RU2777644C2 - Delivery systems for local application for active substances - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to viscous or gel-like delivery systems based on oil nano-regions, dispersed in a continuous aqueous phase with increased viscosity/gel-like continuous aqueous phase, which are suitable for prolongated and/or slowed delivery of different active substances during local application.

EFFECT: obtaining delivery systems for active substances.

13 cl, 13 tbl, 23 dwg

Description

Technical field

The present invention relates to novel viscous or gel-like delivery systems based on oily nano-domains dispersed in a highly viscous continuous aqueous phase/gelled aqueous continuous phase, which are suitable for sustained and/or sustained delivery with topical application of various active substances.

State of the art

Delivery systems for topical application of active substances are often based on lipophilic carriers that dissolve the active substance in them, for example, ointments based on petrolatum, liquid paraffin or other oily carriers. Other delivery systems are emulsion-based creams and ointments in which drops of an oil in which the active substance is dissolved are dispersed in an aqueous phase. Although there are various commercial products for topical delivery of actives, delivery of topical actives from such systems has proven problematic in terms of mixing, delivery profile and efficiency.

In particular, when mixing such systems, it has been difficult to obtain topical formulations that combine long-term stability, the desired release profile of the active substance, controlled penetration into the layers of the skin (i.e. calculated taking into account limited systemic exposure or the prevention of such exposure), as well as have a good texture.

Thus, the present application proposes submicron structures, i.e., nano-domains of delivery systems that are self-assembling, based on a unique multi-component oil phase that has a low oil content and is dispersed in a continuous aqueous phase with increased viscosity or a gel-like continuous aqueous phase. Such systems are designed to load various active agents and are suitable for topical administration of the active agent in controlled, usually sustained, release. In addition, as will be described herein, viscous/gelled formulations provide a deposition effect in the desired layer of the skin to provide increased delivery of active agent material, as well as a prolonged and substantially constant rate of release of the active agent upon administration. These systems, although composed of several components, are isotropic, self-assembling systems (i.e., spontaneously formed), thermodynamically stable, exhibit high solvent power, and have improved bioavailability of the active agent. Other advantages of these systems will become apparent from the following description.

Links

[1] W02008/058366

[2] A. Kogan, N, Garti, Advances in Colloid and Interface Science 2006, 123-126, 369-385

[3] A. Spernath, A. Aserin, Advances in Colloid and Interface Science 2006, 128

[4] A. Spernath, A. Aserin, N. Garti, Journal of Colloid and Interface Science 2006, 299, 900-909

[5] A. Spernath, A. Aserin, N. Garti, Journal of Thermal Analysis and Calorimetry 2006, 83

[6] N. Garti, A. Spernath, A. Aserin, R. Lutz, Soft Matter 2005, 1

[7] A. Spernath, A. Aserin, L. Ziserman, D. Danino, N. Garti, Journal of Controlled Release 2007, 119

[8] WO 03/105607

[9] J. Lademann, U. Jacobi, C. Surber, H.J. Weigmann, J.W. Fluhr, European Journal of Pharmaceutics and Biopharmaceutics 2009, 72, 317-323

[10] W02016/038553

[11] W02010/045415

[12] W02007/065281

[13] WO 1997/042944

[14] WO 1993/000873

[15] WO 2008/065451 A2

[16] WO2005/110370

[17] W02007/060177

The essence of the invention

The present invention relates to topical formulations for dermal (ie topical) delivery of an active agent which provide a prolonged and improved release of the active agent through a deposition effect in the desired layer of the skin. The unique combination of ingredients in a topical formulation allows for high stratum corneum penetration (but can be adapted for controlled penetration to limit or prevent systemic effects) while achieving a controlled, desirable release profile of the active agent over an extended period of time as described in this application. While existing high viscosity/gel formulations that are emulsions or dispersions have proven to have limited thermodynamic stability and/or limited penetration of the active agent (see e.g. LUMiFuge™ commercial emulsion test results shown in Fig. 1), the compositions of the present invention show high stability over prolonged periods of time, high levels of penetration of the active substance they carry, controlled and prolonged release of the active substance, as well as improved sensitivity properties. It should also be noted that the formulations of the present invention are intended to ensure complete dissolution of the active agent in the formulation, thus ensuring long-term stability of the formulation and reproducible release of the active agent from the formulation when applied to the skin.

In one aspect of the present invention, a topical formulation is provided comprising an oil phase and a gelled aqueous continuous phase, wherein the oily phase is in the form of oil droplet regions that are dispersed in the gelled aqueous continuous phase; wherein the oil phase contains an active substance or a pharmaceutically acceptable salt thereof, at least one oil, at least two hydrophilic surfactants, at least one auxiliary surfactant (for example, a lipophilic auxiliary surfactant), according to at least two polar solvents and at least two penetration enhancers, and the gelled aqueous continuous phase contains an aqueous diluent and at least one gelling agent.

According to other aspects of the present invention, there is provided a topical formulation comprising an oily phase and a gelled aqueous continuous phase, wherein the oily phase is in the form of oily nano-regions that are dispersed in the gelled aqueous continuous phase; moreover, the oil phase contains the active substance or its pharmaceutically acceptable salt, at least one oil, at least two hydrophilic surfactants, at least two polar solvents and at least two penetration stimulants, and optionally contains at least one auxiliary surfactant α-active agent (for example, a lipophilic co-surfactant), and the gelled aqueous continuous phase contains an aqueous diluent and at least one gelling agent.

Topical formulations comprise an active agent-loaded delivery system and consist of an oil phase in the form of discrete regions (eg, droplets, which may or may not be spherical) that are dispersed in a continuous aqueous phase. The continuous phase is a gel, so that the composition has an increased viscosity in terms of consistency, which allows to obtain a long retention time on the skin upon application, as well as a pleasant and smooth texture. As noted above, the compositions are self-organizing systems (that is, they are formed spontaneously), and, firstly, they are designed to dissolve and stabilize the active substance, and, secondly, they provide high permeability through the skin and prolonged release of the active substance from the composition when delivery to the desired layer of the skin. Unlike conventional emulsion or microemulsion formulations, these self-assembling structures are poor in oil phase and, as will be explained below, also have a very low oil content in the oil phase. The oil phase is formed by nanoclusters or small regions of oil and surfactants, co-solvents and co-surfactants, but differs from classic reverse micelles or swollen reverse micelles. When mixing more than 60% (mass.) of water, oily areas are formed, structured by surfactants and the active substance itself; namely, in the oil regions of the composition, the active substance acts as a surfactant ("texturing agent" or "spatial agent") located at the interface of the oil phase or included within the interface, being part of the structure of the region and providing the formation of oil areas. The unique oil phase used in the formulations of the present invention therefore differs from known topical delivery systems in which the active agent is merely a guest molecule, i.e. usually dissolved in the oil or oil phase without significantly affecting the structure of the formulation. In adapting the oil phase to allow entrapment of the active agent between the surfactant tails, the active agent is introduced into the structure of the oil region and it acts to stabilize the structure of the regions. In other words, in the compositions of the present invention, the active agent dissolves within the oil/surfactant region interface, thus not so much forming the structure of the oil regions and the interface as dissolving into the core of the oil region.

The compositions of the invention are thermodynamically stable submicron structures (having submicron size regions) that can be safely stored for extended periods of time without emulsion breaking, aggregation, coalescence, or phase separation, and which are characterized by substantially uniform and stable oily nanosized regions, typically having a narrow size distribution in the aqueous phase. In addition to formulation stability considerations, the uniformity of the size of the regions and their size distribution allows better control of the rate of release of the active agent from the formulation, as well as improved transfer/penetration into the skin.

It should be emphasized that the structures of the compositions of the present invention are formed spontaneously when the active substance is introduced into the oil mixture and the aqueous component is added in the required amount (i.e. above about 60%), without the need for high shear, cavitation or high pressure homogenization methods, but rather with simple mixing of components at low mixing speeds. In some embodiments, the oily regions (in the gel system) are about 5 to 150 nm (nanometers) in size, or even 10 to 100 nm. The region size refers to the arithmetic mean of the measured region diameters, with the diameters varying within a range of ±15% of the mean.

In other embodiments, the oil regions (in a gel system) may be about 10 to 75 nm, about 10 to 50 nm, or even 10 to 25 nm in size. In some other embodiments, the oil regions (in a gel system) may be about 15 to 75 nm in size, or even about 20 to 50 nm in size.

It should be noted that the regions need not necessarily be spherical. In some embodiments, the oil regions in the composition are elongated, namely ellipsoidal, oblong, or worm-shaped, with at least 2 different dimensions. In such cases, the average region size refers to an imaginary sphere having the diameter of the largest region size.

In some embodiments, the elongated oil regions have an aspect ratio of about 1.1 to 1.5.

Regulation of skin penetration and release rates is also obtained by adjusting the viscosity of the formulations, ie gelling the aqueous phase to form a low to medium viscosity formulation, usually in the form of a gel. The authors of the present invention have found that the delivery system can have increased viscosity up to the desired viscosity with controlled rheological properties, which increases the stability of the system and prolongs the release of the active substance from the composition when administered topically. Controlled increase in viscosity also improves the spreadability of the composition on the skin, and also provides a longer contact time of the skin and the composition, as will be explained in this application.

It should be noted that the compositions of the present invention are able to maintain their nanosize without interaction with gel molecules and without flocculation or agglomeration and remain mobile within the gel phases. This unique property is achieved by selecting gelling agents that do not have surface activity and that do not interact with the active substance.

According to the present invention, the term "viscous" or any form thereof, in relation to the aqueous phase and/or composition, means a viscosity greater than that of water (ie, a viscosity greater than 1 centipoise at 25°C). Typically, the gelled aqueous phase itself has a viscosity of at least 100 cP (centipoise or mPa/s), and the formulation may have a viscosity of at least 400 cP (as measured with a Brookfield DV-II viscometer, 15 rpm with pin LV4 at a concentration of gelling agent of 2.85% (mass.)). Unless otherwise stated, all viscosity values described in this application refer to the viscosity measured at 25°C.

The increased viscosity is advantageously obtained by using a gelling agent, in particular a gelling agent that does not affect the structure of the nano-regions described later in this application. The gelling agent forms a three-dimensional molecular network in the aqueous phase, thereby increasing the viscosity of the composition. In addition, it should be noted that since the structures of the nanoregions in the gel phase are not Newtonian, the rheological properties can be an indicator of the viscous properties of the system. Empty (i.e. no active substance) and loaded nanosystems have higher loss modulus (G') and storage modulus (G'') than aqueous gel systems (i.e. gelled aqueous phase without nanoregions), exhibiting rheological properties similar to soft viscoelastic gels.

The complex viscosity of the gelled nanoregions is higher than that of the aqueous gel phase at low shear rate (12 vs. 8 Pa⋅s at a shear rate of 0.1 1/s), but equal to the viscosity of the gel system at high shear rates of about 0.6 Pa⋅ s at 80 1/s.

The viscosity of the gel formulation does not change with storage time and is fully reproduced even after several cycles of shear stress, indicating that the nano-regions are not attached to the viscoelastic network. In addition, unlike formulations that must be completely absorbed into the skin, a gel formulation forms a thin film on the surface of the skin upon application. This film has a longer residence time on the skin, while increasing the contact time of the composition with the skin, which allows the diffusion of the active substance from the oily areas and into the deeper layers of the skin (providing a deposition effect) for a longer period of time.

The term "composition for topical application" refers in this application to the composition intended for application to the skin and provides dermal and/or transdermal delivery of the active substance. As the term is used in this application, it refers to the application of a formulation directly to at least a portion of a subject's skin (human or non-human skin) to achieve a desired effect, such as a cosmetic or therapeutic effect, at the site of application and adjacent areas. or fabrics. In some embodiments, the desired effect is achieved at the site of application without causing one or more systemic effects. In other embodiments, the composition of the present invention causes at least a partial, limited, systemic effect that contributes to the occurrence of at least one desired effect.

As you know, human skin consists of many layers, which can be divided into three main groups of layers: the stratum corneum, which is located on the outer surface of the skin, the epidermis and the dermis. While the stratum corneum is a keratin-filled layer of cells in a lipid-rich extracellular matrix that is the de facto major barrier to drug delivery into the skin, the epidermal and dermal layers are viable tissues. The epidermis is free of blood vessels, but the dermis contains capillary loops that can carry drugs for transepithelial systemic distribution.

While dermal drug delivery may only be the preferred route, only a limited number of drugs can be administered by this route. The inability to deliver a wide range of drugs by dermal delivery depends mainly on the requirement of low molecular weight (drugs with a molecular weight of no higher than 500 Da) to facilitate skin penetration, lipophilicity and relatively small doses of drug that can be loaded into known carriers. . The compositions of the present invention provide transfer of active substances through at least one layer of the skin, through the stratum corneum (PC), layers of the epidermis and dermis. Without wishing to be bound by any particular theory, the ability of a delivery system to transport an active agent across the stratum corneum depends on a number of factors, including controlled diffusion of the active agent through the hydrated keratin layer and into the deeper layers of the skin. As will be explained below, this controlled diffusion is achieved by combining increased viscosity with interface interaction between active agent and surfactants from the oil phase.

In some embodiments, the formulations are for epidermal and/or dermal administration of at least one active agent. In other embodiments, the composition may be designed to deliver the active substance through the layers of the skin, and in particular through the stratum corneum. In some other embodiments, the composition is intended for dermal delivery of the active substance without causing an appreciable systemic effect. In still other embodiments, the composition is designed to deliver the active agent through the stratum corneum to produce an effect in the desired tissue (muscle, synovial fluid, synovium, patella, etc.).

In the scope of this application, the term "skin" refers to any area of the skin of a mammal (including human skin), including the scalp, hair and nails. The area of the skin to which the composition can be applied depends, among other things, on the parameters discussed in this application.

In another aspect of the present invention, there is provided a topical formulation for providing sustained release of at least one active agent, the formulation comprising an oil phase and a gelled aqueous continuous phase, the oily phase being in the form of oily regions that are dispersed in the gelled aqueous continuous phase; the oil phase contains the specified active substance, at least one oil, at least two hydrophilic surfactants, at least one auxiliary surfactant, at least two polar solvents and at least two penetration stimulants, and the gel-like aqueous the continuous phase contains an aqueous diluent and at least one gelling agent; wherein said formulation is intended to form a film on a skin area when applied thereto, such that said active is released from said oil droplets over a period of time upon contact with the skin area, thereby providing prolonged and increased release.

In another aspect of the invention, a topical formulation for providing sustained release of at least one active is provided which comprises an oil phase and a gelled aqueous continuous phase, wherein the oily phase is in the form of oily regions that are dispersed in the gelled aqueous continuous phase; moreover, the oil phase contains the specified active substance, at least one oil, at least two hydrophilic surfactants, at least one auxiliary surfactant, at least two polar solvents and at least two penetration stimulants, and the gel-like the aqueous continuous phase contains an aqueous diluent and at least one gelling agent; moreover, the specified active substance is only physically associated with the oily areas and the aqueous phase, which allows the active substance to be released from these oily areas upon contact with the skin area for a prolonged and increased period of time.

Compositions according to the present application can provide prolonged release of the active substance when applied topically; namely, the active substance is released from the formulation to the area desired to be administered within a period of at least 12 hours from the time of administration. In some embodiments, the active agent is released from the formulation over a period of time of at least 24 hours, sometimes up to 48 hours, when applied to the subject's skin. In some embodiments, as measured by a diffusion chamber (Franz cell), the accumulated amount of active substance that has passed through the barrier increases by about 2 times every 2 hours over a period of 0.5-12 hours from the time of application and/or about 6 times within a period of 12 to 24 hours and 2 times from 24 to 48 hours from the moment of application.

It is noteworthy that, according to measurements using a diffusion chamber, the amount of active substance in the receiving vessel (simulating blood flow) is minimal, for example, from 0.5 to 2% of the total amount of applied active substance, which demonstrates minimal systemic exposure.

In other embodiments, the accumulated amount of the active substance in the surface layers of the skin within 24 hours from the moment of application is at least 4-8% of the amount applied to the skin.

The compositions of the present invention may also provide a deposition effect where, once applied to the desired skin layer, the composition acts as an active agent reservoir from which the active agent is released in a controlled manner over a predetermined period of time. Namely, the compositions of the present invention are designed to form a thin film of a gel-like composition on an area of skin when applied to it. Due to the uniqueness of the structure of the oil regions and the careful selection of the diffusion coefficients of the components in the formulation, the active substance is released in a controlled manner (at a constant rate) over an extended period of time from the oil phase into the skin, when the formulation is brought into contact with the skin (as will be explained in detail in this application ).

Thus, in another aspect, a depot formulation for topical delivery of at least one active agent is provided, which comprises an oil phase and a gelled aqueous continuous phase, the oily phase being in the form of oily regions that are dispersed in the gelled aqueous continuous phase; while the oil phase contains the specified active substance, at least one oil, at least two hydrophilic surfactants, at least one auxiliary surfactant, at least two polar solvents and at least two penetration stimulants, and the gelled aqueous continuous phase contains an aqueous diluent and at least one gelling agent; moreover, the specified active substance has a diffusion coefficient in the composition, close to the coefficient of the hydrophilic surfactant, and the specified aqueous phase is gel-like, which allows the active substance to be released from these oily areas upon contact with the skin area for an extended period of time.

The term "obstruction coefficient" (KO) means the diffusive transfer capacity (diffusion coefficient) of each component in the composition, referred to the diffusion coefficient of the component itself in the liquid state or in the reference solution [KO=D/D ₀ ]. The obstruction coefficient indicates the stability of the components in the oil areas released from the structure at a given concentration of the active substance. Low KO values indicate binding effects between components having close KO values.

As noted above, the compositions of the present invention consist of oil areas dispersed in a gel-like aqueous continuous phase. The oil phase is a unique multicomponent mixture that is essentially (sometimes completely) water-free and contains at least one oil, at least two hydrophilic surfactants, at least one co-surfactant (typically lipophilic co-surfactant), at least two polar solvents, and at least two penetration enhancers. In contrast to classical emulsion and microemulsion systems, which are saturated with oil, so that the active substance is usually dissolved inside the oil core, in the compositions of the present invention the oil phase is poor in oil. This low oil content is insufficient to solubilize the active agent, forcing the active agent to be trapped in surfactant tails, and hence to be located at the interface between the oil regions and the aqueous phase. This solubilization within the interface between the oil and the surfactant results in a high thermodynamic stability of the composition, which is not subject to phase separation or release of the active substance from the droplets over an extended period of time, while upon contact with the biological membrane, the active substance can be released from composition. Due to the combination of oil phase components, relatively high amounts of active substance can be loaded into the oil phase, for example, up to 20% (wt.) or more, usually up to 15% (wt.) of the oil phase (it is noteworthy, however, that after dilution with an aqueous carrier, the concentration of the active substance in the entire formulation should be recalculated according to the respective dilution rate).

After the addition of the aqueous phase to the oil phase, the oil phase rearranges itself to form oil regions. Through careful selection of components, the system spontaneously structures itself into the final structure due to the structural conformity of surfactants, co-surfactant and active agent (i.e. due to the high compatibility of these molecules), as well as the formation of an interface having essentially zero surface tension. This matching of the components ensures that the system exhibits interface resiliency, which allows the interface curvature that spontaneously forms between the oil regions and the aqueous phase to be modified to accumulate the active agent and facilitate its physical interactions with surfactant tailings. This system is also designed to provide an effective critical fill factor (ECPP) at the interface, as well as a suitable obstruction factor (as will be explained in this application), thus, firstly, stabilizing the oil areas and, secondly, providing improved release active substance from the area after contact with the skin.

Thus, according to another aspect of the invention, this application relates to a viscous composition for topical application, containing an oil phase in the form of oil areas, which are dispersed in a gel-like aqueous continuous phase, and the oil phase contains at least the following 9 components: the specified active substance, according to at least one oil, at least two hydrophilic surfactants, at least one lipophilic co-surfactant, at least two polar solvents, and at least two penetration promoters, and the gel-like aqueous continuous phase contains an aqueous diluent and at least one gelling agent.

The term "oil" refers to a lipophilic substance that is immiscible with water and capable of forming discrete regions when introduced into an aqueous liquid. In some embodiments, the oil is selected from isopropyl myristate (IPM), ethyl oleate, methyl oleate, lauryl lactate, oleyl lactate, oleic acid, linoleic acid, monoglyceridoleate and monoglycerid linoleate, coco caprylocaprate, hexyl laurate, oleylamine, oleyl alcohol, hexane, heptanes, nonane, decane, dodecane, short chain paraffinic compounds, terpenes, D-limonene, L-limonene, DL-limonene, olive oil, soybean oil, rapeseed oil, cottonseed oil, palmolein, sunflower oil, corn oil, essential oils such as peppermint oil, pine oil, tangerine oil, lemon oil, lime oil, orange oil, citrus oil, neem oil, lavender oil, anise oil, pomegranate seed oil, grape seed oil, rose oil, clove oil, sage oil, eucalyptus oil, jasmine oil, oil oregano, capsaicin and similar essential oils, triglycerides (e.g. unsaturated and polyunsaturated tocopherols), medium-long triglycerides chain oil (MCT), avocado oil, grape seed oil, pumpkin seed oil, pomegranate (omega 5 fatty) acids and CLA fatty acids, omega 3-, 6-, 9-fatty acids and ethyl esters of omega fatty acids and mixtures thereof.

In other embodiments, the oil may be selected from isopropyl myristate (IPM), oleic acid, oleyl alcohol, vegetable oils, terpenes, peppermint oil, eucalyptus oil, and mixtures thereof.

In another embodiment, the oil is isopropyl myristate (IPM).

As noted above, the oil phase is poor in oil in order to move the active towards the interface rather than cause the active to solubilize in the oil. Thus, according to one of the embodiments, the oil may be present in the composition in an amount of not more than 3% (mass). According to other embodiments, the oil may be present in the composition in an amount from about 0.5 to 3% by weight of the composition. According to some other embodiments, the oil may be present in the composition in an amount of about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4 , 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2 .7, 2.8, 2.9 or even 3% by weight of the composition. According to still other embodiments, the oil may be present in the composition in an amount from about 0.5 to 1% by weight of the composition.

Hydrophilic surfactants are surfactants that have a hydrophilic head group and lipophilic tails that are capable of solubilizing the active substance. The head groups are able to interact with the active substance and penetration stimulators, while providing the formation of oil areas. Depending on the nature of the active agent loaded into the formulation, hydrophilic surfactants may include ionic, cationic zwitterionic or non-ionic surfactants having a hydrophilic nature (i.e. having large head groups), thereby providing the surfactant affinity for water. Typical surfactants are polyoxyethylene sorbitan monolaurate (polysorbate 20 or T20), polyoxyethylene sorbitan monopalmitate (T40), polyoxyethylene sorbitan monooleate (T80), polyoxyethylene sorbitan monostearate (T60), and polyoxyethylene esters of saturated (hydrogenated) and unsaturated castor oil ( e.g. HECO25, HECO40, HECO60, ECO35, ECO40, ECO60, PEG 25, PEG40, PEG45, PEG60 ethylene glycols, PEG45 copra and other ethoxylated monoglycerol esters (such as PEG 5, 6, 7, 20, 40 - caprylic/ capric, lauric and oleic acids), hydroxystearate, ethoxylated fatty acids and ethoxylated fatty alcohols of short, medium and long chain fatty acids, esters of sugars and saturated and unsaturated fatty acids, sucrose mono and poly esters, polyglycerol esters (3, 6, 8, 10 glycerols) fatty acids, ethoxylated monoglycerides (8, 10, 12, 20, 40 EO) and ethoxylated di glycerides, ethoxylated fatty acids and ethoxylated fatty alcohols.

The oil phase contains at least two hydrophilic surfactants. The hydrophilic surfactants are selected and selected so that their combination forms a "Sherman complex". Sherman complex refers to the combination of two or more surfactants that form a dense, well-packed and compact layer at the interface resulting from the combination of two surfactants with two lipophilic tails: namely, one having a longer tail, and others with a shorter tail, which are integrated into one another in the core of the region. In the Sherman complex, the two surfactants have hydrophilic head groups, one with a larger head group and the other with a smaller head group, forming a strong hydrogen bond between the head groups. Such complexes provide increased solubilization of biologically active substances (active substance) in nano-regions and better chemical stabilization of the active substance in surfactant tails.

In other words, the formulation comprises a first hydrophilic surfactant and a second hydrophilic surfactant, the first hydrophilic surfactant being different from the second hydrophilic surfactant.

In some embodiments, each of the hydrophilic surfactants can be selected from polyoxyethylenes, ethoxylated (20EO) sorbitan monolaurate (T20), ethoxylated (20EO) sorbitan monostearate/palmitate (T60), ethoxylated (20EO) sorbitan monooleate/linoleate (T80), ethoxylated (20EO) sorbitan trioleate (T85), ethoxylated castor oil (from 20EO to 60EO); ethoxylated hydrogenated castor oil (20 to 60 EO), ethoxylated (5-40 EO) stearate/palmitate monoglyceride, polyoxyl 35 and 40 EO castor oil. In other embodiments, each of the hydrophilic surfactants can be independently selected from polyoxyl 35 castor oil, polysorbate 20 (Tween 20), polysorbate 40 (Tween 40), polysorbate 60 (Tween 60), polysorbate 80 (Tween 80), Mirj S40, Mirj S20, oleoyl macrogol glycerides, oolyglyceryl-3-dioleate, ethoxylated hydroxyl stearic acid (Solutol HS15), sugar esters such as sucrose monooleate, sucrose monolaurate, sucrose monostearate, polyglycerol esters such as decaglycerol monooleate or monolaurate, hexaglycerol monolaurate or monooleate

In some embodiments, the first hydrophilic surfactant may be selected from polysorbate 40 (T40), polysorbate 60 (T60), polysorbate 80 (T80), Mirj S40, oleoyl macrogol glycerides, polyglyceryl-3-dioleate, ethoxylated hydroxyl stearic acid (Solutol HS15), or sugar esters, while the second surfactant may be selected from ethoxylated castor oil (20EO to 40EO); ethoxylated hydrogenated castor oil (20 to 40EO).

In one embodiment, the first hydrophilic surfactant is polysorbate 60 (Tween 60) and the second hydrophilic surfactant is hydrogenated castor oil (40EO, HECO 40).

In some embodiments, the ratio of the first hydrophilic surfactant to the second is from about 5:1 to 2:1 (w/w).

In some embodiments, the first hydrophilic surfactant may be present in the composition in an amount of from about 1.75 to 8.0% (w/w), while the second hydrophilic surfactant may be present in an amount of from about 0.45 up to 3.8% (mass.). In other embodiments, the first hydrophilic surfactant may be present in the composition in an amount of from about 2.5 to 4.5% (w/w), while the second hydrophilic surfactant may be present in an amount of from about 0.5 up to 1.8% (mass.). According to some other embodiments, the total amount of hydrophilic surfactants in the composition is from 2 to 12% (wt.).

The composition contains at least two polar solvents. According to the present invention, the term "solvent" refers to any polar organic solvent that is miscible with water and is suitable for assisting in the solubilization of the active substance. A combination of two polar solvents is used to facilitate complete coverage of the interface with a hydrophilic surfactant at any degree of dilution of the composition with water. Solvents provide solubilization conditions for the gradual migration of surfactants to the interface upon dilution. At low water levels, solvents are essential components that impart lipophilic-like properties to a hydrophilic surfactant, adjusting its effective critical packing parameter (ECPP) to >1.3, and at high water levels (>50%), solvents "push" the surface-active active substances to the interface and cause significant changes in ECPP to <0.5. In other words, hydrophilic surfactants regulate and adjust the hydrophilicity/lipophilicity of surfactants at any water content. Thus, the combination of solvents is necessary to ensure complete geometric packing of the two solvents to fill the space (voids) between the surfactants at the interface.

Thus, in some embodiments, the formulation comprises at least a first solvent and a second solvent, the first solvent being different from the second solvent.

According to one embodiment, the first polar solvent may be selected from short chain alcohols (e.g., ethanol, propanol, isopropanol, butanol, etc.), while the second polar solvent may be selected from polyols (e.g., propylene glycol ( PG), glycerol, xylitol and other monomeric or dimeric sugar units, and polyethylene glycol (PEG) such as PEG 200, PEG 400, etc.).

In some embodiments, the composition may contain isopropanol (IPA) as the first polar solvent and propylene glycol (PG) as the second polar solvent. In other embodiments, the composition may contain ethanol as the first polar solvent and propylene glycol as the second polar solvent.

According to other embodiments, the composition contains at least three solvents. In such embodiments, the composition may contain IPA, ethanol and PG as polar solvents.

According to other embodiments, the first polar solvent is selected from ethanol, IPA, and combinations thereof.

Without wishing to be bound by any particular theory, the first polar solvent(s) is located deeper within the interface (ie, ethanol and/or IPA). The first polar solvent(s) act to provide curvature elasticity (R ^e ) and spontaneous curvature (R ^s or R ⁰ ) of the interface between the oily region and the aqueous phase. The second polar solvent (ie the polyol) is located closer to the head groups of the surfactant, thereby dehydrating them and solubilizing the active agent.

In some embodiments, the ratio between the first solvent(s) and the second solvent is from about 1:1.5 to about 1:3.

In some embodiments, the total amount of solvents in the composition is from about 2.5 to 25% (wt.). In other embodiments, the total amount of solvents in the composition may be from about 3 to 20% (wt.), from about 3.5 to 18% (wt.), from about 4 to 16% (wt.), or even from about 5 up to 15% (wt.).

As noted above, the system active agent-surfactants-solvents forms strong molecular interactions, thereby ensuring the solubilization and stabilization of the active agent within the interface of the oil regions. The combination of surfactants and active agent in the presence of solvents provides for interactions between surfactants and the active agent (i.e. physical binding of the active agent to surfactant molecules), while slowing down the migration of the active agent from the oily region into the aqueous phase, thereby thereby increasing the shelf life of the composition.

The other component of the oil phase is at least one co-surfactant, typically a lipophilic or amphiphilic co-surfactant, which, in some embodiments, may be present in the formulation in an amount of between about 0.4 and 2.0% (w/w) .). In other embodiments, the co-surfactant may be present in the composition in an amount of from about 0.45 and 1.8% (wt.), or even from about 0.5 and 1.5% (wt.). The term "co-surfactant" should be understood to include any lipophilic or amphiphilic substance, other than surfactants, that contributes (together with surfactants) to reducing the surface tension between the oil phase and the aqueous phase to substantially zero ( or zero), which ensures the formation of thermodynamically stable oil regions.

In one embodiment, the co-surfactant may be a phospholipid.

The phospholipid forming the oil phase component is generally lipophilic or amphiphilic to cause a structural change or temporary disruption in the biological lipid membrane upon contact (fusion); the structural change may be one or more of a change in membrane curvature, a change in surface charge, promotion of non-bilayer lipid phases, adherence to the membrane, and a change in spacing of phospholipid head groups within the bilayer.

In some embodiments, the phospholipid may be a glycerophospholipid selected from mono-phosphatidylglycerols, bis-phosphatidylglycerols, and tris-phosphatidylglycerols. Non-limiting examples of such phospholipids are phosphatidylcholine (PC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), palmitoylstearoylphosphatidylcholine (DSDC), palmitoyloleylcholine (PODC) and any other mixed fatty acid glycerolphosphatidylcholine, any phosphatidylethanolamine (PE) (Cephalin), any phosphatidylinositol ( PI), any phosphatidylserine (PS), cardiolipin, plasmalogen, lysophosphatidylcholine (LPC), lysophosphatidylic acid, phosphatidylinositol (3,4)-bisphosphate, phosphatidylinositol (3,5)-bisphosphate, phosphatidylinositol (4,5)-bisphosphate, phosphatidylinositol 4 -phosphate, phosphatidylinositol (3,4,5)-triphosphate, phosphatidylinositol 3-phosphate, soy lecithin, rapeseed lecithin, corn or sunflower lecithin, egg lecithin, Epicorn 200, Epicorn 100, phosphalipon 90G, LIPOID R-100 (rapeseed ), LIPOID H-100 (sunflower), LIPOID-S100 (soybean), LIPOID-S75, phosal 50PG, dioleylphosphatidylcholine (DOPC), oleylpalmitoylphosphatidylcholine (POPC) and their respective existing serines, ethanolamines, glycerin and others.

In other embodiments, the co-surfactant can be selected from lecithins, egg lecithins, soybean lecithins, canola or sunflower lecithins, phospholipids such as phosphatidylcholine (PC) (GMO - genetically modified organism and non-GMO), fosal, phospholipons, Epicorn 200, LIPOID H100, LIPOID R100, LIPOID S100, LIPOID S75, POPC, SOPC, PHOSPHOLIPON 90G or PHOSPHOLIPON 90H and others, and combinations thereof.

The phospholipid may, in some embodiments, be present in the formulation in an amount between about 0.4% and 2.0% (w/w).

Increased penetration of the composition into the skin can be at least partially obtained by using penetration stimulants, which are compounds capable of changing the polarity of the stratum corneum, while improving the penetration of the composition through it. Without being limited to any particular theory, permeability stimulators act to locally and temporarily distort the phospholipid structure of the stratum corneum phospholipid membrane, while increasing the mobility of the molecular components of the stratum corneum (both lipids and proteins), thereby making the stratum corneum more permeable to the active substance. , which is usually lipophilic.

In some embodiments, the total amount of penetration enhancer in the formulation is between about 2% and 10% (w/w). In other embodiments, the total amount of penetration enhancer in the composition may be between about 2.2 and 10% (wt.), between about 2.5 and 8% (wt.), or even between 2.5 and 6% (wt.) .

The composition contains at least two penetration enhancers, the combination of which regulates the penetration of the active substance into the desired layer of the skin. Therefore, by selecting specific combinations of penetration stimulants, the active substance can be delivered to the dermis or epidermis with only little systemic exposure. In some embodiments, the combination of said two or more penetration enhancers provides a synergistic penetration and a synergistic penetration effect of the active agent.

According to one embodiment, penetration stimulants can be selected from sulfoxide derivatives such as dimethyl sulfoxide (DMSO), dimethyl isosorbide (DMI), isopropyl myristate (IPM), 2-(2-ethoxyethoxy)ethanol (Transcutol), phosphatidylcholine (PC), ethanol, isopropyl alcohol (IPA), ethyl acetate, oleyl alcohol, oleic acid, oleyl esters, beta-cyclodextrins, urea and its derivatives such as dimethyl or diphenylurea, glycerin and propylene glycol (PG), pyrrolidone and derivatives, peppermint oil or terpene oils and terpenoids (essential oils), as well as their combinations. In one embodiment, the composition may contain at least two penetration enhancers selected from DMI, PC, terpenes, and Transcutol.

According to other embodiments, the formulation may contain at least two penetration enhancers selected from DMI, PC and Transcutol.

In some embodiments, the composition may contain (i) DMI and Transcutol, (ii) DMI and PC, (iii) DMI and terpenes, (iv) PC and terpenes, (v) Transcutol and terpenes, or (vi) PC and Transcutol, in as permeability stimulants.

In other embodiments, the composition may contain three penetration enhancers, which in some embodiments are DMI, Transcutol, and terpenes.

In some other embodiments, the formulation may contain three penetration enhancers, which in some embodiments are DMI, Transcutol, and PC.

As noted above, the active substance, or a pharmaceutically acceptable salt, hydrate, derivative or analogue thereof, is solubilized within the oil phase interface (ie, between surfactant tails that form oily nano-regions).

The term "pharmaceutically acceptable salt(s)", as used in this application, means those organic salts of the active substance, which are safe and effective for pharmaceutical use in mammals and which have the desired biological activity. Pharmaceutically acceptable salts include salts of acidic groups present in the compounds of the invention.

In some embodiments, the active agent can be selected from diclofenac, diclofenac sodium (DCF-Na), diclofenac potassium (DCF-K), DCF-ammonium, diclofenac diethylamine (DCF-DEA) and mixtures thereof, or any other pharmaceutically acceptable salt of diclofenac.

In some embodiments, the composition contains the specified active substance in an amount of from about 1 to 6% (wt.). In other embodiments, the composition contains the specified active substance in an amount of from about 1.5 to 5% (wt.) or even from about 2 to 4.5% (wt.).

The continuous phase of the formulation is a gel-like, viscous aqueous phase in which regions of the oil phase are dispersed. As noted above, the aqueous phase is given increased viscosity/gelling by the gelling agent. A gelling agent is a substance capable of contributing to the resilience and viscosification of the aqueous phase to the desired viscosity, as well as to the formation of a thin film in contact with the skin layer, and therefore to increase the viscosity of the composition, as described in this application.

Gelling agents are substances that are capable of forming a 3-dimensional network of macromolecules, for example a viscoelastic network of polymer chains, into which oil regions are embedded and evenly distributed, thereby increasing the viscosity and modifying the rheological properties of the aqueous phase. For example, the gelling agent may be selected from water-soluble or colloidal water-soluble polymers (hydrocolloids) such as cellulose ethers (e.g., hydroxyethylcellulose, methylcellulose, hydroxypropyl methylcellulose), polyvinyl alcohol, polyquaternium-10, guar gum, hydroxypropyl guar gum, xanthan gum (e.g., keltrals (Keltral), xanturals (Xantural) such as Xantural 11K, Xantural 180K, Xantural 75 (CP Kelco US) and others), gellans (kelogels (Kelogel)), Aloe vera gel, amla, carrageenan, oatmeal, starch and modified starch (from corn, rice and other plants), gelatin (from pig and fish skin), ghatti gum, gum arabic, inulin (from chicory), konjac gum, locust bean gum (LBG), fenugreek, marshmallow root, pectin (highly and low methoxyl) and modified pectins, quinoa (quinoa) extract, red algae, cork gum (solagum), gum tragacanth (TG) and any mixtures thereof.

In other embodiments, the gelling agent may be selected from acrylic acid/ethyl acrylate copolymers and carboxyvinyl polymers under the tradename Carbopol. Examples include Carbopol 934, Carbopol 940, Carbopol 950, Carbopol 980, Carbopol 951, and Carbopol 981. Carbopol 934 is a water-soluble acrylic acid polymer cross-linked with about 1 sucrose polyallyl ether having an average of about 5.8 allyl groups per sucrose molecule. . Hydrophobically modified, cross-linked acrylic acid polymers having amphiphilic properties, available under the trade names Carbopol 1382, Carbopol 1342 and Pemulen TR-1, are also suitable for use according to this application. A combination of an acrylic acid crosslinked polyalkenyl polyester polymer and a hydrophobically modified acrylic acid crosslinked polymer may also be suitable.

Other gelling agents may be substances that are crosslinkable with a suitable linker to form a 3-dimensional interconnected network of molecules. Typical gelling agents of this type are crosslinked alkyl methyl vinyl esters of maleic anhydride and copolymers commercially available as Stabilizes QM (manufactured by International Specialty Products (ISP)), carbomer, crosslinked polymethacrylate copolymer.

In one embodiment, the gelling agent may be selected from xanthan gum, gellan, sodium alginate, pectin, low and high molecular weight methoxy pectin, and carbomers.

In other embodiments, the gelling agent is xanthan gum or gellan.

In some embodiments, the composition contains the specified at least one gelling agent in an amount of from about 0.75 to 3.5% (wt.).

The aqueous diluent that is viscosified/gelled by the gelling agent can be any aqueous liquid, e.g. water, purified water, distilled (DW), double distilled (DDW) and triple distilled water (TDW), deionized water, water for injection, saline solution, dextrose solution or buffer pH 4 to 8.

In some embodiments, the composition contains from about 50 to about 90% (wt.) diluent, usually about 65-80% (wt.).

As one skilled in the art will appreciate, the ratio between the various components of the formulations can be adjusted according to the type of active agent and its desired loading into the formulation, and can also be selected to provide certain formulation characteristics (such as desired area size and electrical charge).

In some embodiments, the formulations may additionally contain various additives such as perfume (e.g. pine oil, lavender oil, peppermint oil, orange oil, lemon oil, eucalyptus oil and compound perfumes, eucalyptol shots, etc.), pH modifiers and buffers (such as citric acid, phosphoric acid, sodium hydroxide, monobasic sodium phosphate, concentrated ammonia, mono-, di- and trimethylamine, mono-, di- and triethanolamine, etc.), neutralizing agents, emulsifiers, humectants, preservatives (such as benzalkonium chloride or parabens (C ₁ -C 7 alkyl esters of 4-hydroxybenzoic acid, e.g. methyl 4-hydroxybenzoate), cetrimonium bromide, benzethonium chloride, alkyltrimethylammonium bromide, EDTA, benzyl alcohol, cetyl alcohol, stearyl alcohol, benzoic acid, sorbic acid, potassium thimerosal sorbate, imidourea, bronopol, chlorhexidine, chloractamide, trichlorocarban, propylparaben, methylparaben, phenylmercury acetate, chlorobutanol, phenoxyethano l and combinations thereof and mixtures thereof) and an antioxidant (such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbyl palmitate, ascorbic acid, TBHQ, tocopherol, tocopherol acetate and combinations thereof).

In contrast to the milky white emulsion-based topical formulations available, the formulations disclosed in the present invention are generally clear (or substantially clear) due to the size of their mono-dispersed submicron oily regions (having a region size of up to 100 nm) and high stability, preserving their transparency for a prolonged period of time. Small area sizes, which are less than one fourth of the average wavelength of visible light (0.560 micrometers), are perceived by the naked eye as a transparent and homogeneous composition, without any visible turbidity or phase separation areas. This allows for easy detection of changes in formulation stability (eg phase separation, precipitation of biologically active substance and/or coalescence of oil droplets will cause detectable haze). In addition, bacterial growth will also cause changes in clarity and haze, thus providing direct detection of contamination.

According to another aspect of the invention, there is provided a topical formulation for the delivery of diclofenac or a pharmaceutically acceptable salt thereof, comprising an oil phase and a gelled aqueous continuous phase, the oily phase being in the form of oily regions which are dispersed in the gelled aqueous continuous phase; wherein the oil phase contains diclofenac or a pharmaceutically acceptable salt thereof, at least one oil, at least two hydrophilic surfactants, at least one auxiliary surfactant, at least two polar solvents, and at least two stimulants permeability; and the gelled aqueous continuous phase contains an aqueous diluent and at least one gelling agent.

Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) administered in various dosage forms. According to the present invention, the term Diclofenac means 2-(2,6-dichloroanilino)phenylacetic acid having the structure shown by formula (I), or any pharmaceutically acceptable salt thereof, including, but not limited to, diclofenac sodium, diclofenac potassium and diclofenac diethylamine .

In some embodiments, the diclofenac-loaded formulation contains xanthan gum (such as Xantural 11K, Xantural 180K, Xantural 75 (CP Kelco US) and others (Kelogel or Keltral) as a gelling agent).

In other embodiments, the oil phase of the diclofenac-loaded formulation contains IPM as the oil; Tween 60 and HECO 40 as hydrophilic surfactants; IPA, ethanol and PG as polar solvents; phospholipid as an auxiliary surfactant; DMI and Transcutol as penetration enhancers, and optionally one or more of flavors, buffers, antioxidants (eg BHT) and preservatives.

According to another aspect of the present invention, there is provided a topical formulation comprising an oil phase integrated into a gelled aqueous continuous phase, wherein the oil phase is in the form of oily regions dispersed in the continuous gelled aqueous phase, the oily phase comprising an active agent, at least one an oil, at least two hydrophilic surfactants, at least one lipophilic co-surfactant, at least two polar solvents, and at least two penetration enhancers, wherein the gelled aqueous continuous phase contains an aqueous diluent and at least at least one gelling agent; moreover, as an active substance, the composition contains at least 2% (wt.) of diclofenac or its pharmaceutically acceptable salt.

The composition described in this application can be loaded with other active substances having a structure similar to that of diclofenac. Such active substances typically have a main aromatic ring substituted with an amino group. Thus, in some embodiments, the active agent may be selected from compounds having a basic aromatic ring substituted with a secondary amino group.

One such active substance is lidocaine having the structure shown by formula (II):

Another such active substance is clonidine having the structure shown by formula (III):

Another such active substance is fentanyl having the structure shown by formula (IV) or analogues thereof (such as sufentanil, alfentanil, remifentanil, lofentanil, etc.):

The other active substance is trebenifine having the structure shown by formula (V) or analogues thereof:

Another active substance is the antibiotic cephalexin, which can be represented by formula VI.

Another active substance may be sulfamethoxazole, shown by formula VII:

Other active substances may be vancomycin, daptomycin, oritavancin and tazabactam.

Another active substance, not necessarily consisting of an aromatic and a secondary amine group, but which can be included in the nano-interface region, is alprostadil (prostaglandin E1) having the structure shown by formula (VIII), or its analogues:

The other active substance is minocycline having the structure shown by formula (IX) or analogues thereof:

The other active substance is doxycycline having the structure shown by formula (X) or analogues thereof:

The other active substance may be one of the group of anesthetic benzocaine or its derivatives of formula XI

Thus, in some embodiments, the active agent may be selected from diclofenac, lidocaine, clonidine, fentanyl, trebenifine, alprostadil, sulfamethoxazole, cephalexin, vancomycin, daptomycin, oritavancin, tazabactam, benzocaine, minocycline, doxocycline, or molecules with a similar tendency to be included in the border. area section.

This application also proposes, according to another aspect of the invention, a method of obtaining a gel-like composition for topical application described in this application, including:

(a) providing an active agent loaded oil composition comprising at least one active agent, at least one oil, at least two hydrophilic surfactants, at least one co-surfactant, at least two polar a solvent and at least two penetration enhancers, wherein said oil composition is essentially (sometimes completely) free of water;

(b) providing an aqueous mixture of an aqueous diluent and at least one gelling agent; and

(c) mixing the oil composition loaded with the active substance and the aqueous mixture to obtain the specified gel composition for topical application.

In the compositions obtained by the methods described in this application, the oil composition loaded with the active substance constitutes the oil phase of the composition, while the aqueous mixture or gel-like aqueous diluent constitutes the gel-like aqueous continuous phase.

In some embodiments, the mixing in step (c) is carried out for a period of about 5 to 60 minutes and/or at a temperature of about 25 to 50°C.

In other embodiments, the gelling agent is in the aqueous mixture in an amount of from about 0.75 to 3.5% (wt.).

Notably, in some embodiments, one or more of the process steps may be carried out under a nitrogen atmosphere. In other embodiments, the entire process is carried out under a nitrogen atmosphere.

According to one embodiment, the method may include adjusting the pH of the composition, either as a separate process step or by adding a pH modifier (eg, buffer) to the aqueous mixture.

In other embodiments, the method may comprise adding an antioxidant to the formulation, either as a separate process step or by adding the antioxidant to the active-loaded oil composition.

According to another aspect of the invention, a method of obtaining a gel-like composition for topical application described in this application is provided, including:

(a) providing an active agent loaded oil composition comprising at least one active agent, at least one oil, at least two hydrophilic surfactants, at least one co-surfactant, at least two polar a solvent and at least two penetration enhancers, wherein said oil composition is essentially (sometimes completely) free of water;

(b) mixing the oil composition loaded with the active substance and an aqueous diluent to obtain a mixture;

(c) adding at least one gelling agent to the mixture; and

(d) causing the aqueous diluent to gel, thereby obtaining said gel-like topical composition.

According to some embodiments, the method may include adjusting the pH of the formulation, either as a separate process step or by adding a pH modifier (eg, buffer) to the aqueous diluent.

In other embodiments, the method may include adding an antioxidant to the formulation, either as a separate process step or by adding an antioxidant and/or preservative to the active-loaded oil composition.

According to some embodiments of the methods described in this application, stage (a) of the method includes at least two separate steps: (a1) providing an oil composition that contains at least one oil, at least two hydrophilic surfactants, at least at least one co-surfactant, at least two polar solvents, and at least one penetration enhancer; and (a2) solubilizing said at least one active agent in an oil composition to obtain said active agent loaded oil composition.

Therefore, according to another aspect of the invention, an oil composition is provided for solubilizing at least one active agent, the oil composition comprising at least one oil, at least two hydrophilic surfactants, at least one co-surfactant. , at least two polar solvents and at least one penetration enhancer, wherein the oil composition is substantially free of water.

Thus, in one aspect of the present invention, there is provided a substantially water-free carrier composition for solubilizing at least one active agent, wherein the carrier composition comprises at least one oil, at least two hydrophilic surfactants, at least one co-surfactant, at least two polar solvents, and at least one penetration enhancer.

In another aspect, an active loaded oil composition is provided comprising at least one active agent, at least one oil, at least two hydrophilic surfactants, at least one co-surfactant, at least two polar solvents and at least two penetration enhancers, wherein said active-loaded oil composition is substantially (sometimes completely) free of water.

The term "active agent-loaded oil composition", which is interchangeably referred to herein as "concentrate", means an essentially (sometimes completely) water-free structured lipid/surfactant oil-based system in which the surfactant tails the active substance is solubilized and stabilized, and the solvent, together with surfactants, contributes, if necessary, to complete dissolution with the help of an aqueous phase (makes it soluble), forming the composition according to the present invention. In other words, the concentrate is designed to dissolve rapidly and completely in a suitable aqueous medium, which is highly viscous/gelatinous in the process of the present invention.

In other words, the nanoregions can be formed as a concentrate (ie, a water-free oil phase concentrate), which can optionally be diluted with an aqueous phase. Thus, in some embodiments, the concentrates are substantially, sometimes completely free of water (ie free of water).

According to one of the embodiments, the specified oil is present in the oil composition loaded with the active substance in an amount of not more than 8% (wt.) (for example, IPM and fragrance). The oil may be selected from the oils disclosed in this application.

According to other embodiments, said at least two hydrophilic surfactants are present in the oil composition loaded with the active substance in a total amount of at least 22% (wt.) (for example, HECO40 and T60). Hydrophilic surfactants may contain at least a first hydrophilic surfactant in an amount of at least 17.5% (wt.) (for example, T60) and a second hydrophilic surfactant in an amount of at least 4.5% (wt.) (for example, HECO40); the ratio of the first hydrophilic surfactant to the second may, in some embodiments, be from about 5:1 to 2:1 (w/w). Each of the hydrophilic surfactants may be selected from the surfactants disclosed in this application, with the first surfactant different from the second surfactant.

According to some other embodiments, said at least two polar solvents include at least a first solvent in an amount of at least 13% (wt.) (for example, EtOH and/or IPA) and a second solvent in an amount of at least 22.5% (wt.) (for example, PG). The first and second polar solvents can be independently selected from the solvents disclosed in this application, and the first solvent is different from the second solvent. The ratio of the first and second solvents may, in some embodiments, be from about 1:1.5 to 1:3 (w/w).

In some embodiments, said at least one co-surfactant is present in the oil composition loaded with active agent in an amount of at least 4.5% (wt.) (for example, PC). Said at least one co-surfactant may be selected from the co-surfactants disclosed in this application.

In some other embodiments, said at least two penetration enhancers are present in an oil composition loaded with an active agent in a total amount of at least 20% (w/w) (eg, DMI and Transcutol). Each of these permeability promoters can be selected from the permeability promoters disclosed in this application.

According to some embodiments, the specified active substance is present in the oil composition loaded with the active substance in an amount of from 5 to 20% (wt.), usually about 10% (wt.), 15% (wt.) or even 20% (wt.) , and may be selected from diclofenac, lidocaine, clonidine, fentanyl, trebenifine, alprostadil, minocycline, doxocycline, or any pharmaceutically acceptable salt, derivative or analog thereof.

In some embodiments, the active agent in the concentrate is diclofenac, sodium diclofenac (DCF-Na), potassium diclofenac (DCF-K), ammonium diclofenac, diclofenac diethylamine (DCF-DEA) and mixtures thereof, or any other pharmaceutically acceptable salt of diclofenac.

This application also provides, according to another aspect of the invention, a process for preparing a gel topically applied formulation for topical delivery of diclofenac or a pharmaceutically acceptable salt thereof, comprising:

(a) providing a diclofenac loaded oil composition comprising diclofenac or a pharmaceutically acceptable salt thereof, at least one oil, at least two hydrophilic surfactants, at least one co-surfactant, at least two polar solvents and at least two penetration enhancers, wherein said oil composition is substantially (sometimes completely) free of water;

(b) providing an aqueous mixture of an aqueous diluent and at least one gelling agent, where the gelling agent is preferably xanthan gum; and

(c) mixing the diclofenac-loaded oil composition and the aqueous mixture to form said topical gel formulation.

According to another aspect of the invention, a method is provided for preparing a gel formulation of diclofenac for topical application described in this application, including:

(a) providing a diclofenac loaded oil composition comprising diclofenac or a pharmaceutically acceptable salt thereof, at least one oil, at least two hydrophilic surfactants, at least one co-surfactant, at least two polar solvents and at least two penetration enhancers, wherein said oil composition is substantially (sometimes completely) free of water;

(b) mixing the oil composition loaded with diclofenac with an aqueous diluent to obtain a mixture;

(c) adding at least one gelling agent to the mixture; and

(d) causing the aqueous diluent to gel to form said gel topically.

In some embodiments of the methods described in this application, the composition may contain at least one additional component selected from at least one buffer and at least one pH modifier, antioxidant and preservative.

According to another aspect of the invention, there is provided a method for delivering an active agent when applied topically to a subject in need thereof, comprising topically administering to the subject an effective amount of the formulation described herein.

According to another aspect of the invention, a method is provided for delivering diclofenac or a pharmaceutically acceptable salt thereof, when applied topically to a subject in need thereof, comprising local administration to the subject of an effective amount of the composition described in this application.

As is known, "effective amount" for the purposes of this application can be defined in terms known in the prior art. The effective amount is usually determined in the course of appropriate clinical trials (studies in the range of doses), and the person skilled in the art knows how to properly conduct such tests to determine the effective amount. As is well known, the effective amount depends on a number of factors including the distribution profile in the body, a number of pharmacological parameters such as elimination half-life from the body, unwanted side effects, if any, factors such as age and sex, etc. ..

The term "subject" refers to a mammal, human or non-human.

According to another aspect of the invention, the composition described in this application is provided for use in the treatment of a disease or condition of a patient or individual in need thereof.

The compositions according to the present invention can be used to cause at least one therapeutic effect, that is, to cause, increase, maintain or reduce at least one effect by treating or preventing undesirable conditions or diseases of the subject. The term "treatment" or any linguistic form thereof, according to this application, refers to the introduction of a therapeutic amount of the composition disclosed in this application, which is effective in alleviating unwanted symptoms associated with a disease or condition, in order to prevent the manifestation of such symptoms before they occur, slow down progression of a disease or condition, slowing the worsening of symptoms, hastening the onset of a period of remission, slowing down the irreversible damage caused by a progressive chronic stage of a disease, delaying the onset of said progressive stage, lessening the severity of a disease or curing a disease, improving survival or faster recovery or preventing the onset of a disease, or combinations of two or more of the above.

In some embodiments, said disease or condition is selected from an inflammatory disease, mild to moderate pain, edema, movement disorders or signs and symptoms of osteoarthritis, joint stiffness or rheumatoid arthritis, and inflammatory skin diseases.

According to another aspect of the invention, a kit is provided that includes the composition described in this application in dosage form and instructions for use.

The term "dosage form" refers to a compartment, or container, or separate section of a vessel for storing or containing a formulation. According to the present invention, the term also refers to separate containers or vessels placed in one body.

Each of the containers may contain one or more doses of the contents. The containers may be presented in any form known in the art, such as vial, ampoules, collapsible bags, tube, spray, roll-on, container with pump and/or spray, tampons, coated pads, etc., providing application of the composition to the desired area of the skin.

In some embodiments, the kit may contain at least one measuring device for measuring the mass, volume or concentration of each component.

The expressions "range/range from" the first specified numeric value to the second specified numeric value are used interchangeably herein and to include the first and second specified numeric values and all fractional and integer numbers in between. It should be noted that if various embodiments are described using a given range, the range is given rather for convenience and brevity and should not be construed as an inflexible limitation on the scope of the present invention. Accordingly, it is to be considered that the description of a range should, in particular, disclose all possible ranges as well as individual numerical values within that range.

According to this application, the term "about" is used to include a deviation of ±10% from a particular specified value of a parameter, such as temperature, pressure, concentration, etc..

Brief description of the drawings

In order to better understand the subject matter of the invention disclosed in this application and demonstrate how it can be carried out in practice, specific examples of embodiments will be given as non-limiting examples with reference to the accompanying drawings.

On FIG. 1 shows the results of LUMiFuge™ testing a commercial emulsion for 17 hours at 3000 rpm, showing that the commercial emulsion is neither clear nor stable over long periods of time.

On FIG. 2 shows the effect of changing the phospholipid component on the clarity of a gel formulation loaded with 2% (w/w) DCF-Na.

On FIG. 3 shows the effect of increasing the gelling agent content on the clarity of a gel formulation loaded with 2% (w/w) DCF-Na.

On FIG. 4 shows the effect of changing fragrance on the clarity of a gel formulation loaded with 2% (w/w) DCF-Na.

On FIG. 5A-5B show the effect of diluting the blank formulation and the formulation loaded with 2% (w/w) DCF-Na as measured by electrical conductivity tests, respectively.

On FIG. 6A-6B show a non-gel formulation without loading and loading with DCF-Na, respectively, at various dilutions.

On FIG. 7 shows the non-gel formulation in loading lidocaine at various dilution rates with water.

On FIG. 8A-8D are micrographs of cryo-TEM non-gel composition A from Table 2 (×650K magnification): 80 wt % water, no DCF-Na loading (FIG. 8A); 80% (wt.) water, 2% (wt.) DCF-Na (Fig. 8B); 90% (w/w) water, no DCF-Na loading (FIG. 8C); and 90% (wt.) water, 2% (wt.) DCF-Na (Fig. 8D).

On FIG. 9 is a cryo-TEM photomicrograph of a gel formulation loaded with 2% (w/w) DCF-Na.

On FIG. 10A-10D are SAXS measurements of composition A from Table 2 at various storage temperatures and dilutions: fresh (FIG. 10A); after storage at 5°C for 2 weeks (Fig. 10B); after storage at 5°C for 6 months (Fig. 10C); and after storage at 25°C for 6 months (Fig. 10D).

On FIG. 11A shows the diffusion coefficients (Dx, m ² /s) of the main components for the composition without loading and the composition with loading 2% (wt.) DCF-Na, 80% (wt.) dilution with water, in non-gel and gel-like systems (0.75 % (wt.) gelling agent). On FIG. 11B shows the diffusion coefficients of the main components of 2% (wt.) DCF-Na at various dilutions with water.

On FIG. 12 shows a comparison of the appearance of 2% (wt.) DCF-Na gel formulation, 80% (wt.) water (named NDS 506(A)) (right) and Voltaren Emulgel® (left).

On FIG. 13A-13B show polarizing light microscope images for Voltaren Emulgel® (FIG. 13A) and NDS 506(A) (FIG. 13B), x10 magnification.

On FIG. 14A-14B show the size distribution of the oil regions of the gelled DCF-Na composition as measured by the DLS (dynamic light scattering) method; the water concentration is 80% (mass.) (Fig. 14A) and 90% (mass.) (Fig. 14B) measured without the addition of gelling agent.

On FIG. 15A-15B show the rheological properties of stress τ (Pa) versus shear rate γ (1/s) for Voltaren Emulgel® (FIG. 15A) and NDS 506(A) (FIG. 15B).

On FIG. 16 shows viscosity measurements at a constant shear rate of 50 Hz as a function of time (s) for a gel aqueous phase (no oil phase) and for gel formulations loaded with DCF-Na for various xanthane contents (0.75%, 0.85% and 1.0%).

On FIG. 17A shows the dynamic complex flow viscosity μ of the gelled aqueous phase (without oil phase) as a function of shear rate (1/s) and gel formulation with 2 wt % DCF-Na loading. On FIG. 17B shows the viscosity of the aqueous phase (without the oil phase) of the unloaded gel formulation and the 2 wt % DCF-Na loaded gel formulation as a function of time at constant shear rate.

On FIG. 18A shows storage and loss moduli (G', G'') for a gelled aqueous phase (no oil phase) and a gelled formulation loaded with 2% (w/w) DCF-Na; and in FIG. 18B shows storage and loss moduli (G', G'') for unloaded gel formulations and loaded with 2% (w/w) DCF-Na.

On FIG. 19 shows complex viscosity measurements for an NDS 506(A) formulation with various xanthan concentrations (ranging from 0.75% (wt) to 2.85% (wt)) compared to Voltaren Emulgel®.

On FIG. 20A-20D show the results of spread tests for Voltaren Emulgel® Forte (FIGS. 20A-20B) and formulation NDS 506(A) (FIGS. 20C-20D).

On FIG. 21 shows the results of Franz diffusion cell ex vivo permeation and permeation after 24 hours (% Na-DCF of applied dose) performed on porcine skin samples compared to NDS 506(A) and Voltaren Emulgel® Forte.

On FIG. 22 shows the penetration profiles of DCF-Na concentration (µg/cm ² ) for NDS 506(A) with increased viscosity with 0.75% (wt.) or 2.85% (wt.) xanthan gum.

On FIG. 23A-23B show the results of LUMiFuge™ tests for NDS 506(A) (FIG. 23A) and a conventional commercial emulsion (FIG. 23B).

Detailed Description of Embodiments

Obtaining a gel-like composition with a loaded active substance

Stage 1: obtaining a concentrate or oil phase

An excipient blend was prepared by mixing phosphatidylcholine phospholipid (PC) (preheated to 45°C until completely melted), hydrogenated castor oil (40EO), Tween 60, propylene glycol (PG), isopropyl myristate (IPM), Transcutol, dimethyl isosorbide (DMI), fragrance , ethanol (EtOH) and isopropyl alcohol (IPA). This mixture was thoroughly mixed at 300-600 rpm at 25°C. The mixture turned into a clear, transparent light yellow liquid.

The active substance was added to the mixture in the form of a powder and stirred for 10-30 minutes to achieve complete capture of the active substance.

Stage 2: obtaining a gel-like composition with a loaded active substance

The active loaded oil composition can be diluted with any desired amount of water to obtain the desired concentration of active. As a rule, the concentrate is diluted by adding from 70 to 90% (wt.) water.

To obtain a gel formulation, xanthan gum was dissolved in purified water that had been buffered to pH 7.2-7.4, with gentle mixing, to obtain a homogeneous xanthan gel free of large chunks.

The xanthan gel was added to the active-loaded oil composition under mixing conditions at room temperature, gently mixing until uniform, and a substantially clear gel was obtained. The composition was placed under vacuum or centrifuged to remove any bubbles that may have been included in the final product having spontaneously formed regions from the oil phase having a size of <20 nm in the gel-like aqueous phase.

In another production sequence, Heco40 and Tween 60 were heated to 45°C and allowed to melt completely. The temperature was lowered and PG, IPA, ethanol, IPM, Transcutol, DMI, perfume and optionally an antioxidant were added and mixed to give a clear solution. The PC was then added to the oil mixture and optionally heated to 45° C. to ensure complete integration of the PC into the oil phase. The system was cooled to room temperature and then powdered Na-DCF was added portionwise to the oil phase to form a concentrate.

The gelled aqueous phase was prepared by dissolving xanthan gum in purified buffered aqueous solution or purified water in which the pH was adjusted to the desired pH. Then the concentrate was added to the aqueous phase at room temperature, with stirring until a homogeneous homogeneous almost clear gel. The composition was placed under vacuum or centrifuged to remove any bubbles that may have been included in the final product.

A system was prepared in a dilute gel formulation with spontaneously formed oil phase regions having a size of <20 nm dispersed in the gel aqueous phase.

The gel-formulation loaded with the composition of the active substance is shown in Table 1.

Line-up change

Table 2 lists some additional exemplary formulations of the present invention, including such formulation variations that include, inter alia, antioxidants (eg, BHT).

All formulations in Table 2 were obtained by mixing the ingredients in accordance with the methods described in this application. The compositions obtained were clear and transparent, with no evidence of phase separation or droplet coalescence.

The inclusion of various fragrances, antioxidants and/or pH modifiers (buffers) did not change the nanostructure of the composition.

Change in phospholipid type

The effect of altering phospholipid components on formulations of the invention was investigated for formulation A of Table 2. Concentrations of various sources of phosphatidylcholine (PC) from various lecithin derivatives and PC were tested ranging from 70% to 94%:

- Lipoid-S75 (70% PC), Lipoid-S100 (94% PC), Phospholipon 90G (94% PC), Epicorn 200 (94% PC) are based on soy;

- Non-GMO Lipoid-P100, 90% PC from soybeans;

- Lipoid-H100 non-GMO, 90% PC from sunflower seeds; and

- Lipoid-R100 non-GMO, 90% PC from rapeseed.

As seen in FIG. 2, all of the phospholipids tested resulted in clear and clear formulations, with no evidence of phase separation or droplet coalescence.

Change in type and amount of gelling agent

The effect of changes in type of gelling agent on formulations of the invention was investigated for formulation A of Table 2. Different types of xanthans were tested at 2 concentrations: 1% (w/w) and 0.75% (w/w) of the formulation. Table 3 shows the performance of the gel formulations tested with three different xanthans (Xantural® 75, 180 and 11K, all from PC Kelco).

As can be seen, the compositions retain their properties when changing the type of xanthan used as a gelling agent.

The effect of the amount of gelling agent was also evaluated. Based on composition A from Table 2, the amount of xanthan (Xantural 11K) was changed from 0.75% (wt.) to 2.85% (wt.). pH, turbidity and long term stability were measured for these formulations as shown in Table 4 (and in FIG. 3).

Despite increasing the amount of xanthan, all formulations remained clear with no noticeable change in pH or haze. No changes in the clarity of the formulations were found in the LUMiFuge™ tests, including increasing the amount of xanthan did not destroy the long-term stability of the formulation.

Fragrant change

Since perfumes are generally oil-based and oil-soluble, the effect of the presence or absence of perfume on the nanostructure and formulation stability, as well as the effect of changing perfume type, were studied. Table 5 details the formulations of the test formulations, all based on formulation A from Table 2, in which 0.6% (wt.) is a varying flavor.

As can be seen from Table 5 and Fig. 4, fragrance substitution and/or omission of fragrance from the formulation does not affect clarity. Optical microscopy and DLS measurement data showed that no change in the nanostructure was noticeable: the samples remained unclouded (transparent), without any visible change in turbidity. In all samples, the nano-region size measured in the non-gel system remained below 10 nm (monodispersed), with no evidence of phase separation or nano-region coalescence, indicating good compatibility between the nano-regions and different perfumes. This suggests that flavors that are oil soluble dissolve in the droplet core and integrate well into the interface. Solubility and transparency were also obtained for gel systems.

This is also confirmed by the DOSY measurements carried out for the examples shown in Table 6. No change in diffusion coefficients was measured, which means that the active substance (DCF-Na) remains within the interface despite by replacing or eliminating an oil-soluble fragrance.

As an indicator of the long-term stability of the formulations, LUMiFuge™ measurements were taken for 17 hours at 3000 rpm, with samples remaining completely clear throughout the duration of the test. These conditions are comparable to storage for 3 years, which indicates that the replacement of the fragrance or its removal from the composition will not affect the long-term stability of the compositions.

Gel formulation loaded with diclofenac sodium (DCF-Na)

Effect of dilution on the structure of the oil phase

An oil composition loaded with 2% (wt.) DCF-Na, which essentially does not contain water, that is, a concentrate, was obtained according to the method described above. The undiluted oil composition consisted of self-assembled oil-dissolved clusters or short regions of surfactants, which are different from classic reverse micelles. The concentrates can be diluted with any suitable diluent, such as purified water, to form a diluted delivery system.

The effect of dilution with water on the structure of the oil regions was investigated using electrical conductivity tests. Electrical conductivity measurements were carried out at 25±2°C using a CDM 730 electrical conductometer (Mettler Toledo GmbH, Greifensee, Switzerland). Measurements were carried out on empty and loaded DCF-Na samples when diluted with water up to 90% (wt.). No electrolytes were added to the samples. The conductivity made it possible to identify the continuous phase and the internal phase. The results are shown in FIG. 5A-5B.

Oil areas undergo phase transitions as the amount of diluent (eg water) increases. When in concentrated form, the oil composition is in the form of oil-dissolved clusters (short regions of surfactants) such that the DCF-Na is within the oil regions. When mixed with increased amounts of water, hydrated regions form; upon further dilution with water, the structure gradually and continuously turns into oily regions dispersed in water, so that DCF-Na molecules are localized and captured by surfactants at the interface between the oily regions and the aqueous phase. It is noteworthy that the absolute conductivity values of the empty system are noticeably lower than those of the loaded system due to the ionic nature of DCF-Na.

It is noteworthy that the oil carrier, ie the oil composition without DCF-Na, cannot be completely diluted. It was only after the addition of DCF-Na that stable oily regions were obtained, as seen in FIG. 6A and 6B. On FIG. 6A, the oil phase without loading the active substance was diluted to various concentrations of water; as can be seen, above 50% (wt.) of water, the system separates into phases. When the oil phase was loaded with 2% (wt.) DCF-Na, the system was completely diluted up to 90% (wt.), giving a clear and transparent composition, as seen in Fig. 6B.

As seen in FIG. 7, similar results were obtained when lidocaine, a structurant similar in function to Na-DCF, was loaded into the oil phase.

This indicates that the function of the active substance is to stabilize the interface between the oily regions; the active substance acts as a structurant, promoting and facilitating the formation of the final structure of the oily areas. This behavior differs from classical carrier systems, in which the active substance is simply loaded into the composition, without being included in the actual structure of the system. Thus, throughout the range of phase transitions occurring upon dilution, DCF-Na stabilized the structure of the delivery system and was trapped within the interface (as will be explained below with respect to SD-NMR analysis).

Additional formulations with various dilution levels are shown in Tables 7-1 and 7-2.

Structure of nanoregions

Micrographs of the dilute formulations (×650K magnification, Figs. 8A-8D) show that the regions are substantially monodispersed in size. The regions are not necessarily spherical and consist of an oil core and an interface containing surfactants and co-surfactants. The regions are dispersed in the aqueous continuous phase. Whereas empty droplets (FIGS. 8A and 8C) are more spherical, loaded systems (FIGS. 8B and 8D) have substantially elongated droplets with an aspect ratio of 1.1 to 1.5. With further dilution (i.e. increasing the dilution from 80% (wt.) water to 90% (wt.) water), the droplets become less packed and with less per unit volume.

As seen in FIG. 9, although the formulation is gel-like, the nano-regions remain structured, which means that the formation of a viscoelastic network in the aqueous phase does not affect solubilization capacity, stability, and release profiles. In other words, the gelling process of the aqueous phase does not affect the structure and stability of the nanoregions.

Small Angle X-ray Scattering (SAXS) measurements show that the regions are well structured with substantially constant droplet size and spacing (lattice parameters) that do not change with time or temperature (FIGS. 10A-10D). All measured samples have similar region sizes ranging from 7.1 nm to 8.6 nm with a spacing of approximately 1.6 nm between droplets.

When comparing empty systems to DCF-loaded systems, it seems that the presence of DCF-Na results in smaller oil areas; namely, when DCF-Na was loaded into the system, smaller, more homogeneous regions were spontaneously obtained (16 nm versus 6-10 nm for empty and loaded with oil phases, respectively). This also speaks to DCF-Na's function as a structurant (functioning as a space tropic agent), as shown in Table 8.

When a gelling agent is added to the composition, the structure is further changed and larger oil areas are formed. These regions are not spherical and their average size increases (by estimated measurements) to about 10-15 nm, as detailed in Table 9.

Thus, the gelling agent itself is thought to have an effect on the structure of the delivery system, since after the addition of the gelling agent, the regions increase slightly in size and elongate rather than collect into globular droplets.

To characterize the structure of the oil regions, NMR self-diffusion analysis (SD-NMR (DOSY)). CD-NMR (DOSY) provides a definition of each component in the structure by calculating the diffusion coefficient of each component in the system. Rapid diffusion (>100×10 ^-11 m ² s ^-1 ) is characteristic of small and unbound molecules in solution, and low diffusion coefficients (<0.1×10 ^-11 m ² s ^-1 ) suggest low mobility of macromolecules or bound / aggregated molecules.

SD-NMR (DOSY) measurements were performed using a Bruker AVII 500 spectrometer equipped with gradients of GREAT 1/10. -gradient coils and with a maximum gradient amplitude of 0.509 and 0.544 T m ^-1 , respectively. Diffusion was measured through an asymmetric bipolar longitudinal eddy current delay (bpLED) experiment or an asymmetric bipolar induced echo experiment (known as single pulsed) with convection compensation and a skewness factor of 20%, increasing the strength of the gradient from 2% to 95% of the maximum value in 32 passes. . The spectra were processed using Bruker TOPSPIN software. NMR spectra were recorded at 25±0.2°C. The components were identified by their chemical shifts in the 1H NMR spectra.

On FIG. 11A shows the diffusion coefficients (Dx, m ² /s) of the main components for the composition without 2% (wt.) DCF-Na and loaded with 2% (wt.) DCF-Na at a water content of 80% (wt.) in systems without high viscosity (non-gelled) and high viscosity (gelled). On FIG. 11B shows the effect of dilution on the diffusion coefficient of the loaded and gel formulation.

As can be seen in FIG. 11A-11B, the diffusion coefficient of DCF-Na is similar to that of hydrophilic surfactants compared to other components in the system. The Na-DCF diffuses slightly faster than the surfactant tails, indicating that the Na-DCF is located at the interface and not within the oil core of the oil regions (because the composition is very oil poor). In addition, the results show that polar solvents are mainly located in a layer remote from the surfactant heads, but interact with the heads and are not completely free (for surfactant tails, Dx=0.02×10 ^-11 and for DCF-Na Dx=0.1×10 ^-11 ).

This suggests that the binding occurs between DCF-Na and the surfactant heads, suggesting that the DCF-Na molecules are trapped between the surfactant tails at the interface of the oil regions, while the DCF-Na molecules may also function as auxiliary surfactant.

It should also be noted that the diffusion coefficient of DCF-Na is lower in a gel formulation than in a system without increased viscosity. This reduction also improves the stability of DCF-Na in the high viscosity/gel system and provides better control of the release of DCF-Na from oily areas when applied to the skin.

Based on the results of SD-NMR, the so-called "obstruction ratio (CO)" can be calculated. This coefficient is derived from the ability of each component in the structure to diffuse at each specific dilution level, referred to the diffusion coefficient of the component itself in liquid form or reference solution [KO=D/D ₀ ]. The obstruction coefficient indicates the stability of the isolated components from the structure at a given concentration of DCF-Na solubilization (2% (wt.)). It can be seen that due to their similar behavior and the correlation of diffusion coefficients, the components that prevent the release of Na-DCF from within the interface are a combination of surfactants. Low KO values of 0.1 to 0.2 indicate noticeable effects of DCF-Na binding to surfactants and hence a slower release to form a deposition effect. Solvents and water do not interfere with the drug molecule (KO values of 0.5 and 0.6).

Gelled DCF-Na formulation compared to a commercial product

Gel DCF-Na formulations were prepared as described above. Their various properties have been compared to Voltaren Emulgel® Forte, which is currently the leading commercial product for topical delivery of diclofenac. Voltaren Emulgel®Forte contains 2.32% (wt.) diclofenac diethylamine (DCF-DEA, which is comparable to 2% (wt.) DCF-Na) in a gel-like emulsion formulation that mainly contains inactive ingredients (excipients), such as butylhydroxytoluene, carbomers, cocoylcaprylocaprate, diethylamine, isopropyl alcohol, liquid paraffin, macrogol cetostearyl ether, oleyl alcohol, propylene glycol and purified water.

Appearance

The physical properties of a 2% (wt.) DCF-Na gel formulation at 80% (wt.) dilution with water (designated NDS 506(A) for simplicity) compared to Voltaren Emulgel® Forte are shown in Table 10.

The appearance difference between NDS 506(A) and Voltaren Emulgel®Forte is shown in FIG. 12 and microscope images are shown in FIG. 13A-13B.

Commercial emulsion-based products such as Voltaren Emulgel® or Voltaren Emulgel® Forte are typically a dispersion of two immiscible liquids formed in the presence of emulsifiers/surfactants that lower the surface tension between the two phases and coat the dispersed droplets for slowing down aggregation, flocculation, coalescence and phase separation. Because emulsifiers do not reduce surface tension to zero and coverage is not complete, emulsions require the use of relatively high shear forces in a multi-stage homogenizer to reduce the droplet size when making an emulsion. The resulting inhomogeneous droplets have a strong tendency to coalesce and/or lead to phase separation, thereby stabilizing the system energetically. Thus, the commercial product shows a relatively non-uniform droplet distribution, together with a large droplet size, far from being homogeneous, resulting in a milky, cloudy white appearance.

By comparison, the NDS 506(A) formulations spontaneously formed as balanced systems due to their essentially zero surface tension. Such formulations are characterized by a small and uniform size of the oil regions, as seen in FIG. 14A-14B, resulting in transparent and stable systems.

Viscosity and rheological properties

The rheological properties of Voltaren Emulgel® and NDS 506(A) were measured with ThermoHaake (Thermo Electron GmbH, Karlsruhe, Germany) using a cone (diameter 60 mm) and a glass plate, at 25±1°C, shear rates were 0-100 s ^-1 as shown in FIG. 15A-15B, respectively.

As can be seen from the viscosity measurements, the viscosity of Voltaren Emulgel®Forte is significantly higher than that of NDS 506(A). As explained above, Voltaren Emulgel® Forte is a thermodynamically unstable emulsion and therefore requires relatively high gelling and high viscosities to stabilize the emulsion. In addition, such high viscosities often reduce the ability of the formulation to penetrate the skin after application and may also reduce the penetration and release of diclofenac into the skin and related tissues.

The viscosity of the gel systems measured at 50 Hz over time, shown in FIG. 16 remains constant over time and generally depends on the concentration of xanthan gum (or other viscosity-increasing agents) in the formulation.

As already noted, the structures of empty systems differ from the structures formed by gel-like systems loaded with DCF-Na. Since these differences were found to have a significant effect on the release of DCF-Na from the delivery system and therefore on the formation of the deposition effect, the rheological properties of each system were characterized.

Thus, the rheological properties of a xanthan gel (ie, a gelled aqueous phase without adding an oil phase), an unloaded gel formulation, and a DCF-Na loaded gel formulation were measured and compared. The comparison provided data on dynamic complex viscosity (η*), as well as storage modulus (G') and loss modulus (G''), which reflect the viscoelastic properties of the systems.

As seen in FIG. 17A, for both the gelled aqueous phase (no oil phase) and the gel formulation loaded with 2% (w/w) DCF-Na, the complex viscosity decreases significantly with increasing shear rate, with the complex viscosity increasing at high shear rates, indicating destruction of the gel structure (gel-sol transition). It is important to note, however, that the loaded gel formulation exhibits higher complex viscosities over the entire shear rate range compared to pure xanthan gel, indicating high formulation stability. As seen in FIG. 17B, the loading of DCF-Na into the gel formulation does not significantly affect the viscosity, and its complex viscosity is similar to that of the unloaded gel system.

As seen in FIG. 18A, the storage and loss moduli (G' and G'') of loaded gel formulations are higher than those of pure xanthan gel, which means that loaded gel formulations have higher storage energy. The energy loss is lower in the loaded gel formulation compared to pure xanthan gel, indicating that the loaded gel formulation exhibits viscoelastic properties and is expected to form a viscoelastic film on the skin upon application. From FIG. 18B, it can be seen that loading DCF-Na into the gel system has no effect on storage and loss modules.

Further study of the rheological properties of the compositions was investigated by measuring the complex viscosity at very low shear rates, carried out for systems loaded with different amounts of xanthan (from 0.75% (wt.) to 2.85% (wt.)) compared to Voltaren Emulgel ® Forte (Fig. 19). At these low shear rates, simulating the rubbing of a gel onto the skin surface, the measured viscosity is lower compared to Voltaren Emulgel® Forte. However, at 2.85% (w/w) gelling agent, the viscosity loss of the composition with increasing shear rate decreases more slowly and eventually becomes the same as the viscosity of commercial emulsions (at 0.99 1/s). Without wishing to be bound by any particular theory, commercial emulsion has relatively large droplets and is highly anisotropic. Therefore, overcoming the interaction between oil droplets in order to cause flow requires more energy input into the system (i.e. higher shear rates). The NDS 506(A) composition, in contrast, has smaller and more homogeneous nano-regions, resulting in a relatively more isotropic system; these systems do not exhibit significant interaction between nano regions, hence flow can be induced and maintained at very low shear rates.

Because the formulations are designed for topical application, the viscosity of the formulations has an effect on their spreading. This is shown when using the spreading test.

Spreading is assessed by placing 350 mg of the test composition in the middle of a clean, dry and uniform glass surface. The sample is covered with another glass surface having a mass of 180 g. After 60 seconds, the diameter of the spread sample is measured and compared with its original diameter (before applying the load). The spreading coefficient S is calculated by the following formula: S=m⋅A/t, in which m denotes the load (g) placed on the sample, A denotes the spreading area (cm ² ) and t (s) denotes the time during which the sample was subjected to load action. Each composition was tested 3 times.

On FIG. 20A-20B show the flow test for Voltaren Emulgel® Forte and FIG. 20C-20D show test results for NDS 506(A). In addition, as can be seen from Table 11, the NDS 506(A) formulation exhibits improved spreading compared to Voltaren Emulgel® Forte, indicating that NDS 506(A) can cover a larger area of the skin when using a given amount of formulation.

Organoleptic analysis

NDS 506(A) was compared with Voltaren Emulgel®Forte in a number of sensory tests. 20 human volunteers were asked to thoroughly wash their hands and dry them completely to remove any residual water. A predetermined mass of formulation (350 mg NDS 506(A) or Voltaren Emulgel®Forte) was placed on the back of the hand. Volunteers were asked to rate the immediate sensation of contact of the gel in terms of its texture, consistency and creaminess on a scale of 1 to 6. The volunteers were then asked to rub in the gel and rate again on a scale of 1 to 6 the feeling of being sticky, greasy and soft. At the last stage, the volunteers were asked to rate the subsequent effect including softness, oiliness, stickiness - residue and possible film formation using the same scoring system as before.

As shown in Tables 12-1 and 12-2, various parameters were evaluated before, during and after application to the skin.

As can be seen from the results of sensory analysis, the NDS 506(A) formulation showed better sensory and texture parameters, suggesting that these formulations are better absorbed into the skin. It may also improve patient compliance with the treatment regimen.

Ex vivo permeation and permeation of DCF-Na

Ex vivo permeability and penetration of NDS 506(A) was measured against Voltaren Emulgel® Forte using the Franz diffusion cell (FC) system (PermeGear, Inc., Hellertown, PA) using fresh porcine ear skin dermatome. A comparison was made between NDS 506(A) and Voltaren Emulgel®Forte (2.32 wt % DCF-DEA). It is noted that 2.32% (wt.) DCF-DEA is comparable to 2.0% (wt.) DCF-Na.

Penetration Procedure Procedure: Five repetitions of the FC penetration tests were performed for each formulation sample. There were no wounds, warts or bruises on the selected skin samples. Skin integrity was determined using transepidermal water loss (TEWL) (Dermalab Cortex Technology instrument, Hadsund, DenMark). Subsequently, only pieces with a TWEL level of less than 10 ± 2.5 g/m ² h were used.

The skin in the receiver chamber was placed with the stratum corneum (SC) facing upwards and the donor parts were secured in place. The receiver was filled with freshly prepared phosphate buffer PBS (pH 7.4) with constant stirring using a Teflon-coated magnetic stirrer, while heating to 34±2°C (depending on room temperature), obtaining 32°C in the acceptor cell. Before the start of the experiment, the skin was left for conditioning with pre-warmed (32°C) 0.5 ml PBS (phosphate-buffered saline) placed in the donor cell.

After 30 minutes, the PBS was removed and some infinitesimal amount (5 mg/cm ² ) of NDS 506(A) and Voltaren Emulgel®Forte were applied to the skin in a homogeneous distribution of formulations. The donor part of the cell was left open for 30 minutes to allow the gel to properly adhere to the membrane and form a thin film on the skin surface. The donor cells and sampling port were then plugged with Parafilm to prevent further evaporation.

Aliquots of 0.5 ml were withdrawn from the acceptor cell at predetermined intervals using a long glass Pasteur pipette to reach the region near the spring and achieve maximum uniformity. The cells were filled up to the mark with fresh heated (32°C) buffer solution. The addition of this solution to the receiver was done with great care to avoid entrapment of air bubbles under the dermis. Samples were collected in 1.5 ml amber glass vials and stored at -20°C until completion of the analysis.

All samples were measured by HPLC (Waters, Milford, MA/Waters 717 plus autosampler fitted with a Waters 996 photodiode array detector) according to the procedure described below. The concentration of diclofenac in the samples was evaluated by a calibration curve of eight points obtained on standard samples, with an R ² value of not more than 0.999. Total drug penetration was calculated (µg/cm2) and plotted against time.

HPLC Waters 600 series; automatic sampling Waters 717 plus; Waters 996 photodiode array detector. Mobile phase: 65% acetonitrile/35% water/0.1% trifluoroacetic acid or formic acid. Column type: aqueous 5 µm, C18, 250 mm×4.6 mm (Phenomenex). Guard column: SecurityGuard cartridge, C18, 4×3.0 mm ID (Phenomenex). Flow rate: 1 ml/min; 30°C; injection volume 5 µl.

Penetration procedure technique (tape scraping) [9]: The technique was performed as above. However, sampling from the acceptor cell was carried out only after 24 hours. The remaining compositions were carefully removed from the donor cell using a spatula. The formulations were placed in a vial containing 10 ml of methanol and the donor portion was thoroughly rinsed using the same volume of methanol to ensure that any remaining formulation remaining on the glass was also removed.

The adhesive tape was applied to the surface of the skin and pressed using a roller of constant weight to avoid striations and wrinkles and ensure uniform adhesion of the tape. An additional strip was taken from the skin (total 3). Strips 1-3 were placed in one vial along with the composition. This vial content is the diclofenac remaining in the sample (composition) from the donor cell after 24 hours, along with what is found on the surface of the skin, which is called "Composition + top" (data not shown).

Seven additional strips (4-10#) were removed and placed together in a separate 10 ml methanol vial to analyze the skin deposition effect of diclofenac, which was called "deep skin".

The remaining skin strips were placed in a third vial with 10 ml of methanol to analyze the content of diclofenac on this skin layer, which was called "skin strips"). As a positive control and to determine the diclofenac content, the same amount of fresh formulation was dissolved in a 10 ml methanol vial and the returns from all collected diclofenac concentrations (from all stages) were pooled from all layers and found to have a penetration of approximately 90-100%.

All vials (except samples taken from the acceptor cell) were shaken at room temperature for 1.5 hours at 200 rpm and sonicated for 15 minutes. Samples were filtered using a 0.45 µm funnel and transferred to clean new amber glass vials. All samples were analyzed by HPLC (as above). The quantitative content of diclofenac was calculated using a calibration curve on eight standard samples having R ² not less than 0.999.

Comparative results of ex vivo tests are shown in FIG. 21. Measurements of DCF-Na levels in skin layers ("deep skin" and "skin stripes") showed increased concentrations of DCF-Na when tested with NDS506(A) formulation compared to commercial Voltaren Emulgel® Forte (2.32% (wt. ) diclofenac diethylamine). However, drug penetration levels measured after 24 hours in the acceptor cell were the same in all three test formulations. This shows that DCF-Na penetration using NDS506(A) reaches deeper layers of the skin at higher concentrations and further to the desired tissue compared to the reference product, with limited systemic exposure. Without wishing to be bound by any particular theory, the results of the diffusion cell assay demonstrate the effect of skin deposition of NDS506(A) and its penetration into topically treated joint tissues with limited systemic exposure.

Increasing the xanthan content from 0.75% (wt.) to 2.85% (wt.) has no effect on the penetration of DCF-Na in the diffusion cell test, as seen in FIG. 22. Namely, although the viscosity of the formulation increased and a denser or stronger network formed in the aqueous phase, this did not prevent the release of DCF-Na from the formulation.

Stability

Antioxidant stability of NDS 506(A) was evaluated over a period of 3 months at four different temperatures and relative humidity (% RH) (4° C., 25° C./60% RH and 40° C./75% RH).

Appearance, pH, % DCF-Na (HPLC method) was determined at each time point for three samples and compared with initial measurements taken immediately after the preparation of the formulations. The results are presented in Table 13.

In addition, NDS506(A) was found to be stable after 72 hours of freezing and thawing to room temperature (data not shown), namely, the structure of the composition was maintained, without any phase separation or change in the appearance of the composition.

As can be observed, DCF-Na loaded gel formulations retain their clearness, pH and active agent concentrations for extended periods of time, ie up to at least 3 months when stored under various storage conditions. Thus, these formulations can be stored for extended periods of time without compromising their properties.

To determine the long-term stability of the formulations, a quick measurement was performed using the LUMiFuge™ Analytical Centrifugation. LUMiFuge™ analysis allows predicting the shelf life of a formulation at its original concentration, even in cases of slow degradation processes such as emulsion separation, sedimentation, flocculation, coalescence and fractionation. During LUMiFuge™ measurements, parallel light illuminates the entire sample cell in a centrifugal field; transmitted light is recorded by sensors arranged linearly along the entire length of the sample cell. Local changes in particles or droplets are recorded due to changes in light transmission over time. The results are presented as a graph showing the percentage of transmitted light (Transmission, %) versus location (mm), showing the corresponding transmission profile over time.

LUMiFuge™ test results for NDS 506(A) and conventional commercial emulsion are shown in FIG. 23A-23B, respectively, over a period of 24 hours.

The analysis of the emulsion (having a milky white appearance), scattering and absorbing light, resulted in a significant decrease in light transmission over time, since the stability of the gel-like emulsion was broken. In contrast, NDS 506(A) formulations (having a clear and transparent appearance) provided light transmission (100%) through the entire measured length of the cell. Transmitted light reflecting the transparency of the sample was obtained even after 24 hours of centrifugation at 3000 rpm, tested during the analysis. These results confirm the expectations associated with the NDS 506(A) formulation having long-term stability properties after long-term storage.

Freeze and thaw resistance

Freeze and thaw resistance was evaluated by placing a sample of NDS506(A) formulation at -20° C. for 72 hours and then thawing at room temperature for 2 hours. The compositions remained clear and homogeneous after freezing and thawing, with no visible changes.

Claims (20)

1. A topical formulation for dermal or transdermal delivery of an active substance, comprising an oil phase integrated into a gel-like aqueous continuous phase, wherein the oil phase is in the form of oily nano-regions dispersed in the continuous phase, moreover, the oil phase contains the active substance, at least one oil, at least two hydrophilic surfactants, at least two polar solvents and at least two penetration stimulators, where the oil phase allows you to control the release of the active substance upon contact with the skin, and wherein the gel-like aqueous continuous phase contains an aqueous diluent and at least one gelling agent, moreover, the specified oil is present in an amount of from about 0.5 to 3% by weight of the composition; wherein said at least two hydrophilic surfactants are independently selected from polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene esters of saturated (hydrogenated) or unsaturated castor oil, ethoxylated monoglycerol esters, hydroxystearate, ethoxylated fatty acids and ethoxylated fatty alcohols, ethoxylated fatty acids and ethoxylated short, medium and long chain fatty alcohols, sugar esters and saturated and unsaturated fatty acids, sucrose mono- and polyester esters, polyglycerol fatty acid esters, ethoxylated monoglycerides and ethoxylated diglycerides, and said at least two hydrophilic surfactants contain the first hydrophilic surfactant in an amount of from about 1.75 to 8.0% by weight of the composition ava and a second hydrophilic surfactant in an amount of from about 0.45 to 3.8% by weight of the composition; where said at least two polar solvents include at least a first polar solvent selected from short chain alcohols and at least a second polar solvent selected from polyols, and the total amount of solvents in the composition is from about 3 to 20 wt. %, the specified gelling agent is in the composition in an amount of from about 0.75 to 3.5 wt. %; and said active substance is diclofenac or a pharmaceutically acceptable salt thereof. 2. The formulation of claim 1, wherein the oil phase further comprises at least one lipophilic co-surfactant, which optionally is a phospholipid. 3. The composition of claim. 1, in which the oil areas have an average area size from 5 to 150 nm. 4. The composition of claim. 1, in which the oil areas have an aspect ratio of from about 1.1 to 1.5. 5. The composition of claim. 1, in which the oil areas have an elongated shape. 6. Composition according to claim 1, wherein the active substance is selected from diclofenac, diclofenac sodium (DCF-Na), diclofenac potassium (DCF-K), DCF-ammonium, diclofenac diethylamine (DCF-DEA) and mixtures thereof. 7. The composition according to p. 6, in which the specified active substance is present in the composition in an amount of from about 1 to about 6 wt. %. 8. Composition according to claim 1, wherein said oil is selected from isopropyl myristate (IPM), ethyl oleate, methyl oleate, lauryl lactate, oleyl lactate, oleic acid, linoleic acid, monoglyceridoleate and monoglyceridlinoleate, coco caprylocaprate, hexyl laurate, oleylamine, oleyl alcohol, hexane, heptanes , nonane, decane, dodecane, short chain paraffinic compounds, terpenes, D-limonene, L-limonene, DL-limonene, olive oil, soybean oil, rapeseed oil, cottonseed oil, palmolein, sunflower oil, corn oil, essential oils, such as peppermint oil, pine oil, mandarin oil, lemon oil, lime oil, orange oil, citrus oil, neem oil, lavender oil, anise oil, pomegranate seed oil, grape seed oil, pumpkin oil, rose oil, clove oil, sage oil, eucalyptus oil, jasmine oil, oil of oregano, capsaicin and similar essential oils, triglycerides (for example, unsaturated and polyunsaturated tocopherols ), medium chain triglycerides (MCTs), avocado oil, pomegranate (omega-5 fatty acids) and CLA fatty acids, omega-3, -6, -9 fatty acids and ethyl esters of omega fatty acids, and mixtures thereof. 9. The composition of claim 1, wherein the oil is selected from isopropyl myristate (IPM), oleic acid, oleyl alcohol, vegetable oils, terpenes, peppermint oil, eucalyptus oil, and mixtures thereof. 10. The formulation of claim 1 wherein said at least two penetration enhancers are independently selected from dimethyl sulfoxide (DMSO), dimethyl isosorbide (DMI), isopropyl myristate (IPM), 2-(2-ethoxyethoxy)ethanol (Transcutol), phosphatidylcholine (PC ), ethanol, isopropyl alcohol (IPA), ethyl acetate, oleyl alcohol, oleic acid, oleyl esters, beta-cyclodextrins, urea and its derivatives such as dimethyl or diphenylurea, glycerol and propylene glycol (PG), pyrrolidone and derivatives, oils peppermint, essential oils - oils of terpenes and terpenoids and their combinations. 11. The formulation of claim 1, wherein said gelling agent is selected from cellulose ethers (e.g., hydroxyethylcellulose, methylcellulose, hydroxypropyl methylcellulose), polyvinyl alcohol, polyquaternium-10, guar gum, hydroxypropyl guar gum, xanthan gum (such as Xantural 11K, Xantural 180K (CP Kelco US) and others), gellan, Aloe vera gel, amla, carrageenan, oatmeal, starch (from corn, rice and other plants), gelatin (pigskin), ghatti gum, gum arabic, inulin (from chicory ), konjac gum, locust bean gum, marshmallow root, pectin (high and low methoxylated), quinoa extract, red algae, cork gum (solagum), gum tragacanth (TG), Carbopol polymers and mixtures thereof. 12. The formulation of claim 1 wherein said diluent is selected from water, purified water, distilled water (DW), double distilled water (DDW), and triple distilled water (TDW), deionized water, water for injection, saline solution, dextrose solution, or buffer having a pH of 4 to 8. 13. The formulation of claim 1 wherein said aqueous diluent to be viscosified/gelled by the gelling agent is any suitable aqueous liquid.

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