EA017434B1 - Stable local and/or mucosal emulsion preparations (embodiments), method for preparing (embodiments) and use thereof (embodiments) - Google Patents

Abstract

The present invention relates to stable local emulsion compositions comprising: a thermo-reversible block copolymer of ethylene oxide and propylene oxide and tea tree oil. In one of embodiments of the present invention the composition may comprise a hydrophilic, non-ionic fatty acid emulsifier. In another embodiment of the present invention the composition may comprise a thermo-reversible block copolymer of ethylene oxide and propylene oxide in an amount from about 10% 50% by weight of the composition, the hydrophilic, non-ionic fatty acid emulsifier in an amount from about 0.5% to 50% by weight of the composition and the tea tree oil in an amount from about 0.1% to 80% by weight of the composition. The present invention also relates to said compositions to be useful to oesophageal, otic, vaginal, rectal or ophthalmic surfaces for the treatment of disorders and imperfections of the skin. The present invention also relates to methods for preparing a stable emulsion composition.

Description

The invention relates to the field of pharmacology, hygiene and cosmetology, specifically to emulsions of biologically active substances, preferably slightly soluble or insoluble in water, for topical use and / or for use on the mucous membranes of the stomach, ears, vagina, rectal and ocular surfaces, for application to the epidermis an animal organism (for example, human skin), including for the treatment of skin disorders and defects; and also to methods for producing such emulsions.

Prior Art Information

Many of the active substances in pharmaceutical and cosmetic preparations contain oils or are not miscible with water or water-insoluble. It is difficult to obtain an effective amount of these active substances in order to ensure the desired therapeutic effect, due to their insufficient solubility in water. That is why it is often sought to obtain such substances in compositions prepared on a water basis (for example, for oral, topical, intravenous, intramuscular, subcutaneous, etc.) use. One of the ways to prepare such compositions is to create an emulsion.

An emulsion is a heterogeneous system consisting of at least two immiscible liquids (such as the aqueous phase and the oil phase), one of which is dispersed in the other in the form of droplets, with continuous and intermittent phases. The discontinuous phase is called the dispersed or internal phase, while the phase in which dispersion occurs is called the continuous phase. When water is a continuous phase, the emulsion is classified as oil-in-water (M / V), and when the oil is a continuous phase, the emulsion is classified as water-in-oil (B / M). M / V emulsions are the most commonly used emulsions. However, B / M emulsions are preferred for many purposes and could be used more extensively when solving an instability problem.

Macro-emulsions are those that are formed by intense crushing mixing and usually have particles ranging in size from 1 to 10 microns. Such emulsions are difficult to obtain, and they have minimal stability, since the oil and water components eventually separate into separate phases. In addition, the size of the droplets of the macroemulsion increases over time. Various methods have been developed to stabilize such emulsions, for example, the introduction of additives such as emulsifiers and finely divided solids.

In contrast, microemulsion systems consisting of oil, water, and corresponding emulsifiers can be formed spontaneously (i.e. they are formed with minimal mixing) and therefore are thermodynamically stable. This level of thermodynamic stability is highly desirable, but rarely achievable.

Microemulsion systems theoretically have an unlimited shelf life under normal conditions, without being separated, as opposed to the limited life of macroemulsions. In addition, the size of the droplets in such microemulsions remains constant and is usually less than 150 nm (mostly in the range from 10 to 50 nm), while the microemulsions have very low surface tension between the oil / water phases.

Emulsions, such as microemulsions, are very important for the development of new effective systems for the delivery of active ingredients, which allows water-insoluble or poorly soluble active substances to be introduced into aqueous solutions intended for human use. The preparation of such microemulsions is a major technological difficulty for pharmaceutical delivery systems, since it is necessary to select materials that are biologically compatible, non-toxic, clinically tolerable and that form stable microemulsions.

In addition, many of the well-known emulsion preparations suffer from the inability to provide controlled and prolonged release of the active ingredient in the intended area, as they have a very short retention time in the fabric to which they are used, due to the fact that they are easily washed out or degraded. This inability is especially unacceptable, since most biologically active substances must remain at the destination for a long time in order to be effective.

In view of the foregoing, there is a need to obtain emulsion preparations to provide active substances that are multipurpose and can be applied, for example, topically or on the mucous membranes of tissues. Such emulsions should, first of all, have a high bioadhesive ability to ensure contact for a long time. In addition, they must, first of all, be able to deliver a large amount of the active substance to the destination for controlled and prolonged release to the desired tissue.

Although stable emulsion preparations have been described, these compositions usually require high temperatures to melt all the ingredients of the oil phase in order to evenly distribute the particles of one phase among the particles of the other phase. Microemulsions are usually formed at temperatures above 75 ° C, usually about 90 ° C, and then the composition is slowly cooled over hours or days to room temperature in order to create an emulsion. For large batches of the drug it is expensive

- 1 017434 costly and time consuming process. There is also a risk that the emulsion will be overheated, which will lead, for example, to the degradation of any ingredients.

Another method by which stable emulsions can be prepared is a method using surfactants or emulsifiers. Typically, surfactants and emulsifiers for the preparation of emulsions are selected from the group consisting of hydrophilic surfactants or mixtures thereof. To function as a surfactant, the compound must necessarily include polar or charged hydrophilic groups, as well as non-polar lipophilic (hydrophobic) groups; that is, the surfactant must be amphiphilic. The empirical parameter commonly used to characterize the relative hydrophilicity or hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (HLB value). Lower HLB surfactants are more lipophilic or hydrophobic and have greater solubility in fats, while surfactants with higher HLB values are more hydrophilic and have greater solubility in aqueous solutions. It is generally considered that hydrophilic surfactants are those that have a HLB value of about more than 10, as well as anionic, cationic and zwitterionic compounds for which the HLB scale is usually not applicable. It is necessary to take into account that the HLB value of surfactant is just an approximate indicator, commonly used to simplify the technology of preparation of industrial, pharmaceutical and cosmetic emulsions.

A group of compounds that are successfully used as surfactants in the production of macro- and microemulsions are block copolymers of ethylene oxide and propylene oxide, poloxamers. A number of these compounds have an unusual property: they become liquid when cooled, but solid when heated, this feature is known as thermal reversibility. Such thermo-reversibility is useful in the preparation of pharmaceutical mixtures, where it is preferable to deal with the material in a liquid state when manufacturing, but it is desirable to have the finished product in the form of a gel or in a more viscous state. Such mixtures can be drawn into a syringe to accurately measure the dose, or easily used from a bottle or sprayed from a dispenser when it is cold. When a poloxamer is heated to body temperature (for example, when applied on surfaces of the skin or mucous membranes) it hardens to the desired consistency to promote proper rubbing and adhesion.

The desired gelatinization temperature can be controlled by adjusting the concentration of the block copolymer, and at lower concentrations of the copolymer, higher gelatinization temperatures are obtained. In order to obtain a mixture that will withstand such a transition at commercially and physiologically used temperatures, the copolymer concentrations must be at least 18 to 20 wt.%. However, it was found that the inclusion of high concentrations of the copolymer leads to the mixture becoming extremely viscous or gelatinized, and solutions containing from 18 to 20 wt.% Poloxamer, as a rule, have a high viscosity even in the liquid phase, which is why these solutions do not can function when low viscosity, free flowing conditions are required before the transition is made. For this reason, typical copolymer emulsions typically contain less than 10% copolymer.

Active substances

Active substances are chemicals or compounds that, when introduced into the body (animal or person, usually a human), induce the necessary pharmacological effect. Many of the active substances in pharmaceutical and cosmetic preparations contain oils or are not miscible or insoluble in water. An example of such an active substance is tea tree oil (TTO). The MHD was isolated by distilling the oil from the stalks and leaves of the tree Mellataisis Ayeshaoya. MDH has medical properties, including antimicrobial, antiviral and antifungal properties. In addition, MHD has a calming effect on contact with human skin. However, the properties of MDB may be involved only in the creation of delivery systems suitable for different conditions that may be required. When an MHE-product in the form of water creams is exposed to air, the MHD-component is oxidized, and some of the chemical components can change their characteristics, affecting the effectiveness and safety of the drug. The presence of many of the emulsifying agents used to solubilize MDH in water also inhibits or inactivates the effect of MDH. When the drug is a gel suspension, TTO has a tendency to separate from the gel base of the preparation, especially when the suspension contains TTO in concentrations higher than 2%; the process is enhanced with temperature changes (for example, at temperatures above 30 ° C) and / or with physical effects, such as mixing the suspension.

In order to deliver effective amounts of MDB, it is advisable to apply the oil in a form that will remain in contact with the skin for a long period of time, and also to provide the highest concentrations of MDB as possible. That is why it is highly desirable to use microemulsion preparations, since they are thermodynamically stable.

US patent 5952004 discloses a pharmaceutical composition comprising an active substance in an emulsion consisting of an oil phase, an aqueous phase and a surface-active compound, such

- 2 017434 as a poloxamer. However, in this patent is not intended to include in the pharmaceutical composition thermostable copolymer. Compositions according to US patent 5952004 do not have thermostable properties. Moreover, the high oil content (which becomes more liquid when heated) in the compositions according to US Patent 5952004 would prevent any thermal reversibility of the poloxamer.

German Patent 19723308 discloses microemulsions with an oil component, fatty acids as an emulsifier, and a copolymer as a surface compound. However, pharmaceutical compositions 19723308 do not contain a co-polymer with thermo-reversible properties and, therefore, similar to the invention disclosed in US Patent 5952004, do not have thermo-reversible properties, and, moreover, the high content of oil in the composition would prevent any thermal reversibility of poloxamer.

In US patent 5698219 disclosed a method of producing oil-in-water nanoemulsions, including oil, a surfactant (poloxamer) and the preservative benzalkonium chloride at temperatures between 45 and 85 ° C. Further, the said patent discloses a method for producing nanoemulsions at temperatures less than 35 ° C. However, the method of US Pat. No. 5,698,219 requires the addition of a solvent (such as ethanol or acetone) to the oil phase before mixing with the aqueous phase, followed by removal of the solvent by evaporation. This patent does not disclose the preparation of emulsions containing an additional emulsion component. Moreover, the compositions according to patent 5698219 include a non-ionic surfactant in a ratio of 0.1-10% (w / v) and do not assume the use of copolymers in higher quantities, it is only mentioned that the proposed use of the copolymer in suitable amounts less than 10 %, creates the ability to keep the nano-emulsion in a stable state.

Summary of Invention

The present invention aims to create safe and effective microemulsion delivery systems for biologically active substances that can be manufactured without resorting to high-temperature processing.

According to this invention, a composition or, more precisely, a microemulsion for the delivery of water-insoluble active substances, comprising an aqueous component and a non-ionic block copolymer, and at least an oil, which is the active substance or has a water-insoluble active substance dissolved therein, is proposed.

In this invention, the term emulsion includes both macroemulsions and microemulsions.

The compositions proposed in this invention have bioadhesive and mucoadhesive properties. Preferably, the composition is in the form of a liquid or gel. Even more conveniently, the microemulsion composition existed in the form of a gel or was a liquid capable of gelatinizing upon contact with skin or mucous tissue.

According to a second embodiment, the invention provides a microemulsion or composition for the delivery of water-insoluble active substances containing an aqueous component and a non-ionic block copolymer, a hydrophilic non-ionic emulsifier in the form of a short-chain fatty acid and at least an oil that is itself active or contains water-insoluble active component dissolved in it.

According to a third embodiment, the invention provides a method for preparing microemulsion compositions, which comprises the following steps:

(a) mixing the copolymer with an aqueous solution at the appropriate temperature for a more complete dissolution of the copolymer in the aqueous solution and

b) mixing at cold temperature the oil, which is the active substance or has a water-insoluble active ingredient dissolved in it, with the aqueous solution of the copolymer obtained in stage (a), with the formation of a microemulsion.

According to a fourth embodiment, the invention provides a method for preparing a microemulsion composition, comprising the following steps:

(a) mixing the copolymer with an aqueous solution at an appropriate temperature to dissolve the copolymer more fully in the aqueous solution;

(b) mixing a non-ionic emulsifier in the form of a short-chain fatty acid with oil, which is the active substance or contains a water-insoluble active ingredient dissolved in it, at a low temperature, to form an oily mixture; and (c) mixing the solution prepared in step (a) with the solution prepared in step (b) at a low temperature to form a microemulsion.

It also proposed microemulsion compositions formed by the methods described above.

The composition proposed by this invention will have a wide range of applications. When used topically on the skin surface of the animal body, the composition may include factors that increase the attractiveness of the body or mask the physical manifestations of the disorder or disease instead of or in addition to treating the physical disorder. The same substance can

- 3 017434 have either a cosmetic or pharmaceutical effect depending on the amounts used and the method of administration.

Another aspect of the invention is that the compositions proposed here can be incorporated into other compositions in order to impart a thickening effect to the resulting compositions. Such properties associated with the ability to cause thickening include an increased overall viscosity, as well as the desired viscosity response to temperature. The composition can be used as a thickener in the pH range when other thickeners are ineffective.

In addition, the compositions of this invention may be included in other compositions to give softness to the compositions. In this aspect, the composition may also act as a film-forming bioactive substance after it has been applied to the skin or other mucous membrane. This film-forming bioactive substance can be used as a barrier to prevent skin loss of water when solving biological problems.

Information confirming the possibility of carrying out the invention

Experts will see that this invention allows variations and modifications other than those specifically described. It will be understood that the invention contains all such variations and modifications. The invention also includes all the steps, properties, compositions, and compounds related to and indicated in the specification, individually or together, and any or all of the combinations, or any two or more stages or properties.

The present invention is not limited to the specific embodiments described herein, which are intended only as an example.

Functionally equivalent products, compositions and methods are undoubtedly within the scope of the invention, as described herein.

A complete list of all publications (including patents, patent applications, journal articles, laboratory manuals, books, or other documents) cited here is hereby incorporated by reference. There are no assumptions that any of the links claim priority or are part of public knowledge for those working in the field to which the invention relates.

Throughout the specification, except as otherwise indicated in the text, it will be clear that the word contain (“co”) or its variations means the inclusion of a specific whole or group of complete systems, but not the exclusion of any other whole or group of complete systems.

Other definitions for individual terms can be found in the detailed description of the invention, they apply throughout. Unless otherwise specified, all other scientific and technical terms used herein have the same meaning as adopted by those skilled in the art to which this invention belongs.

The present invention provides a microemulsion composition containing a copolymer of at least 10% by weight, which advantageously has a thermally reversible property.

This number of copolymers exceeds, as far as the applicant knows, their content in other microemulsions based on oil copolymer.

When the copolymer used in the microemulsion is thermally reversible, compositions based on oil copolymers can be made at a cold temperature (in cold).

The applicant found out, however, that combining the emulsifier with the oil before adding the copolymer unexpectedly allows the preparation of a microemulsion at a low temperature.

According to the present invention, a composition, and more specifically a microemulsion, is proposed for the delivery of water-insoluble active substances, which contains an aqueous component and a non-ionic block copolymer and at least an oil, which is the active substance or contains a water-insoluble active substance dissolved in it.

Microemulsions, as described herein, will contain a block copolymer in an amount of from about 10 to about 50 wt.%, More preferably, the weight amount of the block copolymer is from about 10.1 to 40 wt.% Of the emulsion, while it is desirable that the weight amount of block copolymer was in any of the subsequent intervals: 10.5-35, 11-30, 12-25, 13-20, or 14-18 wt.% of the emulsion. Thus, as the invention shows, the block copolymer may comprise 15% by weight of the emulsion.

In addition to the fact that the copolymer is present in the microemulsion in the above-mentioned weight ranges, it is also desirable that it be a thermally reversible copolymer.

In a preferred embodiment of the invention, the microemulsion or composition will have bioadhesive or mucoadhesive properties. Such properties will be compatible with the microemulsion or composition, which is prepared either in the form of a liquid or, more preferably, in the form of a gel. A microemulsion prepared in this way or a composition of water-insoluble or poorly soluble active substances will be suitable for topical application and / or application to the mucous membranes of the gastric, aural, vaginal, rectal or ophthalmic surfaces, or for use on the epidermis of an animal organism (for example, human skin), and / or in order to treat skin damage and blemishes. It is desirable that the microemulsion or mixture either existed in the form of a gel, or was made in such a way as to have the ability to gelatinization upon contact with the skin tissue

- 4 017434 or mucous.

When preparing a microemulsion in accordance with the first embodiment of the invention, ideally, when the oil and the thermally reversible copolymer are mixed at a cold temperature (in cold). When this is done in the cold, in the weight range established here, the mixture forms a stable microemulsion suitable for use on the skin of the mucous membranes.

In the second embodiment, the invention provides a composition or more precisely a microemulsion for the delivery of water-insoluble active substances, containing an aqueous component and a non-ionic block copolymer, a hydrophilic non-ionic emulsifier with short-chain fatty acid and at least an oil that is active or contains a water-insoluble active substance, dissolved in him.

When preparing a microemulsion in accordance with the second embodiment of the invention, it is ideal that the oil and the emulsifier are first mixed, and then the mixture is added to the thermally reversible copolymer.

When this is done at a low temperature in the weight range established here, the mixture quickly forms a stable microemulsion suitable for use on the skin and mucous membranes.

The copolymer for use in the present invention is preferably ethylene oxide and propylene oxide block copolymer (poloxamer), preferably represented by the following formula:

BUT (C ₂ H ₄ O) _a (C ₃ H ₆ O) _b (C _g H ₄ O) _a H, where b takes values from 15 to 67, and a - from 2 to 130, and the total content of a-elements reaches from 20 to 90 wt.% poloxamer. The molecular weight of the poloxamer ranges from about 1,000 to about 20,000, and it preferably has thermo-reversible properties. Only as an example, a poloxamer 407 (a-hydro-hydro-hydroxypoly (oxyethenyl) ₁₀₁ poly (oxypropenyl) ₅₆ poly (hydroxyethenyl) ₁₀₁ ), which is sold as Pitox® P127 (VL8E SotroGodOi) or 8 uiregos PE / R127 (Ishs. | Sta).

According to the invention, the preferred emulsifier is a component containing a fatty acid with a polyethoxylated side chain. For example, suitable emulsifiers can be Eite1-4, Eite1-9, Eite1-23, PPC-26-Bile1-26 / RES-40 hydrogenated castor oil or RES-40 hydrogenated castor oil. When such emulsifiers are used in the invention, the weight amount of emulsifier will usually vary from about 0.5 to 50 wt.% Of the microemulsion.

The physicochemical characteristics of the present invention make the microemulsion suitable as a means of delivering water-insoluble or poorly soluble active substances. It is particularly suitable for transdermal and transmucosal transport. In this aspect, the oil phase may contain oils commonly used in the food, cosmetic and pharmaceutical industries, for example oils of natural or synthetic origin, long-chain alcohols, glycerol fatty acid esters or monohydric alcohols. Esters and alcohols can be straight or branched chain, saturated or unsaturated and can be liquids at room temperature.

The oil phase may also contain active substances that are soluble in or mixed with the oil phase.

The oil in this invention may have inherent pharmaceutical properties and be an active component of the microemulsion and / or may contain dissolved active substances that are soluble in the oil or mixed with it. Active substances may include (but are not limited to) antimicrobial (such as antibiotics, antifungal and antiviral agents), anti-inflammatory and antihistamines, antidepressants, anesthetics, anticancer drugs, enzymes, cardiovascular drugs, polynucleotides, genetic material, viral vectors, immuno -active substances, visualization tools, immunosuppressants, peptides, proteins, etc., as well as their combinations.

Pharmaceutically effective amounts of the selected actives can be determined using well known techniques.

Preferably, the weight amount of the oil used in the microemulsion is from about 0.1 to 80% by weight of the emulsion, more preferably from 1 to 30, with the most optimal range being from 3 to 15% by weight of the emulsion. In a preferred example of the present invention, the oil will be about 6% by weight of the total emulsion.

The most preferred form of the invention is one in which the oil is tea tree oil (TRE). In cases where the active substance is TTO, the microemulsion has bactericidal activity. Such a mixture can be used to treat, for example, sexually transmitted diseases (for example, HIV) by introducing it into the vagina; impetigo and herpes simplex - with the help of local treatment, to remove the MRSA by intra-nasal applications and to treat such diseases as otitis of the middle and outer ear, acne, paradontosis, gingivitis, paronychia, onychomycosis and secondary infections due to operations, dermatitis, burns, etc. d.

According to a third embodiment, the invention provides a method for preparing a microemulsion.

- 5 017434 mixture, which includes the following stages:

(a) mixing the copolymer with an aqueous solution at an appropriate temperature to dissolve the copolymer most fully in the aqueous solution;

(b) mixing, at a cold temperature, the oil, which is the active substance or contains a water-insoluble active substance dissolved in it, with the aqueous solution of the copolymer prepared in step (a), to form a microemulsion.

In accordance with step (a) of this method, the copolymer is mixed with an aqueous solution at a suitable temperature for a more complete dissolution of the copolymer in the aqueous solution. The dissolution of the copolymer in an aqueous solution will occur almost instantaneously at a temperature of about 6 ° C. Alternatively, the copolymer can be mixed with an aqueous solution at room temperature, if you leave the mixture overnight with semi-permanent or constant stirring.

As is customary in this application, the words cold (cold) mean temperatures below 15 ° C, preferably from about 4 to 12 ° C, but even more preferably less than 10 ° C.

According to a fourth embodiment, this invention provides a method for preparing a microemulsion mixture, comprising the following steps:

(a) mixing the copolymer with an aqueous solution at a temperature suitable for more completely dissolving the copolymer in the aqueous solution;

(b) mixing a hydrophilic non-ionic emulsifier containing short-chain fatty acid with oil, which is the active substance or contains a water-insoluble active ingredient dissolved in it at a low temperature to form an oil mixture; and (c) mixing the solution prepared in step (a) ), with the solution prepared in stage (b), at a low temperature to form a microemulsion.

As is customary in this application, the words low temperature mean temperatures below about 60 ° C, preferably from about 15 to 40 ° C, but more preferably from about 20 to 30 ° C and most often at room temperature.

The ability to create microemulsions of this invention at such temperatures is very important, since it constitutes the distinctive quality of this method compared to most other methods of manufacturing microemulsions, according to which microemulsions are prepared at a temperature of about 90 ° C.

It was found that microemulsion mixtures prepared in accordance with the present invention have the surprising property that adding an oil / emulsifier mixture to an aqueous solution of a poloxamer at room temperature changes the thermally reversible nature of the poloxamer, leading to a change in the solidification temperature. This effect is most pronounced at high poloxamer / oil ratios.

The microemulsion compositions of the present invention are clear, colorless gels that are particularly well suited for pharmaceutical use and for personal hygiene. For example, a very small sediment is formed during dehydration, which may be important in some applications, for example in the manufacturing techniques of medicines used in relation to vision and eyes.

An additional advantage of the microemulsion compositions of the present invention is that they remain transparent and translucent before and after the change in the environment. These characteristics of a reversible thickening microemulsion mixture make it very suitable for use in pharmaceutical formulations.

The practical advantage of such a microemulsion mixture is that the drug can be used as a fluid at ambient temperature. On contact with tissues, it thickens, thus changing its fluidity, and, more importantly, its clearance (removal) from the place of use decreases sharply.

Experts will appreciate that the microemulsion composition proposed in this invention can be used for a wide range of pharmaceutical applications and for personal care. To prepare the pharmaceutical composition, an effective amount of a pharmaceutically active substance that gives the desired pharmaceutical effect is incorporated into the reversibly thickening mixture proposed in this invention.

In the case of preparation according to the method proposed in this invention, the microemulsion composition may further include one or more pharmaceutically acceptable additives, excipients and solvents. Such additives, fillers and solvents include (without limitation) water, saline, ethanol, dextrose, glycerin, lactose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphates, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, aqueous syrup, methylcellulose, methyl- and propyloxybenzoates, talc, magnesium stearate and mineral oil, or combinations thereof.

Medicinal preparations may also contain lubricating substances, substances that maintain pH, moisturizers, emulsifying and suspending agents, preservatives, sweeteners, flavoring agents, polymers, antioxidants, complexing agents, density modulators,

- 6 017434 tonic substances, seasonings, dyes, odorants, dimmers, binders, fillers, plasticizers, lubricants, and mixtures thereof.

An individually selected constituent substance that can be included in the compositions described herein will usually depend on the type of preparation.

In addition, an acid or base can be included in the microemulsion mixture to facilitate the process, increase stability, or for other reasons. Examples of pharmaceutically transferable bases include amino acids, amino acid esters, hydroxyammonium, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium oxyaluminate, diisopropylethylene amine, ethanolamine, ethylaminohydrin, ethylenediamine, ethylenediamine, synthetic hydrocalcite, magnesium oxyaluminate, diisopropylethylene amine, ethanolamine, ethylenediamine, synthetic hydrocalcite, magnesium oxyaluminate, diisopropylethylene amine, ethanol amine, ethylenediamine, synthetic hydrocalcite, magnesium hydroxyl ammonium triethylamine, triisopropanolamine, trimethylamine, tris (hydroxymethyl) aminomethane (TRIS) and the like.

In addition, bases which are salts of pharmaceutically acceptable acids, namely acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, are acceptable. fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, parabromophenylsulfonic acid propionic acid, para-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like.

Polybasic acid salts such as sodium phosphate, disubstituted sodium phosphate, and monosodium phosphate can also be used. When the salt acts as a base, the cation can be any convenient and pharmaceutically tolerable cation, such as ammonium, alkali metals, alkaline earth metals, etc.

Preferred cations are sodium, potassium, lithium, magnesium, calcium and ammonium cations.

Suitable acids are pharmaceutically tolerable organic and inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like.

Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, parabromophenylsulfonic acid, propionic acid lot, para-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc.

When a hydrophilic active substance is subject to enzymatic degradation, mixtures proposed herein may also include an enzyme inhibitor. Substances inhibiting enzymes are presented as an example in the article Vegkkkor-Shpigsy (1998), The use of inhibitors to overcome the enzymatic barrier in relation to the oral therapeutic peptides and proteins used, Sop1go11 Pc1c5c 52: 1-16.

In general, inhibitors can be divided into the following classes: amino acid-based inhibitors (such as para-aminobenzamidine, PK-448, camostat-mesylate, and sodium glycocholate); amino acids and modified amino acids (such as derivatives of aminoboric acid and n-acetylcysteine); peptides and modified peptides (such as bacitracin, derivatives of dipeptides and phosphinic acid, pepstatin, antipain, leupeptin, chemostatin, elastatin, bestatin, phosphoramndone, puromycin, cytochalasin, potato carboxypeptidase inhibitor and amastatin); protease polypeptide inhibitors (such as aprotinin, an inhibitor of Bog ^ Vic, a trypsin inhibitor of soybeans, a chicken egg protein trypsin inhibitor, a chicken ovo inhibitor, and a human pancreatic trypsin inhibitor); complexing agents (such as EDTA, EGTA, and 1,10-phenanthroline hydroxyquinoline) and mucoadhesive polymers and polymer conjugates and inhibitor (such as polyacrylate derivatives, chitosan, cellulose, chitosan-EDTA, Chitosan-EDTA-antipain, bacitracin-polyacrylic acid, carboxymethylcellulose-pepstatin and polyacrylic acid-inhibitor (Utap-Vik). The choice and content of an enzyme inhibitor is based on toxicity, protease specificity and degree of inhibition.

Various forms of use

The use of the composition is esophageal, oral and buccal. The only requirement for using this microemulsion blend should be to provide a suitable method for delivering pharmaceutical exposure into the esophagus. In this aspect, the mucoadhesive properties of the proposed microemulsion composition make it able to control and create favorable conditions for pharmaceutical effects on the lining of the esophagus. Sensory

- 7 017434 Micro-emulsion preparation for grinding is also considered an advantage when used when treatment is performed by spraying liquid into the oral cavity under conditions of continuous grinding, where the solution sticks and thickens, creating a reservoir for antibacterial agents such as chlorhexidine or a breath freshener.

Treatment of eye diseases.

Most ophthalmic preparations are applied to the eyes, usually in the area of the protrusion. The most common dosage form is liquid droplets. The bioavailability of the drug is usually low, because liquid preparations are quickly washed out of the eye during lacrimation and blinking, which leads to the need for frequent use and unbalanced medication.

The microemulsion preparation described here provides a new delivery method for achieving greater bioavailability of applied topically insoluble or poorly soluble ophthalmic active agents. Drugs containing such active substances can be used in the form of droplets, which thicken or gelatinize upon contact with the eye. Since gelatinization can occur at low polymer concentrations, blurring of vision can be minimized when instillation of the drug.

When used in this way, the microemulsion mixture will preferably be used for the delivery of bioactive substances such as anesthetic, mydriatic and cycloplegic agents, antimicrobial agents (antibacterial, antifungal, antiviral), anti-inflammatory drugs, means for treating glaucoma, eye swelling agents, diagnostic tools wound healing agents.

Application nasal.

Microemulsion mixtures proposed in this invention can also be used to deliver drugs into the nasal cavity. Nasal drug administration is considered as an alternative to parenteral routes of administration for medicinal substances that demonstrate low oral bioavailability. In order to increase the bioavailability of nasally injected drugs, attempts were made to increase the lifetime of the drugs in the nasal cavity. The nasal delivery of drugs can give advantages over other methods, including faster systemic absorption, lower doses, a faster onset of the desired therapeutic effects and improved pharmacokinetic properties.

Microemulsion compositions can potentially be used to supply such agents as decongestants, antihistamines, anti-osteoporosis substances, hormones, anti-cancer drugs, anti-Parkinson's, etc. This composition can also be used for the use of vaccines, for example, against influenza virus.

Vaginal / Rectal Use.

The microemulsion compositions proposed in this invention also have indications for the supply of bioactive substances (such as MDB) into the vaginal or rectal cavity. Such delivery methods are considered as an alternative to the parenteral route of administration of bioactive substances that exhibit low oral bioavailability. In order to increase the bioavailability of vaginally or rectally injected bioactive substances, attempts were made to increase the lifetime of the drugs in these cavities. Such routes offer advantages over other delivery methods, including faster systemic absorption, lower doses, faster onset of desired therapeutic effects, and improved pharmacokinetic properties.

Use in veterinary medicine.

The microemulsion compositions proposed in this invention may be applicable not only in the treatment of humans, but also in the treatment of animals. As for veterinary products, microemulsion compositions are indicated for the preparation of topical agents for the skin, such as antibacterial, antifungal, antipruritic agents, as well as anti-seborrhea, odor, antiseptic and wound healing agents. Ear care products should include ear cleaning products with or without active ingredients, such as antifungals. Ophthalmic products should include eye moisturizers and antimicrobials.

Application for personal care.

The microemulsion compositions of this invention may very well be suitable for cosmetic purposes. For example, a very small sediment is formed during dehydration, which can be very important in some applications, for example, when applying cosmetics locally. An additional advantage of the composition proposed in this invention is that it remains transparent and translucent at a temperature or pH of the medium above or below the critical. These qualities of microemulsion compositions make them very suitable for use in cosmetic compositions.

In order to prepare a cosmetic composition, an effective amount of a cosmetically active substance or substances that have the desired cosmetic effect is incorporated into the microemulsion composition proposed in this invention. Preferably, the selected substance is a homogeneous dispersion in the composition of the microemulsion preparation. Assume in frames

- 8 017434 Kah of this invention, which reversibly gelatinizing mixtures of this invention can be prepared under sterile conditions.

Cosmetic composition can be in any form. Applicable forms include the following (but not limited to them): lotions, creams, pencils, roll-on preparations, mousses, aerosol dispensers, soft pads, and film-forming preparations.

The preparation of the above and other cosmetic compositions can be improved in accordance with the recommendation of any of the cosmetic reference books or special magazines available to the cosmetic industry. These recommendations offer standard preparations that can be modified by adding or replacing a microemulsion mixture in a standard preparation. Recommended directories include Sokteisk ap Toyoytek Madakhte, Wo1. 111 (Matsy, 1966); Horn: 1Geak Gog Regkopa Sage; Sgoya, 1ps, Ratyrrapu, N.1. (1993); and Sokteysop: Sokteys Rottilagu, VL8R, which, therefore, are fully incorporated by reference.

The preparation of pharmaceutical compositions can be improved in accordance with the recommendation of any of the pharmaceutical reference books or specialized journals available to the pharmaceutical industry. These recommendations offer standard preparations that can be modified by adding or replacing microemulsion compositions proposed in the present invention. Recommended directories include Ryattaseiisk ap Toyayek Madahte, Wo1. 111 (Matsy, 1996); Rottiagu: 1eak Goth Regkopa Sage; Sgoya, 1ps, Ragyrrapa, N.1. (1993); and Ryattaseiysop: Ryattaseiys Rottilaga, VL8R, which are hereby incorporated in full by reference.

Typical drugs or therapeutic delivery systems that can be used in the use of aqueous sensitive (reactive) compositions of this invention include (but are not limited to) mucosal therapy, i.e. use on the esophagus, ear, rectal, intrabukkalno, orally, vaginally, as well as in urology; local therapy, such as wound care, skin care, and intravenous / subcutaneous therapy, such as intramuscular, intraosseous (eg, joints), spinal and subcutaneous therapy, tissue replacement, adhesion prevention, and drug delivery parenterally.

The term animal means mammals, such as primates, including humans, sheep, horses, cattle, pigs, dogs, cats, rats, mice; It also includes birds, reptiles and fish.

As those skilled in the art will understand, two or more pharmaceutical agents can be combined for specific effects. The required amount of active ingredient can be determined by simple experiment.

The invention is described with reference to the following examples, which are presented only for the purpose of illustrating it, but not limiting it.

Example 1. The manufacture of vaginal gel B.

Part A.

15.6 g of Li-1®P127 is added to 84.4 g of deionized water, the temperature of which is 6 ° C, slowly stirring to reduce air entrapment, then placed under vacuum for several minutes to remove the entrapped air after the Li-1®P127 is dissolved .

Part B.

Add 0.20 g of fumaric acid to 5.0 g of alcohol, stirring until dissolved. The solution is cooled to 10 ° C.

Part C.

3.0 g of tea tree oil, 5.0 g of propylene glycol and 2.0 g of undecylenic acid are combined and stirred to dissolve all the ingredients. Cool the solution to 10 ° C.

Gel preparation.

84.8 g of a solution of LiO1®P127 from part A are placed in a vessel and kept at a temperature of 10 ° C. 5.2 g of a solution of fumaric acid of part B are slowly added and stirred well, maintaining the temperature of the solution at 10 ° C. Slowly add 10.0 g of a solution of tea tree oil part C, gently stirring, maintaining the temperature at 10 ° C. If necessary, remove the air by placing the gel under vacuum. The gel is allowed to warm to room temperature.

Example 2. The manufacture of the gel poloxamer 8C.

Part A.

76.3 g of deionized water are heated to 60-65 ° C, 16.7 g of poloxamer 407 are slowly added and gently stirred for about 2 hours or until the poloxamer is dissolved and the solution thickens. Allow the solution to cool to room temperature and leave overnight. The pH of the solution is adjusted to 4.2-5.0 with potassium hydroxide.

Part B.

3.0 g of PPC-26-BSCHE111-26 / RES-40 hydrogenated castor oil, 3.0 g of tea tree oil and 1.0 g of Y-a-tocopheryl acetate are combined with gentle stirring.

- 9 017434

Gel preparation.

7.0 g of a part B tea tree oil solution is added to 93.0 g a poloxamer part A solution at room temperature. Mix with gentle shaking until the solution thickens.

Example 3. The manufacture of a poloxamer 8E gel.

Part A.

73.4 g of deionized water are heated to 60-65 ° C, 16.0 g of poloxamer 407 are slowly added and gently stirred for about 2 hours or until all of the poloxamer has dissolved and the solution thickens. Allow the solution to cool to room temperature and leave overnight. The pH of the solution is adjusted to 4.2-5.0 with potassium hydroxide.

Part B.

Put together 2.0 g of Bulk-4, 1.0 g of Eaige-23, 6.0 g of tea tree oil and 1.0 g of atcopherylacetate, 0.1 g of 1.0 M (1 U / g) retinyl palmitate and 0 , 5 g of panthenol. Heat the solution to 4045 ° C with gentle stirring to dissolve all the components.

Gel preparation.

Add 10.6 g of a part B tea tree oil solution to 89.4 g a part A poloxamer solution, which is at room temperature. Stir, gently shaking, until the solution thickens.

Example 4. Testing gel preparations on microorganisms.

The resulting compositions are tested using macrodilution and microdilution on a 96-well microtitre tray. The highest concentration of the tested gel was 50%. The test organisms were § 1 hayosssi8 иг е из из Ы 65, 71 6571, еп й й Ы Ы Ы 104,, зе ош ош оп аз С С С and С з А yeast.

Cultures for sowing were prepared in a double Müller-Hinton broth, bringing its final concentration to a single one, and the final concentration of organisms to about 5x10 ⁵ colony-forming units per 1 ml.

Samples were incubated at 37 ° C for 24 hours. At the end of this time, the trays were passaged, taking 5 μl from the wells and putting drops on Mueller-Hinton agar. All subcultures were incubated for 24 hours and the number of colonies was determined.

The minimum inhibitory concentration (MIC) was defined as the lowest concentration of the product, leading to the maintenance or weakening of the inoculum. The minimum cidal concentration (MCC) was determined as the lowest concentration of the product, resulting in the death of 99.9% of the inoculum.

Product TTO% mic / m to S.a1b1sap8 Z.Aigeiz E.soP R. Aegiosa Vaginal gel B 3.0 <0.78 / <0.78 <2.1 / <2.1 4.2 / 4.2 33.0 / 33 Vaginal gel B 3.0 - > 1.5 /> 1.5 - > 1.5 /> 1.5 Poloxamer gel 8 С 6.0 0.38 / 0.38 0.75 / 0.75 <0.19 / <0.19 > 3.0 /> 3.0

Claims (22)

CLAIM 1. A stable topical and / or mucosal emulsion composition for pharmaceutical and / or cosmetic use, comprising an aqueous component, a non-ionic thermally reversible block copolymer of ethylene oxide and propylene oxide (poloxamer), tea tree oil and a hydrophilic non-ionic emulsifier based on a fatty acid in which the copolymer mixed with water component, is a flowing liquid at a temperature below 15 ° C, tea tree oil is presented in an effective amount sufficient to impart pharmaceutical and / or smeticheskogo effect of the composition and the emulsion composition and is capable of thermoreversible gelation or thickening when contacted with the dermal, ocular or mucosal tissue to the manifestation of bioadhesive or mucoadhesive properties. 2. The composition according to claim 1, which is stable at a temperature of less than 15 ° C. 3. The composition according to claim 2, the content of the copolymer in which is at least 18 to 20 wt.%. 4. A stable topical and / or mucosal emulsion composition suitable for pharmaceutical and / or cosmetic use, comprising an aqueous component, a nonionic thermally reversible block copolymer of ethylene oxide and propylene oxide in an amount of from 10 to 50 wt.%, A hydrophilic non-ionic emulsifier based on fatty acid in in an amount of from 0.5 to 50 wt.% and tea tree oil in an amount of from 0.1 to 80 wt.%, in which tea tree oil is present in an effective amount sufficient to impart a pharmaceutical and / or cosmetic effect to the composition, and the emulsion is thermally reversible and is capable of gelatinization or thickening upon contact with skin, ocular or mucous tissue with the manifestation of bioadhesive or mucoadhesive properties. - 10 017434 5. The composition according to claim 4, which is stable in the temperature range from 15 to 40 ° C. 6. The composition according to claim 4, the content of the copolymer in which is at least 18 to 20 wt.%. 7. The composition according to any one of claims 1 to 6, in which the hydrophilic nonionic emulsifier based on a fatty acid is a compound selected from the group comprising Laigens 111-4. Baig111-9. Laigue1y-23, PPC-26-Vi1e1y-26 / RES-40 hydrogenated castor oil and RES-40 hydrogenated castor oil. 8. The composition according to any one of claims 1 to 6, in which the copolymer is a-hydro-ω-hydroxypoly (oxyethenyl) 101poly (oxypropenyl) 56poly (oxyethenyl) 101 (poloxamer 407). 9. A stable topical and / or mucosal emulsion composition suitable for pharmaceutical and / or cosmetic use, comprising an aqueous component, a nonionic thermally reversible block copolymer of ethylene oxide and propylene oxide, tea tree oil and a hydrophilic nonionic emulsifier based on a fatty acid in which the copolymer is mixed with an aqueous component, is a flowing liquid at a temperature below 15 ° C, tea tree oil is presented in an effective amount sufficient to impart a pharmaceutical or braid of the composition’s metabolic effect, the temperature when mixing tea tree oil with a copolymer is lower than room temperature, and the emulsion composition is thermally reversible and can gel or thicken when in contact with skin, ocular or other mucous tissue with bioadhesive or mucoadhesive properties. 10. A stable topical and / or mucosal emulsion composition suitable for pharmaceutical and / or cosmetic use, comprising an aqueous component, a hydrophilic non-ionic thermoreversible block copolymer of ethylene oxide and propylene oxide in an amount of from 10.5 to 35 wt.%, A hydrophilic non-ionic emulsifier based on fatty acid in an amount of from 0.5 to 50 wt.%, tea tree oil in an amount of from 0.1 to 80 wt.%, obtained by a method comprising mixing the copolymer with an aqueous solution at a temperature optimal for a more complete solution mixing the hydrophilic non-ionic emulsifier based on a fatty acid containing a polyethoxylated side chain with oil, which is an active substance or contains a water-insoluble active dissolved substance in it, at a temperature of 15 to 40 ° C to form an oil mixture and mixing the resulting oil mixture with an aqueous solution at a temperature of from 15 to 40 ° C with the formation of a stable emulsion composition in which tea tree oil is present in an effective amount sufficient to impart pharmaceutical the eutical or cosmetic effect of the composition, and the emulsion composition is thermally reversible and is capable of gelatinization or thickening upon contact with skin, ocular or other mucous tissue with the manifestation of bioadhesive or mucoadhesive properties. 11. A method of preparing a stable emulsion composition, comprising mixing a thermally reversible block copolymer of ethylene oxide and propylene oxide (poloxamer) with an aqueous solution at a temperature optimal for its more complete dissolution, mixing the resulting aqueous solution of a block copolymer at a temperature below 15 ° C with tea tree oil with the formation of a stable emulsion composition, while at the stage of mixing with an aqueous solution, the thermally reversible poloxamer is a liquid or a flowing gel at a temperature 15 ° C, and the amount of thermo-reversible poloxamer is from 10 to 50 wt.% and is effective for giving the emulsion thermo-reversibility with the possibility of gelatinization or thickening upon contact with skin, ocular or mucous tissue with the manifestation of bioadhesive or mucoadhesive properties. 12. The method according to claim 11, in which the mixing of oil and poloxameric solution occurs at a temperature of from about 4 to 12 ° C. 13. A method of preparing a stable emulsion composition, comprising mixing a thermally reversible poloxamer with an aqueous solution at a temperature optimal for its more complete dissolution, mixing a hydrophilic non-ionic emulsifier based on short-chain fatty acid at a temperature of 15 to 40 ° C with tea tree oil to produce an oil mixture and mixing the resulting aqueous solution of a copolymer with the specified oil mixture at a temperature of from 15 to 40 ° C to obtain an emulsion composition in which the amount of thermo a reversible poloxamer is from 10 to 50 wt.% and is effective for giving the emulsion heat reversibility with the possibility of gelatinization or thickening upon contact with skin, ocular or mucous tissue with the manifestation of bioadhesive and mucoadhesive properties. 14. The method according to item 13, in which the stage of obtaining the oil mixture and obtain a stable emulsion is carried out at a temperature of from about 20 to 30 ° C. 15. The method according to item 13, in which the stage of formation of the oil mixture and the formation of microemulsions is carried out at room temperature. 16. The use of the emulsion composition according to any one of claims 1, 4, 9 or 10 as a local agent on the epidermal surfaces of the animal organism. 17. The use of the emulsion composition according to any one of claims 1, 4, 9 or 10 as a means for the mucous surfaces of the esophagus, ear, vagina, rectum or eye of an animal organism. - 11 017434 18. The application of clause 16 or 17, in which the composition further comprises substances that promote the attractiveness of the body or mask the physical manifestations of the disorder or disease. 19. The use of the emulsion composition according to any one of claims 1, 4, 9 or 10 in the manufacture of the composition as a means of imparting viscous properties. 20. The application of clause 16 or 17, in which the composition is a film-forming agent on the skin or mucous membrane. 21. The use according to claim 20, in which the film-forming agent acts as a barrier that protects the skin from water loss. 22. The use of the emulsion composition according to any one of claims 1, 4, 9 and 10 for the manufacture of a medicament for the treatment of a disease selected from the group consisting of sexually transmitted diseases, HIV, impetigo, herpes simplex, otitis media of the middle and outer ear, acne , periodontal disease, gingivitis, paronychia, onychomycosis, secondary infections associated with operations, dermatitis, burns. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2