and even possibly less than 90 days. In a preferred embodiment of the invention, where therapeutic agent is completely or essentially completely (i.e., at least 90 wt.%) non-steroidal anti-inflammatory drugs, such as nepafenac, preferably less than 80% or even less than 50 wt.% a therapeutic agent would be released in BSS during the period of time that is at least 2 days, more often, at least one week and more typical, at least 10 days and preferably more than 50% or even more than 80 wt.% a therapeutic agent would be released in BSS within periodaverage, which is less than 180 days, typical less than 45 days, more typical less than 25 days and even possibly less than 15 days.
In addition to or as an alternative to the use of attraction between the ophthalmic material and therapeutic tool can be used by the shell to facilitate loading a therapeutic agent to an ocular device. Such membranes can increase or decrease the load of a therapeutic agent to a specific ophthalmic material and/or to increase or decrease the rate of release of therapeutic agent from the ophthalmic material. Such membranes can also be used for applying a therapeutic agent to an ocular device, where there is little or absolutely no attraction between the ophthalmic material that forms the device, and therapeutic tool.
In one embodiment of the invention therapeutic agent is mixed into the shell and then the shell is applied to (for example, application of a membrane dipping) ophthalmic material and/or device. In an alternative embodiment of the invention the shell is applied to (for example, by applying a shell dipping) ophthalmic material and/or device, and then therapeutic agent may be applied about locku using techniques of solvent/therapeutic agent, described above, or other methods.
The shell can be obtained from a variety of materials, but preferably comprises one or more polymers. In one embodiment of the invention, the shell is a shell is water-based, which includes one or more polymers, which are typically biocompatible. Preferably one or more polymers can form a matrix that captures a therapeutic tool only to release funds within a period of time finding eye device on the eye. Such a matrix can be formed by heating the shell and/or ocular device to which is applied the shell. Examples of potentially suitable membranes are described in U.S. patent No. 6238799 and 6866936, both of which are included in the present description by reference for all purposes. One suitable membrane sold under the trade name LubrilAST and is commercially available from AST (Advanced Surface Technology Products, Inc., 9 Linnell Circle, Billerica, MA, 01821. In one embodiment of the invention using a membrane with a polymer matrix can provide a pathway for the introduction of hydrophilic drugs (e.g. diclofenac sodium: log P=1,1, colchicine: Log P=1.3 and mitomycin C: Log P=0,44) of hydrophobic intraocular implant (for example, acrylic IOL or rings).
Also envisaged is foreseen, that prolonged release of therapeutic agent from the ocular device can be achieved by direct load nanospheres microspheres or liposomes loaded with drug, where capsules are made from acrylate or other hydrophobic polymers. Additionally or alternatively, therapeutic agent may be pre-processed to produce essentially uniform in size/shape of the nano - or microparticles, which will then be loaded in ocular device for the controlled long-term release of the drug.
Further provides that a laser or other energy can be focused on the ophthalmic material to heat the material to modify the release kinetics and/or the opening of additional porosity to release a therapeutic agent of the ocular device. In addition, it is envisaged that in the process of obtaining ophthalmic devices, appropriate processing conditions can be used to generate micro - or nanocarbon or vacuoles within the material of the device. Pockets or vacuoles can then act as additional storage tanks to increase the load of the medicinal product. The size and density of micro - or nanocarbon/vacuoles can be controlled, the AK that they will not influence the optical characteristics of the implant.
Mainly, the ocular device according to the present invention can, when using or with shell or without shell, to provide complete desired release profiles for a therapeutic agent that is released during the time period. Moreover, especially when the ocular device is located inside the eye (for example, as an intraocular lens or capsular tension ring), ocular device according to the present invention can be very effective to provide a therapeutic agent in the inner parts of the eye. Additionally, it was found that the loading of therapeutic agent loaded ophthalmic devices of the present invention exhibits very little, if any, loss of optical and/or mechanical characteristics.
The EXAMPLES AND the COMPARATIVE DATA
Solid hydrophobic soft acrylic IOL was obtained from 65% 2-generatesecret (REA), 30% 2-generatesecret (REM), 3,2% 1,4-potentialtarget (BDDA) and 1.8% On-methylthiophene P (OMTP, UV absorber) and called A1 IOL. Solid hydrophobic soft acrylic IOL was obtained from 80% REA, 15% hydroxyethylmethacrylate (DUMB), AND 3.2% BDDA and 1.8% OMTP and called A2 IOL. The equivalent water content at 37°C was determined as 0.25% and 1.4% for IOL A1 and A2, respectively. Disks with a diameter of 6 mm and a thickness of 1 mm were also obtained in accordance with the above recipe and they were called in this way the disks A1 and A2. The surface area of the disks was 75,36 mm2. 9 mm inner annular implant formed from a material A1 was also received and it was called intraocular implant A1. The surface area of the annular implant was 121,62 mm2.
10 mg/ml drug solution nepafenac received in a solution of acetone/methanol 5:1. A1 IOL was immersed in a solution of a medicinal product within 48 hours at room temperature (KT ~23°C) for absorption of the drug. IOL loaded drug was then removed from the solution of the medicinal product, washed with pure methanol solvent for cleaning the surface of the medicinal product, followed by drying in vacuum at 50°C for 4 hours to remove residual solvent. To study the release of drugs each IOL loaded drug was placed individually in 0.5 ml of BSS and incubated at 37°C. the Total amount of the released drug after 1, 12, 30 and 75 days was assessed by high performance liquid chromatography (HPLC), and the results are shown graphically in figure 1.
10,23 mg/ml of nepafenac received in a solution of acetone/methanol 5:1. A1 intraocular implant was immersed in the solution for 48 hours at RT for absorption of l is drug money. The disk loaded drug was then removed from the solution, washed clean with a solution of acetone/methanol 5:1 (without drug) for cleaning the surface of the medicinal product, followed by drying in vacuum at 50°C for 4 hours to remove residual solvents. To study the release of drugs each disc loaded drug was placed individually in 0.5 ml of BSS and incubated at 37°C. BSS was replaced daily for 26 days. Daily selection of drugs was assessed by HPLC and the results are shown graphically in figure 2.
10,23 mg/ml of nepafenac received in a solution of acetone/methanol 5:1. Drives A1 and disks A2 immersed in the solution for 48 hours at RT for absorption of the drug. The disk loaded drug was then removed from the solution, washed clean with a solution of acetone/methanol 5:1 (without drug) for cleaning the surface of the medicinal product, followed by drying in vacuum at 50°C for 4 hours to remove residual solvents. To study the release of drugs each disc loaded drug was placed individually in 0.5 ml of BSS and incubated at 37°C. BSS replaced daily in those who tell of the week. Daily selection of medicines of the disks A1 and A2 were evaluated by HPLC and the results are shown graphically in figure 3.
For the evaluation of other acrylic IOL in relation to the uptake and release of drugs, in the composition A2 varied the ratio REA and DUMB for receiving drive from an acrylic copolymer with a wide range of material properties from the more hydrophobic to more rigid, hydrophilic IOL materials, details of which are shown in table a below. The study of absorption were carried out by dipping the samples drives in 2.5 mg/ml of nepafenac in a solution of acetone/methanol 5:1 for 48 hours at RT, followed by cleaning with a mixture of acetone/methanol 1:1 (without drugs) to remove the surface of the medicinal product. Study of release of drug was performed by incubation of the sample separately in 0.5 ml of BSS at 37°C. BSS was replaced daily for 10 days. The daily release of drug was assessed by HPLC and the results are shown graphically in figure 4.
|Group name||The composition||Loading quantity is cartonnage means (µg)|
|G1||80% REA/15% DUMB||52,52|
|G2||75% REA/20% DUMB||52,10|
|G3||70% REA/25% DUMB||49,60|
|G4||60% REA/35% DUMB||35,28|
As can be seen, the more hydrophobic acrylate materials lead to higher absorption of the medicinal product, the more hydrophilic acrylate material, but result in a slower release of material medicines.
For comparison, the load of the medicinal product and the release of various IOLs and contact lenses conducted using commercially available lenses, including acrylic IOL, silicone IOL and hydrophilic contact lenses. Components of the solution was mixed with maximize load capacity of the medicinal product each lens material. However, the concentration and load of drug solution were the same, regardless of the lens material. The load conditions of the medicinal product are shown in the table below. Study of the release of Les is artenova funds spent up to 2 weeks, and the results are shown in figure 5.
|Group||The solution nepafenac||The dive time||Method of leaching|
|Acrylic (A)||0.5 mg/ml of 5:1 acetone:methanol||4 hours||Rinsing with methanol|
|Silicone (S)||0.5 mg/ml of 5:1 THF:methanol||4 hours||Rinsing with methanol|
|Contact lenses ()||0.5 mg/ml of 5:1 N2About:methanol||4 hours||Rinsing with methanol|
As can be seen, the load ability of the medicinal product silicone IOL and hydrogel contact lenses was significantly lower than that of acrylic IOL. In addition, the loaded drug was rapidly released from silicone and hydrogel lenses during the first five days. On the contrary acrylic lenses were able to retain more of the medicinal product and to release it gradually over a length which is a high period of time.
IOL A1 were loaded with drug by immersing IOL 5 mg/ml drug curcumin in acetone for 12 hours. After cleaning the surface with acetone and BSS IOL implanted as aphaktic IOL in one of the two eyes of new Zealand white rabbit. Before implantation, the natural lens of the rabbit was removed by standard techniques of cataract extraction by phacoemulsification. 2nd eye without implant served as a control. Rabbits were killed at different time periods and eyes were removed. Fluorescence light emission molecule drug curcumin in each study eye visualized scanning microscopy with laser confocal mirrors (CLSM) to obtain images of the distribution of medicines high resolution. The results are shown graphically in Fig.6 and specifically shown for plots a and C (the lateral areas of the sclera) of the eye area (the area of the cornea and anterior chamber) of the eye and area D (the area of the Central fossa and yellow spots) eyes.
Received and 2.5 mg/ml of nepafenac (RS logP=2.1 and 2.5 mg/ml solution of diclofenac (RS logP=1,1). Drives A1 and A2 dipped for absorption of the drug in each solution for 4 hours. Study daily release of drugs BSS conducted within 2 weeks. The number of loading and release of drugs is illustrated in Fig.7. As can be seen, the more hydrophobic the material A1 captures more drugs, and nepafenac, and diclofenac sodium than less hydrophobic material A2. Both materials have captured a large number of hydrophobic drugs of nepafenac, but only to a limited extent less hydrophobic drug, diclofenac sodium.
Through experiments with different concentrations of the drug in solution and different length of time of immersion in these solutions, it was found that the amount of therapeutic agent loaded in the ocular device can be changed. However, the hydrophobicity of ophthalmic material and/or hydrophobic therapeutic agent are usually the most important factors that determine the ability to capture the number of funds in the device.
IOL covered by the shell using a mortar shell/medicines LubrilAST. Diclofenac mixed directly with the mortar shell and the IOL was coated by dipping in a solution of shell/drugs. The composition of the shell is modified so that the concentration of PVP in the solution shell/drugs accounted for 20%, 14%, 5 and 2 wt.%. Diclofenac concentration was maintained constant at 31 mg/ml Lenses are covered by one layer by dipping and dried at 65°C in an oven for 4 hours. Lenses tested in BSS in the same manner as previously described, and measured using a spectrophotometer.
It was found that the rate of release of drug was decreased by reducing the content of PVP, as can be seen in figure 11. With PVP content 20%, 98.2% of drug was released in the middle for 5 days (n=3). However, 2% PVP only 71.9% of all drug was released in the middle for 5 days (n=3) (figs). Moreover, the number of free diclofenac on a daily basis significantly influenced the content of PVP. As can be seen in Fig, shell with 2% PVP released diclofenac with constant speed for 4 days, while others concentration was significantly decreased after 1 day of release. Therefore, the decrease in the content of PVP significantly lengthens the duration of release of the medicinal product within 5 days.
The solution to cover the membrane with diclofenac varied to determine the speed of release for different concentrations of the drugs included in the shell. The range of concentrations included 5,2, 14,9, and 42,8 of 80.1 mg/ml of diclofenac on rest the p shell. The calculated total load medications for each concentration was 0,5453, 1,636, 4,699 and 8,795 mg, respectively. Diclofenac is soluble in water up to 50 mg/ml of the same concentration was chosen outside this range to determine the effects of concentration on the stability of the membranes and effects on the rate of release. Other easily dissolved in the solution of the shell, whereas high concentrations of no, indicating the presence of undissolved crystals in the solution of the shell. The content of the crosslinking agent was 1.5% for all shells. The lenses were covered with 7 layers of each shell. Shell thickness did not differ significantly, as shown by measuring the dry weight of the lenses coated.
Lens investigated in BSS in the same manner as previously described, and measured using a spectrophotometer. Speed of release for each shell within the first 3 days were significantly different. From day 4 to day 10 the rate of release of drug was decreased and remained almost constant throughout this time period. The level of the medicinal product by the end of the period of 10 days for other concentrations also declined below the limit of detection of the proposed method of research.
The rate of release of colchicine were obtained for membranes with a range of concentric the th, including 2,6, 10,5, 30,3, and to 61.2 mg/ml Amount of drug contained in the shell for each lens, calculated based on the mass of the lens after covering sheath and known shrinkage and weight changes of the membrane after drying. Lenses coated with 2.6 mg/ml solution to cover the membrane, contained approximately 0,0316 mg of colchicine. Lenses coated with a solution containing 10.5 mg/ml of the medicinal product contained approximately 0,116 mg of colchicine. Lenses coated with a solution containing of 30.3 mg/ml of the medicinal product contained approximately 0,336 mg of colchicine. Lenses coated with a solution containing 61,2 mg/ml of the medicinal product contained approximately 0,694 mg of colchicine. On the basis of in vitro target concentration of colchicine was 0.0005 mg/ml based on the results, which showed that the migration and proliferation of LEC inhibited at concentrations as low as 0.0005 mg/ml Limit of detection for colchicine using this analytical method was 0,0083 mg/ml concentration of a medicinal product was obtained for each sample within 8 days. However, after 8 days at all concentrations fell below the limit of detection. At this point, the test solution was replaced and the lens allowed the impregnated for an additional 18 days (total 28 days) to obtain the measured concentrations of the drug. Data release drugs in vitro show that the lenses coated with 2.6 mg/ml solution for coating the shell, released the same quantities for 8 days and then decreased below the limit of detection. Lenses coated with 10.5 mg/ml solution for coating the shell, as well as solutions for coating the membrane with a higher concentration of released amount more 0,0083 mg/ml for at least 8 days. The release of colchicine was determined after 28 days in BSS at 37°C (n=3) for shells loaded with different concentrations of drugs.
The amount of drug contained in the shell for each lens, was calculated by the previously described methods. Lens, covered with a solution to cover the membrane containing 2 mg/ml, contained approximately was 0.138 mg of Mitomycin-C (MMC). On the basis of in vitro target concentration for MMS was 0.0005 mg/ml based on the results, which show that the migration and proliferation of LEC inhibited at concentrations as low as 0.0005 mg/ml Limit of detection of MMS using this analytical method was 0,010 mg/ml After 11 days MMS continued to escape from the shell above the limit of detection. After the first 2 days of release of the drug the frame means the rate of release of drug is not significantly varied. Approximately 20% of the total MMC-loaded, lens, remained after 11 days of soaking in BSS at 37°C. MMS was released from the shell up to about 11 days after hydration in BSS at 37°C (n=3). Levels 11 days were below the limit of detection for MMS for such a method.
Acrylic lenses (lenses ACRYSOFT® II) were loaded separately six different therapeutic means: ascorbic acid, aspirin, colchicine, nepafenac, Ketorolac and lidocaine. The release of each of therapeutic agents of the lenses was determined over a period of 7 days using HPLC. The concentration of released drug was measured using modules separation of A Waters 2695 with the detector Waters 2699 PDA and column Symmetry® C18 (of 4.6×75 mm). Calibration curves were created for each drug using different concentrations(10, 50, 100, 500, 1000 µg/ml).
Lenses were loaded using a solution of a therapeutic agent, made from acetone and a therapeutic agent at a concentration of 3 mg/ml of the Lens was dipped in this solution for 90 minutes. The solutions were poured through a sieve for retaining the lens and the lens was air-dried overnight in a closed chamber. The next day the lens was dipped into a solution of acetone:methanol (1:1) for 5 minutes and gently mixed using a vortex. Then l is NZ was taken out and allowed to air dry for about 2 hours. Then the lens was dried in vacuum at 50°C during the night. Lens, loaded with therapeutic agent (1 lens for each drug), were placed in an Eppendorf tube, to which was added 0.5 ml of water quality HPLC. The disk is incubated at 37°C, 5% CCh and environment release was replaced every 24 hours during 7 days. The number of drugs in the environment for release were analyzed using HPLC.
Used a variety of conditions and HPLC method was optimized for each therapeutic agent.
Nepafenac investigated in accordance with the methods HPLC, as essentially described above.
For ascorbic acid the mobile phase consisted of distilled water and 2 mm sodium salts of 1-octanesulfonic acid, methanol and glacial acetic acid [55:44,5:0,5 (V/V)]. Standards were made in the mobile phase. The volume of injection was 25 μl and the flow rate was 0.5 ml/min wavelength determination recorded at 263 nm.
For aspirin the mobile phase consisted of methanol, glacial acetic acid, distilled water [30:2:68 (V/V)]. Standards were made in water and the volume of injection was 25 µl. The flow rate of the sample was maintained as 1 ml/min and the determination was carried out at 254 nm.
For colchicine the mobile phase consisted of acetonitrile and 3% acetic acid [60:40 (V/V)] and the standards made in the mobile phase. RMSE is the awn current HPLC supported as of 1 ml/min with a volume of injection of 25 µl. The determination was carried out at 245 nm.
For Ketorolac mobile phase consisted of acetonitrile and 0.2% V/V glacial acetic acid [40:60 (V/V)]. Standards were made in methanol and the volume of injection was 20 µl. The flow rate was maintained as 1 ml/min with a wavelength of definitions installed at 313 nm.
For lidocaine mobile phase consisted of a mixture of 350 ml of methanol, 150 ml of distilled water, 10 ml of glacial acetic acid and 1.6 g of sodium dodecyl sulfate. Mobile phase was filtered through a 0.22 μm filter. Standards lidocaine made in the mobile phase. The volume of injection was set as 25 µl and the flow rate 1 ml/min Determination was carried out at 250 nm.
The total release of therapeutic agent from the lens through the 7 days are summarized in table 1 below.
|The release of 7 days (g)||MM||TP (°C)||Exp. Log P/hydrophobicity||Predicted Log S||Solubility in water|
|Ascorbic acid||0,0||176||191||-0,5||0,16||40 g/l|
|Bromfenac||the concentration is||334||the concentration is||3,4||-4,42||0,0126 mg/ml|
As shown in the above table, the higher values of Log P therapeutic agent (i.e. showing greater lipophilicity or hydrophobicity) showed the desired release of the drug from the lenses.
Applicants have specifically included the full content of all of these links in this description. Moreover, when an amount, concentration, or other value or parameter is given in the form or a range, preferred range or a list of high-preferable values and lower preferable values, it is necessary to understand what is specifically described all ranges formed from any pair of any upper range limit or preferred value and any lower limit of the range or preferred value, regardless of described whether the ranges separately. When the range of the numerical values indicated in the present description, unless otherwise specified, the range is intended to include its endpoints and all integers and fractions within the range. Is not intended that the range of the invention was limited to specific values that you specified when defining a range.
Other embodiments of the present invention will be obvious what idny specialist in engineering from consideration of the present description and implementation of the present invention, as described here. Is intended that the present description and examples were regarded only as approximate with the invention specified in the following claims and its equivalents.
1. Ophthalmic device, comprising:
nonbiodegradable mass of material, where the mass of material includes a hydrophobic component, a hydrophobic component is present in an amount sufficient to ensure that the contact angle of the material was greater than 50°, the hydrophobic component is formed of at least 80% by weight of acrylic material; and
a therapeutic tool, located on the peripheral surface of the mass of the material, where therapeutic agent is hydrophobic and has a distribution coefficient in the system of the octane/water PC Log P equal to at least 1.0;
where the mass of material formed for introduction into the human eye, and which gravity of therapeutic agent to the hydrophobic parts of the controlled slow release of therapeutic agent so that less than 50% by weight of therapeutic agent released from the ocular device in the basic salt solution (BSS) for at least three days.
2. Ocular device according to claim 1, where therapeutic agent is a distribution coefficient in the system of the octane/water PC Log P equal to at least a 2.0.
3. Ophthalmic device according to claim 2, Ni is sustained fashion containing hydrophilic acrylate, which includes 2-fenilatilmalonamid DUMB.
4. Ocular device according to claim 1, where the mass of material includes acrylic material, including a substantial part of the hydrophilic acrylate.
5. Ophthalmic device according to claim 4, where the hydrophobic acrylate includes hydroxyethylmethacrylate REM.
6. Ophthalmic device according to claim 4 or 5, where the mass of material releases a controlled amount of a therapeutic agent when immersed in a solution of a basic salt and where the hydrophobic acrylate and hydrophilic acrylate present in the mass of material in quantities such that a controlled amount of therapeutic agent is less than 60% of the total therapeutic agent in a time period that is at least 5 days.
7. Ophthalmic device according to claim 4 or 5, where therapeutic agent is an ophthalmic drug, consisting of anti-inflammatory agents, antiproliferative means or combinations thereof.
8. Ocular device according to claim 1, where therapeutic agent includes an anti-inflammatory agent.
9. The ocular device of claim 8, where the anti-inflammatory agent is nepafenac.
10. Ocular device according to claim 1, where the mass of the IOL material is a selected from aphaktic Aphakic intraocular lens IOL, anterior chamber phakic vnutriglaznaya PC Phakic IOL and the anterior chamber phakic intraocular lens gear Phakic IOL.
11. Ocular device according to claim 1, where the mass of material is scleral mass intraocular lens IOL.
12. Ocular device according to claim 1, where the mass of material is in the eye of the patient.
13. Ocular device according to claim 1, where the mass of material formed as part of or entire intraocular lens IOL scleral mass intraocular lens IOL or as a separate part that is inserted into the eye with or without intraocular lens IOL.
14. Ocular device according to claim 1, where the mass of material releases a controlled amount of a therapeutic agent when immersed in a solution of a basic salt.
15. Ocular device according to 14, where less than 50% by weight of therapeutic agent released from the ocular device in the solution of the basic salt in the period which is at least one week.
16. Ocular device according to 14, where less than 50% by weight of therapeutic agent released from the ocular device in the solution of the basic salt for at least two weeks.
17. Ocular device according to 14, where less than 80% by weight of therapeutic agent released from the ocular device in the solution of the basic salt for at least three days.
18. Ocular device according to claim 1, where therapeutic agent is associated with the mass of material other way, other than forming relationships through mutually is deystviya.
19. The method of obtaining ophthalmic device according to any one of claims 1 to 18, including:
dive mass of the material in a solution which includes a solvent, representing acetone, methanol, benzene, toluene, alcohol, or combination thereof and a therapeutic agent, representing nepafenac.
SUBSTANCE: preparation comprises branched polyhexamethylene guanidine in the form of hydrochloride, taurine, a promoting ingredient, additives and water. The promoting ingredient is specified in succinic acid or its pharmaceutically acceptable salt, while the additives are specified in a group consisting of physiologically acceptable alkaline or acidic agents and a salt tonic agent specified in physiologically acceptable sodium or potassium salts or mixtures thereof.
EFFECT: more effective therapeutic effectiveness for pathological conditions of the eyes, and a potential comorbid bacterial infection.
3 cl, 3 tbl, 4 ex
SUBSTANCE: physiotherapeutic goggle device BLEPHASTEAM is placed over an orbital cavity. Restasis is applied on cotton pads in the amount of 4 drops equally spaced over each cotton pad. The pads are placed into the device. The physiotherapeutic exposure covers open eyelids for 10 minutes daily. The therapeutic course consists of 20 sessions.
EFFECT: method provides a pronounced anti-inflammatory, reparative, anti-allergic effect with reducing the length of treatment and ensuring cost advantages of using the expensive drug Restasis evaporated in the goggle BLEPHASTEAM, allowing for the simultaneous effect on the cornea, conjunctiva and eyelids.
8 dwg, 2 ex
SUBSTANCE: treating retinal and/or vitreous hemorrhages is ensured by a session of subcutaneous administration of Histochrom 0.5 ml into a mastoid bone, Echinacea compositum 1.0 ml into a temporal fossa, Gemase 2500-5000 IU parabulbary dissolved in Lymphomyosot 0.5-1.0 ml. The therapeutic course is 10-15 sessions, either daily or every second day.
EFFECT: faster resolution of the intraocular hemorrhages, prevention of retinal injuries by toxic decay products, higher visual acuity.
SUBSTANCE: invention refers to medicine, namely to ophthalmology, to preparations for the treatment and prevention of eye diseases, and may be used in visual impairment, development and progression of eye diseases, as well as for the prevention and maintenance therapy of oxular diseases. Substance of the invention consists in the fact that a therapeutic eye balsam is characterised by the fact that it contains the ingredients in ratio in grams per 100 g of the therapeutic eye balsam of the following formulation: Siberian fir extract - 48.540 g, 5% propolis extract - 10.000 g, 0.9% physiological saline - 38.540 g, neoselen (food supplement) - 0.971 g, vitamin B2 - 0.007 g, citric acid - 0.971 g, ascorbic acid - 0.971 g that promotes achieving the declared technical effect ensured by the given proportions. The presented balsam enables the higher clinical effectiveness in all the forms of ocular pathologies, provides the anti-inflammatory effect on the eye mucosa and cornea, as well as delivers a good result in the post-traumatic and post-operative treatment.
EFFECT: therapeutic eye balsam containing the natural ingredients in certain proportions provides the integrated therapeutic effect on the visual organs and has found use in a great number of grateful patients.
FIELD: medicine, pharmaceutics.
SUBSTANCE: group of inventions refers to a pharmaceutical composition and methods of using it in treating insufficient eye lubrication, related symptoms or adverse conditions related to insufficient eye lubrication. The pharmaceutical composition contains human PRG4, its wetting fragment, a homologue or an isoform suspended in ophthalmologically acceptable balanced saline. The pharmaceutical composition can also contain one or more ophthalmologically acceptable agents specified in a group consisting of a sedative, an excipient, a binding agent, a vasoconstrictor, an emollient, sodium hyaluronate, hyaluronic acid and surface active phospholipids in a pharmaceutically acceptable carrier for topical use.
EFFECT: group of inventions provides treating the diseases related to impaired corneal and conjunctival wetting.
15 cl, 10 dwg, 3 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: what is presented is a method for the suppression of physiological disorders related to abnormal angiogenesis, specified in retinopathy, diabetic retinopathy, macular degeneration, retinopathy of prematurity, age-related macular degeneration, pancreatic tumour and glioma, involving the administration of an effective amount of 3-[(5-(2,3-dimethoxy-6-methyl-1,4-benzoquinolinyl)]-2-nonyl-2-propenoic acid (E3330) or its pharmaceutically acceptable salts or solvates. The decreased EHF-1α, NFKβ, AP-1 activity by E3330 and the suppression thereby of the growth, survival. Migration and metastasis of tumour cells are accompanied by the absence of the major suppression of the growth of normal cells (hemopoietic embyo cells or CD34+ human progenitors). Besides, E3330 has enhanced the therapeutic effect of other cytotoxic preparations.
EFFECT: reducing the amount of VGEF and proliferation of retinal endothelial cells by E333O even in the presence of a fibroblast growth factor, both in the normal oxygen conditions, and in the hypoxia by the inhibition of the oxidation-reduction activity of Apel/Ref-1.
12 cl, 35 dwg
SUBSTANCE: invention refers to medicine, namely to eye drops, and aims at treating dry eye syndrome, as well as bacterial conjunctivitis and/or blepharitis. The preparation comprises a combination of the ingredients, a prolonging ingredient, additives and water. The combination of the active ingredients contains branched polyhexamethylene guanidine and sulphacetamide; the prolonging ingredient is specified in a group consisting of polyvinyl alcohol, water-soluble methyl cellulose or hydroxypropyl methyl cellulose; the additives are specified in a group consisting of a group consisting of physiologically acceptable alkaline or acid agents, and a saline tonic agent.
EFFECT: using the invention enables higher clinical effectiveness of dry eye syndrome, as well as a comorbid bacterial infection, as the preparation possesses the bactericidal effect consistent with the effect of 20% sulphacetamide causing no irritant effect on long use.
4 cl, 3 tbl, 6 ex
SUBSTANCE: invention relates to medicine, namely ophthalmology. The method involves a transepithelial corneal collagen crosslinking. That is preceded with a single bath electrophoresis with 1% riboflavin mononucleotide. That is ensured by an initial current of 0.2 mA to be increased gradually to 1 mA, at a pitch of 0.2 mA for 2 minutes. That is followed by an ultraviolet corneal exposure. The exposure is conducted at wave length 370 nm, power 3 mWt/cm2 and combined with instillation of a riboflavin solution. The solution contains 0.1% riboflavin mononucleotide and 20% dextran.
EFFECT: method provides more effective riboflavin delivery to the corneal stroma for one procedure providing the intraocular protection against ultraviolet light.
2 cl, 1 ex
SUBSTANCE: invention refers to medicine, ophthalmology. A method involves a sinus trabeculectomy, a local sclerectomy and a drug delivery to a posterior pole of eyeball following by a restorative treatment. The local sclerectomy is performed in an inferior-internal segment of the eye with a cross-section of the incision being semi-circular. The local sclerectomy uses Histochrom as a drug substance. The restorative treatment comprises subconjunctival drug injections in a combination with the exposure to a physical factor. Starting from the first postoperative day, Histochrom is injected into a sub-Tenon's space. There are 9 injections performed once a day. Starting from the second postoperative day, a magnetic stimulation is used at frequency 100 Hz, length 16 minutes once a day for 7-10 days. The first 3 sessions involve the exposure to a pulsating monopolar magnetic field of intensity 6.25 mT. The following 4-7 sessions involve the exposure to an alternating bipolar magnetic field of intensity 12.5 mT.
EFFECT: method provides stabilising and enhancing the visual functions.
5 cl, 1 dwg, 1 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to medicine, namely to ophthalmic preparations presented in the form of eye drops and applicable for treating dry eye syndrome and bacterial conjunctivitis. The preparation contains polyhexamethylene guanidine that is presented by branched oligomers in the form of hydrochloride; besides, phosphate buffered saline, poly(N-vinylpyrrolidone) and water are the ingredients.
EFFECT: using the invention provides the higher clinical effectiveness in dry eye syndrome, as well as potential comorbid bacterial infection whereas the declared preparation has no irritant effect if used for a long period of time.
3 cl, 2 tbl, 3 ex
FIELD: process engineering.
SUBSTANCE: invention relates to production of cardio implants from titanium nickelid-based alloy with shape memory and superelasticity effects modified surface layer. Said implants are intended for long-term operation in cardiovascular system and feature corrosion resistance, biocompatibility and nontoxicity in biological media. Proposed method comprises making said cardio implant, chemical and electrochemical surface cleaning, surface cleaning by silicon ion flows produced by spraying silicon cathode in vacuum under conditions of high-dose ion implantation with fluence of (0.5÷6.0)×1017 cm-2 to obtain modified 80-95 nm-thick surface layer. The latter consists of at least two sublayers. Outer 20-25 nm-thick sublayer contains oxygen, carbon, silicon and titanium at the following ratio of components, at.%: oxygen - 25-65, carbon - 1-5, silicon - 1-10, titanium making the rest. Mid 60-70 nm-thick sublayer contains oxygen, carbon, silicon, titanium and nickel at the following ratio of components, at.%: oxygen - 5-30, carbon - 1-5, silicon - 10-30, nickel - 1-50, titanium making the rest. Note here that maximum concentration of silicon is reached at 30-35 nm from the surface.
EFFECT: modified surface layer features no apparent interface between sublayers.
9 cl, 1 dwg
SUBSTANCE: invention refers to medicine, more specifically to artificial biomaterials, methods for making and using them. There are described collagen biopolymers and biocomposites. Making an oriented fibre biopolymer material is ensured by preparing a solution of fibre biopolymer gel in a liquid crystal phase; a uniform layer of the solution is applied on a substrate and dried by fibre biopolymer orientation. If necessary, the biopolymer is removed from the substrate as a film. For making the biopolymer fibre, a tape of the oriented biopolymer material is immersed into the solution, then removed from the solution so that the biopolymer material is rolled as a fibre at the boundary of air and liquid.
EFFECT: simplifying and cheapening the method for making the oriented biopolymer materials, improving producibility, enhancing biocompatibility of such materials with living tissues.
38 cl, 4 tbl, 14 dwg
SUBSTANCE: invention refers to using a tracer agent for magnetic particle imaging (MPI) for the purpose of visual monitoring of a biocompatible product. The biocompatible product contains the tracer agent for magnetic particle imaging (MPI) by imaging technique using magnetic particles. The biocompatible product represents a microcontainer comprising a solid or semi-solid material applicable for cell culture support. The invention also refers to a method for visual monitoring of the biocompatible product. The declared method involves the stages of providing the biocompatible product containing the tracer agent for MPI, introducing the biocompatible product into a target area, and detecting signals generated by the tracer agent for MPI by imaging technique using magnetic particles.
EFFECT: invention provides monitoring of the targeted cell or active agent delivery into the target area.
10 cl, 2 ex
SUBSTANCE: claimed invention is aimed at manufacturing intraocular lens (IOL), for introduction of posterior eye chamber in form of PC Phakic lens. IOL is formed from hydrogel material, formed by cross-linked polymer and copolymer component. Lens includes UV chromophore, which is benzotriazole.
EFFECT: IOL hydrogel material usually has relatively high index of refraction and/or possesses desirable degree of protection against irradiation.
12 cl, 3 tbl
SUBSTANCE: invention relates to medicine and pharmaceutical industry, in particular to method of manufacturing elongated hollow body (1). Body, containing crystalline cellulose, has multiple projections (3, 4), which project into lumen of hollow body (1), on internal wall. Method of manufacturing elongated hollow body (1), includes stages: manufacturing hollow form (12), cultivation of cellulose-forming organisms in internal space, formed by hollow form (12), aimed at providing growth of hollow body (1) in internal space; operation of removal of hollow body from form (12). At the stage of removal from form (12), at least, part of hollow form (12) is irreversibly deformed.
EFFECT: increased efficiency of manufacturing method.
16 cl, 8 dwg
SUBSTANCE: group of inventions refers to surgery and may be used for making external osteosynthesis implants. An osteosynthesis system comprises a piece part on an external surface of which there is a layer of a polymer film in the electret state with the layer of the polymer film made of a fusible element. The group of inventions refers to a method for making the osteosynthesis system involving preparation the layer of the polymer film on an external surface of the piece part by coating the surface of the piece system with a fine fusible polymer powder, fusion thereof on the surface of the piece part and electrostatic charging of the prepared film.
EFFECT: group of invention provides making a uniform coating of the electret layer on the surface of the piece part of the osteosynthesis system firmly attached to the surface of the piece part that enables faster fusion of bone fragments due to electric stimulation and prevented implant corrosion.
10 cl, 1 ex
SUBSTANCE: described are soft, having high index of refraction acrylic materials for devices. Materials include di-block or tri-block macromers, containing hydrophilic side chains.
EFFECT: materials have improved stability to reflections.
17 cl, 6 tbl, 12 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to medicine. There are described soft acrylic materials having a high refraction coefficient for apparatuses. The materials contain diblock- or triblock-marcomers containing a hydrophilic block in a polymer backbone.
EFFECT: materials have better gloss resistance.
17 cl, 3 tbl, 7 ex
SUBSTANCE: invention relates to medicine. Described are soft acryl materials for ophthalmologic or otorhinolaryngologic devices, which have high refraction coefficient.
EFFECT: materials contain macromer with hydrophilic side chain for giving stability to appearance of glitter.
20 cl, 6 tbl, 1 ex
SUBSTANCE: invention refers to medicine. There are described medical implanted devices made of a polymer material and a separation agent wherein the device is a cast reservoir implant, while the separation agent has a molecular weight (M.w.) of min. 1000. The separation agent can be presented by a non-ionic surfactant, such as Bridge-35, polyoxyethylene (20) sorbitan trioleate, Tween 20, Tween 80, vitamin E TPGS, and a mixture of any two or more of them. The hydrated implants can have a surface area of approximately 500 mm2 or more.
EFFECT: used separation agents causes no undesired reactions with cartridge polymer and are safely introducible in a patient.
29 cl, 5 tbl, 3 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: pharmaceutical dosed form contains a hard dispersion product of, at least, one active ingredient, dispersed in a polymer carrier composition. The polymer carrier composition contains a) vinylpyrrolidone homopolymer, in which, at least, 95 wt % of homopolymer have a molecular weight in the range from 1000 to 13000; and b) vinylpyrrolidone copolymer, which has an average molecular weight from 5000 to 1500000. The dosed form, preferably, is obtained by a melt extrusion method.
EFFECT: polymer carrier composition by the invention forms from the said polymers a homogeneous mixture which has only one vitrification temperature Tg, and has high ability to dissolve a medication.
13 cl, 5 dwg, 1 ex