Microimplants for ophthalmologic introduction
SUBSTANCE: invention claims implants and microimplants containing homogenous mixes of active component and biodegradable polymer, including microimplants with 0.019 inch diametre or less and 1 mm length or less, which can be inserted into an eye by methods based on eye self-recovery. Also invention claims methods of implant and microimplant manufacturing allowing obtainment of uniform implant and microimplant batches with extremely narrow tolerance range.
EFFECT: novel implants and methods of implant manufacturing.
38 cl, 1 tbl, 3 ex
This invention relates to implants that contain active ingredients such as drugs or other therapeutic agents. More specifically, this invention relates to implants that can be placed in the eye for the treatment of diseases or pathological conditions of the eye.
The main difficulty in treating diseases or pathological conditions of the eye is an introduction to the eyes of active ingredients such as drugs or other therapeutic agents, and maintaining a therapeutically effective concentration of these agents in the eye within the required time period. Systematic introduction may not be the best solution, as it is often necessary to achieve intraocular concentration requires a systematic introduction unacceptably large doses, and increases the risk of symptoms of adverse side effects active ingredients. Regular eye installation or application, in many cases, is not an acceptable alternative because the active ingredients can be quickly removed as a result of tearing or can be removed from the eye into the bloodstream. Also apply suprachoroidal injection solutions of the drugs, but again, they provide medication only for short is about the period. To maintain the desired concentration of the medicinal substance within the required period of time, without resorting to repeated introduction, is still difficult.
Efforts aimed at the resolution of this problem has led to the development of implants that can be placed in the eye so that a controlled amount of active ingredient may be constant during the period of several days, weeks or even months. Previously it has been described many similar devices. For example, in U.S. patent No. 4853224 disclosed biocompatible implant for introduction into the anterior or posterior segment of the eye for the treatment of pathological conditions of the eye. In U.S. patent No. 5164188 disclosed are methods of treating pathological conditions of the eye by introducing a biodegradable implant, carrying the necessary medication in suprachoroidal space or pars plana of the eye. Cm. the U.S. patents№№ 5824072; 5476511; 4997652; 4959217; 4668506 and 4144317. Other methods include attaching pad or tab carrying the drug in the sclera of the eye (see, for example, U.S. patent No. 5466233).
In the document US 2004/0054374 described biodegradable ocular microimplants containing therapeutically active agents, which has a diameter 0,018 inches or less, and can be obtained in the form of tubes 22 gauge, and microimplants with dia is the ETP of 0.015 inches or less can be obtained in the form of tubes caliber 23. Because of the very small cross-sections of microimplant length must be proportionally larger to accommodate a therapeutic dose of the active agents, that is, the normal length is 6-7 mm Microimplants with a length of 7 mm or less is more preferable than microimplants greater length, because such implants can interfere with the line of sight of the patient. This solution can be considered as the closest analogue to the proposed invention.
In the eye there are various sites where you can enter the implant, such as the vitreous body, front and rear cameras, eyes, and other areas of the eye including intraretinal, subretinal, intrathoracically, suprachoroidal, intracleanse, episcleral, subconjuctival, intracorneal and epicardial space. Regardless of the desired place of introduction, all the typical routes of administration require relatively invasively surgical procedures cause the risk of excessive trauma to the eye, and require more effort when handling the implant. For example, a typical method of placing an implant in the vitreous body requires dissection of the sclera, the implant is delivered into the vitreous body with pliers or similar manual gripping device. After the introduction of the forceps (or more to the life of the device) is removed, and place cut sew. In another case, a cut through the sclera, in the place of dissection can be inserted into the trocar, and the implant can be delivered through the trocar. Similar methods can be applied during delivery of the implant to other areas, such as delivery to the anterior chamber of the eye through an incision in the sclera.
Side effects such diverse ways. In the case of using such technologies must osushestvljali a lot of manipulation of the implant, which creates the risk of damaging the implant. Many of these implants have a polymer base and are relatively fragile. If part of the installed implant will be povrejdeniy or broken, will significantly change the effective therapeutic dose to be delivered with this implant. In addition, using such methods it is impossible to achieve reproducible results in different patients. Also pay attention to the fact that all of these technologies require the application of eye incision or puncture, and sufficiently large that require mending. Thus, these techniques typically are made using surgical equipment.
Accordingly, the required minimally invasive methods of introducing the implant in the eye, minimizing or even eliminating surgical intervention is the primary objective, including methods based on the introduction of implants, small enough to avoid closing and allow the eye to repair themselves. An important feature of such minimally invasive methods should be the use of implants as small as possible, which, in turn, will lead to less eye injury during implantation. However, these small implants are difficult to make, particularly, because these little implicate must have a homogeneous composition and appropriate shape, size and structure in order to maintain the desired concentration of active ingredients over a time period. Even slight variations concerning homogeneity of composition or matching shapes, sizes and structure of such small implants can cause the flow amount of the active ingredient, significantly different from the desired, and thus change the course of treatment of diseases or pathological conditions of the eye. Accordingly, the implants of small size, having a uniform shape, size and structure, and in particular, their production on a commercial scale is of great interest.
Brief description of the invention.
This invention satisfies the above needs, and also has the other advantages. In certain aspects of the invention proposed microimplants containing a homogeneous mixture of the active ingredient, such as one or more therapeutic agents, and biodegradable polymer or polymers which have a diameter of approximately 0.020 inch or less, preferably 0,019 inches or less, and particularly preferably 0,018 inches or less. Preferably, the diameter values are within ±0,0003 from the average diameter, i.e. the diameter, of the above. According to other aspects of the present invention can be made of the party of microimplants and implants of larger size, have to meet strict requirements, including the acceptable deviation from the desired planned mass less than 10% or less. Similarly, such implants or microimplants can be made by the parties, in which the average deviation of the mass is about 5% or less. In one aspect of the invention proposed microimplants carrying an anti-inflammatory agent such as dexamethasone, and used biodegradable polymers based on copolymers of polylactic acid and polyglycolic acid (PMHC). Such microimplants have a length of about 7 mm or less and may have a diameter of about 0,019 inches and less. In another aspect of this microimplants also include the additional amount is polimerov polylactic and polyglycolic acid (PMGC), having a terminal free acid groups. According to the invention also proposed lot or a series of such microimplants mass, oscillating within a few percent of the required planned mass and/or with a certain standard deviation of the mass.
In another aspect of the invention proposed ways to create implants and microimplants with a very hard-coded standard deviation of the composition and/or size. These methods include the steps of obtaining particles or powders of one or more active ingedients, polymers and/or additional substances, fillers (for example, modulators release, buffers etc), mixing these particles to obtain a mixture, extruding the mixture to obtain fibers, granulation and extrusion of the fibers using a twin-screw extruder to obtain a high degree of homogeneity and directly cutting the fibers to obtain the desired microimplants. Can be used extrusion in one and two channel.
In other aspects of the invention disclosed methods and criteria for acceptance or rejection of lots microimplants on the basis of optical measurements, measurements of size and weight and other.
All of the characteristics described here, everything and every combination of two or more of these signs included webjam of the present invention, provided what are the signs that make up this combination are not mutually exclusive. In addition, any sign or combination of signs may be in a particular case were excluded from any modification of this invention.
Additional aspects and advantages of this invention are outlined in the following description and the claims, in particular, in combination with appropriate illustrations.
To provide a more accurate understanding of the present invention in posleduushie description contains many specific details, such as specific configurations, settings, and so on. It should be noted, however, that this description does not purport to limit the scope of this invention, but is aimed at a more complete coverage cited as examples of modifications.
The implants and microimplants made in accordance with this invention, can be placed in the eye for the treatment of diseases and pathological conditions of the eye. Such implants or microimplant will have, as a rule, compounds active ingredient(tov) and the biodegradable polymer(s), with the possible inclusion of additional excipients.
Used herein, the term "implant" refers to any ocular implant or device for delivery of medication, which can be maesano l is the fight of the many possible areas of the eye and can release a controlled amount of active ingredient over an extended period of time, within days, weeks or even months. Such implants are biocompatible and in many, but not all, cases are made from biodegradable substances, such as a biodegradable polymer. The term "microimplants" refers to implants having a sufficiently small cross-sectional area, which can be installed using sposobov, implying samsuiluna eyes at the site of dissection, resulting from the implant. In particular, such microimplants have such sizes that can be set via cannula 20, 21, 22 or smaller caliber. Can be made thin-walled options needles 21 gauge having an inner diameter of up to 0,028 inches, thus microimplants cylindrical shape, which can be installed through the cannula should have an outer diameter of less than 0.028 inches. Microimplants also may not be round in cross section and can be installed via cannula having a corresponding cross-section geometry. In that case, if microimplant is not circular in cross-section, the cross-sectional area can reach 0,00025 square inches or more, depending on the specifics of the geometry of the cross section. Assume that the implants, including microimplants contain unit is underwater or more active ingredients, having even smaller dimensions. For example, the implant may contain a collection of particles of the active ingredient. According to the above example, the particles can have different shape and size, smaller than the size of the implant used to treat pathological conditions of the patient's eye. Unlike liquid ophthalmic compositions, these implants are solid enough, at least initially, before the introduction of the patient, if necessary, therapy eye.
Used herein, the term "active ingredient" refers to any pharmacologically active agent, either by itself or as part of a combination of agents, for which it is desirable and can be done slow and controlled release, including substances listed below, but not limited to.
The term "biodegradable polymer" refers to polymer and polymers, which are degradable in vivo and for which destruction over time is a necessary condition to achieve the desired release kinetics of the agent.
Microimplants made in accordance with this invention, can be quite small or minimallyinvasive in size and shape, so that they can be installed in the eye without requiring application of a cut or puncture requiring sewing or other surgeon is standard procedure for healing, as usually happens in the case of implantation of implants of larger size. When using data microimplants and in accordance with the following technologies eye can "self sajustice" after you install microimplant, this eliminates the need for sewing or surgical procedures, as well as the attendant trauma and pain, and it also eliminates the costs, time costs and other inconveniences associated with the implementation of these procedures using surgical equipment. Used herein, the term "self-healing" in relation to the delivery of microimplants in the eye relates to a method of introducing one or more microimplants through the cannula in the desired area of the patient's eye without any need for sewing or other methods of wound closure at the puncture cannula. Such methods are "self-healing" does not require that the puncture site was fully restored immediately after withdrawal of the cannula, but rather imply that the initial damage is minimal and is recovering quickly, so that the surgeon or other specialist in the field of technology, guided by sound judgment on clinical need, not be forced to sew or use other similar stitching ability, which would be to close the puncture site.
Implants as larger and smaller, made in accordance with this izrecheniem, will have substantially uniform characteristics, which, in turn, will create the ability to deliver accurate and correct amount of the active ingredient and provide, therefore, a highly controlled flow of active ingredient in the eye during a certain period of time. The active ingredient released from such implant may selectively act on a specific area of the eye. For example, implants placed in the posterior segment of an eye of the patient, active ingredient may be released so that upon release to provide a therapeutic effect on the retina or on the part of the retina that has the implant.
These implants can be made by combining particles of the active ingredient or ingredients and particulate biodegradable polymer or polymers. In accordance with some ways microimplants can be poluchenii using the method of manufacture, which includes the sorting of the particles of the active ingredient or ingredients and particles of a biodegradable polymer or polymers by size, mixing of these particles before formation of a homogeneous mixture of active ingredient(s) and b is razlagaemogo polymer(s), the extrusion through the extrusion in one or two channels) with receiving threads and cutting threads on microimplants, as well as the analysis of these microimplants for compliance to specifications. This manufacturing method can be used for parties or series of uniform microimplants having the desired characteristics such as weight, dimensions such as length, diameter, area, volume), the area rasprostraneniya active ingredient, the kinetics of release and so on. For example, the party of implants can be evaluated according to specific acceptance criteria, including, for example, the criterion of mass, whereby the mass of microimplant can be expressed as the percentage of a given deviation from the desired planned mass, or, for example, a certain standard deviation for microimplants each party. A definite correlation Lekarstva/polymer also calculated so that each individual implant party or a series of implants could contain the same amount of the active ingredient. Thus, the party of implants, such as the party of implants in the package, can carry a special designation of the strength or dose of the active ingredient on each individual implant such series.
1. The composition of the Implants and Microindentation.>
Typically, implants and microimplants made in accordance with this invention, may be made from a mixture of the active ingredient or ingredients and biodegradable polymer or polymers, which together can control the kinetics of release of the active ingredient eyes. The specific composition can varieeruvusi, for example, depending on the desired characteristics of the output medications, specific to the active ingredient or ingredients, the sites of implantation, pathological condition and medical history of the patient. These implants are made of particles of the active ingredient enclosed in a matrix of biodegradable polymer. The release of the active ingredient or ingredients is the result of erosion of the polymer with the subsequent release of previously withheld or dispersed particles of the active ingredient in the eye, and then dissolving and releasing agent. The conditions that determine the kinetics of the release, include, but are not limited to, such factors as the size of the drug particles, the solubility of Lekarstva in water, the ratio lekarstvennogo substances and polymer, the specific methods of manufacture, the shape of the implant, the surface area and the degree of erosion of the polymer.
In this implant can be included is of hypoxia required farmacologicas active agents, medicinal substances and medicines. A nonexhaustive list of pharmacologically active agents include medicines for glaucoma, such as beta-blockers: maleate thymol, betaxolol and metipranolol; mitotic agents: pilocarpine, acetylcholine chloride, isoflurophate, bromide demecarium, iodide echothiophate, phospholine iodide, carbachol and physostigmine; epinephrine and salts such as dipivefrin hydrochloride; and dichlorphenamide, acetazolamide and methazolamide; anti-cataract and anti diabetic retinopathies, such as hibitory alsoreported: tolrestat, lisinopril, enalapril and static; medication based cross-stitched thiol in addition to the previously listed; antitumor drugs such as retinoic acid, methotrexate, adriamycin, bleomycin, triamcinolone, mitomycin, CIS-platinum, vincristine, vinblastine, actinomycin-D, Ara-C (cytarabine), pesantren, CCNU (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea - 1-(chlorethyl)-3-cyclohexyl-1-nitrosoanatabine), activated cytoxan, DTIC (Dimethyl Triazeno Imidazole Carboxamide - dimethyl triazeno imidazol carboxamide), MMOs (hexamethyl melanine - hexamethylmelamine), melphalan, mithramycin, procarbazine, VM26 (teniposide), VP16 and tamoxifen; immunomodulators in addition to the previously listed; anticoagulation agents, such as tissue activator of plasminogen, urokinase, and streptokinase; substances for preventing tissue damage, such as superoxiddismutase; proteins and nucleic acids, such as mono - and polyclonal antibodies, enzymes, protein hormones and genes, gene fragments and plasmids; steroids, including steroid anti-inflammatory agents or protivovirusnye tools, such as cortisone, hydrocortisone, prednisolone, prednisone, dexamethasone, progesterone-like compound, Madison (HMS) and fluorometholone; non-steroidal anti-inflammatory drugs, such as Ketorolac tromethamine, diclofenac sodium, suprofen; antibiotics such as loridin (tsefaloridin), chloramphenicol, clindamycin, amikacin, tobramycin, methicillin, lincomycin, oxacillin, penicillin, amphotericin b, polymyxin B, the family of cephalosporins, ampicillin, bacitracin, carbenicillin, cephalothin, colistin, erythromycin, streptomycin, neomycin, sulfacetamide, vanomycin, silver nitrate, sulfisoxazole diolamine and tetracycline; other protivopolojnye means, including antiviral agents, such as idoxuridine, triptorelin, vidarabine (arabinosyl adenine), acyclovir (acycloguanosine), ganciclovir, pyrimethamine, trisulfide-2, clindamycin, nystatin, fluctin, natamycin, miconazole and piperazine derivatives, such as diethylcarbamazine; midriatichesky and causing paralysis accommodative muscle substance, such as atropine, cyclogyl, scope the amine, gomatropin and mydriacyl.
Other agents include antiholinergicescoe, anticoagulation, antifibrinolytic, antihistamine, antimalarial, antioxidant, chelating agents, hormones, immunosuppressants, thrombolytic agents, vitamins, salts, desensitizing agents, prostaglandins, amino acids, metabolites and anti-allergic medicines.
Some active ingredients can be combined in these implants modulators release. The use of modulators release will benefit from the use of certain therapeutically active hydrophobic agents included in these implants, including cyclosporine, such as cyclosporine a, cyclosporine G, etc.; Vinca alkaloids, such as vincristine and vinblastine; methotrexate; retinoic acid; some antibiotics, such as ansamycins were such as rifampin; nitrofurans, such as nifuroxazide; nonsteroidal protivovospalitelnye drugs, such as diclofenac, Ketorolac, flurbiprofen, naproxen, suprofen, ibuprofen, aspirin, etc. Also it can be steroids, including those mentioned above and others such as estrogens, progesterones and similar substances.
These implants may also contain a therapeutic combination of two or more active hagenow providing delayed the release agents. Combinations can include steroids, as noted above, as a hydrophobic agent and a water-soluble antibiotics, such as aminoglycosides, such as gentamicin, kanamycin, neomycin and vancomycin; amphenicol, such as chloramphenicol; cephalosporins such as Cefazolin HCl; penicillins, such as ampicillin, penicillin, carbenicillin, oxacillin, methicillin; lincosamides, such as lincomycin; polypetide antibiotics, such as polymyxin and bacitracin; tetracyclines, such as tetracycline; quinolones such as ciproflaxin and he podanie connection; sulfa drugs such as chloramine T; and sulfones, such as sulfanilic acid as hydrophilic substances. The combination of non-steroidal protivovospolitelnyh drugs noted above, with vodorastvorimami antibiotics is also of interest. Combinations of antiviral drugs such as acyclovir, ganciclovir, vidarabine, azidothymidine, dideoxyinosine, dideoxycytidine with steroid or nonsteroidal anti-inflammatory drugs, noted above, is also of interest.
Combined anti-inflammatory and antibiotic or antiviral agent may further be combined with an additional therapeutic agent. An additional agent, which can also be used independently and in different combinations, may be analgesic such as codeine, morphine, Ketorolac, naproxen and the like substance, anesthetic, such as lidocaine; β-blocker or β-adrenoagonists, such as ephedrine, epinephrine and similar substances; inhibitor alsoreported, such as epalrestat, sorbinil, tolrestat; antiallergic agent, such as kromolin, beclomethasone, dexamethasone and flunisolide; colchicine. Anthelminthic agents, such as ivermectin and sodium suramin; protivooterne agents, such as Harkin and chlortetracycline; antifungal agents such as amphotericin and similar substances can be used independently or in combination with antibiotic and/or anti-inflammatory drug. In the case of intraocular use interest protivoglaucomny agents, for example acetazolamid, befunolol and the like, by themselves or in combinations with anti-inflammatory and antimicrobial agents. For the treatment of neoplasia can be used antineoplastics drugs or combinations containing antineoplastics drugs, in particular, vinblastine, vincristine, interferon α, β and γ, the antimetabolites, such as analogs of folic acid, analogs of purine analogues primidone. Interest immunosuppressants, such to the to azatioprin, cyclosporine and mizoribine, by themselves or in combinations. Can also be used by themselves or in combinations, mitotic agents such as carbachol, midriatichesky agents, such as atropine and similar substances, inhibitors of proteases, such as Aprotinin, chemostat, gabexate, vasodilator, such as bradykinin, and similar substances, and many growth factors such as epidermal growth factor, the main factor in the growth of fibroblasts, nerve growth factor and the like.
Additional therapeutic agents, such as antimetabolites and/or antibiotics may be used by themselves or in combination. The list of antimetabolites include, but are not limited presents substances, analogues of folic acid (e.g., deeperin, edatrexate, methotrexate, piritrexim, peripteral, Tomudex®, trimetrexate), analogs of purines (e.g., cladribine, fludarabine, 6-mercaptopurine, timipre, Tieguanyin) and pyrimidine analogues (for example, ancitabine, azacytidine, 6-azauridine, carmofur, cytarabine, doxifluridine, Amateur, enocitabine, floxuridine, fluorouracil, gemcitabine, tegafur).
For steroid substances and anti-inflammatory agents agent preferably selected from the group consisting of such substances as 21-acetoxyphenyl, alcomate, Alveston, amcinonide, b is clemetson, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortisol, deflazacort, daconil, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, flashcart, fluchloralin, flumetazon, flunisolide, fluoqinolona acetonide, fluocinonide, fluocortin butyl, fluocortolone, formatron, flaperon acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, horicontal, halcinonide, halobetasol propionate, halobetasol, halopedia acetate, hydrocortamate, hydrocortison, loteprednol etabonate, mazipredon, Madison, meprednisone, methylprednisolone, mometasone furoate, promethazin, prednicarbate, prednisolone, prednisolone 25-diethylamine acetate, prednisolone sodium phosphate, prednisone, prednesol, prednisone, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetone and triamcinolone hexacetonide. In a preferred modification of steroid anti-inflammatory agent selected from the group consisting of cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone. In the preferred modification of steroid anti-inflammatory agent is dexamethasone. In another modification of biodegradable implant contains more than one is teroidnyh anti-inflammatory agent.
Specific antibiotics that can be used include, but are not limited to, the following substances: antibacterial antibiotics such as aminoglycosides (e.g., amikacin, apramycin, arbekacin, bambermycin, butirosin, dibekacin, dihydrostreptomycin, fertilizin(s), gentamicin, isepamicin, kanamycin, micronomicin, neomycin, neomycin undecylenate, neomycin, paromomycin, ribostamycin, sisomicin, spectinomycin, streptomycin, tobramycin, trospectomycin), amphenicol (for example, azidophenyl, chloramphenicol, florfenicol, thiamphenicol), ansamycins were (for example, rifamide, rifampin, rifamycin sv, rifapentine, rifaximin), β-lactams (e.g., carbacephem (for example, loracarbef), carbapenems (e.g., biapenem, imipenem, Meropenem, panipenem), cephalosporins (e.g., cefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone, Cefazolin, cefcapene pivoxil, ceciley, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefmenoxime, cefodizime, cefonicid, cefoperazone, ceforanide, Cefotaxime, cefotiam, cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime proxetil, cefprozil, cefroxadine, cefsulodin, ceftazidime, cefteram, ceftezole, ceftibuten ceftizoxime, Ceftriaxone, cefuroxime, carusona, cefacetrile sodium, cephalexin, cephaloglycin, tsefaloridin, cephalosporins, cephalothin, cevapi is in sodium, cefradine, pureflex) cephamycin (for example, cefbuperazone, cefmetazole, cefminox, cefotetan, cefoxitin), carbapenems (e.g., aztreonam, carumonam, Tiemann), oxazepam, flomoxef, moxalactam), penicillins (e.g., amdinocillin, amdinocillin pivoxil, amoxicillin, ampicillin, apalcillin, aspoxicillin, azidocillin, azlotillin, bacampicillin, benzilpenitsillina acid, benzylpenicillin sodium, carbenicillin, carindacillin, climatically, cloxacillin, ciclacillin, dicloxacillin, ampicillin, finanically, floxacillin, hetacillin, lemoncelli, metampicillin, methicillin sodium, methacillin, nafcillin sodium, oxacillin, pennicillin, penetrate hydroiodic, penicillin g Benyamin, penicillin g benzathine, penicillin g benzhydrylamine, penicillin g calcium, penicillin g hydrobasin, penicillin g potassium, penicillin g procaine, penicillin n, penicillin o, penicillin v benzathine, penicillin v geranamine, primarily, phenethicillin potassium, piperacillin, pivampicillin, propicillin, quinazoline, sulbenicillin, sultamicillin, talampicillin, temocillin, ticarcillin), others (for example, riipinen), lincosamides (e.g. clindamycin, lincomycin), macrolides (eg, azithromycin, carbomycin, clarithomycin, dirithromycin, erythromycin, erythromycin acistrate, erythromycin estolate, erythromycin glycol ptonet, erythromycin lactobionate, erythromycin propionate, erythromycin stearate, josamycin, leucomycin, midecamycin, mikamycin, oleandomitsin, primycin, rokitamycin, rosaramicin, roxithromycin, spiramycin, troleandomycin), polypeptides (e.g., ambomycin, bacitracin, capreomycin, colistin, induration, antimycin, fusafungine, gramicidin s, gramicidin(s), mikamycin, polymyxin, pristinamycin, ristocetin, teicoplanin, thiostrepton, tubercidin, tyrocidin, tyrothricin, vancomycin, viomycin, virginiamycin, zinc bacitracin), tetracyclines (e.g., ampicillin, chlortetracycline, clomocycline, demeclocycline, doxycycline grimalkin, lymecycline, meclocycline, metatsiklina, minocycline, oxytetracycline, primarily, epicillin, rolitetracycline, sancycline, tetracycline) and others (e.g., cycloserine, mupirocin, tuberin).
Synthetic antibacterial agents, such as 2,4-diaminopyrimidine (for example, brodimoprim, tetrasodium, trimethoprim), nitrofurans (e.g., furaltadone, furazolidone chloride, nifuratel, nifuratel, nifuratel, nifurpirinol, nitocris, niforeika, nitrofurantoin), quinolones and analogs (e.g., cinoxacin, ciprofloxacin, clinafloxacin, difloxacin, enoxacin, fleroxacin, flanagin, grepafloxacin, lomefloxacin, Eloxatin, nadifloxacin, nalidixic acid, norflo satin, ofloxacin, oxolinic acid, pazufloxacin, pefloxacin, pipemidinova acid, pyramidula acid, rosoxacin, rufloxacin, sparfloxacin, temafloxacin, tosufloxacin, trovafloxacin), sulfonamides (for example, acetyl sulfamethoxypyrazine, bansilalpet, chloramine b, chloramine-t, dichloramine t, n2-formylmethionine, n4-β-d-glucosylceramide, mafenide, 4'-(methylsulfonyl)sulfanilamide, nobelsmile, caliculated, caliculation, salazosulfapyridine, succinylsulfathiazole, sulfabenzamide, sulfacetamide, sulfachloropyridazine, sulfurization, sulfation, sulfadiazine, sulfacetamide sulfadimetoksin, sulfadoxine, sulfatides, sulfaguanidine, alfaguara, sulfalen, sulfamoxole acid, sulfamerazine, sulfamate, sulfamethazine, sulfamethizole, sulfanilamide, sulfamethoxazole, sulfamethoxypyridazine, sulfometuron, sulfamethizole, sulfamoxole, sulfanilamide, 4-sulfanilamidnaya acid, n4-sulfonilmorpholid, sulfanilamide, n-effect-free remedy 3,4-xiemed, sulfanitran, solfataric, sulfaphenazole, sulfuration, sulfapyrazine, sulfapiridin, sulfanomides, sulfasalazin, sulfathiazole, sulfuration, sulfapyrazine, sulfapiridin, sulfanomides, sulfasalazin, sulfisoxazole), sulfones (for example, acedapsone, Azadi the sulfon, acetosolv sodium, dapson, detersion, glucosone sodium, solusulfon, successive, sulfanilic acid, p-sulfanilamilny, sulfation sodium, isolalion) and others (for example, clofoctol, hexagen, methenamine, methenamine angermeier-citrate, methenamine hippurate, methenamine mandelate, methenamine, sulfosalicylate, nitroxoline, taurolidine, sibornal).
Antifungal antibiotics, such as polyene (e.g., amphotericin b, conditin, termostatic, filipin, hungarain, hachimitsu, gamitin, senzamici, mepartricin, natamycin, nystatin, pellotine, primycin), others (for example, azaserine, griseofulvin, oligomycin, neomycin undecylenate, pyrrolnitrin, sickenin, tubercidin, viridin).
Synthetic antifungal drugs, such as allylamine (for example, butenafine, naftifine, terbinafine), imidazoles (for example, bifonazole, butoconazole, Chlordecone, chloridazon, gluconazole, clotrimazole, econazole, enilconazole, fenticonazole, flutrimazole, isoconazole, ketoconazole, lanoconazole, miconazole, omoconazole, oxiconazole nitrate, sertaconazole, sulconazole, tioconazole), THIOCARBAMATE (for example, tolciclate, talinda, tolnaftate), triazole (e.g., fluconazole, Itraconazole, saperconazole, terconazole), others (for example, grisactin, amorolfine, mefenamic, bromosalicylaldehyde, beclazone, propionate to Lycia, chlorphenesin, ciclopirox, Klochikhin, sopraffina, deltasol the dihydrochloride, exalted, flucytosine, galetta, hexetidine, lowcarbon, nifuratel, potassium iodide, propionic acid, pyrithione, salicylanilide, sodium propionate, Albertin, demonicrats, triacetin, auotion, undecylenoyl acid, propionate zinc).
Can also be applied to other antibiotics and their analogues (e.g., aclacinomycin, actinomycin f1astromicin, azaserine, bleomycin, actinomycin, karubitsin, calcination, chromomycin, dactinomycin, daunorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, idarubitsin, menogaril, mitomycin, mycofenolate acid, nogalamycin, olivomycin, peplomycin, pirarubicin, plicamycin, porfiromycin, puromycin, streptonigrin, streptozocin, tubercidin, zinostatin, zorubicin), antimetabolites (e.g., analogs of folic acid (e.g., deeperin, edatrexate, methotrexate, piritrexim, peripherin, Tomudex®, trimetrexate), purine analogues (for example, cladribine, fludarabine, 6-mercaptopurine, Temerin, tioguanin), pyrimidine analogues (for example, ancitabine, azacytidine, 6-azauridine, carmofur, cytarabine, doxifluridine, Amateur, enocitabine, floxuridine, fluorouracil inside the body, gemcitabine, tegafur).
Also of interest is the use of such drugs as hydrocortisone, gentamicin, 5-forour the cyl, sorbinil, Interleukin-2 (IL-2), factor tumor necrosis (TNF - tumor necrosis factor), Pakan-a (a component of glutathione), thiol-tiopronin, Bendazac, acetylsalicylic acid, triptorelin, interferon (α, β and γ), immunomodulators, for example, lymphokines, Monokini and growth factors, cytokines and antagonists of growth factors and so on. Other pharmacological agents that can be used, can be found, for example, in U.S. patent No. 4327725, 4474451 and 4997652 included in this text by reference.
In order to achieve maximum homogeneity of implants or microimplants, it is desirable that the active ingredient or ingredients were available in the dry form and were processed to obtain a uniform particle size. In particular, preferably, but not necessarily to the active ingredient or ingredients consisted of particles with a diameter of approximately 80 μm or less. Depending on the selected active ingredient particles can be sorted by size to obtain particles of the same size. As described below, such methods sortitoutsi may include the use of a strainer or ultracentrifuging devices for grinding. The particle size of the active ingredient (tov) can be in a certain numerical range. For example, a series of particles of the active ingredient may have environments is their diameter, approximately 50 μm. Implants are created on the basis of such series of particles may include particles having a diameter different from the mean on one or two values of the standard deviation. In some modifications of the particles of the active ingredient have a diameter or other dimension exceeding 3 microns. By controlling the particle size in a series of particles, obtained for the implant, it is possible to improve the release characteristics of the active ingredient and therapeutic effect of the treatment. For example, implants made of particles of the active ingredient, which has a diameter greater than 3 microns, provide prolonged release of the active ingredient, providing therapeutic effect, which cannot be achieved by using particles having a size less than 3 microns.
The choice of polymer used in the composition depends on the place of application, the intended treatment period, individual sensitivity of the patient, the nature of the disease, and so forth. Characteristics of the polymers include the ability to biodegrade in the implantation site, compatibility with interesting pharmacological agent, the expected half-life in the physiological environment, solubility in water, and so forth. The selected polymer or mixture of polymers should, as a rule, costal shall be approximately 10 wt.% up to 90 wt.% the manufactured implant, other ratios also depend on the specific combination of active ingredient and polymer and the desired release kinetics.
Can be used such biodegradable polymeric composition as simple or complex organic esters, decompose with the formation of physiologically acceptable products, including monomers. Can also find the use of anhydrides, amides, orthoepy and similar compounds, by themselves or in combination with other monomers. Used polymers can be condensation polymers. The polymers can be cross-stitched or not, as a rule, may require a small amount of crosslinking, typically less than 5%, usually less than 1%. For the most part, in addition to carbon and hydrogen polymers may include oxygen and nitrogen, in particular oxygen. Oxygen can be present in the form of actigraphy, for example hydroxy or ether, carbonyl, for example, do not oxycarbonyl, such as ether carboxylic acids, and similar forms. Nitrogen can be present in the form of an amide, cyano and amino. Can be used biodegradable polymers, the corresponding described in Heller, Biodegrable Polymers in Controlled Drug Delivery, CRC Critical Reviews in Therapeutic Drug Carrier Systems, Vol. 1. CRC Press, Boca Raton, FL (1987).
Of particular interest are the polymers hydroxyapatites carboxylic Ki the lot, such as Homo - or copolymers, and polysaccharides. In the list of noteworthy polyesters are polymers of D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid, polycaprolactone and combinations thereof. When using L-lactate or D-lactate turns slowly biodegradable polymer, however, in the case of the racemate decomposition greatly enhanced. Copolymers of glycolic and lactic acid deserve special attention, for them, the degree of biodegradation is determined by the ratio of the amount of glycolic acid to lactic. The percentage of the polylactic acid copolymer and polylactic polyglycolic acid (PMHC) can range from 0 to 100%, preferably about 15-85%, more preferably about 35-65%. In a particularly preferred modification use the 50/50 copolymer PMGC. The copolymer, which decomposes fastest, contains approximately equal amounts of glycolic and lactic acid, and a homopolymer of each of them more resistant to decay. The ratio of glycolic acid to lactic also affects the fragility of the implant, the flexible implant can be preferred depending on the size, shape and selected the implant site. Also of interest as themselves, or as part of combination copolymers PMGC, Essie free acid end groups. Preferably, the particle size of the polymers is about 1-100 microns in diameter, more preferably about 5-50 μm in diameter, more preferably 9-12 microns in diameter, more preferably about 10 microns in diameter. In the manufacture of these implants may be used particles of polymers a number of dimensions. For example, the polymer particles can have a diameter or other dimension of from about 5 microns to about 15 microns. In certain modification of more than approximately 50% of the polymer particles in scree polymer particles have a diameter from about 5 microns to about 15 microns. Additional modifications more than 90% of the polymer particles have a diameter less than 20 microns.
Additionally, the implant can be included modulators release, including accelerators and retarders, such as described in U.S. patent 5869079 included in this text by reference. The amount of modulator of the release will depend on the required release characteristics, activity modulator and release characteristics of the active agent in the absence of the modulator.
Accelerators can be physiologically inert, water-soluble polymers such as low molecular weight methylcellulose or hypromellose (HPMC); sugars, such as monosaccharides, such as fructose and glucose, disaccharides such as lactose, sucrose, or polysaccharides, such as cellulose, amylose, dextran etc. In other cases, the accelerator may be physiologically active agent that allows you to create a combined therapeutic drug. The choice of the accelerator in this case is determined by the desired combination of therapeutic properties.
The release retarders are hydrophobic compounds that reduce the rate of release of hydrophilic drugs, which makes possible a longer release. Of interest hydrophilic drugs advantages of using modulators release can be obtained for the water-soluble antibiotics, according to the above description, nucleotide analogues, such as acyclovir, ganciclovir, vidarabine, azidocillin, dideoxyinosine, dideoxycytidine; epinephrine; isoflurophate; adriamycin; bleomycin; mitomycin; cytosine arabinoside (Ara-C); actinomycin D; scopolamine and other.
Agents of interest as a possible inhibitor of the release, include water-insoluble polymers, for example high molecular weight methylcellulose and ethylcellulose, etc., poorly water-soluble organic compounds and farmacologicas active g is dropable agents, as explained above.
The preparation may include other agents that serve for different purposes. For example, can be used buffering agents and preservatives. In the list of water-soluble preservatives which may be used include sodium bisulfite, sodium bisulfate, sodium thiosulfate, benzalkonium chloride, chlorobutanol, thimerosal, acetate finalstate, nitrate of finalstate, methylparaben, polyvinyl alcohol and phenethyl alcohol. These agents may be present in amounts of from about preferably about 0.001 wt.% to preferably 5 wt.% and preferably 0.01 wt.% to preferably 2%. Suitable water soluble buffering agents that may be used are sodium carbonate, sodium borate, sodium phosphate, sodium acetate, sodium bicarbonate, and so on in accordance with the permission of the Department of supervision of food and drugs (FDA - Food and Drug Administration) for the respective application. These agents may be present in quantities sufficient to maintain the pH of the system in the range between 2 and 9, preferably between 4 and 8. The mass of the buffer agent as such may be 5% of the mass of the whole composition. The preparation can also include such electrolytes as sodium chloride and potassium chloride. In that case, if the buffer agent and the and political is a hydrophilic substance, it can also act as an accelerator release. Hydrophilic additives act as accelerators release, providing a more rapid dissolution of the material surrounding the particles of drug substance, which increases the available surface area of the drug and, thus, increases the speed of his bioerosion. Similarly, hydrophobic buffer agents or amplifiers dissolve more slowly, slowing down access to the particles lekarstvennogo substances and, thus, reducing the speed of its bioerosion.
The proportions of the active ingredient, polymer, and any other modifiers may be determined empirically by developing formulations of several implants with varying proportions. The U.S. Pharmacopoeia (USP - United States Pharmacopoeia) was approved method for determination of dissolution or release, which can be used to measure the speed of release (USP 23; NF (National Formulary - national formulary) 18 (1995), str-1798). For example, when using the method of multiple drains weighted sample delivery system drugs contribute to containing 0.9% NaCl aqueous solution, the volume of which is known, the volume of the solution is such that the concentration of drugs after release will not exceed 5% of the saturation level. The mixture is kept at 37°C and honey is i.i.d. stir so to plantati was suspended. The appearance of the dissolved drug compound as a function of time can be determined using various known methods, such as spectrophotometry, high performance liquid chromatography (HPLC), mass spectrophotometry, and so on, up until the absorption coefficient will not cease to change, or more than 90% of the drug substance is released.
2. Characteristics of microimplants.
As mentioned earlier, the implants and microimplants made in accordance with these methods, are uniform in size, shape and weight. In the case of microimplants full edinoobraziya characteristics is especially important, because due to the very small size of microimplants, especially in the case of microimplants high ratio of surface area to volume, slight differences in the characteristics of microimplants can lead to significant changes in the amount of released drug and the time of its release. In particular, the presence of relatively small individual points or areas in microimplants, which have greater or lesser concentration of the active ingredient in the polymer (the so-called "hot spots" or "cold spots")can lead to negative passedst the pits. In particular, any violation of the homogeneity of the mixture, even local, may entail the delivery of active ingredient in number, are very different from what is expected, and can change the course of treatment of diseases or pathological conditions of the eye. On the other hand, are located similarly "hot spots" and "cold spots" in the structure of the implant of larger size can be well tolerated and still have acceptable performance characteristics General release due to the fact that the implant is larger has a larger total mass and large surface area. The nature of distribution of active ingredient in the implant can be assessed by analyzing the uniformity of composition of the samples of the implants from the party of implants as understand an ordinary specialist in the field.
These implants are preferably monolithic, and that is the active ingredient uniformly distributed along their polymer matrix. The implants, which can be produced from the composition, which preferably has been preheated include uniformly distributed particles of the active ingredient, uniform size and uniform particle size biodegradable polymer. For example, particles of the active ingredient and/or the polymer particles may have a size in a specific range as described above. COI is lsua uniform particle size, you can achieve the proper degree of mixing of the particles of active ingredient and polymer(s) prior to the step of extrusion or further processing of the implant. After or during extrusion of the polymer particles to grind education continuous matrix. The selection of a particular polymer used in the composition will depend on the desired release characteristics, the selected site of implantation, individual sensitivity of the patient, the nature of the disease, and so forth. To the characteristics of the polymer include: the ability to biodegrade in the implantation site, the compatibility with the selected agent, the ease of encapsulation, solubility in water, and so forth. Preferably, the polymer matrix does not completely decompose until then, until the full release of drug substance.
In part, the kinetics of isoberlinia described in the invention of microimplants depends on their surface. The large surface makes available to impact the environment in the site of implantation larger volume of the polymer, which leads to more rapid destruction and dissolution of particles of drug substance, held by the polymer. To achieve a certain speed of release, duration of treatment and the drug concentration at the site of implantation can be used the Ana particular size and shape of microimplants. They are larger in size can deliver a proportionately larger dose of the medicinal substance, but because the ratio of surface to volume may have a lesser rate of release. Microimplants can be of any size and shape suitable for implantation in a selected area, provided the possession of the necessary kinetics of release. Preferably, microimplants made from extruded filament (or filaments made by injection molding), which is then cut to obtain the desired product. The upper size limit microimplant is determined by such factors as the desired release kinetics, the tolerance of the implant, the size limitations associated with a specific site of implantation, ease of manipulation, etc.
Also preferably, microimplants were somewhat flexible (i.e. nelomky) to facilitate both the insertion of the implant, and getting used to it. If too fragile microimplants implantation, and any manipulations involve a risk of breakage. Fragile implants can be implanted using and/or delivered to the applicators implant suitable for insertion of the implant in the eye. As discussed above, if the applicator has one or more microimplants, it can between eyes and removed without creating the necessity of closing wounds. Thus, as described, these implants, including flexible and fragile implants may be sufficiently rigid elements or means for delivery of drugs, at least until the introduction of the patient's eye. In addition, it is desirable that the obtained microimplants had a length (size)that do not affect the patient's vision after insertion in the eye. Accordingly, the choice of the length of microimplant may depend on the site of injection. For example, microimplants introduced into the vitreous body from the back of the eye, can have a length, reaching values up to 10 mm, and preferably up to 7 mm, in order to avoid impact on the patient's vision. Accordingly, microimplants, according to this invention may generally have a length less than 10 mm, for different applications and implantation in different locations within the eye. In the case of the implant through the sclera rather, thickness, not length, is of greater importance.
In one given as an example of the data modification implants using the methods described here make microimplants having a cylindrical or rounded cross-section diametral about 0,018 inches or less. Microimplants having such dimensions can be introduced into the eye through a cannula, according to the size of the corresponding needles 22 gauge or needle with PTS is ery thin walls, the internal diameter of which generally ranges from 0,019 up is 0.023 inches. In another cited as an example of modification of the present invention are made microimplants diameter of 0.015 inch or less, which can pass through the cannula having dimensions corresponding to the 23 gauge thin or very thin needles, the inner diameter of which, as a rule, is from 0.06 to 0.020 inches. The cannula of this size can be entered in the eye and derived using methods commonly used by ordinary experts in the field of technology. The cannula may be components of the apparatus for introduction of the implant and is designed in such a way that the introduction of these implants did not cause excessive separation of liquid eye, which can lead to disturbance of the normal fluid pressure in the eye. Such technologies, methods and apparatus allow the use of ways of introducing microimplants in the eye, based on self-healing, and avoids the necessity of sewing or other surgical procedures to repair the puncture site after withdrawal of the cannula.
In other modifications of these implants in sootvetsvtvii with ways described here can be made microimplants having a non-circular shape, which can be introduced through the cannula, imoudu the cross-section of the appropriate form. For example, in one embodiment, these implants these implants may have such a configuration that their cross-sectional area was 0,00025 square inches or more, depending on the exact cross-sectional shape.
3. The manufacturing methods.
Microimplants mentioned sizes can be manufactured using these methods with high uniformity. As a result, can be made of the party of microimplants, in which each microimplant has a minimum deviation of the composition, including local characteristics, and/or linear dimensions. As shown in the example methods, microimplants made, receiving particles of one or more active ingredients, polymers and/or other additional fillers (e.g., modulators release, buffers and so on), with a very high degree of uniform size, mixing these particles with the mixture by extrusion of the mixture with receiving threads and directly cutting these threads on the required microimplants. There are additional methods of quality control for data evaluation of microimplants for compliance with desired characteristics. In another case, such a highly homogeneous filament can be granulated and re-extruded or molded under pressure is to be neglected. In at least one embodiment, the data microimplants formed using the method, which involves the extrusion of the material of the implant in two channel.
In particular, in accordance with the example method, relevant to this invention, particles of the active ingredient, the particles of the biodegradable polymer and particles possible additional substances, fillers may be subjected to sorting to obtain aggregate particles of uniform size, with careful stirring which is obtained a mixture containing a high degree of uniformly distributed particles of active ingredient and polymer. For example, particles in the mixture may have a size within the size of one or two standard deviations from the average particle size of the mixture. As noted earlier, if the particle size is not sufficiently monitored and has a relatively wide range of particle sizes of the active ingredient, the presence of particles of larger or smaller size may result in higher or lower concentration of the active ingredient in certain parts of the mixture and the final implant. Such areas of higher concentration may lead to incorrect dosage of the substance in the biodegradable implant made from a mixture, and thus m which may lead to ineffective treatment of diseases or pathological conditions of the eye, for treatment which was created by the implant. Also, as already mentioned, a certain degree of variation of particle sizes may be acceptable for implants of larger size, for which, in many cases, local variations of the levels of active ingredient can neutralize each other, given the overall size of the implant. However, in accordance with this invention, for microimplants, especially for those for which the ratio of surface area to volume is large, this degree of variation can make microimplants less suitable for the purposes intended and to cause unwanted peaks or dips in the desired release kinetics.
The particles can be sorted by size using such devices as, for example, a mesh filter and ultracentrifugal mill. In one example, the method is used ultracentrifugal mill. The desired particle size of the active ingredient, polymer and additional substances, fillers can vary depending on the requirements of the final composition of each specific microimplant. As for the polymer, in the General case, the particle size of the polymer may be in the range of 1-100 μm, or in the range of 5-50 μm, or within 9-12 μm, or about 10 μm. As described, a large part of the population of polymer particles may have a diameter the ETP, not exceeding 20 microns. For example, more than 90% of the population of polymer particles can have a diameter not exceeding 20 μm. In certain modifications of the average size of the polymer particles may be from about 10 μm to 15 μm. Particles of the active ingredient may have a diameter of not exceeding the size of about 80 microns, or from about 1 micron to about 20 microns, or from about 2 microns to about 8 microns, or about 5 microns. As described herein, in some modifications of the particles of the active ingredient have a size greater than 3 microns. For best results it is desirable to sort the particles having dimensions within +/- 10% of the allowable deviation from a standard diameter, preferably within +/- 5%, more preferably+/- 2 standard diameter. Controlling the particle size, i.e. reducing and/or eliminating random small particles of the active ingredient or of the polymer and reducing and/or eliminating too large particles, it is possible to achieve a high degree of homogeneity or uniformity of content of active ingredient in these implants.
In one particular modification for the manufacture of implant use particles of dexamethasone. In this modification all particles of dexamethasone have a diameter of not more than 15 μm and a 90% particle index is Casona have a diameter, not greater than or equal to 5 microns.
In another specific modification is 75% or more of particles of dexamethasone have a diameter of not exceeding 10 μm, and 99% or more of particles of dexamethasone have a diameter not exceeding 20 μm.
After received uniform particles having a maximum deviation from the standard size, the required amount of the active ingredient or ingredients are thoroughly mixed with the desired quantity of particles of the biodegradable polymer and particles of additional substances, fillers to achieve a relatively uniform distribution of the active ingredient in the mixture. The choice of specific proportions will depend on many factors, including the desired release kinetics, etc. Specific non-limiting examples of ratios of active ingredients and biodegradable polymers that may be used are described in U.S. patent No. 5869079 and the application for U.S. patent No. 09/693008 included in this text in its entirety by reference. As an example, the method of mixing particles comprising placing one or more ball bearings or similar devices into the vessel together with the necessary number of particles. The vessel is placed in a commercially available blender or similar apparatus and shaken for a period of time sufficient for a thorough peremeshivaniem.
After the particles are thoroughly mixed, they are ready for extrusion. The effect of combining and mixing, which gives the extrusion process, for example, by means of a screw extruder, also provides and ensures a greater degree of uniformity of mixing of the active ingredient and a polymer, and a concomitant melting of the polymer around the particles of the active ingredient also reduces the likelihood of local variations in the composition of the final product-microimplant.
In the case of a reciprocating belt press stir the mixture, as a rule, carry parts in appropriate packing cylinders and placed in a pneumatic device for compaction and removal of a mixture of air pores. After using a reciprocating belt press may need additional processing to increase the degree of homogeneity of the distribution of the implant components. After the first portion of the mixture in the packing cylinder enough compaction, in the packing cylinder can add the next portion of the mixture, and the process can be repeated several times until the cylinder is completely filled. After the required amount of the mixture introduced into the packing cylinder, the latter can be loaded into an extruder and extruded to obtain a filament the century
It is preferable to use a twin-screw extruders, which neperian melt and mix the mixture during extrusion it in the thread. It is desirable, but not required, to use twin-screw extruders having a conical screw and cylinder, and not the standard screws and cylinders. This combination of melting and continuous stirring of the mixture maintains its homogeneity and even increases the degree of homogeneity of the mixture in the extruded filaments, preventing thereby the formation of local variations in the distribution of the active ingredient by the length of the extruded filament. To achieve greater homogeneity of the extruded filament can be converted into granules by conventional cutting or grinding, and then re-extruded or subjected to injection molding.
By adjusting the rotation speed of the screw of the extruder, the temperature and pressure of the cylinder of the extruder and/or the geometry of the head of the extruder, can be ekstradiroval the given thread form. The geometry of the head or the nozzle of the extruder, in particular the diameter, the ratio of length to diameter (1/d) and the presence of head or nozzle on the end and used in the extruder speed vitginia, determines the final diameter of the extruded filament. Head or heads, as a rule, can be related to 1/d from the arr is siteline 1:1 to 10:1 and, in addition, can have different shapes, including cylindrical or non-circular. As an example, to obtain microimplant able to pass through the cannula 22 caliber, can be used dvuhsimovyiy extruder, for example having a capacity of 5 cm3(full load) and suitable for use in the continuous mode, and tapered cylinders and nozzles. The extruder can be operated at a temperature of 90-110°C, with a speed of rotation of the auger from about 100-150/m In some embodiment, the implant can be obtained by extrusion of the mixture at one temperature, for example 105°C. in the extruder and at the other, for example, temperature 102°C, in the nozzle of the extruder at a speed of 120 Rev/m It can be considered as the first stage of the extrusion process. Thereafter, the extruded mixture may be subjected to a second extrusion at a temperature of 107°C in the cylinder and 90°C in the nozzle, when the speed of screw rotation of 100 rpm meters Extruder may be equipped with nozzles having a diameter in diabase of 0.4-0.5 mm and the ratio length/diameter from approximately 1 to 10, for example from 2 to 6. The obtained filament may have a diameter equal 0,019 inch (482.6 μm) or less, and they may be cut with getting microimplants of the same diameter. In some modifications of this invention the required diameter of the filaments or microimplants is 0,018 inches (i.e 457.2 mm).
Soon the industry pulling extrudable thread also affects the final diameter of the thread. For example, if extrudable thread exits the extruder at such a speed that it sags, the final diameter of the extruded filaments is less than the diameter of the head or nozzle of the extruder. Thus, for example, extruded filament having a diameter of less than 0,0019 inches, can be obtained by using an extruder equipped with a nozzle or head, having a diameter 0,019 inches or less.
Once the head of the extruder goes a long thread, this thread can be cut into fragments of desired length for further processing and manipulation, usually fragments of about 6 inches. After the thread was extrudible and cut into fragments of the working length, these threads can then accurately cut into fragments of desired length to obtain the required microimplants. The resulting microimplants can have a length not exceeding 1 mm or less, or may be a length of 7 m or even more. Length restrictions are made of microimplants are not a consequence of the manufacturing process as such, but are rather a consequence of limitations in the practical application of microimplants. For example, long microimplants, for example having a length of 10 mm or more, can disrupt the patient's vision when placed in the vitreous body. In addition, so long Microm entity can easily break during routine manipulations solely due to their length.
After the second extrusion ability to accurately cutting the extruded strands into fragments of equal length becomes especially important for getting implants or microimplants, which can provide uniform delivery of the necessary dose of the active ingredient, in particular, taking into account the fact that microimplants have a relatively large ratio of length to diameter and, thus, a proportionately larger ratio of surface area to volume. That is, the length change will entail major changes delivered amount of the active ingredient compared with those that would have occurred if these relationships were less, as in the case of ordinary implants are larger in size. One way to accurately cut microimplant-based system that combines an oscillating wire saw and cutting platform or stand designed to hold the extruded filaments or threads. In this example, platform or other stand may be designed to hold the thread or yarn in place, for example, using vacuum pressure. A wire saw is preferably equipped with a wire with the inclusion of diamonds to achieve greater precision cutting. Relatively flat sections of threads can be obtained by slowly cutting Nita is oscillating dvijeniem. To achieve an accurate and smooth cutting, remove all waste generated in the cutting process, so that the area cut was not clusters. This can be realized, for example, by using a vacuum source. Once the desired section as a platform, and the wire saw can be positioned again to re-cut the threads. In another case, both platform and wire saw reinstall for the implementation of re-cutting the threads or filaments. This process can be repeated to obtain the necessary number of microimplants in the volumes of the party.
Another method of making these microimplants may involve the use of cutting ustroystva type guillotine. Preferably, the cutter operates is automatically. For example, for accurate and reproducible cutting threads on the implant can be used automated cutter type guillotine. In certain modifications of it may be supplemented by the passing of one or more threads through additional cutting device, the cutting or forming implants with a certain velocity, which can be determined by the speed of movement of the implants. Can be used in other ways with the use of automated cutter type Guiglo the ins and other similar devices.
After thread just exploded into fragments of desired length to obtain the party of microimplants, each microimplant in the party may be subjected to inspection and sorting. Can be used many ways, based on the measurement of certain characteristics of microimplants, such as linear dimensions, mass, weight, uniformity of composition, activity of the active ingredient, the release characteristics of the active ingredient and so on, to determine how the implant itself and/or party microimplants meets the requirements of the magnitudes of the deviations from the mean. Based on such measurements, microimplants or party microimplants can be accepted or rejected.
According to one such method can produce optical measurements of the characteristics of each microimplant or series of microimplants from different positions or angles. The results of optical measurements can be compared with the results from algorithm to determine whether microimplants the right amount of active ingredient, based on measurements of the volume and shape of microimplants, as well as to determine whether microimplants necessary to provide the desired release kinetics of the active ingredient form and/or characteristics of the surface. Such a comparison may be based on the assessment of uniformity, for example, the ratio of the active ingredient/polymer. On the basis of this comparison microimplants may also be accepted or rejected.
In the case of use of another method, according to which microimplants represent a solid mixture of the active ingredient and a biodegradable polymer, the acceptance or rejection of microimplants may be based on an assessment of how the deviation of the mass of each microimplant valid. The deviation may be determined based on the magnitude of the acceptable doses of the active ingredient. For most cases, the deviation for the implant must be +/- 10 wt.% the required planned mass, preferably +/- 5 wt.%, more preferably +/-2 wt.%. In another case, because the deflection masses normally distributed, and thus, the average weight will correspond to the planned mass, the acceptability of the party of microimplants may be a function of the standard deviation of the masses of party principle, the smaller the standard deviation, the less the deviation of the mass of each individual implant of the unknown. In turn, for most cases, the appropriate standard deviation of the mass party of microimplants status is made by 6 or less, preferably 4 or less, and more preferably 2 or less. The use of such criteria as the standard deviation has the advantage that it can be based on measurements of the mass of a statistically significant number of microimplants to implement the right decisions about acceptance or rejection of the party, containing a large number of microimplants, and not on the weighting of each individual microimplant party separately. Estimates of standard deviation and evaluation of microimplants can be used for content analysis of drugs, distribution uniformity and release characteristics of drug substances, among other parameters, either separately or in combination.
4. The introduction of implants/microimplants.
As noted earlier, the implants and microimplants, in accordance with this invention, can be injected or implanted in different areas of the eye for the treatment of diseases and pathological conditions of the eye. Thus these implants, you can enter the patient, i.e. the person who will be treating one or more symptoms of diseases of the eye or diseases in General. The implants and microimplants can enter in different parts of the eye depending on the shape and composition of the implant, state that tre is the duty to regulate the treatment, etc. Suitable for introduction of the implant are such parts of the eye as the anterior chamber, posterior chamber, vitreous cavity, suprachoroidal space, the subconjunctival space, episcleral space, the inner part of the cornea, the outer part of the cornea and sclera. Suitable areas lying outside of the vitreous body, include suprachoroidal space, pars plana, and so forth. Implantation can be intraparietal or suprachoroidal. Suprachoroidal space is a potential injection site, lying between the interior of the sclera on the one hand and the vascular sheath with the other. Implants, introduced in suprachoroidal space, can deliver drugs into the vascular membrane and the retina, anatomically located on the opposite side, depending on the possibilities of diffusion of drug substances from the implant, the concentration of the drug, part of the implant, and similar factors. Implantation can also be intraretinal or subretinal and intrasternally or episcleral. Moreover, implantation in areas of the brain in the optic nerve and/or inside the optical nerve is able to deliver a medicinal substance in the Central nervous system and provide a way about the tee through the blood-brain barrier.
Implants, which are injected directly into the vitreous body can release the drug in the vitreous cavity, which can ensure the access of medicinal substances to the tissues located at the back of the eye such as the retina, or to provide access to the tissues in the anterior segment of the eye such as the lens, or tissue of the anterior chamber. The implants and microimplants can be entered in or deprived of the choroid plot. This may be deprived of the choroid plot of natural origin, such as the pars plana, or the area that is deprived of blood vessels surgically. Devoid of vascular areas of the eye, created by surgery, can be obtained by using such well-known in this field of methods as laser ablation, photocoagulation, cryotherapy, thermal coagulation, cauterization, and so forth. In some cases it is desirable to create such an avascular area in the site of implantation or beside it, in particular, if the desired site of implantation is far from the pars plana or the introduction of the implant in the pars plana is not possible. The introduction of the implant in an avascular area will ensure the diffusion of the drug substance from the implant in the inner part of the eye and avoid diffusion into the bloodstream. Other parts of the implant can be used for delivery against the tumor funds in the areas of neoplasia, for example, tumors, or in the damaged area, for example, adjacent tissue, or, in the case when the tumor mass is removed, the tissue lying next to the former tumor site, and/or in the cavity left after removal of the tumor.
The implants and microimplants can be entered using a variety of suitable methods, including surgical procedures, such as applying a cut and install surgically or using a trocar. As noted earlier, such methods are usually carried out by means of surgical equipment and can personalno require application of eye incision, which should be sewn after the procedure. One of the many benefits of microimplants produced in accordance with this invention, is that due to their exceptionally small size they can be entered using methods based on self-healing, allowing you to avoid applying the cut and sewing required when using other methods. In particular, based on self-healing introduction of microimplants can be implemented in accordance with techniques and methods known to experts in this field.
The following examples are given to provide a more complete understanding of this invention. Should the tmetal, however, what these examples illustrate the invention but do not restrict it.
Example 1: Manufacture of microimplants way single-channel extrusion
Microimplants for insertion into the vitreous cavity were made as follows. The active agent dexamethasone mixed 50/50 with polymer polylactic acid-polyglycolic acid (PMGC), used as a biodegradable polymer. The agent and the polymer were thoroughly mixed in a ratio of 60/30/10 by weight of dexamethasone (Pharmacia Corp., Peapack, NJ), 50/50 PMCG having free terminal acid group (RG502H, Boehringer Ingelheim GmbH, Germany) and 50/50 PMHC (RG502, Boehringer Ingelheim GmbH, Germany), respectively.
Portions of the mixture of drug and polymer weight of 20 g or less then transferred into 5 cm3twin-screw extruder (with a full load that can operate in continuous mode (DACA MicroCompounder, DACA Instruments, Goleta, CA or Haake Minilab, Thermo Haake, Madison, WI). The extruder was equipped with a conical screws and cylinders, in contrast to commonly used cylinder having a cylindrical shape. The extruder operated at a temperature of 90-110°C. the rotation speed of the screw equal to 20-30 rpm, 500-2000 N. The extruder was equipped with various nozzles having a diameter in the range of 0.4-0.5 mm and the total ratio of length to diameter in the range of 2 to 6. Extruded neither the and collected, typically, when you reach a length up to 10 inches, and the final diameter of the filaments regulate the speed of extrusion of the extruder.
Filaments having a diameter of about 0,018 inches, then with high precision cut using an automatic cutting machine type guillotine with obtaining a series of microimplants cylindrical shape having a diameter of about 0,018 inches, a length of 6 mm and containing about 700 μg of dexamethasone on the implant.
Filaments having a diameter of 0.015 inch, with high precision cut into fragments with a length of 10 mm to produce batches of microimplants cylindrical shape having a diameter of 0.015 inch, a length of 10 mm and containing, therefore, approximately 700 μg of dexamethasone on the implant.
Example 2: Production of microimplants way multi-channel extrusion
Party a mixture of drug and polymer described in Example 1 was molded with obtaining the extruded filaments through a dual extrusion on the Haake Minilab. Microimplants were obtained using an automatic cutting machine guillotine type, as described in Example 1 description.
Example 3: the Assessment and decision containing the dexamethasone of microimplants (700 μg) on the basis of measurements of weight
Party microimplants produced as in Example 2. Part of the parties was assessed by mass, linear size of the frames, homogeneity of composition and release characteristics. Planned weight of each microimplant was, in total, about 1.2 mg (for example, 1.167 mg), of which 700 µg accounted for dexamethasone, and the remainder on the polymer. Microimplants with the deviation in mass within +/- 10% of the target weight (+/- 0,1167 mg)were acceptable (e.g., implants, with mass in the range from 1.050 mg to 1.284 mg).
The homogeneity of the composition of the implants ranged from 85.0% to 115.0% of least-squares.
The table below contains the results of the mass measurements of the implants from the same batch.
|Table No. 1.|
|No. sample||Mass (mg)|
The average weight of these microimplants was 1.176 mg This party microimplants had srednekvadratichnoe deviation 0,012 and % TOC (relative standard deviation) of 1.06%.
In a series of microimplants obtained using the methods described here, the average diameter 1321 of microimplant was 0,0181 inch with standard deviation equal to is 0.0002, and % TOC equal to 1.10%.
In a series of microimplants created using the methods described here, the average length of 1302 of the microimplants the s was 0,2295 inches with standard deviation, equal 0,0011, and % TOC), equal to 0.48%.
In another series of 10 microimplants average weight of microimplants was 1177.8 mcg with standard deviation equal to 13.77, and % TOC equal to 1.17%. Average weight in mg of dexamethasone in this series of microimplants was 0.70 mg with a standard deviation of 0.01, and % TOC equal to 1.24. The average percentage of dexamethasone (standardized weight) was 99.11% with standard deviation equal to 0.22, and % TOC), equal to 0.22. The average percentage of dexamethasone in a planned weight 0.7 mg was 100,06% with standard deviation equal to 1.24, and % TOC equal to 1.24. Analysis of the release characteristics of this series of microimplants showed that about 10% of dexamethasone was released within 7 days after placing microimplants in the aquatic environment, approximately 40-50% of dexamethasone was released after 14 days after placing in the aquatic environment and 70-80% of dexamethasone was released after 21 days after placing in the aquatic environment.
In another series of 10 microimplants average weight of microimplants was 1160,5 mcg with standard deviation equal to 8.33, and % TOC), equal to 0.72%. Average weight in mg of dexamethasone in this party microimplants was 0,684 mg Average percentage of dexamethasone (standardizer the data by weight) was 98.14% with standard deviation, equal to 0.75, and % of CCA, is 0,77. The average percentage of dexamethasone in a planned weight 0.7 mg was 97.62% with standard deviation equal to 1.24, and % TOC equal to 1.24. Analysis of the release characteristics of this party microimplants showed that less than 10% dexamethasone was released within 7 days after placing microimplants in the aquatic environment, approximately 50-70% of dexamethasone was released after 14 days after placing in the aquatic environment and 80-90% of dexamethasone was released after 21 days after placing in the aquatic environment.
In another series of 10 microimplants average weight of microimplants was 1.1582 mg with a standard deviation equal to 0.02, and % TOC), equal to 2.1%.
Average weight in mg of dexamethasone in this party microimplants was 0,682 mg Average percentage of dexamethasone (standardized weight) was 98.02% with standard deviation equal to 0.24, and % TOC equal to 0.25. The average percentage of dexamethasone in a planned weight 0.7 mg was 97.31% with standard deviation equal to 2.18, and % TOC equal to 2.24. Analysis of the release characteristics of this series of microimplants showed that about 10% of dexamethasone was released within 7 days after placing microimplants in the aquatic environment, approximately 40-60% d is camerasony was released after 14 days after placing in the aquatic environment and 70-80% of dexamethasone was released after 21 days after placing in the aquatic environment.
Although this invention has been described by considering certain modifications, configurations, examples, applications and experiments, for specialists in this area should be clear that the use of various modifications and changes can be made without going beyond the scope of the invention.
1. Eye microimplants for implantation in the eye, containing a homogeneous mixture of one or more of the active ingredient and one or more biodegradable polymer, characterized in that it has a diameter of 0,019 inches or less and a length of 1 mm or less.
2. Microimplants according to claim 1, characterized in that the specified one or more biodegradable polymer is a copolymer of polylactic and polyglycolic acids (PMHC).
3. Microimplants according to claim 1, characterized in that the active ingredient is an anti-inflammatory agent.
4. Microimplants according to claim 3, characterized in that said anti-inflammatory agent is a steroidal anti-inflammatory agent selected from the group consisting of cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone.
5. Microimplants according to claim 3, characterized in that said anti-inflammatory agent represents the t of a dexamethasone.
6. Microimplants according to claim 5, characterized in that the specified one or more biodegradable polymer is a copolymer of polylactic and polyglycolic acids (PMHC).
7. Microimplants according to claim 5, characterized in that the specified one or more biodegradable polymer comprises a mixture of a copolymer of polylactic and polyglycolic acids (PMHC) and copolymer of polylactic and polyglycolic acids (PMGC), having a free acid end group.
8. Microimplants according to claim 5 also containing hypromellose (HPMC).
9. Party eye microimplants comprising a set of microimplants having the requisite planned weight of each microimplant, characterized in that each microimplant contains a homogeneous mixture of one or more of the active ingredient and one or more biodegradable polymer, has a diameter 0,019 inches or less and has a mass that differs by no more than 10 wt.% the required planned mass.
10. Party microimplants according to claim 9, characterized in that each microimplant has a mass that differs by no more than 5 wt.% the required planned mass.
11. Party microimplants according to claim 9, characterized in that each microimplant has a diameter of 0.015 inches or 381 microns or less.
12. Party microimplants according to claim 9, characterized in that each microimplant who meet the length of 10 mm or less.
13. Party microimplants according to claim 9, characterized in that each microimplant has a length of 7 mm or less.
14. Party microimplants according to claim 9, characterized in that each microimplant has a length of 1 mm or less.
15. Party microimplants according to claim 9, characterized in that the specified one or more biodegradable polymer is a copolymer of polylactic and polyglycolic acids (PMHC).
16. Party microimplants according to claim 9, characterized in that the specified one or more active ingredient is an anti-inflammatory agent.
17. Party microimplants on item 16, characterized in that said anti-inflammatory agent is a steroidal anti-inflammatory agent selected from the group consisting of cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone.
18. Party microimplants on item 16, characterized in that said anti-inflammatory agent is a dexamethasone.
19. Party microimplants on p, characterized in that the specified one or more biodegradable polymer is a copolymer of polylactic and polyglycolic acids (PMHC).
20. Party microimplants on p, characterized in that the specified one or more biodegradable copolymer comprises a mixture of a copolymer is olivacea and polyglycolic acids (PMHC) and copolymer of polylactic and polyglycolic acids (PMGC), having free terminal acid group.
21. Party microimplants on article 16, which contains also a hypromellose (HPMC).
22. Party eye microimplants comprising a set of microimplants having the requisite planned weight of each implant, characterized in that each microimplant contains a homogeneous mixture of one or more of the active ingredient and one or more biodegradable polymer and has a diameter 0,019 inches or less, and the standard deviation of the weight in the aggregate of microimplants is 5 or less.
23. Party microimplants according to item 22, wherein the standard deviation of the weight in the aggregate of microimplants is 2 or less.
24. Party microimplants according to item 22, wherein each microimplant has a diameter of 0.015 inches or less.
25. Party microimplants according to item 22, wherein each microimplant has a length of 10 mm or less.
26. Party microimplants according to item 22, wherein each microimplant has a length of 7 mm or less.
27. Party microimplants according to item 22, wherein each microimplant has a length of 1 mm or less.
28. Party microimplants according to item 22, wherein the specified one or more biodegradable polymer is a copolymer of the floor of the breast and polyglycolic acids (PMHC).
29. Party microimplants according to article 22, characterized in that the active ingredient is an anti-inflammatory agent.
30. Party microimplants on clause 29, characterized in that said anti-inflammatory agent is a steroidal anti-inflammatory agent selected from the group consisting of cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone.
31. Party microimplants on clause 29, characterized in that said anti-inflammatory agent is a dexamethasone.
32. Party microimplants on p, characterized in that the specified one or more biodegradable polymer is a copolymer of polylactic and polyglycolic acids (PMHC).
33. Party microimplants on p, characterized in that the specified one or more bearsley polymer includes a mixture of a copolymer of polylactic and polyglycolic acids (PMHC) and copolymer of polylactic and polyglycolic acids (PMGC), having a free acid end group.
34. Party microimplants on clause 29, containing a hypromellose (HPMC).
35. Eye microimplants for insertion into the eye, containing a homogeneous mixture of dexamethasone and copolymer of polylactic and polyglycolic acids (PMGC), characterized in that the n has a diameter 0,019 inches or less.
36. Microimplants on p, characterized in that it has a length of 7 mm or less.
37. Microimplants on p, also containing copolymer of polylactic and polyglycolic acids (PMGC), having a free acid end group.
38. Microimplants on clause 37, wherein the specified dexamethasone specified copolymer of polylactic and polyglycolic acids (PMGC), having a free acid end group, and the copolymer of polylactic and polyglycolic acids (PMHC) are present in a ratio of 60:30:10, respectively.
SUBSTANCE: retainer accommodates an open ring or its part comprising a segment of the radius corresponding to that of capsular sac, and haptic elements. At least one haptic element comprises a hook across the ring generatrix with "П"-shaped or semiannular end at its top, made of a wire piece, with ring rakers of its ends located at the bottom of the ring and mounted so that, at least the hook end within ring plane transcends.
EFFECT: retainer allows improving vision quality due to relocation of ligature attaching point outside of a ring or a convex part of the segment with high-quality capsular support of intraocular lens.
2 cl, 4 dwg
SUBSTANCE: invention relates to ophthalmology and can be used in treatment of progressive myopia. Cuts of conjunctiva and Tenon's membrane are made in four quadrants between rectus muscles parallel to limb, with 6-8 mm indent from it. Conjunctiva and Tenon's membrane are separated from sclera at 5-6 mm depth. In formed canals bioimplants made of collagen isolatd from spongy bone of farm animals and preliminarily kept in viscoelastic from 2 to 5 minites are introduced. Bioimplants are made in form of plates 20 mm long, 10 mm wide and 1.0 mm thick.
EFFECT: stable steady position of bioimplant in sub-Tenon's space and its close contact with sclera, sclera strengthening, improvement if its trophism and elimination of appearing of cosmetic defect.
SUBSTANCE: invention relates to ophthalmology and can be used in refractory glaucoma treatment. Three recesses 15-18 mm deep are formed between Tenon's capsule and episclera in three quadrants between rectus muscles. Each cut of conjunctiva and Tenon's capsule is made 5-6 mm long with 6-8 mm indent from limb. In each recess near posterior eye pole in area of optic nerve collagen porous biological drainage is placed, made in form of plate 15 mm long, 8 mm wide from material containing bone collagen, isolated from spongy bone of farm animals. Then in fourth quadrant non-penetrating deep sclerlimbectomy with exposure of Shlemm's canal and limb edge of Descemet's membrane. Collagen porous biological drainage in form of plate 4.0 mm long, 1.0 mm wide and 0.5 mm thick made from material which contains bone collagen, isolated from spongy bone of farm animals and saturated with sulphated glycosaminoglycans is sewn with one end to Shlemm's canal. The other drainage end must protrude 1.0 mm from under superficial scleral flap, performing filtration pillow plasty. Superficial scleral flap is returned onto place and operation wound is sealed.
EFFECT: long-term IOP stabilisation, strengthening of eye posterior pole and improvement of optic nerve blood circulation, elimination of complications and possibility to perform YAG-laser goniopuncture in case of IOP rise.
SUBSTANCE: invention relates to ophthalmology and can be used for surgical treatment of dacryocystitis and accompanying it nasolacrimal canal obstruction. All tissue cuts are carried out using radio-wave energy with power 3-4 by device scale. Cuts of skin at inner eye angle, underlying soft tissues, tear-bag wall and nasal mucosa are made, with further formation of fistula between tear-bag and nasal cavity. Method ensures simultaneous with cut hemostasis and performing operation in "dry" field, fast healing, minimal necrosis and edema of tissues, reduction of pain reaction.
EFFECT: maximally bloodless, slightly traumatic tissue cuts, which do not result in growth of granulations and crude scarring.
SUBSTANCE: invention relates to surgery and can be applied for surgical treatment of cosmetic defects of medial face zone. Super-periosteal lift of soft tissues of medial face zone is carried out, with fixation of lifted soft tissues to fascial nodes of orbit lower wall edge by means of allotendinous threads. Plasty of tarsoorbital fascia is perfomed by means of biomaterial Alloplant for conjunctiva plasty, which is applied on tarsoorbital fascia and fixed with allotendinous thread to fascial nodes of orbit walls. External canthopexy is performed with allotendinous threads.
EFFECT: strengthening tarsoorbital fascia, reduction of risk of orbital cellular tissue falling out.
SUBSTANCE: invention relates to ophthalmology and can be applied in surgical treatment of recurrent pterigium. Pterigium head and body are separated from cornea and sclera and excised. Bleeding episcleral vessels on internal limb edge are coagulated. Pathologically changed bulbar conjunctiva above pterigium body is excised. Conjunctiva above semilunar fold is slightly excised, separated, turned toward eye corner and sewn with interrupted suture to eyelid fornix. In formed after pterigium removal bed transplant is laid. As transplant ophtalmotransplant "Ufaplant" from kidney capsule is used. Transplant is fixed to sclera on limb and on edges from internal rectus muscle tendon. Lateral sides of transplant are brought 2 mm under conjunctiva. Bulbar conjunctiva is fixed to transplant by applying interrupted sutures on conjunctiva defect edges.
EFFECT: elimination of conjunctiva growth zone, which prevents pterigium recurrence.
4 cl, 2 ex, 5 dwg
SUBSTANCE: invention refers to ophthalmology and aims at therapy of recurrent aching bullous keratopathy following excimer laser phototherapeutic glaucoma eye keratostromectomy. Each bulla is pricked with a pointed microdiathermocoagulating microelectrode needle thereby forming cicatrical canal between bulla and anterior layers of cornea stroma. Manipulation is carries out at temperature +80°C and current strength 1.0-2.0 mA.
EFFECT: method allows for rapid relief of pain syndrome, for stopped recurrent bullae and for reduced risk of cornea bacillosis.
1 ex, 2 dwg
SUBSTANCE: invention refers to ophthalmology and to be used in children for therapy of Marfan's syndrome. The operation is performed through scleral tunnel incision 3.5 mm wide and additional 5 corneocenteses. Pupil edge is pulled up to cornea, inserted through corneocenteses. Anterior capsule of lens is notched within ectopy at equator. Vertical incision of capsule is started either side from the notch to Zinn ligament origin. The incisions are traced further either side along the equator perpendicularly to vertical incision to the opposite edge of lens. Formed "П"-shaped flap of anterior capsule of lens is unfolded and covers iris. Leaf of anterior capsule is fixed to iris with a needle through corneocentesis. Lenticular matters are removed. Also the needle and irisretractors are removed. Anterior capsule flap is tucked in iris. Elastic intraocular lens RSP-3 model is inserted with haptic elements in iris on leaf of anterior capsule. While implanted one haptic element of lens covers the dysplasia of Zinn ligament and on leaf of anterior capsule. Pupillary edge is sutured.
EFFECT: method provides preservation of lenticular capsule and anterior hyaloid membrane of vitreous body in removing lens, provides central and stable position of IOL, reduces risk of complications, reduces rehabilitation time.
SUBSTANCE: invention refers to ophthalmosurgery and can be used for lensectomy as dislocated into vitreous body. Vitrectomy is followed with filling the vitreal cavity with perfluororganic compound (PFOC). The lens floated into the pupillary zone is removed by phacoemulsification combined with constant adding of PFOC for maintenance of anatomic lens position within the posterior chamber.
EFFECT: reduced number of post-operative injuries, complications and potential injuries of corneal endothelial cell, as well as in possibility for hard cataract extraction.
SUBSTANCE: invention refers to ophthalmosurgery and can be used for cataract extraction. High-vacuum capsulorexis, hydrodissection and hydrodelineation steps are followed with equatorial aspiration of cortical matter of cataract crystalline lens. Cortical matter between nucleus of lens and posterior capsule is kept to protect posterior capsule as nucleus being manipulated thereafter. Central nucleus is recessed with ultrasound by 2/3 of nucleus thickness. Ultrasound is disabled, while nucleus fixed by vacuum aspiration on a tip of a phacofragmentation unit, is destroyed by a chopper. Nucleus fragments are aspirated at minimal ultrasonic power output.
EFFECT: method provides lower ultrasonic exposition during cataract phacoemulsification procedure, thereby reducing operation length and risk of operative complications.
SUBSTANCE: retainer accommodates an open ring or its part comprising a segment of the radius corresponding to that of capsular sac, and haptic elements. At least one haptic element comprises a hook across the ring generatrix with "П"-shaped or semiannular end at its top, made of a wire piece, with ring rakers of its ends located at the bottom of the ring and mounted so that, at least the hook end within ring plane transcends.
EFFECT: retainer allows improving vision quality due to relocation of ligature attaching point outside of a ring or a convex part of the segment with high-quality capsular support of intraocular lens.
2 cl, 4 dwg
SUBSTANCE: invention refers to ophthalmology. An intraocular lens (IOL) contains an optical part and bearing supports bent towards a front face of the optical part at an acute angle to its principal plane. The front face of the optical part is concave, while its back face is convex. There are four identical bearing supports comprising curvilinear figures of the thickness decreasing to periphery and located radially, in pairs and symmetrically relative to the principal axis of the optical part. One lateral face of each bearing support lies rectilinearly and in parallel to the longitudinal axis of the bearing support. The angle between the longitudinal axes of two bearing supports in each pair with straight lateral facing each other is 60-70 degrees. The periphery of each bearing support lies on a circular arc concentric with the optical part. The other lateral face is bent, and starting from the periphery it is convex, and further to the optical part is bent. Interfaces of all the areas of the bearing support are chamfered. Each bearing support is notched starting from the interface of the optical part and bearing support and shaped the same way. The IOL is integral to be bent relative eto the principal axis.
EFFECT: application of the present IOL allows implanting it through a minute incision that reduces operative injuries and risk of postoperative complications.
2 dwg, 2 ex
FIELD: medicine; ophthalmology.
SUBSTANCE: intraocular lens contains haptic and optical part including spherical surface. The optical part consists of one component with anterior surface containing two surfaces. The first surface is designed as a segment of convex spherical surface with convex towards a cornea. The symmetry axis of spherical surface matches principal symmetry axis of intraocular lens. The second surface is shaped as hyperbolic paraboloid. Haptic part includes marking elements shaped as rectilinear lines direction of which matches that of longitudinal symmetry axis of hyperbolic paraboloid. Posterior surface of optical and haptic parts are flat.
EFFECT: correction of presbyopia combined with mixed astigmatism, extended range of intraocular lenses.
FIELD: medicine; ophthalmology.
SUBSTANCE: intraocular lens implant (ILI) contains optical and haptic elements. Anterior surface of optical element is convex surface segment of two-sheet hyperboloid with convexity directed the cornea. Back surface of the optical element is flat and elliptic. Haptic element contains markers designed as straight lines directed so that to be aligned with direction of the big axis of myopic astigmatism. Herewith the back surface of the haptic element is flat.
EFFECT: higher accuracy of myopic astigmatism correction.
SUBSTANCE: capsular ring has form of open circle with closed loops on ends. The ring is undulated, its internal surface bearing 1-2 arched fastening elements with closed loops at their ends and reaching out of the ring plane.
EFFECT: possibility to centre chrysalis during operation and ensure stable positioning of artificial chrysalis in eye.
2 dwg, 2 ex
FIELD: medicine; ophthalmology.
SUBSTANCE: method includes measurement of refraction of cornea, lengths of eye, prognosticated position of the intraocular lense (IOL) concerning the cornea top, led to cornea top the set ametropia pseudophakial eye and calculation of optical force of IOL under the formula. Determination of optical force make under formula Diol=(1336/(A-ACD-0.05))-(1.336/((1.336/Ks+R))-((ACD+0.05)/1000))) Diol - optical force of IOL, diopter.; ACD - prognosticated value of IOL position concerning cornea top; A - length of an eye, mm; R - the set ametropia of the pseudophakial eye led to cornea top; Ks=K (n-1)/(1.3375-1), where To - the refraction of a cornea measured value, diopter.; Ks - the modified value of optical force of a cornea; n=1.3331 - modified reduced indicator of diffraction of a cornea "IOL-MASTER", "Zeiss" company, Germany; ACD=pACD+0.3 (A - 23.5)+(tan K)2 - (0.1 (23.5 - A)2 (tan (0.1 (23.5-A)2))-0.99166 - prognosticated value of position IOL concerning cornea top; pACD personalised constant of IOL model; tan () - trigonometrical function of a tangent; R=RX / (1-0.012 Rx), where Rx - the set ametropia of the pseudophakial eye.
EFFECT: rising of accuracy of definition of optical force of intraocular lense.
FIELD: medicine; ophthalmology.
SUBSTANCE: intraocular lens of eye (ILE) contains haptic and optical part including a spherical surface. The forward surface of an optical part contains two surfaces. The first surface is executed in the form of a segment of the concave spherical surface turned by concavity towards a cornea of a cornea. The axis of symmetry of a spherical surface coincides with the main axis of symmetry of ILE. The second surface is executed in the form of an elliptic segment bent three-axis ellipsoidal surface turned by concavity towards a cornea. On the haptic part are executed marking elements in the form of the rectilinear lines which direction coincides with a direction of the big axis of an elliptic segment. The back surface of the optical and haptic parts is executed flat.
EFFECT: presbyopy correction in a combination with difficult myopic astigmatism, expansion of potential of ILE.
FIELD: medicine; ophthalmology.
SUBSTANCE: intraocular lens of eye (ILE) contains haptic and optical part including spherical surface. The forward surface of optical part contains two surfaces. The first surface is executed in the form of segment of the convex spherical surface turned by camber towards a cornea. The axis of symmetry of spherical surface coincides with the main axis of symmetry of artificial lens of eye. The second surface is executed in the form of ellipsoidal segment bent three-axis ellipsoidal surface turned by concavity towards a cornea. The marking elements in the form of the rectilinear lines which direction coincides with a direction of the big axis of an elliptic segment are executed on the haptic part. Back surface optical and haptic part are executed flat.
EFFECT: presbyopy correction in combination with difficult myopic astigmatism, expansion of arsenal of ILE.
SUBSTANCE: artificial lens of an eye contains a haptic and an optical part including a spherical surface. The optical part consists of one component which forward surface contains two surfaces. The first surface is executed in the form of a segment of the convex spherical surface turned by camber towards the cornea. The axis of symmetry of the spherical surface coincides with the main axis of symmetry of an artificial lens of an eye. The second surface of the component is executed in the form of the ellipsoidal segment of the convex three-axis ellipsoidal surface turned by camber towards a cornea. The marking elements in the form of the rectilinear lines which direction coincides with a direction of the big axis of an elliptic segmentare executed on the haptic part. The back surface of the optical and haptic parts is executed flat.
EFFECT: allows to provide presbyopy correction in combination with difficult hypermetropic astigmatism, and also to dilate an arsenal of artificial lenses of an eye.
FIELD: medicine; ophthalmology.
SUBSTANCE: intrascleral implant for surgical treatment of presbyopy is executed from a synthetic material and looks like a bracket with the basis and two pads executed conjointly with basis at an angle of 90 degrees to it. There is a polymeric elastic magnet in the basis of the implant. At implantation perform 4 pairs of slanting cuts of sclera for 3/4 of its thickness and form scleral pockets by stratifying of sclera from the bottom of each of pair cuts towards each other. Place the basis of the implant in a scleral pocket, and deduce its pads in the scleral cuts so that they occupy position upright upwards from sclera.
EFFECT: high visual functions without additional eyeglass corrections, decrease of number of complications, long lasting effect of operation.
5 cl, 1 ex
FIELD: medical engineering.
SUBSTANCE: implant is manufactured from porous polytetrafluoroethylene produced by pressing thermostatically controlled polytetrafluoroethylene powder fraction of 0.25-1.60 mm at 30±10°C and having structure composed of polymer elements and empty space elements with elements joined into three-dimensional network possessing empty space element volume share of 15-40%, specific space element surface of 0.25-0.55 mcm2/mcm3, mean distance between empty spaces in a volume of 25-50 mcm and mean spatial chord of 8-25 mcm.
EFFECT: high heat resistance properties; reliable integration into connective eye tissue.