WO2014204358A1 - Médicament destiné à la prophylaxie et au traitement de la myopie pernicieuse et préparations pharmaceutiques sur la base de celui-ci - Google Patents

Médicament destiné à la prophylaxie et au traitement de la myopie pernicieuse et préparations pharmaceutiques sur la base de celui-ci Download PDF

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WO2014204358A1
WO2014204358A1 PCT/RU2014/000439 RU2014000439W WO2014204358A1 WO 2014204358 A1 WO2014204358 A1 WO 2014204358A1 RU 2014000439 W RU2014000439 W RU 2014000439W WO 2014204358 A1 WO2014204358 A1 WO 2014204358A1
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lysine
acid
drug
drug according
mixture
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PCT/RU2014/000439
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English (en)
Russian (ru)
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Иван Дмитриевич ЗАХАРОВ
Александр Робертович КОРИГОДСКИЙ
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Zakharov Ivan Dmitrievich
Korigodskiy Aleksandr Robertovich
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Publication of WO2014204358A1 publication Critical patent/WO2014204358A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/34—Copper; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/133—Amines having hydroxy groups, e.g. sphingosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/223—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of alpha-aminoacids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A61K31/78—Polymers containing oxygen of acrylic acid or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/02—Peptides of undefined number of amino acids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia

Definitions

  • the invention relates to medicine, in particular to ophthalmology, and is intended to strengthen the sclera with progressive myopia.
  • myopia leading pathogenetic factors in the occurrence and progression of myopia (myopia), accompanied by lengthening of the eyeball in the anteroposterior direction, is the stretching and weakening of the scleral membrane of the eye associated with the development of a dystrophic process in its connective tissue (see Avetisov ES “Myopia.” M., 1999, 285 pp. - [2]; Iomdina EN “Biomechanical and biochemical disorders of the sclera with progressive myopia and methods for their correction // Visual functions and their cor projection in children ”/ Edited by S.E. Avetisov, T. P. Kashchenko, A. M. Shamshinova.
  • cross-links intra- and intermolecular bonds that stabilize scleral collagen
  • cross-linking plays an extremely important role in the formation of optimal biomechanical characteristics of the tissue, therefore, the revealed decrease in the level of transverse connectivity of the collagen of the sclera with progressive myopia is an important factor leading to a weakening of its support function and, as a result, to anterior-posterior axis of the eye and the progression of myopia [3].
  • a drawback of existing sclerotomy interventions is that the clinically significant effect (stabilization of the length of the anteroposterior axis of the eye and refraction) is limited mainly to 1-2 years, and then (in the long term follow-up) the progression of myopia resumes [6]. This is due to the fact that the structure of the myopic sclera itself remains pathologically changed after treatment, and the supporting properties of implant implants weaken over time.
  • a method was also used that included the introduction of an eye under the tenon capsule (fascia) on the posterior surface of the sclera is an expandable gel-like polymer composition based on a dry component, a liquid aqueous component, a 3% solution of hydrogen peroxide and a complex compound of copper and pyridoxine — dichloride [2-methyl-3-hydroxy-4,5-di (oxymethyl) pyridine ] copper (II) (INN - “Cupir”), the content of which in the composition is 0.1 1-0.31 weight%. (see RF Patent 2012336.
  • composition for the treatment of progressive myopia Avetisov ES, Vinetskaya MI, Iomdina EN and others - [8]).
  • the resulting foamed composition in the process of gradual degradation was replaced by a newly formed connective tissue (capsule) on the surface of the sclera, as a result of which a new biocomposite “sclera-connective tissue” was formed.
  • the thickness of the formed capsule is on average 146 ⁇ m, while with the introduction of the polymer composition without Cupir it is 109 ⁇ m.
  • the biomechanical properties of the newly formed complex “sclera-connective tissue” change insignificantly and statistically insignificantly: for example, the elastic modulus (the most important parameter indicating the effect of scleral reinforcement) after administration of the composition with Cupir is 27.1 ⁇ 2.3 MPa, and when the composition is introduced without Cupir, 25.3 ⁇ 1.9 MPa.
  • Cupir the content of which in the composition used is only 0.1 1-0.31 weight%, helps to accelerate the formation of connective tissue capsule and significantly increases its thickness, but practically does not contribute to hardening of the sclera as a whole, which is necessary for prevention and treatment of progressive myopia.
  • the process of foaming the composition can lead to irreproducible results, and the foamed composition itself, located under the tenon capsule for at least 12 months. until complete resorption, can significantly injure adjacent eye tissue.
  • a complex compound of copper and pyridoxine accelerates the formation of a connective tissue capsule on the surface of the sclera and increases its thickness.
  • Cupir copper and pyridoxine
  • the measured modulus of elasticity is the average of 5 parallel measurements.
  • the objective of the invention is to create a medicinal product (hereinafter also referred to as composition), which contributes to a significant and rapid increase in the elastic-strength characteristics of the sclera and ensures the achievement of reproducible results in the process of strengthening these eye membranes.
  • a medicinal product hereinafter also referred to as composition
  • Another objective is the creation of a medicinal product, the main components of which would preferably be products of natural origin or obtained on the basis of such products and, accordingly, would be characterized by a minimal immune response of the body and a lower likelihood of side effects than analogues known from the prior art.
  • the technical result from the use of the proposed solution is to strengthen the sclera with progressive myopia and reduce the time of such strengthening by activating the cross-linking of the collagen molecules of the sclera, eliminating the traumatic, toxic and inflammatory effects on the eyeball and surrounding orbit tissues in the treatment of progressive blizorukosti.
  • a medicine for the prevention and treatment of progressive myopia containing as an active component an effective amount of an amine with functional groups in the form of a salt or as part of a transition metal complex compound or mixture thereof.
  • amine with functional groups of various nature, helps to strengthen the sclera and increase its biomechanical stability due to the effective cross-linking of collagen chains.
  • Used amines with functional groups (hereinafter also AFG) in accordance with the present invention comprise primary and / or secondary and / or tertiary amino groups, as well as guanidine and / or hydroxyl and / or aldehyde groups.
  • amino alcohols, amino acids, derivatives of these amino acids, oligopeptides, polypeptides, polyamines, derivatives of 3-hydroxy-2-methylpyridine, amino saccharides or a mixture thereof can be used as amines with functional groups.
  • Synthetic primary amines containing two or more hydroxymethyl groups are used as amino alcohols, for example: 2-amino-2-methyl-1,3-propanediol, tris (hydroxymethyl) aminomethane or a mixture thereof.
  • amino acids known natural and synthetic amino acids are used that contain the main amino or guanidine groups, for example: 2,4-diaminobutanoic acid, ornithine (2,5-diaminopentanoic acid), lysine (2,6-diaminohexanoic acid), hydroxylisine (2 , 6-diamino-5-hydroxyhexanoic acid), 2,7-diaminoheptanoic acid, 2,8-diamino-octanoic acid, 2,9-diaminononanoic acid, 2,10-diaminodecanoic acid, 2,12-diaminododecanoic acid, arginine (2- amino-5-guanidinovaleric acid) or a mixture thereof.
  • D-, b- (natural) optical isomers or their D, L-CMecb (racemate) of the indicated amino acids can be used.
  • lactams used are the lactams of 2,4-diaminobutanoic acid, ornithine (2,5-diaminopentanoic acid), lysine (2,6-diaminohexanoic ABOUT
  • lactams of D-, L- (natural) optical isomers or their D, L-CMecb (racemate) of the indicated amino acids can be used.
  • Ethyl esters, propyl ether, isopropyl ether, tert-butyl ether, caprylic ether, undecyl ether, lauryl ether, myristyl ether, oleyl ether, stearyl ether, 1,2-propylene glycol ether are used as esters of the above amino acids.
  • esters of D-, b- (natural) optical isomers or their D, L-CMecb (racemate) of the indicated amino acids can be used.
  • heteromeric oligopeptides are used having at least one L-ornithine, L-lysine or L-hydroxylisine unit, for example, dipeptides: L-alanine, L-lysine, L-arginine, L-lysine, L-valine L-lysine, L-hydroxylysine-L-lysine, L-hydroxyproline-L-lysine, L-histidine-L-lysine, glycine-L-lysine, L-isoleucine-L-lysine, L-leucine-L-lysine , L- methionine-L-lysine, L-proline-L-lysine, L-serine-L-lysine, L-tyrosine-L-lysine, L-threonine-L-lysine, L-tryptophan-L-lysine, b -phenylalanine-b-lysine, b-c
  • ⁇ ISTIDIN-L-LYSINE L- ⁇ p03 ⁇ H-L- ⁇ -L- ⁇ , L-TpeOHHH-L-rnCTHflHH-L-lysine,
  • polypeptides homomeric compounds based on amino acids containing two amino groups are used: nojra-L-ornithine, poly-L-lysine, poly ⁇ hydroxylysine, poly ⁇ arginine, or a mixture thereof.
  • polyamines natural or modified natural compounds containing 2-4 basic amino groups or guanidine groups can be used, in particular:
  • -diamines or aminoguanidines putrescine (1,4-diaminbutane), 2-hydroxyputrescin, cadaverine (1,5-pentamethylenediamine), agmatine [1- (4-aminobutyl) guanidine], 1,8-diamino-octane, 1,12-diaminododecane 2,2'- (ethylenedioxy) bis (ethylamine), 4,9-dioxa-1,12-dodecandiamine, 3,6,9-trioxa-1,11-undecandiamine, 4,7,10-trioxa-1, 13-tridecandiamine or a mixture thereof;
  • -spermidine and its derivatives 1-methyl spermidine, 2-methylspermidine, 3-methylspermidine, 8-methylspermidine, 1,1-dimethylspermidine, 2,2-dimethylspermidine, 3,3-dimethylspermidine, 5,5-dimethylspermidine, 5.8 - dimethylspermidine, 8,8-dimethylspermidine, 2-hydroxy spermidine, homospermidine or a mixture thereof;
  • spermine and its derivatives spermine, 1-methylspermine, 6-methylspermine, 1, 12-dimethylspermine, 5,8-dimethylspermine, 1, 1, 12, 12-tetramethyl spermine, 3,3,10,10 - tetramethylspermine, norspermine , or a mixture thereof.
  • pyridoxine As derivatives of 3-hydroxy-2-methylpyridine, natural compounds of various structures containing the main tertiary amino group are used, for example: pyridoxine, pyridoxine-5-phosphate, pyridoxal, pyridoxal-5-phosphate, pyridoxamine, pyridoxamine-5-phosphate or a mixture thereof.
  • amino saccharides natural compounds containing a basic primary amino group are used, for example: D-glucosamine (chitosamine) (2-amino-2-deoxy-0-glucose), D-galactosamine (chondrosamine) (2-amino-2-deoxy-D -galactose), D-mannosamine (2-amino-2-deoxy-0-mannose), D-fucosamine (2-amino-2,6-dideoxy-0-galactose), neuraminic acid (5-amino-3,5 -deoxy-0-glycero-O-galactononulosonic acid) or a mixture thereof.
  • D-glucosamine chitosamine
  • D-galactosamine chondrosamine
  • D-mannosamine (2-amino-2-deoxy-0-mannose
  • D-fucosamine (2-amino-2,6-dideoxy-0-galactose
  • neuraminic acid (5-amino
  • the concentration may be 0.05-0.3 wt.%. However, it is preferable to use them in combination with other APH, for example, with amino acids, so that the total concentration of both types of crosslinkers is in the claimed range.
  • AFGs incorporate basic amino groups and their aqueous solutions have an alkaline reaction. Therefore, their use is possible only in a neutralized form - in the form of a salt or complex compound with a transition metal cation.
  • This kind of salt can be obtained by neutralizing an amine with functional groups with an acid.
  • low molecular weight acids of synthetic or natural origin having one or more acid groups and forming non-toxic or low toxic salts, for example: inorganic - hydrochloric, hydrobromic, nitric, sulfuric, phosphoric acid or organic acids - acetic, dichloroacetic, pivalic (trimethylacetic acid), glycolic, lactic, glutamic, or pyroglutamic, or aspartic acid, or ascorbic, or valerianic, or pelargonic, or capric, or undecyl, or lauric, or myristic, or undecylenic, or sorbic, or pyruvic acid, or succinic, or fumaric, or maleic, or adipic, or pimelic, or pimelic or acid, or malic, or tartaric, or citric, nicotinic (vitamin PP), salicylic, 2 - [(2,6-dichloroph), salicylic, 2 - [(2,6-dichloroph
  • Low molecular weight acids can also be used in partially neutralized form, which is obtained by neutralizing them with a base to a degree of neutralization of not more than 0.8.
  • alkali and alkaline earth metal hydroxides Na, K, Ca, Mg
  • amines ammonia, primary, secondary, tertiary organic amines or a mixture thereof are used as a base.
  • polymeric acids can be used to neutralize AFH: polyacrylic acid, copolymers of acrylic acid, their partially neutralized salt or their mixture, and paragraph
  • acrylic acid copolymers methacrylic, maleic, itaconic acid, ⁇ -vinylpyrrolidone or a mixture thereof is used.
  • These polyacrylic acid and acrylic acid copolymers have a relatively small molecular weight of 300-30000 and are oligomeric compounds.
  • the corresponding macromolecular compounds having a molecular weight of Mp more than 30,000 cannot be used to solve the problem, since their removal from the body is difficult.
  • supramolecular systems Based on the used polymeric acids and organic amines containing two or more amino groups, with a stoichiometric ratio of the components or close to it, supramolecular systems, respectively, of a ladder or lattice structure, are obtained. Sustained action can be expected from ordered systems due to the multicenter binding of polyamines and the reduced diffusion mobility of this supramolecular system as a whole.
  • transition metals in accordance with the present invention are their use in immobilized form - in the form of complex compounds with amines used. These transition metal cations interact with basic amines, as well as amino acids, giving stable neutral complexes (coordination thesis).
  • the central atom binds one or more ligand molecules depending on the coordination number of the complexing agent and ligand identity (the number of functional groups in it - binding centers).
  • transition metals - Cu 2+ and Zn 2+ cations are used in salts with the following anions: chloride, bromide, nitrate, sulfate, acetate, glycolate, lactate, or a mixture thereof.
  • AFG compounds can be prepared in an aqueous medium and used without isolation as a solution.
  • AFG compounds can be prepared in ethanol or in a water-ethanol mixture, preferably in concentrated form, and used without isolation, for example, for the preparation of medicinal films or microcapsules.
  • AFG compounds can be isolated after being prepared in a dry form by removing the solvents used and subsequently used to prepare the appropriate solutions. However, some AFG compounds are available as a reagent.
  • AFG compounds when melted, can be processed together with the polymer binder into microcapsules and other prolonged-action products, for example, by extrusion.
  • the claimed drug based on the AFG salt is prepared by neutralizing the initial basic AFG with the appropriate acid, taken in stoichiometric amount or close to it, which is determined by the required final pH value. Since the acids used to neutralize AFH in accordance with the present invention are mostly weak, they must be used in amounts exceeding stoichiometric in order to achieve neutral pH values.
  • the reaction of the production of the AFG salt is carried out in distilled water, isotonic solution, ethanol, or a mixture thereof.
  • a medicine can also be obtained by dissolving in an aqueous medium an existing (previously obtained) functional amine salt and an acid, usually strong, for example, hydrochloric.
  • an acid usually strong, for example, hydrochloric.
  • the adjustment of the pH to the desired value can be carried out by adding the appropriate amounts of a base, preferably an amine, for example, Tris (hydroxymethyl) aminomethane, or pyridoxine.
  • the inventive drug composition should have a pH of 6.5-8.0, preferably 7.0-7.4.
  • polyacrylic acid or acrylic acid copolymers As well as their partially neutralized form or a mixture thereof, are used as the polymeric acid.
  • Partially neutralized L a is partially neutralized
  • the form of polymer acids is obtained by neutralizing the polymer acid with a base to a degree of neutralization of not more than 0.7.
  • alkali metal hydroxides Na, K
  • amines ammonia, primary, secondary, tertiary amines or mixtures thereof are used as the base.
  • compositions based on a transition metal complex compound are prepared by reacting AFH with a salt of the corresponding transition metal (Cu OR Zn), taken in stoichiometric amount or close to it, which is determined by the required final pH value.
  • the reaction is carried out in distilled water, isotonic solution or ethanol.
  • Aqueous solutions based on the claimed drug can be used as a drug to strengthen sclera by injection.
  • An aqueous solution of the claimed drug can be obtained on the basis of distilled water, an isotonic solution or a mixture thereof.
  • physiological 0.9 wt.% NaCl
  • balanced physiological saline BBS Hydrophils solution
  • aqueous solutions of nonionic compounds such as glycerin, sorbitol, mannitol, propylene glycol or dextrose are used, preferably in an amount up to 5 wt. %
  • an isotonic additive in dry form
  • a polymer gelling agent can be added in an amount of 0.1-5.0 wt.%., which can be used, in particular, hyaluronic acid, polyvinyl alcohol, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, Na- carboxymethyl cellulose, hydroxypropyl guar, or a mixture thereof.
  • Table 3 Composition of a pharmaceutical preparation based on an aqueous solution of a drug
  • HFP ophthalmic medicinal films
  • the drug described above may be included in the composition of the eye films 20. Its content in medicinal films is preferably 5-50% by weight.
  • the polymer binder used must bind the drug used for a sufficiently long time, providing a prolonged therapeutic effect, and be water-soluble or 25 bio-soluble.
  • various synthetic and natural polymers are used as a polymer binder for HFP: polyacryl amide and its copolymers, polyvinyl pyrrole and don and its copolymers, polyvinyl alcohol, Na-carboxymethyl cellulose, hydroxypropyl cellulose, sodium alginate, chitosan.
  • composition of the pharmaceutical preparation in the form of SOD for strengthening sclera is presented in table 4.
  • Table 4 Composition of a pharmaceutical preparation in the form of HFR based on an aqueous solution of a medicinal product
  • plasticizer and auxiliary components 1.0-10.0
  • a joint solution is prepared on the basis of the drug described above and a polymer carrier in an aqueous, aqueous-alcoholic or alcoholic medium. Additionally, plasticizer and auxiliary components (for example, surfactants) can also be added to this solution. After that, the resulting homogeneous solution of the components is poured onto a substrate and dried. Films of the required shape and size are cut out or cut out of the formed polymer tape.
  • Such a drug in the form of SOD can also be prepared by co-extrusion processing of the claimed drug and a polymer binder.
  • a pharmaceutical preparation in the form of an SOD containing a drug is placed through a thin incision under a tenon capsule on the surface of the sclera and, wetted with intraocular fluid, passes into an elastic mild state, performing the healing action until it is completely dissolved.
  • the present application also provides a pharmaceutical preparation for the prophylaxis and treatment of progressive myopia based on the above-described drug in the form of microparticles (microcapsules containing the drug).
  • This type of drug is injected under a tenon capsule onto the sclera surface in the form of an aqueous suspension of polymer microcapsules.
  • These microcapsules can be obtained, in particular, by a method disclosed in the patent of the Russian Federation 2103005 (“Pharmaceutical composition of prolonged action, the polymer composition used in it and the method for its preparation” Minoru Y., Seiko I., Yasuaki O. - [13]). The use of such a drug provides prolonged release of the drug with subtenon administration .
  • a double water-oil-water double emulsion is preliminarily prepared, which makes it possible to obtain them on the basis of water-soluble preparations, which include all AFH compounds.
  • polyesters preferably polylactide, polyglycolide and lactide-glycolide copolymers having a molecular weight of from 10,000 to 100,000
  • the molar ratio of lactide to lycolide is from 75 : 25 to 25:75, with a ratio of from 60:40 to 40:60 being most preferred.
  • Microcapsules obtained by this method may have a diameter of from 0.05 ⁇ m to 1.0 mm. From a pharmaceutical point of view, microparticles with a diameter not exceeding 250 microns, more preferably from 10 to 60 microns, should be used to facilitate passage through the injection needle.
  • Microcapsules obtained in accordance with the present invention have several advantages. For example, they practically do not undergo aggregation or cohesion with each other during the production stage. You can get microcapsules, almost spherical in shape and having an arbitrary size. The step of removing the solvent from the oil phase is easy to control, whereby it is possible to control, respectively, the surface structure of the microcapsules, which is crucial for the release rate of the active compound.
  • the drug content in the microcapsules or microparticles of another form is preferably 3-90% by weight.
  • composition of the microcapsules may include auxiliary components, for example, surfactants.
  • composition of the drug in the form of microcapsules with the drug is presented in table 5.
  • Table 5 The composition of the pharmaceutical preparation in the form of microcapsules with a drug to strengthen the sclera.
  • the exact amount of active drug encapsulated in the polymer (capsule) that you want to enter depends on many factors that can be determined using known methods in vitro or in vivo. Once, by a single injection, you can enter large quantities of the active substance, up to 30-50 mg of the active substance in the form of an aqueous suspension.
  • Polymer compositions in the form of rods, cylinders or other microparticles can be formed from the obtained microcapsules by melting or extrusion.
  • a suspension based on the obtained microparticles can be prepared ex tempera by adding water for injection to them.
  • the solids content in the resulting aqueous suspensions is 5.0-50.0 wt.%.
  • the microparticles After subtenon administration of a suspension of the claimed preparation, the microparticles are completely resorbed for 1-6 months, releasing the active substance during this period.
  • the conjunctiva is cut 2 mm 7 mm from the limbus in the upper quadrant of the eyeball.
  • the subconjunctival fusion is disconnected by a curved spatula.
  • LI with the help of suture forceps is injected under the tenon capsule to the posterior pole of the eye.
  • the incision is sealed with 1-2 interrupted sutures (Vicryl 8/0).
  • the degree of increase in the elastic modulus can be reduced by decreasing the concentration of the introduced components within the claimed range or by reducing the number of injections or the duration of the installation course.
  • AFH compounds the claimed drug
  • AFH compounds react with aldehyde groups of al-lysine in adjacent peptide chains to form the corresponding Schiff base with its subsequent reduction to a stable saturated structure.
  • free hydroxyl containing groups in their composition can react with aldehyde groups of al-lysine in neighboring collagen fibers to form acetal groups;
  • free amino groups in the composition of these compounds can react with aldehyde groups of al-lysine in neighboring collagen fibers;
  • - derivatives of 3-hydroxy-2-methylpyridine contain at least two functional groups: aldehyde, primary amino group, alcohol groups, which can directly react with the corresponding functional groups in neighboring collagen fibers.
  • An indication for the use of the claimed medicinal product and preparations based on it for strengthening sclera is progressive myopia, primarily in children and adolescents. Strengthening of the sclera is carried out in order to stabilize the myopic process and prevent the development of myopic complications in the fundus. It is in this age period that the intense progression of myopia (with a high annual gradient, i.e. an increase in the degree of myopia by more than 1 diopters / year.), Accompanied by pathological stretching of the scleral membrane of the eye, leads to complications that are localized at first primarily on the periphery of the fundus .
  • Example 1 0.225 g of L-lysine hydrochloride, Sigma in 50.0 ml of physiological saline (0.9% sodium chloride solution) are dissolved in a glass flask under stirring with a magnetic stirrer, after which a 50 wt.% Aqueous solution of Tris (hydroxymethyl) is added dropwise. ) aminomethane to pH 7.0. The resulting 0.45 weight. A% solution of an amine salt with functional groups is poured into 5 ml glass vials that are autoclaved at 121 ° C (1.1 atm) for 10 minutes.
  • the resulting solution was injected in the upper outer quadrant (in the area free of extraocular muscles) under a tenon capsule on the sclera surface of the right eye of the Chinchilla rabbit with an interval of 4-5 days, the left intact eye served as control.
  • the course of treatment consisted of 6 injections. During the course of injections and one month after its completion, the eye condition was monitored by biomicroscopy. rabbits. No toxic or inflammatory events were found. At the end of the observation period, the eyes were enucleated and used to prepare scleral samples.
  • Example 2 1.68 g (1.27 * 10-2 mol) of D-ornithine, Sigma in 97.5 ml of distilled water are dissolved in a glass flask while stirring with a magnetic stir bar, and then 0.829 g (0.423 * 10 "is neutralized, the dissolved amine is neutralized 2 mol) 50 wt.% Phosphoric acid. Further, an additional amount of phosphoric acid solution was used to adjust the pH to 7.4. The prepared 2.0 wt.% AFH salt solution was sterile filtered through a 0.22 ⁇ m Millipore membrane and in sterile conditions are poured into 5 ml glass vials.
  • Example 3 In a glass flask, while stirring with a magnetic stir bar, 1.04 g (0.857 * 10 " mol) of Tris (hydroxymethyl) aminomethane, Aldrich are dissolved in 50.0 ml of a 1.5 wt.% Aqueous solution of sodium carboxymethyl cellulose, Blanose 7HF-PH , Hercules, and then the dissolved amine, neutralize 0.960 g (0.857 * 10 "2 mol) of sorbic acid dissolved in 48 ml of distilled water. Next, an additional amount of sorbic acid solution was used to adjust the pH to 7.4. The prepared 2.0 wt% AFG salt solution is autoclaved at 121 ° C (1.1 atm) for 10 minutes and poured into 5 ml glass vials.
  • Example 4 In a glass flask with magnetic stirrer 1.0 g of poly-L-lysine hydrochloride, Sigma (M n 15000-30000) was dissolved in 100.0 ml of 0.8 wt.% Of an aqueous hyaluronic acid solution (1.9 M -2.7 * 10 6 ), HA 20, Shiseido), after which a 50 wt.% Aqueous solution of Tris (hydroxymethyl) aminomethanado is added dropwise to pH 7.4. The resulting 1.0 wt.% APH salt solution was autoclaved at 121 ° C (1.1 atm) for 10 minutes and poured into 5 ml glass vials.
  • Example 5 This composition was used to strengthen the sclera by injection according to the method described in example 1.
  • Example 5. 2.80 g (1.65 * 10 "3 mol) of pyridoxine, Sigma in 60.0 ml of distilled water are dissolved in a glass flask while stirring with a magnetic stir bar, and then 1.19 g (1.65 * 10 of neutralized amine are neutralized) "3 ) polyacrylic acid ( Mw 1800), Aldrich, dissolved in 36.0 g of distilled water. Next, an additional amount of polyacrylic acid solution was used to adjust the pH to 7.4. The prepared 4 wt.% Solution of AFH salt was sterilely filtered through a 0.22 ⁇ m Millipore membrane and poured into 5 ml glass vials.
  • This composition was used to strengthen the sclera by injection according to the method described in example 1.
  • Example 6 In a glass flask, 6.00 g of pyridoxine hydrochloride, Sigma is dissolved in 96.0 ml of distilled water with stirring with a magnetic stir bar, after which a 50 wt.% Aqueous solution of pyridoxine is added dropwise to pH 7.4. The resulting 6.0 wt.% APH salt solution is sterile filtered through a 0.22 ⁇ m Millipore membrane and poured into 5 ml glass vials.
  • pyridoxine hydrochloride Sigma is dissolved in 96.0 ml of distilled water with stirring with a magnetic stir bar, after which a 50 wt.% Aqueous solution of pyridoxine is added dropwise to pH 7.4.
  • the resulting 6.0 wt.% APH salt solution is sterile filtered through a 0.22 ⁇ m Millipore membrane and poured into 5 ml glass vials.
  • This composition was used to strengthen the sclera by injection according to the method described in example 1.
  • Example 7 In a glass flask, 4.00 g of D-galactosamine hydrochloride, Sigma is dissolved in 96.0 ml of distilled water with stirring with a magnetic stir bar, after which a 50 wt.% Aqueous solution of tris (hydroxymethyl) aminomethane is added dropwise to pH 7. 0. The resulting 4.0 wt% AFH salt solution was sterilely filtered through a 0.22 ⁇ m Millipore membrane and poured into 5 ml glass vials.
  • This composition was used to strengthen the sclera by injection according to the method described in example 1.
  • Example 8 In a glass flask of 0.444 g (0.304 * 10 "2 mol) of L-lysine, Sigma is dissolved in 98.0 ml of distilled water with stirring with a magnetic stir bar, and then 0.356 g (0.152 * 10 " mol) are added successively to the resulting solution . ) CuBr 2 and 1.20 g of L-lysine hydrochloride. The resulting 2.0 wt.% Solution of the mixture of the complex compound and the APG salt is sterile filtered through a 0.22 ⁇ m Millipore membrane and poured into 5 ml glass vials. _.
  • Example 9 In a glass flask, 3.49 g (1.62 * 10 "2 mol) of D-glucosamine hydrochloride, Sigma is dissolved in 60.0 ml of distilled water with magnetic stirring, and then 0 is added to the resulting solution over 5 minutes 65 g (1.62 x 10 'mole) NaOH, dissolved in 16 ml of distilled water, and then the resulting free amine is added 1.09 g (0.812 * 10 -2 mol) SiS1 2, dissolved in 20 ml of distilled water. The obtained 4.0 wt.% Solution of the APH complex compound is sterile filtered through a 0.22 ⁇ m Millipore membrane and poured into 5 ml glass vials.
  • Example 10 Obtaining an ophthalmic drug film.
  • the temperature in the apparatus is maintained within the range of 50-60 ° C. After 2 hours, the solution was cooled to 25 ° C and 20.0 g of D-glucosamine hydrochloride, Sigma (10.0 wt.%) Was added to the apparatus. Stirring is continued for another 0.5 hours. Then the solution is applied in an even layer on a non-corrosive substrate and dried at a temperature of 40 ° C until a polymer tape or plate is formed, from which oval-shaped films with smooth edges of 9.0 * 4.5 * 0.35 mm in size are cut using a special stamp weighing 15 mg. After this, the films are laid out in individual packages and sterilized by the radiation method. The obtained HFRs are used as a treatment for progressive myopia, implanted under a tenon capsule.
  • Example 11 Obtaining microcapsules with the composition.
  • this B / M / B emulsion is stirred at room temperature to vaporize methylene chloride and to solidify the internal B / M emulsion that is collected, centrifuged to wash unbound drug, and the like.
  • the collected microcapsules are freeze dried to form a powder, which is a microsphere with a diameter of 20-30 microns.
  • the microspheres are sterilized by the radiation method and used for subtenon injections in the form of a 25 wt.% Suspension (in water for injection).
  • Iomdina EN "Biomechanical and biochemical disorders of the sclera with progressive myopia and methods for their correction // Visual functions and their correction in children" / Ed. Avetisova S.E., Kashchenko T.P., Shamshinova A.M .. M., 2006, 163-183;
  • Tarutta E.P. "Sclerotherapy and prevention of complications of progressive myopia // Visual functions and their correction in children” / Edited by S.E. Avetisova, T.P. Kashchenko, A.M. Shamshinova. M., 2006, 191-202;

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Abstract

L'invention concerne le domaine de la médecine et notamment l'ophtalmologie et est destinée à renforcer la sclérotique en cas de myopie pernicieuse. Dans l'un des aspects, l'invention porte sur un médicament destiné à la prophylaxie et au traitement de la myopie pernicieuse et comprend en tant que principe actif une quantité efficace d'amine avec des fonctions sous forme de sel ou dans la composition d'un composé complexe de métal de transition, ou leurs mélanges. Dans d'autres aspects, l'invention porte sur d'autres préparations pharmaceutiques dans lesquelles on emploie le médicament, et notamment : 1) une solution aqueuse ; 2) un film oculaire médicamenteux comprenant le médicament ; 3) une suspension d'eau et de microcapsules polymères contenant le médicament.
PCT/RU2014/000439 2013-06-18 2014-06-18 Médicament destiné à la prophylaxie et au traitement de la myopie pernicieuse et préparations pharmaceutiques sur la base de celui-ci WO2014204358A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2133597C1 (ru) * 1996-10-29 1999-07-27 Пятигорская государственная фармацевтическая академия Способ лечения и профилактики миопии
RU2302231C1 (ru) * 2006-02-08 2007-07-10 Александр Егорович Петренко Глазные капли для лечения синдрома сухого глаза
EA012581B1 (ru) * 2004-07-28 2009-10-30 Коатекс С.А.С. Полимеры акриловой кислоты, получаемые с применением соединений серы в качестве агентов передачи цепи, их применение и содержащие их водные суспензии, водные дисперсии и составы
WO2010094906A1 (fr) * 2009-07-16 2010-08-26 Arecor Limited Stabilisation des proteines
WO2012075154A1 (fr) * 2010-11-30 2012-06-07 Schlumberger Canada Limited Gel réticulé d'interpolymère et procédé d'utilisation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2133597C1 (ru) * 1996-10-29 1999-07-27 Пятигорская государственная фармацевтическая академия Способ лечения и профилактики миопии
EA012581B1 (ru) * 2004-07-28 2009-10-30 Коатекс С.А.С. Полимеры акриловой кислоты, получаемые с применением соединений серы в качестве агентов передачи цепи, их применение и содержащие их водные суспензии, водные дисперсии и составы
RU2302231C1 (ru) * 2006-02-08 2007-07-10 Александр Егорович Петренко Глазные капли для лечения синдрома сухого глаза
WO2010094906A1 (fr) * 2009-07-16 2010-08-26 Arecor Limited Stabilisation des proteines
WO2012075154A1 (fr) * 2010-11-30 2012-06-07 Schlumberger Canada Limited Gel réticulé d'interpolymère et procédé d'utilisation

Non-Patent Citations (2)

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Title
ANDREEVA L. D. ET AL.: "Eksperimentalnoe obosnovanie novogo metoda skleroukreplyajuschego lecheniya progressirujuschei miopii.", REFRAKTSIONNAYA KHIRURGIYA I OFTALMOLOGIYA, 2004, pages 36 - 39, Retrieved from the Internet <URL:http://www.fesmu.ru/elib/Article.aspx?id=123870> [retrieved on 20141020] *
POLUNINA E.V. ET AL.: "« Sindrom sukhogo glaza v oftalmogicheskoi praktike»", LECHASCHII VRACH, 2004, pages 1 - 6, Retrieved from the Internet <URL:http://www.lvrach.ru/2004/07/4531533> [retrieved on 20141020] *

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