Pharmaceutical formulations of non-polar and polar lipids for ophthalmological application

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to pharmaceutical formulations and methods for preparing them of lipids for ophthalmological application containing a phospholipid ingredient containing natural zwitterion phospholipids, and an oil ingredient containing natural oil-in-water emulsions. The oil ingredient and phospholipid ingredient are preferentially related as 3:1; the phospholipid ingredient is found in the amount of 0.1%-5%, and the oil ingredient is found in the amount of 0.3%-15%.

EFFECT: group of inventions provides ocular drug delivery applicable for treating dry eye syndrome; it has an ability to recover the lipid lachrymal film layer, inhibits the inflammatory element observed.

37 cl, 19 tbl, 4 ex, 7 dwg

 

The technical field to which the invention relates.

The present invention relates to pharmaceutical compositions for lipid basis for ophthalmic use. Specifically, the invention relates to ophthalmic compositions, applicable, for example, for drug delivery in the eye and in the treatment of dry eye, because they are able to restore the lipid layer of the tear film. Specifically, when the enduring pathological conditions such as dry eye syndrome, such compositions also reduce often present inflammatory components.

The level of technology

It is known that the function of the tear film is to maintain the surface of the eye in the wetted state that protects the epithelium of the cornea and conjunctiva and provides the transfer of biologically active substances necessary for the physiology of the eye (nutrients, oxygen). To preserve the physical characteristics of the ocular epithelium tear film must have the necessary surface tension (necessary capacity of the mucous layer, allowing the aqueous phase to spread the epithelium) and must have a physiological rate of evaporation. Changing these properties leads to an increase in dryness of the eyes and perhaps to the dry eye syndrome.

Tear film mainly consists of three layers. First priloga the t to the surface of the eye (cornea, conjunctiva) and consists mainly of mucin; the intermediate layer consists mainly of an aqueous solution containing ions, proteins and so on; the third layer is in contact with air, consists mainly of non-polar and polar lipids of different nature (cholesterol esters cholesterol, phospholipids type triglycerides, ceramides, cerebrosides, and so on)that have the property to prevent the rapid evaporation of the intermediate water layer.

In fact, these layers are in dynamic equilibrium with each other due to the blinking of the eyelids, which leads, in General, to more complex and homogeneous tear film.

One of the reasons for the occurrence of dry eye and specifically dry eye syndrome is the excessive evaporation of the aqueous layer of the tear film caused by failure of function of the external lipid layer due to qualitative and quantitative changes in its composition.

On sale there are ophthalmic compositions containing polymers, which reduce the evaporation of the tear film due to a certain level of viscosity.

Other compositions on the basis of phospholipid or oil emulsions in water is used to restore the natural lipid layer of the tear film always with the function of lowering the evaporation of the water film. These compositions, for example, presented in the patent Glonek, US No. 5578586.

In particular the above-mentioned patent describes specific metastable composition, consisting of phospholipid components and the oil components in certain concentrations and at a certain ratio, emulsified in water.

In the above-mentioned patent phospholipid component consists of charged phospholipids (with positive or negative charge) in an amount in the range of 0.01-7% by weight of the total weight of the composition, while the oil component comprises mineral oil in an amount of 0.1% - 12.5 percent by weight of the total weight of the composition.

The patent discloses, inter alia, that this type of oil called "non-polar"is preferred with respect to oils of animal or vegetable origin, called "polar" (because they contain significant amounts of acid and/or ester groups), since the latter would lead to undesirable effects hazy field of view and instability of the composition compared to synthetic oils.

It should be noted that among the lipids zwitterionic molecules, such as phosphatidylethanolamine and phosphatidylcholine (lecithin), completely excluded from the scope of the claims of US patent No. 5578586, because they carry a positive charge at pH 7 compensates the negative charge of the phosphate group. Negatively charged phospholipids are preferred according to this patent, because of their negative charge which should facilitate the spreading of the composition on the surface of the eye through a small electrostatic repulsion from the negatively charged surface of the eye.

Additionally, formulations containing lipids, commercially available at present, need to be stored at low temperature (4°C) because of the low stability of the lipid components, which becomes rancid at room temperature.

Disclosure of inventions

The technical task of the present invention, therefore, is the discovery of pharmaceutical compositions for use in ophthalmology, which would differ from the known compositions and which would be safe and well tolerated and additionally would be useful as a means of delivery of active substances. In particular, the provided compositions according to the invention with optimum efficiency for the treatment of dry eye and/or dry eye even in a small size.

This problem is solved by using pharmaceutical compositions comprising a set of specific lipids (phospholipids and oils of natural origin. In fact, unexpectedly discovered that the use of non-polar lipids, in particular of vegetable or animal origin (for example, soybean oil, olive oil, fish oil) and polar lipids, such as phospholipids, derived from egg yolk or lecithin soybeans, or a mixture of phospholipids, such as phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, reduces isarene the water portion of the tear film in a similar manner to the action of lipids meibomian gland (natural lipid layer of the tears)), to reduce this evaporation in a more efficient manner than in the case of compounds, emulsified or containing polymers, commercially available at present.

As will be seen from the examples, the compositions according to the invention are more efficient than other formulations help reduce evaporation of the tear film. Additionally, other tested compounds, the products found on the market, can not integrate with the natural meibomiae glands, as do the compositions described below.

Additionally, unexpectedly discovered that several of the compositions according to the invention is effective in combating allergic or inflammatory conditions of the eye, associated or not with dry eye syndrome.

Additionally, the composition can be applied as a means of delivery of active substances in the pathology of the eye (glaucoma, age-related macular degeneration AMD, diabetic retinopathy, neuropathy, bacterial or viral infections and the like) and, in particular, substances with anti-allergic and/or anti-inflammatory activity, also not associated with dry eye syndrome, which can help the efficiency of emulsions.

It should be noted that the pharmaceutical composition can preferably be used as a carrier of active substances due to its superior structure and capacity in respect of the above-mentioned substances, such as active substances per se due to the above-described therapeutic action and/or such as active substances, demonstrating additional or synergistic action of the active substances with anti-allergic or anti-inflammatory activity.

The first object of the invention therefore is to develop pharmaceutical compositions for ophthalmic use, as described in the main clause appended claims.

A second object is to ensure the stability of the mentioned structures even at room temperature.

A third object is to develop a method of obtaining mentioned pharmaceutical compositions.

The fourth object is the use of the above compositions for the preparation of drugs for the treatment of ocular pathologies, such as glaucoma, age-related macular degeneration AMD, diabetic retinopathy, neuropathy, bacterial or viral infections, dry eyes and dry eye.

The fifth object is the use of the above compositions for the treatment of inflammatory conditions associated or not associated with dry eye syndrome or allergic conditions of the eye.

The sixth object is to use songs as a means of delivery of active agents for ophthalmic use and concretely such the efficiency can be enhanced by the pharmacological activity characterizing the claimed composition (antiallergic, anti-inflammatory).

Brief description of figures

Additional features and advantages of the invention will become more apparent from the following description of several implementations, data as examples and not limitation with reference to figures relating to the stability of the claimed composition.

Figure 1A is a graph comparing the change of pH of the three compositions according to the invention during storage at 25°C.

Figure 1B is a graph comparing the change of pH of the three compositions according to the invention during storage at 30°C.

Figure 1B is a graph comparing the change of pH of the three compositions according to the invention during storage at 40°C.

Figure 2 represents a table with the percentage of esters of fatty acids in the triglycerides of different origin.

Figure 3 is a graph which compares the percentage of delay evaporation of the aqueous layer of the tear under the action of the compositions according to the invention, meibomian gland and several products available on the market.

Figure 4 is a graph which compares the effectiveness of different concentrations of dexamethasone sodium phosphate in the ratio of inhibition, however, is of PGE2 (prostaglandin E2) in aqueous liquids rabbits, which intravenous bacterial lipopolysaccharide.

Figure 5 is a graph which compares the effectiveness of different methods of treatment of PMN infiltration into the conjunctiva of a rabbit model of superficial inflammation.

Figure 6 is a graph which shows a comparison of anti-allergic efficacy of glucocorticoids and emulsions in vivo in a model of allergic rats.

Figure 7 represents a graph comparing the extravasation of EB (Evans Blue) in the tissue of the eye in the presence of glucocorticoids or composition according to the invention.

The implementation of the invention

Ophthalmic compositions according to the invention include fosfolipidnogo component consisting of zwitterionic phospholipids of natural origin, and the oil component consisting of oils of natural origin, emulsified in water.

When developing compositions which are the object of the present invention unexpectedly discovered that no electric charge composition (due to it contains phospholipids) is the cause of its ability to spread over the surface of the eye is effective to reduce evaporation of the tear film image, and the specific composition of the oil phase in terms of identity and preferred percentage as phospholipids and oils and their mutual soo is wearing.

The ratio between the oil component and a phospholipid component may vary from 4:1 to 1:1, preferably it is 3:1, more preferably the ratio is approximately 2.3:1.

Usually phospholipids present in the ophthalmic compositions in amounts ranging from 0.01 to 7% by weight of the total weight of the composition, preferably they range from 0.1 to 5%, more preferably from 0.3 to 3%.

In particular, the phospholipid component comprises zwitterionic phospholipids of natural origin, for example, mainly phosphatidylcholine in the amount of 50-70% and others at lower levels, including phosphatidylethanolamine 5-20%, sphingomyelin 1-10%, lysophosphatidylcholine 1-10%, neutral lipids 2-15%, etc. relative to the total amount of phospholipids. For example, the phospholipid component, including all of the above phospholipids, commercially available under the commercial name "phospholipids eggs 90" (Egg Phospholipid 90) company Fresenius Kabi.

Mainly, to further increase the stability and efficiency of the claimed compositions of the fatty acid esters present in the phospholipid fatty parts, preferably chosen from myristic acid ≤1%, palmitic acid 20-40%, palmitoleic acid ≤5%, stearic acid ≤30%, oleic acid 20-40%, linoleic acid (LA) ≤30%, eicosanoic key is lots of ≤10%, arachidonic acid (AA) ≤5%, docosahexanoic acid (DHA) ≤20% other fatty acids omega-3 series.

Among them, fatty acids containing double bonds that stabilize the emulsion, playing the role of antioxidants.

The oil component includes oil mainly of natural origin, for example, soybean oil, olive oil, sunflower oil, fish oil, borage oil, sesame oil, hemp oil, corn oil, cottonseed oil. It should be understood that the oil component must contain only natural oils in the form of a non-polar triglycerides except synthetic oils and oils of mineral origin.

The term non-polar triglycerides in the present description refers to molecules of lipids consisting of a molecule of glycerol, hydroxyl (-OH) group which is esterified with three fatty acids, which may be the same or different.

The triglycerides present in the composition, representing the object of the invention, in quantities varying in the range of 0.01 to 28% by weight of the total weight of the composition, preferably from 0.3 to 15%, more preferably 0.7 to 7%.

Detected, as shown in the table in figure 2, in contrast to mineral oils, animal and vegetable oils of natural origin often are esters of glycerol and fatty acid is t with a long chain, containing one or more double bond, mainly linoleic acid C18:2, oleic acid C18:1, palmitoleic acid C16:1, linolenic acid C18:3 fatty acids omega-3 series, for example, eicosapentaenoic acid C20:5 n3, docosanoic acid C22:6. These oils are additionally stabilized composition which is the object of the present invention.

In particular, it is known that fatty acids (EFA) omega-3 rows (for example, α-linolenic acid (ALA), eicosapentanoic acid (EPA) and docosanoic acid (BHA) and omega-6 series (for example, linoleic acid (LA) and arachidonic acid (AA) function as modulators of inflammatory and immune responses.

Further discovered that compositions comprising the above-mentioned triglycerides and phospholipids in the described percent concentration, mainly to allow a more homogeneous distribution of lipid components on the surface of the eye without the formation of oily: droplets and thus darken the field of view due to nonuniform coating the surface of the eye.

As described above, the relationship between triglycerides and phospholipids is in the range from 4:1 to 1:1, preferably it is 3:1, more preferably from 2.3:1.

Additionally unexpectedly discovered that the addition to the composition buffer with low ionic strength becoming the public allows stable way to maintain pH, compatible with physiological pH tears at room temperature for a long period of time (storage) without disturbing the physico-chemical properties and tolerability of the product itself.

Preferably, the buffer is chosen from the group comprising Tris, NaOH, histidine, tricin, lysine, glycine, serine, brought to the desired pH with acid compounds with low ionic strength.

In particular, at different stages of development of compositions in the form of emulsions among the developed compositions the best from the point of view of stability were those where the buffer used Tris and those used histidine.

To test the behavior of these compositions as compared to compositions without the buffer conducting a pilot test based on the measurement of pH during stability studies (compositions without buffer, formulated with histidine or Tris as buffer). As shown in figures 1A-1B, the results show a sharp decrease in pH over time in the case of the emulsion without the buffer with the formation of free fatty acids at room temperature, whereas emulsions, containing a histidine buffer or Tris, pH value is more stable at room temperature (25°C)and at higher temperatures (30 and 40°C) over a period of time not less than 24 months.

Compositions according to the invention could have the t optionally include an agent for regulating the osmotic pressure, non-ionic or low ionic strength, so that the osmotic pressure of the final product was in the range 0,100-0,320 Osmol/kg. In particular, the said agent regulating the osmotic pressure, which are selected from glycerol, sorbitol, mannitol, ethylene glycol, propylene glycol, dextrose. The agent regulating the osmotic pressure, is present in a quantity sufficient to obtain the osmotic pressure close to that in the tear fluid.

The composition may also include stabilizing agents, surfactants, antioxidants and/or antimicrobial agents, thickeners, linear or branched polymers, amino acids, for example, Tocopherols, free fatty acids and their salts, Polysorbate, pluronic®, cremophor®, a receiver array, hyaluronic acid, xanthan resin, parabens, benzalconi chloride, polyhexamethylene biguanide (RNPS), arginine, lysine, glycine, etc.

As mentioned above, the compositions according to the invention are in the form of emulsions of oil-in-water, which change in the moment of contact with the ocular surface, so that their structure is transformed. This means that the composition is able to be distributed over the surface of the eye, in particular, to integrate meibomian gland, as shown in experiments in vitro to reduce evaporation of tears, described below.

In vivo, the course is built with the participation of the people further discovered that a lipid film on the eye surface is obtained by homogeneous only if the composition contains the above-described oil and preferably at a particular specified proportions between them and phospholipids. For example, the presence of triglycerides of medium chain length (MCT) or short chains, or a mixture of MCT and long-chain triglycerides, specifies the distribution of the lipid inhomogeneous part of the tear film, resulting in a blurred field of vision and poor tolerance eye, and all because of the specific length of the carbon chains in the oil.

The following describes an example of a method of producing compositions of the subject invention.

The method of obtaining pharmaceutical compositions based on non-polar and polar lipids for ophthalmic use.

The method of obtaining pharmaceutical compositions based on non-polar and polar lipids, as described above, includes the following steps:

- receiving at a temperature of about 70±15°C in the same container aqueous phase comprising water and optionally, all described water-soluble components,

separately receiving at a temperature of about 70±15°With the oil phase, comprising a phospholipid component and an oil component and, if necessary, all fat-soluble components, mixing until obtaining omogenei mixture,

add oil phase to the aqueous phase or Vice versa,

- bringing to the desired volume with water,

- obtaining the coarse emulsion through the turbine,

- bringing the pH to physiological values with a solution of acid or alkali, if necessary,

- homogenization and stabilization of the emulsion through the homogenizer under high pressure,

- sterilization of the emulsion at a temperature of 120±10°C for the time necessary to achieve the F0(destruction of microbes necessary to ensure sterility of the product),

- cooling the emulsion to a temperature of 20±10°C.

Preferably, water-soluble components corresponding to the first stage is chosen among those described above.

Preferably, the fat-soluble components corresponding to the second stage, chosen among those described above.

In the case of emulsions containing a lipophilic active substance, it can be included in the oil phase prior to the addition of phospholipids.

Amphoteric active agent can instead be included in the finished oil phase (oil + phospholipids).

Amphoteric active substance can be included in a complete composition prior to sterilization if they are thermostable, or add in aseptic conditions to a pre-sterilized finished composition.

In connection with the stabilization of the of mposite according to the invention, considering the fact that the oil portion of the emulsion may begin to rancid already at the stage of obtaining further its stability at room temperature, found that the more stable product is obtained if the working operations with raw materials and unfinished product up to the stage sterilization of the final product is carried out in an atmosphere without oxygen or oxygen pressure less than 3%. It actually helps to prevent oxidation of double bonds present in the chains of fatty acids of natural phospholipids and triglycerides that make up the composition. Possible oxidation product is actually the cause of instability structures (rancidification, phase separation and formation of toxic molecules (peroxy radical). Product packaging is also needed in terms of protecting the composition from the air immediately after sterilization.

In accordance with a specific implementation of the method described above, the method of obtaining carried out in an atmosphere without oxygen or under a very low pressure of oxygen consists of placing two containers with magnetic stirring at a controlled temperature (70°C), where one contains an oil phase containing phospholipids and fatty or fat-soluble components in the above proportions and quantities, and the other contains the aqueous phase containing water-soluble in the de components. When both phases become homogeneous, the oil phase is added slowly to the aqueous phase using turbogenerator or homogenizer under high pressure at a speed of 5000 revolutions/min. and the Mixture is stirred for approximately 15 min, after which it is sterilized, cooled and Packed.

All the options possible in any case to carry out in the most suitable conditions known to the person skilled in the technical field.

Preferred, but non-limiting examples of compositions according to the invention, shown in the following tables.

Table 1
10% Emulsion without buffer(Weight %)
Soybean oil7,0%
The phospholipids of egg yolk3,0%
Glycerin2,0%
Water (if necessary)100 ml

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Table 2
5% Emulsion without buffer(Weight %)
Soybean oil3,5%
The phospholipids of egg yolk1,5%
Glycerin2,2%
Water (if necessary)100 ml

Table 3
1% Emulsion without buffer(Weight %)
Soybean oil0,7%
The phospholipids of egg yolk0,3%
Glycerin2,2%
Water (if necessary)100 ml

Table 4
10% Emulsion with histidine as a buffer(Weight %)
Soybean oil7,0%
Phopholipid egg yolks3,0%
Glycerin1,7%
L-Histidine0,4%
HCl (heart and soul is on) to a pH of 7.5
Water (if necessary)100 ml

Table 5
10% Emulsion with Tris as buffer(Weight %)
Soybean oil7,0%
Phopholipid egg yolks3,0%
Glycerin1,8%
Tris base0,242%
HCl (if necessary) to a pH of 7.6-
Water (if necessary)100 ml

Table 6
5% Emulsion with trichina as buffer(Weight %)
Fish oil3,5%
Phopholipid egg yolks1,5%
Glycerin2,0%
Tretin0,32%
HCl (if necessary) to a pH of 7.6-
Water (if necessary)100 ml

Table 7
10% Emulsion with glycine as a buffer(Weight %)
Fish oil7,0%
Phopholipid egg yolks3,0%
Glycerin1,8%
Glycine0,16%
HCl (if necessary) to a pH of 7.6-
Water (if necessary)100 ml

Table 8
10% Emulsion with NaOH as a buffer(Weight %)
Soybean oil7,0%
Phopholipid egg yolks3,0%
Glycerin1,8%
0.01 M NaOH0,05%
HCl (if necessary) to a pH of 7.6-
Water (if necessary)100 ml

Table 9
10% of the Drug emulsion with L-histidine as a buffer(Weight %)
Dexamethasone 21 β-palmitate0,16%
Soybean oil7,0%
Phopholipid egg yolks3,0%
Glycerin1,7%
L-Histidine0,40%
HCl (if necessary) to a pH of 7.2-
Water (if necessary)100 ml

Table 10
10% of the Drug emulsion with Tris as buffer(Weight %)
Levocabastine0,05%
Soybean oil7,0%
Phopholipid egg yolks3,0%
Glycerin1,8%
Tris base0,24%
HCl (if necessary) to a pH of 7.2-
Water (if necessary)100 ml

Table 11
10% of the Drug emulsion buffer with L-histidine as(Weight %)
Olopatadineof 0.1% or 0.2%
Soybean oil6,0%
Phopholipid egg yolks4,0%
Glycerin1,7%
L-Histidine0,60%
HCl (if necessary) to pH 7.0-
Water (if necessary)100 ml

Table 12
10% of the Drug emulsion buffer with L-histidine as(Weight %)
Latanoprost0,005%
Soybean oil6,0%
Phopholipid egg yolks4,0%
Glycerin1,7%
L-Histidine0,60%
HCl (if necessary) to pH 7.0-
Water (if necessary)100 ml

Such examples can also be made with different salts of the active substances or active substances, other than those specified in the examples.

Additionally, olopatadine, levocabastine can also be used in a concentration of between 0.02 and 0.2% by themselves or in combination with each other or with glucocorticoids, whereas latanoprost can be used in concentrations in the range from 0.002 to 0.01%. For example, glucocorticoids, you can choose from fluoqinolona acetonide, fluticasone propionate, fludroxycortide, difluprednate, flumetazon pivalate, beclometasone dipropionate, beta is amazona, budezonida, alklometazon dipropionate, clobetasol propionate, clobetasone of butyrate, desonide, desoximetasone, diflorasone diacetate, fluocinonide, halometasone, triamcinolone acetonide, blobette propionate, amcinonide, clocortolone pivalate, dexamethasone, diflucortolone, fludrocortisone acetate, fluprednidene acetate, halcinonide, mometasone furoate, prednicarbate, fluchloralin acetonide, diflorasone acetate, fluocortolone, methylprednisolone, hydrocortisone, fluocortin butyl, their salts and esters and mixtures thereof.

In the experimental model of uveitis in rabbits shown that dexamethasone sodium phosphate able to show significant anti-inflammatory effect in such low concentrations as 0.001% (Figure 4).

It is widely accepted that long-term ophthalmologic introduction (>2 weeks) glucocorticoids in commonly used therapeutic concentrations is associated with increased risk of ocular hypertension and cataract. In fact, clinical application ophthalmic corticosteroids is limited to two-week courses of therapy. Especially adverse effects of ophthalmic corticosteroids are directly related to the amount of the drug delivered to the eye.

According to this line of reasoning, the use of concentrations in the lower part of the chosen interval is (0,001%-1%) can be particularly useful when long-term treatment of conditions of the ocular surface, characterized by inflammation, for example, allergies, dry eye, or treatment after photorefractive keratectomy (PRK) or corneal transplantation.

It can be concluded that especially in inflammatory pathologies of the ocular surface glucocorticoids used in concentration of the lower part of the chosen interval, maintain its effectiveness, at the same time demonstrating enhanced profile ophthalmic security that allows them to apply for longer courses of therapy.

Additional active substances can be selected from the group including fluoroquinolones, preferably the second, third and fourth generation, for example, ciprofloxacin, ofloxacin, levofloxacin, trovafloxacin, moxifloxacin, gemifloxacin or their mixtures or their "fixed" combination (compounds containing at least two different active substances with anti-inflammatory substances, for example, glukokortikoidami, or with other antimicrobial agents such as macrolides, cephalosporins or betalactamase. Concentrations of fluoroquinolones may vary between 0.1 and 0.6%.

Define the following parameters of several songs, which is the object of the present invention: stability, portability, efficiency to reduce evaporation of the tear film, the ability to diffusion in meibomian is elesa, anti-allergic/anti-inflammatory effect.

Stability and portability

All songs presented in the description of the object of the present invention, are well tolerated at eye level.

The stability of the compositions of the buffer is at least 24 months at room temperature.

The effectiveness of the compositions against evaporation of the water components of the tear film

Experts in the field of ophthalmology know that the lipid layer of the tears produced by the meibomian glands, capable of lowering the surface tension of the tear film and to significantly slow the rate of evaporation of water from the subject layer.

The emulsion, which is the object of the present invention, showing the special properties compared to other ophthalmic formulations containing lipids and/or polymers, in particular, the ability to reduce the surface tension of balanced saline solution for at least 30 mn/m after adding about 1% by volume relative to the volume drops in the system hanging drops, are described below and presented in the work of F. Miano et al., J. Phys: Condens. Matter 16(2004)S2461-S2467.

The composition which is the object of the present invention, additionally suddenly able to maintain the rate of evaporation of balanced saline solution at a low level is ezavisimo from temperature conditions, relative humidity, presence or absence of natural lipid layer and the volume ratio between the solution and the emulsion.

To test the ability of the compositions which are the object of the present invention, to reduce evaporation of the water portion of the tears, determine the rate of evaporation of balanced saline solution (HBSS) and the absence or in the presence of marojevic glands in the case of the emulsion, which is the object of the present invention, or in the case of commercial control product.

Apply model hanging drops in the system for measuring the contact angle (OCA, Dataphysics, Germany), consisting of two Hamiltonian syringe with an electronic measuring device, and a chamber with controlled temperature and relative humidity (RH), which is located inside the drop.

The evaporation rate is calculated as the change in the size of the drops after a preset time interval (15 seconds), by processing the images obtained by CCD camera. The measurement of the rate of evaporation is repeated 80 times in total for 20 min in each experiment.

Experimental data are expressed as the reduction in the rate of evaporation is relatively balanced saline solution using the following formula:

Jw=K* 100-R.H.)100

where Jwmean transpiration, expressed in g m-2*with-1, R.H. mean relative humidity and mean constant dependent on temperature.

The ratio between the flux of evaporation (Jmin the presence of marojevic glands or marojevic glands together with the ophthalmic composition is a composition which is the object of the invention, or commercial reference product) and Jw(by evaporation of a solution, expressed in g m-2*with-1defined as

ϕ=1-(Jm/Jw)

where the value of ϕ in the interval 0-1 represents the resistance to evaporation, asked homogeneous distribution of lipids on the surface of the section with the water layer. Data is processed using the program DATAPHYSICS (F. Miano et al. J. Phys: Condens. Matter 16 (2004) S2461-S2467). In the following experiments to determine the rate of evaporation of aqueous solutions compared with the phenomenon of evaporation of tears from patients with dry eye syndrome caused by evaporation. Together with the evaporation rate measured surface tension of the liquid, which is an important property of the lacrimal fluid. The data relating to the action of several drugs for ophthalmic applications on the speed of the COI is to be placed in the model system, representing the tear film.

After applying drops of a balanced Hanks solution (HBSS, Hank''s Balanced Salt Solution containing CaCl2·H2Oh, 0.19 mg/ml; MgSO4, 0,098 mg/ml; KCl, and 0.40 mg/ml; H2PO4, 0.06 mg/ml; NaHCO3, 0.35 mg/ml; NaCl, 8.0 mg/ml D-glucose, 1.0 mg/ml) volume of 12 ál specialist adds a known amount, for example 1 μl of natural lipid solution in chloroform, and waiting for 2 minutes to evaporate the chloroform and the simultaneous formation of the lipid layer on the boundary surface of the liquid-air. Then add a known volume of the investigational ophthalmic solution in the range of 10%-50% by volume relative to the volume drops. Test compounds are presented in the following table 13.

Table 13
The tested compoundsTrack
10% emulsion without bufferEmulsion without buffer containing 7% of the seed oil of soybean; 3% lecithin; 2.2% glycerol in purified water
10% Emulsion with histidine as a bufferEmulsion containing 7% of the seed oil of soybean; 3% lecithin; 2.2% glycerol in purified water with histidine as a buffer
10% Emulsion with Tris in quality is TBE buffer Emulsion containing 7% of the seed oil of soybean; 3% lecithin; 1,8% glycerol in purified water with Tris as buffer
Refresh Endura (USA)A commercial product containing 1% glycerol, 1% Polysorbate 80, carbomer, mannitol, castor oil, sodium hydroxide in water
TSP (tamarind seed polysaccharide)Polysacharide extracted from tamarind seed (0.5% or 1.0%), mannitol, benzalkonium chloride in water

Example 1

Measure the rate of evaporation of balanced saline solution (HBSS) and ophthalmic compositions in different conditions of temperature and relative humidity.

Conditions: T=25±1°C; R.H.=66%, is controlled with a saturated solution of NaNO2.

Table 14
TrackJw
HBSScompared to 8.26×10-5±3,1×10-6g/m2/c
HBSS + meibomian glandof 4.46×10-5±1,67×10-6g/m2/s
10% Emulsion6,37×10-5±2,54×10-6g/m2/s

Conditions: T=36±1°C R.H.=15%, is controlled with a saturated solution of LiCl.

Table 15
TrackJw
HBSS3,919×10-4±4,1×10-5g/m2/c
HBSS + meibomian gland2,555×10-4±5,4×10-5g/m2/c
10% Emulsion2,802×10-4±4,01×10-5g/m2/s

This example shows how the composition which is the object of the invention is able to reduce the rate of evaporation of an aqueous solution in a similar manner with meibomianitis glands in different environmental conditions and in particular at low relative humidity, which often takes place in institutions, airports, airplanes, cars, etc.

Example 2

Measure the rate of evaporation of balanced saline solution (HBSS) compared with a solution with meibomianitis glands under different temperature and relative humidity and adding different volumes of the investigated compositions or control composition.

Conditions; T=36±1°C; R.H.=15%.

Add 1 ál 10 ál of the test or control composition.

Table 16
Meibomian glandRefresh Endura1% TSP10% Emulsion
Fof 0.337±0,0860,341±0,0500,032±0,0610,322±0,097

Conditions: T=36±1°C; R.H.=15%.

Add 5 ál 10 ál of the test or control composition. The ratio between the ophthalmic drug and the liquid is closer to that of drops eye wash (eyewash) in the eye than additive only 1 mm.

Table 17
Meibomian glandRefresh Endura1%TSP10% Emulsion
Fof 0.337±0,0860,041±0,0770,120±0,0480,325±0,080

The optimal value of f, is obtained for marojevic glands. The closer the value of the f test compounds to this value, the more effective these compounds for physiologists the definition reduce evaporation of the water portion of the tear film. From this example we can conclude that Refresh Endura, effectively adding small amounts to drop, adding in the volume close to that of eye wash, disrupts lipid film, whereas TSP never gets close to the physiological value of F. on the other hand, emulsions demonstrate physiological efficiency to reduce evaporation of an aqueous solution in all the applied experimental conditions.

Example 3

Measure the surface tension of balanced saline solution (HBSS), physiological solution in the presence of lipids marojevic glands and ophthalmic solutions and emulsions described above.

Conditions: T=25°C; U.R.=95% for a solution, disubstituted saturated sodium sulfate dvenadtsatiletny.

Table 18
Trackγ(10-3N/m)Notes
HBSS saline72,38±0,27
HBSS saline with meibomianitis glands48,60±1,25of 0.05 ál* 15 ál HBSS
10% emulsion with histidine in the quality of the ve buffer 55,11±0,29
10% emulsion with histidine as a buffer in HBSS26,64±0,450.1 µl to 10 µl HBSS
10% emulsion with histidine as a buffer in HBSS39,66±0,213 ál 12 ál HBSS
Refresh Endura39,72±0,28
Refresh Endura in HBSS42,15±0,450.1 µl to 10 µl HBSS
0.5% of TSP47,39±0,60
1,0% TSP47,71±0,66
0.5% of TSP in HBSSup 66,78±0,481 ál 15 ál HBSS
* 0.4% solution.

The experiment shows an unexpected property of the emulsions according to the invention to reduce the surface tension when they are in contact with a physiological solution containing divalent cations (CA2+, Mg2+).

From the experiment it is clear that the mere presence of conventional surface-active agent (compositions RefreshEndura or TSP) does not decrease the effective surface tension, as happens in the case of emulsions, which is the object of the invention.

The data obtained for Refresh Endura or TSP indicate that when applied to systems close to nature, they do not achieve good distribution in lipids marojevic glands.

The decrease in the values of the surface tension obtained for emulsions, which is the object of the invention, and the proportionality of the volume added to the aqueous solution, indicates that such compositions are well integrated with lipids marojevic glands.

Example 4

To assess the ability of the compositions which are the object of the present invention, to integrate and to reproduce the function of lipids marojevic glands, estimate the reduction in the rate of evaporation in the presence of various compositions currently available at the national and international market, in comparison with compositions according to the invention and with the natural lipids marojevic glands. In this case also using hanging drops. These compositions are compared in the following table 19.

Table 19
10% Emulsion (SIFI)Egg yolk lecithin, soybean oil in Tris buffer
Refresh endura* RE (USA) Castor oil, Polysorbate-80, Carbomer 1342 and glycerin
10% Intralipid (Intralipid) **Soybean oil, lecithin, glycerin
The softener (Soothe)*4,5% mineral oil (Restoril), Polysorbate-80
* ophthalmic composition
** intravenous nutrient composition

As you can see on the graph presented on figure 5, in contrast to other test compositions of the lipid emulsion, which is the object of the invention (SIFI), reduces the evaporation model in vitro statistically significant way similar to the action of lipids marojevic glands (28% and 31%, respectively), whereas the products available on the market, are statistically less effective.

Using rheological measurements has also been found that the film of natural lipids marojevic glands usually manifests elasticity under compression of the surface caused by the movement of the eyelids during blinking, which helps to restore the tear film after a blink.

Discovered that compositions which are the object of the invention substantially correspond to physical properties characterizing the diffusion of natural films lipids meibomian the x glands on the surface of section air/water.

This characteristic fluidity promotes proper reconstruction of the tear film after a blink. This is not an obvious result, since discovered that other compositions containing phospholipids, and a separate commercial emulsion form markedly different surface section.

The composition of the emulsion SIFI show physical properties that are characteristic of the natural diffusion of lipid films marojevic glands on the surface section of the air is water.

These specific properties make the compositions according to the invention particularly suitable for the delivery of drugs for ophthalmic applications that require rapid diffusion, integration and compatibility with lacrimal fluid, determining a good distribution and kinetics in the eye tissues and synergistic effects of some medications.

After introduction into the conjunctival SAC due to the presence in the tear ions phase, the components of the emulsion are separated, releasing the active substance.

In particular, when you change the quantitative and qualitative composition of the lipid layer, as occurs in subjects suffering from dry eyes, dry eye syndrome, caused by evaporation, allergies, bacterial or viral infections, etc., compositions according to the present invention is able to integrate inadequate lipid layer,restoring its physiological state.

Anti-allergic and anti-inflammatory effect

As mentioned in the introductory part of the present description, a number of compositions, which is the object of the present invention, showing an unexpected anti-allergic and anti-inflammatory properties. It is also noticed that the introduction of the compositions according to the invention, including anti-inflammatory and anti-allergic drugs, unexpectedly results in a significantly improved therapeutic responses compared with responses to the application of the mentioned drugs in the composition of the known compositions. In one experiment conducted with glucocorticoids in the model surface inflammation in vivo, the compositions according to the invention unexpectedly show performance comparable to that of glucocorticoids (figure 6).

This effect is further examined in vivo in a model of immunological allergies, specifically with active ocular anaphylaxis in rats. The eye tissues of the rat actually respond to the phenomenon of systemic anaphylaxis. Used experimental model has characteristics similar to those observed in human pathology, clinical manifestations of which are the dilation of blood capillaries, conjunctival edema and increased vascular permeability (Bloch JK, Ohman J, Waltin J, and Cygan RN. "Potentiated reagin response: Initiation with minute doses of antigen and alum followed by infectin with Nippostrongylus brasiliensis" J Immunol 110:197, 1973).

Apply twenty male rats Wistar rats weighing 150-175, Animals subjected to immunization with intraperitoneal injections of 100 mg of ovalbumin and 20 mg of alum in 1 ml of sterile 0.9% NaCl. After 14 days the animals are divided into groups and they receive topical allergic provocation with antigen (10 ml solution of ovalbumin in PBS, 100 mg/ml). Immediately before applying allergic provocation is injected dye Evans blue (EB) (1.25 mg/100 g/1 ml PBS) into the caudal vein of the animal with pre-anaesthetic ether.

After the onset of eye anaphylactic reactions from mastocytes and basophils released mediators of allergic (histamine, serotonin, leukotrienes, platelet activating factor PAF, eosinophilic chemotactic factor, and so on)that define the above clinical signs.

In particular, the histamine released activated mastocytoma and basophils, causing increased vascular permeability and consequently the radiolabeled dye Evans blue and albumin from blood flow and accumulation in the eye tissues, resulting in swelling (Baird RS, Bloch JK, and Allansmith MR. "Edema test for assessing ocular anaphylaxis". Curr Eye Res 2: 657,1983).

Considering the permeability of blood vessels adequate parameter estimation of the intensity of the allergic response, the radiolabeled dye into the eye tissue, measured 30 min after which Nuccio anaphylaxis, used as a marker for allergic reactions.

Tested with the following composition:

Control: water and 2.2% glycerol
10% emulsion
5% emulsion
1% emulsion
0,15% solution of dexamethasone sodium phosphate
0.14% of dexamethasone palmitate 10% emulsion

Substances are applied topicaine (15 μl) into the right eye of the animals, whereas the left eye is processed.

The emulsion is administered within 5, 4, 3, 2, 1 hour before making eye allergic provocation Protocol found in the literature for corticosubcortical (Calonge MS, Pastor JC, Herreras JM and Gonzales JL. "Pharmacologic modulation of vascular permeability in ocular allergy in the rat". Invest Ophthalmol Vis Sci 28: 264, 1987).

After making allergic provocation animals to develop an allergic reaction to the conjunctival level, visible already after the first five minutes, with swelling of the conjunctiva and eyelids with maximum development in 30 minutes

30 minutes after allergic provocation slaughtered by spine n the level of the neck (cervical dislocation). Eyes and eyelids removed, weighed and immersed in a solution for extraction, consisting of acetone and 0.5% of sodium sulfate in the ratio of 14:6 and kept at room temperature under stirring. After 24 hours, the samples are centrifuged at 2000 rpm for 10 min and the colour intensity of the supernatant was measured with a spectrophotometer at 620 nm.

For each experiment to obtain the standard calibration curves for conversion of optical density to concentration in mg/ml solution, and then normalize data on mg tissue. Data expressed in percentage of EB extravasation into the tissues of the animal eyes are affected, compared to control animals not subjected to pharmacological effects.

As can be seen in figure 7, the applied model the observed dependence of the effective dose for the tested compositions, which implies statistical significance in the case of emulsions containing oil component in concentrations above 1%.

In particular, it is observed that 10% emulsions show a 50% inhibition of extravasation of the dye compared to the control and 5% emulsions have approximately 37% inhibition of allergic reactions. In the experiment it is observed that the emulsion containing dexamethasone palmitate, showing a synergistic effect of the active substance, which is already in the concentratie of 0.14% shows greater effect than the solution of 0.15% dexamethasone sodium phosphate.

In addition, a synergistic effect of the emulsion on the effect of dexamethasone palmitate is evident when compared with the effectiveness of media (10% emulsion), with greater statistical significance than is obtained when compared to 0.15% solution and PBS (Figure 6).

As is clear from the above, the present patent application is a pharmaceutical composition for ophthalmic use, which allows primarette natural substances.

Additionally, the specialist in this field can get numerous options composition, where they are all covered by the scope of the claims appended claims.

1. Pharmaceutical composition for ophthalmic use, including phospholipid component, consisting of zwitterionic phospholipids of natural origin, and the oil component consisting of oils of natural origin, emulsified in water, and optionally a buffer with low ionic strength selected from Tris or histidine, where the ratio between the oil component and a phospholipid component is preferably 3:1, the phospholipid component is present in an amount of 0.1%-5%, and the oil component is present in the amount of 0.3%to 15%.

2. The pharmaceutical composition according to claim 1, in which the ratio is s between the oil component and a phospholipid component is 2.3:1.

3. The pharmaceutical composition according to claim 1 or 2, in which the phospholipid component is present in the amount of 0.3%to 3%, and the oil component is present in the amount of 0.7%-7%.

4. The pharmaceutical composition according to claim 1, in which the phospholipid component comprises phosphatidylcholine in the amount of 50-70%, phosphatidylethanolamine 5-20%, sphingomyelin 1-10%, lysophosphatidylcholine 1-10%, neutral lipids 2-15% relative to the total weight of phospholipid.

5. The pharmaceutical composition according to claim 1, in which the oil component includes oil mainly of natural origin, such as soybean oil, olive oil, sunflower oil, fish oil, borage oil, sesame oil, hemp oil, corn oil, cottonseed oil.

6. The pharmaceutical composition according to claim 1, in which the oil component includes oil in the form of non-polar triglycerides.

7. The pharmaceutical composition according to claim 6, in which the fatty acids included in the non-polar triglycerides, choose, for example, myristic acid, linoleic acid, oleic acid, linolenic acid, palmitic acid, palmitoleic acid, stearic acid, eicosapentanoic acid, arachidonic acid, docosanoic acid.

8. The pharmaceutical composition according to claim 1, in which the pH is in the range of 6.5-8.

9. The pharmaceutical composition according to claim 1, updat the enforcement including the agent, non-ionic or low ionic strength, regulating the osmotic pressure, for regulating the osmotic pressure of the composition, to obtain a value in the range 0,100-0,320 Osmol/kg

10. The pharmaceutical composition according to claim 9, in which the said agent regulating the osmotic pressure, which are selected from glycerol, sorbitol, mannitol, ethylene glycol, propylene glycol, dextrose.

11. The pharmaceutical composition according to claim 1, additionally comprising at least one agent selected from stabilizers, surface-active substances, substances that promote surfactant, antioxidant and/or antimicrobial agents, thickeners, linear or branched polymers of amino acids.

12. The pharmaceutical composition according to claim 11, in which the mentioned stabilizing agent, a surfactant, a substance promoting surfactant, antioxidant and/or antimicrobial agent, thickener, go linear branched polymer, amino acid selected from tocopherol, free fatty acids and their salts or derivatives, Polysorbate, pluronic®, cremophor®, Receiver array, hyaluronic acid, xanthan resin, parabens, benzalconi chloride, polyhexamethylene of biguanide (RNPS). arginine, lysine, glycine, alcohols.

13. The pharmaceutical composition according to claim 1, dopolnitelbnaya active substance or a given combination of active substances.

14. The pharmaceutical composition according to item 13, in which the mentioned active substances are selected from olopatadine, levocabastine, latanoprosta, glucocorticoids, fluoroquinolones second, third or fourth generation, and mixtures thereof.

15. The pharmaceutical composition according to 14, in which the mentioned active substances can be applied in predetermined combinations betalactamase, cephalosporins and macrolides.

16. The pharmaceutical composition according to 14, in which olopatadine, levocabastine used at a concentration of between 0.02% and 0.2%, latanoprost used at a concentration of between 0,002% and 0.01%, glucocorticoids are used in concentrations between about 0.001% and 1%, fluoroquinolones second, third or fourth generation used at a concentration of between 0.1% and 0.6%.

17. The pharmaceutical composition according to claim 1, consisting of:

10% Emulsion(Weight %)
Soybean oil7,0%
The phospholipids of egg yolk3,0%
Glycerin2,0%
Water (if necessary)100 ml

18. The pharmaceutical composition according to claim 1, consisting of:

5% Emulsion(Weight %)
Soybean oil3,5%
The phospholipids of egg yolk1,5%
Glycerin2,2%
Water (if necessary)100 ml

19. The pharmaceutical composition according to claim 1, consisting of:

1% Emulsion(Weight %)
Soybean oil0,7%
The phospholipids of egg yolk0,3%
Glycerin2,2%
Water (if necessary)100 ml

Any composition according to claim 1, consisting of:

3,0%
10% Emulsion with histidine as a buffer(Weight %)
Soybean oil7,0%
Phopholipid egg yolks
Glycerin1,7%
L-Histidine0,4%
HCl (if necessary) to a pH of 7.5-
Water (if necessary)100 ml

21. The pharmaceutical composition according to claim 1, consisting of:

10% Emulsion with Tris as buffer(Weight %)
Soybean oil7,0%
Phopholipid egg yolks3,0%
Glycerin1,8%
Tris base0,242%
HCl (if necessary) to a pH of 7.6-
Water (if necessary)100 ml

22. The pharmaceutical composition according to claim 1, consisting of:

5% Emulsion with trichina as buffer(Weight %)
Fish oil3,5%
Phopholipid egg yolks1,5%
Glycerin2,0%
Tretin0,32%
HCl (if necessary) to a pH of 7.6-
Water (if necessary)100 ml

23. The pharmaceutical composition according to claim 1, consisting of:

10% Emulsion with glycine as a buffer(Weight %)
Fish oil7,0%
Phopholipid egg yolks3,0%
Glycerin1,8%
Glycine0,16%
HCl (if necessary) to a pH of 7.6-
Water (if necessary)100 ml

24. The pharmaceutical composition according to claim 1, consisting of:

10% Emulsion with NaOH as a buffer(Weight %)
Soybean oil 7,0%
phopholipid egg yolks3,0%
Glycerin1,8%
0,01 MNaOH0,05%
HCl (if necessary) to a pH of 7.6-
Water (if necessary)100 ml

25. The pharmaceutical composition according to claim 1, consisting of:

10% of the Drug emulsion with L-histidine as a buffer(Weight %)
Dexamethasone 21 β-palmitate0,16%
Soybean oil7,0%
Phopholipid egg yolks3,0%
Glycerin1,7%
L-Histidine0,40%
Model HC1 (if necessary) to a pH of 7.2-
Water (if necessary)100 ml

26. The pharmaceutical composition according to claim 1, consisting of:

10% of the Drug emulsion with Tris as buffer(Weight %)
Levocabastine0,05%
Soybean oil7,0%
Phopholipid egg yolks3,0%
Glycerin1,8%
Tris base0,24%
HCl (if necessary) to a pH of 7.2-
Water (if necessary)100 ml

27. The pharmaceutical composition according to claim 1, consisting of:

10% of the Drug emulsion with L-histidine in the buffer(Weight %)
Olopatadineof 0.1% or 0.2%
Soybean oil6,0%
Phopholipid egg yolks4,0%
Glycerin1,7%
L-Histidine0,60%
HCl (if necessary) to pH 7.0-
Water (if necessary)100 ml

28. The pharmaceutical composition according to claim 1, consisting of:

10% of the Drug emulsion with L-histidine in the buffer(Weight %)
Latanoprost0,005%
Soybean oil6,0%
Phopholipid egg yolks4,0%
Glycerin1,7%
L-Histidine0,60%
Water (if necessary)100 ml

29. The pharmaceutical composition according to any one of PP-28, in which the active substance include any salts or esters mentioned active substances.

30. A method of obtaining a pharmaceutical composition according to any one of claims 1 to 29, including the steps:
receiving at a temperature of about 70±15°C in the same container aqueous phase comprising water and optionally, all water-soluble components PP-13,
separately receiving at a temperature of about 70±15°With the oil phase is, including a phospholipid component and an oil component and, if necessary, all fat-soluble components, pp.5-7 and 12-13, stirring until a homogeneous mixture,
add oil phase to the aqueous phase or Vice versa,
bringing to the desired volume with water,
obtain a coarse emulsion through the turbine,
bringing the pH to physiological values with a solution of acid or alkali, if necessary,
homogenization and stabilization of the emulsion through the homogenizer under high pressure,
sterilization of the emulsion at 120±10°C for the time necessary to achieve the F0(destruction of microbes necessary to ensure sterility of the product),
cooling the emulsion to 20±10°C.

31. A method of obtaining a pharmaceutical composition according to any one of claims 1 to 29, characterized in that the working operations with raw materials and unfinished product until the sterilization and packaging of the final product is carried out in an atmosphere without oxygen or oxygen pressure less than 3%.

32. The method of obtaining medicinal pharmaceutical composition according to any one of p-29, characterized in that the hydrophobic active substance included in the oil phase prior to the addition of phospholipids.

33. The method of obtaining medicinal pharmaceutical composition according to any one of p-29, characterized in that the amphoteric active substances the CTB include a complete fatty phase (oil + phospholipids) or complete composition prior to sterilization, if it is thermostable, or under aseptic conditions in a pre-sterilized complete composition, if it thermolabile.

34. The pharmaceutical composition according to any one of claims 1 to 29 as a medicine.

35. The use of pharmaceutical compositions according to any one of claims 1 to 24 as a means of delivery of systemic drugs.

36. The use of pharmaceutical compositions according to any one of claims 1 to 24 and 29 to obtain drugs for the treatment of dry eye or dry eye syndrome, to reduce evaporation of the aqueous layer of the tear film, characterized in that the amount of phospholipid and an oil component is greater than or equal to 1% by weight relative to the total weight of the composition to obtain ophthalmic drug with anti-inflammatory/anti-allergic activity.

37. The use of pharmaceutical compositions for p as a means of delivery of ophthalmic drugs.



 

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1 tbl, 2 ex

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2 ex

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1 ex

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17 cl, 14 tbl, 143 ex

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Nanoemulsion // 2491917

FIELD: medicine.

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25 cl, 6 dwg, 9 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: group of inventions relates to field of biochemistry. Claimed is preparation for preservation of culture of stem and differentiated human and animal cells in cultivation, storage and cryoconservation. Preparation represents gel, which contains emulsion of perfluororganic compounds (PFOC) in their stabilisation in emulsified state with water solution of non-ionogenic surface active compounds (SAS) based on block-copolymer of polyethylene oxide (PEO) and polypropylene oxide (PPO) with ratio PEO/PPO from 9:1 to 7:3. SAS concentration in preparation constitutes from 20 to 90% with average molecular weight of SAS from 5000 Da to 21000 Da. Content of PFOC in emulsion constitutes from 5 to 70 vol.%. Size of PFOC emulsion particles lies in the interval from 15 nm to 2000 nm. Water phase of gel contains osmolytes of organic and/or inorganic nature for supporting in it osmotic pressure from 250 to 350 mOsm. As PFOC emulsion, emulsion of perfluorodecalin, perfluoro methylcyclohexyl piperidine and perfluorotributylamine mixture can be used. Also claimed is method of obtaining said preparation. Extrusion of coarse mixture of water SAS solution and liquid PFOCs or PFOC mixture is performed under pressure 400-700 atm until emulsion is obtained. After that, it is mixed in hot condition with concentrated water solution of inorganic salts or osmolytes are added into it until osmotic pressure equal from 250 to 350 mOsm is obtained. Then obtained composition is cooled. After that, partial freeze-drying or centrifugation of gel with observation of temperature gradient and acceleration from 15000 g to 35000 g is performed. Methods of preservation of culture of stem and differentiated human and animal cells in storage, cryoconservation and cultivation are claimed. In storage of cells preparation with PFOC content from 15 to 59 vol.% is added to culture medium with controlled value pH=7.0-7.4, temperature 37°C in CO2 incubator atmosphere or with low pH<6.0, temperature 20°C in air atmosphere. In cryoconservation resuspended in fresh culture medium cells are placed into medium, which contains preparation with PFOC content 59-70 vol.%. After that, cooling is carried out in two stages: first at rate 1 degree per min to -80°C, then with maximally possibly rate to temperature -196°C. In cultivation of cells as medium component preparation with PFOC content from 15 to 70 vol.% is used.

EFFECT: cell cultures after cryoconservation, storage or cultivation in presence of PFOC-containing gels have on average 90% of viable cells, are easily separated from gel, re-inoculated in standard conditions, divided and fully preserve their functions and ability to differentiate.

16 cl, 23 dwg, 1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmaceutical industry, particularly to creating a pharmaceutical composition of a submicron emulsion for parenteral administration, having anticonvulsant activity. The composition contains 5-carbamoyl-5H-dibenz-(b,f)-azepine, and additionally it contains soya been oil and sodium deoxycholate in the following proportions, wt %: 5-carbamoyl-5H-dibenz-(b,f)-azepine - 18.5-23.2, soya been oil - 2.1-2.3, sodium deoxycholate - 74.5-79.4. The composition has an average size of the deagglomerated microparticles of 108-132 nm.

EFFECT: composition enables the intravenous intraperitoneal administration of a low therapeutic dose with a high efficacy of the preparation, and reduction of dose-dependent adverse reactions, and extends the range of such preparations.

4 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a formulation for delivery of amphotericin B and other drugs, wherein the formulation contains an active ingredient, one or more esters of glycerol and fatty acids and one or more esters of fatty acids containing polyoxyethylene oxide, wherein the ratio of esters of glycerol and fatty acids and esters of fatty acids containing polyoxyethylene oxide makes from approximately 20:80 to approximately 80:20 vol/vol.

EFFECT: formulation is applicable for preparing the drug with improved bioavailability for infectious diseases.

13 cl, 21 dwg, 8 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine and pharmaceutical industry, and concerns a combined pharmaceutical composition with antibacterial and antifungal activity. The composition comprises clindamycin phosphate, butoconazole nitrate as active ingredients. As a basis, the composition comprises a combination of a hydrophobic ingredient, a hydrophilic ingredient and an emulsifier and a gelling agent. A method of preparing the declared composition involves that a solution of clindamycin salt or ester in a part of the hydrophilic ingredient is added with the gelling polymer, then the emulsion prepared of a solution of butoconazole in the remained part of the hydrophilic ingredient, the hydrophobic ingredient and the emulsifier, and the prepared mixture is agitated until smooth.

EFFECT: new pharmaceutical composition is characterised by a high level of antibacterial and antifungal activity, stability both at the storage temperature (25°C), and at temperature of use (37°C), good packaging extrusion and high osmotic activity.

13 cl, 1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an agent for treating skin purulent infections, containing microcrystalline fusidic acid, an emulsion base (butylhydroxyanisol, emulsifier No.1, distilled glycerol, Vaseline oil, potassium sorbate, tween 80, medical white Vaseline, purified water) and additionally zinc oxide. The invention also concerns methods for preparing the specified agent.

EFFECT: developing an integrated preparation for treating purulent skin infections on the emulsion base that enables higher therapeutic effectiveness and reduced length of treatment.

3 cl, 2 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: stable fat emulsion contains prostaglandin as an active ingredient and phospholipids containing phosphatidylcholine and phosphatidyl glycerol in mass ratio 85:15 to 99.7:0.3. The fat emulsion under the invention and its active ingredient (prostaglandin) possess physical and chemical stability thereby increasing shelf life to approximately two years, and/or extended range of storage temperature to 10°C as compared with a commercially available fat prostaglandin emulsion.

EFFECT: fat emulsion under the invention enables satisfactory effectiveness even in the introduction of a low amount.

25 cl, 10 tbl, 12 ex

FIELD: medicine.

SUBSTANCE: invention refers to fine stable emulsions of perfluoroorganic compounds (PFOC) which may be used as a base for preparing blood substitutes with gas transport function, as well as radiopaque contrast agents and mediums for organ preservation. The emulsion contains PFOC in the amount of 8÷80.0 wt %, an emulsifying and stabilising additive in the amount of 0.25÷8.0 wt % and a physiologically acceptable solution - the rest. The emulsifying and stabilising additive of the emulsion is presented by a non-ionic surfactant presenting mixed block copolymers of ethylene oxide and/or propylene oxide and/or polyalkylene glycol esters of tocopherol with polyglycidyl esters of fluorinated alcohols in relation 2:1 to 0.5:1, or the anionic surfactant presenting a monoester salt of dicarboxylic acid with aliphatic and/or pxyalkylated aliphatic and/or perfluorinated alcohols, or mixed said non-ionic and anionic surfactants in relation 39:1 to 1:39.

EFFECT: emulsion under the invention is aggregation- and sedimentation-stable; average particle size is no more than 200 nm; it is stored for a long period of time at room and high temperature with no substantial change in emulsion particle size.

11 cl, 24 tbl, 23 ex

FIELD: medicine.

SUBSTANCE: phospholipid emulsion contains lecithin with the phosphatidylcholine content min. 60%, ethanol, water and diclofenac sodium in the amounts specified in the patent claim. The phospholipid emulsion represents liposomes (nanosomes) of a mean diameter of 20 to 500 nm. The composition is used for the liposomal introduction of biologically active substances and/or drugs into a human body. The emulsion nanosomes may additionally contain one or more substances specified in a group: carotinoids, flavonoids, vitamins, resveratrol, vitamin-like substances, cartilage protectors, amino acids, preserving agents.

EFFECT: emulsion provides selectivity of the effect of the active compound on body tissues, enables adjusting skin penetration rate of the active substance, dosing the active ingredients, increasing bioavailability of the active substances, reducing their negative effect of the body.

13 cl, 7 dwg, 1 tbl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is the use of L-carnosine for making a nanopreparation having antihypoxic and antioxidant activity combined with a combination of substances selected from the group of phospholipids, non-polar lipids in the following ratio, wt %: L-carnosine - 1.1-1.2, non-polar lipids such as triglycerides, cholesterol, free fatty acids, DL-α-Tocopherol - 1.2-2.5, phospholipids such as phosphatidylcholine, phosphatidylethanolamine, lysophosphatidylcholine, lysophosphatidylethanolamine, sphingomyelin - 95.3-96.3 for preparing a drug having antihypoxic and antioxidant activity. The drug can be presented in the form of liposomes containing L-carnosine.

EFFECT: invention provides higher stability of L-carnosine and its lifetime up to three days with underlying higher effectiveness in small doses, as well as to improve the cerebral ischemia tolerance, the recovery after acute hypoxia and to increase the antioxidant status of the brain tissue.

3 cl, 4 dwg

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