Ophthalmological composition, based on polyunsaturated fatty acids omega-3 and omega-6

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

 

The technical field to which the invention relates

The present invention relates to ophthalmic compositions based on polyunsaturated fatty acids omega-3 and omega-6. More specifically, the invention relates to preparations of local action for the prevention and treatment of ocular pathologies, in particular inflammatory keratitis and conjunctivitis and dry eye syndrome, containing as active ingredients polyunsaturated fatty acids such as omega-3 and omega-6, United into a stable composition in the hydrogel. The proposed composition is particularly indicated for use as artificial tears.

The level of technology

As you know, preocular tear film is a complex fluid structure that covers the exposed surface of the eyeball and the conjunctiva of the eyeball and eyelids. This structure is formed by the interaction of the solid layer formed by a complex epithelium of the cornea and glycocalyx (i.e., glycoprotein coating of epithelial cells, consisting of their secret), with a liquid layer, in fact, with the tear film. Solid layer serves to promote adhesion of the liquid portion of the tear film to the ocular surface, and the liquid layer is formed, in turn, three overlapping layers, a mucous layer a water layer and a lipid layer.

Inner slimy SL�th the tear film consists of a mixture of hydrated viscoelastic glycoproteins (mucin), which desirous to the solid layer, and forming a hydrophobic surface. The aqueous layer is an intermediate portion of the tear film, which is distributed on the hydrophobic surface and is formed mainly from water, organic and inorganic salts, sugars, proteins, enzymes and other biopolymers complex structures (such as Mucins). Compounds in the solution in this layer perform structural, osmotic, buffered and nutrient functions and determine the protective effect of the tear film on the tissues of the eye surface. Thin outer lipid layer is formed of waxes, fatty acids and esters of cholesterol and serves to stabilize the tear film, controlling the loss of water by evaporation.

Described three-layer structure creates a complex physiological system whose main function is to protect the surface of the eye, maintain hydration, lubrication and cleanliness of the surface of the cornea and interact while ensuring the correct view. Perfect balance and constant turnover of the tear film are the necessary conditions for the performance of its functions. In particular, there must be a constant, but not excessive evaporation of water from the tear fluid to maintain the osmolality at a physiological level, and tear film needs constant� be redistributed over the surface of the cornea during blinking.

As a result of anomalies or imbalance of one or more of the described layers may be a condition known as dry eye syndrome (keratoconjunctivitis sicca), which is a chronic disease observed mainly in elderly women. Dry eye is a multifactorial pathology characterized by changes in the qualitative and quantitative composition of the tear film, which is manifested in the feeling of a foreign body, the symptoms of irritation (discomfort), visual impairment and instability of the tear film with possible damage to the surface of the eye and is accompanied by hyperosmolarity the tear film. Indeed, patients suffering from this pathology, there is increased evaporation and reduced movement of the lacrimal fluid and, as a consequence, increase the osmolarity of the film, which reaches 330-340 mOsm/l, while the normal value is about 300 mOsm/L. it is also Known that dry eye syndrome is often accompanied by inflammatory phenomena, which are distributed from the surface of the eye to the lacrimal gland and to meibomian glands.

Dry eye syndrome is usually greatly affects the quality of life that suffers from its patient and significant public costs due to the fact that the symptoms are chronic, decreased vision both at work and in everyday �activities (reading, watching TV (TV), driving) that often need to be screened by an ophthalmologist and resort to medical therapy. Given the constant increase in the average age of the human population, the disease will acquire increasing importance in the future.

Therapy of dry eye syndrome is focused mainly on the restoration of the tear film, for example, using slow-release ocular inserts, inserted into the conjunctival SAC, and, above all, with liquid ophthalmic preparations, commonly called "artificial tears" that is instilled drop by drop, to replace or enhance the natural formation of tears. In the simplest case, these drugs have only moisturizes the skin, since they consist of neutral and isotonic relative to the tear fluid of saline solutions on the basis of one of sodium chloride or of balanced mixtures of various electrolytes. In other cases, to overcome the errors of the reduced delay in the conjunctival SAC, to lubricate tissues and more effective prevention of the formation of dry areas of the corneal epithelium, the composition of the tears substitutes enriched high molecular weight components having a function of thickeners. Such components are normal water-soluble synthetic polymers�, semi-synthetic or natural environment, many of which, such as hyaluronic acid and cellulose derivatives, are widely used for reporting purposes.

It should be noted that in case of changes or failure of the outer lipid layer of the tear film continuous interaction between the film and the external environment can lead to the evaporation of the water component, the exposure of the surface of the eye with infectious agents and subsequent inflammation of the ocular surface. These mechanisms are the basis of clinical symptoms and signs of dry eye syndrome, but can also be observed in healthy individuals under conditions of low humidity and low air flow.

Due to the inflammatory components that are typically found in the dry eye syndrome, compounds such as polyunsaturated fatty acids, particularly omega-3 and omega-6, are very interesting for possible inclusion in their preparations, replacing the tears. As you know, polyunsaturated fatty acids, or PUFA, are carboxylic compounds with aliphatic chain having two or more double bonds in the chain, which is characterized by the position of the first double bond counting from the terminal atom of the chain (ω position). Among the polyunsaturated fatty acids omega-3 PUFA, n=3) and omega-6 (or PUFA, n=6) represent a group of essential fatty acids, nezam�nimāi for the proper functioning of the body. Examples of fatty acids such as omega-3 α-linolenic acid (18:3, n-3; ALA), eicosapentaenoic acid (C20:5 n-3; EPA) and docosahexaenoic acid (C22:6, n-3; DHA); examples of fatty acids such as omega-6 include linoleic acid (C18:2, n-6; LA) and γ-linolenic acid (C18:3, n-6; GLA).

In the literature it is reported (N. L. J. Verbey, N. J. van Haeringen, P. T. V. M. de Jong. Current Eye Research, 1988, 7(6) 549-556), local treatment of the ocular surface in unsaturated fatty acids such as omega-3 and omega-6 effectively inhibits various processes, such as infiltration of leukocytes, neovascularization and corneal edema, all of which are manifestations of the phenomenon of inflammation. It was shown that the most active fatty acids are eicosapentaenoic acid (EPA, omega-3) and γ-linolenic acid (GLA, omega-6). The mechanism of action of these acids is associated with the mechanism of action of arachidonic acid in the inflammatory cascade: indeed, they compete with arachidonic acid, inhibiting the formation of prostaglandins E1 (PGE1) and Pro-inflammatory leukotrienes.

Food additives on the basis of polyunsaturated fatty acids enriched in fatty acids such as omega-3 from fish oil (especially fats salmon and herring) and fatty acids such as omega-6, mainly of plant origin (black currant, Bur�CNIC) is widely used because of their positive effect on cardiovascular, the immune and nervous systems, as well as, specifically, for use as additives in the treatment of dry eye. In fact, recent work has shown that both EPA and GLA are showing a marked therapeutic activity when dry eye syndrome. (Aragona, P., et. al., Systemic omega-6 essential fatty acid treatment and PGE1 tear content in Sjogren''s syndrome patients. Invest. Ophthalmol. Vis. Sci., 2005. 46(12): 4474-9; Barabino, S., et. al., Systemic linoleic and gamma-linolenic acid therapy in dry eye syndrome with an inflammatory component. Cornea, 2003. 22(2):97-101; Creuzot-Gracher, S., et. al., Improvement of dry eye symptoms with polyunsaturated fatty acids. J. Fr. Ophthalmol., 2006 29(8):868-73). It should be noted that the products in the case of ophthalmic manifestations are also products for oral administration.

Although nearly two decades have passed since then, when it was shown that topical application of fatty acids omega-3 and omega-6 has a positive effect in diseases of the eye surface, currently there is no commercially available eye drops containing mentioned fatty acids. It is obvious that their availability would have significant benefits for the treatment of dry eye syndrome, primarily because of better local tolerability of ophthalmic drug versus drug for oral administration, the use of which affects the gastrointestinal tract. The lack of such a drug should be attributed to the difficulty of developing a recipe using fat Ki�lot type EPA and GLA, primarily due to poor water solubility and low chemical stability of these active ingredients.

Thus, currently polyunsaturated fatty acids, being highly lipophilic and poorly water soluble molecules, a challenge to researchers seeking new water-soluble ophthalmic drugs for topical administration.

Lipid emulsions used for parenteral use, was investigated with the aim of developing a formulation of several lipophilic active ingredients and enhance their ophthalmic bioavailability (T. F. Vandamme, Microemulsions as ocular drug delivery systems: recent developments and future challenges, Prog. Retin. Eye Res. 21 (2002) 15-34; S. Tamilvanan, R. N. et. al., Emulsion-based delivery systems for enhanced drug absorption, Pharm. Tech. 131 (2002) 156-161). As you know, emulsions are disperse systems formed by two immiscible liquid phases prepared with mechanical stirring. Due to the difference of the mutual attraction between different molecules between two liquid phases at each point of contact of the two liquid interfacial tension is generated, and due to the aforementioned tension of the two phases tend to separate from each other to minimize the contact surface. Interfacial tension can be significantly reduced by the addition of amphiphilic molecules or surface-active agents, soluble, m�Nisha least in one of the two phases comprising the emulsion. Thus, the addition of a suitable surface active agent avoids separation of the aqueous phase from the oil phase or at least to slow its progress.

Lipid emulsions for use as medicines, in particular, pharmaceutical compositions comprising emulsions of the type oil-in-water for use as carriers of lipophilic active ingredients, described in document EP 0391369 (Yissum Resarch Development Company of the Hebrew University of Jerusalem, Alexandria, B. Simon and L. Menashe). Such compositions contain oil and a carrier consisting of medium chain triglycerides (MCTS), in some cases combined with vegetable oil, such as, for example, soybean oil, together with phospholipids (e.g., pectin, and soy phospholipids) and surface-active agents, in particular non-ionic surfactants (such as Polysorbate 80 or tween 80) and ionic surfactants (in particular, haliewa and desoxycholate acid).

Relative to the compositions described in the cited document, it is reported that they form emulsions with high stability and are available for oral, parenteral, and local ophthalmic the introduction of lipophilic active ingredients. They include examples of amphotericin b and the base of Mykonos�La.

In the context of the claimant's study with the aim of obtaining ophthalmic product in the form of eye drops on the basis of polyunsaturated fatty acids, studied the possibility of preparing a composition containing eicosapentaenoic acid (EPA) and γ-linolenic acid (GLA) as the active ingredients, using model lipid emulsion patent EP 0391369. The results of this study are outlined next (see comparative example 1), showed that emulsions based on fatty acids such as omega-3 and omega-6 obtained in this way, it is not stable from a physical point of view as they seek to evolve in the direction of phase separation and, furthermore, they are not stable from a chemical point of view, since the content of the two active ingredients significantly decreased after one month of storage in the refrigerator (at 4°C), very likely due to oxidation

Since the main degradation products responsible for the decrease of concentration of EPA and GLA, in this study the oxidation products, was also made an attempt to prepare such an emulsion in a nitrogen atmosphere, barbotine nitrogen at the stage of emulsification in the presence of antioxidants (such as vitamin E and Trolox, its water-soluble derivative). However, in this case, the emulsion also�anvils chemically unstable, and after one month storage at room temperature the concentration of EPA and GLA was reduced to unsatisfactory values (see comparative example 2). The obtained experimental results prove the impossibility of this drug store of eye drops during the time intervals required for pharmaceutical preparations at room temperature or in the refrigerator.

Later in the International patent application publ. N WO 2006/007510 (R. Dana et al., assigned to Schepens Eye Research and Johnson & Johnson Vision Care, Inc.), reported ophthalmic compositions of local action on the basis of fatty acids omega-6 and omega-3 as the active ingredients, starting with the known anti-inflammatory activity of these agents and with estimates, according to which long ago used their oral administration may be poorly ported or desirable.

The drugs given as examples in this document, omega-3 and omega-6 directly emulsified with suitable surfactants, such as, for example, polyethoxysiloxane sorbitane esters of fatty acids (namely, Polysorbate, such as "twin") and polyethoxysiloxane methylglucoside (such as "Glitches"). Specifically, in the described process of preparation of the first surfactant was added to a buffered physiological solution, and the mixture was stirred for PR� stirring at room temperature for a period of time, sufficient to obtain a clear solution, was then added to the second surfactant and at follow-up, after a further period of stirring, is slowly added fatty acid (or fatty acid, if more than one). Finally, add a drop of vitamin E (which has the function of antioxidant), and the emulsion was kept under stirring for several hours.

The same group of issledovatel (S. Rashid et al., Topical Omega-3 and Omega-6 Fatty Acids for Treatment of Dry Eye, Arch. Ophthalmol. 126(2) (2008) 219-225) recently published results of clinical trials of the effectiveness of local drug administration of α-linolenic acid (ALA) and linoleic acid (LA) in the treatment of dry eye, where the studied preparations were obtained by emulsification of the active ingredients by Tween-80 (2.6 per cent) and Glucagon E-20 (2.6 percent) in aqueous solution, as reported in the cited patent document.

However, neither patent publication WO 2006/007510 or in relevant scientific article, nothing was reported about the physical stability of polyunsaturated fatty acids in such ophthalmic preparations, nor their chemical stability. The Complainant further reported (see comparative example 3), the preparations on the basis of EPA, DHA and GLA that are obtained in the form of an emulsion in accordance with the instructions in this document, susceptible to oxidative damage, similar to those observed with the previously op�given drugs in phospholipid emulsion.

Hampered physical stability of the emulsions obtained using only significant amounts of surface-active agents (which are considered toxic to the corneal surface) and, in addition, the chemical instability of the considered polyunsaturated acids require new pharmaceutical systems, an alternative to that discussed above with reference to prior art.

Disclosure of the invention

In the framework of research carried out in connection with the present invention take into account that water hydrogels formed by hydrophilic polymers that can capture and hold in suspension a highly hydrophobic active ingredients without the need to resort to emulsion technology. It was discovered, according to the present invention that it is possible to incorporate some specific polyunsaturated fatty acids such as omega-3 and omega-6, or their suitable derivatives in solutions with a family of antioxidant vitamin E (i.e., Tocopherols and their pharmaceutically acceptable esters), the structure of the three-dimensional network of the hydrogel, and the resulting preparations are stable when stored in the refrigerator and at room temperature, are easy to put in the form of eye drops and very well tolerated by the eye.

Currently on the market there are several m�of dokumentow, which is produced in the form of a gel for topical application, such as Timoptol HYE (Merck Sharp & Dohme) on the basis of timolol maleate with a gelling system containing gum, and Nyogel (Novartis), also contains as the active ingredient timolol maleate, a prisoner in PVA (polyvinyl alcohol, PVA) gel and Carbomer 974 (belonging to the family carboxyvinyl polymers, also known as the "Carbopol"). Today, however, these systems are used for the sole purpose of improving the bioavailability of hydrophilic active ingredients such as actually of timolol maleate in order to get a delivery system with a slow release, where the number of daily doses of the drug can be reduced, and not with the purpose of improving the stability of lipophilic active ingredients.

Proposed according to the present invention the ophthalmic preparation is in the process of synthesis of micrometric dispersion of oils, which are sources of fatty acids omega-3 and omega-6, vitamin E, preferably in acetate form, in an aqueous medium, and the dispersion obtained by using appropriate geleobrazujushchim polymers. As will be more clearly with reference to the experimental section below, the hydrogels containing Tocopheryl acetate together with Pauline�saturated fatty acids as tolerated active ingredients be remarkably stable during storage and retain the content of active ingredients virtually unchanged for a long time.

It should be noted that ophthalmic products in the gel according to the invention not only acts as a carrier of anti-inflammatory foods, but are used to protect and unite the thin lipid layer of the tear film, as active ingredients, referred to, consist of lipid molecules. The Association of the lipid component can reduce excessive evaporation of the tear fluid, restoring the protective function of the external lipid film. It is known that in the case of inflammation and especially in inflammation of the meibomian glands is subject to change and may not affect the increased evaporation of the water layer (which is often observed in patients suffering from keratitis (keratoconjunctivitis sicca).

Thus, the present invention relates to ophthalmic compositions for topical use containing as active ingredient one or more omega-3 polyunsaturated fatty acids and one or more omega-6, polyunsaturated fatty acids, and mentioned fatty acids have an aliphatic chain of from 16 to 24 carbon atoms or their pharmaceutically acceptable derivatives are selected from their esters with C1/sub> -C6alkyl groups, triglycerides and phospholipids in solution with vitamin E or its pharmaceutically acceptable ester, wherein the said solution is dispersed in the form of a hydrogel based on an aqueous carrier containing one or more geleobrazujushchim polymers.

In the preparations according to the present invention, vitamin E may be represented by one of the eight component of the family of α-, β-, γ-, δ - tocopherol and α-, β-, γ-, δ-tocotrienol, but α-tocopherol is preferred because of its greater diffusion. Among the esters, except succinate or esters of long chain acids, the most suitable and common product is acetate. The preferred antioxidant for the procedures of the present invention is α - tocopherylacetate, which is compared with the corresponding α-tocopherol is better transfer when local ophthalmic administration.

It is important to note that in the formulation proposed here α-tocopherylacetate can be applied in large quantities, unlike used in the classical formulation of emulsions, where emulsified quantities are very small. On the eye surface α-tocopherylacetate forms during the hydrolysis of α-tocopherol (vitamin E), who, having, moreover, a strong antioxidant effect, is an inhibitor of cyclooxygenase-2 (COX-2) responsible for sin�ithout prostaglandin E2(PGE2). The latter, as is well known, plays an important role in inflammation. In addition, vitamin E can inhibit the formation of interleukin-1, which is responsible for reducing slezootdelenia.

According to some specific applications of this invention, each of the mentioned fatty acids omega-3 and omega-6 aliphatic chain with two or more double bonds, and length from 18 to 22 carbon atoms, and the carboxyl end of the formula COOR, where R may be hydrogen or linear or branched alkyl group, C1-C6. In addition, the carbon atoms of the R group may be chiral.

Terminal group R is preferably selected from ethyl, propyl and isobutyl, and the compounds formed thereby is ethyl, propyl or isobutyl esters of the corresponding fatty acid.

Specifically, a preferred composition according to the present invention, or contains omega-3 active ingredients in the solution of α-Tocopheryl-acetate, in turn, dispersed in a solution of a hydrogel, eicosapentanoic acid (EPA), docosahexaenoic acid or mixtures thereof, or one or both of the corresponding C1-C6alkyl ethers, or one or both of the corresponding triglycerides, or one or both of the respective phospholipids.

Similarly, according to another� preferred application of this invention, the proposed composition is or contains omega-6 active ingredient in the solution of α-Tocopheryl-acetate, in turn, dispersed in the hydrogel solution, γ-linolenic acid (GLA) or C1-C6its alkyl esters, or their respective triglycerides or phospholipids.

Preferably, the ophthalmic composition according to the present invention comprises as active ingredients EPA, DHA and GLA, or their ethyl esters, triglycerides or phospholipids.

Sources of polyunsaturated fatty acids enriched acids families, omega-6 (such as GLA), can be selected from the group of vegetable oils, including:

Flaxseed oil, borage oil, oil of wheat germ, hemp oil, olive oil, peanut oil, black currant oil, and soybean oil.

Sources of polyunsaturated fatty acids enriched acids of the omega-3 family (such as EPA and DHA), can be easily found in high concentrations in fish oil and can be selected from

fat salmon, fat mackerel, fat fatty fish (e.g. anchovies and sardines), krill fat, and mixtures thereof.

In particular, krill fat is the fat that is extracted from tiny crustaceans that are part of the zooplankton, particularly one species of krill that lives in detectable concentrations in polar and cold waters. Takauji especially enriched with fatty acids omega-3, like fish oils and essential fatty acids omega-3, conjugated with phospholipids, mainly phosphatidylcholine (which for this reason is often referred to as food additives under the name marine lecithin).

Fatty acids of the omega-3 family is usually contained in fats such as percentages, varying from 40% to 50%, and are also present in vegetable oils mentioned above as a source of fatty acids omega-6.

In particular, the pharmaceutical application of EPA, GLA and DHA can be put into practice by using starting materials of high purity. This requires the separation of the mentioned fatty acids from mixtures of fatty acids of fish oil and/or vegetable oils to achieve a purity of 90% and 70% for EPA and GLA respectively. Currently known processes used for this purpose include extraction, molecular distillation and low-temperature crystallization.

Thus, according to preferred embodiments of this invention, the polyunsaturated fatty acids omega-3 and omega-6 contained in the drugs as the active ingredients are contained in one or more vegetable oils and/or one or more fish oils, mixed, in turn, formulated with antioxidant tocopherol, which they are soluble, and the mixture is dispersed to a micron droplets in an aqueous gel. �predpochtitelno vegetable oil extracted from linseed oil, borage oil, oil of wheat germ, hemp oil, olive oil, peanut oil, black currant oil and soybean oil, and fish oils extracted from the fat of salmon, fat mackerel, fat, fatty fish and their mixtures.

According to the present invention, the ratio of omega-3 to omega-6 can vary from 20:1 to 1:20, preferably from 1:10 to 10:1. In particularly preferred compositions the weight ratio of (EPA+DHA) to GLA is between 4:1 and 1:4.

As will be more apparent from reference to the following examples, the amount of vitamin E in an oil mixture with omega-3 and omega-6, preferably not less than 50% by weight, and in some preferred formulations of the content between 50% and 75% by weight. The drug, based on the optionally esterified vitamin E, containing polyunsaturated fatty acids, can be easily dispersed in the hydrogel, where it is stably dispersed without any phase separation and, in addition, he continues to preserve the integrity of the solution and stability as well as chemical composition. Surprisingly, the dispersion solution of acetate of vitamin E, containing polyunsaturated fatty acids omega 3 and 6, may be exercised up to 25% of the weight mentioned oil solution relative to the weight of the entire drug. In accordance with the proposals of the present invention α-Tocopheryl-acetate pre-mixed with the source �mega-3 and omega-6, with a ratio between them in the range of from 4:1 to 1:4, preferably from 3:1 to 1:3 and still more preferably from 3:1 to 1:1 and a final concentration in the product, which can vary from 0.1% to 20%.

Celebritysee polymers proposed for the preparation of the hydrogel according to the invention is, preferably, the products are already used in General clinical practice, in particular, as components of tears substitutes. Such components are selected from products that do not alter the qualitative composition of the tear film and, in addition, may have an additional effect, besides anti-inflammatory effects of polyunsaturated fatty acids.

From geleobrazujushchim polymers which can be used in ophthalmic compositions of the present invention, including, in combination, should be considered preferably carboxyvinyl polymers (known as Kargopol or Carbomer), hyaluronic acid, and their salts of alkaline and alkaline-earth metals, ethers and esters of cellulose (such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, etc.), xanthan gum, alginic acid, alginates and gums. However, for purposes of this invention may also be used other celebritysee polymers used in the formulation of artificial tears, suitable to prevent excessive evaporation of the aqueous tear layer�.

In the preferred embodiments of the ophthalmic compositions according to the present invention mentioned geleobrazuyuschie polymer belongs to the family variously transversely crosslinked polymers known as Carbopol (or carbomer). In particular, the compositions on the basis of EPA and GLA or EPA, DHA and GLA as main active ingredients, some examples of which are presented here, the use of 980 or HPMC HPMC 974 had special advantages in concentrations in the range of from 0.01% to 5% of the total weight of the composition, preferably about 0.2% by weight.

In accordance with this invention, the composition may also contain one or more polymeric emulsifying agents selected from, for example, polymers of acrylic acid such as the product known under the commercial name "Pemulen", high molecular weight copolymer of acrylic acid and long chain alkylsalicylate, transversely cross-linked with allyl ethers of pentaerythritol) and poloxamers (block copolymers polyoxyethylene - polyoxypropylene, such as the products known as "Pluronic". In preferred compositions according to the invention on the basis of EPA and GLA or EPA, DHA and GLA, Permalien preferably used in concentrations contained between 0.001% and 2% of the total weight of the preparation, the preferred concentration� is 0,007% of the weight.

The proposed composition can also contain, as a rule, pH stabilizers, buffers and chelating agents such as EDTA (EDTA), and osmotically active agents selected from those currently used in pharmaceutical technology. In preferred compositions according to the invention is used such osmotically active agent such as glycerol, in an amount suitable to obtain a slightly hypotonic drug, and this property is necessary to counteract the functional and anatomical discomfort epithelium of the ocular surface. Indeed, in cases of excessive evaporation or reduced ketoprofene the increase in salt concentration leads to the increased emotionaly the tear film, thus affecting the surface of the eye.

Finally, according to some specific embodiments of this invention the ophthalmic preparations of polyunsaturated fatty acids according to the invention can also contain one or more other additional Tocopheryl acetate antioxidant agents.

As for the cooking process, it is known that the sequence of the various additions of fillers and active ingredients in the cooking process of the hydrogel can affect many physical and chemical characteristics of the composition.�and, such as viscosity, particle size, degree of dispersion of active ingredients, as well as the homogeneity of the system. Among the various possible technological procedures the following were the best:

- dissolution celebritysee polymer (e.g., HPMC);

- adding osmotically active agent;

- possible dissolution of the polymer emulsifier (for example, Pemulen);

- the addition of a mixture of polyunsaturated fatty acids, already mixed with vitamin E, preferably in the form of acetate ester

- add a buffer (e.g. phosphate buffer);

- gelation by the addition of NaOH.

All additions must be carried out under mechanical stirring, preferably at 200 R/min (rpm).

As previously stated, the ophthalmic composition of polyunsaturated fatty acids dissolved in vitamin E and dispersed in the hydrogel according to the invention are significantly more storage stable than compositions in the emulsion in accordance with the prior art. With reference to the preparation in accordance with the preferred embodiment of this invention, containing ethyl ester of EPA and GLA ethyl ester as the active ingredients and α-Tocopheryl acetate as an antioxidant, Carbopol as celebritysee polymer and glycerol as OSM�cally active agent, the study demonstrated an unexpected storage stability of the product.

In the same experimental conditions preparation of EPA and GLA in the emulsion exhibited rapid kinetics of degradation, resulting in a month to the value of the concentration of the active ingredients on average 95%, despite the fact that the preparation was performed in a nitrogen atmosphere and in the presence of antioxidants. It is also remarkable that the emulsion prepared in accordance with the prior art when stored at low temperatures (4°C), less stable than the hydrogel prepared in accordance with the present invention stored at 25°C.

It is believed that the best stability of fatty acids omega-3 and omega-6, dissolved in vitamin E, and dispersed in the hydrogel relative to the stability of the emulsions prepared in accordance with the prior art, due to the fact that the surface of the dispersed oil phase, subjected to oxidation, thousands of times more in the case of emulsion droplets (nanometer size) compared with the surface subjected to the oxidation product of the present invention. The stirring is necessary for the formation of this product, indeed, can be adjusted to obtain droplets with average size of about 3 μm and preferably not less than 1 μm. Below atively manifestations of degradation become significant due to the high value of the surface which solutions polyunsaturated fatty acids in vitamin E exhibit when interacting with the hydrogel. Thus, the average droplet size of dispersed phase in polymer hydrogel must be greater than 1 μm and preferably in the range from 2 to 5 microns.

The composition proposed in accordance with this invention, can be used as such in the form of a hydrogel or they can be included in the solution or carrier consisting of a gel, ointment, cream or liposomes or in any suitable matrix for local ophthalmic preparation, or ophthalmic administration, that is, with the condition that this system retains and does not violate the homogeneity of a solution of fatty acids omega-3 and omega-6 in acetate vitamin E.

Specific features of this invention and its advantages will appear more clearly with reference to the detailed description below of examples together with the results of research carried out in connection with this invention, and comparison with the prior art. Some experimental results are also presented in the attached drawings, where

fgure 1 shows in a diagram the results of the study of chemical stability, made in the preparation of EPA and GLA in phospholipid emulsion stored in the refrigerator (4°C);

figure 2 shows the time of rupture of the tear film (BUT) at day zero and on day 7 in patients receiving drug treatment hydrogel in accordance with the present invention, in comparison with a commercial substitute for tears in phospholipid emulsion, for example, Liponexol (Tubilux, Italy);

figure 3 demonstrates the tearing measured with Schirmer I test at day zero and on day 7 in patients receiving drug treatment hydrogel in accordance with the present invention, in comparison with the commercial product (a substitute for tears in phospholipid emulsion) figure 2.

Examples of fatty acids omega-3 and omega-6 in the form of the corresponding ethyl esters (EE) introduced in hidrogeno system according to the present invention, is presented below.

EXAMPLE 1

The hydrogel with EPA and GLA

In the product prepared according to the invention, used as EPA with a purity of 90% and GLA with a purity of 70% in the form of ethylates. Used the following ingredients:

Components% /Function
Ethyl ester of EPA (EPA EE)0,40active ingredient
Ethyl ester of GLA (GLA EE) 0,10active ingredient
α-Tocopheryl-acetate0,50antioxidant
Carbopol 9800,20Geleobrazuyuschie agent
Glycerin1,15osmotically active agent
NaOH0,07A pH Adjuster
Disodium phosphate sodium0,10A pH Adjuster
Water for injectionsQSP 100The aqueous phase

pH 6.90 mOsm=155

The preparation was performed according to the procedure as described above.

EXAMPLE 2

The hydrogel with EPA and GLA, with the addition of Pemulen

For the preparation was performed in the same procedure as in the previous example.

For the preparation was performed in the same procedure as in the previous example.

Components% /in (w/w)Function

Ethyl ester of EPA (EPA EE)0,40active ingredient
Ethyl ester of GLA (GLA ER0,10active ingredient
α-Tocopheryl-acetate0,30antioxidant
Carbopol 9800,20Geleobrazuyuschie agent
Glycerin1,15osmotically active agent
Permalien0,007Polymeric emulsifier
NaOH0,07A pH Adjuster
Disodium phosphate sodium0,10A pH Adjuster
Water for injectionsQSP 100The aqueous phase

the pH of 6.96 mOsm-165

EXAMPLES 3-7

The hydrogel with EPA, DHA and GLA, with the addition of Pemulen

In the following examples, in preparations used omega-3 polyunsaturated fatty acids EPA and DHA and omega-6 polyunsaturated acids� GLA, all in the form of the corresponding ethyl esters. They were able to mix in all proportions with acetate of vitamin E and connected in different relations in the oil phase.

Accordingly, solutions of fatty acids in acetate of vitamin E is distributed in different proportions in the hydrogel Carbopol 980/Pemulen according to previously described procedure, making sure that the oil solution is dispersed in the gel without phase separation, and continues to preserve the integrity of the solution dispersed in the gel on the droplets of micron size.

Various full composition containing 1% by weight of oil phase in the hydrogel was pH=7, osmolarity=155 mOsm/kg and the average size of 3 µm oil droplets.

Example No34567
Ethyl ester of EPA (EPA EE)the 6.25%5%20%25%12,5%
Ethyl ester of DHA(DHA EE)the 6.25%5%20%25% 12,5%
Ethyl ester of GLA(GLA EE)12,5%40%10%25%50%
Acetate Vit. E75%50%50%25%25%
the ratio of omega 3/61:11:44:12:11:2
The total quantity of polyunsaturated fatty acids (PUFA)25%50%50%75%75%
The oil phase (PUFA+acetate Vit. (E)
1,001,001,001,001,00
Carbopol 980 (geleobrazuyuschie agent)
0,200,200,200,200,20
glycerin (osmotically agent)
1,151,151,151,151,15
Peralin (polymer emulsifier)
0,0070,0070,0070,007

NaOH (pH Adjuster)
0,070,070,070,070,07
Dibasic sodium phosphate (pH Adjuster)
0,100,100,100,100,10
PTS�sacred water to 100to 100to 100to 100to 100

PHYSICAL CHARACTERISTICS AND STABILITY STUDY

The aqueous phase may be dispersed in the gel and can remain stable under these conditions, if the viscosity of the medium is large enough to prevent the interpenetration of the oil droplets. Studies performed in the framework of the present invention, demonstrated that the gel is able to "capture" useful amount of oil phase consisting of polyunsaturated omega-3/omega-6 fatty acids, acetate dissolved in α-Tocopheryl, and to maintain their stability, both physical and chemical.

Developed gels described in examples 1-7, by centrifugation for 15 minutes and centrifugation force 11200 g showed no signs of phase separation between the dispersed phase and oil-phase dispersing hydrogel. Optical measurements taken for evidence of a possible phase separation, also confirmed amazing physical stability of this system.

Chemical stability

After one month of storage at 25°C EPA and GLA contained in the product of Example 1 showed a concentration of 100% and 101% respectively. The luxurious design�but after three months of storage under the same experimental conditions, the concentration remained substantially unchanged, as shown in the following table.

Table 1
The stability of the hydrogel of example 1 at a temperature of 25°C
MeasurementpHThe osmolarity% EPA% GLA
Temperaturemonths6,2-7,4135-170 mOsm/kg90,0%-110%90,0%-110%
1of 6.99150100101
25°C27,01155100101
36,9515899,099,0

�uravnitelny example 1

To compare the characteristics of the drug obtained according to this invention, with the drugs in the emulsion of the type described in accordance with the prior art, with special reference to the document EP 0391369, prepared emulsion containing fatty acids omega-3 and omega-6, using MCT (triglycerides of medium length) as an oil and polyoxyethylene sorbitan monooleate (tween 80) as a surface active agent as shown below.

Example EPA-GLA of the drug to phospholipid emulsion

Components% /Function
SCONCE0,4active ingredient
GLA0,1active ingredient
triglycerides of medium length (MST)1,5the oil phase
Phospholipon 90 gthe 0.375emulsifier
Tween 800,5surfactant
Glycerin1,125 The osmolarity regulator
α-tocopheryl0,2antioxidant
EDTA-Na20,1gelirmi agent
Water for injectionsQSP 100the aqueous phase

The preparation was carried out following the instructions cited patent document.

The resulting emulsion was investigated to evaluate its chemical and physical stability.

Physical stability of the emulsion was evaluated in experiments on the scattering using a laser He-Ne source (633 nm) with a power of 10 mw. It is shown that the average hydrodynamic radius of the particles in the emulsion (r) equal to 110 nm, and the polydispersity is equal to 0,07%. Measuring electrophoretic mobility was evaluated by Z-potential, which was equal to 39±3 mV. This means that particles with a negatively charged surface, repel each other, thus avoiding phenomena of fusion and aggregation.

One month after the preparation of these values remain essentially unchanged, suggesting that the emulsion system has good physical stability, but the experiments performed during the second month, show that the Z-potential with�novelsa much less negative, and that the particle size increases significantly (table 2).

Table 2
The stability of size and Z potential of the oil particles in phospholipid emulsion

Time (months)EPA-GLA Size (nm)Zeta potential (mV)
0110-39
1135-40
2176-24

All shown above demonstrates the evolution of the emulsion in the direction of phase separation.

To study the stability of the emulsion from the chemical point of view, we measured the concentrations of EPA and GLA by gas chromatography. As shown in the following table 3 and in chart form in figure 1, the measured concentrations after storage of dosage forms at a temperature of 4°C shows after the first month, a significant decrease in the concentration of EPA and GLA, respectively equal to 97.5% and 97.4% of the concentration at the zero moment. The trend towards the degradation of p�was tweedles in the following months, as seen from table 3 and the corresponding graph.

Table 3
The stability of the EPA-GLA in phospholipid emulsion at 4°C
MeasurementpHThe osmolarity% EPA% GLA
Temperaturemonths6,2-7,4135-170 mOsm/kg90,0%-110%90,0%-110%
1of 7.0315097,597,4
4°C27,0215594,998,9
46,901508590

In conclusion, the studied composition was unstable from the physical point of view.

Comparative in�EP 2

Since the main degradation products responsible for the decrease of concentration of EPA and GLA in comparative example 1, the oxidation products, the same product is produced in such a way as to limit oxidation of the product flowing nitrogen at the stage of emulsification and acting in the presence of antioxidants.

Analyzed chemical stability thus obtained drug phospholipid emulsion using the same procedural in the previous example. As shown in the following table, after one month of storage at 25°C EPA and GLA had a concentration of 96% and about 95.2 percent relative to the zero point, respectively.

Table 4
Stability at 25°C EPA-GLA in phospholipid emulsion prepared in a nitrogen atmosphere
MeasurementpHThe osmolarity% EPA% GLA
Temperaturemonths6,2-7,4135-170 mOsm/kg90,0%-110%90,0%-110%
0the 7.25145100100
25°C16,8615096,095,2

Despite the preparation in a nitrogen atmosphere and the presence of additional antioxidants, the data on the chemical stability of this drug are disappointing. These data suggest the impossibility of storing eye drops for possible commercial use, neither at room temperature or in the refrigerator.

Comparative example 3

Emulsion polyunsaturated omega-3 and omega-6 fatty acids, are directly obtained by using surfactants in accordance with the message of document WO 2006/007510, were tested in the laboratories of the Applicant.

In particular, it was determined the minimum concentration of surfactant used to create drugs active ingredients, and it was found that values less than 1% is insufficient to obtain the emulsion, stable from a physical point of view. Preparations with a higher content of surfactants in any case would be undesirable, since it is known that they are very often responsible for toxic problems the eye tissues, and especially�NGOs are not suitable for chronic therapy.

It is shown that from a chemical point of view, such drugs have oxidation problems, similar to those observed in comparative examples 1 and 2. Indeed, it was shown that after one month of storage of the composition at 25°WITH EPA and GLA have concentrations 96,5% 97,0%, respectively, indicating a rapid decline with time both of the "active ingredients" and in this type of the drug, as shown in the following table.

Table 5
The stability of EPA and GLA in the emulsion according to WO 2006/007510

MeasurementpHThe osmolarity% EPA% GLA
Temperaturemonths6,2-7,4135-170 mOsm/kg90,0%-110%90,0%-110%
0the 7.25150100100
25°C16,9515596,597,0

For added security, the compositions described in table 1 WO 2006/007510, reproduced below in table 6, were repeated using EPA and DHA omega-3, in the form of ethyl esters, and the corresponding triglycerides (EPA EE, DHA EE EPA TG DHA TG) (EPA HER, HER DHA, EPA TG, TG DHA), GLA and omega-6, in the form of ethyl esters, and the corresponding triglycerides (L uh, GLA TG) (ITS GLA, GLA TG).

Table 6
Illustrative preparations according to WO 2006/007510
Drug No1234
% the ratio by weight of omega-3/omega-60,1/0,10,4/011,0/1,04,0/1,0
Weight(g)/%g%g %g%g%
Glitch E-2014,791,4819,641,96419,571,9619,233,81
Tween 8014,711,4719,801,98019,601,9619,433,85
Buffer solution,1968,496,85955,895,5894294,20442,0387,55
omega 31,010,14,010,40110,01,019,233,81
omega 6 0,990,0990,990,0999,971,0of 4.950,98
vitamin E1 drop--1 drop--1 drop--1 drop-
1Buffer solution: NaCl 0,83%; H3BO30,89%; Na2B4O7×10 H2O 0,23%; EDTA 0,01% H2O to 98.04%,

The measurement results of stability obtained for each of the four drugs, and for each of the three tested fatty acids in the form of the ethyl ester, and triglyceride, at 4°C or at 25°C, presented in the following tables 7-10.

Table 7
Stability of drugs No, 1 table 6
Omega 3 % EPA EEOmega 3 % DHA EEOmega 6 % GLA ER
Measurement
TemperatureMonthsConcentration, %Concentration, %Concentration, %
1969596
4°C2929191

3888685
4828481
Omega 3 %EPA TGOmega 3 %DHA TGOmega 6 %GLA TG
Measurement
TemperatureMonthsConcentration, %Concentration, %
1999997
4°C2979896
3959594
4919189
Omega 3 %EPA EEOmega 3 %DHA EEOmega 6 %GLA ER
Measurement
TemperatureMonthsConcentration, %Concentration, %Concentration, %
1888990
25° 2828079
3656764
4495147
Omega 3 %EPA TGOmega 3 %DHA TGOmega 6 %GLA TG
Measurement
TemperatureMonthsConcentration, %Concentration, %Concentration, %
1909192
25°C2818382
3767777
4676764

Table 8
The stability of the drugs No. 2 of table 6
Omega 3 %EPA EEOmega 3 %DHA EEOmega 6 %GLA ER
Measurement
TemperatureMonthsConcentration, %Concentration, %Concentration, %
1969698
4°C2919093
3878787
4 828581
Omega 3 %EPA TGOmega 3 %DHA TGOmega 6 %GLA TG
Measurement
TemperatureMonthsConcentration, %Concentration, %Concentration, %
19810098
4°C2979996
3949795
4929591
Omega 3 %EPA EEOmega 3 %DHA EEOmega 6 %GL EE
Measurement
TemperatureMonthsConcentration, %Concentration, %Concentration, %
1949593
25°C2858482
3787875
4666864
Omega 3 %EPA TGOmega 3 %DHA TGOmega 6 %GLA TG
Measurement
TemperatureMonthsConcentration, % Concentration, %Concentration, %
19898100
25°C2919090
3828182
4737370

Table 9

Stability of drugs No, 3 tables 6
Omega 3 %EPA EEOmega 3 %DHA EEOmega 6 %GLA ER
Measurement
TemperatureMonthsConcentration, Concentration, %Concentration ,%
1959697
4°C2929191
3888786
4818482
Omega 3 %EPA TGOmega 3 DHA TGOmega 6 GLA TG
Measurement
TemperatureMonthsConcentration,%Concentration, %Concentration, %
1 989998
4°C2979897
3949594
4919189
Omega 3 EPA EEOmega 3 DHA EEOmega 6 %GLA ER
Measurement
TemperatureMonthsConcentration, %Concentration, %Concentration, %
1949394
25°C287 8782
3757474
4686968
Omega 3 EPA TGOmega 3 DHA TGOmega 6 %GLA TG
Measurement
TemperatureMonthsConcentration, %Concentration, %Concentration, %
1999898
25°C2929291
3828480
4737571

Table 10
Stability of drugs No, 4 table 6

Omega 3 EPA EEOmega 3 DHA EEOmega 6 %GLA ER
Measurement
TemperatureMonthsConcentration, %Concentration, %Concentration %,
1949696
4°C2909591
3869086
4818382
Omega 3 EPA TGOmega 3 DHA TGOmega 6 GLA TG
Measurement
TemperatureMonthsConcentration, %Concentration, %Concentration, %
19810097
4°C2969895
3949693
4929389
Omega 3 EPA EE Omega 3 %DHA EEOmega 6 %GLA ER
Measurement
TemperatureMonthsConcentration, %Concentration, %Concentration, %
1959392
25°C2898881
3757774
4677068
Omega 3 %EPA TGOmega 3 %DHA TGOmega 6 %GLA TG
Measurement
TemperatureMonths Concentration %Concentration %Concentration %
1979899
25°C2909292
3838384
4757473

The above data further confirm that the polyunsaturated fatty acids omega-3 and omega-6, combined in an emulsion for topical application, quickly degrade as in the case where they are included in the preparation in the form of ethyl ester, and in that case, when using the corresponding triglycerides. Such instability typical of other emulsion systems prepared according to prior art and, generally speaking, confirms literature data concerning the chemical stability of polyunsaturated fatty acids.

Stability studies of the compositions of approx�ditch 3-7

For an accurate comparison between the stability of the compositions prepared according to prior art, and stability of ophthalmic preparations of the present invention, first, evaluated the chemical stability of the oil phases of the compositions described in examples 3-7. Relevant data are shown in the following table.

Table 11
The stability of the oil phase in examples 3-7, according to the present invention, the concentration of polyunsaturated fatty acids (PUFA), as defined in 12 months at 25°C
Example, N34567
EPA EEthe 6.25%5%20%25%12,5
D EEthe 6.25%5%20%25%12,5
GL EE12,5%40%10%2% 50
Acetate Vit.E75%50%50%25%25%
The ratio of omega 3/61:11:44:12:11:2
General PNET(RCRA)25%50%50%75%75%
EPA conc. %100100999796
DHA conc. %99991009696
GLA conc. %100991009797

These data show that compositions with full concentration of polyunsaturated fatty acids up to 50% acetate α-t�coterie find amazing stability. Only at concentrations of fatty acids above 50%, if the acetate of vitamin E less than 50%, it becomes noticeable degradation. In addition, fatty acids omega-3 and omega-6 in the form of triglycerides, and in the form of phospholipids (especially krill fat) showed even greater stability. Thus, the preceding table demonstrates the "worst" stability in the case of ethyl esters of omega-3 and omega-6.

Being extremely stable, drugs polyunsaturated fatty acids in acetate vitamin E not suitable for ophthalmic preparations because of poor tolerability; however they can be kept unchanged for a long time, more than during the same stability pure polyunsaturated fatty acids (PUFA).

Based on the described oil blends, just add Carbopol 980 and Pemulen and accordingly to form a polymeric hydrogel to obtain the excellent tolerability and to ensure the stability of the composition. Below are the results of the stability tests full preparations of examples 3-6 (table, examples 3-7).

Table 12
The stability of the preparation from example 3, prepared according to the present invention. Concentration in the hydrogel of 1%. The average size of the oil drops 3 mi�Ron
Omega 3 %EPA EEOmega 3 %DHA EEOmega 6 %GLA ER
Measurement
TemperatureMonthsConcentration, %Concentration, %Concentration, %
3100100101
4°C610199101
999100100
121009998
Omega 3 %EPA TGOmega 3 %DHA TGOmega 6 %GLA TG
Measured�deposits
TemperatureMonthsConcentration, %Concentration, %Concentration, %
310099100
4°C6102100101
910099100
121009998
Omega 3 %EPA EEOmega 3 %DHA EEOmega 6 %GLA ER
Measurement
TemperatureMonthsConcentration, %Concentration, %Con�entrace, %
310010099
25°C61009999
9979897
12959596
Omega 3 %EPA TGOmega 3 %DHA TGOmega 6 %GLA TG
Measurement
TemperatureMonthsConcentration, %Concentration, %Concentration, %
310199100
25°C6 99100100
91009798
12979798

Table 13
The stability of the drug of example 4 prepared according to the present invention. Concentration in the hydrogel of 1%. The average size of 3 µm oil droplets

Omega 3 %EPA EEOmega 3 %DHA EEOmega 6 %GLA ER
Measurement
TemperatureMonthsConcentration, %Concentration, %Concentration,%
3101 100100
4°C610010199
9989799
129810099
Omega 3 %EPA TGOmega 3 %DHA TGOmega 6 %GLA TG
Measurement
TemperatureMonthsConcentration, %Concentration, %Concentration, %
310099101
4°C69810099
910099
1210098100
Omega 3 %EPA EEOmega 3 %DHA EEOmega 6 %GLA ER
Measurement
TemperatureMonthsConcentration, %Concentration, %Concentration, %
39999100
25°C610010099
9989795
12959694
Omega 3 %EPA TGOmega 3 %DHA TGOmega 6 %GLA TG
Measurement
TemperatureMonthsConcentration, %Concentration, %Concentration, %
310099100
25°C699100101
9999698
12969797

Table 14
The stability of the drug in example 5, prepared according to the present invention. Concentration in the hydrogel of 1%. The average size of wt�anyh drops 3 microns

Omega 3 %EPA EEOmega 3 %DHA EEOmega 6 %GLA ER
Measurement
TemperatureMonthsConcentration, %Concentration, %Concentration, %
310199100
4°C699100101
91009899
12989999
Omega 3 %EPA TGOmega 3 %DHA TG Omega 6 %GLA TG
Measurement
TemperatureMonthsConcentration, %Concentration, %Concentration, %
31009899
4°C6101101100
91009998
1210110099
Omega 3 %EPA EEOmega 3 %DHA EEOmega 6 %GLA ER
Measurement
TemperatureMonthsConcentration, % Concentration, %Concentration, %
39899100
25°C6979899
9959797
12959594
Omega 3 %EPA TGOmega 3 %DHA TGOmega 6 %GLA TG
Measurement
TemperatureMonthsConcentration, %Concentration, %Concentration, %
3999899
25°C698100100
91009897
12969796

Table 15
The stability of the drug in example 6, prepared according to the present invention. Concentration in the hydrogel of 1%. The average size of 3 µm oil droplets

Omega 3 %EPA EEOmega 3 %DHA EEOmega 6 %GLA ER
Measurement
TemperatureMonthsConcentration, %Concentration, %Concentration, %
3101100100
4°C610010199
9989798
12989898
Omega 3 %EPA TGOmega 3 %DHA TGOmega 6 %GLA TG
Measurement
TemperatureMonthsConcentration, %Concentration, %Concentration, %
310099101
4°C698100 99
9999998
12989899
MeasurementOmega 3 %EPA EEOmega 3 %DHA EEOmega 6 %GLA ER
TemperatureMonthsConcentration, %Concentration, %Concentration, %
39999101
25°C6999898
9979695
129392 93
Omega 3 %EPA TGOmega 3 %DHA TGOmega 6 %GLA TG
Measurement
TemperatureMonthsConcentration, %Concentration, %Concentration, %
310099101
25°C6989898
9979697
12949594

TESTS ON the TOLERABILITY AND ACTIVITY

Acute ocular tolerability of eye drops prepared according to the present invention

Ocular tolerability of eye drops in the hydrogel of example 1 (MDV0705 IDROGEL) was evaluated after t�ex instilling into the eyes of rabbits after 2 hours, one after the other. Two drops of the product buried in the right eye of each animal 3 times a day with an interval of 2 hours. A group of rabbits consisted of 8 animals (4 males, 4 females).

The condition of the ocular tissues was evaluated according to Draize test.

The study was performed after the third instillation on the day of treatment and again after 24, 48 and 72 hours after the first instillation, assigning conditional indices various indices of the conjunctiva, iris and cornea.

Was not observed visible signs of redness of the conjunctiva over the entire period of testing nor in the eyes treated MDV0705 IDROGEL, nor in the eyes treated with placebo.

There was no edema or opacities at the level of the cornea. In addition, there was marked involvement of the iris.

The presence of drainage material remain at a normal level.

The results show that the ophthalmic drug in the hydrogel, prepared according to the present invention, is well tolerated upon repeated instillation (three for 6 hours), and there is no evidence of differences compared to placebo.

Clinical tests for portability

Instillation of eye drops MDV0705 IDROGEL the group of healthy individuals without signs of pathology on the surface of the eye and with the normal tearing is not caused noticeable unwanted effects.

In particular, the persons receiving Testino�by eye drops, handing out the questionnaire 2 questions they had to answer after 1, 5, 10 and 60 minutes. On question 1 ("do you Feel pain after instillation of the eye drops?") 100% of people answered "no" for each scan; to question 2 ("do you Feel uncomfortable after instillation of the eye drops?") 100% of people answered "no" for each scan.

Evaluation of the activity of the drug in the hydrogel of the present invention in the treatment of dry eye syndrome.

Taking into account that the drug MDV0705 IDROGEL containing fatty acids omega-3 and omega-6, has properties of protecting the surface of the eye and reduce inflammation, and making sure earlier in his endurance, was installed its activity in the treatment of patients suffering from dry eye syndrome. This product was compared with a commercial substitute of tears consists of a lipid emulsion, that is, with eye drops Lipemic (Tubilux, Italy), the only one currently on the market substitute for tears, contain lipids.

Activity MDV0705 IDROGEL was evaluated in a group of patients (n=5) with dry eye syndrome and used a control (n=5) of patients with dry eye syndrome treated with Liponexol. Patients were buried MDV0705 IDROGEL and Lipemic 3 times a day in both eyes, and measurements were performed after 7 days of treatment. For statistical analysis of the results used right eye.

Patients with Shin�rum dry eye were selected according to internationally agreed criteria for the inclusion (Definition and classification of dry eye disease. The Subcommittee of the International working group dry eye, Ocul, Surf 2007; 5:75-92) and more precisely:

By symptoms of eye dryness, determined using an appropriate questionnaire with a codified system of affixing assessment (Shiffman RM, Dale Christianson M, Jacobsen G, Hirsch JD, Reis BL, Reliability and validity of the Ocular Surface Disease Index (OSDI), Arch, Ophthalmol, 2000; 118:615-21);

- Painting fluorescein cornea, measured according to the NEI/Industry workshop Scale>3 (Lemp MA, Report of the National Eye Institute/Industry workshop on clinical trials in dry eyes, the CLAO J, 1995; 21:221-232);

- Time gap (BUT)<10 seconds;

- Schirmer test I<8 mm in 5 minutes.

Exclusion criteria: infectious keratoconjunctivitis, a positive history of ocular allergies, surgery on eyes or eyelids during the 3 months preceding the study, rhinitis, the use of eye drops based steroids within 4 weeks prior to the study, diabetes, glaucoma eye drops.

To evaluate the activity of MDV 0705 IDROGEL compared with the control used the following settings:

Symptoms of dry eye (discovered by using an appropriate questionnaire.)

The time of rupture of the tear film (BUT)

- The Schirmer test I

- Procedures for the evaluation of the time of rupture of the tear film (BUT)

BUT seen as an indicator of the stability of the tear film. The test consists of observing the film surface after instillation �of fluorescein using a slit lamp with a cobalt blue filter. In the process of testing the patient keeps the eye open without blinking and looking straight ahead, and measure the reduction in the time between the last blink and the formation of a small dry areas (which look darker) on the surface of the cornea, then computing the average of three successive determinations.

The Schirmer test I

- The Schirmer test I gives information about the secretion of the lacrimal fluid. It is performed in a dimly lit room, placing the paper strip on the outer side of the lower fornix of the conjunctiva and measuring permeation through 5 minutes. The test should be performed in accordance with standardized procedures, as there are many different variables involved in the determination of this value. The most important variable arises from the fact that the absorption of absorbent paper strip and the length of the wet part of the effect of capillary force and wettability cellulosic fibers. It is therefore important to perform the test verified paper strips.

- The research results, according to observations concerning BUT and Schirmer test I, shown in figures 2 and 3 of the enclosed drawings. The results on day 7 showed significant improvement of symptoms and characteristics of the ocular surface in patients with dry eye syndrome treated MDV0705 IDROGEL, compared with baseline values (day 0). Furthermore, on day 7 in patients treated MDV0705 IDROGEL, showed a significant improvement (p<0.05) of symptoms compared with the control group.

The time of rupture of the tear film (BUT) (figure 2) on day 7 showed a significant increase compared to baseline (day 0) only in the group of patients treated with MDV 0705 IDROGEL.

Secretion of tear fluid (figure 3), measured by Schirmer test I, showed a significant increase compared to baseline in the group of patients treated with MDV 0705 IDROGEL, while in the group of patients treated with Liponexol demonstrated a slight increase in ketoprofene after 7 days. Comparison on day 7 between patients treated MDV0705 IDROGEL and Liponexol, demonstrated a significant increase in the first group than the second.

In conclusion, it is confirmed that the use of fatty acids omega-3 and omega-6 in eye drops is an important innovation for treatment of patients suffering from dry eye syndrome as reducing the symptoms reported by patients and improving the stability of eye protectors, and consequently, the characteristics of the surface of the eye. This efficient therapeutic agent is readily available from a pharmaceutical point of view, thanks to improved storage tracks in the hydrogel in with�according to the invention.

The present invention has been described with specific references to some of the specifics of its implementation, however, it should be understood that the possible alteration by persons versed in the art, without departing from the scope of this invention as defined in the appended claims.

1. Ophthalmic composition for topical use for the prevention or treatment of eye pathologies selected from inflammatory keratitis, conjunctivitis and dry eye syndrome, containing as active ingredient one or more omega-3 polyunsaturated fatty acids and one or more omega-6-polyunsaturated fatty acid selected from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and omega-6 polyunsaturated fatty acids, or their pharmaceutically acceptable derivatives are selected from complex (C1-C6alkyl esters and triglycerides in solution with vitamin E or a pharmaceutically acceptable his ether, and the said solution is dispersed in the form of a hydrogel on the basis of an aqueous solution containing one or more gel-forming polymers in which one or more gel-forming polymers are carboxyvinyl polymers, and omega-6 polyunsaturated fatty acid is γ-linolenic acid (GLA).

2. OFTAL�chemical composition according to claim 1, in which the vitamin E or its ester is an acetate α-Tocopheryl.

3. A composition according to claim 1 or 2, in which the mass ratio of omega-3 and omega-6 is in the range of 20:1-1:20.

4. A composition according to claim 2, in which the weight ratio of acetate α-Tocopheryl to omega-3 and omega-6 polyunsaturated fatty acids is in the range 4:1-1:4.

5. A composition according to claim 1 or 2, containing as the active ingredients EPA, DHA and GLA or their esters ethyl, triglycerides.

6. A composition according to claim 1 or 2, containing as omega-3 polyunsaturated fatty acids a mixture of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and in which the weight ratio of omega-3 (EPA+DHA) and omega 6 (GLA) is in the range 4:1-1:4.

7. A composition according to claim 1, containing as active ingredient one or more omega-3 polyunsaturated acids selected from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and γ-linolenic acid (GLA), both in the form of triglycerides.

8. The composition of claim 1 containing the following ingredients in the ratio of wt./wt.%:
- 0,40% EPA complex ethyl ester;
- 0,10% GLA complex ethyl ester;
to 0.50% of α-Tocopheryl acetate; and
to 0.20% Carbopol 980;
to 1.1% of glycerol;
- 0,07% NaOH;
- 0,10% sodium phosphate; and
- water for injection to 100%,
where these ethyl esters are in the form of ethylates.

p> 9. A composition according to claim 1, further comprising one or more agents that regulate the osmolarity.

10. A composition according to claim 1, further comprising one or more polymeric emulsifying agents.

11. A composition according to claim 10, in which the specified polymer emulsifying agent selected from poloxamers and polymers of acrylic acid.

12. A composition according to claim 11, in which the specified polymer emulsifying agent is an acrylic polymer.

13. A composition according to claim 1, containing as active ingredient a complex of ethyl ester of EPA, complex ethyl ester of DHA and simple GLA ethyl ester in a solution of acetate of α-Tocopheryl, Carbopol as gelling polymer and Pemylen as a polymer emulsifying agent.

14. A composition according to claim 1, in which mentioned polyunsaturated fatty acids omega-3 and omega-6 contained in one or more vegetable and/or fish oil and/or krill oil, combined, in turn, with the vitamin E or its complex ether, and the resulting mixture is dispersed in the form mentioned in the hydrogel.

15. A composition according to claim 14, in which the mentioned vegetable oil selected from linseed oil, borage oil, oil of wheat germ, hemp oil, olive oil, peanut oil, black currant oil, soybean oil and mixtures thereof, and the said rib� fats selected from the fat salmon mackerel oily fish, krill fat, and mixtures thereof.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, more specifically to a composition for treating dermatologic diseases, preferentially skin itching. The composition causes antiallergic action and is used in treating allergic reactions (rash, urticaria), insect bites, ultraviolet erythema and skin burns. The pharmaceutical composition contains azelastine hydrochloride and benzocaine as active substances, and a hydrophobic ingredient, a hydrophilic ingredient, an emulsifying agent and a pH corrective agent as additive agents. As the pH corrective agent, the composition contains preferentially succinic acid. The pharmaceutical composition is presented as a soft dosage form, preferentially in the form of a cream.

EFFECT: composition according to the invention is characterised by high pharmacologic activity, good package extrusion, and storage-stability.

9 cl, 1 tbl, 14 ex

FIELD: medicine.

SUBSTANCE: therapeutic agent contains carboxymethyl cellulose sodium salt as a base and a combination of antiseptic, 0.01% Myramistinum and metronidazole as therapeutic ingredients. The invention provides preparing the therapeutic agent possessing the antiseptic, wound-healing and sorption action on local pyoinflammatory processes in soft tissues and mucous membranes, used in surgery, dermatology, obstetrics and gynaecology, otorhinolaryngology.

EFFECT: agent possesses the higher efficacy.

2 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: therapeutic agent contains an alloy of polyethylene oxide of molecular weight 400 and 1500 as a base and comprises a combination of antiseptic, benzalkonium chloride and metronidazole as therapeutic ingredients. The invention provides preparing the therapeutic agent possessing the antimicrobial, sorption and wound-healing action on local pyoinflammatory processes in soft tissues and mucous membranes, used in surgery, dermatology, obstetrics and gynaecology, otorhinolaryngology.

EFFECT: agent possesses the higher efficacy.

2 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: first, the method involves teeth cleaning, surgical site isolation with cotton swabs, drug-induced treatment of 2% chlorhexidine and drying. Then, an erosion surface and adjoining solid dental tissues are coated with a phytoapipreparation for 15-20 minutes. The preparation is presented in the form of an ointment and has the following composition, weight fractions: 40% alcoholate (1:10) of tartarian catchfly or rhizomes and roots of maral root 10 ml, 40% alcoholate (1:10) of spirea herb 5 ml, apilac 0.5 g, clove ester 0.5 ml, lanolin 25.2 g, Vaselin 58.8 g. The ointment is used once a day for 10 days with the patients advised to avoid eating for one hour.

EFFECT: method is easy-to-use and physiological, and ensures an absolute recovery.

2 ex

FIELD: medicine.

SUBSTANCE: pharmacological composition contains a therapeutic agent and a pharmaceutically acceptable base. As a therapeutic agent, it contains recombinant interferon specified in a group: recombinant interferon alpha, recombinant interferon beta, recombinant interferon gamma, as well as hypromellose, boric acid as an antiseptic, anesthesin or lidocaine as local anaesthetics in the following proportions, g per 1 ml of the mixture: recombinant interferon, IU 100-10,000,000, hypromellose 0.00001-0.5, boric acid 0.00001-0.5, anesthesin or lidocaine 0.00001-0.5, a pharmaceutically acceptable base - the rest. Besides, the pharmaceutical composition contains heparin in an amount of 0.00001-0.5 g; antibiotics specified in a group of: baneocin, levomycin, tetracycline, amoxicilline in an amount of 0.00001-0.5 g. And as a pharmaceutically acceptable base, the pharmaceutical composition contains macrogol 400, or macrogol 1500, or macrogol 4000.

EFFECT: more effective treatment.

4 cl, 9 ex

FIELD: medicine.

SUBSTANCE: ulcer region is coated with macroporous hydrogel with the concentration of lightly cross-linked acrylic polymer 0.2-0.6 wt %, gel viscosity 45-85 poises at pH from 7.0 to 7.8. The wound floor is coated with a layer 2-4mm thick, and the wound edges - 1.5-3 mm, while a periulcerous region - 1-3 mm thick.

EFFECT: healing trophic ulcer 5-15 days later and no recurrence for 1-2 years as shown by patient's follow-up.

3 ex

FIELD: medicine.

SUBSTANCE: as an active substance, the composition contains butoconazol, a base that is a combination of a hydrophobic ingredient, a hydrophilic ingredient and an emulsifier, and also a gel-forming polymer. Hydroxypropylstarch phosphate is preferentially used as the gel-forming polymer. A method for preparing the declared composition consists in the fact that a mixture of butoconazol with a portion of the hydrophilic ingredient, the hydrophobic ingredient and emulsifier is added with a dispersion of the gel-forming polymer in the rest of the hydrophilic ingredient; the produced mixture is agitated homogenously with a preserving agent added where it might be necessary.

EFFECT: new pharmaceutical composition is characterised by a high level of antifungal activity, stability both at a storage temperature, and at a use temperature, and good pack extrusion.

14 cl, 2 tbl, 10 ex

FIELD: medicine.

SUBSTANCE: invention represents a drug for treating osteoarthrosis presented as a soft dosage form, containing glucosamine and methyl salicylate as active substances, and additive agents.

EFFECT: enhanced anaesthetic action and lower toxicity of methyl salicylate.

10 cl, 1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly represents a pharmaceutical composition for treating viral diseases and represents a soft dosage form. The maximum positive effect of the invention is ensured by an exact combination of the dosage form ingredients, a sequence of introducing them with taking into account of the stage of the disease when selecting additives.

EFFECT: soft dosage form (0,5% Hiporhamine liniment) based on polymeric hydrophilic additives - polymethacrylic acid (Carbopol) in a combination of glycerol, Tween and castor oil possesses the high biological availability and storage stability.

4 cl, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention represents a pharmaceutical composition for treating papillomatosis of various localisations, containing a recombinant interferon specified in a group: recombinant interferon-alpha, recombinant interferon-beta, recombinant interferon-gamma, and further cysteine, and vitamin A or beta-carotene, and a pharmaceutically acceptable carrier, wherein the ingredients in the compositions are taken in certain proportions, g per 1 g.

EFFECT: increasing therapeutic efficacy of the treatment, reducing the length of treatment and minimising the potential recurrence.

10 cl, 13 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: chemistry.

SUBSTANCE: invention provides a method of encapsulating antiseptic-stimulator Dorogova (ASD) fraction 2. The method is a physical-chemical non-solvent deposition method. When carrying out the method, the cladding of the microcapsules used is sodium alginate and the precipitation agent is carbon tetrachloride.

EFFECT: simple and faster process of producing microcapsules and higher mass output.

2 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, namely to ophthalmology, and aims at treating eye discomfort. Treating the eye discomfort is ensured by applying a liquid composition containing a cooling agent. The cooling agent represents 2,3-dihydroxypropyl ester of (1R,2S,5R)-2-isopropyl-5-methylcyclohexane carboxylic acid (or CPS-030). The liquid composition of the cooling agent is applied locally on at least a part of the outer surface of the eyelid (preferentially a closed one) to be treated. Preferentially, the liquid composition of the cooling agent is applied on a tissue, a tampon or a wipe or is enclosed into a tissue, a tampon or a wipe, e.g. an eye wipe.

EFFECT: using the group of inventions provides the prolonged relief of the eye discomfort with no eye irritation.

57 cl, 1 tbl, 1 dwg, 6 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, specifically to pharmaceutical compositions possessing prolonged antiarrhythmic actions and applicable to correct the cardiac arrhythmia, including that of the ischemic origin. What is presented is a pharmaceutical composition with the prolonged antiarrhythmic acitivity containing bis[2-(diethylamino)]-N-(2,6-dimethylphenyl)acetamide L-glutaminate, L-glutamic acid, 2-aminoethane sulpho-acid and excipients.

EFFECT: prolonged antiarrhythmic action and stability of the dosage form (tablets, capsules for oral application or solution for injections).

3 cl, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the pharmaceutical industry and represents a product in the form of a kit containing the first composition containing a compound specified in azelaic acid or its salts in an amount of approximately 5 wt % to 10 wt % of the total weight of the first composition, and the second composition different from the first one and containing a compound specified in a group consisting of brimonidine or its salts, in an amount of approximately 0.1 wt % to 0.2 wt % of the total weight of the second composition, as a combined product used as a therapeutic agent for treating inflammatory skin diseases, wherein the first and second compositions can be used either simultaneously, separately or at a time delay.

EFFECT: invention provides the more effective treatment of the inflammatory skin diseases than the treatment using each compound separately with the minimum side effect notwithstanding the time of using the above combination.

13 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the encapsulation of a hydrophobic liquid by an enteric matrix without the application of organic solvents. A material of the enteric matrix is selected from the group, consisting of zein, shellac and their mixtures. A method of microencapsulation of an active ingredient by the enteric matrix includes mixing of a combination of water, material of the enteric matrix at pH higher than the solubility of enteric polymers, which is used to support complete dissolution, and an emulsifier. The combination is in fact free of organic solvents. After that, the addition of the hydrophobic liquid and homogenisation with obtaining a fine stable emulsion are carried out. Then, the titration of the emulsion with acid with mixing in an amount, efficient for obtaining sediment in the form of particles, is carried out.

EFFECT: invention makes it possible to obtain the composition, possessing enteric properties.

45 cl, 6 dwg, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a percutaneously absorbable layer having a base and an adhesive layer which is placed on the base and which comprises an adhesive agent and a therapeutic ingredient. The adhesive agent contains a mixture of resins containing 100 portions by weight of an acrylic copolymer (A) and 0.1 to 30 portions by weight of an acrylic copolymer (B) or 0.05 to 2 portions by weight of a low-molecular polyamine compound having at least two amino groups in one molecule and non-polymerising with a polymer or an oligomer formed. The adhesive layer additionally contains an organic acid. The acrylic copolymer (A) represents an acrylic copolymer, which contains acrylic ester of (meth)acrylic acid as a main monomer ingredient and contains 3 to 45 wt % of diacetone acrylamide as a target monomer ingredient, but free from a free carboxylic group. The acrylic copolymer (B) represents an acrylic copolymer, which contains acrylic ester of (meth)acrylic acid as a main monomer ingredient and contains a primary amino group and/or carboxyhydrazidase group on side chains, but free from a free carboxylic group.

EFFECT: reducing the aging period of the adhesive layer considerably.

7 cl, 8 tbl, 39 ex

Up!