Cream for medical application containing fusidic acid prepared with using sodium fusidate and containing biopolymer, and method for preparing it

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the pharmaceutical industry and represents a cream for medical application for local treatment of bacterial infections and for wound healing, which contains fusidic acid in an amount of 0.1 wt % to 25 wt % and a biopolymer, preferentially chitosan; fusidic acid is formed in situ in an oxygen-free medium; the above cream contains fusidic acid formed in situ by transforming sodium fusidate at adding the acid slowly, with a particle size of an active agent of the substance of 2.33 mcm to 16.3 mcm, while the biopolymer is introduced into a cream base containing at least one ingredient of each type: primary and secondary emulsifying agents specified in a group containing ketostearyl alcohol, ketomacrogol-1000, polysorbate-80, Span-80, paraffin as a wax product, a combined solvent specified in a group containing propylene glycol, hexylene glycol, polyethylene glycol-400, nitric acid or lactic acid and water.

EFFECT: invention provides the high stability of the active ingredient during the whole shelf life.

12 cl, 18 tbl, 2 dwg

 

The technical field

This invention relates to primary and secondary bacterial skin infections and wounds including burn wounds. In particular, it relates to a cream, including fuseboy acid and a biopolymer in the form of chitosan, and the method of its manufacture and its use in the treatment of such infections, and wounds. In addition, positiva acid in the specified cream is formed in situ using fusidate of sodium as the source of pharmaceutically active substances.

Background of invention

Currently, there are many types of treatment, both local and systemic, primary and secondary skin infections caused by gram-positive organisms such as Staphylococcus aureus, Staphylococcus spp, etc., In compositions for topical and systemic treatment of bacterial infections is usually used at least one active pharmaceutical ingredient (AI) in combination with the component framework. When using the cream, the AI usually include antibiotic/antibacterial such as positiva acid, etc.,

In the present creams containing fuseboy acid, positiva acid in the form of a fine powder is used as AI. The small particle size increases its contact with skin and penetration due to the formation of large-area specific surface is t, and provides a sensation when applied to the skin. However, a serious disadvantage arising from the small size of the particles fuseboy acid is that it formed a huge surface area for contact and reaction with molecular oxygen during manufacturing and processing of this cream. This has serious implications for its chemical stability and can lead to a rapid decrease in the efficiency of AI (fuseboy acid) in the final cream.

Degradation due to oxidation is the main cause of instability currently available creams. Table 1 shows that the degradation in the samples AI (fuseboy acid) when exposed to oxygen ranged from 7.7% to 11% in conditions varying from room temperature to 45°C, in the analysis three months, during which they were exposed to these conditions.

You know, the longer the time during which positiva acid as the source of AI is exposed to oxygen, the more there will be restrictions on the stabilization of fuseboy acid in the recipe. However, no published data on the stability of fuseboy acid within a certain period of time.

Alternatively, fuseboy acid, know the use of fusidate sodium when is otoplenie dermatological medicines for local use. However, they are presented in the form of ointments and creams not. Disadvantages ointments compared to the creams are well known, and for local use, in General, preferable to use lotions, not creams.

Well there are several aspects of the use of fuseboy acid as AI:

it is thermolabile;

- it is available in the formulation of the cream;

is it possible to get out of fusidate sodium by dissolving the latter in the aqueous phase and add to this acid solution, while positiva acid precipitates. However, besieged fuseboy acid is difficult to enter into the cream, firstly, due to the large and uneven size of its particles and, secondly, removing fuseboy acid from a crude sediment layer assumes its drying and further processing, which cause deterioration in the quality of fuseboy acid due to exposure to oxygen;

- stability of the AI in the cream containing fuseboy acid, is unreliable due to the lability fuseboy acid.

Stabilization of medicines containing fuseboy acid against oxidation includes compliance with the many precautions during its production and storage. They include the following:

- substitution of oxygen in the pharmaceutical containers inert gases such as nitrogen, carbon dioxide, g is Lee and so on;

- excluding contact of the drug with ions of heavy metals, which are catalysts of oxidation;

- keeping the AI at a lower temperature throughout its period of storage before processing.

In practice, this means strict control during manufacture and storage of such AI (usually stored at temperatures between 2°C to 8°C in airtight containers during the entire storage period).

Therefore, there is a need to develop a method of manufacture of a cream containing fuseboy acid, which positiva acid had greater stability than the stability of fuseboy acid in traditional creams, especially during the manufacture of the cream, and would preserve its stability at an acceptable level throughout the storage period.

Next, let's look at the types of skin diseases and the currently available methods for their treatment. Skin disease can broadly be divided into those that are caused by bacteria, and those caused by fungi. Antifungal and antibacterial compositions are traditionally applied in the form of lotions, creams or ointments. In addition, in many cases it is difficult to establish whether this is due to the condition of the skin bacterial agent, or fungus.

One approach to treatment is skin diseases is the method of trial and error. Antibacterial or antifungal composition is applied in turn, monitor the response and modify the treatment. A significant drawback of this approach is that the treatment should be carried out many times a day during the whole time of treatment. It's extremely not comfortable, and also has the lowest "cost-effectiveness" for the majority of the population, particularly in countries with low levels of economic development.

There are several types of therapy for the treatment of skin diseases caused by bacteria or fungi. In typical cases of such compositions use steroids, antibacterial or antifungal agents (or combination of them in a certain dose) and the greatest attention is paid to these pharmaceutical active ingredients. Composition with a similar composition aims to improve their profile, physico-chemical and biological release.

Many skin diseases are caused by inflammation and bacteria, leading to itching and subsequent scratching, which, among other reasons, may in turn lead to serious and complicated by secondary infections. The existing traditional methods of treatment do not pay enough attention to the healing of the skin or rejuvenation; it is generally assumed that these two processes will take place in a natural way.

Words is "healing" in relation to skin damage, cuts, wounds, infection, inflammation, abrasions, etc., involves not only the prevention, control and elimination of the main causes such as bacteria or fungi, but also restores the skin to its state prior to infection.

Modern approaches to the treatment of skin can in General be divided into two stages: a) healing and recovery skin before illness. Stage of healing involves eliminating as far as possible the main cause of the disease. This may eliminate the bacteria or fungus that caused the infection, using appropriate treatment, antibacterial or antifungal agents or reducing inflammation by treatment with steroids. During this treatment the skin lesions continues to be in the same condition and remains susceptible to secondary infections, which can be quite serious. In case of scratches or wounds of the skin, it is important that coagulation occurred quickly, because it reduces the likelihood of secondary infections. The focus in these kinds of treatment which is carried out with the help of creams, lotions, ointments, refers to the action of active pharmaceutical ingredients. Bases for creams and ointments are considered only as carriers of active substances to the site of an injury.

However, AU is known to restore skin to its state, preceding the disease is almost entirely left to the forces of nature. Therefore, one of the main drawbacks of the existing approaches to the treatment of the skin is that they leave the risk of secondary infections due to slow blood clotting and slow the healing process.

In addition, the study of the prior art become apparent disadvantages of the existing prescription dermatological products used for local treatment of skin diseases. This is evident in the underestimation of the possible therapeutic benefits enclosed in the matrix of the cream and ointment base. In particular, none of the known solutions does not imply that:

Compositions for topical treatment of skin can spread the healing and recovery of the skin over the effects of the main active substances in such a way that they reinforce therapeutic result from the effects of the main active substances.

- Add a biologically active polymers (so-called biopolymers) is a complex process, which may affect the stability of the composition, if not properly consider and not to optimize the choice of the right biopolymer or natural way of interacting with each other excipients in the composition is whether the parameters of a process to strengthen and complement therapeutic effects already at the stage of drug development.

- The inclusion of excipients in the form of a functionally bioactive polymer in the matrix of cream while maintaining functional stability of the active substance in the format of one drug in the form of a dermatological cream involves solving the problems of determining the physical stability of the matrix of cream.

Review some of the existing patents illustrate disclosed above paragraphs.

Positiva acid was used in the form of a cream. In PCT application WO 2009063493 disclosed combination therapy antibiotic for local use and steroid medication for topical application for the treatment of inflammatory dermatoses associated with secondary bacterial infections. In particular, this invention relates to pharmaceutical compositions for topical application, comprising the combination of fuseboy acid and corticosteroid such as mometazon furoate, and used in the treatment of infected eczema such as secondary infected dermatoses, including secondary infected contact dermatitis, psoriasis, allergic contact dermatitis and atopic dermatitis, accompanied by secondary bacterial skin infections. In particular, it argues that this Declaration is ka relates to pharmaceutical compositions for local application, with a combination of fuseboy acid and corticosteroid such as mometasone furoate used for the prevention of infection in cases of dermatitis, particularly in patients suffering from atopic dermatitis, which is exposed to the risk of secondary bacterial infection.

The application is approved, the presence of inventive step on the basis of the fact that in the existing prior art has not described a composition comprising a combination of fuseboy acid with corticosteroid, especially mometazon or halobetasol. It is obvious that the authors of the application WO 2009063493 unexpectedly discovered that the antibiotic effect of fuseboy acid and anti-inflammatory effects of corticosteroids such as mometazon play an important role in the inhibition of S. aureus and the improvement of symptoms and signs of inflammatory skin infections. It is also clear that the authors of WO 2009063493 unexpectedly discovered that the antibiotic effect of fuseboy acid and anti-inflammatory effects of corticosteroids such as halobetasol play an important in the prevention of secondary bacterial infections in patients with non-infected dermatoses and in the treatment of infected sensitive to steroids to dermatoses such as secondary infected dermatoses, including secondary infected contact dermis is it allergic contact dermatitis, atopic dermatitis, psoriasis and other dermatoses responsive to steroids (CRD), accompanied by secondary bacterial skin infections.

The invention disclosed in WO 2009063493? refers to the combination therapy antibiotic for local use and steroid medication for topical application for the treatment of inflammatory dermatoses associated with secondary bacterial infections. In particular, this invention relates to pharmaceutical compositions for topical application, comprising the combination of fuseboy acid and corticosteroid such as mometazon furoate, and used in the treatment of infected eczema such as secondary infected dermatoses, including secondary infected contact dermatitis, psoriasis, allergic contact dermatitis and atopic dermatitis, accompanied by secondary bacterial skin infections. In particular, it argues that this application relates to pharmaceutical compositions for topical application, comprising the combination of fuseboy acid and corticosteroid such as mometasone furoate used for the prevention of infection in cases of dermatitis, particularly in patients suffering from atopic dermatitis, which is exposed to the risk of secondary bacterial infection.

And the above example and other similar sources becomes apparent in the existing technical solutions are not approved and not available:

- Use matrix cream base as a functional element of the cream, and not just media the main active substances.

- Using known biopolymer as a functional filler with fusidate sodium.

- Achieving a much superior healing effects, since education microfilms, blood coagulation, promoting growth of the epidermis, the electrostatic immobilization of microbes occur simultaneously, not one after another, as in the case of the use of traditional therapy with one drug.

- Improvement of General medical properties of the cream that complements active substance used in the matrix of cream.

Therefore, there is a need in the local treatment of one medicinal product containing the active substance will be in a cream base, this cream Foundation should have additional therapeutic value in relation to the main active substance and be used for purposes beyond simple media or transport.

Objectives and advantages of this invention

Therefore, one purpose of this invention to provide a method of manufacturing a cream medicines the who purpose which as the active substance contains fuseboy acid, but in which this active substance has a higher resistance than positiva acid produced by other methods, throughout its period of storage, using the functional basis of the cream, which contains chitosan, which provides effective treatment of bacterial infections and is also actively promotes healing and rejuvenation of the skin.

Another purpose of this invention is to provide a cream medical purpose, is effective in the treatment of wounds including burn wounds.

Other objectives of this invention consist in the creation of drugs prescription, intended for the local treatment of the skin, which are:

- Can extend the action of fusidate sodium for healing or regeneration of the skin in such a way as to enhance therapeutic effect of the main active substances.

- Contain biologically active polymers (so-called biopolymers), without compromising the stability of the composition, which may be affected by improper selection of the biopolymer.

- Include functionally bioactive polymer and excipients in matrix cream, while maintaining functional stability of the substance in the format of a single drug.

Brief description of drawings

F the year 1 - inhomogeneous nature of creams containing chitosan with incompatible auxiliary substance such as carbomer.

Fig.2 - film formation using chitosan.

Summary of the invention

The subject of this invention is a pharmaceutical composition intended for the treatment of bacterial skin infections and related wounds, and also other wounds on the skin, including wounds caused by burns. The cream also causes the skin's rejuvenation through the process of epithelialization.

The cream contains:

a) a biopolymer in the form of chitosan

b) an active pharmaceutical substance in the form of fuseboy acid, which was formed in situ from fusidate sodium

c) a cream base containing primary and secondary emulsifiers, waxy materials, co solvents, acids, preservatives, buffering agents, antioxidants, chelating additives and hygroscopic means,

d) water.

Active ingredients, namely chitosan and fucicola acid included in a creamy base for the treatment of bacterial infections of the skin, accompanied by allergies, itching and sores on the skin that involves the contact of human skin with the above-described composition.

The invention also discloses a method of manufacturing cream medical devices containing fuseboy acid, which is about azueta in situ of fusidate of sodium as the source material, thus fusidate sodium becomes fuseboy acid without oxygen environment created using inert gas, preferably nitrogen, and chitosan. Cream, made in accordance with the method proposed in this invention has greater stability during the storage period and the particles of the active substance is smaller in comparison with traditional creams containing fuseboy acid. The cream is manufactured according to the method proposed in this invention, contains fuseboy acid as AI, which is formed in situ from fusidate sodium cream base containing preservative, an acid, a co-solvent, an emulsifier and a waxy product with water, preferably purified water. The cream is manufactured according to the method proposed in this invention may, additionally, contain an ingredient selected from the group comprising: a buffering agent, antioxidant, chelating additive and hygroscopic means or any combination of them.

Detailed description of the invention

Earlier we discussed the known aspects of the compositions for topical application which contain fuseboy acid and fusidate sodium as the active ingredients. It is now known that:

Creams containing fuseboy acid, which are manufactured using fusidate is the atrium as the original AI, are not available.

- There are no published data on the stability of fusidate sodium as AI.

- It is believed that fusidate sodium has nothing more stability as an AI than positiva acid.

- Creams containing chitosan and fusicology acid, which was formed in situ from fusidate sodium, not available on the market.

With this in mind, it has been unexpectedly discovered that fusidate sodium as the AI is much more stable than positiva acid, and that positiva acid breaks down much faster than fusidate sodium.

There are no published data on the stability of fusidate sodium as AI. The applicant conducted a series of experiments with fusidate sodium in order to assess its stability. From Table 2 one can see that the degradation of fusidate sodium in the temperature range from room temperature up to 45°C ranged from 2.45 per cent to 6 per cent.

In Table 1 and 2 also shows a comparison between the stability of fuseboy acid and fusidate sodium used as the source of AI. The study was conducted using the method of liquid chromatography high pressure developed by the applicant, which, according to the applicant, is an accurate method of determining stability compared with the titration method proposed in British Pharmacopea (BP). This is vsledstvii is also what method BP does not distinguish between intact AI and its degraded form.

Stability studies fuseboy acid

Table 1
The results of stability studies fuseboy acid AI after three months of storage by liquid chromatography high pressure and titration method.
No.conditions* initial (%)sample fuseboy acid(%)reduction (%)comments
titrationliquid chromatography high pressuretitrationliquid chromatography high pressureAI
1room temperature (open)100,699,2192,931,39to 7.67the analysis is the very in 3 months
345°C (open)98,5289,522,0811,08
445°C (closed)99,1092,121,508,48

Sample name: positiva acid BP

Container: open and closed Petri dish.

Stability studies of fusidate sodium

Table 2
The results of stability studies of fusidate sodium (AI) after three months storage by liquid chromatography high pressure and titration method.
no conditions* initial (%)samples of fusidate sodium (%)reduction (%)comments
titrationliquid is nomatophobia high pressure titrationliquid chromatographyAI was analyzed after 3 months
1room temperature (open)98,797,7196,250,992,45
2room temperature (closed)98,8597,67-0,151,03
345°C (open)97,0792,651,636,05
445°C (closed)

Sample name: fusidate sodium BP

Container: open and closed Cup Pet is I.

In both studies, *denotes the Initial results related to the samples analysed during the receipt of AI from the provider.

From Tables 1 and 2 we can draw the following conclusions:

- In case for fuseboy acid, there is a loss of about 7.7% for the 3 months of storage at room temperature (open container) and about 11% for 3 months at 45°C (open container).

- In the case of fusidate sodium has lost about 2.5% for the 3 months of storage at room temperature (open container) and about 6% for 3 months at 45°C (open container).

Thus, these data show that fusidate sodium used as the active ingredient, is more stable than positiva acid.

Applicants investigated the possibility of making the cream rather than the ointment) using fusidate sodium (and not fuseboy acid) as the starting material. Although fusidate sodium is used in dermatological practice, it was impossible to produce creams that use fusidate sodium. This is due to the inherent fusidate sodium alkalinity (pH from 7.5 to 9), which means that it cannot be used in cream form, so all the products are manufactured using fusidate sodium is the quality of the original product, are ointments. Dermatological cream, which uses fusidate sodium, has the advantage consisting in the fact that fusidate sodium has a greater stability than positiva acid, and it allows you to create a recipe of cream, which is much higher than the ointment on quality when applying. Thus, it will fill an existing need in the cream, which would have had better stability than currently available creams containing fuseboy acid.

Thus, the applicant has unexpectedly found that, in order to achieve greater stability of the AI in dermatological cream, as the source of AI at the time of manufacture of the cream is preferable to use fusidate sodium, and not fuseboy acid. The use of fusidate of sodium as the source of the product eliminates the disadvantages associated with the manufacture and storage of existing creams containing fuseboy acid.

The applicant has also found that a cream containing fuseboy acid, manufactured using fusidate of sodium as the source of AI, showed good chemical stability, efficiency and antibacterial activity.

This application discloses a method of manufacturing a cream containing fuseboy acid (AI), which was manufactured using fusidate sodium as the outcome of the CSO AI and in which positiva acid is formed in situ in completely devoid of oxygen environment, created through the use of an inert gas, preferably nitrogen by slowly adding any acid in molecular variance (due to the presence of co-solvent) at the intermediate stage, and positiva acid is recovered in the form of extremely fine dispersion when added to the final cream base, which leads to the formation of fine and homogeneous dispersion of fuseboy acid in the final cream. All these operations are performed in an environment free of atmospheric oxygen, created through the use of an inert gas, preferably nitrogen. Cream, manufactured using the method proposed in this invention? contains fuseboy acid as the AI, which was formed in situ from fusidate sodium cream base containing a buffering agent, a preservative, an acid, a co-solvent, an emulsifier and a waxy product with water, preferably purified water.

Fusidate sodium, which can be used in the method proposed in this invention, as the source of active substances is well known in the field of treatment of primary and secondary bacterial infections.

Active connection of fusidate sodium requires the use of a pharmaceutical composition comprising this compound, component framework, because itacoatiara itself cannot be applied directly to human skin due to its cropropamide.

Component framework typically contains a biopolymer, primary and secondary emulsifiers, waxy products, compatible solvents, acids, preservatives, purified water and the like.

Base cream, manufactured using the method proposed in this invention may, additionally, contain an ingredient selected from the group comprising antioxidants, chelating additive and hygroscopic means or any combination of them.

The present invention proposes a method of manufacture of a new cream that was made with the use of fusidate of sodium as the source material, this cream contains fuseboy acid, which has a high therapeutic efficacy and chemical stability, which is usually greater than the industrial manufactured creams containing fuseboy acid.

Cream containing fuseboy acid, manufactured using the method proposed in this invention, was made in an environment completely devoid of oxygen, injecting an inert gas and vacuum, with an inert gas, preferably represents nitrogen. Under these conditions, fusidate sodium is converted in situ in fuseboy acid. Cream, proposed in the present invention, is used in the treatment of bacterial skin infections.

When studying predtest the existing level of technology become apparent several weaknesses in existing compositions for topical treatment, related to prescription medicines. In the known technical solutions are not approved or not proposed that:

- Composition for the local treatment of skin mo;t to extend the basic AB by healing or regeneration of the skin in such a way as to enhance therapeutic effect of the basic AB.

- Add a biologically active polymers (so-called biopolymers) is a complex process, which may be degraded stability of the composition, if the biopolymer is selected correctly.

- The inclusion of functionally bioactive polymer excipients in matrix cream while maintaining functional stability of AVI format is one of the medicinal product in the form of a dermatological cream includes solving the problems of determining the physical stability of the matrix of cream.

Examples of suitable antibacterial agents for topical applications that can be used include neomycin sulfate, fusidate sodium, mupirocin calcium, gentamicin, sulfadiazine, ciprofloxacin, framycetin sulfate, hindocha, povidone-iodine, sizomitsin, nitrofural and the like, but is not limited to them.

Examples of suitable biopolymer that can be used include chitosan and the like, but are not limited to.

Chitosan

Chitosan is the way the th linear polysaccharide, consisting of distributed randomly β-(1-4)-linked D-glucosamine (dezazetilirovanie molecule) and N-acetyl-D-glucosamine (acetylated molecule). It is known that he has wide application in agriculture and horticulture, water treatment, chemical industry, pharmaceuticals and Biomedicine.

Its known properties include acceleration of blood clotting. However, experts in this area is unknown, that it should be handled with caution and take into account the behavior of chitosan in its impact with the pharmaceutically active ingredient such as an antibacterial or antifungal agent.

It is known to possess properties to form a film, to increase the viscosity and has mucoadhesive and that it is used as a binding and grinding substances in tablets.

In General, chitosan absorbs moisture from the atmosphere/environment, and the number of absorbing moisture depends on the initial moisture content, temperature and relative humidity environment.

It is considered to be non-toxic and does not cause irritation substance. It is biologically compatible with both healthy and infected skin, and it was shown that it is biodegradable because it is derived from shrimp, squid and crab.

Chitosan due SV is their unique properties, accelerates wound healing and regeneration. It has a positive charge and is soluble in solutions of from acidic to neutral. Chitosan has bioadhesive and readily binds to negatively charged surfaces, such as mucous membranes. Chitosan increases the migration of polar drugs across epithelial surfaces. Properties of chitosan allows him to quickly collapse the blood, and he recently received approval in the USA for use in bandages and other hemostatic materials.

Chitosan does not cause allergies and has natural antibacterial properties, even more conducive to its use. As biomaterial forming microfilm, chitosan helps to reduce the width of the wound, control the penetration of oxygen to this place, absorbs secretion from the wound and is decomposed by enzymes in the tissues, which are used to accelerate healing. It also reduces itching, creating a calming effect. He also acts as a hygroscopic agent. It is also helpful in the treatment of the usual minor cuts and wounds, burns, keloids, diabetic and venous ulcers. The chitosan used in this invention comes with different molecular weight in the range from 1 kdal to 5000 kdal.

Chitosan is discussed on the forum USP with respect to the ability to attribute it to the auxiliary functional is substances. Since the chitosan-based polymer is, there are several varieties of it, differing in molecular weight. Different varieties include chitosan chitosan long chain, chitosan chain of medium length and chitosan with a short chain. Varieties with long, medium and short circuits correspond to the molecular weight of chitosan.

In the General case, the sort of long-chain has a molecular weight in the range from 500000 to 5000000 Da, grade with average chain length has a molecular weight in the range of from 100000 to 2000000 Da, and sort of short-chain has a molecular weight of 50,000 to 1,000,000 Da.

The molecular weight of chitosan plays an important role in this composition. Chitosan with a higher molecular weight gives the system a higher viscosity and chitosan with low molecular weight gives the system a lower viscosity.

However, the grade of chitosan with chains of medium length gave the song an optimum level of viscosity. Since the dosage form is a cream, appropriate levels of viscosity is necessary in order to achieve a good distribution on the skin.

The authors have made a final choice in favor of chitosan with an average chain length for the present invention because it gave the necessary rheological properties of the cream, without reducing therapeutic activity as active ingredients, and chitosan. The concentration of chitosan with C is pami average length was carefully chosen on the basis of several laboratory tests and preclinical efficacy studies in animals.

Antibacterial drugs for local application

Antibacterial drugs for local application are intended to be applied on the skin in cases of bacterial infections caused by Staphylococcus aureus, Staphylococcus epidermidis resistant to meticillin Staphylococcus aureus (MRSA), etc.

Antibacterial agents act by inhibiting the synthesis of cell walls due to the connection with the ribosomes of bacteria and inhibiting combination of ribosomes mPHK.

According to another hypothesis, suppose that Antibacterials force ribosomes to produce chains of peptides with the wrong amino acids that completely destroys the bacterial cell.

Fusidate sodium

Fusidate sodium belongs to a group of medicines known as antibiotics. It is used to treat bacterial infections such as infections of bones and joints, because it has the property to kill the bacteria that caused the infection, or stop their growth.

Molecular formula of fusidate sodium31H47. Its chemical name 3,11,16 β-trihydroxy 29-nor-8,9 β,13,14 β-dammara-17(20)[of 10.21-cis], 24-Dien-21-OIC acid 16-acetate, sodium salt. It is a white crystalline powder, soluble in one part of water at 20°C.

Pharmacology and mechanism of action

Fusidate sodium inhibits protein synthesis in bacteria, PQS is lku it prevents the transfer aminority from the aminoacyl-sPHK to the protein on ribosomes. Fusidate sodium may have a bacteriostatic or bactericidal depending on the size of the inoculum.

Although the bacteria cells stop dividing in almost two minutes after contact with the antibiotic in vitro synthesis of DNA and RNA lasts for 45 minutes and 1-2 hours, respectively. Fusidate sodium is not actually active against gram-negative bacteria. The difference in activity against gram-negative and gram-positive organisms was observed, presumably due to differences in the permeability of cell walls.

Mammalian cells are much less susceptible to inhibition of protein synthesis by fusidate sodium than sensitive cells of bacteria. It is assumed that these differences arise mainly due to differences in the permeability of cell walls.

Indications for use: Fusidate sodium indicated for the treatment of primary and secondary skin infections caused by sensitive strains of S. aureus, Streptococcus species and C. minutissimum. Primary skin infections, which are expected to respond to local treatment fusidate sodium include:

contagious impetigo, eritrazma and secondary skin infections such as infected wounds and infected burns.

Most of the products for local use have the form of either creams or ointments. CR is m is a product for local use, used for application on the skin. Creams are semi-solid emulsions are mixtures of oil and water, in which the active pharmaceutical substance (AB). They are divided into two types: creams of type oil-in-water (M/V), which consist of small droplets of oil dispersed in a continuous aqueous phase, and creams of the type water-in-oil (W/M), which consist of small droplets of water dispersed in a continuous oil phase. Creams of the type water-in-oil easy to use and, therefore? cosmetically acceptable because they are less greasy and lighter washed with water. An ointment is a viscous semisolid preparation containing active substances which are applied topically on a variety of body surfaces. Binder ointment known as the basis for ointments. The choice of basis ointments depends on the clinical application of ointments and are typically used bases ointments of the following types:

- Hydrocarbon bases, such as solid paraffin, soft paraffin.

- Absorbing bases such as lanolin, beeswax.

Both of the above bases are oily and fatty in nature, and this leads to undesirable consequences such as difficulties applying to the skin and remove the skin. In addition, this also leads to the appearance of stains on clothing. Most of the products for local application available in the form of cream is in due to the greater cosmetic appeal.

The value of pH for acidic ranges from 1 to 7, and pH for alkaline environment is from 7 to 14. The pH value of human skin is approximately between 4.5 and 6. The pH value of the skin of a newborn baby is closer to neutral (pH=7), but quickly turns sour. Apparently, this natural mechanism is formed in order to protect the skin of small children, because the acid kills bacteria. As people get older, their skin becomes more and more neutral and can't kill as much bacteria as before. This is why the skin becomes weak, and the problems begin. When the pH falls below 6, patients will have real problems with the skin or skin diseases. This suggests that it is necessary to choose drugs for local use where the value of the pH close to the pH value at young people.

A slight shift of the pH towards alkalinity will create an environment conducive to the rapid multiplication of microorganisms. Most of the products for local use comes in the form of creams. The active ingredients in the cream are available in the ionized state. In General, formulations of creams are the first choice of pharmacists in the design and development of dosage forms for local use, because of the formulation of creams cosmetically attractive the flaxes, and because the active component is available in the ionized state and medication can quickly penetrate into the skin layer, which makes this structure is favorable for the patient.

The pH value of a cream containing chitosan antibacterial agent fusidate sodium, proposed in this invention is from about 3 to 6. On the other hand? industrial output ointments are greasy and cosmetically unappealing. Moreover, because the active ingredient in the ointment is located in the UN-ionized form, he slowly penetrates the skin.

It is important that the active drug into the skin and provide the skin with optimal biological performance. Here the important role played by the particle size of the active drug. It is necessary that the active drug was available in the state and / or molecular dispersion in order that the product had a high efficiency. Also, it is necessary to achieve in an environment that is safe compatible with the skin on the value of pH (4.0-6.0). In order to achieve this, it is important to choose the appropriate media or co-solvents for dissolving or dispersing the drug. The product proposed in this invention has a very high efficiency due to the pronounced activity active in the substances as antibacterial and wound healing agents, available in colloidal form with ultra-fine particulate matter that contributes to their penetration into the skin.

The rationale for the combination of fuseboy acid produced from fusidate sodium, chitosan

Currently used numerous types of local treatment for the treatment of bacterial infections. However, there is no effective therapy for one drug for skin protection, control of surface bleeding, heal wounds and burns. To satisfy this need and to provide affordable and safe therapy for the population spread across the countries/communities, offers therapy using a unique combination of chitosan, a biopolymer, has anti-aging properties, and fusidate sodium in the form of a new cream.

Fusidate sodium in the case of local application has high efficacy against primary and secondary bacterial skin infections of various etiologies due to its antibacterial properties. The disadvantage alone one local antibacterial agent is relatively slow onset of effect.

Using the composition of fusidate sodium and chitosan, it is possible to optimize the properties of antibacterial drug and chitosan. Since chitosan is a product of forming the film, Biokovo is valid and non-allergenic, it helps to protect the skin, acting as a barrier. It also reduces surface bleeding caused by combing, and stops the mobility of pathogenic microorganisms due to their cationic charge.

Properties of fusidate sodium and chitosan in relation to the regeneration of the skin are widely used in this invention, and they provide the maximum therapeutic benefit to the patient, promoting rapid healing. This provides a beneficial effect on the patient in the treatment of wounds and skin burns, accompanied by bacterial infections.

The inclusion of chitosan in the composition provides the appearance of many of the properties that are considered extremely important in the treatment of skin diseases. The combination of chitosan with fusidate sodium is a unique and new because it is not available anywhere else in the world on an industrial scale.

The idea of such a combination is justified by consideration of the physical, chemical and therapeutic properties of chitosan, which is used in conjunction with fusidate sodium/fuseboy acid formed in situ from fusidate sodium.

Other inventive aspects of the present invention

Another inventive aspect of the present invention is that adding in a cream base functional auxiliary ve is esta is not a direct process of simple addition. The inventor has found that the compatibility of the functional filler such as chitosan, with other substances in the cream is critical. This is because the incompatibility affects the stability of the final product. For example, the inventors have found that a well-known excipients, such as xanthan gum and carbopol, which have been used in various cases as stabilizers, may be used in combination with functional biopolymers such as chitosan.

Excipients in dosage forms local applications include polymers, surfactants, emulsifiers, etc., the Polymers are used as gelling substances, suspendida agents, thickeners, release modifiers, diluents, etc., Surfactants are used as moisturizers, emulsifiers, solvents, amplifiers, release, etc.

In General, polymers and surfactants can have or not to have an ionic charge. They are, by their nature, can be anionic, cationogenic or nonionic. If anionic filler included in the composition, they interact with cationogenic fillers of the composition and form due to the incompatibility of the product is, which are not homogeneous and aesthetically attractive, and create undesirable by-products may, allergens, pollutants, toxic substances, etc.,

Since the dosage form is suitable for the treatment of sick people, the incompatibility of the products should not be allowed, and this creates additional difficulties for patients.

The inventors have carefully checked all auxiliary substances, including polymers and surfactants, prior to the development of the composition. In-depth study was conducted after he was selected a short list of excipients. Special attention was paid to possible interactions between excipients, and were conducted detailed experiments.

In order to make it possible to give a few examples of the anionic-cationic interaction in the cream, the inventors have produced several songs, including fusidate sodium (see Table 3-7) and containing xanthan gum and chitosan, polyacrylate and chitosan, sodium lauryl sulphate and chitosan, sodium docusinate and chitosan, as well as the Arabian gum and chitosan. The results clearly indicate the presence of interaction, which could well be seen as separate pieces in the entire system. The final product was also deprived of aesthetic Pref is catalinotto and uniformity. The Attached Fig.1 clearly explains the interaction between chitosan and inappropriate anionic auxiliaries. On the basis of these observations and in-depth knowledge of auxiliary substances inventors have come to a reasonable formula without any possible interactions.

7
Table 3
Cream containing fuseboy acid and containing chitosan and xanthan gum
№p/pIngredients% (in weight ratio)
1Fusidate sodium (equivalent to education 2% of fuseboy acid)2,08
2Chitosan0,25
3Lactic acid0,1
4Xanthan gum1,0
5Cetosteatil alcohol12,5
6White soft paraffin12,5
Polysorbate Macrogol2
8Propylene glycol25
9Benzoic acid0,2
10Butylhydroxytoluene0,01
11The disodium salt of EDTA0,1
121M solution of nitric acid4
13Dvuhkamernyi orthophosphoric acid sodium0,5
14Purified water40

4
Table 4
Cream containing fuseboy acid and containing chitosan and polyacrylate
№p/pIngredients% (in weight ratio)
1Fusidate sodium (equivalent to education 2% FSD the annual acid) 2,08
2Chitosan0,25
3Lactic acid0,1
4Polyacrylate1,0
5Cetosteatil alcohol12,5
6White soft paraffin12,5
7Polysorbate Macrogol2
8Propylene glycol25
9Benzoic acid0,2
10Butylhydroxytoluene0,01
11The disodium salt of EDTA0,1
121M solution of nitric acid
13Dvuhkamernyi orthophosphoric acid sodium0,5
14Purified water40
Table 5
Cream containing fuseboy acid and containing chitosan and sodium lauryl sulfate
№p/pIngredients% (in weight ratio)
1Fusidate sodium (equivalent to education 2% of fuseboy acid)2,08
2Chitosan0,25
3Lactic acid0,1
4Sodium lauryl sulfate1,0
5Cetosteatil alcohol12,5
6White soft paraffin 12,5
7Polysorbate Macrogol2
8Propylene glycol25
9Benzoic acid0,2
10Butylhydroxytoluene0,01
11The disodium salt of EDTA0,1
121M solution of nitric acid4
13Dvuhkamernyi orthophosphoric acid sodium0,5
14Purified water40
Table 6
Cream containing fuseboy acid and containing chitosan and sodium docusinate
№p/pIngredients % (in weight ratio)
1Fusidate sodium (equivalent to education 2% of fuseboy acid)2,08
2Chitosan0,25
3Lactic acid0,1
4The sodium docusinate1,0
5Cetosteatil alcohol12,5
6White soft paraffin12,5
7Polysorbate Macrogol2
8Propylene glycol25

9Benzoic acid0,2
10Butylhydroxytoluene0,01
11The disodium salt of EDTA0,1
121M solution of nitric acid4
13Dvuhkamernyi orthophosphoric acid sodium0,5
14Purified water40
Table 7
Cream containing fuseboy acid and containing chitosan and the Arabian gum
№p/pIngredients% (in weight ratio)
1Fusidate sodium (equivalent to education 2% of fuseboy acid)2,08
2Chitosan0,25
3Lactic acid0,1
4Arabian gum1,0
5Cetosteatil alcohol12,5
6White soft paraffin12,5
7Polysorbate Macrogol2
8Propylene glycol25
9Benzoic acid0,2
10Butylhydroxytoluene0,01
11The disodium salt of EDTA0,1
121M solution of nitric acid4
13Dvuhkamernyi orthophosphoric acid sodium0,5
14Purified water40

The above products (Table 3-7) are examples of products that do not form a homogeneous creams, but form inhomogeneous creams such as the one shown in Fig.1. However, the proportions specified in these examples, are what may make use of a specialist in this field, based on currently available information. Only after deep and numerous trials and errors, you will come to the correct types and proportions of the excipients.

As mentioned earlier, when treatment using fuseboy acid is improvement in bacterial infections. However, treatment with one medicine that includes fuseboy acid formed in situ from fusidate sodium was not decided until the present time such issues as protection of the skin, bleeding in this place, the mobility of pathogenic microorganisms and their movement from one place to another and so on

This invention, giving the opportunity to use one drug, fills this gap by inserting x is tosana and obtain the desired effect of protecting the skin (due to the ability to form a film), stop the bleeding (due to the ability to collapse the blood) and immobilization of pathogenic microorganisms (thanks nationalincome electrostatic property).

Therapeutic value increases due to the inclusion of functional excipients in the form of chitosan, which is a biopolymer matrix of the cream. Increasing value is a combination of the following functional characteristics of biopolymer:

- education microfilms on the surface of the skin;

- accelerated blood coagulation compared to creams that do not contain linkoeping biopolymers;

- electrostatic surface immobilization of microbes due to the cationic charge of the biopolymer;

- significant acceleration of epithelialization or regeneration of the skin, which is particularly useful for skin damage caused by serious infections, and wounds and burns.

It took the following inventive efforts in the development of technology, including the introduction of a functional biopolymer in dermatological products prescription:

- identify additional therapeutic value, which gives this introduction;

- identify the problems associated with the physico-chemical stability of the product resulting from the introduction of the biopolymer;

- creation of the drug in the form of the e one dosage form for those cases when it was revealed bacterial infection.

The importance of treatment in the format of one of the medicinal product, in particular in countries with low levels of economic development cannot be overemphasized. In the absence of access to the General practitioner in most parts of South Asia or Africa, not to mention the dermatologists, the composition is in the format of one drug increases the opportunity to resolve the root cause of skin diseases and, at the same time to allow the skin to recover.

When used for dermatological disorders currently available treatments do not solve problems such as the protection of the skin, stop bleeding, etc., Unique innovative composition proposed in this invention, improves the condition of skin, restoring it simultaneously with the suppression of surface bleeding in this place. It is well known that if the surface bleeding left untreated, it will lead to secondary microbial infections. The present invention successfully address this unmet need.

In addition, as increasing pressure on health services and failure/high cost of personnel, around the world there was an urgent need to solve the following problems in such cases:

- Patients expect Le is too long to be placed;

When they enter the hospital, you stay there too long;

- They have to go back more often than required.

Reducing the residence time is a key problem that must be solved in most cases. This invention, in which the proposed therapy with one drug, significantly reduces the total time of treatment of serious skin diseases.

Detailed description of the cream medical purpose, in the present invention, and its method of preparation

It is given in the form of various embodiments, which describes the product as proposed in the present invention, and the manufacturing method.

The preferred embodiment of No. 1

Cream medical devices for topical treatment of bacterial skin infections and wound healing associated RAS, and the indicated cream contains antibacterial, fusidate sodium and biopolymer included in a cream base, and the said cream base contains at least one substance from each of the following groups:

preservative, a primary and a secondary emulsifier, a waxy product, joint solvent, an acid and water, preferably purified water.

Option run No. 1

Cream medical purpose, as he revealed in a preferred embodiment, the implementation of the Oia No. 1, when this is specified, the cream also contains any substance from the group comprising a buffering agent, antioxidant, chelating additive, hygroscopic agent, or any combination thereof. Option run No. 2

A new dermatological cream, as he revealed in a preferred embodiment of No. 1, and in embodiment No. 1, in which:

- this positiva acid is present in an amount of approximately 0.1% in weight ratio to approximately 25% in weight ratio, preferably from about 0.5% in weight ratio to approximately 5% in terms of weight and more preferably about 2,00% in weight ratio, and in which the number specified fusidate sodium used for formation of the in situ fuseboy acid is in the range between approximately 0.1% significant with respect to approximately 25% in weight ratio, preferably from about 0.5% in weight ratio to approximately 5% in terms of weight and more preferably of 2.08% in weight ratio, and

this biopolymer is presented in the form of chitosan, added in an amount of from approximately 0.01% to approximately 1% in weight ratio, preferably from about 0.01% to about 0.5% in weight ratio, and in the preferred embodiment, approximately 0.25% in weight ratio,

- the shown primary and secondary emulsifiers are selected from the group including cetostearyl alcohol, cetomacrogol-1000, Polysorbate-80, Span-80 and the like, and are added in amounts of from approximately 1% in weight ratio to 20% in weight ratio; these waxy products are selected from a group comprising white soft paraffin, liquid paraffin, hard paraffin and the like or any combination thereof, and added in an amount of from about 5% in weight ratio to 30% in weight ratio; this collaborative solvent is selected from a group comprising propylene glycol, hexyleneglycol, polyethylene glycol-400, isopropyl-myristate and the like or any combination thereof, and added in an amount of from about 5% in weight ratio to 50% in weight ratio; this acid is selected from a group comprising HCl, H2SO4, HNO3and lactic acid and the like or any combination thereof, and added in an amount of from about 0,005% in weight ratio to 0.5% in weight ratio; the specified preservative is selected from the group comprising methyl parahydroxybenzoate, sodium propyl parahydroxybenzoate, chlorocresol, potassium sorbate, benzoic acid, and the like or any combination thereof, and added in an amount of from about 0.05% in weight ratio to 0.5% in weight ratio; the specified water is added in the range of from 20% in weight ratio to 75% in weight is ω regards, preferably from 30% in weight ratio to 50% in weight ratio, more preferably from 35% in weight ratio to 45% in weight ratio, preferably purified water.

Option run No. 3

New cream for medical purposes, as it has been disclosed in preferred embodiment 1 and embodiment No. 2, containing, in addition, a buffering agent which is selected from the group comprising dvuhkamernyi orthophosphoric acid sodium, phosphoric acid, sodium and the like or any combination thereof, and added in an amount of from about 0,001% in weight ratio to 1.00% in terms of weight.

Option run No. 4

New cream for medical purposes, as he revealed in a preferred embodiment of No. 1 and versions of the No. 2 and No. 3, which includes, in addition, the antioxidant is selected from the group including butylhydroxyanisole, butylhydroxytoluene and the like or any combination thereof, and added in an amount of from about 0,001% in weight with respect to 1% in weight ratio.

Option run No. 5

New cream for medical purposes, as he revealed in a preferred embodiment of No. 1 and variants of execution No. 2-4, includes, in addition, chelating additive, which is selected from a group comprising disodium salt of EDTA and the like, or lubowich combination, and is added in an amount of from about 0.05% in weight with respect to 1% in weight ratio.

Option run No. 6

New cream for medical purposes, as he revealed in a preferred embodiment of No. 1 and variants of execution No. 2-5, includes, in addition, hygroscopic agent, which is selected from groppi, including glycerol, sorbitol, propylene glycol and the like or any combination thereof, and added in an amount of from about 5% in weight ratio to 50% in weight ratio.

The preferred embodiment of No. 2

The method of manufacture of a dermatological cream containing fuseboy acid, while the method includes a step of using fusidate of sodium as the source of active ingredient (AI) and turning it in situ in fuseboy acid cream base not containing oxygen environment.

Option run No. 7

In one embodiment, the present invention discloses a method of manufacturing a composition in which phase transformations of fusidate sodium in situ in fuseboy acid in a preferred embodiment of No. 2 includes the following steps:

A. heating purified water in an amount of from 20% (in weight ratio) to 75% in weight ratio, preferably from 30% in weight ratio to 50% in weight ratio, more preferably from 35 in weight ratio to 45% in weight ratio in the vessel for the aqueous phase to a temperature from 70°C to 80°C,

C. adding a specified vessel for the aqueous phase of a preservative selected from the group comprising methylparaben, propylparaben, chlorocresol, potassium sorbate, benzoic acid and the like, or one, or any combination thereof in amounts of from 0.05% in weight ratio to 0.5% in weight ratio, preferably 0.3% in terms of weight, more preferably 0.2% in terms of weight, more preferably benzoic acid,

C. stirring the mixture using a mixer at a speed of from 10 to 50 rpm and the temperature of the mixture from 70°C to 80°C,

d. adding waxy products selected from the group comprising white soft paraffin, liquid paraffin, hard paraffin and the like, or one, or any combination thereof in an amount of from 5% in weight ratio to 20% in weight ratio, preferably 15% in weight ratio, more preferably 12.5% in weight with respect to the vessel for the oil phase and the melting of the specified wax by heating it to a temperature of from 70°C to 80°C,

E. adding a specified vessel for the oil phase of the primary emulsifier, preferably in the form of a nonionic surfactant selected from the group comprising cetostearyl alcohol, cetomacrogol-1000, or one, or any combination thereof, preferably cetostearyl alcohol in quantities is from 1% in weight ratio to 15% in weight ratio, preferably 15% in weight ratio, more preferably 12.5% in weight ratio, and possibly a secondary emulsifier selected from the group comprising Polysorbate-80, Span-80 and the like, preferably Polysorbate-80 in an amount of from 1 to 5% in weight ratio, more preferably 2% in weight ratio, and thoroughly stirring the mixture, preferably using a stirrer at a speed of from 10 to 50 rpm while maintaining the temperature of the mixture from 70°C to 80°C,

f. transfer the contents of the vessel for the aqueous phase and oil phase in the mixer under vacuum in the range from -1000 to -300 mm RT.article and at a temperature from 70°C to 80°C and thoroughly stirring the mixture, preferably using a stirrer at a speed of from 10 to 50 rpm before formation of the emulsion,

g. the specified cooling the emulsion to 45°C, preferably by creating a circulation of cold water, preferably with temperatures ranging from 8 to 15°C from the tower in the cooling jacket of the mixer,

h. adding to the vessel for the active ingredient joint solvent selected from the group comprising propylene glycol, hexyleneglycol, polyethylene glycol-400 and the like, or one, or any combination thereof, in an amount of from 5% in weight ratio to 40% in weight ratio, preferably 30% in weight ratio, more preference is sustained fashion 25% in weight ratio, preferably propylene glycol, the impact on the contents of the vessel for the active ingredient by blowing an inert gas, with the specified inert gas is preferably nitrogen, and adding to the mixture of fusidate sodium, while fusidate sodium is added in an amount of from 0.1% in weight ratio to approximately 25% in weight ratio, preferably from about 0.5% in weight ratio to approximately 5% in terms of weight and more preferably approximately 2,08% in weight ratio, and dissolving the specified fusidate sodium in the mixture,

i. regulation of the pH of the mixture formed in the vessel for the active substance in step h, to values below 2 by using an acid, selected from the group consisting of acid such as HCl, H2SO4, HNO3, lactic acid and the like, or one, or any combination thereof, preferably nitric acid in an amount of from about 0,005% in weight ratio to 0.5% in weight ratio, preferably 0.3% in terms of weight, more preferably 0.25% in weight ratio,

j. transfer the contents of the vessel with the active substance obtained in step i, in the mixer described in step g with continuous stirring at a speed ranging from 10 to 50 rpm and homogenizing the mixture at a speed ranging from 1000 to 3000 rpm by injecting an inert gas under vacuum from -1000 to -300 mm RT.art., if e is ω specified inert gas is preferably nitrogen,

k. add in a jar of acid selected from the group comprising acid such as HCl, N2SO4, HNO3, lactic acid and the like, or one, or any combination thereof, preferably lactic acid, in amounts of between about 0.005% and in terms of weight and 0.5% in weight ratio, preferably 0.3% in terms of weight, more preferably 0.1% in terms of weight and purified water in an amount of approximately 0.1% in weight ratio to 10% in weight ratio, preferably 8% in terms of weight, more preferably 5% in weight ratio, to form a mixture and dissolving the specified biopolymer, chitosan, in amounts of between about 0.01% and about 1% in weight ratio, preferably from about 0.01% in weight ratio to approximately 0.5% in terms of weight and most preferably approximately 0.25% in weight ratio,

l. transfer content of the mixture containing the biopolymer obtained in step k, in the mixer described in step g with continuous stirring at a speed of from 10 to 50 rpm and homogenizing the mixture at a speed of from 1000 to 3000 rpm by injecting an inert gas under vacuum from -1000 to -300 mm RT.art., when this is specified, the inert gas is preferably nitrogen,

m. cooling the contents with which esites to a temperature from 30°C to 37°C using circulation of cooled water with temperatures ranging from 8°C to 15°C from the tower in the cooling jacket of the mixer,

n. off the agitator and the homogenizer and removing the mixture obtained in step m, from the mixer to the storage container.

Option run No. 8

In one embodiment of the present invention a joint solvent described above in step h option run No. 7 is also used as an absorbent means. However, in another embodiment, the present invention can add additional hygroscopic agent selected from the group comprising glycerin, sorbitol, propylene glycol and the like, any one, or any combination thereof in an amount of from about 5% in weight ratio to 40% in weight ratio, preferably 30% in terms of weight, more preferably 25% in terms of weight.

Option run No. 9

In another embodiment, the present invention is the method described in embodiment No. 8, includes, besides adding a chelating additive selected from the group comprising disodium salt of EDTA and the like, or one, or any combination thereof, in an amount of from about 0.01% in weight with respect to 1% in weight ratio, preferably 0.5% in terms of weight, more preferably 0.1% in terms of weight.

Variant of execution No. 10

In yet another embodiment, the present invention is the method described in versions of the No. 8 and 9, VC is uchet in addition, adding a buffering agent selected from the group comprising dvuhkamernyi orthophosphoric acid sodium, phosphoric acid, sodium and the like in an amount of from about 0,001% in weight ratio to 1.00% in terms of weight, preferably 0.05% in terms of weight, more preferably 0.5% in terms of weight.

Option run No. 11

In yet another embodiment, the present invention is the method described in the variants of execution No. 8-10, includes, in addition, the addition of an antioxidant selected from the group including butylhydroxyanisole, butylhydroxytoluene and the like in an amount of from about 0,001% in weight ratio to 5% in weight ratio, preferably 0.1% in terms of weight, more preferably 0.01% in terms of weight.

Option run No. 12

Discloses another method of manufacturing a composition according to a preferred variant implementation, while this method includes the following steps:

A. heating purified water in an amount of from 20% (in weight ratio) to 75% in weight ratio, preferably from 30% in weight ratio to 50% in weight ratio, more preferably from 35% in weight ratio to 45% in weight ratio in the vessel for the aqueous phase to a temperature from 70°C to 80°C,

b. add in the specified vessel for the aqueous phase of a preservative selected the CSOs from the group including methylparaben, propylparaben, chlorocresol, potassium sorbate, benzoic acid and the like, or one, or any combination thereof in amounts of from 0.05% in weight ratio to 0.5% in weight ratio, preferably 0.3% in terms of weight, more preferably 0.2% in terms of weight, more preferably benzoic acid,

C. adding a specified vessel for the aqueous phase, described in step b, the chelate additives selected from the group comprising disodium salt of EDTA and the like, or one, or any combination thereof, in an amount of from about 0.01% in weight with respect to 1% in weight ratio, preferably 0.5% in terms of weight, more preferably 0.1% in weight ratio,

d. add in the specified vessel for the aqueous phase, described in step C, a buffering agent selected from the group comprising dvuhkamernyi orthophosphoric acid sodium, phosphoric acid, sodium and the like in an amount of from about 0,001% in weight ratio to 1.00% in terms of weight, preferably 0.05% in terms of weight, more preferably 0.5% in weight ratio,

E. mixing the mixture obtained in step d, using a stirrer at a speed of from 10 to 50 rpm while maintaining the temperature of the mixture from 70°C to 80°C,

f. adding waxy products selected from the group, enabling the th white soft paraffin, liquid paraffin, solid paraffin and the like, or one, or any combination thereof in an amount of from 5% in weight ratio to 20% in weight ratio, preferably 15% in weight ratio, more preferably 12.5% in weight with respect to the vessel for the oil phase and the melting of the specified wax by heating it to a temperature of from 70°C to 80°C,

g. add in the specified vessel for the oil phase obtained in step f, the primary emulsifier, preferably in the form of a nonionic surfactant selected from the group comprising cetostearyl alcohol, cetomacrogol-1000, or one, or any combination thereof, preferably cetostearyl alcohol in an amount of from 1% in weight ratio to 15% in weight ratio, preferably 15% in weight ratio, more preferably 12.5% in weight ratio, and possibly a secondary emulsifier selected from the group comprising Polysorbate-80, Span-80 and preferably similar, preferably Polysorbate-80 in an amount of from 1 to 5% in weight ratio, more preferably 2% in weight ratio, and thoroughly stirring the mixture, preferably using a stirrer at a speed of from 10 to 50 rpm while maintaining the temperature of the mixture from 75±5°C,

h. transfer the contents of the vessel for the aqueous phase and oil phase in the mixer in terms of the vacuum in the range from -1000 to -300 mm RT.article and at a temperature of 75±5°C and thoroughly stirring the mixture, preferably using a stirrer at a speed of from 10 to 50 rpm before formation of the emulsion,

i. the specified cooling the emulsion to 45°C, preferably by creating a circulation of cold water, preferably with temperatures ranging from 8 to 15°C from the tower in the cooling jacket of the mixer,

j. adding to the vessel for the active ingredient joint solvent selected from the group comprising propylene glycol, hexyleneglycol, polyethylene glycol-400 and the like, or one, or any combination thereof, in an amount of from 5% in weight ratio to 40% in weight ratio, preferably 30% in terms of weight, more preferably 25% in weight ratio, preferably propylene glycol, and the dissolution of an antioxidant selected from the group including butylhydroxyanisole, butylhydroxytoluene and the like, or one, or any combination thereof in amounts of from 0.001% in weight ratio to 5% in terms of weight, preferably 0.1% in terms of weight, more preferably 0.01% in weight ratio, preferably butylhydroxytoluene in the specified glycol by continuous mixing,

k. the impact on the contents of the vessel for the active ingredient by blowing an inert gas, with the specified inert gas predpochtitel is but is nitrogen, and adding to the mixture of fusidate sodium, while fusidate sodium is added in an amount of from 0.1% in weight ratio to approximately 25% in weight ratio, preferably from about 0.5% in weight ratio to approximately 5% in terms of weight and more preferably approximately 2,08% in weight ratio, and dissolving the specified fusidate sodium in the mixture,

l. regulation of the pH of the mixture formed in the vessel for the active substance in step k, to values below 2 by using an acid, selected from the group consisting of acid such as HCl, H2SO4, HNO3, lactic acid and the like, or one, or any combination thereof, preferably nitric acid in an amount of from about 0,005% in weight ratio to 0.5% in weight ratio, preferably 0.3% in terms of weight, more preferably 0.25% in weight ratio,

m. transfer the contents of the vessel with the active substance obtained in step l, the mixer described PA step i, with continuous stirring speed of 10 to 50 rpm and homogenizing the mixture at a speed ranging from 1000 to 3000 rpm by injecting an inert gas under vacuum from -1000 to -300 mm RT.art., when this is specified, the inert gas is preferably nitrogen,

n. add in a jar of acid selected from the group including such acids, ka is HCl, H2SO4, HNO3, lactic acid and the like, or one, or any combination thereof, preferably lactic acid, in amounts of between about 0.005% and in terms of weight and 0.5% in weight ratio, preferably 0.3% in terms of weight, more preferably 0.1% in terms of weight and purified water in an amount of approximately 0.1% in weight ratio to 10% in weight ratio, preferably 8% in terms of weight, more preferably 5% in weight ratio, to form a mixture and dissolving the specified biopolymer, chitosan, in amounts of between about 0.01% and about 1% in weight ratio, preferably from about 0.01% in weight ratio to approximately 0.5% in terms of weight and most preferably approximately 0.25% in weight ratio,

O. transfer content of the mixture containing the biopolymer obtained at step n, in the mixer described in step i, with continuous stirring at a speed of from 10 to 50 rpm and homogenizing the mixture at a speed of from 1000 to 3000 rpm by injecting an inert gas under vacuum from -1000 to -300 mm RT.art., when this is specified, the inert gas is preferably nitrogen,

R. cooling the contents of the mixer from step to a temperature from 30°C to 37°C using circulating a cooling gap is military water with temperatures ranging from 8°C to 15° from the tower in the cooling jacket of the mixer,

q. off the agitator and the homogenizer and removing the mixture from step n from the mixer into the container for storage.

Joint solvent as described in step j, it also serves as a hygroscopic means. However, in another embodiment, the present invention can add additional hygroscopic agent selected from the group comprising glycerin, sorbitol, propylene glycol and the like, or one, or any combination thereof in an amount of from about 5% in weight ratio to 40% in weight ratio, preferably 30% in terms of weight, more preferably 25% in terms of weight.

The cream obtained using the method proposed in this invention is a homogeneous, white to cream color and has a viscous consistency. Product made in accordance with the method proposed in this invention has a pH of about 3 to 6. On the other hand, industrial manufactured ointments that contain fusidate sodium, are greasy and cosmetically unappealing.

It is important that the active substance has penetrated into the skin for optimal bioeffectives in the skin. Here the important role played by the particle size of the active substance. It is necessary that the active substance was available in fine form for the product was uh is effective. It also should be achieved in an environment that is safe compatible pH of the skin (pH 4.0 to 6.0). To satisfy these requirements, it is important to choose the appropriate transporting substances or co-solvents for dissolving or dispersing the drug.

Analysis of particle size was carried out for creams that are designed using the method proposed in this invention, and for the few examples of industrial manufactured products (samples a, C, D, F, G, and K). Were estimated maximum and minimum particle sizes, the average particle size and standard deviation, and coefficient of variation.

Table 8
the minimum particle size (µm)the maximum particle size (microns)the average particle size (µm)the standard deviationthe coefficient of variation
this invention2,3316,3010,013,9820,397
Andof 7.2339,58 18,099,2510,511
6,0732,6914,116,6920,474
D9,827,5218,48to 4.980,269
Fto 7.9319,9014,824,0330,272
G7,2929,48of 14.256,0650,398
Toof 5.7532,63Ls 16.808,1120,483

The results of the analysis of the distribution of particle size are shown in Table 8, clearly show that the presence of fuseboy acid in the form of fine particles in the product as proposed in the present invention, the size of which is significantly less than traditional products. This can be attributed to the fact that the direct product of izgotavlivaet is consistent with the use of fusidate sodium, using the reaction conversion in situ of fusidate sodium fuseboy acid in fine form. All measured parameters were better than the industrial manufacture of creams containing fuseboy acid. This is another obvious benefit of the product, unveiled here, compared to industrially produced products.

The product offered by the present invention, is effective through the apparent antibacterial activity restored fuseboy acid, which is available in the form of smaller particles than traditional products, and in fine form.

The inventor has selected different co-solvents such as propylene glycol, hexyleneglycol, polyethylene glycol-400 and so on, and dissolved fusidate sodium in one of the above joint solvents, the content of which varied from approximately 5% (in weight ratio) to 40% (in weight ratio), injecting an inert gas in the vacuum and turned it into fuseboy acid in situ by adding an acid such as HCl, H2SO4, HNO3, lactic acid, etc., in the amount of approximately 0.005% (in weight ratio) to about 0.5% (in weight ratio) with stirring and received fuseboy acid is more stable and soluble form, which helped to make our OK Nately product on cream base, which easily penetrates the skin and makes it highly efficient and highly compatible with the skin due to the fact that it has a pH from about 3.0 to about 6,0.

The stability of the product is confirmed by the stability studies that were performed within 6 months according to the ICH guidelines, and comparison studies of adverse factors, conducted for manufactured at the place of product and samples of industrially produced comparable products.

Experimental data

Experiments to determine the stability of the active ingredients was conducted (see Table 10-15) using the product proposed in this invention, and products, industrial currently produced. The tests were carried out to observe (or measure, respectively) the appearance of the product, the pH value and the quantitative analysis of the active ingredient within a certain period of time. Trials were also conducted to assess the stability when exposed to the product of adverse factors, such as tests in an autoclave and test for oxidative degradation. In addition, a study was carried out in vitro antimicrobial zone of suppression and preclinical research such as research in blood clotting and healing research ozegovich RAS during the PE the iodine-time. Each gram of the product proposed in this invention and used in the test contained fusidate of sodium as the source material in a quantity necessary for the formation of 2% (in weight ratio) of fuseboy acid in the final product.

The product used in the stability studies and trials in the autoclave and the test for oxidative degradation, contained approximately 10% excess of the AI. The product of this invention, used for research, contained the cream with fuseboy acid, produced using fusidate of sodium as the source material. He was Packed in soft aluminum tube, and each gram of the product contained 20,8 mg of fusidate sodium (according to BP), which is equivalent to 20 mg of fuseboy acid (according to BP). The details of this analysis are comparable industrial products (creams containing fuseboy acid) are presented in Tables 14 and 15, respectively.

When considering Tables 10-12 becomes obvious that all items: pH, appearance, and stability, the product offered by the present invention has a high quality.

In table 13 are the key dates for samples A-I, which was taken for analysis from a number of industrial manufactured creams containing fuseboy acid.

Next, data is e invention will be explained with reference to accompanying examples, contains the structure and data of the stability studies, which, however, does not in any way intended to limit the present invention.

The final composition of the cream is given below in Table 9.

Example: table 9 - the Cream containing fuseboy acid (equivalent of 2.08% in weight ratio of fusidate sodium) and chitosan 0.25% in terms of weight.

No.IngredientsSpecificationThe number to 350 kg% in weight ratio
1Fusidate sodium (equivalent to obtain 2% of fuseboy acid)BP7,282,08
2ChitosanUSP/NF0,8750,25
3Lactic acidIP0,3500,1
4Cetostearyl alcoholIP43,7512,5
5White soft paraffinIP43,7512,5
6Polysorbate-80IP7,02
7Propylene glycolIP87,525
8Benzoic acidIP0,70,2
9ButylhydroxytolueneIP0,0350,01
10The disodium salt of EDTAIP0,350,1
111M solution of nitric acidIP14,014
12Dvuhkamernyi orthophosphoric acid sodiumIP1,750,5
13Purified waterIP142,740,77

Product: Cream containing fusidic sodium

Packing: Soft aluminum tuba

Composition: each gram: Fusidate sodium BP equivalent to 2% of fuseboy acid BP

Table 10: Descriptive test, Batch No. SCC-41

Measured parameter: appearance

The best possible values of measured parameter: Homogeneous white to cream-colored viscous cream.

Method of measurement: Observation by naked eyes

conditionsthe initial valuethe first monthThe second monthThe third monthSixth month
40°C 75% relative humidityhomogeneous viscous cream white to cream-colouredthe best possible valuesthe best possible valuesthe best possible valuesthe best possible values
30°C, 65% relative humidity the same thingthe same thingthe same thingthe same thing
25°C 60% relative humiditythe same thingthe same thingthe same thingthe same thing
thermal Cyclingthe same thing---
freeze-thawthe same thing---

Table 11: Measurement of pH, Batch No. SCC-41

Measured parameter: pH

The limits of measured parameter: 3-6

Method of measurement: Digital pH meter

conditionsthe initial valuethe first monthThe second monthThe third monthSixth month
40°C 75% relative humidity4,32or 4.31or 4.314,30 4,29
30°C, 65% relative humidity4,32or 4.314,304,30
25°C 60% relative humidity4,324,32or 4.314,30
thermal Cycling-4,28---
freeze-thaw-4,29---

Table 12: Quantitative analysis(%), Batch No. SCC-41

Measured parameter: Quantitative analysis (%)

The limits of measured parameter: 90-110%

Method of measurement: the method of liquid chromatography high pressure

conditionsthe initial valuethe first monthThe second monthThe third monthSixth month

Jul 09
40°C 75% relative humidity109,10108,86108,66108,21108,05
30°C, 65% relative humidity108,73108,71108,58108,31
25°C 60% relative humidity108,89108,75108,64108,45
thermal Cycling-108,13---
freeze-thaw-108,22---
Table 13
Sample number date of manufactureDate of expiration
this inventionOct 09Sep 11
a sample AndAug 09Jul 11
sampleAug 09Jul 11
sampleJul 09Jun 11
sample DJul 09Jun 11
sample EAug 09Jul 11
sample FAug 09Jul 11
sample GAug 09Jul 11
sample HJun 11
the sample IDec 09Nov 11

Table 14: comparative analysis (%) when tested in the autoclave.

Measured parameter: Quantitative analysis(%)

The limits of measured parameter: 90-110%

Measurement method: Method of liquid chromatography high pressure.

No.product name and detailsAnalysis I (%)Analysis II (%)Average reduction in Analysis I and Analysis II (%)
the initial valueAfter the autoclavereduction(%)the initial valueAfter the autoclavereduction(%)
1this invention110,47104,615,86110,62104,865,76of 5.81
2A sample And101,8191,7910,02100,9391,659.28 are9,65
3Sample92,69at 83.549,1591,1383,088,058,6
4Sample110,4798,5611,91110,299,2110,99of 11.45
5Sample D101,394,846,46102,1394,65of 7.486,97
6Sample E100,9994,516,48100,21 93,516,706,59
7Sample F96,3384,1512,1895,8885,1210,7611,47
8Sample G104,7593,19to 11.56103,2593,1210,1310,84
9Sample N101,2688,3512,91100,8687,9812,8812,89
10The sample I101,5887,0614,52100,6188,0112,613.56MHz

Table 15: Quantitative analysis in the test for oxidative degradation.

Measured parameter: Quantitative analysis (%)

The limits of measured pairs is m: Missing

Measurement method: Method of liquid chromatography high pressure.

5,52
No.product name and detailsAnalysis (%)
the initial valueafter oxidationdegradation (%)
1this invention110,47106,753,72
2A sample And101,8195,636,18
3Sample92,6983,159,54
4Sample110,47101,938,54
5Sample D101,393,258,05
6Sample E100,9995,47
7Sample F96,3390,705,63
8Sample G104,7596,468,29
9Sample N101,2694,53of 6.73
10The sample I101,5888,9212,66

The conclusion from Table 14: Results of quantitative analysis when tested in an autoclave (121°C, heated for 15 minutes) show that samples of industrially produced cream containing fuseboy acid (№p/p 2-10), show a more significant decrease in the percentage content of active ingredient, compared to the product offered in this invention (№p/p 1).

Conclusions from Table 15: the above results of quantitative analysis when tested in oxidative degradation (30% solution of hydrogen peroxide was affected in 12 hours) show that different samples present on the market creams containing fuseboy acid (№p/p 2-10) shows the significantly greater degradation of the active ingredient (shown as a reduction of AI per cent) compared with the product, proposed in the present invention (№p/p 1).

From the above data it is obvious that the product proposed in this invention is quite stable when stored in ambient conditions and in conditions of high temperature and humidity. Research in the autoclave and studies of oxidative degradation is even more confirmed the stability of this product. This is its main advantage compared to currently available creams with fuseboy acid. The stability of the product, in addition, confirmed the prediction of the shelf life of this recipe by using curve degradation Arrhenius equation using the software Nova-LIMS.

Antimicrobial/antibacterial activity of this product is confirmed by studies of antimicrobial zone of suppression for a given product against Staphylococcus aureus, performed in vitro. Details of these studies are provided below in Table 16.

Table 16
No.sampledosethe diameters of the zones (mm)conclusion
1this is LON (positiva acid) 10 mg21-33sensitive
20 mcg20-30sensitive
50 mcg25-32sensitive
2the positive control (Pinicillin G)10 units21-27stable
3the negative control (DMSO 1%)no datanullnull
4sample(test substance)-the product of this invention, 2%)10 mg21-23sensitive
20 mcg24-26sensitive
50 mcg21-24sensitive

From the above data it is obvious that this product has an appropriate antimicrobial/antibacterial activity for the treatment of primary and WTO the ranks of bacterial infections.

Comparing Table 9 with Table 3-7 illustrate the difference in the products due to the traditional composition of the medicinal product and the new approach adopted in this invention.

How to apply cream

The cream is applied after thoroughly cleaning and drying the affected area. Apply enough cream to cover the affected skin and surrounding area. The cream should be applied 2-4 times a day depending on the condition of the skin throughout the treatment period, even in case of improvement of symptoms.

Experiments

The experiments were carried out with the cream in the laboratory, as well as using suitable animal, which was applied to the wound by cutting. We investigated four aspects of reduction of the area of wound epithelialization, the clotting time of blood and the formation of the film. A joint study of these aspects suggest that the microbes were immobilized, and this led to effective wound healing.

A. a Reduction in the area of RAS

The activity of the cream, in the present invention, in the healing of cut wounds was determined by testing on animals. Cut the wound with a diameter of 2.5 cm was applied by cutting the skin to its full thickness. The value of reduction of area of the wound, observed over a certain period of lying is neither, pointed to the fact that the cream is proposed in this invention, showed significantly better results in terms of reduction of the area of the wound compared to those that were achieved when applying traditional cream.

Century Time epithelialization

When using the cream, proposed in this invention, the epithelization of the wound occurs in fewer days compared to the time required for epithelialization, using traditional cream. Therefore, one of the advantages of the cream is proposed in this invention is that it promotes more rapid epithelialization of the skin than when using traditional creams.

C. blood Clotting

Observed clotting time of blood in both groups of animals: not receiving treatment control group and the test group of animals treated product of the present invention. A statistically significant reduction in the clotting time of blood in the treated group of animals was noted compared with the control group animals. Average decrease in the clotting time of blood, comprising from 10 to 40%, was observed when using the product of this invention.

The ability to form a film

It Is Evident From Fig.1 it is evident that chitosan does not lose its properties to form a film in the presence of an auxiliary in the substances used in the formulation of the cream is proposed in this invention.

Results and discussion

Obviously, the property of chitosan in the case when it is used in formulations containing excipients used in this invention does not deteriorate. This was achieved by careful selection of excipients. For example, our experiments show that such a widely used excipients as xanthan gum or carbopol, in combination with chitosan to form a precipitate due to cationic, anionic interactions.

As shown by tests on animals, therapeutic effect due to the addition of chitosan to the antimicrobial agent to fusidate Natia presented in the following table when considering various aspects of therapeutic treatment to the poor condition of the skin:

Table 17
therapeutic aspectExisting creamsThe product of this invention
1. The clotting timeclearly not declaredA statistically significant reduction in clotting time, as evidenced by documentary is Inocencia animal testing
2. Immobilization of microbesclearly not declaredIt is expected the surface immobilization of microbes due to the cationic charge of chitosan
3. Promoting the growth of the epidermisclearly not declaredIt is well known that chitosan possesses properties which determine

significant favorable effect on the growth of the epidermis. This functional aspect of chitosan is stored in the product of this invention
4. Education microfilmsclearly not declaredYes (see Fig.2)
5. The full effect of drugs on wound healingStandard for existing productsHas better healing properties
Table 18
The properties of the present invention to heal wounds
Measured valueGroupMean ± SEM(standard error of the mean) (days)A value of PStatistical significance
Time epithelializationcontrola 21.75±0,25-
this inventionto 17.25±1,50,042Significant
% reduction of wound(mean ± SEM) on day 4 after application of the woundcontrol0,028±3,76-
this invention34,03±5,660,004Significant
% reduction of wound(mean ± SEM) on day 8 after application of the woundcontrol15,63±4,24
this invention53,4±3,90,0001Significant
% reduction of wound(mean ± SEM) on day 12 after application of the woundcontrol23,4±3,44
this invention71,6±to 7.670,0001Significant
% reduction of wound(mean ± SEM) on day 16 after application of the woundcontrol58,1±8,4
this inventionto 92.4±7,50,0001Significant

Research ability to heal wounds were conducted on animals with cream, proposed in this invention. The results included in Table 18.

It is obvious that the ability to form a film of chitosan included in the cream provides the best access fu the date of sodium to the infected area and leads to better effect of this active substance.

Therapeutic efficacy of the local application of cream, proposed in this invention, due to the pronounced antibacterial activity of fusidate sodium against organisms that cause skin infections, the unique ability of active substances to penetrate the intact skin and properties of chitosan to heal and soothe.

From Table 18 it is obvious that the cream is proposed in this invention has the ability to provide a statistically significant level epithelialization, and reducing the area of RAS, which significantly exceeds the ability of currently available treatment methods.

From the above discussion it becomes apparent that this invention offers the following advantages and unique aspects compared to currently available dermatological compositions for the treatment of bacterial infections and heal wounds on the skin.

1. The cream is proposed in this invention, includes a positive current to the skin of the biopolymer in the form of chitosan, which enhances therapeutic effect. This is evident from the reduction of the clotting time of blood, increases the effect of epithelization and faster getting rid of the infection and recovery and reduction of the area of the Russian Academy of Sciences.

2. The cream is proposed in this invention, VK is uchet biopolymer, without sacrificing the stability matrix of the cream and without negative effects on the properties of a known active pharmaceutical ingredients. This was achieved by careful selection of functional excipients that will allow undesirable aspects of physico-chemical compatibility/stability and biological release.

3. Cream, this invention provides an integrated treatment with a single drug, which so far has not been achieved in dermatological compositions prescription.

4. New cream, proposed in the present invention, stores the corresponding stability/efficiency in environmental conditions and does not require temperature control during transport/storage - therefore, he will advance very far in achieving these social goals.

According to another variant implementation of the present invention also proposes a method of treatment of bacterial skin infections and wound healing, comprising contacting human skin with the disclosed above composition.

Although the above description contains much specificity, this should not be construed as limiting the scope of the invention, but only as an illustrated example of the preferred option it is running. You need to understand that based on the above, R is hiding it is possible to make various modifications and variants, which will not go beyond the nature and scope of this invention. Therefore, the scope of this invention should be determined not illustrated variants of execution, but the accompanying paragraphs patent claims and their legal equivalents.

1. Cream medical purpose for the local treatment of bacterial infections and healing wounds, which contains fuseboy acid in amount of from 0.1% in weight ratio to 25% in weight ratio, and a biopolymer, preferably chitosan, with fucicola acid is formed in situ in an environment devoid of oxygen, this cream contains fuseboy acid formed in situ by conversion of fusidate sodium slow addition of acid, the particle size of the active substance from 2,33 μm to 16.3 microns, and the biopolymer entered in a cream base containing at least one ingredient each type: primary and secondary emulsifiers are selected from the group consisting of cetostearyl alcohol, cetomacrogol-1000, Polysorbate-80, Span-80; paraffin wax as a wax-like product; joint solvent selected from the group comprising propylene glycol, hexyleneglycol and polyethylene glycol-400; nitric acid or lactic acid and water.

2. Cream under item 1, in which the cream base further comprises a preservative.

3. Cream under item 2, in which
science is data positiva acid is present in an amount of preferably from 0.5% in weight ratio to 5% in weight ratio, and more preferably about 2,00% in weight ratio, and in which the number specified fusidate sodium used for formation of the in situ fuseboy acid is in the range between 0.1% in weight ratio to 25% in weight ratio, preferably from 0.5% in weight ratio to 5% in weight ratio, and more preferably of 2.08% in terms of weight,
this biopolymer is presented in the form of chitosan, added in an amount of from 0.01% to 1% in weight ratio, preferably from 0.01% to 0.5% in weight ratio, and in the most preferred embodiment of 0.25% in weight ratio,
- specified primary and secondary emulsifiers are added in an amount of from 1% in weight ratio to 20% in weight ratio; these waxy products are selected from a group comprising white soft paraffin, liquid paraffin, paraffin wax, or combination thereof, and added in an amount of from 5% in weight ratio to 30% in weight ratio; this collaborative solvent is added in an amount of from 5% in weight ratio to 50% in weight ratio; specified nitric acid or lactic acid, or combination thereof is added in amounts of 0.005% in weight ratio to 0.5% in terms of weight; the specified preservative is selected from the group comprising methyl parahydroxybenzoate, sodium propyl parahydroxybenzoate, chlorocresol, potassium sorbate, benzoic acid or the x combination and is added in amounts of from 0.05% in weight ratio to 0.5% in weight ratio; the specified water is added in the range of from 20% in weight ratio to 75% in weight ratio, preferably from 30% in weight ratio to 50% in weight ratio, more preferably from 35% in weight ratio to 45% in weight ratio, preferably purified water.

4. Cream under item 1 or 3, containing, in addition, a buffering agent which is selected from the group comprising dvuhkamernyi orthophosphoric acid sodium, phosphoric acid, sodium or combination thereof, and added in quantities of from 0.001% in weight ratio to 1.00% in terms of weight.

5. Cream under item 1 or 3, containing, in addition, the antioxidant is selected from the group including butylhydroxyanisole, butylhydroxytoluene or combination thereof, and added in quantities of from 0.001% by weight with respect to 1% in weight ratio.

6. Cream under item 1 or 3, containing, in addition, chelating additive disodium salt of EDTA in an amount of from 0.05% in weight with respect to 1% in weight ratio.

7. Cream under item 1 or 3, containing, in addition, hygroscopic agent, which is selected from a group comprising glycerin, sorbitol, propylene glycol or a combination thereof, and added in an amount of from 5% in weight ratio to 50% in weight ratio.

8. A method of manufacturing a cream under item 1 on the et the following steps:
A. heating purified water in an amount of from 20% in weight ratio to 75% in weight ratio, preferably from 30% in weight ratio to 50% in weight ratio, more preferably from 35% in weight ratio to 45% in weight ratio in the vessel for the aqueous phase to a temperature from 70°C to 80°C,
b) adding to the specified vessel for the aqueous phase of a preservative selected from the group comprising methylparaben, propylparaben, chlorocresol, potassium sorbate, benzoic acid, or combination thereof in the amount of from 0.05% in weight ratio to 0.5% in weight ratio, preferably 0.3% in terms of weight, more preferably 0.2% in terms of weight, more preferably benzoic acid,
C) stirring the mixture using a mixer at a speed of from 10 to 50 rpm and the temperature of the mixture from 70°C to 80°C,
d) adding waxy products selected from the group comprising white soft paraffin, liquid paraffin, paraffin wax, or combination thereof in an amount of from 5% in weight ratio to 20% in weight ratio, preferably 15% in weight ratio, more preferably 12.5% in weight with respect to the vessel for the oil phase and the melting of the specified paraffin by heating it to a temperature of from 70°C to 80°C,
e) adding a specified vessel for the oil phase of the primary emulsifier, preferably in f is RME nonionic surfactants, selected from the group comprising cetostearyl alcohol and cetomacrogol-1000, or a combination of both, preferably cetostearyl alcohol in an amount of from 1% in weight ratio to 15% in weight ratio, preferably 15% in weight ratio, more preferably 12.5% in weight ratio, and possibly a secondary emulsifier selected from the group comprising Polysorbate 80 and Span 80, preferably Polysorbate-80 in an amount of from 1 to 5% in weight ratio, more preferably 2% in weight ratio, and thoroughly stirring the mixture, preferably using a stirrer at a speed of from 10 to 50 rpm while maintaining the temperature of the mixture from 70°C to 80°C,
f) transferring the contents of the vessel for the aqueous phase and oil phase in the mixer under vacuum in the range from -1000 to -300 mm RT.article and at a temperature from 70°C to 80°C and thoroughly stirring the mixture, preferably using a stirrer at a speed of from 10 to about 50./minutes before formation of the emulsion,
g) cooling the specified emulsion to 45°C, preferably by creating a circulation of cold water, preferably with temperatures ranging from 8 to 15°C from the tower in the cooling jacket of the mixer,
h) adding to the vessel for the active ingredient joint solvent selected from the group comprising propylene glycol, hexyleneglycol, the polyethylene is glycol-400, or combination thereof, in an amount of from 5% in weight ratio to 40% in weight ratio, preferably 30% in terms of weight, more preferably 25% in weight ratio, preferably propylene glycol, the impact on the contents of the vessel for the active ingredient by blowing an inert gas, with the specified inert gas is preferably nitrogen, and adding fusidate sodium in amounts of from 0.1% in weight ratio to 25% in weight ratio, preferably from 0.5% in weight ratio to 5% in weight ratio, and more preferably of 2.08% in weight ratio, and the dissolution of the specified fusidate sodium in the mix,
i) adjusting the pH of the mixture formed in the vessel for the active substance in step h, to values below 2 by using an acid, selected from the group consisting of acid such as HCl, H2SO4, HNO3, lactic acid, or any combination thereof, preferably nitric acid in an amount of 0.005% in weight ratio to 0.5% in weight ratio, preferably 0.3% in terms of weight, more preferably 0.25% in terms of weight,
j) transferring the contents of the vessel with the active substance obtained in step i, in the mixer described in step g with continuous stirring at a speed ranging from 10 to 50 rpm and homogenizing the mixture at a speed ranging from 1000 to 3000 rpm by injecting inert ha the om and in vacuum conditions from -1000 to -300 mm RT.art., when this is specified, the inert gas is preferably nitrogen,
k) add in a jar of acid selected from the group comprising acid such as HCl, H2SO4, HNO3, lactic acid, or combinations thereof, preferably lactic acid, in amounts of between 0.005% and in terms of weight and 0.5% in weight ratio, preferably 0.3% in terms of weight, more preferably 0.1% in terms of weight and purified water in an amount of from 0.1% in weight with respect to 10% in weight ratio, preferably 8% in terms of weight, more preferably 5% in weight ratio, to form a mixture and dissolving the specified biopolymer chitosan, in amounts of between 0.01% and 1% in weight ratio, preferably from 0.01% in terms of weight to 0.5% in terms of weight and most preferably from 0.25% in weight ratio,
l) transferring the contents of the mixture containing the biopolymer obtained in step k, in the mixer described in step g with continuous stirring at a speed of from 10 to 50 rpm and homogenizing the mixture at a speed of from 1000 to 3000 rpm by injecting an inert gas under vacuum from -1000 to -300 mm RT.art., when this is specified, the inert gas is preferably nitrogen,
(m) cooling the contents of the mixer from step j to a temperature from 30°C to 37°C using circus the ablation chilled water with temperatures ranging from 8°C to 15°C from the tower in the cooling jacket of the mixer,
n) to turn off the agitator and the homogenizer and removing the mixture obtained in step m, from the mixer to the storage container.

9. A method of manufacturing a cream under item 8, in which, in addition, in the mixer on the step and add a hygroscopic agent, such hygroscopic agent selected from a group comprising glycerin, sorbitol, propylene glycol, or a combination thereof in an amount of from 5% in weight ratio to 40% in weight ratio, preferably 30% in terms of weight, more preferably 25% in terms of weight.

10. A method of manufacturing a cream under item 8 or 9, in which, in addition, in the mixer on the step and add chelate additive disodium salt of EDTA in an amount of from 0.01% in weight with respect to 1% in weight ratio, preferably 0.5% in terms of weight, more preferably 0.1% in terms of weight.

11. A method of manufacturing a cream under item 8 or 9, in which, in addition, on the step and add a buffering agent, such as a buffering agent - dvuhkamernyi orthophosphoric acid sodium or phosphoric acid sodium type in the amount of from 0.001% in weight ratio to 1.00% in terms of weight, preferably 0.05% in terms of weight, more preferably 0.5% in terms of weight.

12. A method of manufacturing a cream under item 8 or 9, in which, in addition, in step h type antioxidant, with yasaryetkin selected from the group includes butylhydroxyanisole and butylhydroxytoluene in the amount of from 0.001% in weight ratio to 5% in weight ratio, preferably 0.1% in terms of weight, more preferably 0.01% in terms of weight.



 

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8 cl, 10 tbl, 2 dwg

FIELD: medicine.

SUBSTANCE: invention represents cream for skin infections, containing fusidic acid formed in situ in an oxygen-free medium with the use of sodium fusidate. The above cream contains fusidic acid prepared in situ by the conversion of sodium fusidate with adding acid slowly, with a particle size of the active substance of 2.33 mcm to 16.3 mcm, and the cream base containing at least one ingredient of each type: primary and secondary emulsifying agents specified in a group containing ketostearyl alcohol, ketomacrogol-1000, Polysorbate-80 and Span-80, paraffin as wax, a combined dissolving agent specified in a group including propylene glycol, hexylene glycol, polyethylene glycol 400, nitric acid or lactic acid and water.

EFFECT: invention provides high stability of the active ingredient throughout the whole shelf life.

10 cl, 16 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine and concerns a pneumococcal vaccine containing saccharide of 4, 6B, 9V, 14, 18C, 19F and 23F serotypes, separately conjugated with CRM197, and at least one Toll-like receptor-9 (TLR-9) agonist as an adjuvant, wherein the above Toll-like receptor-9 agonist represents CpG-oligonucleotide. Also, the group of inventions concerns using the pneumococcal vaccine for preparing the therapeutic agent for preventing or treating diseases caused by S.pneumoniae; a method for individual's immunisation against the diseases caused by S.pneumoniae infection, involving administering the immunoprotective dose of the vaccine into the above individual.

EFFECT: adding B-class CpG to the conjugated pneumococcal vaccine provides the considerable increase of the proportion of highly responsive patients, good tolerance and cell memory induction in relation to pneumococcal polysaccharides.

45 cl, 9 dwg, 4 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention represents an antimicrobial agent for preventing an implant-associated infection containing gentamicin sulphate 0.96 g, dioxidine 1.0 g, medium-molecular-weight medical collidone (molecular weight 30000D) 10.0 g, distilled water up to 100.0 ml.

EFFECT: extending the range of products preventing the developing implant-associated infection and prevents preserving the antimicrobial activity of the tissues surrounding the implantation area.

2 cl, 1 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: agent possessing the anti-inflammatory, antipyretic and antimicrobial action representing a dry extract of drug hedge hyssop leaves and blossom by grinding them, extracting in 96% alcohol on a water bath to a boil, and boiling, evaporating, diluting the evaporated residue by distilled water first, adding chloroform then, cooling to a room temperature and centrifuging, separating a water fraction and drying it in the certain environment.

EFFECT: agent possesses the pronounced anti-inflammatory, antipyretic and antimicrobial action.

5 dwg, 5 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents a skin care agent possessing the antifungal properties, containing propolis, ethanol, and a sulphur-containing component, differing the fact that the sulphur-containing component contains elemental nanodispersed sulphur with the components of the agent taken in certain amounts, wt %.

EFFECT: invention provides extending the range of products possessing a wide spectrum of fungicidal action, and promotes the tissue regeneration processes.

3 cl, 3 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention represents cream for skin infections, containing fusidic acid formed in situ in an oxygen-free medium with the use of sodium fusidate. The above cream contains fusidic acid prepared in situ by the conversion of sodium fusidate with adding acid slowly, with a particle size of the active substance of 2.33 mcm to 16.3 mcm, and the cream base containing at least one ingredient of each type: primary and secondary emulsifying agents specified in a group containing ketostearyl alcohol, ketomacrogol-1000, Polysorbate-80 and Span-80, paraffin as wax, a combined dissolving agent specified in a group including propylene glycol, hexylene glycol, polyethylene glycol 400, nitric acid or lactic acid and water.

EFFECT: invention provides high stability of the active ingredient throughout the whole shelf life.

10 cl, 16 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and represents a gel biologically active composition for topical application containing chitosan hydrochloride in an amount of 10-20 wt %, an organic acid in an amount of 1-10 wt %, distilled water - the rest. The above organic acid is specified in acetic, ascorbic, glycolic, lactic, citric or succinic acids.

EFFECT: providing a lower toxicity and a wider spectrum of biological action of the composition ensured by the synergetic effect of a reaction of chitosan hydrochloride and the organic acid.

11 ex, 11 tbl, 2 dwg

FIELD: veterinary science.

SUBSTANCE: preparation of local therapy contains pine resin, chlorophyll carotin paste, birch oil, castor oil in the following proportions: pine resin: chlorophyll carotin paste: birch oil: castor oil - 10:5:5:80.

EFFECT: using the declared preparation enables the higher therapeutic effect as compared to the existing agents for treating animal skin diseases, including dermatitis.

1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the field of cosmetology. Described is a stable and safe antioxidant composition, which can be applied daily. In particular, described is the antioxidant composition, which contains one or more compounds, selected from the group, which consists of D-aspartic acid, its derivatives and/or its salts. The composition can be applied with the purpose of suppressing and/or relief of a skin condition. Conditions of skin can include, but are not limited by them, small wrinkles, rough skin, dry skin, skin cancer, skin allergy, skin inflammation, and light-sensitive dermatosis. The composition can be applied as a medication for the external application on the skin.

EFFECT: invention ensures an increase of the antioxidant effect of the composition.

4 cl, 5 dwg, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the pharmaceutical industry and represents a local pharmaceutical composition for treating rosacea containing at least 0.02% berberine or a biologically equivalent berberine analogue, such as palmatine, and an ingredient specified in a group consisting of water, methanol, ethanol and dimethylsulphoxide, wherein berberine or the biologically equivalent berberine analogue represents the major pharmaceutically active ingredient.

EFFECT: invention provides extending the range of products for treating rosacea.

4 cl, 6 ex, 2 dwg

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, namely to dermatology, and can be used for treating such diseases, as rosacea, psoriasis, topic dermatitis or acne. That is ensured by a local application on an individual's skin area of a topical composition, which can be an ingredient of a kit and contains a therapeutically effective amount of an α2-adrenergic receptor agonist, wherein the α2-adrenergic receptor agonist is specified in a group consisting of: a compound of formula (Ia) wherein each of R1, R2 and R3 independently means hydrogen, halogen, (C1-C8)alkyl or alkoxy; each of R4 and R5 independently means hydrogen, (C1-C8)alkyl or alkoxy; each of R6 and R7 independently means hydrogen, nitro, (C1-C8)alkyl or alkoxy; alkoxy is specified in methoxy, ethoxy, n-propoxy, sec-butoxy, tret-butoxy, n-hexyloxy; and a therapeutically effective amount of the non-steroid anti-inflammatory agent diclofenac and a pharmaceutically acceptable carrier, wherein the skin area is subject to or can be injured by an inflammatory skin disease or a symptom related to the above disease. The α2-adrenergic receptor agonist can be presented by, e.g. brimonidine.

EFFECT: ensuring the synergetic effect when using the declared combination which shows the synergetic effect by improving the anti-inflammatory action of diclofenac that leads to the complete relief of any symptoms of the inflammatory disease.

21 cl, 3 ex, 6 tbl, 2 dwg

FIELD: medicine.

SUBSTANCE: topical cosmetic composition effective for stimulating each of SIRT1, Gadd45b and SOD2, which contains a senna alata leaves extract, a great morinda leaves extract and a melon flesh extract taken in certain proportions. A method for the protection against or recovery of an oxidative injury involving administering the topical composition containing the senna alata leaves extract, the great morinda leaves extract and the melon flesh extract taken in certain proportions. The topical cosmetic or dermatological composition for stimulating each of SIRT1, Gadd45b and SOD2. Using the above composition for producing a drug preparation for treating the oxidative injury.

EFFECT: composition is effective for stimulating each of SIRT1, Gadd45b and SOD2.

8 cl, 1 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining a polymer conjugate of an indolocarbazole compound of formula (I), where R1, R2, R3, W1 and W2 represent hydrogen, X represents methoxy-polyethyleneglycol. The method includes the interaction of a polymer compound of formula (II) with an indolocarbazole compound of formula (III), where Y stands for a methoxygroup. The nvention also relates to a polymer conjugate of formula (I), a pharmaceutical composition, containing the conjugate of formula (I) as an active ingredient, and to the application of the polymer conjugate of formula (I).

EFFECT: obtaining the polymer conjugate of the formula with a high output, the polymer conjugate of the formula for treatment of skin pathologies and HMGB1-associated pathologies.

48 cl, 7 dwg, 7 tbl, 15 ex

FIELD: pharmacology.

SUBSTANCE: method involves preparing a liquid composition containing a pharmaceutical active ingredient, a mixture of solvents containing water, isopropanol in an amount of 5 wt % to 20 wt % and propylene glycol in an amount of 2 wt % to 25 wt %, and a phospholipid foaming agent in an amount of 2 wt % to 25 wt %, foaming the liquid composition mechanically with no propellant used, and measuring the foam volume and stability. That is followed by transforming the nature and/or changing the concentration of the pharmaceutically active ingredient and/or the phospholipid foaming agent and/or changing the concentration of one of the solvents to produce 250 ml of the liquid composition. The above liquid composition is expected to produce foam in the volume of 400 ml and with the stability so that 50% of an initial foam volume is observed so far after the 10-minute hold-up and measured by the standard SITA procedure. The invention also relates to a composition applicable for topical use and prepared by the method described above.

EFFECT: preparing the composition presented by the stable foam.

22 cl, 18 dwg, 1 tbl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents a topical composition containing a combination of natural salt or pure sodium chloride and glucose mixed in ratio 1:1-30 (wt/wt) as an active ingredient in an amount effective for treating bacterial vaginosis caused by Cardnerella vaginalis together with a pharmaceutically acceptable carrier.

EFFECT: invention provides the higher pharmacological activity.

4 cl, 4 ex, 5 tbl

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