Method of treating atrophic age-related macular degeneration

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, namely to ophthalmology, and may be used for treating dry age-related macular degeneration (dry ARMD). That is ensured by preparing a biocompatible prolonged release drug delivery system containing bevacizumab from 5 mcg to 20 mcg, and a carrier made of a polymer hyaluronic acid associated with bevacizumab administered into a vitreous body with using a 25-30-measuring syringe. In average, bevacizumab from 14 to 120 ng is released for 24 hours in the period of three to six months. The delivery system has a viscosity of 130,000 cPs to 300,000 cPs at the shear velocity of 0.1/second at 25°C.

EFFECT: using the given inventions enables treating dry ARMD with preventing or delaying wet ARMD.

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Cross-reference

This application claims priority nepredvidatelne application for U.S. patent No. 12/176238, filed July 18, 2008, a full description of which is incorporated herein by this specific reference.

Background of the invention

The present invention relates to compositions (i.e. delivery systems drugs and methods of treatment of eye conditions and prevent certain eye conditions. In particular, the present invention relates to pharmaceutical compositions and methods for the treatment and prevention States the back of the eye, for example, by preventing retinal, choroidal and/or macular neovascularization, and/or for the treatment of various types of macular degeneration such as age-related macular degeneration (AMD) through the use of the delivery system for drugs, containing onlineoakley agent.

In industrialized countries the expected life expectancy is over 80 years and is constantly growing. Unfortunately, the quality of life in old age significantly reduced the eye condition known as age-related macular degeneration (AMD). AMD is the leading cause of blindness in the world and according to estimates of the world Organization of Health is Anania approximately 14 million people are blind or have significantly impaired vision due to AMD. Disease AMD has a great impact on physical and mental health of the elderly population and their families and is a significant problem for public health. The main characteristic of AMD is a progressive loss of Central vision due to degenerative and neovascular changes in the macula, a specialized region in the center of the retina.

There are two types of AMD: atrophic or dry and neovascular or wet AMD. Usually AMD begins in the form of dry AMD. Dry AMD is characterized yellow plaque-like deposits called druses in the macula, between the pigment epithelium of the retina (PES) and is subject to chorioidal. Approximately 15% of patients with dry AMD is developing wet AMD, which is characterized by the choroidal neovascularization, which is the result of the formation of new blood vessels chorioidea, and loss of vision.

While there is no cure for AMD, there are ways to treat wet AMD (less common form of AMD) such as the use antineoplaston agents and phototherapy (laser irradiation yellow spots). Onlinebaccarat agents for the treatment of wet AMD include agents that block the action of growth factor vascular endothelial (VEGF), thereby inhibiting angiogenesis (formation but who's blood vessels in the retina), which leads to choroidal neovascularization and loss of vision in patients with wet AMD. Such "anti-VEGF agents for the treatment of wet AMD, proven or clinically studied include bevacizumab (Avastin), ranibizumab (Lucentis) and pegaptanib (Macugen). Bevacizumab is a full-size anti-VEGF antibody approved for use in metastatic cancer of the colon. Ranibizumab is a fragment of a human anti-VEGF monoclonalnoe antibodies, inhibiting all isotypes of VEGF, and pegaptanib is a VEGF-neutralizing aptamers, which specifically inhibits one of the isoforms of VEGF (VEGF-165).

Other known anti-VEGF agents include small interfering RNA (siRNA); corticosteroids such as anecortave acetate, acetonide triamcinolone and acetonide fluocinolone; inhibitors of the receptor tyrosine kinase (such as vatalanib and ruboxistaurin (reduces the activity of protein kinase C)); lactate squalamine, and growth factors, including factor derived from the pigment epithelium. miRNAs can inhibit the production of VEGF and the production of VEGF receptor, corticosteroids can heal the type of DME (diabetic edema yellow spots) wet AMD, inhibitors of receptor tyrosine kinase inhibit subsequent actions of VEGF, and lactate squalamine inhib which induces plasma membrane ion channels with subsequent effects on VEGF.

Ocular condition can include a disease, ailment or condition which affects or involves the eye or one of the parts or sections of the eye. In General terms, the eye include eye and tissue and fluid components of the eyeball, the eye muscles such as oblique and direct muscle) and part of the optic nerve that is located within or adjacent to the eyeball. The front side of the eye or the condition of the front part of the eye is a disease, ailment or condition which affects or involves the eye region or site such as eye muscle, eye lid or tissue of the eyeball or the liquid located in front of the rear wall of the membrane of the lens or ciliary muscles. Thus, the ocular condition of the front part of the eye primarily affects or involves the conjunctiva, cornea, anterior chamber, the iris, the posterior chamber (behind the iris but in front of the back wall membrane of the lens), the lens and the diaphragm of the lens, as well as blood vessels, lymphatic vessels and nerves, which vascularizing support or innerviews anterior ocular region or site.

The condition of the front part of the eye can include a disease, ailment or condition such as, for example, aphakia, pseudophakia, astigmatism, blepharospasm, cataracts, Zab is diseases of the conjunctiva, conjunctivitis, diseases of the cornea, corneal ulcer, dry eye syndromes, diseases of the eye age, diseases of the lacrimal apparatus, the obstruction of the lacrimal ducts, myopia, presbyopia, pupillary disorder, refractive disorders and strabismus. Glaucoma can be considered as the condition of the front part of the eye, because clinical for the treatment of glaucoma may be the reduction of high pressure aqueous fluid in the anterior chamber of the eye (i.e. the reduction of intraocular pressure).

The condition of the back of the eye is a disease, ailment or condition which primarily affects or involves a posterior ocular region or site such as choroid or sclera (in a rear position with respect to the plane passing through the rear wall of the membrane of the lens), vitreous, vitreous chamber, retina, optic nerve (i.e. the optic disc), and blood vessels and nerves that vascularizing and nerveroot posterior ocular region or site.

Thus, the condition of the back of the eye can include a disease, ailment or condition such as, for example, macular degeneration (such as nonexudative age-related macular degeneration or exudative age-related macular degeneration (AMD), the choroidal neovascularization,acute macular neuromyopathy, macular edema (such as cystic macular edema and diabetic macular edema), Behcet's disease, retinal disorders, diabetic retinopathy (including proliferative diabetic retinopathy), occlusion of the retinal artery, occlusion of the Central retinal vein, Weitnau disease of the retina, retinal detachment, eye injury, affecting posteriorly part of the eye or the area posteriore ocular condition caused by or influenced by the treatment laser eye posteriorly ocular condition caused by or influenced by therapy, photocoagulation, radiation retinopathy, epiretinal membrane disorders, occlusion of the branches of the veins of the retina, anterior ischemic optic neuropathy, keratinocytes diabetic retinal dysfunction, pigmentary degeneration of the retina and glaucoma. Glaucoma can be considered as the state of the back of the eye, because therapeutic goal of glaucoma treatment is to prevent losses or reduce the occurrence of loss of vision due to damage or loss of retinal cells or cells of the optic nerve (i.e. neuroprotection).

As indicated, macular degeneration, such as AMD, is the leading cause of blindness in the world and estimated thirteen million Americans have symptoms what s macular degeneration. Macular degeneration leads to the destruction of the yellow spot, the light-sensitive part of the retina responsible for clear, direct vision necessary for reading or driving. Especially affects the Central vision. Macular degeneration is diagnosed or dry (atrophic) or wet (exudative). The dry form of macular degeneration is most common than the wet form of macular degeneration, approximately 90% of patients with AMD are diagnosed with dry AMD. The wet form of the disease usually leads to more serious vision loss. The cause of macular degeneration is not clear. The dry form of AMD may be the result of aging and thinning of the tissues yellow spots, deposition of pigment in the macula, or a combination of two processes. In wet AMD, new blood vessels grow from the bottom side of the retina and passed blood and fluid. This leakage leads to cell death in the retina and creates blind spots in Central vision.

Macular edema ("MO") can lead to tumor yellow spots. Swelling is caused by fluid flowing from the blood vessels of the retina. Blood seeps through weak blood vessels in a very small region of the yellow spot, rich in cones, nerve endings that detect color and depends on the vision in the daytime. Then proiskhozhdenie visual acuity in the middle or slightly to the side from the Central field of vision. Loss of vision may progress after months. Obstruction of the blood vessels of the retina, eye inflammation and age-related macular degeneration all associated with macular edema. Yellow spot can also be affected by swelling due to cataract removal. Symptoms of MO include decreased acuity of Central vision, distorted vision, sight, painted pink, and light sensitivity. The reasons for the MIS can include occlusion of the veins of the retina, macular degeneration, diabetic macular after, eye inflammation, idiopathic Central serous homeopatia, anterior and posterior uveitis, intermediate uveitis, pigmentary degeneration of the retina, radiation retinopathy, posteriore detachment of the vitreous body, the formation of epiretinal membranes, idiopathic juxtafoveal telangiectasia retina, capsulotomy or iridotomy using a neodymium laser alumina-yttrium garnet. Some patients with MO may have a history of use for glaucoma local analogues of epinephrine or prostaglandin. The primary treatment for MO are local anti-inflammatory drops applied topically. The increased capillary permeability in the retina and subsequent retinal edema macular edema can occur as a result of the destruction of the blood retinal barrier, partially op is radovanovi factor vascular endothelial growth (VEGF), 45 kDa glycoprotein. It is known that VEGF can increase vascular permeability, possibly by increasing phosphorylation of proteins dense contacts such as occludin and zonula occluden. Similarly, when neglasnyj painful conditions such as ascites, VEGF has been described as a strong factor vascular permeability (FPS).

Biochemically it is known that VEGF is the main factor of increasing the number of capillaries in the tissue undergoing angiogenesis. Bovine endothelial cells of the capillaries will proliferate and show signs of tubular structures in vitro when stimulated by VEGF. Increased expression of VEGF is a major component of the physiological response to stress and its role in angiogenesis, presumably, is the best treatment for vascular lesions.

The VEGF induces intracellular signaling cascade in endothelial cells. Of VEGF joining the VEGF receptor-2, initiates tyrosinekinase signaling cascade that stimulates the production of factors that stimulate different vascular permeability (epithelial synthase nitric oxide; endothelial MO-synthase), proliferation/survival (FGF; basic fibroblast growth factor), migration (molecules intracellular adhesion (ICAMs); adhesion molecules vascular cells (VCAMs); metalloprotease matrix (MMM)and the horse is strong differentiation into Mature blood vessels. As part of the angiogenic signaling cascade, NO widely regarded as the main factor angiogenic response, since NO inhibition significantly reduces the effects of angiogenic growth factors.

The normal human retina contains little or does not contain the VEGF; however, hypoxia causes increased expression of the production of VEGF. Painful condition characterized by an increased expression of VEGF induced by hypoxia include, without limitation, occlusion of the Central retinal vein and occlusion branch retinal vein. This hypoxia-induced increased expression of VEGF may be ingibirovany pharmacologically. PE'er J. et al. Vascular Endothelial Growth Factor Upregulation in Human Central Retinal Vein Occlusion, OPHTHALMOLOGY, 1998; 105:412-416. It was demonstrated that anti-VEGF antibodies can inhibit the VEGF-driven proliferation of endothelial cells of capillaries. Thus, the weakening effects of VEGF contributes to the justification for the treatment of macular edema in the occlusive diseases of the veins.

In addition, increased expression of VEGF causes increased permeability of blood vessels in addition to stimulating angiogenesis. When wet or exudative form of AMD, VEGF induces proliferation of capillaries in the retina. After that increase angiogenesis also causes swelling, blood, and other gidrostaticheski seep into the retina, leading to loss of vision. The invention includes a new method of treating macular degeneration without neovascularization through the use of anti-neovascular agent such as VEGF-inhibiting aptamer or more of VEGF-inhibiting compound is to stop the main signaling cascade angiogenesis, thereby preventing these symptoms.

Diabetic retinopathy is a major cause of blindness among adults ages 20 to 74 years. Macular ischemia is the main cause of irreversible acute visual loss and reduced contrast sensitivity in patients with diabetic retinopathy. Capillary reperfuse and reduced capillary blood flow is responsible for the ischemia is seen clinically in fluoresceine the angiogram as an increase in foveal avascular zone (PHASE) or the roughness of the boundaries of the PHASES. These discoveries are precursors to other, perhaps more well known, the complications of diabetic retinopathy, threatening loss of vision, including macular edema and proliferative retinopathy. Perhaps more important, extensive capillary reperfuse is also a precursor adverse visual prognosis due to diabetic retinopathy.

There are available or under development methods of treatment macular the CSOs edema and proliferative retinopathy such as laser photocoagulation, intravitreal corticosteroids and anti-VEGF therapy. Although laser photocoagulation examined in relation to loss of vision, directly associated with macular ischemia, currently no known treatment for this symptom.

The external surface of the eyeball mammals has a layer of tissue known as the conjunctival epithelium, under which is a layer of tissue called tenon's fascia (also called the conjunctival stroma). Plot Ternovoi fascia, extending back across the eyeball, forms a fascial sheath, known as tennova capsule. Under tenon's fascia is episclera. In aggregate, the conjunctival epithelium and teanaway the fascia called the conjunctiva. As noted, under tenon's fascia is episclera, below which lies the sclera, followed chorioid. Most lymphatic vessels and associated with them the drainage system, which is very effective at moving therapeutic agents, located nearby, is present in the conjunctiva of the eye.

therapeutic agent can be injected into the eye to treat eye conditions. For example, target-tissue for antihypertensive therapeutic agents for the treatment of elevated intraocular what Alenia, typical for glaucoma, can be ciliary body and/or the trabecular network. Unfortunately, the introduction of local ocular antihypertensive drug in the form of eye drops can lead to rapid washout the most part, if not all of therapeutic agent before it reaches the target tissue, the ciliary body and/or trabecular network, therefore, for effective treatment of hypertensive status is often necessary to re-enter the dose. In addition, side effects in patients with local introduction antiglaucomatous drugs and preservatives vary from discomfort in the eyes to the changes of the ocular surface, threatening loss of vision, including conjunctive hyperemia (redness), pain, pain, decreased production and action of tears, the reduced stability of the tear film, spot, superficial keratitis, jesuisiamyosoy metaplasia and changes in cell morphology. These adverse effects local antiglaucoma eye drops may interfere with the glaucoma treatment in the result of the unwillingness of the patient to comply with the prescribed mode of application doses and prolonged treatment with the help of eye drops associated with increased failure of filtration surgery. P.A. Asbell et al. Effects of topical antiglaucoma medications on the ocular surface, Ocul Surf 2005 Jan; 3(1):27-40; M. Mueller et al. Tear film break up time and Schirmer est after different antiglaucomatous medications, Invest Opthtalmol Vis Sci 2000 Mar 15; 41(4):S283.

You know the introduction of the drug depot in the rear (i.e., near yellow spots) subtenancies space. See, for example, section 4, publ. U.S. patent 6413245. In addition, it is known introduction of polylactic acid implant in subtenancies space or suprachoroidal region (see, for example, U.S. patent 5264188 and publ. patent application U.S. 20050244463).

Onlineoakley agent can be applied to treat eye condition such as the condition of the back of the eye, including angiogenesis such as choroidal neovascularization (CNV). Shipping in the eye a therapeutic amount antineoplastons agent (drug) can be difficult, but not impossible, for drugs with a short half-life in plasma, since the effects of drugs on intraocular tissues is limited. Thus, a more effective way of delivering drugs to treat conditions back of the eye such as CNV, is the introduction of medication directly into the eye, as for example, directly into the vitreous body. Maurice D.M. (1983) Micropharmaceutics of the eye, Ocular Inflammation Ther. 1:97-102; V.H.L. Lee et al. (1989), Drug delivery to the posterior segment" Chapter 25 In the Retina. I.E. Ogden and A.P. Schachat eds., St. Louis: CV Mosby, Vol.1, pp.483-98; and T.W. Olsen et al. (1995), Human scleral permeability: effects of age, cryotherapy, transscleral diode laser, and surgical thinning, Invest. Ophhalmol. Vis. Sci. 36:1893-1903.

Methods such as intravitreal injection drug showed promising results, but because of the short half-life of the active agent within the eye, including onlinebaccarat agents, intravitreal injections must be repeated frequently to maintain a therapeutic level of the drug. In turn, such an iterative process increases the likelihood of side effects such as infection, retinal detachment, endophthalmitis and cataract.

Intraocular delivery system of the medicinal product may be made from a biodegradable polymer such as poly(lactide)nye (PLP) polymers, poly(lactide-co-glycolide)nye (PLGP) polymers and copolymers PLP and PLGP polymers. PLP and PLGP polymers degrade by hydrolysis and degradation products, lactic acid and glycolic acid, are metabolized to carbon dioxide and water.

The delivery system of the drug can be prepared using a variety of active agents. For example, it is known preparation of implants of polymer 2-methoxyestradiol acid (as sticks and capsules)intended for intraocular use, by way of extrusion of the melt (see, for example, publ. patent application US 2005/0244471). In addition, it is known preparation is implantol of polymer brominecontaining acid microspheres, designed for intraocular use (see, for example, publ. patent application US 2005/0244463 and 2005/0244506 and patent application US 11/395019). Moreover, it is known cooking bimatoprost-containing implants polymer polylactic acid microspheres designed for intraocular use (see, for example, published patent application 2005/464 and 2006/0182781 and patent application US 11/303462 and 11/371118).

In EP 488401 discussed intraocular implants made of certain polylactic acid, in order to apply inside the eye after surgery due to abnormalities of the retina/vitreous body or glaucoma. EP 430539 discusses the use biorazlagaemykh implant, which implement suprachoroidal.

Claim US 11/565917, filed December 1, 2006, discloses an intraocular (including podchinenova) the introduction of various solid implants containing a drug.

Known intraocular delivery system of medicines which are sewn or fixed in place. Stitching or other means of fixation require sensitive eye tissue in contact with the components of the delivery system for drugs that are not required for the maintenance of therapeutic agent in or on the delivery system of the medicinal product, or to allow therapeutic agent is svobodas in vivo. Essentially, stitching or eye fixation means only minor or an additional factor, and their use can increase the recovery time, patient discomfort and the risk of infection or other complications.

In patent applications US 11/742350; 11/859310; 11/952938; 11/364687 discusses the use of intraocular compositions containing anti-VEGF therapeutic agent such as bevacizumab. Known drugs of macromolecules for intraocular application, see, for example, application serial number 11/370301; 11/364687; 60/721600; 11/116698 and 60/567423.

It is important, though dry AMD is the most common form of AMD, not counting the use of antioxidants (such as high doses of vitamin C, E, beta-carotene and/or zinc to neutralize reactive oxygen species in the retina) "there is no modern therapy for the most common "dry" AMD". K. Gehrs et al., Age-related macular degeneration - emerging pathogenetic and therapeutic concepts, Ann Med 2006; 38:450-471. Thus, there is no way treatment for most predominant atrophic (dry) form of AMD". Petrukhin K. New therapeutic targets in atrophic age-related macular degeneration, Expert Opin. Ther. Targets 92007) 11(5): 625-639.

Thus, it would be preferable to have a system for delivery of drugs with a slow release, suitable for intraocular use to treat dry AMD. Thus, the required performance, which provides a composition and method for the treatment of dry AMD.

Brief description of the invention

The present invention satisfies this need by providing compositions and methods for treatment of dry AMD. In particular, the present invention provides an effective intraocular therapy for the treatment of dry AMD through the use of the delivery system for drugs with a slow release, suitable for intraocular (i.e. intravitreal) applications.

Definition

The following terms have the following meanings:

"Onlineoakley agent" means a compound which has antiangiogenic effect when injected into the eye, as for example, by intravitreal injection or implantation.

"Anti-VEGF agent" means a compound inhibiting the activity or effect of VEGF, bevacizumab, ranibizumab, pegaptanib, VEGF-neutralizing aptamers, anti-VEGF monoclonal antibodies, siRNA, corticosteroids such as anecortave acetate, acetonide triamcinolone and acetonide fluoqinolona; inhibitors of the receptor tyrosine kinase such as vatalanib and ruboxistaurin, lactate squalamine and; growth factors, including growth factor secreted from the pigment epithelium.

"About" means approximately or about in the context of a numerical value or range stated in this document describes a value of ±10%expelled value or range, described or claimed.

"Active agent", "drug" and "therapeutic agent" is herein used interchangeably and refer to any substance (including biological or macromolecule), used to treat the eye condition.

"Biologically compatible" with respect to the delivery system of the medicinal product means that when intraocular introduction of the delivery system of the drug in the eye of the mammal does not occur significant immunogenic reaction.

"Birthdaaay polymer" means a polymer that degrades in vivo. The polymer may be a gel or hydrogel type polymer, PLP or PLGP polymer or mixtures thereof, or derivatives. The words "birthdaaay" and "biodegradable" are synonymous in this document are used interchangeably.

"The delivery system of the medicinal product" means a liquid, gel, hydrogel, high viscosity product, solid implant or microspheres, of which a therapeutic amount of therapeutic agent can be released with the introduction of in vivo delivery system of the medicinal product by sewing into the fabric of the eye or otherwise secured in place by means of the attachment.

"Dry AMD" (also applies to atrophic age-related macular degeneration) means with the being of the human retina, when in the macula are Druze, but with no or little neovascularization of the retina. Dry AMD include AMD category 1 (there is little or only a small Druze), AMD category 2 (early AMD, in which the Druze are a small or medium size) and AMD category 3 (intermediate AMD, in which there are numerous medium-sized or large drusen). On the contrary, "wet AMD" refers to the condition of the retina of a person, characterized by the presence of retinal neovascularization (category 4 or progressive AMD or vision loss. Small Druze have a diameter of less than 63 microns, Druze medium size have a diameter of between 63 and 124 microns and large Druze have a diameter of 125 microns or more.

"Inner" means inside or under the cloth eyes. Intraocular introduction of the delivery system for drugs includes the introduction of the delivery system for drugs in subtenancy, subconjunctival, suprachoroidal, intravitreal, and related areas. Intraocular introduction of the delivery system for drugs preclude the introduction of systems for delivery of drugs topically, systemically, intramuscularly, subcutaneously, administered intraperitoneally and the like.

"Ocular condition" means a disease, ailment or condition which Paraga is t or involves the eye or one of the parts or areas of the eye such as a disease of the retina. The eye includes the eyeball and the tissues and fluids that make up the eyeball, eye muscles such as oblique and rectus muscles) and part of the optic nerve, which is located within or adjacent to the eyeball.

"The state of the back of the eye" means a disease, ailment or condition which affects or involves a posterior part of the eye or of this section, as choroid or sclera (in a position projection to the plane passing through posteriorly wall membrane of the lens), vitreous, vitreous chamber, retina, optic nerve (i.e. the optic disc), and blood vessels and nerves that vascularizing or innerviews rear portion or segment of the eye.

"Essentially" means between 51% and 100% numeric values or amounts so indicated.

"Suitable for implementation (or implantation) in (or inside) of the eye or area" in relation to the delivery system of the medicinal product means a delivery system of the medicinal product, which has the size (magnitude) so that it can be inserted, injected, implanted or implanted without causing increased tissue damage and without excessive physical obstruction of an existing patient's vision, which are implanted or deploying the implant.

"Slow", "slow period" or "time release" means the period of time over three days, preferably at least 20 days (i.e. the period of time from 20 to 365 days), and most preferably at least 30 days. Slow release can last from about two months to about four months.

"Therapeutic levels" or "therapeutic amount" means the amount or concentration of active agent that is delivered topically to parts of the eye, designed for the safe treatment of eye conditions, to reduce or prevent a symptom of the ocular condition.

"Treatment" means the administration of treatment to the patient. Treatment involves a course of treatment aimed at reducing the existing clinical symptom (such as the number and size present druses) of this diagnosed eye conditions (such as dry AMD), as well as preventing deterioration (or slow deterioration) of this diagnosed eye condition to the other eye conditions (such as wet AMD), which has additional or new clinical symptoms (such as loss of vision and/or neovascularization).

The embodiment of the present invention is a method for the treatment of Zabol is of the retina such as macular degeneration, such as dry age-related macular degeneration (dry AMD). The method may include the step of introducing antineoplastons agent in the patient's eye with dry AMD, thus curing dry AMD. Onlineoakley agent can be antivascular agent endothelial growth factor (VEGF) and an example of an anti-VEGF agent may be bevacizumab, ranibizumab and pegaptanib and derivatives, esters, salts and mixtures of these anti-VEGF agents.

Preferably, onlineoakley agent is administered according to a method within the present invention as or as part of a biocompatible delivery system of the drug. Thus, biocompatible delivery system of the medicinal product may contain onlineoakley agent and a polymeric carrier associated with antineoplastons agent. The polymeric carrier may be selected from the group consisting of a polymer of lactic acid (PLA)polymer of glycolic acid (PGA), a copolymer of lactic and glycolic acids (PMGC), polymer hydroxypropylmethylcellulose and a polymeric hyaluronic acid and mixtures thereof.

Onlineoakley agent can be associated with a polymer carrier via a homogeneous dispersion throughout the polymer carrier, and the phase of wedenesday can be performed by injecting antineoplastons agent in the anterior ocular region or the rear inner region such as the vitreous cavity.

Another embodiment of the invention is a method for the treatment of dry AMD by creating a biocompatible delivery system medicines containing onlineoakley agent (i.e. bevacizumab or its derivative, ester or salt) and a polymeric carrier associated with antineoplastons agent, and injecting the delivery system of the drug in the vitreous cavity of the eye of a patient with dry AMD, thus, feleciana dry AMD.

Preferably the delivery system of the drug in the scope of the invention may include or contain from about 5 μg to about 3 mg antineoplastons agent, involving bevacizumab Installed with some differences, the delivery system of the drug in the scope of the invention can release in vivo on average from about 10 ng to about 40 μg antineoplastons agent (such as bevacizumab) for a period of 24 hours after intraocular injection of the implant delivery system of the drug. Preferably, the delivery system drug releases from an average of approximately 14 μg to about 28 μg antineoplastons agent (i.e. bevacizumab) within a period of 24 hours after intraocular injection of implant system the volumes of shipping drugs. More preferably, the delivery system drug could release an average of from about 7 μg to about 14 μg antineoplastons agent (i.e. bevacizumab) within a period of 24 hours after intraocular injection of the implant delivery system of the drug. In one embodiment the delivery system drug can release from about 10 ng to about 200 μg antineoplastons agent (such as bevacizumab) for a period of 24 hours after intraocular injection of the implant delivery system of the drug.

The detailed way in the scope of the invention is a method for the treatment of dry AMD in a patient with dry AMD in one eye and wet AMD in the other eye, the method including the step of injection of biocompatible delivery system medicines containing onlineoakley agent and a polymeric carrier associated with antineoplastons agent into the vitreous cavity of the eye of a patient with dry AMD, thus curing dry AMD by preventing or slowing the development of dry AMD to wet AMD in the treated eye.

For more detailed way in the scope of the invention is a method of low doses for the treatment of dry AMD, the method containing the steps: (a) sentence is the service biocompatible delivery system drug delayed release, containing from about 5 μg to about 20 μg of bevacizumab and media from polymeric hyaluronic acid associated with bevacizumab, (b) injecting the delivery system of the drug in the vitreous cavity of the eye of a patient with dry AMD, and (C) release from the delivery system of medicines from an average of approximately 14 ng to about 120 ng of bevacizumab within a period of 24 hours over a period of time of approximately 1 month or more or, for about 2 months, or within about 3 months or more (preferably, the delivery system drug can release the active agent for from about 3 to about 6 months), thus curing dry AMD using low doses of bevacizumab released from the delivery system for drugs. The remaining, penjelasannya the patient's eye may have wet AMD and dry AMD, cure by preventing or delaying the occurrence of neovascularization of the retina in injectable eye with dry AMD.

The delivery system drug may have a viscosity from about 130000 JV to approximately 300,000 CPS (at shear rate 0.1/s at about 25°C, and the delivery system of medicines which can be injected using a 25-30-dimensional syringe.

The present invention also includes a method with low doses for the treatment of dry AMD, the method includes the steps: (a) preparing a biocompatible delivery system drug delayed release containing from about 5 μg to about 20 μg of bevacizumab and media from a polymeric hyaluronic acid associated with bevacizumab, (b) injection system for the delivery of drugs using 25-30-dimensional syringe into the vitreous cavity of the eye of a patient with dry AMD, where another penjelasannya the patient's eye has wet AMD, and; (C) release from the delivery system of medicines from an average of approximately 14 ng to about 120 ng of bevacizumab within a period of 24 hours over a period of time from about 3 months to about 6 months, thus curing dry AMD using low doses of bevacizumab released from the delivery system for drugs, by preventing or delaying the occurrence of neovascularization of the retina in the injected eye with dry AMD, where the delivery system of the medicinal product has a viscosity between approximately 130000 JV and approximately 300,000 CPS (at shear rate 0.1/s at about 25°C.

Another way in the scope of the invention before the hat is way to prevent the development of choroidal neovascularization, the method includes the steps: (a) preparing a biocompatible delivery system medicines containing onlinebaccarat drug and a polymeric hyaluronic acid associated with antineoplastons drug, and; (b) injecting the delivery system for drugs in the inner region (such as Sultanova, subconjunctival, suprachoroidal, intrasternally, intravitreal or retro-bulbar inner region), thus preventing the development of choroidal neovascularization. Polymeric hyaluronic acid can be cross stitched hyaluronic acid or cross unstitched hyaluronic acid or mixtures thereof and preferably, the polymeric hyaluronic acid has a molecular weight of about 1 million daltons to about 2 million daltons.

Summarizing, the invention includes compositions and method of treating ocular condition by preparing biocompatible delivery system medicines containing the drug and the polymeric carrier for drugs, and injecting or implantation of the delivery system for drugs in the inner region. The polymeric carrier may be, for example, collagen is, a polysaccharide (such as hydroxymethylcellulose, alginate, chitosan, agar and pectin), hyaluronic acid or biodegradiruemym polymer such as PGP or PLP polymer. The inner region can be front or rear inner area, and the eye condition may be a condition of the front or back of the eye. The inner region can be subcanonical, subconjunctival, suprachoroidal, intrasternally, intravitreal or retro-bulbar intraocular areas.

A brief description of graphic materials

Figure 1 presents a graph showing the percent viability (Y-axis) in vitro ARPE-19 cells of the pigment epithelium (y-axis 100% viability represents the viability of ARPE-19 cells at time zero) after incubation periods of 24, 48 and 72 hours in vitro at concentrations of Polysorbate 80, shown on the x-axis.

Detailed description of the invention

This invention is based on the discovery that onlineoakley agent can be applied to treat a condition such as dry AMD, even in the absence of neovascularization in the eye with dry AMD patient to be treated. Before the present invention it was not known that onlineoakley agent can be applied to treat a condition such as dry AMD, which in the eye of the patient, mean the containing treatment, no neovascularization (see, for example, Lin J. et al., Vascular Endothelial Growth Factor Gene Polymorphisms in Age-related Macular Degeneration, Am J Ophthalmol. 2008 Mar 29 (of VEGF gene are not associated with DNA of a patient with dry AMD) and Cook, H. et al., Age-related macular degeneration: diagnosis and management, Br Med Bull. 2008; 85: 127-49) ("...there is no treatment for the running dry AMD..."). This invention treats dry AMD by preventing or by slowing down the development of dry AMD to wet AMD.

Not wishing to be bound by theory, assume that in this document the mechanism of the effectiveness of the present invention and embodiments. Thus, it can be estimated that a patient with wet AMD in one eye has a 10% chance (every year) the development of neovascularization (wet AMD in the other eye. This percentage is cumulative so that in 5 years the patient with wet AMD in one eye has a 50% chance of developing wet AMD in the other eye, possibly due to the presence of mutations in the gene for complement factor H. the inventors believe that genetically mediated processes that lead to the development of wet AMD will eventually prevail in the other eye so that such patients are at very high risk for the development of wet (neovascular) AMD in both eyes and therefore preventive measures are specified reduction of the chance of a patient develops a serious the Oh loss of vision in both eyes.

Thus, we postulate that antineoplaston therapy may be an effective treatment for dry AMD, thus preventing its development in wet AMD, even if the eyes with dry AMD, which lichty has little vascularization or her absence. To reduce the chance of development of dry to wet AMD relevant targets include the path of growth factor vascular endothelial (VEGF). The VEGF is an important signaling protein involved in vasculogenesis and angiogenesis. In patients with dry AMD, increased expression of VEGF has been associated with the development of CNV. Of VEGF is considered as an important target in connection with the VEGF-inhibitors such as Macugen™ (pegaptanib), pegylated aptamer that specifically blocking FRESH and, more importantly, Avastin™ (bevacizumab), a monoclonal antibody, which is more promiscuous and blocks all known isoforms of VEGF, FRESH and FRESH, FRESH and FRESH. Of VEGF-inhibitors are widely used for CNV associated with AMD, proliferative diabetic retinopathy (PDR), neovascular glaucoma, diabetic macular edema (DME) and macular edema in the background occlusion retinal vein (SVG). The results with anti-VEGF blockade are the most impressive for CNV associated with AMD.

Although now without the approval of Management to whom ntrol over products and medicines of the USA, injection from 1.25 to 2.5 mg of water (i.e. with quick release) bevacizumab (i.e. not as the delivery system for drugs with a slow or extended release) in the vitreous cavity perform without significant ocular toxicity observed in studies with both humans and animals. The half-life in the vitreous body of the anti-VEGF monoclonal antibodies such as bevacizumab, after injection into the vitreous body of the drug quick release (i.e. water) is only 5-6 days. Onlinebaccarat drugs fast release, thus, may not provide any permanent or prolonged therapeutic effect (due to the rapid, one-time release) and require frequent painful reinjected for the treatment of eye conditions.

Thus, although the dose intravitreal water preparation bevacizumab to 1.25-2.5 mg administered for the treatment of macular neovascularization (wet AMD), the inventors believe that, perhaps, dose bevacizumab less than 1% of known intravitreal doses (i.e. less than 12 µg) can suppress neovascularization. The inventors suggest that the dose of bevacizumab less of 6.2 µg (i.e. less than 0.5% of the known dose 1.25 mg) can be used for treatment or prevention of intraocular NeoV is scolarizarii people (for the treatment of dry AMD). Thus, 1,25-2,5 mg antineoplastons agent such as bevacizumab, can be released into the vitreous body during a period of 3-6 months from the delivery system for drugs with a slow release to ensure the long-term treatment of chronic eye condition such as dry AMD.

The hydrogel is a colloidal gel formed in the form of a dispersion in water or other aqueous medium. Thus, the hydrogel is formed in the preparation of the colloid in which the disperse phase (polymer) combined with dispersing phase (i.e. water) to form a viscous gel-like product; for example, coagulated silica. A hydrogel is a three-dimensional network of hydrophilic polymer chains that are cross stitched or through chemical or physical connection. Effect of hydrophilic nature of the polymer chains hydrogels absorb water and swell (except when they already have adsorbing the maximum amount of water). The process of swelling identical dissolution of cross unstitched hydrophilic polymers. By definition, water is at least 10% of the total mass (or volume) of the hydrogel.

Examples of hydrogels include synthetic polymers such as polyhydroxyethylmethacrylate and chemically or physically cross is embroidered polyvinyl alcohol, polyacrylamide, poly(M-vinylpyrrolidone), polyethylene oxide and hydrolyzed polyacrylonitrile. Examples of hydrogels that are organic polymers include covalent or ionic transverse cross-linked hydrogels based on polysaccharides such as salts of alginate with polyvalent metals, pectin, carboxymethyl cellulose, heparin, hyaluronate and hydrogels of chitin, chitosan, pullulan, Helena and xanthan gum. Specific hydrogels used in this experiment were the connection of cellulose (i.e. hypromellose (HPMC)) and hyaluronic acid (ha) with high molecular weight.

As an embodiment of the present invention was prepared, the preparation of hydrogel for intravitreal injections with application of polymeric hyaluronic acid and anti-VEGF monoclonal antibody. This system of delivering medicines can provide daily slow-release low-dose anti-VEGF monoclonal antibodies during the period from 3 to 6 months and prevent the conversion of dry AMD to wet. The delivery system of the medicinal product may also contain microsphere encapsulation of anti-VEGF antibody in the hydrogel. The delivery system drug delayed release can provide the necessary anti-VEGF blockade in the eye for slimming the chances of developing dry AMD in neovascular. In addition, the low doses that are released into the eye for a long period of time, do not provide the overall level of toxicity antineoplastons agent.

Also the delivery system drug delayed release according to the invention can be used to provide slow release of the antagonist anti-VEGF in patients with occlusion of the Central retinal vein, which are a risk group for neovascularization, and in patients with severe nonproliferative diabetic retinopathy, which are a risk group for the development of neovascular disease.

Otherwise, the delivery system of the medicinal product can be PLGP implant, antibodies, encapsulated in liposomes, optionally surrounded by a transversely crosslinked hyaluronic acid. In addition, microspheres, microcapsules (ranging in size from 0.001 to 100 microns) and liposomes with modified surfaces to create interaction hydrogel polymer in order to modify the release.

Other anti-VEGF compounds may be used instead of the anti-VEGF monoclonal antibody (such as bevacizumab), and they include anti-VEGF aptamers (e.g., pegaptanib), soluble recombinant receptor-traps (e.g., VEGF trap), fragments of antibodies (e.g., ranibizumab), corticosteroid is, small interfering RNA that reduces the expression of VEGF-receptor (FRASER) and the VEGF-a ligand, post-FRASER blockade by inhibitors tyrosinekinase, inhibitors metalloprotease, IFSB-3 inhibitors PRK-1, FDPA, gamma secretase, Delta-like ligand 4, antagonists of integrins, alpha blockade HYPHAE-1, blockade of protein kinase W2 and inhibition of stem cells (i.e. endothelial cell precursor), returning to the site of neovascularization using Katherina vascular endothelium (CD 144) and antibodies to stromal growth factor (SRF)-1. Agents with activity against knw that are not necessary anti-VEGF compounds can also be used and include anti-inflammatory drug, rapamycin, cyclosporine, anti-TNF agents and anti-complement agents.

The present invention also includes specific drug delivery systems drugs and the ways of introducing these systems deliver drugs for the treatment of eye condition such as dry AMD. The present invention includes a delivery system of medicines which are structured and configured only for intraocular, unlike local or systemic injection. Intraocular introduction can be produced by implantation or injection into STEKLONiT the second cavity (rear camera) eye. The delivery system of the drug in the scope of the present invention can be biorazlagaemykh implants and/or microspheres. The delivery system of the drug can be monolithic, in which the active agent can be homogeneous distributed or dispersed throughout boorstosima the polymer. therapeutic agent can be released from a delivery system for drugs, manufactured in accordance with the present invention for a period of time from 2 hours to 12 months or more. An important feature of the present delivery systems drugs is that they do not include any device (such as a capsule, protrusion and suture contact) for fixing the delivery system of the drug in the inner region, in which it is injected.

An important characteristic of the delivery system for drugs in the scope of the present invention is that it can be implanted or injected in the inner region (such as the front Sultanova, subconjunctival, intravitreal and suprachoroidal region) to provide slow release of therapeutic agent without the occurrence or persistence of significant immunogenicity in and near the site of intraocular implantation or injection.

Polylactide polymers (PLP)exist in two chemical forms, poly(L-pacted) and poly(D,L-lactide). Pure poly(L-lactide) is regioregular and, thus, is highly crystalline, thus, degrades in vivo with very low speed. Poly(D,L-lactide) is regierungsebenen, which leads to more rapid degradation in vivo. Thus, the polymer PLP, which is a mixture of mainly polymer poly(L-lactide), the remainder is the polymer poly(D-lactide), will degrade in vivo at a speed lower than that of polymer PLP, which is mainly a polymer poly(D-lactide). PLGP is a copolymer combining poly(D,L-lactide) with poly(glycolide) in various possible ratios. The higher the content of glycolide in PLGP, the faster the degradation of the polymer.

In one embodiment of the invention, the delivery system drugs for intraocular injection (i.e. intravitreal implantation or injection) contains a preconfigured, comprising or essentially consisting of at least 75 wt.% PLP and not more than about 25 wt.% polymer poly(D,L-lactide-co-glycolide).

In the scope of the invention are suspensions and microspheres (including onlineoakley agent)that can be inserted into the inner region through the needle of the syringe. The introduction of such suspension requires that the viscosity of suspen the AI microspheres at 25°C was less than approximately 300,000 SP. The viscosity of water at 25°C is approximately 1 SP (SP is a CP, the value of viscosity measurements). At 25°C. the viscosity of olive oil is 84 SP, castor oil 986 P and glycerol 1490 SP.

The delivery system of the medicinal product according to the present invention may include a therapeutic agent that is mixed with or dispersed in biodegradation the polymer. Composition delivery system for drugs can vary according to a preferred curve release of drugs, specific applied active agent, ophthalmic condition to be treated and the medical history of the patient. Therapeutic agents that can be used in drug-delivery systems according to the invention, include, but are not limited to (as themselves in the delivery system of the drug in the scope of the present invention, and in combination with another therapeutic agent): ACE inhibitors, endogenous cytokines, agents that affect the basement membrane, agents that influence the growth of endothelial cells, adrenergicheskie agonists or blockers, cholinergic agonists or blockers, inhibitors aldareguia, analgesics, anesthetics, anti-allergic agents anti-inflammatory agents, anti-hypertensive medium spans the VA, substances that increase blood pressure, antibacterial, antiviral, antifungal, antibacterial, anti-infective, anticancer agents, antimetabolite, antiangiogenic agents, inhibitors tyrosinekinase, antibiotics such as aminoglycosides such as gentamicin, kanamycin, neomycin and vancomycin; amphenicol such as chloramphenicol; cephalosporins such as Cefazolin model HC1; penicilina such as ampicillin, penicillin, carbenicillin, oxacillin, methicillin; lincosamides such as lincomycin; polypeptide antibiotics such as polymyxin and bacitracin; tetracyclines such as tetracycline; quinolones such as ciproflaxin etc.; sulfonamides such as chloramine T; and sulfones such as sulfanilic acid as an active ingredient, antiviral drugs such as acyclovir, ganciclovir, vidarabine, azidothymidine, azathioprin, dideoxyinosine, dideoxycytidine, dexamethasone, ciproflaxin, water soluble antibiotics such as acyclovir, ganciclovir, vidarabine, azidothymidine, dideoxyinosine, dideoxycytidine; epinephrine, isoflurophate; adriamycin; bleomycin; mitomycin; Ara-C; actinomycin D; scopolamine; and others, analgesics such as codeine, morphine, Ketorolac, naproxen etc., anesthetics, for example, lidocaine, beta-adrenergicheskie blockers or b is TA-adrenergicheskie agonists, for example, efedrin, epinephrine, etc.; inhibitor elderadostone, for example, epalrestat, ponalrestat, sorbinil, tolrestat; ANTIALLERGICS, e.g., kromolin, beclomethasone, dexamethasone and flunisolide; colchicine, antihelminthic agents, for example, ivermectin and suramin sodium; antiamebic agents, such as chloroquine and chlortetracycline; and antifungal agents, for example, amphotericin, etc., antiangiogenic compounds such as acetate anecortave, retinoids such as Tazarotene, protivoglaukomatoznyh agents such as brimonidine (Alphagan and Alphagan R), acetazolamide, bimatoprost (Lumigan), timolol, befunolol; memantine, latanoprost (Ksalatan); agonists alpha-2 adrenergicheskoj receptor; 2-methoxyestradiol; antineoplastic such as vinblastine, vincristine, interferon; alpha, beta and gamma, antimetabolites such as analogs of folic acid, purine analogues, and pyrimidine analogues; immunosuppressants such as azathioprine, cyclosporine and mizoribine; mystical agents such as carbachol, midriatichesky agents such as atropine, protease inhibitors such as atropine, chemostat, gabexate, vasodilatory such as bradykinin and various growth factors such as epidermal growth factor, basic fibroblast growth factor, nerve growth factors, inhibitors of carbamides and other

In private embodiments us Otsego of the invention the active agent may be a connection, blocking or reducing the expression of VEGF receptors (FRASER) or VEGF ligand, including, but not limited to, anti-VEGF aptamers (e.g., Pegaptanib), soluble recombinant receptor-traps (e.g., VEGF trap), fragments of anti-VEGF monoclonal antibodies and/or fragments of antibodies (e.g., Ranibizumab), small interfering RNA that reduces the expression of FRASER and the VEGF-a ligand, post-FRASER blockade by inhibitors tyrosinekinase, inhibitors metalloprotease, IFSB-3 inhibitors PRK-1, FDPA, gamma secretase, Delta-like the ligand 4, antagonists of integrins, alpha blockade HYPHAE-1, blockade of protein kinase W2 and inhibition of stem cells (i.e. endothelial cell precursor), returning to the site of neovascularization using Katherina vascular endothelium (CD 144) and antibodies to stromal growth factor (SRF)-1.

In another embodiment of the present invention the active agent is methotrexate. In another embodiment the active agent is retinoic acid. In another embodiment the active agent is an anti-inflammatory agent such as non-steroidal anti-inflammatory agent. Nonsteroidal anti-inflammatory agents that may be used include, but are not limited to, aspirin, diclofenac, flurbiprofen, ibuprofen, Ketorolac, naproxen, and soup is open. In a further embodiment, an anti-inflammatory agent is a steroidal anti-inflammatory agent such, kandaxallen.

Steroid anti-inflammatory agents that can be used in the delivery systems of the medicinal product according to the invention may include, but are not limited to, 21-acetoxyphenyl, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortisol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, flashcart, fluchloralin, flumetazon, flunisolide, acetonide fluoqinolona, fluocinonide, fluocortin, fluocortolone, fluorometer, acetate flaperon, acetate of fluprednidene, fluprednisolone, flurandrenolide, fluticasone propionate, farmacita, halcinonide, propionate halobetasol, halometasone, acetate of halopedia, hydrocortamate, hydrocortisone, notpregnant, mediprene, Madison, meprednisone, methylprednisolone, mometasone, paramethasone, prednicarbate, prednisolone, 25 diethylamino-acetate prednisolone, nutrifaster prednisolone, prednisone, prednesol, prednisone, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, benetone triamcinolone, hexacetonide triamcinolone and any of their derivatives is adnie.

In one embodiment of cortisone, dexamethasone, fluotsinolon, hydrocortisone, methylprednisolone, prednisolone, prednisone, and triamcinolone, and their derivatives are preferred steroidal anti-inflammatory agents. In another preferred embodiment steroid anti-inflammatory agent is a dexamethasone.

In another embodiment of a biodegradable implant includes a combination of two or more steroidal anti-inflammatory agents.

Active agent such as onlineoakley agent may contain from about 1 wt.% to about 90 wt.% implant or delivery system of the drug. In one embodiment, the agent comprises from about 5 wt.% to about 80 wt.% the implant. In a preferred embodiment, the agent contains from about 10 wt.% to about 60 wt.% the implant. In a more preferred embodiment of the present invention, the agent can contain about 50 wt.% the implant.

therapeutic agent present in the data delivery system of the medicinal product may be homogeneous dispersed in biodegradation the polymer delivery system of the drug. The choice of the applied biodegradable polymer may depend on the desired release kinetics and tolerance of the patient, the nature of the disease, ogliastro treatment, and Consider other characteristics of the polymer include, but are not limited to, biocompatibility and Biodegradability in the site of implantation, compatible with the interests of the active agent and the temperature treatment. A biodegradable polymer matrix typically contains at least about 10, at least about 20, at least about 30, at least about 40, at least about 50, at least about 60, at least about 70, at least about 80, or at least about 90 wt.% the implant. In one embodiment, the biodegradable polymer matrix contains from about 40 wt.% to about 50 wt.% the delivery system of the drug.

Biodegradable polymers that may be used include, but are not limited to, polymers made from monomers such as organic complex and simple ecrire which, by decomposition, give physiologically acceptable degradation products. Anhydrides, amides, orthoepy, etc. alone or in combination with other monomers may also be used. The polymers are typically condensation polymers. The polymers can be cross stitched or transversely unstitched.

Basically, in addition to carbon and hydrogen polymers include oxygen and azo is, especially oxygen. Oxygen can be present as hydroxy, such as hydroxy or ether, carbonyl, for example, non-oxo-carbonyl, such as ether carboxylic acids and other Nitrogen may be present as amide, cyano and amino. A sample list of biodegradable polymers that may be used is described in Heller, Biodegradable Polymers in Controlled Drug Delivery, In: "CRC Critical Reviews in Therapeutic Drug Carrier Systems", Vol.1. CRC Press, Boca Raton, FL (1987).

Of particular interest are polymers hydroxyapatites carboxylic acids, esters of Homo - and copolymers, and polysaccharides. Included in the polyol, of particular interest are Homo - and copolymers of D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid, caprolactone and combinations thereof. Copolymers of glycolic and lactic acid are of particular interest, where the rate of biodegradation is controlled by the ratio of glycolic and lactic acids. The percentage of each monomer in the copolymer poly(lactic-co-glycolic)acid (PLGP) can be 0-100%, about 15-85%, about 25-75% or approximately 35-65%. In certain embodiments, the copolymers used 25/75 PGP and/or 50/50 PLGP. In other embodiments, the copolymers PLGP used in combination with polylactide polymers.

Other agents can be used in the drug delivery system of lekarstvennogo for different purposes. For example, can be applied buffering agents and preservatives. Preservatives that may be used include, but are not limited to, sodium bisulfite, sodium bisulfate, sodium thiosulfate, benzalkonium chloride, chlorobutanol, thimerosal, fenilsalicilat, venertalented, methylparaben, polyvinyl alcohol and politology alcohol. Examples of buffering agents that may be used include, but are not limited to, sodium carbonate, sodium borate, sodium phosphate, sodium acetate, sodium bicarbonate, etc. approved by Management under the control over products and medicines of the USA, for the desired route of administration. Also the drug can be included surfactants that can be used to stabilize the particles in the colloid and/or electrolytes such as sodium chloride and potassium chloride. The delivery system of the medicinal product may also include acidic or basic excipients to control the pH in the microenvironment, as well as interfase (diffusion stagnant layer).

Biodegradable delivery system of the medicinal product may also include additional hydrophilic or hydrophobic compounds that accelerate or slow down the release of the active agent. In addition, modulators of release, such as these described in U.S. patent No. 5869079, can be included in the implants. The number of premenapause release will depend on the desired curve release activity of the modulator and the curve release glucocorticoid in the absence of the modulator. When the buffer agent or power release or modulator is hydrophilic, it can also act as an accelerator release. The effect of hydrophilic additives increases the speed of release by the rapid dissolution of the material surrounding the particles of the drug, which increases the surface area exposed medicines, thereby increasing the diffusion rate of the drug. Similarly, hydrophobic buffer agent or the amplifier, or modulator can be dissolved more slowly, slowing placing particles of a drug and thus slowing down the diffusion rate of the drug.

The delivery system of the medicinal product according to the present invention can be prepared using particles of an active agent dispersed within a biodegradable polymer. Without regard to theory, it is assumed that the release of the active agent can be performed by erosion of the biodegradable polymer matrix through diffusion corpuscular agent in ocular fluid, for example, vitreous body, with subsequent dissolution of the polymer matrix and release of the active Agay is the same. Factors affecting the kinetics of release of the active agent from the implant can include such characteristics as the size and shape of the implant, the size of the particles of active agent, the solubility of the active agent, the ratio of active agent to the polymer(s), method of production, the area of exposed surface, the density of the implant and the rate of erosion of the polymer(s).

The rate of release of active agent may depend at least partially on the rate of degradation of a component of the main chain of the polymer or components that comprise a biodegradable polymeric matrix. For example, condensation polymers can be degraded by hydrolysis (among other mechanisms), and thus any change in the composition, which increases the water absorption of the implant, is likely to increase the rate of hydrolysis, thereby increasing the rate of degradation of the polymer and erosion, and thus increasing the rate of release of active agent. The rate of release of the active agent may also affect the crystallinity of the active agent, the pH in the implant and pH interfase.

The kinetics of release delivery systems drug of the present invention may also partly depend on the surface area of the delivery systems of medicines. Large surface area of the exhibition is yet more polymer and active agent in ocular fluid, causing faster erosion of the polymer and dissolving the particles of active agent in the liquid.

Examples of eye conditions that can be cured by delivery systems drugs and methods according to the invention, include, but are not limited to, glaucoma, uveitis, macular edema, macular degeneration, retinal detachment, posteriorly ocular tumors, fungal and viral infections, multifocal chorioidea, diabetic retinopathy, a proliferative vitreoretinopathy (PVR), sympathetic ophthalmia, syndrome Vogt-Canary-Harada, histoplasmosis, uveal diffusion and occlusion of vessels. In one embodiment, the implants are particularly useful in the treatment of such medical conditions as uveitis, macular edema, a condition of vascular occlusion, proliferative vitreoretinopathy (PVR) and various other retinopathy.

Delivery systems of drugs in our invention can be injected in the inner region by means of a syringe or can be injected (implanted) into the eye through a number of ways, including the location using tongs, trocar or through other types of applicators, after making the incision in the sclera. In some cases trocar or applicator can be applied without creating an incision, manual applicator is used to implement one or more bio is degradiruem implants in the eye. Manual applicator generally includes a needle 18-30 GA stainless steel lever, the actuator and the piston. Acceptable devices for introduction of the implant or implants in posteriorly eye piece or parcel includes those disclosed in the patent application U.S. serial number 10/666872.

Route of administration usually involves first accessing the field target inside the eye area with a needle, trocar or device implantation. Once inside the target area, for example, the vitreous cavity, the lever on the manual applicator is pressed, it means the drive will cause movement of the piston forward. As the piston moves forward, it can push the implant or implants inside the target area (i.e. vitreous body).

Various methods can be used to create implants within the present invention. Useful methods include a method of phase separation, interfacial methods, extrusion methods, compression methods, methods, casting methods, injection molding methods of hot pressing and other

The delivery system of the medicinal product according to the present invention can be applied to prevent or treat various ocular diseases or conditions, including the following: maculopathy/retinal degeneration: macular degeneration, including in the age macular degeneration (AMD) such as nonexudative age-related macular degeneration and exudative age-related macular degeneration, the choroidal neovascularization, retinopathy, including diabetic retinopathy, acute and chronic macular neuromyopathy, Central serous the horioretinopatia and macular edema, including cystic macular edema and diabetic macular edema. Uveitis/retinitis/chorioidea: acute multifocal Placida pigment epitheliopathy, Behcet's disease, drobina retinochoroidopathy, infections (syphilis, Lyme disease, tuberculosis, toxoplasmosis), uveitis, including intermediary uveitis (intermediate uveitis) and anteriorly uveitis, multifocal chorionic syndrome multiple vanishing white dots, ocular sarcoidosis, posteriorly scleritis, serpiginosa chorioidea, subretinal fibrosis, uveitis syndrome and syndrome Vogt-Canary-Harada. Vascular diseases/exudative diseases: occlusive disease of the retinal artery, occlusion of the Central retinal vein, hypertensive changes of bottom, ocular ischemic syndrome, microaneurysms the retinal arteries, a disease Coates, parafoveal telangiectasia, generationally occlusion of veins, papillovirus, occlusion of the Central retinal artery, occlusion of branches of the retinal artery, carotid artery disease (ZSA), zamorozennimi branches, sickle cell retinopathy and other hemoglobinopathy, angioini strip retinal hereditary vitreoretinopathy, disease ILSA. Traumatic/surgical: sympathetic ophthalmia, uveitis retina, retinal detachment, trauma, laser, photodynamic therapy, photocoagulation, hypoperfusion during surgery, radiation retinopathy, retinopathy after bone marrow transplantation. Proliferative disorders: proliferative vitreal retinopathy and epiretinal membranes, and proliferative diabetic retinopathy. Infectious disorders: ocular histoplasmosis, ocular toxocariasis, syndrome expected histoplasmosis, endophthalmitis, toxoplasmosis, retinal disease associated with HIV infection, choroidal disease associate with HIV infection, Weitnau disease associated with HIV infection, viral retinitis, acute retinal necrosis, progressive outer retinal necrosis, fungal retinal disease, syphilis of the eye, the eye of tuberculosis, diffuse unilateral subacute neuroretinitis and MIAS. Genetic disorders: pigmentary retinal degeneration, systemic diseases associated with retinal dystrophy, congenital stable night blindness, cone dystrophy, a disease of Stargardt and getpathdata abiotrophy retinal disease best, mosaic distri what I pigment epithelium of the retina, X-linked retinoschisis, dystrophy, fundus, Sorsby, benign concentric maculopathy, degeneration of the lens Bietti, elastic, pseudoxanthoma. Gaps/holes in the retina: retinal detachment, macular hole, a large retinal break. Tumor: a disease of the retina associated with tumors, congenital hypertrophy of the PES, posteriorly uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined hamartoma of the retina and pigment epithelium of the retina, retinoblastoma, vasoproliferative tumors of the ocular fundus, retinal astrocytoma, intraocular lymphoid tumors. Versatile: point internal choroidopathy, acute posteriorly multifocal Placida pigment epitheliopathy, myopic retinal degeneration, acute retinal pigment epithelitis, etc.

Examples

The following examples illustrate aspects and embodiments of the invention.

Example 1

Intravitreal bevacizumab-PLGP microspheres for the treatment of dry AMD

78-year-old man suffering from age-related macular degeneration and cataracts in both eyes. The patient also may have a history of cardiovascular disease and myocardial bottom wall infarction 6 months earlier. The patient may complain of blurred vision and it is psiu in his right eye, and research can show a visual acuity of 20/400 in the right eye and 20/32 in the left eye. The study of the retina may show subfoveal the choroidal neovascularization (CNV) (wet AMD right eye) approximately 1 disk area with surrounding hemorrhage and edema in the right eye. Pair left eye may show features of high risk for the development of wet AMD such as soft amorphous speakers Druze, the prisoners in the pit, but do not show signs of choroidal neovascularization and can be confirmed by fluorescent angiography (dry AMD in the left eye). The patient can be scheduled monthly intravitreal injections of ranibizumab (onlineoakley agent) in the right eye with wet AMD with resolution of edema and hemorrhage and may be refunded visual acuity to 20/125 within 4 months.

In the left eye, the patient may receive intravitreal injection of the drug with a slow release anti-VEGF monoclonal antibodies (optionally with a substance that promotes penetration) for prophylaxis against the development of CNV in the eye, provided that he currently has a high risk of developing wet AMD in better seers left eye. The injection volume can be 50 ál containing bevacizumab incorporated in PLGP microspheres with the total weight bevacizumab (medicines) of 2.5 mg

Polysorbate 20 PLGP microspheres with a speed of release in vitro of 10 ág/day can also be placed in preparation for increasing the permeability of the retina. Bevacizumab and Polysorbate 20 microspheres are placed in a cross crosslinked hyaluronic acid at a concentration of 1.2% with moderate cross through a needle with a needle 27G.

The patient can take in the left eye intravitreal injection of 50 µl of bevacizumab-PLGP microspheres (total mass of drug 2.5 mg) of the invention every 6 months and at the end of the seven-year observation period, the patient may have supported the vision in my left eye 20/32. The risk lesions developed wet AMD in this left eye was more than 50%, but the second study failed to reveal signs of CNV in the left eye. Unfortunately, by the end of the seven-year period of observation, the vision in his right eye could deteriorate to 20/400 with the presence of organized discoid scar in the study of the Central macular area. Provided that he does not lose the sight in his left eye, the patient is able to maintain a driver's license and an independent lifestyle during this time period. Despite the exposure of the eye to anti-VEGF therapy low-dose slow-release, cardiovascular disease the patient may remain unchanged without the occurrence of any thromboembolitic is their complications.

Microspheres used therapeutically in examples 1-3, can be prepared by the method of solvent evaporation from a solution of methylene chloride in PVA (polyvinyl alcohol). From 10 to 100 mg/ml microspheres can be suspended in isotonic phosphate buffer and 50 to 200 μl of the suspension of the microspheres can be inserted into the eye area.

Microspheres containing onlineoakley agent, with antineoplastons agent is homogeneous distributed or dispersed throughout the polymer polylactic acid (PLP) or PGP can be prepared using the method of evaporation of the emulsion/solvent. Herstorical (continuous aqueous phase) saturate onlinebaccarat agent to prevent loss antineoplastons agent from the polymer phase and to increase the degree of loading. In addition, onlineoakley agent, saturated with methanol, can be used for cooling the emulsion. Methanol acts as a sink for quick removal of dichloromethane, otorita microspheres before onlineoakley agent can diffuse out of them.

Example 2

Low doses of intravitreal bevacizumab-PLGP microspheres for the treatment of dry AMD

74-year-old man with a diagnosis of dry age-JP one (right) eye and wet AMD in the other (left) GLA is in. His vision in his right eye; 20/40. He was treated by intravitreal injection delivery system drug delayed release in eyes with dry AMD. The delivery system drug delayed release contains a total of approximately 6 micrograms (low dose) active agent bevacizumab in polymer media. The polymeric carrier is a high viscosity hyaluronic acid or PGP, or PLP associated with bevacizumab onlinebaccarat agent for forming or multiple microspheres or a single monolithic implant, which is homogeneous distributed bevacizumab. On the other hand, the delivery system with a slow release may contain microspheres with bevacizumab or implant in hyaluronic acid (cross stitched or transversely unstitched), so that both viscous (hyaluronic acid) and solid (PLP or PLGP microspheres, or implant) polymeric carriers are present in a single delivery system of the drug. The delivery system of the medicinal product may release 6 µg of bevacizumab in the vitreous body during the period from 1 to 6 months, after which the right eye of the patient shows no evidence of neovascularization and the same vision (20/40) is supported in his right eye.

Example 3

Intravitreal Rani is isuma-PLGP microspheres for the treatment of dry AMD

83-year-old woman can Wake up with a vague vision in my left eye. She may have a history of glaucoma, the condition after removal of cataract by THEIR (artificial lens), and dry AMD in both eyes, and can take eye drops Alphagan P. Ophthalmologist patient could explore and she could be diagnosed with wet AMD in the left eye and it immediately sent to a retina specialist. Vision may be 20/25 in the right eye and 20/200 in the left. The study of the retina may show dry changes in the macula of the right eye, but no high-risk features such as large Druze and numerous pigment changes in subfoveal area. The macula of the left eye may show subfoveal CNV size approximately 2 disk area with the surrounding macular edema and intraretinal hemorrhage. Fluoresceine angiography can confirm the presence in the left eye CNV, mainly classical in appearance. The patient can be immediately assigned monthly intravitreal injections of ranibizumab in the left eye with wet AMD with a resolution of retinal edema over the period of 3 months, but it can be experienced only a slight improvement in visual acuity of the left eye to 20/100. Since the patient was at high risk for the development of CNV in her right eye and the vision is in my left eye could not significantly improve over the period of 3 months, it can take intravitreal injection to right eye 50 ál, containing 4.8 mg of ranibizumab included in PLGP microspheres, for prophylaxis against the development of CNV in his right eye. PLGP microspheres Polysorbate 20 with the speed of release in vitro with 5 μg/day can also be placed in the drug to increase the permeability of the retina. Microspheres can be placed in a partially cross crosslinked hyaluronic acid (ha) when the GA concentration is 2.1%. This cross stitched CC can be obtained from AIlergan Medical (Irvine, California) under the trademarks Juvederm Ultra Plus, Juvederm 30, Captique and Voluma.

She can repeat intravitreal injection to right eye 50 ál, containing 4.8 mg ranibizumab-PLGP microspheres every 6 months through 4-year period from continuing visual acuity of 20/25 in the right eye and 20/200 in the left eye. The study of the retina may show dry AMD in my right eye and organized by the disc-shaped scar in the left eye with moderate subfoveal fibrosis. It may be capable of independent life in her own home provided excellent vision, which she can support her right eye.

Example 4

The delivery system drug antineoplastons means steering the permeability of the retina

For toxicity studies Polysorbate amplifier permeability of the retina was performed exp is riment on the cells of the pigment epithelium ("KPIs"). Thus, cells ARPE-19 (see Dunn, K. et al., ARPE-19, a human retinal pigment epithelial cell line with differentiated properties, Exp Eye Res. 1996 Feb; 62(2): 155-69) were incubated in vitro at a concentration of Polysorbate 80, ranging from 0% to 0.10% m/m and were tested the viability of the cells.

The Protocol for this experiment in vitro was as follows: cells ARPE-19 (passage 11-23) were sown on the day before the experiment in a 24-well plate at 125,000 cells/well in a mixture of modified according to the method of Dulbecco eagle medium and substrate ham, supplemented with 10% FBS. The validity and effect of dose simultaneously performed on cells ARPE-19. Parameters incubate solution such as pH, osmolarity was measured for each concentration. The incubation time was 24 h, 48 h, 72 h Were included one negative (untreated) and one positive control (5 mm H2H2). Untreated state was the culture medium, supplemented with serum. 5 mm H2O2prepared from 3% of the basic solution of N2O2(875 mm). Concentration applied to the cells was determined, taking into account some parameters such as: (a) widely used concentration in the product;

(b) the maximum allowable concentration to the solubility of the compounds;

(c) the maximum allowable concentration for suitable levels of viscosity, osmolarity and pH.

In the first method, the concentrations were covered wide is the range (example 1). After the preliminary results of the second set of experiments (example 2-4) identified a more accurate concentration of the compound leading to 50% inhibition of cell viability, based on the analysis of cell viability and morphological aspects. All variants concentrations were obtained using a series dilution of the more concentrated state in the cell-culture medium (DMEM:F12 supplemented with 10% FBS). The results of the MTT test was expressed as a percentage of viable cells calculated as follows:

% cell viability=ODsample/ODcontrolThe X100.

3 following experiment was performed independently under the same conditions, built schedule for the three sets of values, giving vnutrispinalnaya value changes. Thus, we determined the range of concentrations leading to 50% cell viability. Morphological appearance were analyzed by semi-quantitative counting, ranging from 5 to 1, from a normal to a lethal phenotype, respectively.

It has been observed that the concentration of Polysorbate 80 over approximately 0,06% (0.6 mg/ml) were associated with a decline in cell viability PES and the concentration of Polysorbate 80 more than approximately 0,09% (0.9 mg/ml) was associated with the vitality of the cells is less than 50%, as shown is a figure 1. Based on the fact that the volume of the vitreous body of the human eye is 4 ml, therefore, the total maximum weight of Polysorbate in the vitreous body at a time should not exceed 3,6 mg

In each of examples 1-3 above, one or more amplifier permeability of the retina can be included in a delivery system of medicines with the aim of increasing the permeability of the retina used for antineoplastons agent. Thus, amplifiers permeability of the retina can be added to the delivery system drug delayed release for release simultaneously with antineoplastons agent (i.e. anti-VEGF compound). Jointly released low dose as an anti-VEGF compounds, and amplifier permeability after a 6 month period, you can optimize the effectiveness of anti-VEGF compounds, especially large joints such as the monoclonal antibody to enrich the subretinal space for the treatment of CNV. The preferred amplifier permeability of the retina is Polysorbate 20 (e.g., tween-20 or C12-sorbitan-E20) and Polysorbate 80 added to the delivery system of the medicinal product as an aqueous solution with a concentration of amplifier permeability of the retina in aqueous solution from about 0,005% to 0.10% (from 0.05 mg to 1 mg Wuxi is Italia permeability of retinal ml of water). Alternative amplifiers permeability of the retina include, but are not limited to, sodium lauryl sulfate, benzalkonium chloride and cyclodextrin.

All the above links, articles, patents, patent applications and publications are incorporated herein in its entirety by reference.

Thus, the nature and scope of the following claims is not limited to the above descriptions of the preferred embodiments.

1. A method of treating dry age-related macular degeneration (AMD) with low doses, comprising the steps:
(a) preparing a biocompatible delivery system drug delayed release containing from about 5 μg to about 20 μg of bevacizumab and media from a polymeric hyaluronic acid associated with bevacizumab,
(b) the injection delivery system of the drug in the vitreous cavity of the eye of a patient with dry AMD, and
(c) release from the delivery system of medicines from an average of approximately 14 ng to about 120 ng of bevacizumab within a period of 24 hours during the period of time from three months to six months.

2. The method according to claim 1, where the other penjelasannya eye of a patient suffering from wet AMD.

3. The method according to claim 1, where the viscosity of the delivery system for drugs is approximately 130000 SDR d is approximately 300,000 centipoise at a shear rate of approximately 0.1/s at about 25°C.

4. The method according to claim 1, where the delivery system for the drug is injected using a 25-30-dimensional syringe.

5. A method for the treatment of dry AMD with low doses, comprising the steps:
(a) preparing a biocompatible delivery system drug delayed release containing from about 5 μg to about 20 μg of bevacizumab, and media from a polymeric hyaluronic acid associated with bevacizumab,
(b) using 25-30-dimensional syringe injection system for the delivery of drugs into the vitreous cavity of the eye of a patient with dry AMD, where another penjelasannya eye of a patient suffering from wet AMD, and
(c) release from the delivery system of medicines from an average of approximately 14 ng to about 120 ng of bevacizumab within a period of 24 hours during the period of time from about three months to about six months, where the delivery system of the medicinal product has a viscosity of from about 130000 centipoise to approximately 300,000 centipoise at a shear rate of approximately 0.1/s at about 25°C.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to a pharmaceutical submicron suspension and to a method for preparing the submicron suspension and is applicable for ophthalmic (local or intravitreal) and nasal application. The ophthalmic aqueous pharmaceutical submicron suspension contains a hydrophobic therapeutic agent prepared in the form of submicron particles with the hydrophobic therapeutic agent presenting nepafenac; where a low-molecular charged polymer contains one or more cellulose polymers which jointly or individually have a molecular weight of less than 200000 kilodalton, and wherein the low-molecular charged polymer has an average degree of polymerisation (DP) making approximately min. 100 and up to approximately 4000; and one or more additives. The low-molecular charged polymer inhibits submicron particle aggregation in the suspension; the submicron particles have an average hydrodynamic radius making less than 1 mcm, and the low-molecular charged polymer represents carboxymethyl cellulose.

EFFECT: using the group of inventions enables preparing the high-active therapeutic agent for ophthalmic application.

16 cl, 5 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention relates to ophthalmological pharmaceutical compositions, namely to sorafenib-based compositions, and is intended for treatment of non-cancer neoangiogenic pathologies of the eye. The invention provides application of sorafenib for production of an ophthalmological pharmaceutical composition for local, subconjunctival, subretinal or periocular introduction, for introduction by means of near-scleral injection or for introduction by means of retrobulbar injection. The said composition additionally includes VDA, corticosteroids, angiostatic cortisones, albendazole, mebendazole, carboanhydrase inhibitors (CAI), canabinoids, non-steroid anti-inflammatory drugs (NSAID), selective COX-2 inhibitors, iNOS inhibitors, molecules, interacting with inflammatory mediators, molecules with immunosuppressive action, beta-lactamines (penicillins, cephalosporins), macrolides, tetracyclines, fluoroquinolones, natural polypeptides with antibacterial activity and their fragments, SiRNA.

EFFECT: invention provides an efficient ophthalmological pharmaceutical sorafenib-based composition for treatment of non-cancer neoangiogenic pathologies of the eye.

7 cl, 2 tbl, 3 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: group of inventions relates to ophthalmology and is intended for delivery of a therapeutic preparation into an eye. An eye device contains a non-biodegradable mass of material, which includes a hydrophobic component, represented in an amount, sufficient for contact angle of the material to be larger than 50° and formed of at least 80% by weight of acryl material. The device also contains the therapeutic preparation, located on the peripheral surface of the material mass. The therapeutic preparation is hydrophobic and has a coefficient of distribution in the system octane/water PC Log P, equal at least to 1.0. The material mass is formed for introduction into the human eye. Attraction of the therapeutic agent to the hydrophobic part controls a delayed release of the therapeutic preparation in such a way that less than 50 wt % of the therapeutic preparation is released from the eye device into the basic salt solution (BSS) within at least three days. The method of the eye device obtaining includes submergence of the material mass into the solution, which contains a solvent and the therapeutic preparation.

EFFECT: application of the group of inventions ensures delivery of the therapeutic preparation into the eye within long period of time.

19 cl, 12 dwg, 1 tbl, 12 ex

FIELD: medicine.

SUBSTANCE: preparation comprises branched polyhexamethylene guanidine in the form of hydrochloride, taurine, a promoting ingredient, additives and water. The promoting ingredient is specified in succinic acid or its pharmaceutically acceptable salt, while the additives are specified in a group consisting of physiologically acceptable alkaline or acidic agents and a salt tonic agent specified in physiologically acceptable sodium or potassium salts or mixtures thereof.

EFFECT: more effective therapeutic effectiveness for pathological conditions of the eyes, and a potential comorbid bacterial infection.

3 cl, 3 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: physiotherapeutic goggle device BLEPHASTEAM is placed over an orbital cavity. Restasis is applied on cotton pads in the amount of 4 drops equally spaced over each cotton pad. The pads are placed into the device. The physiotherapeutic exposure covers open eyelids for 10 minutes daily. The therapeutic course consists of 20 sessions.

EFFECT: method provides a pronounced anti-inflammatory, reparative, anti-allergic effect with reducing the length of treatment and ensuring cost advantages of using the expensive drug Restasis evaporated in the goggle BLEPHASTEAM, allowing for the simultaneous effect on the cornea, conjunctiva and eyelids.

8 dwg, 2 ex

FIELD: medicine.

SUBSTANCE: treating retinal and/or vitreous hemorrhages is ensured by a session of subcutaneous administration of Histochrom 0.5 ml into a mastoid bone, Echinacea compositum 1.0 ml into a temporal fossa, Gemase 2500-5000 IU parabulbary dissolved in Lymphomyosot 0.5-1.0 ml. The therapeutic course is 10-15 sessions, either daily or every second day.

EFFECT: faster resolution of the intraocular hemorrhages, prevention of retinal injuries by toxic decay products, higher visual acuity.

3 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to ophthalmology, to preparations for the treatment and prevention of eye diseases, and may be used in visual impairment, development and progression of eye diseases, as well as for the prevention and maintenance therapy of oxular diseases. Substance of the invention consists in the fact that a therapeutic eye balsam is characterised by the fact that it contains the ingredients in ratio in grams per 100 g of the therapeutic eye balsam of the following formulation: Siberian fir extract - 48.540 g, 5% propolis extract - 10.000 g, 0.9% physiological saline - 38.540 g, neoselen (food supplement) - 0.971 g, vitamin B2 - 0.007 g, citric acid - 0.971 g, ascorbic acid - 0.971 g that promotes achieving the declared technical effect ensured by the given proportions. The presented balsam enables the higher clinical effectiveness in all the forms of ocular pathologies, provides the anti-inflammatory effect on the eye mucosa and cornea, as well as delivers a good result in the post-traumatic and post-operative treatment.

EFFECT: therapeutic eye balsam containing the natural ingredients in certain proportions provides the integrated therapeutic effect on the visual organs and has found use in a great number of grateful patients.

1 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to a pharmaceutical composition and methods of using it in treating insufficient eye lubrication, related symptoms or adverse conditions related to insufficient eye lubrication. The pharmaceutical composition contains human PRG4, its wetting fragment, a homologue or an isoform suspended in ophthalmologically acceptable balanced saline. The pharmaceutical composition can also contain one or more ophthalmologically acceptable agents specified in a group consisting of a sedative, an excipient, a binding agent, a vasoconstrictor, an emollient, sodium hyaluronate, hyaluronic acid and surface active phospholipids in a pharmaceutically acceptable carrier for topical use.

EFFECT: group of inventions provides treating the diseases related to impaired corneal and conjunctival wetting.

15 cl, 10 dwg, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is a method for the suppression of physiological disorders related to abnormal angiogenesis, specified in retinopathy, diabetic retinopathy, macular degeneration, retinopathy of prematurity, age-related macular degeneration, pancreatic tumour and glioma, involving the administration of an effective amount of 3-[(5-(2,3-dimethoxy-6-methyl-1,4-benzoquinolinyl)]-2-nonyl-2-propenoic acid (E3330) or its pharmaceutically acceptable salts or solvates. The decreased EHF-1α, NFKβ, AP-1 activity by E3330 and the suppression thereby of the growth, survival. Migration and metastasis of tumour cells are accompanied by the absence of the major suppression of the growth of normal cells (hemopoietic embyo cells or CD34+ human progenitors). Besides, E3330 has enhanced the therapeutic effect of other cytotoxic preparations.

EFFECT: reducing the amount of VGEF and proliferation of retinal endothelial cells by E333O even in the presence of a fibroblast growth factor, both in the normal oxygen conditions, and in the hypoxia by the inhibition of the oxidation-reduction activity of Apel/Ref-1.

12 cl, 35 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to eye drops, and aims at treating dry eye syndrome, as well as bacterial conjunctivitis and/or blepharitis. The preparation comprises a combination of the ingredients, a prolonging ingredient, additives and water. The combination of the active ingredients contains branched polyhexamethylene guanidine and sulphacetamide; the prolonging ingredient is specified in a group consisting of polyvinyl alcohol, water-soluble methyl cellulose or hydroxypropyl methyl cellulose; the additives are specified in a group consisting of a group consisting of physiologically acceptable alkaline or acid agents, and a saline tonic agent.

EFFECT: using the invention enables higher clinical effectiveness of dry eye syndrome, as well as a comorbid bacterial infection, as the preparation possesses the bactericidal effect consistent with the effect of 20% sulphacetamide causing no irritant effect on long use.

4 cl, 3 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to methods of obtaining a lyophilised preparation of tetrodotoxin and to a tetrodotoxin preparation for relief of the drug withdrawal in case of addiction to opiates. The method of obtaining the lyophilised preparation of tetrodoxin includes the following stages: 0.1-20 mcg/dose of tetrodotoxin is dissolved with 0.1% solution of citric acid to regulate pH within the range of 3.5-4.5 in injection water and filtered to remove pyrogen; separately dissolved are: a stabiliser - dextran or trehalose - and a filling agent, representing an isotonic solution of sodium chloride or mannit in injection water. After that, 0.1% solution of citric acid is added to regulate pH within 3.5-4.5, then, activated carbon is added with keeping at a temperature of 60°C and mixing for more than 30 minutes, filtering to remove pyrogen and cooling to room temperature. After homogeneous mixing of the obtained solutions and realisation of ultrafiltration, lyophilic drying is carried out. Lyophilic drying consists in preliminary freezing, drying under vacuum at reduced temperature, drying under vacuum at increased temperature, with each drying being performed at a certain temperature for the specified time period. After that, filling with inert gas is performed with control of water content at 3% level, with further sealing. Another version includes addition of additional solution of lidocaine chloride to the solution of tetrodotoxin and citric acid at the first stage. Also disclosed is the tetrodotoxin preparation for relief of the drug withdrawal in case of addiction to opiates, obtained by the said method, which is characterised by the weight ratio tetrodotoxin:filling agent:stabiliser, equal to 1:(150-3000):(50-6000).

EFFECT: claimed group of inventions ensures obtaining the stable tetrodotoxin solution with accurate dosage, which is used for introduction into the human organism.

25 cl, 9 tbl, 14 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to pharmaceutics, namely to a pharmaceutical composition (a solid oral dosage form (a tablet or a capsule)) of tyrosine kinase Bcr-Abl inhibitor - imatinib(4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)-pyrimidin-2-ylamino)phenyl]benzamide). The pharmaceutical composition contains 25-45 wt % of imatinib, preferentially imatinib mesylate, more preferentially an α-crystalline form of imatinib mesylate, a binding agent representing povidone, and at least two desintegrant representing low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch.

EFFECT: invention provides the min 80% imatinib release from the tablet for 15 minutes after oral administration and enables extending the range of drugs used for leukaemia.

14 cl, 4 dwg, 3 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to microcapsulation of cephalosporins related to β-lactam antibiotics. The method is characterised by the fact that konjac gum is used as a microcapsule membrane; a konjak solution cerocon in butyl alcohol is added with the preparation E472 as a surfactant; a powdered antibiotic of cephalosporin is dissolved in water and transferred into the konjak solution cerocon in butyl alcohol; after the antibiotic forms an independent solid phase, carbinol and distilled water are added slowly drop-by-drop; the prepared microcapsule suspension is filtered in acetone and dried; the microcapsule process is performed at 25°C with no special equipment required; the relation of carbinol and butyl alcohol makes 1:3.

EFFECT: invention provides simplified and accelerated preparation of the water-soluble drug microcapsules of cephalosporins in konjac gum, loss reduction in preparing the microcapsules (higher yield-mass).

6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to application of a pharmaceutical drug form for peroral introduction to reduce inter-individual variability in paracetamol-containing compositions in a diabetic patient with gastric dismotility. The said drug form contains in a form of a granulate: paracetamol in amount 60-80 wt %, calcium carbonate in amount 5-20 wt %, at least, one first binding substance and, at least, one disintegrating substance, as well as, at least, one hydrophilic colloid as an extragranular component.

EFFECT: invention ensures improvement of an active substance absorption in the patient with gastric dismotility.

13 cl, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to method of obtaining microcapsules of medication of cephalosporin group in konjac gum. In accordance with claimed method cephalosporin powder, preliminarily dissolved in dimethylformamide, and surface-active substance are added to konjac gum solution in isopropyl alcohol, with addition of carbinol after formation of independent solid phase by cephalosporin. Obtained suspension of microcapsules is filtered, washed with acetone and dried in dessicator.

EFFECT: invention makes it possible to simplify and accelerate process of obtaining microcapsules of water-soluble medications of cephalosporin groups in konjac gum, as well as to increase their output by weight.

4 ex

FIELD: medicine.

SUBSTANCE: drug preparation represents a composition containing: lappaconitine hydrobromide 0.02 - 0.06 g, pregelatinised starch 0.0335 - 0.0536 g, lactose monohydrate 0.058 - 0.122 g, hypromellose 0.078 - 0.161 g, calcium stearate 0.002 - 0.004 g and colloidal silicone dioxide 0.002 - 0.004 g.

EFFECT: prolonged antiarrhythmic action of the active ingredient lappaconitine hydrobromide with accessory alkaloids.

5 cl, 1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to a method for preparing a pectin gel of an elevated part of willow herb. The declared method enables dissolving pre-recovered pectin from the elevated part of willow herb in water, cooling and applying onto a frozen chitosan solution and further gel formation.

EFFECT: invention enables preparing a degradable biomaterial possessing the antimicrobial activity on Escherichia coli and Staphylococcus aureus cells.

1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for preparing drug microcapsules of cephalosporins in konjak gum in dioxane. According to the declared method, a konjak gum solution in dioxane is added with a surfactant that is a cephalosporin powder pre-dissolved in ethanol, and with carbinol after cephalosporin forms an independent solid phase. The prepared microcapsule suspension is filtered, washed in acetone and dried in a drying oven.

EFFECT: invention enables simplifying and accelerating the process of water-soluble drug microcapsules of cephalosporins in konjak gum, as well as increasing a mass yield.

4 ex

FIELD: chemistry.

SUBSTANCE: disclosed is a polysaccharide containing carboxyl functional groups, one of which is substituted with a hydrophobic alcohol derivative. Also disclosed is a pharmaceutical composition containing one of the disclosed polysaccharides and one active ingredient.

EFFECT: invention enables to obtain novel amphiphilic polysaccharide derivatives, having good biocompatibility.

26 cl, 1 tbl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical composition in the form of a skin protection paste. The composition contains a film-forming agent representing poly(butyl methacrylate-co-methyl methacrylate), hydrocolloid, a filling agent, a softening agent and an alcoholic diluent in the certain proportions.

EFFECT: pharmaceutical composition has a prolonged shelf life and is able to ensure a uniform skin coverage which is characterised by the balanced characteristics of durability and flexibility.

3 cl, 2 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to pharmacy and medicine, and concerns a composition, a method and a kit which enable a controlled release of octreotide, e.g. octreotide acetate in an individual. The composition contains a preparation containing octreotide basically enclosed in a hydrophilic polymer specified in polyurethane polymers and methacrylate polymers; it is effective for providing octreotide release at a rate of 30 mcg to 800 mcg a day for six months in vivo, wherein the hydrophilic polymer, but not the preparation, additionally contains a releasing substance with molecular weight of at least approximately 1,000 Dalton, wherein the preparation contains octreotide 40 to 120 mg, and the releasing substance is specified in a group consisting of Brij 35 (polyoxyethylene lauryl ester), polyoxyethylene(20)sorbitan trioleate, Tween 20, Tween 80, vitamin E TPGS and mixtures of any of the two or more.The method for reducing GH levels or IGF-1 levels and/or treating an octreotide-sensitive disease involving a subcutaneous implantation of at least one dry implanted device comprising the declared preparation. The kit comprising the declared composition for octreotide controlled release.

EFFECT: group of inventions provides a therapeutically effective amount of octreotide for a long period of time with treating hormonal conditions.

25 cl, 11 ex, 7 tbl, 21 dwg

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