RU2457830C2 - Compositions for local application - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to chemical-pharmaceutical industry, and deals with single-phase pharmaceutical compositions for local application, as well as sets and methods of application and introduction. Compositions include biologically active agent carrier for delivery, which contains, at least, non-polymer crystallisation inhibitor and film-forming agent; and volatile solvent; where in composition biologically active agent is present in partially saturated state, in carrier for delivery biologically active agent is present in oversaturated state, and crystallisation inhibitor is capable of slowing down crystallisation of biologically active agent in carrier for delivery. Terbinafine and acyclovir belong to biologically active agents.

EFFECT: claimed are methods of treating onychomicosis and infection with Varicella zoster, HSV-1 or HSV-2.

33 cl, 12 ex, 12 tbl

Description

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority advantage of provisional application US No. 60/813372, filed June 14, 2006, 60/820542, filed July 27, 2006 and 60/820546, filed July 27, 2006, the contents of which are incorporated herein by reference in full.

FIELD OF TECHNOLOGY

The present invention relates to single-phase topical compositions containing a biologically active carrier agent for delivery and a volatile component. The biologically active agent must be released from the composition after its application.

BACKGROUND

Local delivery of the pharmaceutical agent depends on the ability of the agent to be released from its formulation and then penetrate a barrier, such as skin, nails and / or hooves, to penetrate an area in need of such treatment. Non-invasive (non-penetrating) methods that require minimal patient skills are preferred.

Some methods, such as iontophoresis, are based on creating a gradient of electrical potential across the barrier to enhance the permeability of the pharmaceutical agent. These methods are mainly aimed at drugs having a total charge.

For most drugs, including uncharged or zwitterionic drugs, methods can be used that target the chemical potential of the drug in the carrier. By increasing the chemical potential of the drug in its carrier, it is possible to enhance the flow of the drug into the body. This is usually accomplished by chemical optimization of the drug composition by adjusting the degree of saturation of the drug in the carrier. The advantages of this approach are that the properties of the barrier itself are relatively less affected, and the time delay for the appearance of the pharmacological effect is reduced. Two aspects of this approach include: i) creating the initially high chemical potential of the drug in the composition and ii) maintaining the high chemical potential of the drug near the barrier after application of the composition. Generally, it is desirable to obtain pharmaceutical compositions that are saturated with respect to the drug. During application, another aspect of the composition is that the solubility and diffusion properties of the drug in the carrier used should prevent the depletion of the drug near the barrier. Examples of compositions used for this purpose are microemulsions and emulsions.

Another approach to maintaining a saturated composition is to use an excess amount of the drug (unsolubilized) in the carrier, as a result of which the drug gradually dissolves, replacing the drug that crosses the barrier.

Another approach is the use of a supersaturated drug composition. In this case, the driving force for the penetration of the drug through the barrier is higher than in the saturated composition, since the drug in the oversaturated composition has a higher chemical potential compared to the corresponding saturated composition. For example, such compositions were prepared according to the following means or principles: i) dissolving the drug at a temperature and / or pressure at which the solubility of the drug is higher compared to the temperatures and / or pressures that are relevant when applying the drug (WL Chou and S Riegelmann, J. Pharm. Sci., Vol. 60, No. 9, pp. 1281-1302, 1971; WO 97/10812), ii) mixing a saturated drug solution with a substance in which it does not dissolve, thus carrying out only a physical process at the moment or before application in the presence or absence of an antinuclear agent (US 4940701, US 4767751), iii) evaporation of the solvent in ambient air (Coldman et al., J. Pharm. Sci., 58, No. 9 (1969), pp. 1098- 1102), iv) the penetration of the solvent into the human body, v) the flow of water into the composition from the human body, or vi) the change in pH in the composition caused by the intake of H + from the human body.

US Pat. No. 6,083,518 describes a biologically active composition comprising a solution of an active agent dissolved in a glass-forming carrier, the carrier comprising a glass-forming substance containing a plasticizer.

US Pat. No. 6,537,576 relates to a new biologically active composition that contains a biologically active agent released from it, said biologically active agent is dissolved and / or dispersed in a supersaturated state in a carrier that contains a liquid and / or a solid non-crystalline ester, and / or a polyester matrix, and in which the precipitation of said biologically active agent is partially or completely inhibited.

From a cosmetic point of view, the amount of formulation (for example, ointment, cream, gel, lotion, cosmetic pencil, etc.) that can be used on the surface of the body is limited to an interval of about 1-10 mg / cm ² , while creating on the surface a thin film for evaporating the evaporating parts, preferably in a volume ratio. The formulation is therefore inevitably subjected to rapid changes in the composition. The limited amount of formulation that can be used further highlights the availability of the drug as an important penetration factor.

Some drug carriers are prone to phase separation based on their solvent and polymer content. To ensure uniform application and effective use of the active drug, single-phase compositions for topical application are desirable.

Currently, there is a need to create stable compositions for topical application, which will increase the bioavailability of pharmaceutical agents in areas where it is necessary.

ESSENCE

Topical compositions are provided containing a biologically active agent, a delivery vehicle and a volatile solvent, as well as kits and methods of use, preparation and treatment. In one aspect of the present invention, there is provided a single phase topical pharmaceutical composition comprising: a biologically active agent; a delivery vehicle containing a non-polymer crystallization inhibitor that is capable of slowing the crystallization of the biologically active agent in the delivery vehicle; and a film former; and volatile solvent; where the biologically active agent is present in the composition in a partially saturated state, and where, after evaporation of the volatile solvent, the biologically active agent is in the carrier for delivery in a supersaturated state. In one or more embodiments, the composition further comprises a plasticizer.

The term “composition” is understood to mean the product as a whole, and the composition is packaged as desired in a tube or the like. By the term “delivery vehicle” is meant a portion of a composition containing a biologically active agent that does not evaporate and which remains in the exposure area after evaporation of the volatile component. By the term “volatile solvent” is meant a portion of the composition that evaporates after application of the composition. That is, a “volatile solvent” refers to one or more solvents, including, if used, an auxiliary solvent that is removed from the carrier, such as a delivery vehicle, in less than 24 hours at a particular selected temperature, usually at room temperature, about 23 ° C. so that the solvent from the composition quickly disappears. Moreover, a “volatile solvent” is capable of dissolving a biologically active agent.

In one embodiment, the volatile solvent has a vapor pressure at 20 ° C. of 0.5 kPa or more; in a detailed embodiment, the vapor pressure is 2 kPa or more; in a more detailed embodiment, the vapor pressure is 5 kPa or more.

In General, the composition is obtained in such a way that in the composition as a whole, the biologically active agent is in a partially saturated state. That is, the entire amount of the biologically active agent present is dissolved in the composition. Upon evaporation of the volatile (s) component (s), the agent is subsequently in the carrier for delivery in a supersaturated state.

By the term “non-polymer crystallization inhibitor” is meant the inclusion of compounds that are considered antinuclear agents, that is, agents that delay or prevent precipitation of a compound (precipitation), such as a biologically active agent. A crystallization inhibitor is, for example, an agent that can prevent crystallization of the active compound for intended periods of time, for example, 2, 4, 8, 12, or even 24 hours or more upon supersaturation of the active compound due to evaporation of the solvent.

In one or more embodiments, the volatile solvent comprises acetic acid, acetone, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, ethanol, ethyl acetate, diethyl ether, formic acid ethyl ester, formic acid, heptane, isobutyl acetate, isopropyl acetate. methyl acetate, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-propanol, 2-propanol, propyl acetate, water, n-butyl ether, isopropanol or combinations thereof.

In one embodiment, the non-polymer crystallization inhibitor comprises hydroxycarboxylic acid. In a detailed embodiment, hydroxycarboxylic acid comprises citric acid, lactic acid, malic acid, or combinations thereof.

In one or more embodiments, the non-polymer crystallization inhibitor renders the composition stable for at least about 24 hours after application. In one embodiment, the composition may be considered stable if crystallization of the biologically active agent in the delivery vehicle is absent up to about 2 (or in other embodiments 4, 8, 12, or even 24) hours after application of the composition. In one or more embodiments, the composition can also be considered sustainable if the intake of the active ingredient after application is maintained over the shelf life of the composition to an acceptable degree. An acceptable degree is common to the active ingredient of interest and would be understood by a person skilled in the art. In one embodiment, the composition remains stable in a suitable storage container for 3 (or other embodiments 6, 9, 12, 18, or even 24) months. By a suitable storage container is meant a container that can fully retain the composition without significant loss of volatile solvent.

By reference to “film former” is meant a substance, such as a polymer, which forms a layer or film on a substrate after application of the composition to it, it is compatible with the delivery vehicle, and can hold the active ingredient at the site of application. The film former gives the composition, for example, the desired consistency and ensures the delivery of the active ingredient for a long time after application. In a detailed embodiment, the film former, also called thickener, comprises a hydrocolloid, a hydrocolloid derivative, or combinations thereof. In one embodiment, the film former comprises starch, pectin, agar, cellulose, a cellulose derivative, carrageenan, galactan, alginate, agarose, xanthan gum, or combinations thereof. In yet another embodiment, comprises cellulose or a cellulose derivative comprising hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), methyl cellulose (MS), carboxymethyl cellulose (CMC), or combinations thereof.

In a specific embodiment, the film former has a cloud point (Cp) in the composition from about 30 ° C to about 100 ° C; specifically from 40 to 70 ° C., more specifically from 45 to 55 ° C.

In one or more embodiments, the delivery carrier further comprises a plasticizer comprising propylene glycol, glycerin, diethylene glycol monoethyl ether, dipropylene glycol, 2-methyl-2,4-pentanediol (MPD), propyl acetate, anisole, or combinations thereof.

In one or more embodiments, the biologically active agent is an antibacterial agent, an antifungal agent, an antiviral agent, a cytostatic agent, a diuretic agent, an immunomodulator, a local anesthetic, an anti-inflammatory agent, an anti-psoriatic agent, a derivative thereof, a prodrug thereof, a salt thereof, or a combination thereof.

In a specific embodiment, the biologically active agent comprises terbinafine, naphthyne, amorolfine, butenafine, their derivatives, their prodrugs, their salts, or combinations thereof. Terbinafine is present in the composition in one or more embodiments in an amount of from about 0.1 to about 10% by weight, more specifically from 0.5 to 5%, and most particularly from 2 to 4%.

In an additional aspect, there is provided a composition effective in the treatment of onychomycosis, comprising terbinafine, acetone, citric acid, glycerin and a film former. In a detailed embodiment, the composition comprises terbinafine in an amount of 2-10% by weight, acetone in an amount of 10-50% by weight, citric acid in an amount of 1-10% by weight, glycerin in an amount of 1-10% by weight. and film former in an amount of 2-8% of the mass. A typical composition is a gel which, in one embodiment, forms a varnish coating after application. A typical film former is hydroxyethyl cellulose. In a detailed embodiment, the composition remains stable in a suitable storage container for about 12 months or longer. In yet another detailed embodiment, the composition remains stable in a suitable storage container for about 24 months or longer. A stable, oversaturated film formed from a composition of terbinafine, acetone, citric acid, glycerol and a film former is also provided.

In yet another detailed embodiment, the biologically active agent comprises acyclovir, a derivative thereof, a prodrug thereof, a salt thereof, or combinations thereof. Acyclovir is present in the composition in one or more embodiments in an amount of from about 0.01 to about 10% by weight, more specifically from 0.05 to 5%, and most specifically from 0.1 to 0.5%.

In one of the embodiments in the composition there is a non-polymer crystallization inhibitor in an amount of from about 5 to about 15% of the mass. In another embodiment, the composition contains a volatile component in an amount of from about 10 to about 95% of the mass. In a further embodiment, a film former is present in the composition in an amount of from about 0.5 to about 5% by weight. In another embodiment, the composition contains a plasticizer in an amount of from about 5 to about 15% of the mass.

Other embodiments may relate to a delivery vehicle further comprising a pharmaceutically acceptable excipient, penetration enhancer, keratolytic or exfoliating agent, chaotropic substance, flavoring, emollient, or combinations thereof.

In another aspect, a kit is provided. The kit contains a single phase pharmaceutical composition comprising: a biologically active agent; a delivery carrier comprising a non-polymer crystallization inhibitor that is capable of slowing the crystallization of a biologically active agent, and a film former; and volatile solvent; where the biologically active agent is present in the composition in a partially saturated state and where the biologically active agent in the delivery vehicle is in a supersaturated state; and an applicator for applying the composition to a site where a biologically active agent is required.

In yet another aspect, a pharmaceutically acceptable composition is provided in the form of a gel, lotion, cream, ointment, aerosol, or spray.

An additional aspect of the present invention relates to the use of compositions in which the biologically active agent is terbinafine or a derivative thereof, a prodrug or salt, for the manufacture of a medicament for the treatment or prevention of onychomycosis. Also provided is a method of treating onychomycosis, which comprises applying a supersaturated antifungal agent. In one embodiment, the method further comprises applying to a limited area in need of such treatment a single-phase composition comprising terbinafine, naphthyne, amorolfine, butenafine, their derivatives, their prodrugs, their salts, or a combination thereof in a therapeutically effective amount; a delivery carrier comprising a film former and a non-polymer crystallization inhibitor; and volatile solvent; where terbinafine or its derivative, prodrug or salt is present in the composition in a partially saturated state; evaporation of a volatile solvent; and after evaporation of the volatile solvent, the production of terbinafine, a derivative thereof, a prodrug or salt in a supersaturated state in a delivery vehicle.

An additional aspect relates to the use of compositions in which the biologically active agent is acyclovir or a derivative thereof, a prodrug or salt, for the manufacture of a medicament for the treatment or prevention of infection with Varicella zoster , HSV-1 or HSV-2. Also provided is a method of treating or preventing infection with Varicella zoster , HSV-1 or HSV-2, which comprises the use of a supersaturated antiviral agent. In one embodiment, the method further comprises applying to a limited area in need of such treatment a single-phase composition comprising acyclovir, a derivative thereof, a prodrug or salt in a therapeutically effective amount; a delivery carrier comprising a film former and a non-polymer crystallization inhibitor; and volatile solvent; where acyclovir or its derivative, prodrug or salt is present in the composition in a partially saturated state; evaporation of a volatile solvent; and after evaporation of the volatile solvent, the preparation of acyclovir, a derivative thereof, a prodrug or salt in a supersaturated state in a delivery vehicle.

In an additional aspect, a method for producing a single phase composition for topical application is provided. The method comprises providing a biologically active agent; the provision of a delivery vehicle containing a non-polymer crystallization inhibitor that is capable of slowing the crystallization of the biologically active agent in the delivery vehicle; the provision of a volatile solvent; and mixing the biologically active agent, the delivery carrier and a volatile solvent to form a composition in which the biologically active agent is present in the composition in a partially saturated state and the biologically active agent is present in the carrier for the delivery in a supersaturated state.

DETAILED DESCRIPTION

Topical compositions containing the biologically active agents of the embodiments of the present invention have unexpected stability and / or a high degree of delivery. Without wishing to be limited by theory, aspects of the described invention work on the principle that evaporation of a volatile component from a composition leads to increased thermodynamic activity of a biologically active agent in a delivery vehicle.

According to an embodiment of the present invention, the biologically active agent is present in the composition in a partially saturated state, thereby providing the product with physical stability during its shelf life by preventing precipitation of the active agent in the composition. Upon evaporation of the volatile component, the thermodynamic activity of the biologically active agent in the delivery vehicle will increase, namely, to a level corresponding to a supersaturated state. Thus, drug delivery through a barrier, such as skin, nails and / or hooves, is increased compared to partially saturated and saturated systems.

A greater degree of saturation of the substance in the mixture will lead to a greater tendency of the substance to leave the mixture (i.e., the release of the substance from the mixture will be higher if the substance is in a supersaturated state compared to partially saturated). A supersaturated state is, however, by definition physically unstable and, ultimately, precipitation will occur (i.e., the phase separation of the substance present in the supersaturated state as a separated liquid or solid phase). A greater degree of supersaturation of the substance in the mixture will be more likely to precipitate the substance.

In vitro release test (IVRT) using a large number of media can be used to evaluate the delivery of a composition across a large number of surface layers. Suitable surface layers include natural and synthetic surface layers. Natural surface layers include, but are not limited to, bull's hooves, pig’s ears, pig’s hooves, horse’s hooves and the like. Synthetic surface layers include, but are not limited to, silastic, taffrin, teflon, nylon, fluoride and other film coatings. Examples of media, also called receptor solutions, include, but are not limited to, phosphate buffered saline and citrate buffered saline.

The use of a crystallization inhibitor in the compositions allows a higher degree of supersaturation of the active agent, which, in turn, creates a higher local concentration of the agent in the tissues of interest.

Compositions for topical application in one or more embodiments of the invention are used in areas in need of treatment, allowing easy or unhindered evaporation of the volatile component of the composition into the surrounding air. The term "local" refers to "dermal, transdermal, nail and trans nail".

A film former, present in one or more embodiments of the present invention, helps to keep the composition for topical application, and therefore the biologically active agent, in the area in need of treatment. In this regard, it was found that the solubility of the film former in the composition affects the amount of active agent released after evaporation of the volatile solvent. It has been found that the optimum amount of the released active agent is achieved with a thickening polymer, possibly slightly soluble in the composition, while at the same time creating a homogeneous / single-phase product. Methods for modifying the solubility of the polymer in the composition are specified below.

The behavior of the polymer in solution (which in this document may be represented by biologically active compositions according to aspects of the invention) is highly dependent on the properties of the solvent. In a good solvent, the polymer expands freely and occupies a large volume. In a weak solvent, the polymer will shrink, taking up a small volume. In the intermediate type of solvent, the solubility of the polymer is moderate, i.e. neither good nor weak.

Depending on the type of polymer and its functional groups, phase separation from a solution can be induced either by a decrease or an increase in temperature. Based on this view, it is possible to determine the critical temperature T _c ; above this temperature, the polymer is soluble in a solvent. For a given polymer, T _c , however, also depends on the degree of polymerization, and therefore there is a large temperature range in which the monomer must be infinitely soluble, while the corresponding polymer is only partially soluble.

Turbidity is another unexpected thermotropic phenomenon that can limit the solubility of some polymers. As a rule, solubility increases with increasing temperature. Turbidity is a phase separation, and it occurs when the temperature rises above the critical temperature for the cloud point (denoted C _p in this document). The mechanism of this phase separation, described below, can be explained by the fact that, as a whole, with increasing temperature, water becomes a weaker solvent for polar groups.

Thus, the cloud point (C _p ) is a suitable and convenient parameter for determining whether a viscosity-increasing polymer is a system in which the polymer is sparingly soluble in the composition, while at the same time creating a homogeneous product.

Phase separation in terms of either critical temperature (T _c ) or cloud point (C _p ), depending on the type of polymer used, is determined only in a particular composition. That is, the separation of phases, due to a possible dependence on concentration, outside a specific composition is not taken into account. Phase separation exists if T <T _s or if T> C _p . For any given polymer, either T _c or C _{p is} measured.

Phase separation can be determined by storing the samples in sealed glass tubes overnight at certain temperatures (for example, at 5 ° C intervals), followed by viewing every other day. The conclusion that phase separation has occurred is made if the previously transparent composition becomes cloudy or opaque during the night, a preliminary stage for macroscopic phase separation. By reference to “phase separation” is meant the precipitation of any ingredient in a composition, such as an active ingredient, a crystallization inhibitor, a film former, or combinations thereof.

Thus, according to some embodiments of the present invention, it was determined as an unexpected finding that the limited solubility of the polymer in the composition facilitates the release of the biologically active ingredient from the carrier for delivery after evaporation of the volatile component, compared with a composition in which the polymer is freely soluble in a pharmaceutically acceptable temperature range .

This embodiment of the present invention thus describes how to limit the solubility in the composition of the polymer, increasing the viscosity, while creating a product that is macroscopically homogeneous in a temperature range acceptable in terms of shelf life [see, for example, Note for Guidance on Declaration of Storage Conditions EMEA / CPMP / QWP / 609/96 / rev1], thereby facilitating the release of the biologically active agent from the delivery vehicle after application.

Various methods for modifying the solubility of the polymer in environments may include, but are not limited to, changing the polymer chain length, switching to the use of a related polymer, changing the type of buffer and buffer concentration, adding electrolytes, using non-solvent substances that are chaotropic (that destroy the structure of water; Wood JM, Osmosensing by Bacteria: Signals and Membrane-Based Sensors , Microbiol. Mol. Biol. Rev., March 1999, p. 230-262, Vol. 63, No. 1) substances cosmotropic (creating the structure of water; Wood JM , supra ) substances, change in pH, etc.

The crystallization inhibitors used in the delivery vehicle for topical compositions of the invention are selected so as to slow down the crystallization of the oversaturated biologically active agent in the delivery vehicle. Such a delay may continue for at least a therapeutically acceptable time interval, such as 0-24 hours and more particularly 0-12 hours after topical application of the biologically active composition. Crystallization inhibitors are non-polymer, but can be either monomeric or oligomeric. As used herein, the term "polymer" means molecules containing more than 10 monomer units, while the term "oligomeric" refers to molecules containing from 2 to 10 monomer units.

A standard procedure for in vitro stability analysis in the presence of crystallization inhibitors involves placing a polymer film (e.g. polyethylene) on the bottom of the Petri dish, applying a test gel or composition containing a candidate crystallization inhibitor uniformly onto the film on the bottom of the Petri dish (~ 160 mg / cm ² ), placing a Petri dish containing the test gel in a chamber at 32 ° C or a thermostat overnight (~ 18 ± 1 hour); and evaluating the test gel under a microscope to visually determine the presence of crystals. Use an increase of 10 to 100 times. In the absence of crystals, the candidate crystallization inhibitor is then considered a crystallization inhibitor.

Such a crystallization inhibitor may contain an organic acid, for example, hydroxycarboxylic acid, specifically α-hydroxy acid (for example, citric acid, malic acid or lactic acid), alone or in combination with a suitable plasticizer (herein defined as a substance that substantially reduces the glass transition temperature of a material to which it is added, thus making it softer and more flexible), for example, low molecular weight di- or trihydric alcohol (for example, dipropylene glycol or litserinom). Alternatively, such a crystallization inhibitor may be an oligomeric ester of the previously mentioned substances and mixtures thereof, where the previously mentioned substances may also be present in monomeric form in amounts of <20% of the mass. A further embodiment relates to a polyol, for example maltitol, as a crystallization inhibitor.

Another crystallization inhibitor may be selected from the group of mono- or oligosaccharides or mixtures thereof.

A suitable crystallization inhibitor may contain, as a glass-forming substance, citric acid or its esters and / or oligoesters in an amount of from 10 to 95 percent by weight and a plasticizer containing propylene glycol or glycerin in an amount of from 5 to 90 percent by weight, where weight percent is based on the total mass of the glass-forming substance and plasticizer. In yet another embodiment, a suitable crystallization inhibitor may comprise esters and / or polyesters of citric acid and plasticizers obtained by the chemical reaction (s) described elsewhere (WO 99/58109, US 6537576). It is worth mentioning that the regulation of the molecular mass and its distribution in the molecules that make up the crystallization inhibitor thus formed allows controlling the solubility of the biologically active agent in the matrix. In one embodiment, the crystallization inhibitor is an oligomer of citric acid and propylene glycol, where the oligomer esters have an amount of monomers from 2 to 8 and the degree of conversion to ester is from about 30 to 100%. As a method of controlling the end point of the reaction (s), monofunctional monomers can be introduced into the chemical reaction (s). As a non-limiting example, the crystallization inhibitor may contain a minor amount of the starting material (s) (c), and yet the present invention encompasses it. The starting material is, for example, a monomer, for example citric acid or propylene glycol. Typically, this method, which is an ester or polyester reaction (s), is carried out in the absence of a biologically active agent.

The film-forming agents, also called thickeners or viscosity-enhancing polymers used in delivery vehicles, give the composition, for example, the desired consistency and allow the active substance to be delivered over a long period of time. They are usually pharmaceutically acceptable hydrocolloids (e.g. polysaccharides).

An example of a suitable film former is a natural hydrocolloid such as starch, cellulose, pectin, agar, carrageenans, galactan, alginates or agarose. Another example of a suitable viscosity increasing polymer is a chemically modified hydrocolloid, such as an anionic or nonionic cellulose derivative. A suitable anionic cellulose derivative is carboxymethyl cellulose (SMS). Suitable non-ionic cellulose derivatives include hydroxyalkyl cellulose derivatives, such as those described in WO 00/24966, which discloses hydrophobically modified water-soluble or water-swellable polymers. Specific examples of such derivatives are i) methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose and ethyl hydroxyethyl cellulose; ii) hydrophobically modified methyl cellulose and hydrophobically modified hydroxypropyl cellulose.

The volatile solvent is selected according to principles well known to those skilled in the art, so as to achieve a pharmaceutically acceptable evaporation rate and create conditions that keep the crystallization inhibitor functionally stable over the shelf life of the composition. Similarly, according to principles well known to those skilled in the art, the stability of the biologically active agent in the composition should be high enough to provide a high degree of saturation of the active substance in the carrier for delivery after application.

Accordingly, suitable solvents contain acetic acid, acetone, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, ethanol, ethyl acetate, diethyl ether, ethyl formic acid, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, methyl acetate methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-propanol, 2-propanol, propyl acetate, water, n-butyl ether, isopropanol or combinations thereof.

The solvent can be used alone or as mixtures. To modify the solubility properties of the solvent mixture, other types of solvents may be included in minor amounts.

A biologically active agent according to embodiments of the present invention may be any pharmaceutically active agent intended for topical administration to a mammal, human or animal. The choice of active agent is generally not limited. Examples of biologically active agents are agents intended for dermal, nail, sublingual, gingival, buccal, transdermal, transnail, nasal, vaginal and rectal administration, so the resulting biological effect can be local and / or systemic. Examples of pharmaceutically active agents suitable for delivery with the biologically active composition of the invention are, but are not limited to, antibacterial agents (e.g. metronidazole, clindamycin), antifungal agents (e.g. clotrimazole, econazole, terbinafine, fluconazole, amorolfine, itraconazole, ket) antiviral agents (e.g. acyclovir, penciclovir, cidofovir, brivudin), cytostatics (e.g. methotrexate, 5-fluorouracil), diuretics (e.g. spironolactone), immunomodulators (e.g. cyclospor n, mycophenolic acid, mycophenolate mofetil, tacrolimus, pimecrolimus), local anesthetics (e.g. lidocaine, bupivacaine), anti-inflammatory agents (e.g. piroxicam, diclofenac, tacrolimus, pimecrolimus), antiporotic agents (e.g., tazarotene) prodrugs or salts. Most suitable are immunomodulators and anti-inflammatory agents.

Thus, embodiments of the invention also relate to biologically active single-phase topical compositions described herein used as medicaments.

In one of the embodiments of the invention, the biologically active agent is terbinafine or its derivative, prodrug or salt, specifically in a concentration of from 0.1 to 10%, more specifically from 0.5 to 5% and most accurately from 1 to 3% of the mass. by weight of the entire composition. Thus, the invention also relates to the use of a biologically active single-phase composition for topical application, as defined herein, in which the biologically active agent is terbinafine or its derivative, prodrug or salt, for the manufacture of a medicament for the treatment or prevention of onychomycosis. In this embodiment, it is preferable to include exfoliating and / or keratolytic agents in the composition, as further discussed below. Alternatively, the invention also relates to a method for the treatment or prophylaxis of onychomycosis, which comprises administering to a patient in need of such treatment a topical biologically active single-phase composition as defined herein, wherein the biologically active agent is terbinafine or a derivative, prodrug or salt thereof, in a therapeutically effective amount.

In yet another embodiment, the biologically active agent is acyclovir or a derivative thereof, a prodrug or salt, specifically in a concentration of from 0.01 to 10%, more specifically from 0.05 to 5%, and most accurately from 0.1 to 0.5 % of the mass. by weight of the entire composition. Thus, embodiments of the invention also relate to the use of a biologically active single-phase composition for topical application, as defined herein, wherein the biologically active agent is acyclovir or a derivative thereof, a prodrug or salt, for the manufacture of a medicament for the treatment or prevention of Varicella zoster infection, HSV-1 or HSV-2. Alternatively, the invention also relates to a method for treating or preventing infection of Varicella zoster , HSV-1 or HSV-2, which comprises administering to a patient in need of such treatment a biologically active single-phase topical composition as defined herein, wherein the biologically active agent is acyclovir or a derivative thereof, a prodrug or salt, in a therapeutically effective amount.

In one embodiment, the composition further comprises a penetration enhancer. The goal is to reversibly change the properties of biological barriers, such as skin or mucous membranes, to facilitate drug delivery. The penetration enhancer can be selected from the simplest in composition alkyl esters, phospholipids, terpenes, nonionic surfactants, azacycloheptanones (e.g., azone and its derivatives), oleyl-containing surfactants, etc. Examples of suitable penetration enhancers are provided in “Pharmaceutical skin penetration enhancement”, Walters K.A. and Hadgraft J., eds., Marcel Dekker NY, 1993 and “Percutaneous penetration enhancers”, 2 ed., Smith E.W. and Maibach H.I., eds., CRC Press, 2005.

An additional enhancement of penetration through the nail, apart from the influence of the increased thermodynamic activity of the biologically active substance, can be obtained by the inclusion of keratolytic agents in the composition, the so-called exfoliators, examples of which are urea, acetylcysteine and thioacids.

The inclusion of a chaotropic substance can further improve penetration by altering hydrophobic interactions (destroying regular hydrogen bond structures in water and breaking hydrophobic complexes bound by hydrogen bond). An example of a chaotropic substance may be urea, allantoin or guanidine.

To make the composition pharmaceutically acceptable, additional adjuvants can be added to it, such as alternative pH buffers, preservatives (e.g. sodium benzoate), etc.

Aspects of the present invention additionally relate to a pharmaceutically acceptable composition in the form of a gel, lotion, cream or ointment containing a biologically active single-phase topical composition as defined herein.

For some biologically active agents, it is preferable to obtain a composition shortly before its administration. In fact, for such preparations, compositions excluding biologically active agents suitable for compositions intended for long-term storage and application can be used.

Examples

The present invention will be further illustrated by the following non-limiting examples. In the examples, the term “room temperature” refers to a temperature in the range of 15-30 ° C., typically in the range of 18-28 ° C.

Example 1

The gel composition containing 3% terbinafine shown in table 1a was prepared in a beaker at room temperature in accordance with the following steps: i) citric acid and sodium hydroxide were dissolved in water, ii) glycerin, acetone, and terbinafine were added; iii) with vigorous stirring, hydroxyethyl cellulose was added and iv) after obtaining a homogeneous gel, the composition was left to balance for 24 hours, thus allowing, for example, hydroxyethyl cellulose to swell and some amount of bubble Air kov dissipate.

Table 1a % (mass.) Terbinafine HCl 3.0 Acetone 30,0 Lemon acid 5,0 Hydroxyethyl cellulose 4.0 Glycerol 2.5 Sodium hydroxide 0.9 Water up to 100

In vitro, the penetration of the three compositions with terbinafine was carried out through the membranes between the hooves of the bull, using Franz diffusion cells and a degassed buffer receptor solution. For each membrane participating in the study, the test composition was applied with a brush. In vitro, the penetration of terbinafine through the hooves of a bull from this 3% terbinafine gel was compared with the penetration from lamisyl dermgel 1% (Novartis, Lot F00049A) and lamisil cream 1% (Novartis, Lot WC114). The average values of the total amount that penetrated after 6 hours, and the standard deviations of the samples in three repetitions are shown in table 1b. The amount of penetrated terbinafine (μg / cm ² ) was calculated by multiplying the concentration of terbinafine in the receptor solution by the cell volume and dividing by the membrane area. Admission was calculated by dividing the amount of penetrated terbinafine by the time of the experiment.

Since the viscosity of the delivery vehicle was too high to determine solubility and degrees of saturation, penetration data from table 1b was used to obtain degrees of saturation. It is well known that the initial penetration of a drug through an inert membrane depends only on the degree of saturation of the drug, but not on its concentration. Thus, to determine the relative degrees of saturation, penetration data obtained using standard saturated drug solutions (e.g., lamisil dermgel 1% and lamisil cream 1% from table 1b) were compared with data obtained using typical compositions of the present invention ( for example, terbinafine gel 3% from table 1b). Since the total amount obtained with terbinafine gel 3% was greater than that obtained with lamisil dermgel 1% and lamisil cream 1%, terbinafine gel 3% was more saturated, for example, oversaturated, in comparison with the examples in which saturated lamisil was used.

Table 1b The total amount (n = 3) μg / cm ² Intake (n = 3) mcg / cm ² h Terbinafine Gel 3% 8.14 ± 1.20 1.36 ± 0.20 Lamisil Dermgel 1% 0.08 ± 0.06 0.01 ± 0.01 Lamisil cream 1% 0.11 ± 0.06 0.02 ± 0.01

Example 2

Clinical study

In an open study, the results of the use of terbinafine gel 3% in the treatment of onychomycosis of the toenail were obtained. In this study, patients with onychomycosis were treated with terbinafine gel 3% or carrier only for 42 days. On day 42, the results of the study showed that 39.3% of the individuals treated, the results of microscopic examination of which were initially KOH-positive, became negative on day 42. 42.8% of treated individuals who initially had PAS positivity were negative at the end of the study. 95.2% of patients whose initial results of a culture study for dermatophytes were positive, were negative at the end of the study. The average concentration of terbinafine in the nail bed (n = 4-5 at time) was 2898 ng / mg on day 14; 2640 ng / mg on day 28 and 795 ng / mg on day 42. After local application of nail polish with 3% terbinafine, terbinafine penetrates into the nail plate in sufficient quantity to be effective in the treatment of onychomycosis.

Example 3

Gels with an acyclovir concentration of 0.1% of compositions A and B, respectively, shown in table 3a, were obtained in a beaker at room temperature in accordance with the following steps: i) acyclovir, a crystallization inhibitor (oligomeric citric acid esters), were dissolved in water sodium benzoate, ii) the pH was adjusted to sodium hydroxide, iii) the mixture was heated to 45 ° C, iv) hydroxypropyl cellulose was added, v) the composition was cooled to room temperature with stirring, vi) after 2 hours, the stirring was stopped.

Table 3a A% (mass.) In% (mass.) Acyclovir 0.1 0.1 Water 92.7 82.6 Crystallization Inhibitor (Oligomeric Citric Acid Esters) 4.9 15.0 Hydroxypropyl cellulose 2.2 2.2 Sodium benzoate 0.1 0.1 Sodium hydroxide Up to pH 4 Up to pH 4

In vitro, the penetration of acyclovir through the skin of a pig excised over the entire thickness of the pig’s ear from 0.1% acyclovir gels A and B was compared with penetration from 5% zovirax cream (Glaxo Wellcome, Lot 0021208). Table 3b presents the average values of 6-8 samples after 6.5 and 12.5 hours, respectively.

The penetration data presented in Table 3b was used to infer the degree of saturation. To determine the relative degrees of saturation, data obtained using a standard saturated drug solution (e.g., Zovirax Cream 5% shown in Table 3b) were compared with data obtained using typical compositions of the present invention (e.g., Acyclovir Gels 0.1% ( A) and (B) are presented in table 3b). Since the total amounts obtained with acyclovir gels of 0.1% (A) and (B) turned out to be larger than those obtained with zovirax cream 5%, acyclovir gels of 0.1% (A) and (B) were more saturated, for example, supersaturated, compared with an example in which saturated zovirax was used.

Table 3b The total amount (n = 6-8) ng / cm ² after 6.5 hours The total amount (n = 6-8) ng / cm ² after 12.5 hours Acyclovir Gel 0.1% (A) 815 899 Acyclovir gel 0.1% (B) 682 822 Zovirax Cream 5% 5 35

Example 4

A number of compositions were obtained containing one of the three thickeners, a biologically active agent (acyclovir), a mixture of solvents and a crystallization inhibitor, and they were left to balance overnight at 32 ° C. The compositions are listed in table 4a.

Table 4a A% (mass.) In% (mass.) C% (mass.) D% (mass.) E% (mass.) Acyclovir 0.20 0.25 0.20 0.25 0.25 Ethanol 20.1 20,0 20,0 20,0 20,0 Crystallization Inhibitor (Oligomeric Citric Acid Esters) 8.1 12.0 8.1 12.0 12.0 Propylene glycol 7.4 7.5 7.5 7.5 7.5 LDC film former 2.2 2.2 HEC film former 2.2 2.2 Film former MS 2.2 Lemon acid 1.9 2.9 1.9 2.9 2.9 NaOH 0.5 0.8 0.5 0.8 0.8 Sodium benzoate 0.1 0.1 0.1 0.1 0.1 RO (reverse osmosis) water up to 100.0 up to 100.0 up to 100.0 up to 100.0 up to 100.0

LDC = hydroxypropyl cellulose (Klucel® MF Pharm)

HEC = hydroxyethyl cellulose (Natrosol® 250M Pharm)

MS = methyl cellulose (Methocel ^TM E10M CR Premium)

In vitro penetration of compositions containing acyclovir was carried out through the skin membranes of the inner ear of a pig using diffusion cells Bronaugh and receptor solution of degassed phosphate-saline buffer (PBS). The compositions were tested for the degree of release in Bronaugh cells. The cloud point was also determined, and these results are presented in table 4b.

Table 4b BUT AT FROM D E Cloud Point (° C) 35 <T <40 40 <T <45 > 100 > 100 > 100 Total amount (mcg / cm ² ; 3 h) 108 112 13 12 fourteen Total amount (μg / cm ² ; 6 h) 135 131 19 23 33

Compositions A and B, both having cloud points below 45 ° C, provided the highest degree of active agent intake. Therefore, when C _p decreases, the supply improves, but if C _p turned out to be too low, phase separation could be expected.

Example 5

A number of compositions were obtained containing hydroxypropyl cellulose (LDCs, Klucel® MF Pharm) as a thickener, a biologically active agent (acyclovir), a mixture of solvents with different concentrations of ethanol and a crystallization inhibitor. The compositions are listed in table 5a.

Table 5a A% (mass.) In% (mass.) C% (mass.) D% (mass.) Acyclovir 0.20 0.25 0.20 0.25 Ethanol 20.1 20,0 30,0 30.1 Crystallization Inhibitor (Oligomeric Citric Acid Esters) 8.1 12.0 8.0 12.0 Propylene glycol 7.4 7.5 7.5 7.5 LDC film former 2.2 2.2 2.2 2.2 Lemon acid 1.9 2.9 1.9 2.9 NaOH 0.5 0.8 0.5 0.8 Sodium benzoate 0.1 0.1 0.1 0.1 RO water up to 100.0 up to 100.0 up to 100.0 up to 100.0

In vitro penetration of compositions containing acyclovir was carried out through the skin membranes of the inner ear of a pig using diffusion cells Bronaugh and receptor solution of degassed phosphate-saline buffer (PBS). The compositions were tested for the degree of release in Bronaugh cells. The penetration of the drug through the skin of the pig’s ear was determined with respect to the initial ethanol content in the solvent mixture. The cloud point was also determined, and the results are presented in table 5b. The cloud point of the LDC film former turned out to be a function of ethanol concentration.

Table 5b BUT AT FROM D Cloud Point (° C) 35 <T <40 40 <T <45 T> 100 T> 100 Total amount (mcg / cm ² ; 3 h) 108 112 66 73 Total amount (μg / cm ² ; 6 h) 135 131 103 86

Compositions A and B, having cloud points in the range of 35-45 ° C, provided the highest degree of receipt of the active agent.

Example 6

Two compositions were obtained containing xanthan gum (X, Xantural 180) as a thickener, a biologically active agent (acyclovir), a mixture of solvents with different concentrations of ethanol and a crystallization inhibitor. The compositions are listed in table 6a.

Table 6a A% (mass.) In% (mass.) Acyclovir 0.25 0.25 Ethanol 20,0 10.0 Crystallization Inhibitor (Oligomeric Citric Acid Esters) 12.0 12.0 Propylene glycol 7.5 7.5 Film former X 1,0 1,0 Lemon acid 2.9 2.9 NaOH 0.8 0.8 Sodium benzoate 0.1 0.1 RO water up to 100.0 up to 100.0

In vitro penetration of compositions containing acyclovir was carried out through the skin membranes of the inner ear of a pig using diffusion cells Bronaugh and receptor solution of degassed phosphate-saline buffer (PBS). The compositions were tested for the degree of release in Bronaugh cells. The penetration of the drug through the skin of the pig’s ear was determined with respect to the initial ethanol content in the solvent mixture, and the results are presented in table 6b.

Table 6b BUT AT Total amount (mcg / cm ² ; 3 h) 189 109 Total amount (μg / cm ² ; 6 h) 270 150

Composition A contained a higher amount of ethanol compared to composition B and provided a greater degree of active agent intake. Composition A, however, was also prone to phase separation. Therefore, for the receipt of the composition, equilibrium is necessary due to the tendency of the composition to phase separation.

Example 7

Six live domestic pigs were applied topically with four gels containing acyclovir (Table 7a) (6, 2, and 0.5 hours before the killing of the pigs). All compositions were applied randomly on the back of each pig in all three times of application. After killing, each area of the skin was washed separately, stripped with a band-aid, cut off, frozen and cut in layers (10 sections 50 μm thick). All fractions were analyzed scintigraphically.

Table 7a A% (mass.) In% (mass.) C% (mass.) D% (mass.) Acyclovir 0.20 0.25 0.25 0.25 Ethanol 25.0 22.5 25.0 35.7 Esters of citric acid 8.0 12.0 12.0 - Propylene glycol 7.5 7.5 7.5 5.7 Lemon acid 1.9 2.9 2.9 5.1 NaOH 0.47 0.75 0.75 1.3 Sodium benzoate 0.10 0.10 0.10 0.05 Glycerol - - - 5.2 Klucel® (HPC) 2.2 2.2 2.2 2.2 Water up to 100 up to 100 up to 100 up to 100

A successful criterion was the minimum concentration of acyclovir in the dermis of at least 0.3 μg / cm ³ for from 0.5 to 6 hours. This criterion was established on the basis of IC ₅₀ values obtained in vitro according to the literature [O'Brien et al. “Acyclovir. An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy. ” Drugs 37 (1989) 233-309; Wagstaff et al. “Aciclovir; A reappraisal of its antiviral activity, pharmacokinetics properties and therapeutic efficacy. ” Drugs 47 (1994) 153-205]. For comparison, intravenous administration of 7.5-10 mg three times a day created serum concentrations of 5-10 μg / cm ³ , while oral administration of 800 mg five times a day created a serum acyclovir concentration of only 1-1.5 μg / cm ³ [Herne et al. “Antiviral therapy of acute herpes zoster in older patients. Drugs and Aging Feb. 8: 2 (1996) 97-112].

All compositions created concentrations in the skin of the back of pigs (0-500 μm) significantly higher than those reported for serum in the treatment of high doses with the oral route of administration (table 7b). Having examined the material balance, it also became clear that the application dose can be reduced from 10 to 2-5 mg / cm ² .

Table 7b The total amount of μg / cm ³ 0.5 h 2 h 6 h Acyclovir Gel 0.20% (A) 1.7 2.5 3.2 Acyclovir Gel 0.25% (B) 2,4 2.5 4.6 Acyclovir gel 0.25% (C) 2.2 2,8 4,5 Acyclovir Gel 0.25% (D) 3,1 3.9 5.3

Example 8

The following tables illustrate the variety of embodiments of the present invention, as well as additives that can be included to optimize the phase separation temperature (i.e. cloud point (C _p ) or critical temperature (T _c ) depending on the type of polymer) with respect to release medicinal product.

Table 8a A% (mass.) In% (mass.) C% (mass.) D% (mass.) E% (mass.) F% (mass.) G% (mass.) H% (mass.) Ethanol - - - - 40,0 40,0 40,0 40,0 Acetone - 30,0 - 30,0 - 30,0 - - Propylene glycol - - 20,0 20,0 - - 20,0 20,0 Glycerol - 5,0 5,0 - 5,0 - - 5,0 Lemon acid 5,0 5,0 5,0 5,0 5,0 5,0 5,0 5,0 LDC film former 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 Sodium hydroxide 1,6 1,1 0.9 0.8 0.9 0.2 0.8 0.6 RO water up to 100 up to 100 up to 100 up to 100 up to 100 up to 100 up to 100 up to 100

Table 8b A B C D E F G H Cloud Point (° C) 20 <T <25 25 <T <30 20 <T <25 T> 100 T> 100 T> 100 T> 100 T> 100

The cloud point can be adjusted in the temperature range of 20-100 ° C by changing compositions containing a plasticizer as a solvent.

Example 9

Examples for comparison

An increase in the amount of crystallization inhibitor in the composition can lead to precipitation of both the plasticizer and the active ingredient. Table 9a shows samples A and B, which were examined 15 hours after application of the drug at 32 ° C. Crystals of both citric acid and acyclovir were observed in sample A. No crystals were observed in sample B with a similar amount of acyclovir.

Table 9a A% (mass.) In% (mass.) Acyclovir 0.24 0.25 Lemon acid 5.99 4.00 NaOH 1.28 0.89 Propylene glycol 7.52 7.48 Glycerol 2,51 5.01 Ethanol 35.01 35.06 Sodium benzoate 0.05 0.05 LDC film former
(Klucel®) 2.22 2.22 RO water up to 100 up to 100

In the presence of a crystallization inhibitor, the amount of active ingredient affects the formation of crystals after evaporation of a volatile solvent. In tables 9b, 9c and 9d, the samples were examined after 1 hour, 4 hours and 26 hours, respectively, at 32 ° C.

In samples A and B shown in Table 9b, no crystals were observed in the film after evaporation. Sample C shows crystals after more than 7 hours. Crystals were observed in sample D after 1 hour.

Table 9b A% (mass.) B% (mass.) C% (mass.) D% (mass.) Acyclovir 0.13 0.19 0.25 0.32 Citric acid ester 8.00 8.00 8.00 8.00 Lemon acid 1.92 1.92 1.92 1.92 NaOH 0.47 0.47 0.47 0.47 LDC Film former (Klucel®) 2.20 2.20 2.20 2.20 Propylene glycol 7.50 7.50 7.50 7.50 Ethanol 25.00 25.00 25.00 25.00 Sodium benzoate 0.10 0.10 0.10 0.10 RO water up to 100 up to 100 up to 100 up to 100

In sample A shown in table 9c, no crystals were observed in the film after evaporation of the crystals. In sample B, crystals were observed after more than 7 hours. In sample C, crystals were observed after 1 hour.

Table 9c A% (mass.) B% (mass.) C% (mass.) Acyclovir 0.18 0.27 0.36 Citric acid ester 12.00 12.00 12.00 Lemon acid 2.88 2.88 2.88 NaOH 0.75 0.75 0.75 LDC Film former (Klucel®) 2.20 2.20 2.20 Propylene glycol 7.50 7.50 7.50 Ethanol 22.50 22.50 22.50 Sodium benzoate 0.10 0.10 0.10 RO water up to 100 up to 100 up to 100

In samples A and B shown in Table 9d, no crystals were observed in the film after evaporation. Crystals were observed in sample C after 1 hour.

Table 9d A% (mass.) B% (mass.) C% (mass.) Acyclovir 0.18 0.27 0.36 Citric acid ester 12.00 12.00 12.00 Lemon acid 2.88 2.88 2.88 NaOH 0.75 0.75 0.75 LDC Film former (Klucel®) 2.20 2.20 2.20 Propylene glycol 7.50 7.50 7.50 Ethanol 25.00 25.00 25.00 Sodium benzoate 0.10 0.10 0.10 RO water up to 100 up to 100 up to 100

Example 10

Example for comparison

Based on the assumption that more concentrated gels would precipitate and create systems saturated with respect to acyclovir, acyclovir gels with various drug concentrations were prepared. Intake from a saturated system could then be compared with independent entry from gels with lower concentrations of acyclovir. When using 0.1% gels, approximately 1.6 times greater intake was observed than when using 0.5 and 0.7% gels, which indicates that 0.06% (mass.) Of acyclovir in this particular carrier after evaporation gives a saturated formulation.

Table 10a A% (mass.) B% (mass.) C% (mass.) Acyclovir 0.1 0.5 0.7 Citric acid ester 8.00 8.00 8.00 Lemon acid 1.9 1.9 1.9 NaOH 0.5 0.5 0.5 LDC Film former (Klucel®) 2.2 2.2 2.2 Ethanol 20,0 20,0 20,0 Sodium benzoate 0.1 0.1 0.1 RO water up to 100 up to 100 up to 100

Example 11

The following tables illustrate a variety of embodiments of the present invention. Hydrocolloids related to embodiments of the present invention are represented by specific polymers from each group: natural hydrocolloid (xanthan gum); non-ionic cellulose derivatives (hydroxypropyl cellulose, LDCs; hydroxyethyl cellulose, HEC; ethyl cellulose, EU); and an anionic cellulose derivative (carboxymethyl cellulose, SMS). Each of these specific polymers can also occur in a large number of modifications with slightly different properties. As one skilled in the art understands, the solubility properties of the biologically active agent determine which type of composition to use.

Table 11a BUT AT FROM D Crystallization Inhibitor 5-12% (mass.) Lactic acid Lactic acid Diethyl citrate * Lemon acid Plasticizer I 5-7.5% (mass.) Propylene glycol Glycerol - Glycerol Plasticizer II 5-7.5% (mass.) - Propylene glycol - Propylene glycol Solvent 10-35% (mass.) Acetone Ethanol Acetone Ethanol Solvent up to 100% (mass.) Water Water 0.1 M citrate buffer Water Film former
1-5% (mass.) Nes LDCs Nes LDCs NaOH or HCl Up to pH4 Up to pH4 Up to pH4 Up to pH4 * Diethyl citrate (Citrofol® Dec; citric acid / diethyl citrate / triethyl citrate / ethanol 5/25/45/25 mixture)

Table 11b E F G H I Crystallization Inhibitor 5-12% (mass.) Apple acid Apple acid Apple acid Apple acid Apple acid Plasticizer I 5-7.5% (mass.) Glycerol Glycerol Propyl acetate Anisole Transcutol Plasticizer II 5-7.5% (mass.) Propylene glycol - - - - Solvent 10-35% (mass.) Ethanol Methyl acetate 2-propanol Methyl-
ethyl ketone Ethyl formate Solvent up to 100% (mass.) Water Water Water Acetone Water Film former 1-5% (mass.) LDCs SMS Nes The EU Xanthan NaOH or HCl Up to pH4 Up to pH4 Up to pH4 Up to pH 4 Up to pH4

Table 11c J K L M N Crystallization Inhibitor
5-12% (mass.) Maltitol Maltitol Maltitol Maltitol Maltitol Plasticizer I 5-7.5% (mass.) Glycerol Transcutol® * Glycerol Dipropylene glycol MPD ** Plasticizer II 5-7.5% (mass.) Propylene glycol - - - - Solvent 10-35% (mass.) Ethanol Acetone Ethanol 2-propanol Methyl acetate Solvent up to 100% (mass.) 0.1 M buffer 0.1 M buffer 0.1 M buffer 0.1 M buffer 0.1 M buffer Film-forming
body 1-5% (mass.) LDCs Nes Xanthan LDCs LDCs NaOH or HCl Up to pH4 Up to pH4 Up to pH4 Up to pH4 Up to pH4 * Transcutol® = diethylene glycol monoethyl ether
** MPD = 2-methyl-2,4-pentanediol

Example 12

In order to study stability, 3% terbinafine gels obtained in Example 1 and having the composition shown in Table 1a were compared. In vitro penetration of these compositions containing terbinafine was carried out through the membranes of the hoof of a bull, as described in example 1, however, for each membrane participating in the analysis, the test composition in the amount of 200 mg / cm ^{2 was used} . Table 12 presents data on admission after 6 hours for two samples taken 24 months after receipt, and for one sample taken less than 1 week after receipt. There was no significant difference in penetration ability, and the intake of 3% terbinafine gels that had been stored for 24 months was comparable to the composition received recently <1 week ago.

Table 12 Time after receipt The total amount (n = 3) μg / cm ² Intake (n = 3) mcg / cm ² h 3% terbinafine gel <1 week 29.19 ± 3.58 4.87 ± 0.60 3% terbinafine gel 24 months 32.69 ± 5.16 5.45 ± 0.86 3% terbinafine gel 24 months 31.91 ± 4.26 5.32 ± 0.71

Throughout this description, with reference to “one of the embodiments”, “some embodiments”, “one or more embodiments” or “embodiment”, it is understood that certain feature, structure, material or characteristic described in connection with the embodiment are included in at least one embodiment of the invention. Thus, the appearance of phrases such as “in one or more embodiments”, “in some embodiments”, “in one embodiment” or “in an embodiment” in a large number of places throughout this description does not necessarily refer to one and the same embodiment of the invention. Moreover, certain features, structures, materials or characteristics may be combined in any suitable manner in one or more embodiments.

Although embodiments of the invention have been described herein with reference to specific embodiments, it should be understood that these embodiments are merely illustrative of the principles and applications of the present invention. One skilled in the art will appreciate that a large number of modifications and variations can be made to the method and apparatus of the present invention without departing from the spirit and scope of the invention. Thus, it is believed that the present invention includes modifications and variations that are covered by the attached claims and their equivalents.

Claims (33)

1. Single-phase pharmaceutical composition for topical application, including:
biologically active agent;
a delivery vehicle containing a non-polymer crystallization inhibitor that is capable of slowing the crystallization of a biologically active agent in a delivery vehicle, and
film former; and
volatile solvent;
where the biologically active agent is in the composition in a partially saturated state and where the biologically active agent in the carrier for delivery after evaporation of the volatile solvent is in a supersaturated state. 2. The composition according to claim 1, in which the volatile solvent at 20 ° C has a vapor pressure of 5 kPa or more. 3. The composition according to claim 1, in which the non-polymer crystallization inhibitor contains hydroxycarboxylic acid. 4. The composition according to claim 3, in which the hydroxycarboxylic acid contains citric acid, lactic acid, malic acid, or combinations thereof. 5. The composition according to claim 1, in which the non-polymer crystallization inhibitor inhibits the crystallization of the biologically active agent in the carrier for delivery up to about 24 hours after application of the composition. 6. The composition according to claim 1, in which the volatile solvent contains acetic acid, acetone, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, ethanol, ethyl acetate, diethyl ether, formic acid ethyl ester, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-propanol, 2-propanol, propyl acetate, water, n-butyl ether, isopropanol or combinations thereof. 7. The composition according to claim 1, in which the film former contains a hydrocolloid, a derivative of a hydrocolloid, or a combination thereof. 8. The composition according to claim 7, in which the film former contains starch, pectin, agar, cellulose, a cellulose derivative, carrageenan, galactan, alginate, agarose, xanthan gum, or combinations thereof. 9. The composition of claim 8, wherein the cellulose derivative comprises hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose, or combinations thereof. 10. The composition according to claim 1, in which the film former has a cloud point (C _p ) in the composition from about 30 ° C to about 100 ° C. 11. The composition according to claim 1, in which the film former has a cloud point (C _p ) in the composition from about 40 ° C to about 70 ° C. 12. The composition according to claim 1, in which the film former has a cloud point (C _p ) in the composition from about 45 ° C to about 55 ° C. 13. The composition according to claim 1, additionally containing a plasticizer. 14. The composition according to item 13, in which the plasticizer contains propylene glycol, glycerin, diethylene glycol monoethyl ether, dipropylene glycol, 2-methyl-2,4-pentanediol (MPD), propyl acetate, anisole, or combinations thereof. 15. The composition according to claim 1, in which the biologically active agent is an antibacterial agent, an antifungal agent, an antiviral agent, a cytostatic agent, a diuretic, an immunomodulator, a local anesthetic, an anti-inflammatory agent, an anti-psoriatic agent, a derivative thereof, a salt thereof, or a combination thereof. 16. The composition according to claim 1, in which the biologically active agent contains terbinafine, naphthyne, amorolfine, butenafine, their derivatives, their salts or combinations thereof. 17. The composition according to claim 1, in which the biologically active agent contains terbinafine, or a derivative thereof, or a salt or combinations thereof, and is present in the composition in an amount of from about 0.1 to about 10 wt.%. 18. The composition according to claim 1, in which the biologically active agent contains terbinafine, a non-polymer crystallization inhibitor contains citric acid, a volatile solvent contains acetone, the film former contains hydroxyethyl cellulose, and the plasticizer contains glycerin. 19. The composition according to claim 1, in which the biologically active agent contains acyclovir, its derivative, its salt, or combinations thereof. 20. The composition according to claim 19, in which acyclovir, its derivative, its salt or combinations thereof are present in the composition in an amount of from about 0.01 to about 10 wt.%. 21. The composition according to claim 1, in which the non-polymer crystallization inhibitor is present in the composition in an amount of from about 5 to about 15 wt.%. 22. The composition according to claim 1, in which the volatile solvent is present in the composition in an amount of from about 10 to about 95 wt.%. 23. The composition according to claim 1, in which the film former is present in the composition in an amount of from about 0.5 to about 5 wt.%. 24. The composition according to item 13, in which the plasticizer is present in the composition in an amount of from about 5 to about 15 wt.%. 25. The composition according to claim 1, in which the carrier for delivery further comprises a pharmaceutically acceptable excipient, penetration enhancer, keratolytic or exfoliating agent, chaotropic substance, flavoring agent, emollient, or a combination thereof. 26. A single-phase pharmaceutical composition for topical application, including terbinafine as a biologically active agent, acetone as a solvent, a delivery vehicle containing citric acid as a non-polymer crystallization inhibitor, glycerin as a plasticizer and a film former. 27. The composition according to p. 26, including terbinafine in an amount of from 2 to 10 wt.%, Acetone in an amount of from 10 to 50 wt.%, Citric acid in an amount of from 1 to 10 wt.%, Glycerin in an amount of from 1 to 10 wt.%, and film former in an amount of from 2 to 8 wt.%. 28. The composition according to p. 26, in which terbinafine is present in the composition in a partially saturated state and in which terbinafine after evaporation of acetone is in the carrier for delivery in a supersaturated state. 29. The composition according to p, where the composition is a gel. 30. The composition according to p. 26, which is effective for the treatment of onychomycosis. 31. A pharmaceutically acceptable composition in the form of a gel, lotion, cream, ointment, aerosol or spray, containing the composition according to claim 1. 32. The use of the composition according to claim 1, in which the biologically active agent is terbinafine, naphthyne, amorolfine, butenafine, their derivatives, their salts or their combination to obtain a medicinal product for the treatment or prevention of onychomycosis. 33. The use of the composition according to claim 1, in which the biologically active agent is acyclovir or its derivative or salt for the manufacture of a medicament for the treatment or prevention of infection with Varicella zoster, HSV-1 or HSV-2.