Methods and compositions for treating dry eye
FIELD: medicine, pharmaceutics.
SUBSTANCE: group of invention refers to ophthalmic compositions containing protease inhibition peptide substrates. The ophthalmic compositions contains a peptide substrate in a solution in the amount of approximately 0.01 wt/vol. % to 10 wt/vol. %, and said substrate is specified in a group consisting of gelatin, ovomacroglobulin, collagen and casein in an ophthalmically acceptable carrier. The composition additionally contains galactomannan and borate. The invention also describes a method for using the composition for treating dry eye.
EFFECT: group of invention provides higher viability and lower water loss of corneal epitheliocytes.
12 cl, 12 dwg, 11 ex
For this application claimed the priority of provisional patent application U.S. serial number 60/988623, dated November 16, 2007, which is incorporated into this description by reference.
The LEVEL of TECHNOLOGY
Dry eyes or xerophthalmia is a state, which for many is the cause of pain and discomfort. For most individuals blinking and replenishment of fluids during the day provides a clean and air-conditioned surface of the eye. If dryness of the eye the eye surface becomes very sensitive, and the result is pain and irritation. The etiology of dry eye is unknown, although there are many theories of the cause or causes of this condition. One theory asserts the existence of glandular defect, where the eye glands, which secrete a fluid to refill when it is lost when flashing, when the outflow and evaporation, become scarce and secrete insufficient amount of fluid. Another possible cause of dry eye includes the nerves that are located in the conjunctiva and the cornea. Nerves become desensitized, which leads to less blinking frequency and, consequently, to drying, or they become oversensitiveness, leading to increased pain and irritation that characterize the symptoms of dry eye. Chronic inflammation can be another causal factor or factor contribute to dry eye, regardless of the origin of the inflammatory lesions. Infection in the eyes can cause dry eyes and inflammation resulting from infection, can cause blockage of the tear ducts. Autoimmune disorder, where the body mistakenly identifying their own tissue as being of alien origin, may expose the eye tissue immunological attack, can also be a factor contributing to the etiology of dry eye. In one such autoimmune disorder sjögren's syndrome, dry eyes and dry mouth) among other distinctive symptoms caused by immune cells attacking cancer external glands that produce tears and saliva. Syndrome Sjogren estimated only in the United States suffer from at least four million people, making it the second most common autoimmune disease. Other possible causes of dry eye include hormonal or vitamin deficiency or excess. In fact, dry eye can be the result of many different conditions, any or many of which can lead to a condition of any individual patient.
Regardless of the causative factor(s) release from the painful and debilitating symptoms, you need to the majority of patients with dry eyes is. For this purpose, have been tried many ways, ranging from surgical procedures to the application of the prescribed medicines and to over-the-counter products in the form of eye drops. Surgery include permanent or temporary removal of the normal ways of draining through the blockage of the lachrymal canal. For temporary clogging of use, known as tampons local action. Non-surgical tools developed for the treatment of dry eye include wet camera used to add moisture to the eyes. Therapeutic agents that can be represented in the form of eye drops or other, seek to redress the main physiological state and, thus, reduce the severity of dry eye or eliminate it completely. However, to date, only one therapeutic agent that has been approved by the FDA for the treatment of dry eye. Although each of these therapeutic or ameliorative methods can provide a beneficial effect for individual patients, these methods entail significant risks, costs and/or inconvenience to the patient. For those suffering from dry eyes freely available there is a convenient, relatively inexpensive and low risk treatment for those suffering from dry eyes as products art is public tears. These local agents usually used in the form of eye drops, when it is necessary to Supplement or restore the tear film. Thus, artificial tears, in the most General sense, are simply another method of moistening eyes. Although in some cases they can provide symptomatic relief, they rarely change any basic ocular pathology or pathology of the cornea.
One of the relatively recent research areas of origin or etiology of dry eye examines the potential role of metalloproteinases in the cornea. Metalloproteinases are a group of proteolytic enzymes, characterized by the necessity of their binding with a metal ion such as Zn2+ or Ca2+in their active site with the aim to give the enzymes catalytic activity. Metalloproteinases, abbreviated to MMP, as you know, included in processes that involve remodeling of the tissue. Thus, physiologically MMP play a role in the metastasis of tumors, embryonic development and in wound healing. There are about 20 known MMP, having the amino acid homology of approximately 40%, each of the enzymes, apparently, is structurally connected to each other. Historically, individual MMP was named on the basis of what they consider their main substrate (for example, () collagenase, degrading the interstitial collagens (types I, II and III); (ii) collagenase type IV and gelatinase that degrade collagen type 4 basal membrane and gelatin (denatured the collagens); (iii) stromelysin that degrade a wide range of substrates, including proteoglycans, laminin, gelatin and fibronectin) or sometimes on the basis of the cellular source of the enzyme (e.g., polymorphonuclear leukocyte, gelatinase). Finally, it was recognized that most of these enzymes break down many substrates, including inactive polypeptide Pro-forma (zymogen) members of other families, and that these enzymes can degrade amatrixia proteins, such as myelin basic protein and alpha-1-antitripsin. Structurally, most of the MMP has a catalytic domain, carboxykinase hemopexin domain (hemopexin domain) and prodomain, which is cleaved during activation of the enzyme.
In an article published H. Nagase et al in 1992, presents numerical nomenclature and dictionary of DFID, currently known (for example, MMP-1, MMP-2 and so on), and open later MMD follow this system. MMP-9 (gelatinase-B, collagenase type IV-B), as a physiological agent remodeling tissue, is active in the degradation of a wide range of extracellular matrix components (ECM) and components of the basal is embrane. Apparently, MMP-9 plays a role in mediating inflammation by transformation of cytokine inflammation is interleukin IL-lβ secreted in its active form by catalysis posttranslational activation of tumor necrosis factor (TNFα), using the potentiation of IL-8, processes chemokines and by degradation of the inhibitors of serine proteases. In addition, MMP-9 may play a role in autoimmunity, because it can stimulate the development of autoimmune neoepitopes. It was shown that the local activity of MMP-9 increases in tear fluid of patients with Sjogren syndrome. Some studies have demonstrated a significant increase in activity gelatinas, including MMP-9 in the tear film of humans and other mammals with ulcerative keratitis compared to the tear film of a healthy cornea. Also explored the role of gelatinase in the pathogenesis of ulcerative keratitis. A study using MMP-9-knockout mice showed that the absence of MMP-9 imparts some degree of resistance against the destruction of the epithelial barrier of the cornea in experimentally induced dry eye.
In their attempts to obtain therapeutic agent that acts by inhibition of the activity of various MMPs in vivo, many different research organizations was synthesized a large number of new imicheskih components. Some of these rationally created MMP-inhibitors have undergone some preclinical testing and demonstrated potential as drugs for a number of pathological conditions, which are considered to be involved MMP. Unfortunately, some of these compounds, for example, marimastat (BB-2516), a broad-spectrum inhibitor of MMP, and traced (Ro 32-3555), a selective inhibitor of MMP-1, were not, despite expectations of clinical trials. One reason contributing to the lack of success lies in the substantial side effects, such as skeletal muscle toxicity, specifically, broad-spectrum inhibitors. The lack of effectiveness of the modification of the disease is another issue, as in the case of trocade, where encouraging results obtained on the model of arthritis rabbit, are not duplicated in trials conducted on people. In fact, marimastat from British Biotech has been subjected to at least five unsuccessful Phase III trials, and Bayer and Pfizer stopped trials of MMP inhibitors in Phase III.
Recently opened a new binding site of gelatin in part hemopexin subunit of MMP-9.
WIPO Publication No. WO 95/2969 relates to compositions for tear replacement therapy containing cytokines or growth factors, specifically, TGFβ8.
U.S. patent No. 6444791 (Quay) relates to a method of treatment of keratoconus with the use of the Finance of protease inhibitors, includes A2-macroglobulin and inhibitor alpha 1-protease.
U.S. patent No. 4923700 (Kaufman) refers to the system of artificial tears, including aqueous suspension of particles of type mucin and lipid substances type. Particle type mucin formed from collagen, gelatin and/or serum.
U.S. patent No. 6455583 (Pflugfelder et al.) refers to the local application of tetracycline to reduce the inflammation associated with slower cleansing with tears.
Now unexpectedly found that a relatively small amount of natural peptide inhibitors of proteases showed significant inhibition of metalloproteinases when ophthalmically compatible media, such as used in the compositions of types of artificial tears. Also unexpectedly been found that the resulting composition may function to increase vitality and reduce moisture loss of epithelial cells of the cornea. The present invention relates to an MMP-inhibiting local ophthalmic compositions comprising proteaseinhibitors peptide substrate in ophthalmically acceptable carrier. The present invention also relates to methods for treating dry eye, comprising applying to the surface of the eye a composition containing proteaseinhibitors peptide the second substrate in ophthalmically acceptable carrier. The first group of embodiments of the present invention relates to local ophthalmic compositions comprising proteaseinhibitors peptide substrate and ophthalmically acceptable carrier. The preferred embodiment in this group of embodiments is proteaseinhibitors peptide substrate and galactomannan in ophthalmically acceptable carrier. The following preferred embodiment is a local ophthalmic composition comprising gelatin and galactomannan. The following preferred embodiment is a composition of alpha-2-macroglobulin and galactomannan. Other embodiments of the present invention include compositions comprising galactomannan and ovomacroglobulin, galactomannan and collagen and galactomannan and casein. The preferred galactomannans is HP-guar.
The second group of embodiments of the present invention relates to a method for treating dry eye, comprising applying to the surface of the eye an effective amount of MMP-9-inhibiting peptide substrate. In the preferred embodiments presented here, the quantities of the peptide substrate is sufficient for inhibition of MMP-9, at least 50%.
Without much connection with theory, it is believed that proteaseinhibitors peptide substrates, functioning with inhibition of the activity of proteases,such as MMP-9, reduce thus the ability of the protease to act on endogenous substrates, usually present in the tissues of the eyes, prone to disorder is dry eye. Thus, they can function with decreasing directly destructive effects of MMP-9 or other proteases of the eye tissue. Some or all of the inhibiting effects proteaseinhibitor peptide substrates provided by proteases, such as MMP-9, may be indirect, that is, to manifest in the form of allosteric inhibition type. The size or molecular weight proteaseinhibitor peptide substrate can affect the effectiveness of this inhibition. In addition, proteaseinhibitors peptide substrates can provide direct or indirect anti-inflammatory effect on the sensitized tissue surface of the eye, and antimoney the effect of remodeling. These functions are considered to be mediated by the interaction of peptide substrates with enzymes MMPs, specifically MMP-9. In addition, certain embodiments of the present invention can extend these therapeutic options by providing prolonged release proteaseinhibitor peptides. For example, in the preferred embodiment of the present invention proteaseinhibitors petigny substrate combine with HP-guar and borate with about the education of the gel. This gel works to improve stability of the tear film and protects the eye surface from moisture loss. In addition, the gel can catch proteaseinhibitors peptide substrate, and thus the substrates are stored in the tear film, resulting in a long period of activity. Proteaseinhibitors peptide substrates can also function as a frame structure for soluble mucin with the formation of gelatin-mucinosa gel matrix, thereby increasing the stability of the tear film.
BRIEF DESCRIPTION of DRAWINGS
The Figure 1 shows dose-dependent inhibition of MMP-9 by Gelatin And Tricine buffer.
The Figure 2 shows that the Gelatin in A concentration of 0.1% wt./about. in combination with softening polymers shows a significant inhibition of MMP-9.
The Figure 3 shows dose-dependent inhibition of MMP-9 by Gelatin And included in Sistan (Systane).
The Figure 4 shows dose-dependent inhibition of MMP-9 by Gelatin And drug Tears Naturale II.
The Figure 5 shows the dose-dependent inhibition of bacterial collagenase Gelatin A.
The Figure 6 shows the dose-dependent inhibition of bacterial collagenase Gelatin And Cysteine.
The Figure 7 shows dose-dependent inhibition of bacterial collagenase Gelatin And drug Tears Naturale II.
Fig is re 8 shows what Gelatin in combination with softening polymers shows various degrees of inhibition of bacterial collagenase.
The Figure 9 shows increased protection from moisture loss and increased cell viability, processed products in the form of artificial tears, including Gelatin A.
The Figure 11 shows the dose-dependent inhibition of MMP-9 using recombinant human gelatin of 8.5 kDa.
The Figure 12 shows dose-dependent inhibition of MMP-9 using recombinant human collagen.
DETAILED description of the INVENTION
When used in the present description, unless otherwise specified, the following terms should be understood in the following values:
The term "protease" includes enzymes that catalyze the cleavage of peptide bonds. Typical protease include collagenase and matrix metalloproteinase. The term "proteaseinhibitors peptide substrate" encompasses substances which are primarily peptide nature, i.e. consist of one or more amino acid chains and possess property of the substrate for protease enzymes. Typical examples proteaseinhibitor peptide substrates include gelatin, alpha-2-macroglobulin, ovomacroglobulin, casein and collagen.
The term "MMP" refers to the matrix metalloproteinases (enzyme).
The term "MMP-9" refers to an enzyme known as matrix metalloproteinase-9.
The term "galactomannan" refers to polysaccharides derived from natural resins or similar natural or synthetic resins containing components mannose or galactose, or both groups as the main structural components.
The term "CMC" means a carboxymethylcellulose and its salts.
The term "HPMC" means hypromellose.
The term "HP-guar" means hydroxypropyl-guar. Hydroxypropyl-guar low molar substitution (e.g., less than 0.6) is preferred.
The term "eye surface" means accessible from the outside of the eye tissue, typical, but not limiting examples of which include the cornea, the conjunctiva, the body and the sclera.
The term "inhibitory amount" refers to a nontoxic but sufficient amount of inhibitory substances to ensure the target activity.
The term "ophthalmically acceptable carrier" refers to a composition having physical properties (e.g., pH and/or osmollnosti), which is physiologically compatible with ophthalmic tissues.
Unexpectedly, it was found that a relatively small amount of natural peptide inhibitors of proteases showed significant inhibition of metalloproteinases when it is notizie types of artificial tears. Even more surprising is the fact that the number proteaseinhibitor peptide substrate can be quite low, since it was found that low concentrations of proteaseinhibitor peptide substrate, as 0.1% wt./about., one of the incarnations of which is gelatin, can provide inhibition of MMP-9 by more than 50%.
Typical proteaseinhibitors peptide substrates include gelatin, alpha-2-macroglobulin, ovomacroglobulin, collagen and casein, as well as the following, are described below. However, it should be understood that other proteaseinhibitors peptide substrates can be used, as found, are within the scope of the present invention.
Gelatin is a protein produced by partial hydrolysis of collagen extracted from the connective tissue of the animal. Commercially available two types of gelatin: type a is obtained from the acid-treated precursor, while type b is obtained from processed with alkali predecessor. Both types of gelatin are substrates of various MMP and function as competitive inhibitors of MMP.
Alpha-2-macroglobulin, a major protein produced by the liver and found in blood, is able to inactivate a number of proteases, including metalloproteinases. The mechanism of this inactivation, it is reported that C is enabled in that is, the region of 35 amino acids, that act as 'seed' for proteases: when proteinase binds and cleaves this plot, it becomes associated with alpha-2-macroglobulin. The resulting complex is then removed from the blood by macrophages.
Casein is a phosphoprotein found in cheese and milk. Casein contains a relatively high number of Proline residues and as a result has little secondary or tertiary structure. Being relatively hydrophobic, it is easily dispersed in diluted alkali and salt solutions.
Ovomacroglobulin, also referred to as avastatin, is a glycoprotein consisting of four subunits that are connected in pairs via disulfide bonds. He demonstrated inhibitory activity of a broad spectrum of activity against different types of proteases, including serine proteases, cysteine proteases, thiol proteases, and metalloproteases.
Collagen is the main protein in animals, providing nearly 25% of the total protein content, and is the main protein in connective tissue. It is a long, fibrous protein and forms a rigid layers or fibers, which together form the extracellular matrix, which provides the structure of tissues and cells. To llagen can also be found inside certain cells. Collagen, the most common in the form of a triple helix, known as tropocollagen. Using partial hydrolysis of tropocollagen gelatin is obtained.
Source proteaseinhibitor peptide substrates used in the present invention, generally, is of animal origin. For example, gelatin derived from bovine or porcine skin or bone, is the prevailing form, currently used in pharmaceutical products. Performed extensive processing in order to obtain as far as possible homogeneous and pure product taking into account its intended use (oral, parenteral vehicle). Collagen and/or gelatin, which is free from transmissible spongy encephalopathy (TSR) and Bovine spongy encephalopathy (BSE), commercially available from several suppliers, including, for example, Gelita (Sergeant Bluff, Iowa) and Rousselot (Sobel, Dubuque, Iowa).
The use of materials produced using synthetic and/or recombinant technology, represents another option. For example, FibroGen (San Francisco, California) produces a fully synthetic gelatin and collagen using a recombinant yeast system. These synthetic materials may possess certain advantages from the point of view of consistency (uniformity from batch to batch, determined by the constituent molecular weight and physico-chemical properties), compliance with the requirements of the customer (pre-defined characteristics, design of molecules) and from the point of view of biocompatibility and safety (reduced risk of inducing an immune response, elimination of contaminants).
Compositions and methods of the present invention include proteaseinhibitors peptide substrates in an amount sufficient for inhibition of metalloproteinases. The preferred metalloproteinase is MMP-9. The number proteaseinhibitor peptide substrate may vary depending on the particular substrate, but usually the amount is from about 0,010% to 10% weight/volume (wt./vol.), more preferably, from about 0.05% to 1% (wt./vol.), even more preferably, about from 0.05% to 0.25% (wt./vol.). The percentage degree of inhibition of MMP is, preferably, more than about 50%, more preferably more than about 60%, even more preferably more than about 70%.
In one embodiment of the present invention proteaseinhibitors peptide substrate combined with the existing pharmaceutical composition for dry eyes, such as Eye drops, SISTAN® Lubricant (SYSTANE® Lubricant Eye Drops) (Alcon Laboratories, Inc.), which contains a softening of the polymer system. Curing the protection of CYSTEINE® is achieved through the interaction of mitigating substances is (polyethylene glycol 400 and propylene glycol), HP-Guar and natural tears of the patient. When combining HP-Guara natural tears chemical reaction occurs. HP-Guar associated with hydrophobic (repelling water) surface with the formation of the network gel-like consistency. HP-Guar also helps to maintain softening system on the surface of the eye longer.
One embodiment of the present invention is a composition comprising galactomannan, Borat and gelatin. Types of galactomannans, which can be used in the present invention, generally derived from the guar gum, gum beans carob and gums of cesalpinia barbed. Additionally, galactomannan can also be obtained using classical synthetic methods or by chemical modification of natural galactomannans.
When used in the present description, the term "galactomannan" refers to polysaccharides obtained from the above natural resins or similar natural or synthetic resins containing components mannose or galactose, or both groups as the main structural components. Preferred galactomannans of the present invention consist of linear chains of (1-4)-beta.-D-mannopyranosyl units saliva.-D-galactopyranosyl units attached using relations (1-6). Predpochtitel what's the galactomannans ratio of D-galactose to D-mannose varies, but, as a rule, is from about 1:2 to 1:4. Galactomannan containing D-galactose and D-mannose with their ratio, amounting to about 1:2 are preferred. Additionally, in the definition of "galactomannan" may also be included other chemically modified variants of polysaccharides. For example, hydroxyethyl, hydroxypropyl and carboxymethyloxime-replacement can be obtained for the galactomannans of the present invention. Particularly preferred non-ionic substitutions in galactomannans, such as containing alkoxy and alkyl groups (C1-C6), if the target is getting soft gel (for example, hydroxyproline replacement). Replacement provisions of hydroxyl, other than cis-position, are preferred. An example of a composition formed by using non-ionic replacement of galactomannan is hydroxypropyl-guar with molar replacement component of about 0.4. Anionic substitutions can also be made with galactomannans. Anionic substitution is particularly preferred when the target is getting silnomagnitnyh gels.
Borate compounds can be used in certain embodiments of the present invention. Borate compounds that can be used in the compositions of the present invention include boric acid and other FA is matemticas acceptable salt, such as sodium borate (borax) and potassium borate. When used in the present description, the term "borate" means any and all pharmaceutically acceptable forms of borates. Borates are common excipients in the ophthalmic pharmaceutical compositions with good buffering capacity at physiological pH, and is also well known for safety and compatibility with a wide range of medicines and preservatives. Borates also have their own bacteriostatic and fungistatic properties and, thus, help in the preservation of songs.
The preferred embodiment of the present invention is a composition comprising gelatin in amounts as low as 0.01%-5% (wt./vol.), one or more of galactomannans in the amount of approximately from 0.1 to 5% (wt./vol.), and borate in the amount of approximately from 0.05 to 5% (wt./vol.). Preferably, the composition will contain 0,01%-1% gelatin (wt./vol.), 0.2 to 2% (wt./about.) galactomannan and 0.1-2% (wt./about.) connection Borat. Most preferably, the compositions will contain the 0.05%and 0.5% gelatin (wt./vol.), 0.3 to 0.8% (wt./about.) galactomannan and 0.25-1% (wt./about.) connection Borat. The specific amount will vary depending on the specific target gelling properties. As a rule, concentralization, Borat or galactomannan can be manipulated with the aim of bringing to a suitable viscosity of the composition upon activation of the gel (i.e. after the introduction). Manipulation of the concentration of gelatin, borate or galactomannan can provide stronger or weaker gelation at a given pH. If the target is a composition with a strong gelation, the concentration of gelatin, borate or galactomannan can be increased. If the target is a composition with weaker gelation, such as the composition with partial gelation, the concentration of gelatin, borate or galactomannan can be reduced. On the gelling properties of the compositions of the present invention may be affected by other factors such as the nature and concentration of the additional ingredients in the composition, such as salt, preservatives, chelating agents and so on. As a rule, preferred nehelenia compositions of the present invention, i.e. the composition, not activating the gel in the eyes, will have a viscosity of approximately from 5 to 1000 CPs. Generally, the preferred gel compositions of the present invention, i.e. the composition, activating the gel in the eyes, will have a viscosity of approximately 50 to 50000 CPS.
One of the earliest and most successful solutions artificial tears is described in the Patent is U.S. No. 4039662 (Hecht, et al.). This solution was present at the market for many years as Lubricant Eye Drops TEARS NATURALETM(Alcon Laboratories, Inc., Fort Worth, Texas). The solution described and claimed Hecht, et al. in patent '662, and the corresponding commercial product based on the unique combination of hydroxypropylmethylcellulose, Dextran 70 and benzalkonium chloride. In a later version of this product, which is currently present on the market under the name of Eye Drops of the Lubricant TEARS NATURALE(TM) II Polyquad® (Alcon Laboratories, Inc.), the benzalkonium chloride was replaced by polyquaternium-1, which is a polymeric antimicrobial agent/preservative.
Examples of the organic buffer that can be used in the present invention, is Tricine, N-[Tris(hydroxymethyl)methyl]glycine. Organic buffer contains both basic and acidic groups, and the result is zwitterions; in conditions of physiological pH of these buffers are simultaneously positive and negative charges.
In the case of contact lenses and ophthalmic solutions add various agents to enhance compatibility with the eyes. To avoid burning or irritation, it is important that the solution had onicescu and in the physiological pH range, e.g., 200-350 mosmol to toychest and 6.5 to 8.5 pH. With this aim often add the various buffer and osmotic agents. Elementary osmotic agent is sodium chloride, because it is the main solute in tears man. In addition, for full or partial replacement of sodium chloride can also be added propylene glycol, lactulose, trehalose, sorbitol, mannitol or other osmotic agents. You can also use different buffer system to maintain the physiological pH range between 6.5 and 8.5, such as citrate, phosphate (suitable mixture of Na2HPO4, NaH2PO4and KN2RHO4), borate (boric acid, sodium borate, potassium tetraborate, metaborate potassium and mixtures), bicarbonate, and tromethamine, as well as other relevant nitrogen-containing buffers (e.g., ACES, BES, BICINE, BIS-Tris, BIS-Tris Propane, HEPES, HEPPS, imidazole, MES, MOPS, PIPES, TAPS, TES, Tricine).
Composition proteaseinhibitor peptide substrate according to the invention can be combined with one or more additional therapeutic agents from other therapeutic classes, which are believed to have beneficial effects in the treatment of dry eye, with such agents, such as antibiotics, immunosuppressants and anti-inflammatory agents.
Anti-inflammatory agents that can be included in compositions according to the invention include steroidal and non-steroidal drug (NSAID). Typical NSAID R is t, but not limited to, Ketorolac tromethamine (Acular®), indomethacin, flurbiprofen sodium, nepafenac, bromfenac, suprofen and diclofenac (Voltaren®). Typical corticosteroids include, but are not limited to, rimexolone, hydrocortisone, fludrocortisone, formation, loteprednol, triamcinolone, dexamethasone, prednisolone, cortisone, aldosterone, Madison and betamethasone. Typical sex steroids include steroids on the basis of androgens, estrogens and/or progestins.
Typical antibiotics include, but are not limited to, tetracycline, doxycycline and chemically modified tetracyclines, beta-lactam antibiotics, such as cefoxitin, n-formamidopyrimidine and other derivatives thienamycin, chloramphenicol, neomycin, carbenicillin, colistin, penicillin G, polymyxin B, vancomycin, Cefazolin, tsefaloridin, Gibraltarian gramicidin, bacitracin, sulfonamides of enoxacin, ofloxacin, cinoxacin, sparfloxacin, thiamphenicol, nalidixic acid, tosufloxacin tosilate, norfloxacin, three-hydrate piperidinol acid, pyramidula acid, fleroxacin, biomicin, ciprofloxacin, erythromycin, gentamicin, norfloxacin, sulfacetamide, sulfisoxazole, tobramycin, moxifloxacin and levofloxacin.
Typical immunosuppressants include, for example, cyclosporine, such as cyclosporine a, and ascomycin, so is f as FK-506, rapamycin and tacrolimus.
The compositions of the present invention may be added other ingredients. Such ingredients typically include agents that regulate toychest, chelating agents, active pharmaceutical agents, solubilizer, preservative agents, agents regulating the pH, and the media. Other polymeric or Monomeric agents such as glycol and glycerol, can also be added for special treatment. Agents toychest used in the compositions of the present invention may include salts such as sodium chloride, potassium chloride and calcium chloride; non-ionic agents toychest may include propylene glycol and glycerol; chelating agents may include propylene glycol and glycerol; chelating agents include EDTA and its salts; solubilizing agents may include Cremophor EL® and tween 80; other carriers may include Amberlite® IRP-60; pH-adjusting agents may include chlorodrol acid, Tris, triethanolamine and sodium hydroxide; and suitable preservatives may include benzalkonium chloride, polyquaternium-1 and polyesterurethane. The above examples are for illustrative purposes and are not intended to be comprehensive. Examples of other agents used for such purposes are well known in the ophthalmic pharmaceutical is x compositions provided by the present invention.
The following additional examples illustrate various embodiments of the invention. Examples are presented to aid in understanding the invention and should not be construed as limiting thereof.
In this and the following examples, while not defined otherwise, the MMP activity was assessed using fluorogenic substrates that are sensitive to MMP-1, -2 and -9, including DNP-Pro-Leu-Gly-Met-Trp-Ser-Arg-OH and DNP-Pro-Cha-Gly-Cys (Me)-His-Ala-Lys (N-Me-Abz)-NH2. These analyses fluorogenic substrates are well known in the prior art; for example, see Bickett et al. Analytical Biochemistry 212, 58-64 (1993) and Netzel-Arnett et al, Analytical Biochemistry 195, 86-92 (1991), both publications included in the present description by reference. Before analysis of Pro-MMP-9 was activated using acetate p-aminophenolate, and required no activation of bacterial collagenase. For analysis was prepared by the main substrate solution with a concentration of 0.1 mM in DMSO, and all analyses of enzyme activity with and without inhibitors was carried out in 50 mM tricine buffer, pH 7.5, containing 0,2M NaCl, 10 mM CaCl2, 50 mM ZnSO4, and 0.05% Brij-35, at room temperature. (Brij-35 is a commercially available surface-active substance, the ether of polyoxyethylenated). The total sample volume is 200 μl, and the analysis is performed in 96-well-microplate. Changes in fluorescence were recorded every minute in t is the treatment for 10 minutes with the device, the reader with fluorescence microplate (Model FL x800I, Bio-Tek Instrument), with plants appropriate wavelength excitation/emission (i.e. λ.=280 nm; λ.=360 nm and λ.=280 nm; λ.=360 nm) for a particular substrate used. The enzyme activity was expressed as changes in fluorescence per minute, which corresponded to the slope of the straight line relative fluorescence versus time recorded for the enzymatic reaction for 10 minutes. The percentage of inhibition was calculated by subtracting the proportion of the sample with the inhibitor fraction of sample without inhibitor and then dividing by the proportion of the sample without inhibitor and multiplying by 100%.
This study was undertaken to explore the potential of Gelatin And in the inhibition of the activity of MMP-9. In this particular study, the concentration of MMP-9 was 360 mladinic/analysis in Tricine buffer, as the gelatin used Gelatin (Sigma catalog #1890-50G, Lot #014K0077, acidic extract from pig skin), and as a substrate used MMP-2/MMP-9 fluorogenic substrate I (Calbiochem Catalog #44215, lot #B47246; peptide structure = DNP-Pro-Leu-Gly-Met-Trp-Ser-Arg-OH.) 20 µm/analysis. Gelatin And Tricine buffer showed dose-dependent inhibition of the activity of MMP-9. Starting from 0.01% to 0.2% (wt./about.) observed a proportional increase in inhibition. After 0.2%, the inhibition began to stabilize. The results of the study are summarized on Figures is 1.
This study was undertaken to explore the potential of Gelatin And in the inhibition of the activity of MMP-9 when used with different softening polymers. For this purpose, was selected to 0.1% wt./about. Gelatin A, which provided approximately 59% inhibition in Example 1. MMP-9 = Calbiochem Cat# 444231;Lot# B56458; human neutrophils. Used activity amounted to 200 mladinic/analysis. Gelatin = A. Gelatin Sigma Cat# 1890-50G, Lot# 014K0077 (acid extract from pig skin). Analytical buffer = 50 mM Tricine, pH 7.5, containing 0,2M NaCl, 10 mM CaCl2. Substrate = MMP-l/MMP-9 fluorogenic substrate. Calbiochem cat# 44221, lot# B54710. Molecular weight, 1077,2; 1 μm in the analysis. Peptide structure = DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(N-Me-Abz)-NH2. Wosb. 365 nm; Emm, 450 nm.
The results of this study show that the Gelatin in a concentration of 0.1% wt./about., in combination with 0.18% mass./about. HP-guar, 0.3% wt./about. HPMC and 0.5% wt./about. CMC is able to provide 74,8%, 71,8% and 79.1% inhibition of MMP-9, respectively, as shown in Figure 2.
The following series of studies have examined the ability of Gelatin And to inhibit the activity of MMP-9 when a representative solutions of artificial tears. For this purpose, selected solutions, artificial tears, known as Sistan and Tears Naturale II. For this series of studies, various concentrations of gelatin And the interval on which of 0.01% to 0.20% (wt./about.) included simultaneously in the existing market solutions Sistan and Tears Naturale II. The analysis was performed using the same enzyme and substrate and following the same procedure as described in Example 2. The results of this study demonstrate that Gelatin And showed dose-dependent inhibition of the activity of MMP-9 when included simultaneously in the solutions Sistan and Tears Naturale II, contributing more than 50% inhibition of 0.01% wt./about. and above Cysteine, and from 0.05% wt./about. and up in Tears Naturale II. The results of these studies are described graphically in Figures 3 and 4.
This study was undertaken to study the inhibitory reactivity of Gelatin And in relation to bacterial collagenase. Bacterial collagenase are exotoxins that contribute to the destruction of the extracellular structures in the process of bacterial pathogenesis. For the study were prepared with different concentrations of gelatin in the range from 0.05% to 0.8% (wt./about.) in 50mM tricine buffer pH 7.5, containing 0.2 M NaCl, 10 mM CaCl2, ZnSO4and Brij-35. The activity of bacterial collagenase was assessed by recording the changes of fluorescence for 10 min at spectrofluorimeter at 25°C. the Activity was expressed as changes in fluorescence per minute. The concentration of bacterial collagenase and substrate I was 20 Units/analysis and 20 μm/analysis, respectively. As collagenase used Clostridiales (Sigma Kata the og #C-7657; lot #107H8632). As the gelatin used Gelatin (Sigma Cat #1890-50G, Lot #014K0077. The acidic extract from pig skin). As the substrate used MMP-2/MMP-9 fluorogenic substrate I (Calbiochem cat #44215, lot #B47246; Peptide structure = DNP-Pro-Leu-Gly-Met-Trp-Ser-Arg-OH). The results show that requires more than 0.4% of the mass./about. Gelatin to achieve A more than 50% inhibition of the bacterial enzyme, whereas gelatin is in the range of 0.05% - 0.1% (wt./about.) can easily provide more than 50% inhibition of MMP-9. Thus, inhibition of Gelatin And bacterial collagenase is not as effective as the inhibition of MMP-9. The results of the study are summarized graphically in Figure 5.
This study tested the ability of Gelatin And to inhibit bacterial collagenase for inclusion in the products of artificial tears. For this series of studies, various concentrations of gelatin in the range from 0.05% to 0.25% (wt./about.) included simultaneously in the existing market solutions Sistan and Tears Naturale II. The analysis was performed using the same procedure and the same substrate, as described in Example 4. The results show that Gelatin And when the products of artificial tears, Sistan and Tears Naturale II may also provide dose-dependent inhibition of bacterial collagenase. However, it is less effective and tributable than 0.25 wt. -%/about. gelatin to achieve 50% inhibition in both products, artificial tears, as shown graphically in Figures 6 and 7.
This study was undertaken to explore the potential of Gelatin And in the inhibition of the activity of bacterial collagenase when used with different softening polymers. For this purpose, Gelatin And 0.1% wt./about. combined with HP-Guar, CMC and HPMC. The study was performed using the same procedure and the same substrate, as described in Example 4. The results show that with 0.18% of HP-guar reach 51% inhibition, while together with 0.3% HPMC and 0.5% CMC reach only 24% and 21% of inhibition, respectively. These results are shown graphically in Figure 8.
This study examined the ability of Gelatin And to provide protection from moisture loss and increase the viability of human epithelial cells of the cornea. In these studies analyzed human epithelial cells CEPI 17 using the Alamar Blue method described here. Cells of the human corneal epithelial cell line (CEPI 17, Alcon Laboratories Inc.) raised to confluent state in a 96-well-microplate. The medium was removed from the test hole was added 100 μl of each test solution. Control wells with medium left separately. The tablet was placed brato in the incubator for 60 minutes. After incubation, all wells are aspirated and washed once with 200 μl per well of buffer HyQ (Modified Dulbecco phosphate buffer solution, Hyclone cat# SH30028.02). Did the dilution 1/10 Alamar Blue (Biosource, DAL 1100) in HyQ and add 100 ál to each well for incubation at 37°C. After 4 hours of incubation, the tablet was reading device for reading fluorescence from the microplate (Model FLx800, Bio-Tek Instrument) with the installation of excitation at 560 nm and emission at 590 nm. The calculation of the % viability of the cells was performed by dividing the average fluorescence of the sample by the average fluorescence of control and multiplied by 100%.
To assess protection against loss of moisture is used, a similar procedure with pre-incubation for 15 minutes and with the period of loss of moisture within 30 minutes. After pre-incubation aspirated all test wells except for the controls. Controls covered by parafilm. The tablet was placed in a hood downdraft air for 30 minutes in order to expose cells to the loss of moisture. After the loss of moisture all wells were washed once with 200 ál of HyQ. Cells were analyzed for viability analysis using Alamar Blue as described in assay procedure on cell viability. Calculation of protection from moisture loss was performed by dividing the average fluorescence of the sample on average fluorescents the Yu control and multiplied by 100%.
The results of this study demonstrate that the inclusion of Gelatin And various products artificial tears, including Sistan, Tears Naturale II and GenTeal Mild, is provides the best protection of cells from moisture loss and increases cell viability. The results of this study are shown graphically in Figure 9.
This study was undertaken to determine the ability of alpha-2-macroglobulin to inhibit the activity of MMP-9. The activity of MMP-9 was assessed by recording the changes of fluorescence within 10 minutes by spectrofluorimeter at 25°C. the Activity was expressed as changes in fluorescence per minute. Used 360 mladinic/analysis of MMP-9 (Calbiochem cat #444231, Lot #B56458; human neutrophils). Alpha-2-macroglobulin (Sigma Cat #M-6159, Lot #118H7606; from human placenta). As the substrate used MMP-2/MMP-9 fluorogenic substrate I to 10 microns/analysis (Calbiochem cat #44215, lot #B47246; Peptide structure = DNP-Pro-Leu-Gly-Met-Trp-Ser-Arg-OH). The results show that alpha-2-macroglobulin inhibits the activity of MMP-9 dose-dependent manner. The results are presented graphically in Figure 10.
This study was undertaken to determine the effect of inhibition of recombinant gelatin known amount of active MMP-9. The activity of MMP-9 was assessed by recording the changes of fluorescence within 10 the minutes using spectrofluorimeter at 25°C. The activity was expressed as changes in fluorescence per minute. The concentration of MMP-9 (Calbiochem catalog #444231, lot #B56458, human neutrophils) was 200 mladinic/analysis in Tricine buffer (50 mM Tricine, pH 7.5, containing 0,2M NaCl, 10 mM CaCl2). As the gelatin used recombinant human gelatin of 8.5 kDa (FibroGen, Lot #04AE001R-01). As the substrate used MMP-l/MMP-9 fluorogenic substrate (Calbiochem Catalog #44221, lot #B54710; peptide structure = DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(N-Me-Abz)-NH2; Vosb. 365 nm; Em. 450 nm). Used 1 μm/analysis. In the analysis to achieve more than 50% inhibition was required recombinant human gelatin of 8.5 kDa with a concentration in the range between 0,15%-0,25% (wt./vol.). The results of the study are summarized graphically in Figure 11.
This study was undertaken to determine the effect of inhibition of recombinant human Collagen Type I activity of MMP-9. The activity of MMP-9 was assessed by recording the changes of fluorescence within 10 minutes using spectrofluorimeter at 25°C. the Activity was expressed as changes in fluorescence per minute. The concentration of MMP-9 (Calbiochem catalog #444231, lot #B56458, human neutrophils) was 200 mladinic/analysis in Tricine buffer (50 mM Tricine, pH 7.5, containing 0,2M NaCl, 10 mM CaCl2). As collagen used recombinant human collagen type I (Fibroen, Lot #04AE001R-01). As the substrate used MMP-1/MMP-9 fluorogenic substrate (Calbiochem Catalog #44221, lot #B54710; peptide structure = DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(N-Me-Abz)-NH2; Vosb. 365 nm; Em. 450 nm). Used 1 μm/analysis. In the analysis to achieve more than 50% inhibition was required of recombinant human collagen type I with a concentration in the range between 0.03%-0,04% (wt./vol.). The results of the study are summarized graphically in Figure 12.
Below is an example of two solutions of artificial tears on the present invention.
|Connection||Number % (wt./about.)|
|Sistan||Tears Naturale II|
|The sodium borate||no||0,35|
|Calcium chloride (anhydrous)||0,0053||no|
|Magnesium chloride (uranyl)||0,0064||no|
|The sodium hydroxide/|
|to pH 7.0||to a pH of 7.4|
|Purified water||qs to 100%||qs to 100%|
1. Local ophthalmic composition, comprising protease-gebarowski peptide substrate in the solution in amounts of from about 0,010% wt./about., up to 10% wt./about., where indicated, the substrate is selected from the group consisting of gelatin, ovomacroglobulin, collagen and casein in ophthalmically acceptable carrier.
2. The composition according to claim 1, further comprising galactomannan and Borat.
3. The composition according to claim 1 or 2, where protease-inhibiting peptide substrate capable of inhibiting the matrix metalloprotease-9.
4. The composition according to claim 2, where galactomannan includes hydroxypropyl-guar.
5. The composition according to claim 1 or 2, additionally containing a therapeutic agent selected from the group consisting of antibiotics, anti-inflammatory agents and immunosuppressants.
6. The composition according to claim 1, where the substrate is a gelatin in the amount of from 0.01% wt./about. to 0.2% wt./about.
7. The composition according to claim 2, where the gelatin is present in amounts of from 0.01% wt./about., up to 5% wt./about., galactomannan is present in amount of from 0.1% wt./about. up to 5% wt./about., and the borate is present in amounts of from 0.05% wt./about. up to 5% wt./about.
8. The composition according to claim 7, where the gelatin is present in amounts of from 0.05% wt./about. up to 0.5% wt./about., galactomannan is present in amount of from 0.3% wt./about. to 0.8% wt./about., and the borate is present in an amount of from 0.25% wt./about. up to 1% wt./about.
9. The composition according to claim 1, where the substrate is a collagen in the amount of more than about 0.03% of wt./about.
10. The composition according to claim 1, additionally containing smahc the Mering polymer.
11. The composition according to claim 10, in which the softening polymer selected from the group consisting of a receiver array, CMC, polyethylene glycol and propylene glycol.
12. A method of treating dry eye, which comprises applying to the surface of the eye a composition comprising protease-inhibiting peptide substrate in the solution in amounts of from about 0,010% wt./about. up to 10% wt./about., where indicated, the substrate is selected from the group consisting of gelatin, ovomacroglobulin, collagen and casein, and ophthalmically acceptable carrier for him.
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to an aqueous pharmaceutical suspension which contains a fine rebamipide of particle size 0.2-5 mcm and polyvinyl alcohol. The invention also refers to a method for preparing said rebamipide suspension which involves mixing water and polyvinyl alcohol to prepare an aqueous solution, adding fine rebamipide particles to said solution, and mixing to produce the aqueous rebamipide suspension.
EFFECT: invention provides preparing the suspension wherein rebamipide may be stably dispersed as fine particles without agglutination that enables store the suspension for a long time.
6 cl, 1 dwg, 1 tbl, 13 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: group of inventions relates to medicine, in particular, to ophthalmology. Ophthalmologic compositions contain from 0.1 ppm to 10 ppm of cationic antimicrobial component, selected from group, consisting of biguanides, polymer biguanides, quaternary ammonium compounds and any their mixture; 0.005-0.15 wt % of hyaluronic acid; and 0.01-1.0 wt % of amphoteric surface-active substance of formula I, where R1 represents R or -(CH2)n-NHC(O)R, where R represents C8-C18 alkyl, which can be replaced by hydroxyl group and equals 2, 3 or 4; R2 and R4 each is independently selected from methyl, ethyl, propyl or isopropyl; and R4 represents C2-C8 alkylene, which can be substituted by hydroxyl group.
EFFECT: invention ensures application of ophthalmologic compositions for purification and disinfection of contact lenses and, in particular, soft silicon hydrogel contact lenses.
12 cl, 15 tbl, 5 dwg, 5 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: group of inventions refers to medicine, particularly to ophthalmology. An aqueous liquid ophthalmic composition contains hyaluronic acid in the concentration of 0.05-0.4% or its pharmaceutically acceptable salt, and additionally contains gluconic acid and its salt with a metal, but does not contain chlorhexidine or its salt. A method for improving the viscosity stability of the aqueous eye-drop ophthalmic composition containing hyaluronic acid is conditioned by introducing gluconic acid and its salt with the metal.
EFFECT: invention provides slowed-down viscosity reduction of the aqueous ophthalmic composition.
6 cl, 6 tbl, 6 ex
SUBSTANCE: invention refers to medicine, namely oncology, and may be used in treating eyelid cancer for prevention of obliteration of the lachrymal ducts. That is ensured by irrigation of the nasolachrymal duct twice a day before each session radiation therapy and in 10-12 days after the session. A solution containing 0.1% dexamethasone min. 2.0 ml and methotrexate 5 mg is injected in the nasolachrymal duct in a lower nasal point through a blunt-ended cannula on a syringe.
EFFECT: method provides prevention of such bothersome symptom as permanent lachrymation, as well as maintenance of light-refringent, protective function of the lachrymal organs, and finally - maintenance of visual functions.
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to pharmaceutical industry and medicine, and concerns a lachrymal substitute preparation which can be used for local therapy in an ocular surface disease. The invention has a composition (g/l): hydroxypropyl methylcellulose 2.5-5.0; disodium phosphate 5.5-16.5; sodium dihydrogen phosphate 0.8-1.5; sodium chloride 2.0-8.0; disodium edetate 0.1-0.5; benzalkonium chloride 0.03-0.09; dextrane 0.5-1.5; water for injections up to 1 l. The composition has the balanced proportions providing the pH value within 6.5 to 7.8, contains a polymeric composition containing hydroxypropyl methylcellulose and dextrane. As dextrane, either dextrane 40, or dextrane 60, or dextrane 70 is used.
EFFECT: invention provides ocular surface moistening that allows relieving or eliminating irritation symptoms caused by the ocular surface disease.
1 tbl, 2 ex
SUBSTANCE: invention relates to medicine, ophthalmology, and can be used in diagnostics and surgical treatment of vision organ diseases. In realisation of the method instruments, products of medicinal purpose and liquids introduced into eye are used heated to +37°C. Open eyeball is irrigated from above with 0.9% of sodium chloride at temperature +37°C continuously by means of dropper with frequency 12 drops per minute, and illuminated by yellow dispersed light with wavelength 570-590 nm. Light formation is provided by light filter. Light brightness is increased under control of visibility of selected eye structures to minimal value, ensuring their visibility.
EFFECT: method eliminates injury of retina by light and injury of conjunctiva by dehydration and cooling.
FIELD: medicine, pharmaceutics.
SUBSTANCE: there is offered an agent for treatment of dry eye syndrome, superficial punctuate keratopathy, corneal epithelium defect, corneal erosion, corneal ulcer, conjunctival epithelium defect, dry keratoconjunctiva, superior limbic keratoconjunctivitis, filamentous keratoconjunctivitis, keratitis or conjunctivitis, containing 2-phenyl-1,2-benzisoselenazol-3(2H)-one (ebselen) or its salts as an active ingredient, its administration and an appropriate therapy.
EFFECT: ebselen reduces corneal ageing in rats with extracted lachrymal gland better than physiologic saline and antioxidant alpha-lipoic acid.
9 cl, 2 tbl, 4 ex
SUBSTANCE: invention relates to medicine, namely to anesthesiology and resuscitation science, and can be used for protection of patient's organ of sight from injuries during narcosis and resuscitation. For this purpose face skin around organ of sight is preliminarily shaven and dubbed with vaseline. After that on region of organ of sight put is hermetically made from transparent waterproof material semi-sphere, whose canal ends from internal side with nozzle of spraying solution in form of aerosol towards semi-sphere base. From external side canal opens into filled with solution cavity of compressed reservoir, located on external surface of semi-sphere. Solution from reservoir is pressed out in portions through canal and nozzle until fog appears in all volume of semi-sphere cavity. Pressing out of solution is repeated when fog disappears and after each short-time removal of semi-sphere for determining size of pupil and its reaction to light until patient's awakening. After that semi-sphere is taken off, Vaseline is removed.
EFFECT: method allows to prevent injury of all surface of eye-ball due to its maximal constant moistening.
SUBSTANCE: invention refers to medicine, namely to ophthalmology and can be used in treating the patients suffering actinomycosis of lachrymal passages. That is ensured by irrigation of lachrymal ducts with Actinolysatum in amount 3 ml 3 times a week, total 10 irrigations. Besides Actinolysatum is injected intramuscularly in a single dose, 2 injections a week, total 10 injections.
EFFECT: method provides higher clinical effectiveness of conservative modalities in the given pathology without a surgical intervention due to combination of a certain local effect Actinolysatum on ray fungi and its systemic action.
SUBSTANCE: invention concerns artificial physiological saline solution for washing of eyes and nose and the method of its manufacturing. The declared solution has the size of reaction of active hydrogen from 0.01 to 1, pH from 6.0 to 7.7 and osmotic pressure from 280 mOsm/l to 305 mOsm/l. The given solution effectively eliminates active oxygen, suppresses chemotactic activity and thus does not possess irritating action on processed organs.
EFFECT: method of obtaining of the declared solution consists in adjustment of properties of the electrolytically restored water in such a manner that the size of reaction of active hydrogen becomes from 0,01 to 1, pH becomes from 6,0 to 7,7 and osmotic pressure becomes from 280 mOsm/l to 305 mOsm/l.
9 cl, 6 ex, 1 tbl, 1 dwg
SUBSTANCE: invention relates to field of medicine, namely to ophthalmology and can be used for drug correction of ocular surface state before refractive intervention. Before refraction intervention patient's age is determined, cornea thickness, type of refraction and degree of its change, results of Lipkoff test and Norn sample, index of antioxidant and immune activity of tear - PRDX6 concentration, presence or absence of gamma-globulin, cornea colour are estimated. Selection of medication is performed on the basis of obtained parameters.
EFFECT: method ensures optimisation of ocular surface state before refractive intervention.
4 ex, 1 tbl
FIELD: chemistry; pharmaceutics.
SUBSTANCE: present invention relates to 6-substituted isoquinoline and isoquinolinone derivatives of formula or stereoisomer and/or tautomer forms thereof, and/or pharmaceutically acceptable salts thereof, where R1 is H or OH; R2 is R', (C7-C8)alkyl, (C1-C6)alkylene-R', (C2-C6)alkenyl; or R2 is (C1-C6)alkyl, under the condition that in said alkyl residue, at least one hydrogen is substituted with OH or OCH3; or R2 is (C1-C6)alkylene, bonded with cycloalkylamine, where (C1-C4)alkylene forms a second bond with another carbon atom of the cycloalkylamine ring and, together with carbon atoms of the cycloalkyalmine, forms a second 5-8-member ring; R3, R5 and R8 denote H; R4 is H, (C1-C6)alkyl or (C1-C6)alkylene-R'; R6 and R6' independently denote H, (C1-C8)alkyl, (C1-C6)alkylene-R' or C(O)O-(C1-C6)alkyl; R7 is H, halogen or (C1-C6)alkyl; n equals 1; m equals 3 or 5; r equals 0 or 1 and L is O(CH2)p, where p=0; where R' is (C3-C8)cycloalkyl, (C6)aryl; where in residues R2-R8 (C6)aryl is unsubstituted or substituted with one or more suitable groups independently selected from halogen, (C1-C6)alkyl, O-(C1-C6)alkyl, where the alkyl group can be substituted with 1-3 halogen atoms. The invention also relates to use of the compound of formula (I) and a medicinal agent based on the compound of formula (I).
EFFECT: obtaining novel 6-substituted isoquinoline and isoquinolinone derivatives suitable for treating and/or preventing diseases associated with Rho-kinase and/or Rho-kinase-mediated myosin light chain phosphatase phosphorylation.
36 cl, 5 tbl
SUBSTANCE: invention refers to medicine, particularly ophthalmology, and may be used for treating peripheral and central tapetoretinal dystrophies. That is ensured by 5-10 procedures of the parabulbar introduction of α-fetoprotein 34-75 mcg in isotonic solution 1-3 ml in each eye once in 1-4 days. It is followed by the sequential parabulbar and retrobulbar injections of equal proportions of a suspension containing 10 mln. autologous mononuclears recovered from bone marrow. Bone marrow is taken 1-1.5 hours before the introduction.
EFFECT: method provides an integrated effect on pathological processes in eye socket tissues with inducing organotypic regeneration and providing considerable and stable improvement of visual functions.
SUBSTANCE: invention refers to medicine, namely ophthalmology and may be used for drug-induced therapy following recurrent refractive operations. Criteria for drug-induced correction are patient's age, as well as tear break-up time scores, corneal colour, corneal thickness, degree of astigmatism, PRDX6 concentration, presence or absence of gamma-globulin evaluated after recurrent surgical operations. The derived values are used to select drug-induced therapy.
EFFECT: method provides optimising the ocular surface state following recurrent refractive operation.
5 ex, 1 tbl
SUBSTANCE: invention refers to medicine, namely ophthalmology and may be used for drug-induced therapy following a first stage of refractive operation. Criteria for drug-induced correction are patient's age, as well as tear break-up time scores, corneal colour, corneal thickness, degree of astigmatism, antioxidant and immune lachrymal activity - PRDX6 concentration, presence or absence of gamma-globulin evaluated after the primary surgical operation. The derived values are used to select a preparation.
EFFECT: method provides optimising the ocular surface state following the primary refractive operation.
5 ex, 1 tbl
SUBSTANCE: invention refers to medicine, namely ophthalmology, and concerns treating wet age-related macular degeneration (AMD). That is ensured by the injections of Lucentis 0.5 mg once a month into vitreous body. It is followed by the parabulbar introduction of alpha-fetoprotein 0.0075 mg in the evening and glutathione-S-transferase 0.0000005 g in the morning in isotonic solution 1.5 ml. The introduction is performed into each eye daily to visualise retina with neovasculature surrounding macula. Then laser vascular coagulation follows without macula damaging. A suspension of autologous bone marrow mononuclears are transplanted parabulbarly and retrobulbarly close to macula. Mononuclear count makes 5-40 mln. The suspension is introduced in NCTF-135 1.5 ml. The introduction is performed 2-4 times every 2 months.
EFFECT: method enables arresting neoangiogenesis, relieving autoimmune process within ocular tissues, ie lead to blocking pathogenetic mechanisms of developing AMD that eliminates recurrence of the disease with creating the conditions for organotypic regeneration of retina and evident improvement of visual function.
SUBSTANCE: group of inventions relates to field of medicine, in particular, to ophthalmology. Group of inventions relate to antibacterial lenses, which contain metals, and methods of there production. Antibacterial lens which contains metal salt, obtained by method (versions), which includes stages: (a) processing hardened lens by solution, which contains metal-containing preparation and efficient quantity of acid substance, where pH of claimed solution constitutes from 2 to 5; and (b) processing of lens from (a) stage with solution, containing, basically containing or consisting of salt precursor and efficient quantity of acid substance, where pH of said solution constitutes from 2 to 5.
EFFECT: group of inventions ensures obtaining contact lenses, which contain antibacterial medications of constant composition.
19 cl, 2 dwg, 2 ex
SUBSTANCE: claimed is method of treatment of unstabilised initial open-angled glaucoma. Non-penetrating deep sclerectomy is performed with ablation of deep layers of sclera with further impact on tissues of deep scleral flap by diode laser radiation. Coagulants are applied by means of laser radiation with application of apparatus ALOD-01 in working mode: wavelength - 810 nm, energy - 3.0-3.6 J, power - 1.8 W, exposition - 2.0 sec, spot diameter - 200 mcm, impact being performed without fistula formation. In post-operation period medication Cytoflavin in dose 0.5 ml is introduced under conjunctiva during 10 days.
EFFECT: method makes it possible to achieve preservation and increase of visual functions by compensation of intraocular pressure with enhancement of uveoscleral outflow and achievement of maximal medication concentration.
SUBSTANCE: invention relates to medicine, namely to ophthalmology, and can be used for treatment of chorioretinal dystrophies after tuberculosis chorioretinitis. For this purpose traditional general vitamin therapy and conventional local anti-dystrophy therapy are carried out to patients. Additionally daily natural bioantioxidant histocrom is introduced in dose 0.5 ml of 0.02% solution. Course consists of 10 procedures.
EFFECT: method ensures stabilisation and preservation of visual function of patient in said category of patients due to indirect protection against free-radical oxidation, therefore against apoptosis of retinal neuron in zones of ischemia of dystrophic foci, resulting from introduction of natural bioantioxidant in definite regimen.
SUBSTANCE: invention relates to medicine, in particular to ophthalmology, and deals with treatment of "dry eye" syndrome. Method includes obturation of respective lachrymal duct. For this purpose into lower lachrymal duct on 1/3-1/2 of its depth introduced is medication based on stabilised hyaluronic acid in dose 0.2-0.4 ml. Introduction can be performed by means of syringe, provided with metal blunt pointed cannula with internal diameter 1 m, 1 cm long, curved in the middle at 45 degrees. As medication based on hyaluronic acid, mainly Restilane (Restilane Sab-Q) is used.
EFFECT: method makes it possible to obdurate lachrymal ducts in efficient, dosed and atraumatic way with simplification and price reduction of treatment.
3 cl, 2 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to pharmaceutical industry, namely a thixotropic oral pharmaceutical composition for drug delivery. The thixotropic pharmaceutical composition contains a pharmacologically active substance, a liquid substrate, a biocompatible gel former having the pre-set thixotropic properties and specified in agar, carrageenin and gellan gum.
EFFECT: composition provides the accurate introduction of the amounts of drugs into a patient, a high degree of appreciation of a drug dose by the patient.
8 cl, 3 dwg, 10 tbl