Pharmaceutical formulations containing 9-cis-retinyl esters in lipid excipient

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics, namely represents pharmaceutical formulations containing 9-cis-retinyl esters in a lipid excipient. The pharmaceutical formulations containing 9-cis-retinyl esters are described to be applicable in a retinoid replacement therapy for treating retinal degenerations in individuals.

EFFECT: using the formulations for the retinoid replacement therapy for treating retinal degenerations in individuals.

73 cl, 14 dwg, 2 tbl, 6 ex

 

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority of patent application U.S. No. 61/242,741, filed September 15, 2009 in accordance with 35 U. S. C. 119(e) of the U. S., which is incorporated herein by reference in full.

Background of the INVENTION

Technical area

This description relates to pharmaceutical compositions containing artificial retinoids, in particular to stable formulations and pharmaceutical metered-dose formulations, suitable for the chromophore-replacement therapy of view.

Background of the invention

Visual perception is the result of biological conversion of light energy in the transmission of electrical signals with the help of photoreceptors in the retina, a process called photopleasure. The process of photopleasure is initiated by the visual pigment comprising a chromophore 11-CIS-retinal associated with receptor opsins connected to apoproteins G-proteins, for the formation of rhodopsin (Palczewski K. G protein-coupled receptor rhodopsin.Annual review of biochemistry2006; 75:743-767). The chromophore absorbs photons which have taken photoisomerization chromophore in hisTRANSform and cause cascades of signal conversion (Palczewski K. above; Ridge KD et al. Visual rhodopsin sees the light: structure and mechanism of G protein signaling.J Biol Chem2007; 282:9297-9301). From�narisovannyi chromophore is fully TRANS-retinal is then reduced to fullyTRANS-retinol is transported to the retinal pigment epithelium (RPE) and converted to a fullyTRANS-retinology esters of fatty acids with the help of lecithin:retinoblastomas (LRAT). Finally, the recovery of 11-CIS-retinal fullyTRANS-retinology esters of fatty acids completes this retinoid cycle (the cycle of transformations of rhodopsin) (see, for example, published applications US Nos. 2004/0242704, 2006/028182, 2006/0221208).

Regeneration of 11-CIS-retinal is essential for the maintenance of vision (Travis GH, et al. Diseases caused by defects in the visual cycle: retinoids as potential therapeutic agents.Annu Rev Pharmacol Toxicol2007; 47:469-512). Defects of education 11-CIS-retinal is linked to several hereditary degenerative retinopathy (Gu SM, et al. Mutations in RPE65 cause autosomal recessive childhood-onset severe retinal dystrophy.Nature genetics1997; 17:194-197). Two examples are congenital blindness Leber (LCA) that begin in childhood retinal disease that causes severe vision impairment; and retinitis pigmentosa (RP), the other retinopathy, occurring in later adolescence.

LCA is an inherited, serious and currently incurable retinal degeneration which is the leading cause of blindness in childhood. At birth or shortly after birth in LCA patients characteristic�m expression serious visual impairment, as evidenced by wandering nystagmus, nevroticheskoi pupils, pigmentary retinopathy with loss of cone and rod sensitivity, absence or severe weakening of the answers to electroretinogram (ERG) and approximately 100-fold reduction of the amplitude of the cone flicker (Perrault I, et al. Leber congenital amaurosis.Mol Genet Metab1999; 68:200-208; However E, et al. Leber''s congenital amaurosis: an update.Eur J Paediatr Neurol2003; 7:13-22; However E, et al. Response to pain in a group of healthy term newborns: behavioral and physiological aspects.Functional neurology1996; 11:35-43).

RPE65, a protein mass CD-specific and abundant in RPE, which catalyzes the isomerization fullyTRANS-retinology esters of fatty acids 11-CIS-retinol, is generally regarded as a retinoid isomerases involved in the regeneration of 11-CIS-retinal (Hamel CP, et al. Molecular cloning and expression of RPE65, a novel retinal pigment epithelium-specific protein do that is post - transcriptionally regulated in vitro.J Biol Chem1993; 268:15751 -15757; Jin M, et al. Rpe65 is the retinoid isomerase in bovine retinal pigment epithelium.Cell2005; 122:449-459; Moiseyev G, et al. RPE65 is the isomerohydrolase in the retinoid visual cycle.Proceedings of the National Academy of Sciences of the United States of America2005; 102:12413-12418; Redmond TM, et al. Mutation of key residues of RPE65 abolishes its enzymatic role as isomerohydrolase in the visual cycle.Proceedings of the National Academy of Sciences of the United States of America2005; 102:13658-13663)). Mutations in the RPE65 are the cause of up to 16% of cases of LCA and 2% of cases of autosomal recessive RP (Gu SM above; Marlhens F, et al. Mutations in RPE65 cause Lebe''s congenital amaurosis. Nature genetics1997;17:139-141 ; Morimura H, et al. Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosisProceedings of the National Academy of Sciences of the United States of America1998; 95:3088-3093; Thompson DA,et al. Genetics and phenotypes of RPE65 mutations in inherited retinal degeneration.Investigative ophthalmology & visual science2000; 41:4293-4299; Lorenz B, et al. Early-onset severe rod-cone dystrophy in young children with RPE65 mutations.Investigative ophthalmology & visual science2000; 41:2735-2742). Spontaneous or directed DeleteMovieRpe65in mice and dogs leads to 11-CIS-retinal failure, beginning in early childhood and is slowly progressive retinal degeneration with a dramatic decrease of the responses to electroretinogram (ERG) and typical LCA-pathology, accompanied by accumulation of fullyTRANS-retinology fatty acid esters in the RPE (Redmond TM, et al. Rpe65 is necessary for production of 11-CIS-vitamin A in the retinal visual cycle.Nature genetics1998; 20:344-351; Pang JJ, et al. Retinal degeneration 12 (rd12): a new, course arising mouse model for human Leber congenital amaurosis (LCA).Molecular vision2005; 11:152-162; Wrigstad A,et al. Ultrastructural changes of the retina and the retinal pigment epithelium in Briard dogs with hereditary congenital night blindness and partial day blindness.Experimental eye research1992; 55:805-818; Acland GM, et al. Gene therapy restores vision in a canine model of childhood blindness.Nature genetics2001; 28:92-95; Imanishi Y, et al. Noninvasive two-photon imaging reveals retinyl ester storage structures in the eye. The Journal of cell biology 2004; 164:373-383).

For the treatment of LCA examines several possible therapies. Therapy based on functional geneRPE65and re�Inal prosthesis has demonstrated encouraging preliminary signs of retention of vision at an early stage of clinical definitions (Bainbridge JW, et al. Effect of gene therapy on visual function in Leber''s congenital amaurosis.The New England journal of medicine2008; 358:2231-2239; Maguire AM, et al. Safety and efficacy of gene transfer for Leber''s congenital amaurosis. The New England journal of medicine 2008;358:2240-2248; Yanai D, et al. Visual performance using a retinal prosthesis in three subjects with retinitis pigmentosa.American journal of ophthalmology2007; 143:820-827).

Recently, the chromophore replacement therapy lens 9-CIS-retinal has been proposed as a new pharmacological workaround for broken retinoid cycle (Van Hooser JP, et al. Rapid restoration of visual pigment and function with oral retinoid in a mouse model of childhood blindness.Proceedings of the National Academy of Sciences of the United States of America2000;97:8623-8628; Van Hooser JP, et al. Recovery of visual functions in a mouse model of Leber congenital amaurosis.J Biol Chem2002; 277:19173-19182; Aleman TS, et al. Impairment of the transient pupillary light reflex in Rpe65(-/-) mice and humans with leber congenital amaurosis.Investigative ophthalmology & visual science2004; 45:1259-1271; Batten ML, et al. Pharmacological and rAAV Gene Therapy Rescue of Visual Functions in a Blind Mouse Model of Leber Congenital Amaurosis.PLoS Med2005; 2:e333). 9-CIS-retinal binds to openam to form a pigment of rod visual cells,every-rhodopsin, which initiates photopleasure similar to rhodopsin. It was shown that oral administration of 9-CIS-retinal or its predecessors were restored in the eyes of opsin asevery-rhodopsin, increased the function of the retina, as measured by the ERG responses, and improved pupillary reflex to light in mice with knockout of genes ofRpe65andLratthat JW�safety two genetic models of LCA. There is a need for further development of synthetic 9-CIS-retinoids in the compositions for oral, gastric, local (e.g., in the vitreous) or intravenous administration for the treatment of various forms of inherited retinal degeneration caused by disturbances in the retinoid cycle.

BRIEF DESCRIPTION

Described pharmaceutical compositions containing artificial retinoids in lipid filler. Artificial retinoids can be used to bypass the critical blockages in the retinoid cycle, such as RPE65 deficiency or mutation, by creating this artificialCIS-retinoid chromophore, which can functionally associate with openam. Also described are pharmaceutical dosage forms of the compositions, including one-time, intermittent and daily dosing schedules.

So, one implementation option provides a pharmaceutical composition comprising the lipid excipient and one or more 9-CIS-retinally esters of the Formula (I):

where R represents an alkyl group or alkenyl group; and a lipid filler contains more than 50 wt./wt.% polyunsaturated fatty acids, including fatty acid omega-6 and fatty acid omega-3 in a ratio (by weight) less than 15.

In con�specific variant of implementation, 9-CIS-retinology ether of the Formula (I) is a 9-CIS-reinjected.

In a particular variant of implementation, the lipid excipient contains soybean oil.

Additional implementation option provides a dosage form suitable for daily dosing 9-CIS-retailinga ether to the needy in this subject, including approximately 1.25-20 mg/ml of 9-CIS-retinella in soybean oil, where the dosage form provides on the area of the body surface of the subject approximately 1.25-20 mg/m29-CIS-retinella within a 24-hour period.

Another variant implementation provides a dosage form suitable for single dosing by injection into the vitreous body of the subject 9-CIS-retinella, including about 18-40% mg/ml 9-CIS-retinella in soybean oil.

Additional implementation option provides a method of treatment of congenital blindness Leber in humans, including: the introduction of a pharmaceutical composition comprising an effective amount of one or more 9-CIS-retinology esters of the Formula (I) in lipid filler containing more than 50 wt./wt.% polyunsaturated fatty acids, including fatty acid omega-6 and fatty acid omega-3 in a ratio (by weight) less than 15.

In a particular embodiment of the, 9-CIS-retinyl�th ether of the formula (I), used in the way that is a 9-CIS-reinjected.

In a particular variant of implementation, the lipid excipient used in the method contains soybean oil.

Additional implementation option provides a method, comprising administering to a person experiencing a deficiency in 11-CIS-the retinal, pharmaceutical composition containing an effective amount of one or more 9-CIS-retinology esters of the Formula (I) in lipid filler containing more than 50 wt./wt.% polyunsaturated fatty acids, including fatty acid omega-6 and fatty acid omega-3 in a ratio (by weight) less than 15.

In a particular embodiment of the, 9-CIS-retinology ether with Formula (I) used in the way that is a 9-CIS-reinjected.

In a particular variant of implementation, the lipid excipient used in the method contains soybean oil.

A BRIEF DESCRIPTION of SOME of the IMAGES of DRAWINGS

Figure 1 (A-D) shows the relative absorption of 9-CIS-retinella in soybean oil and retention in the plasma to its active metabolites, including 9-CIS-retinology esters of fatty acids and 9-CIS-the retinol.

Figure 2 (A-C) demonstrates a dose-dependent increase of the amplitudes of both a-wave and b-wave in mice treated with a single dose of 9-CIS- retinella in soybean oil.

Figure 3 shows the dosage for a 14-day period in which ERG was recorded from one outbreak and determined retinoid levels in the eyes.

Figure 4 (A-D) demonstrates ERG in a dose-dependent increase of the amplitudes of both a-waves and b-waves in the treatment compared with the baseline level of 5-week-old miceRpe65-/-.

Figure 5 shows the dosage and evaluation of ERG and retinoid analyses after three daily doses of 9-CIS-retinella in soybean oil.

Figure 6 (A-F) demonstrates dose-dependent amplitudes of a - and b-waves of ERG responses recorded up to 9 days after three daily doses of 9-CIS-retinella in soybean oil.

Figure 7 shows intermittent dosing and daily dosing regimen during the 8-week period.

Figure 8 (A-D) demonstrates dose-dependent increase in the amplitude of a - and b-waves on day 28 and day 56 with intermittent dosing and daily dosing regimen.

Figure 9 (A-I) shows that followed the introduction of long-term 9-CIS-retinella dose-dependent protective effect on the retina, measured by the lengths of the outer segments of photoreceptors.

Figure 10 shows the levels of retinoids in plasma, as determined using HPLC, after the introduction of 9-CIS-retinella.

Figure 11(A) shows retinoids in the eyes and liver after 14 days of daily treatment 9- CIS-reconiliation.

Figure 12 shows the kinetics of disappearance of 9-CIS-retinal eye after 3 daily doses of 9-CIS-retinella.

Figure 13 (A-B) shows the contents of retinoids in the eyes of mice, Rpe65-/- after intermittent and daily treatment with 9-CIS-R ACE for 8 weeks.

Figure 14 (A-C) shows the analysis of retinoids in the liver of mice Rpe65-/- after a 56-day intermittent and daily treatment with 9-CIS-reconiliation.

DETAILED description of the INVENTION

Described pharmaceutical compositions 9-CIS-retinology esters suitable for retinoid replacement therapy. More specifically, the pharmaceutical compositions contain one or more 9-CIS-retinology esters and lipid filler.

As used herein, "retinoid" refers to the class of chemical compounds, natural or artificial, akin to vitamin A. Structural retinoids have a common core structure consisting of a cyclic end group, a conjugated polyene side chain and a polar end group. Retinoids natural origin include, for example, vitamin A (11-TRANS-retinol), 11-TRANS-retinal and 11-TRANS-retinoic acid. Artificial and synthetic retinoids suitable for retinoid replacement therapy include, for example, 9-CIS-R�tinylove esters, as defined herein, 9-CIS-retinal and 9-CIS-the retinol.

As noted herein, 9-CIS-retinology esters can act as precursors Pro-drug form, or prodrug 9-CIS-retinal, which is able functionally to unite with opsins, thus, completing the retinoid cycle, although, for example, RPE65 deficiency or mutation.

Thus, one version of the implementation describes a pharmaceutical composition comprising: one or more 9-CIS-retinology esters and lipid excipient, one or more 9-CIS-retinology esters suspended in a lipid filler.

9-CIS-retinology esters

9-CIS-retinology esters include the following typical structure of Formula (I):

where R represents an alkyl group or alkenyl group.

"Alkyl" refers to a radical with unbranched or branched hydrocarbon chain consisting solely of carbon atoms and hydrogen, containing no unsaturated hydrocarbons containing up to twenty-two carbon atoms. In some embodiments, alkyl may contain from twelve to seventeen carbon atoms (also referred to as "C12-17-alkyl"). In some embodiments, the implementation, and�keel may contain from twelve to fifteen carbon atoms (also referred to as "C 12-15-alkyl"). In some embodiments, alkyl may contain from one to eight carbon atoms (also referred to as "C1-8-alkyl"). In other embodiments, alkyl may contain from one to six carbon atoms (also referred to as "C1-6-alkyl"). In additional embodiments, alkyl may contain from one to four carbon atoms (also referred to as "C1-4-alkyl"). The alkyl is attached to the rest of the molecule through a simple connection, for example methyl, ethyl,n-propyl, 1-methylethyl (every-propyl),n-butyl,n-pentyl, 1,1-dimethylethyl (tert-butyl), 3-etylhexyl, 2-etylhexyl and the like. If the description does not specifically stated otherwise, the alkyl group may be optionally substituted by one or more of the following substituents: halo (including F, -Br, -Cl and-I), cyano (-CN), nitro (-NO2), oxo (=O) and hydroxyl (-OH).

"Alkenyl" refers to a radical with unbranched or branched hydrocarbon chain consisting solely of carbon atoms and hydrogen, containing at least one unsaturated hydrocarbon (i.e., C=C), having from two to twenty carbon atoms. In various embodiments, R is C12-17-of alkenyl, C1-8-alkenyl, C1-6-alkenyl or C1-4-alkenyl. If the description �specialno otherwise indicated, the alkyl group may be optionally substituted by one or more of the following substituent groups: halo (including F, -Br, -Cl and-I), cyano (-CN), nitro (-NO2), oxo (=O) and hydroxyl (-OH).

In some embodiments, 9-CIS-retinology esters are artificial retinoids, which act as precursors (i.e., pre-drugs) Pro-drug form 9-CIS-retinal. More specifically, 9-CIS-retinology esters may be converted by the liver in metabolic Pro-drug form, namely 9-CIS-retinology esters of fatty acids stored in the liver in hepatic lipid droplets. 9-CIS-retinology esters of fatty acids and retinol is mobilized from the liver and enter the circulation where they migrate to the eye and RPE. There they are converted to 9-CIS-retinal, which ultimately connects to the photoreceptor opsins to form active visual pigments.

Preferred 9-CIS-retinaculum ester is 9-CIS-retinella (i.e., R is methyl). Also referred to as "9-CIS-R-Ac, 9-CIS-reinjected is a pharmaceutical pre-drug that is metabolized in the liver to 9-CIS-retinology esters of fatty acids such as 9-CIS-remineralised. 9-CIS-retinology esters LM�tion of acids and retinol is then converted into 9- CIS-retinal in the eye and RPE, as a substitute of missing chromophores, such as 11-CIS-retinal.

9-CIS-R-AC can be prepared by initial conversion fullyTRANS-retinella (Sigma-Aldrich) in a mixture of 9-CIS-retinella and completelyTRANS-retinella in the presence of a palladium catalyst (e.g., palladium oxides, palladium). A mixture of 9-CIS-retinella and completelyTRANS-retinella then hydrolysed for the formation of a mixture of 9-CIS-retinol and completelyTRANS-retinol. Clean 9-CIS-retinol is possible to highlight by selective recrystallization and subsequent esterification to clear 9-CIS-R-Ac. Detailed description of the processes for preparing and purifying 9-CIS-R-Ac can be found, for example, in British patent GB No. 1452012.

In other embodiments, retinology esters are prodrugs (not a prodrug precursors) and can be directly converted to 9-CIS-retinal in the eye and RPE. Pro-drug form 9-CIS-retinology esters are typically 9-CIS-retinylidene esters of fatty acids, in which R represents C11-12-alkyl. Herein, "fatty acid" refers to carboxylic acid with a long aliphatic chain, which may be on�isenay (alkyl) or unsaturated (alkenylamine). Typically, the aliphatic chain contains at least 11 carbon and can reach up to 21 carbon in length. Typical fatty acids include, as non-limiting examples, lauric acid, palmitic acid, palmitoleic acid, oleic acid, linoleic acid and linolenic acid.

Thus, in one embodiment of the implementation, R is a C15-alkyl and 9-CIS-retinology ester of the Formula (I) is a 9-CIS-remineralised.

In an additional variant of implementation, R is a C17-alkyl and 9-CIS-retinology ether of the Formula (I) is a 9-CIS-reminiscent.

In another embodiment of the implementation, R is a C17-alkenyl, and 9-CIS-retinology ether of the Formula (I) is a 9-CIS-retinella.

9-CIS-retinology esters described herein can be obtained from 9-CIS-retinol, using suitable esterifying agents in a manner similar to the method of producing 9-CIS-R-AC, which are in the competence of specialists in this field.

As shown herein, low doses (1 and 4 mg/kg) typical pre-drug, 9-CIS-R-Ac as shown to be clinically safe and effective in maintaining visual function in miceRpe65 -/-estimated by the ERG registrations, levels of retinoids in the eyes, histology of the retina and of view-dependent behavioral research. This connection is used for the treatment of, for example, people with retinopathy associated with lack of education retinoid chromophore.

Lipid fillers

Generally, 9-CIS-retinology esters are oily substances and are lipophilic. Thus, the described pharmaceutical composition may further comprise a lipid filler.

Since 9-CIS-retinology esters are sensitive to light and oxygen, their stability is critical to the efficiency and shelf life of the composition. In this regard, a suitable lipid excipient is chosen for its ability to stabilize 9-CIS-retinology esters, suspended or solubilized therein.

As used herein, "lipid" or "lipid excipient" refers to one or mixtures of esters of fatty acids. In various embodiments, the lipid excipient comprises one or more triglycerides, which are formed when glycerol is esterified with three fatty acids. Triglycerides include vegetable oils and animal fats.

In the context of lipid excipients, triglycerides referred to simply by their corresponding fatty acids. The fatty acid triglycerides can be saturated, monounsaturated or polyunsaturated depending on the number of carbon-carbon double bonds (C=C) in the aliphatic chains. Saturated fatty acid contains no carbon-carbon double bonds in the aliphatic chains. Examples of saturated fatty acids include, for example, palmitic and stearic acid. Monounsaturated fatty acid contains only single carbon-carbon double bond (C=C) in the aliphatic chain. Examples of monounsaturated fatty acids include, for example, oleic and palmitoleic acid. Polyunsaturated fatty acid contains at least two carbon-carbon double bond in the aliphatic chain. Examples of polyunsaturated fatty acids include, for example, linoleic acid (two C=C) and linolenic acid (three C=C). Further, polyunsaturated fatty acids include fatty acids omega-3 and omega-6, depending on the location of the destination C=C-bond in the aliphatic chain. For example, linoleic acid is the fatty acid omega-6, whereas linolenic fatty acid is omega-3.

Typically, the lipid excipient is a mixture of fatty acids, the relative content of each of which can affect the General characteristics of the lipid excipient, especially on its ability prep�estvovati oxidation and stabilize suspendiruemye in it 9- CIS-retinology the air.

In some embodiments, the lipid excipient is more than 50 wt./wt.% polyunsaturated fatty acids, including fatty acids omega-6 and omega-3 in a ratio (by weight) less than 15. In specific embodiments, the lipid excipient contains triglyceride-linoleic acid and triglyceride-linolenate in the ratio (by weight) less than 15, which together make up more than 50% of the total weight of the lipid aggregate.

In other embodiments, the lipid excipient may be a vegetable oil or mixture of oils, which contains more than 50 wt./wt.% polyunsaturated fatty acids, including fatty acids omega-6 and omega-3 in a ratio (by weight) less than 15.

Table 1 shows a number of vegetable oils and their component fatty acids in percent by weight (see, for example, patent publication U.S. No. 2007071872).

Soybean oil is a suitable lipid filler because it contains about 62% polyunsaturated fatty acids (54% linoleic acid and 8% linolenic), 25% monounsaturated fatty acids (oleic) and 16% saturated fatty acids (11% palmitic acid and 5% stearic acid).

Soybean oil is a transparent oil without smell that mixed�is from 9- CIS-retinylidene esters described herein. Compared with fatty acids containing a lower concentration of polyunsaturated fatty acids (e.g. rapeseed oil and olive oil, which contain about 30% and less than 20% polyunsaturated fatty acids, respectively), soybean oil unexpectedly exhibits improved stabilizing effect, as evidenced by the increased content of pure 9-CIS-retinella, preserved in the compositions after a two-week period.

In addition, when compared with fatty acids that have a higher ratio of polyunsaturated fatty acids omega-6 to omega-3, soybean oil also demonstrate excellent stabilizing effect. For example, sunflower oil, despite the total amount of polyunsaturated fatty acids (61%), comparable to that for soybean oil has a much higher ratio of polyunsaturated fatty acids omega-6 to omega-3 (over 600) than soybean oil (about 7). As shown in Table 2 (Example 1), the stabilizing effect of sunflower oil is comparable to that of rapeseed oil, for both are much lower than for soybean oil (USP-grade).

It is also essential that the compositions of soybean oil are the most stable in comparison with the compositions of other fillers when the temperature�, close to physiological conditions (e.g. 40°C). Highly refined soybean oil, which meets the USP monogram, is preferred (e.g., as provided by the Assortment of chemicals), as it was noted that soybean oil USP class provides more stabilization than the commercial grade soya oil (see Example 1).

In addition, the filler based on soybean oil provides the highest level of plasma metabolites 9-CIS-retinology esters. Figure 1 shows the relative absorption of 9-CIS-R-AC and saving in the plasma of its active metabolite, 9-CIS-retinology esters of fatty acids and 9-CIS-retinol.

Thus, it is shown that soybean oil at the same time and gives stability 9-CIS-retinology esters, and high retention in plasma active metabolites, thereby providing compounds synergistic benefits.

In an additional variant of implementation, the lipid excipient is walnut oil, which contains 72% of polyunsaturated fatty acids (62% linoleic acid, 12% linoleic).

And in another variant implementation, the lipid excipient is an oil of wheat germ, which contains 62% of polyunsaturated fatty acids (55% linoleic acid and 7% linolenic).

Compositions:

In the majority of cases�in, pharmaceutical compositions can include any of 9-CIS-retinology esters described herein, in combination with a suitable lipid filler.

One version of the implementation describes a pharmaceutical composition containing one or more 9-CIS-retinology esters in lipid excipient, where the lipid filler is more than 50 wt./wt.% polyunsaturated fatty acids, including fatty acid omega-6 and fatty acid omega-3 in a ratio (by weight) less than 15.

An additional variant of the implementation describes a pharmaceutical composition containing 9-CIS-reinjected in lipid excipient, where the lipid filler is more than 50 wt./wt.% polyunsaturated fatty acids, including fatty acid omega-6 and fatty acid omega-3 in a ratio (by weight) less than 15.

An additional variant of the implementation describes a pharmaceutical composition containing 9-CIS-reinjected in lipid excipient, where the lipid filler contains triglyceride-linoleic acid and triglyceride-linolenate in the ratio (by weight) less than 15, which together make up more than 50% of the total weight of the lipid aggregate.

An additional variant of the implementation describes a pharmaceutical composition containing 9-CIS-reinjected in soybean oil.

Another VA�iant describes the implementation of the pharmaceutical composition, containing 9-CIS-reinjected in walnut oil.

Another version of the implementation describes a pharmaceutical composition containing 9-CIS-reinjected in wheat germ oil.

In various embodiments, the pharmaceutical composition contains up to 40% (by weight) 9-CIS-retinology esters, up to 30% (by weight) 9-CIS-retinology esters, up to 25% (by weight) 9-CIS-retinology ethers, up to 10% (by weight) 9-CIS-retinology esters, up to 5% (by weight) 9-CIS-retinology esters.

Optional components:

The pharmaceutical compositions described herein can optionally include additional components that enhance the stability and palatability. For example, to provide additional stabilizing effect can be included one or more stabilizers (e.g., antioxidants). Further, to improve the taste of compositions for oral administration can be added flavoring.

The antioxidant used in the present disclosure, may represent one or more of the following: α-tocopherol, butylated hydroxyanisole (.), butylated hydroxytoluene (OSH), ascorbyl palmitate and propylgallate,tert-butylhydroquinone (TBHQ). It is possible to use complexing agents, such as dimitriades and cal�identifiedat.

Flavouring substances and flavour enhancers of the pharmaceutical properties make the compositions more palatable for the patient. It is well-known flavouring substances and flavour enhancers properties of pharmaceutical products that may be incorporated into the composition of the present invention include maltol, vanillin, ethylvanillin, menthol, citric acid, fumaric acid, eternality and tartaric acid. Preferred flavored oils (e.g. lemon oil), because they are miscible with the lipid excipient. Sweeteners such as sorbitol, saccharin, nutrisari, sucrose, aspartame, fructose, mannitol and invert sugar may be added to improve the taste.

Water, surfactants or emulsifiers can be added to the compositions of oil-based for the formation of a mixture suitable for oral use (for example, in the form of a drink) or intravenous injection. Suitable surfactants and emulsifiers include, for example, soy lecithin and dipalmitoylphosphatidylcholine. Beverages such as soy milk also can be added directly to the compositions described herein.

Thus, one implementation option provides a beverage containing one or more 9-CIS-retinology esters and lipid filler, g�e lipid filler contains more than 50 wt./wt.% polyunsaturated fatty acids, including fatty acid omega-6 and fatty acid omega-3 in a ratio (by weight) less than 15.

Additional implementation option provides a recipe of a beverage, an emulsion or a drink containing 9-CIS-retinella, soy oil and drinking fluid. In certain embodiments, drinking liquid medium is in the form of an emulsion type "oil in water" (e.g., milk or soy milk). Can also be used for more emulsifiers, such as, for example, acacia, tragacanth gum and cellulose.

Additional implementation option provides a composition for oral administration in capsule form containing 9-CIS-retinella, soybean oil. May include additional excipients, such as antioxidants, as determined by a specialist in that field.

The compositions for administration and dosage forms

Pharmaceutical composition described herein can be administered to the subject by oral, gastric or local administration, such as injection into the vitreous body, and intravenous injection.

Oral administration may be oral using a probe or the drinking or beverage composition that includes one or more 9-CIS-retinology esters, lipid filler and beverage, such as soy�th milk.

Gastric introduction can be carried out using a stomach probe (e.g., gastric tube).

Topical administration, such as injection into the vitreous body and intravenous injection, carried out with the help of syringes.

As used herein, "subject" refers to the patient who can belong to any mammalian species, such as primates, particularly humans; rodents, including mice, rats and hamsters; rabbits; equine animals; cattle; dog; cat and more. Animal models, particularly genetically modified animals are of interest for experimental investigations, providing a model for treatment of human diseases, such as LCA.

As a rule, all doses of 9-CIS-R-Ac fully mixed in lipid excipients, including soybean oil, USP (Spectrum Chemicals). In various embodiments, the described one-time, intermittent and daily administration. Further, based on the levels of the pharmacologically active metabolite 9-CIS-retinology esters in plasma after absorption, the dosage, and proper performance 9-CIS-retinology esters can be estimated by the ERG, visual acuity testing when incentives full excitation, analysis of visual field, color vision test.

As shown in the Examples, doses�dependent increase as level, and duration of retinal function was observed in mice with knockoutRpe65andLratwho are the two genetic models of LCA. Importantly, the pharmacological activity is maintained for a sufficiently long period of time after dosing to give the opportunity to be flexible, intermittent dosing scheme.

More specifically, a single dose of 9-CIS-R-Ac (from 6.25 to 50 mg/kg) resulted in significant dose-dependent improvement of ERG responses. Daily doses (1, 4 and 12.5 mg/kg) for two weeks was well tolerated and induced a remarkable improvement in retinal function. A significant dose-dependent improvement of ERG responses was observed 6 days after administration of 9-CIS-R-Ac daily for 3 days and 1, 4 and 12.5 mg/kg. Mice treated with daily or intermittent treatment 9-CIS-R-Ac with 1 and 4 mg/kg/day and evaluated after two months, showed a dose-dependent improvement in retinal function and morphology 8 weeks later, while we compared the 3-month control animals retinal function has deteriorated.

Thus, in one embodiment, the implementation described in this document are provided a dosage form suitable for 24 hour or daily dosing of 9-CIS-R-Ac needy in this subject, containing approximately 1.25-20 mg/ml 9-CIS-R-Ac in soybean oil drug� shape provides approximately 1.25-40 mg/m 29-CIS-R-Ac on the area of the body surface of the subject over a 24-hour period.

In another embodiment, the implementation, the dosage form provides a time to maximum or peak plasma concentrations of 9-CIS-retinology esters of about 3-6 hours after oral or gastric administration of the drug composition. As used herein "peak concentration in plasma is a pharmacokinetic measure to assess the bioavailability of the medicinal product. Plasma drug concentration increases with the degree of absorption; the peak is reached when the elimination rate of a drug equals the rate of absorption. In addition to the maximum (peak) concentration of drug in the plasma pharmacokinetics parameters are the corresponding peak time (when the maximum drug concentration in plasma and area under the curve plasma concentration from time to time.

In an additional variant of the implementation described in this document are provided pharmaceutical composition, suitable for single dosing the introduction into the vitreous body 9-CIS-retinella entity containing about 18-40% mg/ml 9-CIS-retinella in soybean oil. It was found that od�okrutna dosage the introduction into the vitreous body of the eye of the subject may continue for several days even weeks, possibly with the help of the method of delayed release.

Using 9-CIS-retinology esters as retinoid replacement therapy

Also described herein are methods of using 9-CIS-retinology esters of the Formula (I) as retinoid replacement therapy retinal degeneration in humans.

Assessment of the efficacy and safety of 9-CIS-retinology esters, as retinoid replacement therapy, were performed with the use of appropriate animal models (see Examples). The animals used are miceRpe65-/-that lack of retinal pigment epithelium-specific protein mass of 65 kDa (RPE65) and developing retinopathy and blindness, reminiscent of LCA in humans.

Pharmacokinetic and pharmacodynamic effects of pre-medication show that in the model in miceRpe65-/-pre-medication in the liver is converted to a prodrug, i.e., mostly in 9-CIS-remineralised (see Examples). Further, in the model in miceRpe65-/-watched 9-CIS-retinoids were delivered to the retina in two ways, that is, above all, rapidly from the circulating blood and, secondly, more slowly, from the stock 9-CIS-retinoids in the liver (see, for example, 5).

Using multiple razlichnyim in mice Rpe65-/-to evaluate the effectiveness of drug action and safety, it was shown that 9-CIS-retinology esters can be used as synthetic retinoids for the treatment of LCA patients person. Was observed as a dose-dependent and depends on the period of introduction of the preservation of visual function, even at the lowest tested doses of 1 and 4 mg/kg (Figure 2, 4, 6, 8). Significantly, dose-dependent prolongation of the efficiency was observed for the pre-meds 9-CIS-R-Ac.

Thus, one implementation provides a method for the treatment of congenital blindness Leber the subject is human, comprising administering a pharmaceutical composition comprising an effective amount of one or more 9-CIS-retinology esters of the Formula (I) in soybean oil. In a more specific embodiment of the, 9-CIS-retinology ethers with Formula (I) represent 9-CIS-retinella.

Additional implementation option provides a method comprising: introducing to a subject-a person with lack of 11-CIS-retinal pharmaceutical composition comprising an effective amount of one or more 9-CIS-retinology esters of the Formula (I) in soybean oil. In a more specific embodiment of the, 9-CIS-retinology ethers with Formula (I) represent 9-CIS-retinella.

Various options for implementation�tion, described in this document, is further illustrated by the following non-limiting examples.

EXAMPLES

Materials, methodology and analysis

Electroretinogram (ERG) - ERG was recorded for anesthetized mice, as described, for example, Maeda A,et al. Role of photoreceptor - specific retinol dehydrogenase in the retinoid cycle in vivo.J Biol Chem2005; 280:18822-18832; and Maeda T,et al. A Critical Role of CaBP4 in the Cone Synapse.Investigative ophthalmology & visual science2005; 46:4320-4327.

Briefly, mice are first adapted to the darkness during the night before registration. Then, when you secure the light mice were anestesiologi by intraperitoneal injection of 20 µg/g body weight of 6 mg/ml ketamine and 0.44 mg/ml xylazine diluted with a solution of 10 mm sodium phosphate, pH 7.2, containing 100 mm NaCl. The pupils expanded 1% Tropicamide. A contact lens electrode was placed on the eye and the control electrode and the ground electrode was positioned respectively on the ear and tail. ERGS were recorded using a universal testing and electrophysiologic system (UTAS E-3000 (LKC Technologies, Inc.).

Registration after a single flash- Stimulating flash of white light was applied in the range of intensities (from -3,7 to 2.8 log cd·s·m2), and the duration of the flash adjusted in accordance with the intensity (from 20 µs to 1 MS). It was made from two to five registrations with eno�governmental intervals between stimulating outbreaks (from 10 s to 10 min), to allow the mice to recover. As a rule, for the registration of each point was used from four to eight animals. One-sided ANOVA test was used for statistical analysis of responses.

Histology and immunohistochemistryHistological procedures were used for the analysis of the eye, as described in Maeda A,et al. above.

Analysis of retinoic acid and nonpolar retinoidsAll experimental procedures related to extraction, obtaining retinoid derivatives and separation of retinoids were performed under dim red light, provide light protection filter 1 from Kodak (transmittance > 560 nm). Extraction of retinoic acid from the liver was performed as previously described, for example, Batten ML.et al. above. Analysis of polar retinoids in plasma, eye and liver was performed using a HPLC Agilent 1100 and two tandem columns with normal-phase: Varian Microsorb Silica 3 µm, a 4.6×100 mm (Varian, Palo Alto, CA) and column (Ultrasphere-Si, 5 µm, a 4.6×250 mm (Aleman TSet al., above). The isocratic normal phase system hexane:2-propanol:glacial acetic acid (1000:4,3:0,675; about./about./about.) was used for elution at a flow rate of 1 ml/min at 20°C with detection at 355 nm. Calibration was performed with standards fullyTRANSretinoic acid and 9-CISretinoic acid, prio�retenue from Sigma-Aldrich. Analysis of nonpolar retinoids in plasma, and liver were carried out using HPLC normal-phase (Ultrasphere-Si, 5 µm, a 4.6×250 mm, Beckman, Fullerton, CA) with 10% ethyl acetate and 90% hexane at a flow rate of 1.4 ml/min with detection at 325 nm by HPLC HP1100 diode-array detector and software HP Chemstation A. 03.03.

EXAMPLE 1

STABILITY TESTS of VARIOUS COMPOSITIONS

Several different formulations based on lipids 9-CIS-R-Ac were prepared to test the stability provided by different lipid fillers. Since 9-CIS-R-Ac were considered as sensitive to light, vials, amber glass was used whenever it was possible, and a connection has been accessed by the Golden light of fluorescent lamps. 9-CIS-R-Ac moved from a freezer at -20°C and warmed to room temperature for 30 minutes. Treatment of compound was performed in the argon gas flow, since the compound was transferred into a preweighed vial, amber glass, and re-weighed to calculate the number of connections, before the vials filled with argon and stored at -20°C until use.

A mixture of 9-CIS-R-AC (from 1.4 to 8 mg/ml) in different carriers/excipients were prepared with the use of amber glass vials containing exactly in�Vesennie connection. The vials with samples were filled with argon and mixed by vigorous shaking. Samples of castor oil with polyoxyl 35 was heated to 60°C. Each sample was divided into two parts and stored at 4°C or 40°C. the Samples were analyzed by HPLC for the content of 9-CIS-retinella immediately upon receipt (day 0) and at time points up to 2 weeks after receipt.

Samples for HPLC analysis were diluted to approximately 0.1 mg/ml in tetrahydrofuran. Samples were immediately analyzed or stored at -20°C or - 70°C up to 1 week before analysis. The percent recovery was calculated relative to the concentration in the composition at day 0 determined by HPLC.

Suddenly, soybean oil (USP), with and without the presence of presence of BGE, provides the most stable suspension of 9-CIS-R-Ac, especially at physiological temperatures (about 40°C), as shown by the percentage of 9-CIS-R-Ac in the composition at day 7 and day 14 (table 2).

EXAMPLE 2

The PRESERVATION of PLASMA METABOLITES 9-CIS-RETINELLA

Developed several different drugs on the basis of the oil to determine the levels of absorption of 9-CIS-R-AC in plasma. More specifically, the single dose of 50 mg/kg 9-CIS-retinella (50 mg/kg) suspended in 4 different filling oils, was administered using a gastric probe 5-weeks�th mice C57/BI6 and after that was determined retinoid levels in plasma (n=5 in each time point per group).

A solution of 9-CIS-R-Ac in soybean or sunflower oil compared to canola oil and rapeseed oil provided the best absorption of 9-CIS-R-Ac, as evidenced by the highest levels 9-CIS-retinology esters of fatty acids and 9-CIS-retinol in plasma, both active metabolite 9-CIS-R-AC (Figure 1A, C, 11). The highest levels in the plasma of these 9-CIS-retinoids were observed in about 3 h. Plasma levels completelyTRANS-retinol and completelyTRANS-retinol esters of fatty acids are not significantly different among the tested fillers, and during the 23-hour period of testing, suggesting thatCIS-retinoids were not fully converted toTRANS-retinoids (Figure 1, B, D).

Figure 10 shows retinoids in plasma, as determined using HPLC. Retinology esters of fatty acids, detected previously in the phase elution (a, b, c), consisted of four peaks 9-CIS-(a, c) and two peaks completelyTRANS-(b) isomers. As 9-CIS-retinol (d), and completelyTRANS-retinol (e) loirevalley later.

EXAMPLE 3

The EFFECTS of SINGLE doses of 9-CIS-R-AC FOR RETINABUY FUNCTION MICERpe65-/-

A single dose (2-50 mg/kg) 9-CIS-R-AC in soybean oil was administered to 5-week-old miceRpe65Rpe65-/-to check whether or not capable of pre-prodrug of 9-<> CIS-R-Ac to deliver the artificial chromophore to the eye.

Mice showed no obvious clinical side effects, even after receiving the highest dose of 50 mg/kg. After adaptation to darkness for 3 days and probe introduction was recorded scotopic ERG from a single outbreaks, and the eyes were collected to assess levels 9-CIS-retinal.

Scotopic ERG of the treated mice showed a dose-dependent increase of the amplitudes of both a-and b-waves (Figure 2A, B); the lowest dose tested, which provided a significant improvement after high-intensity stimulus consisted of 6.25 mg/kg. similarly, a dose-dependent accumulation of 9-CIS-retinella was detected in the eyes of treated mice that correlated with the improvement of retinova functions (Figure 2C). In none of the studied eyes there were no 9-CIS-retinology esters of fatty acids, whereas theTRANS-retinology esters of fatty acids were in the range of from about 1 to 1.6 nmol/eye and do not differ significantly between the four treatment groups. In addition, theTRANS-retinology esters of fatty acids were similar with 1.2 nmol/eye reported for non-treated 5-week-old miceRpe65-/-.

9-CIS-retinol (43 pmol/eye) was detected only in the eyes of mice, dosed with 50 mg/kg, while theTRANS-retinol, ranging from 14 to 22 pmol/eye, did not differ significantly between the four treatment groups. In none of the eyes 11-CIP-retinoids were found.

Thus, the results indicate that 9-CIS-retinal recombines with openam with the formation of ISO-rhodopsin. Importantly, reduced doses of 9-CIS-R-Ac (2 and 4 mg/kg) evoked ERG positive effects, despite the fact that only trace levels 9-CIS-retinal was detected in the eye (Figure 2).

EXAMPLE 4

EFFECTS 9-CIS-R-AC, ADMINISTERED DAILY FOR 14 DAYS

Retinabuy function miceRpe65-/-and C57BI/6 tested after repeated daily dosing of 9-CIS-R-Ac. To test this directly, 5-week-old miceRpe65-/-daily gavage was administered to 9-CIS-R-Ac in soybean oil at doses of 1, 4 or 12.5 mg/kg for 14 days. Mice were exposed to external conditions that change with the dark and the fluorescent light (the brightness range 500-1500 suites) during the last 11 days of treatment. Scotopic ERG from a single outbreaks were recorded and identified retinoid levels in the eyes (Figure 3).

ERG showed a dose-dependent increase of the amplitudes of a - and b-waves in treated mice compared with the baseline level of 5-week-old miceRpe65 -/-(Figure 4A, B). Even the lowest check the daily dose of 1 mg/kg caused a significant improvement in retinova function compared with the control group.

9-CIS-retinal easily detected in the eyes of animals with a knockout of genes, but no 9-CIS-retinology esters of fatty acid or 9-CIS-retinol was not present (Figure 11A-C). 9-CIS-retinology esters of fatty acids accumulated dose-dependent manner in the liver of both mice C57BI/6 and miceRpe65-/-(Figure 11D). The presence of 9-CIS-retinal in the eyes of these mice involves improving retinova function, as was observed in studies with single doses in miceRpe65-/-. In the eyes of treated mice was also a corresponding dose-dependent accumulation of 9-CIS-retinal (Figure 4C). In the eyes of the control group and the group held treatment 1 mg/kg, 9-CIS-retinal were detected, while in groups with daily doses of 4 and 12.5 mg/kg was determined respectively 38±4 and 95±14 pmol. Levels 9-CIS-retinology esters of fatty acids were low (1 pmol/eye) in groups with a daily 4 and 12.5 mg/kg and did not show up in the eyes of the other groups (Figure 4D). In any group were not detected in either fullyTRANS-retinol or 9-CIS-retinol. TheTRANS-retinology esters of fatty acids (� mainly palmitate, stearate and oleate) in the eyes of mice exposed to 9-CIS-R-Ac were in the range of from 1.2 to 1.4 nmol/eye and was not significantly different from those in the controls (1.2 nmol/eye at 5 weeks of age).

The ERG responses indicate an increase in efficiency and improvement of the kinetics of 9-CIS-R-AC dose-dependent manner. The lowest dose (1 mg/kg) significantly improved ERG responses compared with the baseline level of 5-week-old miceRpe65-/-despite the fact that 9-CIS-retinal and 9-CIS-retinology esters of fatty acids were detected in the eye (Figure 4). This suggests that 9-CIS-retinal disappears upon exposure to light (8 h light/16 h dark) and that 9-CIS-retinology esters of fatty acids instead used for the regeneration ofevery-rhodopsin. Indeed, the accumulation of 9-CIS-retinology esters of fatty acids showed a dose-dependent manner in the liver samples, which suggests that the stock 9-CIS-retinology esters of fatty acids in the liver can serve as a source for the formation of 9-CIS-retinal andevery-rhodopsin in the eye.

In this 14-day study, each daily dosages of 1, 4, and 12.5-50 mg/kg was well tolerated as 5-week-old mice C57BI/6 and 5-week-old miceRpe65-/-that indicates the security of a 9 -R-Ac.

EXAMPLE 5

The DURATION of the IMPROVED RETINOVA FUNCTION AFTER 3 DAILY doses of 9-CIS-R-AC

9-CIS-retinol in the form of 9-CIS-retinology esters of fatty acids accumulated in the liver of miceRpe65-/-receiving repeated doses of 9-CIS-R-AC of at least 12.5 mg/kg for 2 weeks (see Figure 11D, Example 4).

To assess the ability of mice to maintain 9-CIS-retinoids and subsequently use them in the retinoid cycle, 9-CIS-R-Ac in soybean oil was administered by gavage once daily for three consecutive days at a dose of 1, 4 or 12.5 mg/kg/day of 5-week-old miceRpe65-/-contained in the dark. Mice were then subjected to cycles of 8 h fluorescent lamp brightness range 500-1500 Lux, followed by 16 h in the dark.

ERG and retinoid analysis was performed at the end of the first (day 4), second (day 5), fourth (day 7) and sixth (day 9) day of exposure to light (Figure 5). The amplitudes of both a-and b-waves of ERG responses recorded before the day 9 (Figure 6A-F) were dose-dependent at each time point and decreased with the number of exposures to light. The highest tested dose (12.5 mg/kg/day) significantly improved as a-and b-wave up to day 9 (Figure 6A-B) at high intensities, while a dose of 4 mg/kg and 1 mg/kg showed an increase of the amplitudes of a-waves up to day 9 and day 7 respectively of amplitude b-wave up to day 9 (Figure 6C-F). Levels 9-CIS-retinal in the eye was also dose-dependent and decreased with time (Figure 12). This compound was detected in the retina of all treated mice on day 4 (Figure 12), but only in the retina of mice exposed to 4 and 12.5 mg/kg on day 5 and only in the group of 12.5 mg/kg on day 7. On day 9 in the retinas treated or control mice 9-CIS-retinal was not detected. Thus, it was not necessary in daily introduction 9-CIS-R-Ac to deliver 9-CIS-R-Ac to the eye and to support the improvement of retinova function in miceRpe65-/-.

Thus, it is shown that the ERG amplitude was improved, mainly dose-dependent manner, and this positive effect was maintained for 4-6 days after treatment. In addition, a similar pattern was observed for levels 9-CIS-retinal, found in the eyes of these animals. Importantly, the improvement of ERG responses at dose level of 4 mg/kg lasted for 4-6 days after stopping treatment when 9-CIS-retinal could no longer be detected in the eyes. These results show that the positive effects of 9-CIS-R-Ac therapy remain at trace levels 9-CIS-retinal in the retina, which stabilizes ROS, whereas the ERG responses in the control group worsened. The kinetics of retinoid levels in the eyes then check�in a time of adaptation to darkness after exposure to light. It is important that the restoration of 9-CIS-retinology esters of fatty acids and 9-CIS-retinal in the eyes occurred during adaptation to the dark.

EXAMPLE 6

RETINOVA FUNCTION IN MICERpe65-/-AFTER INTERMITTENT AND DAILY INTRODUCTION 9-CIS-R-AC FOR 8 WEEKS

Because 3 low daily doses of 9-CIS-R-Ac improved ERG responses after 6 days of exposure to light (Figure 6A-F), was held for a long period of 8-week intermittent dosing regimen.

MouseRpe65-/-were divided into two groups (intermittent group and daily group), each of which treated a total of 8 weeks with 1 or 4 mg/kg 9-CIS-R-Ac. Intermittent group dosed out daily for 3 days, followed by 4-day break in reception of a medicinal product, in the course of each week, 8-week mode. Daily group dosed out daily for the entire 8-week period. Dosing regimens are illustrated in Figure 7. Mice were exposed to a daily cycle of 8 h of fluorescent light with a brightness range 500-1500 Lux, followed by 16 h in the dark. ERG was recorded on day 28 and again on day 56, after which tissue was collected for retinoid analysis of the eyes and liver and histology of the eye.

The ERG responses treated mice in the intermittent group and daily groups were snecial�but better than those of controls, both at day 28 and day 56, and a moderate decrease in the amplitude between day 28 and day 56 as noted in mice treated 9-CIS-R-Ac and control mice. As a mode of intermittent dosing and daily dosing caused a dose-dependent increase in the amplitude of a - and b-waves on days 28 and 56 (Figure 8A-D). Responses were more pronounced in the group daily dosing than in the group of intermittent dosing. A lower dose (1 mg/kg) was sufficient to cause a significant improvement of ERG responses in the control group at high stimulation intensities, regardless of treatment. In addition, the amplitudes of a - and b-waves were similar at day 28 and day 56, gave reason to assume that can be achieved is a balance between intake and storage of 9-CIS-retinol, on the one hand, and its mobilization in the retina to maintain the retinoid cycle. In agreement with these results, ERG, 9-CIS-retinal was detected dose-dependent manner in the eyes, where the levels were higher in mice dosed daily (Figure 13A). 9-CIS-retinology esters of fatty acids on low volatile levels were also found in both groups of treated animals (Figure 13B). Dose-dependent slight increase completelyTRANS-retinology esters of fatty acids has also been observed� in the eyes of treated mice regardless of the mode. In the liver 9-CIS-retinol is essentially preserved in the form of 9-CIS-retinology esters of fatty acids dose-dependent, and mode-dependent manner (Figure 14A, B). The levels of fatty acids completelyTRANS-retinology esters, essentially, did not depend on these modes, although could be slightly increased in mice treated with 4 mg/kg 9-CIS-R-Ac. Long-term introduction 9-CIS-R-Ac had a dose-dependent protective effect on the retina, which is estimated by the length of the outer segments of photoreceptors (Figure 9A, C) and number of nuclei in the outer nuclear layer (Figure 9B, D). These effects were more pronounced in the outer than in the inner region of the retina. Image at the higher magnification of cross sections of the retina showed an improvement of the morphology of rod outer segment (ROS) and a decrease in structures similar to oil droplets, in parts of the external and internal areas of retinas of mice treated regimes or 4 mg/kg daily or 4 mg/kg intermittently (Figure 9E, F). While there were no significant changes in the retinas of mice that received a dose of 1 mg/kg 9-CIS-R-Ac in aid of any scheme (Figure 9G, H), compared with retinas of control mice (Figure 9).

It is important that the ERG responses of mice that underwent intermittent treatment 9-CIS-R-Ac showed no significant difference�rd between groups doses of 1 and 4 mg/kg / day 56, suggesting that the lower dose of 1 mg/kg may have similar performance, if given continuously. As shown in Figure 9, the observed morphological improvements ROS, such that the length of ROS were significantly larger at the outer areas of the retina of mice treated with 4 mg/kg, while in animals treated with the dose of 1 mg/kg, no significant changes were observed. These observations allow us to make an educated guess that the modes of treatment in 1 and 4 mg/kg maintained the function of the mouse retinaRpe65-/-without significant clinical toxicity or abnormal retinoid accumulation in the eyes and liver.

All of the above U.S. patents, publications of patent applications U.S. patent application U.S., foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the instructions for use, included herein by reference in their entirety.

From the foregoing it should be clear that, although specific embodiments of the invention have been described herein for illustrative purposes, various modifications can be made without deviation from the spirit and scope of the invention. Accordingly, the invention is not limited to anything except PR�the proposed claims.

1. Liquid oral pharmaceutical composition for delivery of retinoid, by oral administration in liquid oral dosage form, in the human eye in an effective amount for the treatment of retinal degradation of the eye, including 9-CIS-retinology ester of the Formula (I):

where R represents an alkyl group; and a lipid excipient, containing more than 50 wt./wt.% polyunsaturated fatty acids, including fatty acids omega-6 and omega-3 in a ratio (by weight) less than 15.

2. The pharmaceutical composition according to claim 1, where R is a C12-17-alkyl, C1-8-alkyl, C1-6-alkyl or C1-4-alkyl.

3. The pharmaceutical composition according to claim 2, where R is a C1-8-alkyl.

4. The pharmaceutical composition according to claim 3, where R is a C1-6-alkyl.

5. The pharmaceutical composition according to claim 4, where R is a C1-4-alkyl.

6. The pharmaceutical composition according to claim 5 where R is methyl and 9-CIS-retinology ester of the Formula (I) is a 9-CIS-retinella.

7. The pharmaceutical composition according to claim 1, wherein the lipid filler contains soybean oil, walnut oil or wheat germ oil.

8. The pharmaceutical composition according to claim 7, where soybean oil is a highly purified soybean oil.

9. Pharmaceutical�ticheskii composition according to claim 7, where the specified soybean oil is soybean oil varieties U. S. R.

10. The pharmaceutical composition according to claim 1, where the specified pharmaceutical composition comprises up to 40 wt.% 9-CIS-retinova ester.

11. The pharmaceutical composition according to claim 1, where the specified pharmaceutical composition comprises up to 30 wt.% 9-CIS-retinova ester.

12. The pharmaceutical composition according to claim 1, where the specified pharmaceutical composition comprises up to 25 wt.% 9-CIS-retinova ester.

13. The pharmaceutical composition according to claim 1, where the specified pharmaceutical composition comprises up to 10 wt.% 9-CIS-retinova ester.

14. The pharmaceutical composition according to claim 1, where the specified pharmaceutical composition comprises up to 5 wt.% 9-CIS-retinova ester.

15. The pharmaceutical composition according to claim 1, containing a 1.25-20 mg/ml of 9-CIS-retinova ester.

16. The pharmaceutical composition according to claim 1, containing 20 mg/ml of 9-CIS-retinova ester.

17. The pharmaceutical composition according to claim 1, further comprising an antioxidant.

18. The pharmaceutical composition according to claim 17, where the antioxidant is an α-tocopherol, butylated hydroxyanisole (.), BHT (butylated hydroxy toluene), ascorbyl palmitate, propylgallate, tert-butylhydroquinone (TBHQ), or chelating agent, or a combination.

19. The pharmaceutical composition according to claim 17, comprising about 0.1 wt./�b.% antioxidant.

20. The pharmaceutical composition according to claim 17, where the specified antioxidant is butylated hydroxyanisole (.).

21. The pharmaceutical composition according to claim 1, further comprising one or more flavoring agents, flavor enhancers, flavored oils and sweeteners funds.

22. The pharmaceutical composition according to claim 1, further comprising a medium suitable for drinking.

23. The pharmaceutical composition according to claim 22, where the specified potable environment includes one or more of water, milk, soy milk, surfactants and emulsifiers.

24. The pharmaceutical composition according to claim 23, where said surfactants and emulsifiers selected from the group consisting of soy lecithin, dipalmitoylphosphatidylcholine, acacia, tragacanth gum and methylcellulose.

25. The pharmaceutical composition according to claim 1, where the specified oral composition is a capsule form.

26. The pharmaceutical composition of claim 1, wherein the introduction of said composition provides a 1.25-40 mg/m29-CIS-retinova ester on the area of the body surface of the subject.

27. The pharmaceutical composition of claim 1, wherein the introduction of said composition provides 40 mg/m29-CIS-retinova ester on the area of the body surface of the subject.

28. Liquid oral pharmaceutical composition for delivery of retinoid by oral administration in the W�dcoi oral dosage form, in the human eye in an effective amount for the treatment of retinal degradation of the eye, including 9-CIS-retinology ester and soybean oil.

29. The pharmaceutical composition according to claim 28, further comprising an antioxidant.

30. The pharmaceutical composition according to claim 29, where the antioxidant is an α-tocopherol, butylated hydroxyanisole (.), BHT (butylated hydroxy toluene), ascorbyl palmitate, propylgallate, tert-butylhydroquinone (TBHQ), or chelating agent, or a combination.

31. The pharmaceutical composition according to claim 29, comprising about 0.1 wt./vol.% antioxidant.

32. The pharmaceutical composition according to claim 30, where the specified antioxidant is butylated hydroxyanisole (.).

33. The pharmaceutical composition according to claim 28, further comprising one or more flavoring agents, flavor enhancers, flavored oils or sweeteners funds.

34. The pharmaceutical composition according to claim 28, further comprising a medium suitable for drinking.

35. The pharmaceutical composition according to claim 34, where the specified potable environment includes one or more of water, milk, soy milk, surfactants and emulsifiers.

36. The pharmaceutical composition according to claim 35, where said surfactants and emulsifiers selected from the group consisting of soy lecithin, dipalmitoylphosphatidylcholine, acacia, tragacanth gum � methylcellulose.

37. The pharmaceutical composition according to claim 28, where soybean oil is highly purified soybean oil.

38. The pharmaceutical composition according to claim 28, where the specified soybean oil is soybean oil varieties U. S. R.

39. The pharmaceutical composition according to claim 28, comprising up to 5 wt.% 9-CIS-retinella.

40. The pharmaceutical composition according to claim 28, which includes a 1.25-20 mg/ml of 9-CIS-retinella.

41. The pharmaceutical composition according to claim 28, comprising 20 mg/ml of 9-CIS-retinella.

42. The pharmaceutical composition according to claim 28, where the specified oral composition is a capsule form.

43. Liquid oral pharmaceutical composition for delivery of retinoid by oral administration in liquid oral dosage form in the human eye in an effective amount for the treatment of retinal degradation of the eye, comprising up to 10 wt.% 9-CIS-retinella, soybean oil and 0.1 wt./vol.% butylated hydroxyanisole (.).

44. Method of application of liquid oral composition according to any one of claims.1-23, comprising administering the oral dosage pharmaceutical composition comprising an effective amount of 9-CIS-retinova ester to a person with retinal degradation.

45. A method according to claim 44, where the introduction of a daily basis.

46. A method according to claim 44, where the introduction is discontinuous.

47. A method according to claim 44, where the introduction of the composition provides a peak concentration�Oia in plasma active metabolites of the specified 9-CIS-retinova ester in 3-6 hours after injection.

48. A method according to claim 44, orally administered composition is a retinoid replacement therapy or chromophore-replacement therapy for the treatment of retinal degradation.

49. A method according to claim 44, where the retinal degradation is a consequence of the 11-CIS-retinal deficiency.

50. A method according to claim 49, where 11-CIS-retinal deficiency is a consequence of mutations in RPE65.

51. A method according to claim 49, where 11-CIS-retinal deficiency is the result of LRAT mutations.

52. A method according to claim 44, where the specified person with retinal degradation has congenital blindness Leber (LCA).

53. A method according to claim 44, where the specified person with retinal degradation has retinitis pigmentosa (RP).

54. Method of application of liquid oral composition according to any one of claims.28-42, comprising administering the oral dosage pharmaceutical composition comprising an effective amount of 9-CIS-retinova ester to a person with retinal degradation.

55. A method according to claim 54, where the introduction of a daily basis.

56. A method according to claim 54, where the introduction is discontinuous.

57. A method according to claim 54, where the introduction of the composition provides a peak plasma concentration of active metabolites of the specified 9-CIS-retinova ester in 3-6 hours after injection.

58. A method according to claim 54, where the oral administration of the composition is a retinoid & nbsp;�ing therapy or chromophore-replacement therapy for the treatment of retinal degradation.

59. A method according to claim 54, where the retinal degradation is a consequence of the 11-CIS-retinal deficiency.

60. A method according to claim 59, where 11-CIS-retinal deficiency is a consequence of mutations in RPE65.

61. A method according to claim 59, where 11-CIS-retinal deficiency is the result of LRAT mutations.

62. A method according to claim 54, where the specified person with retinal degradation has congenital blindness Leber (LCA).

63. A method according to claim 54, where the specified person with retinal degradation has retinitis pigmentosa (RP).

64. Method of application of liquid oral composition according to claim 43, comprising administering the oral dosage pharmaceutical composition comprising an effective amount of 9-CIS-retinella person with retinal degradation.

65. A method according to claim 64, where the introduction of a daily basis.

66. A method according to claim 64, where the introduction is discontinuous.

67. A method according to claim 64, where the introduction of the composition provides a peak plasma concentration of active metabolites of the specified 9-CIS-retinova ester in 3-6 hours after injection.

68. A method according to claim 64, orally administered composition is a retinoid replacement therapy or chromophore-replacement therapy for the treatment of retinal degradation.

69. A method according to claim 64, where the retinal degradation is a consequence of the 11-CIS-retinal deficiency.

70. Method pop.69, where 11-CIS-retinal deficiency is a consequence of mutations in RPE65.

71. A method according to claim 69, where 11-CIS-retinal deficiency is the result of LRAT mutations.

72. A method according to claim 64, where the specified person with retinal degradation has congenital blindness Leber (LCA).

73. A method according to claim 64, where the specified person with retinal degradation has retinitis pigmentosa (RP).



 

Same patents:

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine. What is described is a method for preparing a high-purity drug preparation for treating degenerative-dystrophic diseases of peripheral synovial joints and spinal column. The method provides introducing L-proline, an amino acid in an amount of 10-70 g/l into aqueous chondroitin sulphate solution containing no more than 11.5% of an active ingredient, and filtering the solution at temperature 20-50°C through ZetaCarbon (Cuno) R54SLP, R51SLP, R53SLP or AKS (Pall) - AKS 1, 2, 6, 7 filters.

EFFECT: method provides preparing the high-grade 99% pure liquid or lyophilised chondroprotective preparation stabilised with L-proline with the residual content of organic purities: protein - no more than 0,2%, lipids (per 1mg of chondroitin sulphate) - no more than 0,05 mcg, bacterial endotoxins (per 1mg of chondroitin sulphate) - no more than 0,05 EU.

6 cl, 3 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to a method for Helicobacter pylori eradication of a gastroduodenal zone by a silver nitrate monotherapy consisting in administering an electrolyte solution of silver ions in the concentration of 300 mcg/l in a daily volume of 960 ml, for the first three days - in an amount of 120 ml every 3 h, 160 ml - every 4 hours and for the following three days - every 6 hours in an amount of 240 ml.

EFFECT: achieving the stable eradication of the vegetative and coccal forms of Helicobacter pylori, reducing the length of treatment by the early recovery of the involved gastric and duodenal mucosa.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: object of the invention is a method and a pharmaceutical composition in the form of a water-alcohol solution of ethanol 30-60° and water 40-70%, wherein at least one hypoglycaemic active substance is stably and completely dissolved, to be used by administering through the oral mucosa as a therapeutic agent in accurate treatment of postprandial hyperglycemia accompanying type II diabetes mellitus in a human or animal; wherein the water-alcohol solution in the composition has a volume of less than 2 ml, wherein an amount of 250mg or less of the above active substance is stably and completely dissolved, while the hypoglycaemic active substance is specified in lipophilic or amphiphilic active substances, such as gliclazide, glinides, incretins and glyphins. The invention also refers to a method for preparing this dosage form.

EFFECT: preparing the therapeutic agent for treating postprandial hyperglycemia accompanying type II diabetes mellitus.

9 cl, 20 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to method of treating proliferative disease in subject, including introduction to subject of (a) therapeutically effective quantity of AC220 or its salt in dose from approximately 27 to 1000 mg/day, and of (b) second agent, selected from azacitidine, cytarabinum, etoposide, daunorubicin, cladribine, where azacitidine is introduced in dose 50-100 mg/m2/day, cytarabinum is introduced in dose from 5 mg/m2/day to 3 mg/m2/day, etoposide is introduced in dose 10-150 mg/m2/day and daunorubicin is introduced is dose 10-60 mg/m2/day.

EFFECT: invention makes it possible to extend arsenal of medications for treating proliferative diseases, including cancer.

39 cl, 10 dwg, 26 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: invention represents a liquid dosage form of a hopantenic acid calcium salt possessing nootropic activity, containing an effective amount of the hopantenic acid calcium salt and additive agents. It represents drops, and as additive agents, it contains benzoic acid, sodium saccharinate, an orange flavour, hydrochloric 1M, Trilon B and water.

EFFECT: higher active substance content by improving its organoleptic properties and reducing a viscosity of the liquid dosage form by reducing the content of viscosity-enhancing agents and increasing the water content.

2 cl, 4 ex

FIELD: medicine.

SUBSTANCE: method involves performing the following stages: - treating a nerve canal with sodium hypochlorite in the concentration of 0.5-5.25 wt %, in an amount of 1-20 ml for one root canal and activating with ultrasound at frequency 20-40 kHz; both one-stage activation with ultrasound accompanying the treatment, and alternating the sodium hypochlorite treatment and activation with ultrasound every 3-5 sec are possible, - treating with ozonised normal saline in the ozone concentration of 10 mcg to 60 mg per one litre, in an amount of 1-20 ml per 1 root canal and activating with ultrasound at frequency 20-40 kHz, - treating with aqueous chlorhexidine in the concentration of 0.12-2 wt %, in an amount of 1-20 ml per one root canal and activating with ultrasound at frequency 20-40 kHz; the above stages are intermitted with time intervals of no more than 3 minutes, and each stage lasts for 3 to 15 minutes.

EFFECT: high quality of treatment by preventing a post-filling aggravation and reducing the length of periodontal tissue regeneration; the method is easy-to-implement and efficient.

2 ex

Drug // 2540509

FIELD: medicine.

SUBSTANCE: drug preparation contains a combination of phenylephrine hydrochloride (or an equivalent amount of the other pharmaceutically acceptable form of phenylephrine) and paracetamol.

EFFECT: combining two active ingredients provides effective relief of cold and influenza symptoms.

14 cl, 5 dwg, 4 ex, 10 tbl

FIELD: medicine.

SUBSTANCE: invention represents a composition for surgical area infiltration in liposuction or lymphedema elimination, containing normal saline, 0.5% Naropin and phosphatidylcholine in ratio 9:1:6 respectively per 10-15 cm3 fat.

EFFECT: reducing oedema, tissue injuries and blood loss volume, preventing microcirculation disorders in soft tissues and complications, reducing a risk of recurrences and promoting a faster rehabilitation of the patients.

2 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to pharmaceutics, namely to an aqueous pharmaceutical composition containing insulin, an insulin analogue or an insulin derivative and methionine; as well as to a method for preparing and using it for treating diabetes mellitus, and to a therapeutic agent for treating diabetes mellitus.

EFFECT: group of inventions provide stability of the above proteins in solution.

29 cl, 10 ex, 6 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the pharmaceutical industry and represents an ophthalmic solution containing riboflavin and vitamin E for the UV-A rays protection of the internal structures of an eyeball and for treating keratoconus by transepithelial crosslinking.

EFFECT: invention provides extending the range of products for the UV-A rays protection of the internal structures of the eyeball and for treating keratoconus by transepithelial crosslinking.

9 cl, 10 dwg

FIELD: medicine.

SUBSTANCE: composition includes glutaryl histamine in an amount of 18.0-75.0 wt % as an active substance, and as auxiliary substances: microcrystalline cellulose in an amount of 18.0-71.0 wt %, sodium croscarmellose in an amount of 0.25-1.0 wt %, colloidal silicon dioxide in an amount of 0.5-2.0 wt %, calcium stearate in an amount of 0.5-2.0 wt % and lactose monohydrate. The invention also relates to a method of obtaining the said composition.

EFFECT: invention is characterised by the high bioavailability of the active component and high pharmacological activity.

4 cl, 6 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: method for preparing a gel for wound and burn healing involving diluting chitosan in an organic acid, combining it with a biologically active substance and water; chitosan is diluted in citric or lactic acid; mussel hydrolysate is used as the biologically active substance; the hydrolysate is added to the chitosan solution before PEG 600 and calcium alhylose are added in the certain environment.

EFFECT: method enables preparing the new effective wound-healing agent.

2 dwg, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine. There are described implanted devices with various versions of biologically active ingredient loading with the version selectable and applicable for creating a prolonged-release profile or a release profile having a low initial ejection of the biologically active ingredient from the implanted device.

EFFECT: there are described the implanted devices with various versions of biologically active ingredient loading.

11 cl, 2 dwg

FIELD: medicine.

SUBSTANCE: what is described is a mesh bioactive wound coating with its base containing disintegrated bacterial cellulose comprising antimicrobial and antioxidant ingredients: silver-modified montmorillonite and fellerenol aiming at optimising the course of the wound process, preventing the development and suppression of a wound infection. The mesh bioactive wound coating is used for treating gunshot wounds, severe mechanical injuries, uninfected and infected wounds, including septic and persistent wounds, granulating wounds following deep thermal, chemical and radiation burns, for conducting the integrated treatment of trophic ulcers and bedsores in hospital, out-patient and field settings.

EFFECT: mesh bioactive wound coating is non-toxic; it causes no local irritant and skin re-absorption action, possesses elasticity, a high degree of wound modelling; it is not fragmented that facilitates a wound care.

5 dwg, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compositions for local application for the prevention and treatment of local eye pathologies, in particular inflammatory keratites and conjunctivitis and the dry eye syndrome, which contain as active ingredients polyunsaturated fatty acids of the omega-3 and omega-6 type, namely, EPA (eicosapentaenoic acid), DHA (docosahexaenoic acid) and GLA (γ-linolenic acid), mixed with vitamin E acetate and combined into a stable composition in a hydrogel, that is in the disperse form in a water solution, containing one or more gel-forming polymers. The claimed compositions are especially recommended for application as artificial tears.

EFFECT: invention provides an increased efficiency of the prevention and treatment of eye pathologies.

15 cl, 15 tbl, 3 dwg, 7 ex

FIELD: medicine.

SUBSTANCE: what is described is a medical semisynthetic biological adhesive based on biopolymer nanocomposites as a semisynthetic polymer matrix containing a substrate presented by low-molecular polyisobutylene, collapan as an excipient, human immunoglobulin, castor aerosol lubricant as a binding agent; faster setting of the microporous sandwich adhesive is ensured by performing an operation by means of a repetitively pulsed laser (CO2 laser) scalpel in a combination with a semiconductor laser. A polyacrylamide hydrogel placed into a polymer bath is used as a setting agent of an upper layer that is a polymer plaster tape.

EFFECT: medical semisynthetic biological adhesive has high adhesion characteristics.

2 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition for treating bladder cancer. The above composition contains an effective amount of valrubicin and dimethyl sulphoxide, as well as polyethoxylated castor oil or one or more substances specified in trimethyl chitosan, mono-N-carboxymethyl chitosan, N-diethylmethyl chitosan, sodium caprylate, cytochalasin B, IL-1, polycarbophil, Carbopol 934P, N-sulphate-N,O-carboxymethyl chitosan, Zonula occludens toxin, 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine, and represents a dosage form for intra-bladder administration by instillation. The invention also refers to liposomal pharmaceutical compositions containing valrubicin, and methods of treating bladder cancer involving administering the above compositions.

EFFECT: invention reduces bladder irritation and increases the clinical effectiveness in bladder cancer.

12 cl, 3 dwg, 3 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a pharmaceutical composition for preventing and treating a skin inflammation and photopathy containing a water-soluble herbal extract of Solarium.

EFFECT: composition possesses the photoprotective action and can be used as a cosmetic composition.

6 cl, 2 tbl

FIELD: medicine.

SUBSTANCE: what is described is a gel containing structured nanovesicles - niosomes prepared from silicone compounds with enclosed albendazole, anthelmintic preparation.

EFFECT: invention enables extending the range of application of the anthelmintic preparations by reducing dyspeptic reactions that makes them applicable in both adults, and children suffering gastrointestinal diseases.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention involves a granule of epidermal growth factor and a sulphur antioxidant specified in a group consisting of methionine and K2S2O7. The granules possess a target solution profile.

EFFECT: there are presented a method for preparing the above granules, a capsule, and using the above granule in treating ulcerative colitis.

20 cl, 7 ex, 8 tbl

FIELD: medicine.

SUBSTANCE: wound surface is treated with 3.0-1.5% hydrogen peroxide; then keeping the wound wet, Ichthyosin dressing prepared by streptocide powder 0.5-2.5g and Ichthyol ointment 5.0-10.0g dissolved in castor oil 94.5-87.5ml is applied. The agent is applied once a day; the therapeutic course makes 16 days. That is combined with performing an integrated treatment.

EFFECT: invention provides both the antibacterial and anti-infectious, and local anti-inflammatory, local anaesthetic, wound-healing effects, improves the blood supply, stimulates the epidermis regeneration, intensifies the keratosis processes that enables accelerating the wound cleansing from the purulonecrosis process, and a length of preparation for aurografting.

1 tbl, 2 ex

Up!