This application claims the priority of European applications EP20168335.6, filed 6 April 2020, and EP20168596.3, filed 7 April 2020, both of which are fully incorporated by reference herein.

The present invention relates to topical (dermal) pharmaceutical formulations for the treatment of pruritus (itching). The formulations are biphasic, containing an aqueous phase and a lipophilic phase, and at least one of the phases contains particles insoluble in that phase, that provide texture to relieve itching, that dissolve in the other phase.

Background of the Invention

The aetiology of pruritus is only partially understood, and despite the frequency and high level of suffering associated with pruritus, there is still no effective universal treatment. Itch is intrinsically linked with scratching (Sanders et al. F1000 Research. 2016, 5: F1000 Faculty Rev-2042). Previously, it was assumed that scratching provokes a pain stimulus drowning out the itching. However, recent studies have demonstrated that the action of scratching provokes a whole series of complex effects in the brain. Unlike pain, scratching strongly activates regions of the brain associated with reward and perception (Mochizuki et al. J. of NeurophysA 1(3): 488-98). Functional magnetic resonance imaging demonstrated that several reward- associated areas were activated during scratching and were correlated with both pleasure and itch-relief (Sanders et al., 2016). In addition, a study showed that active scratching by the participant gives better itch-relief and is perceived as more pleasant than being passively scratched by an experimenter (Papoiu et al. PloS one 2013. 8(12):e82389). Management of pruritus has until now, aimed to break the “vicious” itch-scratch cycle, in as it is argued that excessive scratching leads to damage of the natural skin barrier, making the skin vulnerable for irritants and pathogens, which again might exacerbate or trigger itching.

Here, a contrary approach was taken: Scratching should no longer be suppressed, but instead incorporated into the treatment procedure. Two well-known itch-relieving methods, namely vehicles with antipruritic properties, and the physical act of scratching itself, were integrated in a single novel formulation for topical application. This resulted in an anti-pruritic emulgel involving two types of dull, non-damaging, granular particles, which prevent skin excoriation, while at the same time mimics the instantaneous feeling of relief brought by scratching.

W02008038807A1 discloses topical formulations comprising butylhydroxytoluene. No second phase or second type of particles are described.

W02009087578A2 discloses an emollient emulsion foam comprising menthol. Based on the above-mentioned state of the art, the objective of the present invention is to provide means and methods to treat pruritus. This objective is attained by the subject-matter of the independent claims of the present specification, with further advantageous embodiments set out in the dependent claims.

Detailed Description of the Invention Terms and definitions

For purposes of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. In the event that any definition set forth below conflicts with any document incorporated herein by reference, the definition set forth shall control.

The terms “comprising,” “having,” “containing,” and “including,” and other similar forms, and grammatical equivalents thereof, as used herein, are intended to be equivalent in meaning and to be open ended in that an item or items following any one of these words is not meant to be an exhaustive listing of such item or items, or meant to be limited to only the listed item or items. For example, an article “comprising” components A, B, and C can consist of (i.e., contain only) components A, B, and C, or can contain not only components A, B, and C but also one or more other components. As such, it is intended and understood that “comprises” and similar forms thereof, and grammatical equivalents thereof, include disclosure of embodiments of “consisting essentially of” or “consisting of.”

Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit, unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

Reference to “about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se.

As used herein, including in the appended claims, the singular forms “a,” “or,” and “the” include plural referents unless the context clearly dictates otherwise.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art (e.g., in cell culture, molecular genetics, nucleic acid chemistry, hybridization techniques and biochemistry). Standard techniques are used for molecular, genetic and biochemical methods (see generally, Sambrook et al., Molecular Cloning: A Laboratory Manual, 4th ed. (2012) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. and Ausubel et al., Short Protocols in Molecular Biology (2002) 5th Ed, John Wiley & Sons, Inc.) and chemical methods.

As used herein, the term treating or treatment of any disease or disorder (e.g. pruritus) refers in one embodiment, to ameliorating the disease or disorder (e.g. slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment "treating" or "treatment" refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. Methods for assessing treatment and/or prevention of disease are generally known in the art, unless specifically described herein below.

The term “pruritus” as used in the context of the invention is defined as an unpleasant sensation, often in the skin, which provokes the urge to scratch. Often referred to as “itch”, pruritus is a characteristic feature of many skin diseases, but can also have, immunologic, neurological or systemic origins. Pruritus can be local or generalised, and can be a chronic or an acute condition.

A first aspect of the invention relates to a composition for topical administration, comprising, or in certain embodiments, consisting of two phases, a hydrophilic phase which contains at least one type of granules or particles, in addition to a lipophilic phase.

The term “phase" as used in the context of the invention refers to a vehicle for the topical administration of a treatment substance to the skin, in other words, a gel, an ointment, or a cream. The combination of two phases in the data in the examples is sometimes described as an emulgel, which is an emulsion made of up gelling agents, particularly useful in the delivery of hydrophobic drugs. An emulsion can be generated by the composition according to the invention. It is understood that the topical composition however is provided in a state where two phases are separate and the emulsion is created by the patient, or a caretaker, in the act of applying or administering the composition.

An alternative of this first aspect of the invention relates to a topical composition comprising a hydrophilic phase and a lipophilic phase provided as two separate phases prior to topical administration, each phase comprising particles, wherein a hydrophilic phase comprises first particles, and wherein a lipophilic phase comprises second particles. The first particles are stably particular, i.e. insoluble in the hydrophilic phase, but are soluble in the lipophilic phase. The second particles are stably particular, i.e. insoluble in the lipophilic phase, but are soluble in the hydrophilic phase. In certain embodiments, the topical composition comprises a hydrophilic phase and a lipophilic phase provided as two separate phases prior to topical administration, the hydrophilic phase comprises first particles that comprise or essentially consist of menthol, and the lipophilic phase comprises second particles that comprise or essentially consist of a water soluble salt.

The term particle in the context of the invention encompasses a substance or pharmaceutical formulation in a solid, or crystalline form, such that the particles are of sufficient size to provide a granular, lightly abrasive texture to the composition.

It is a desirable aspect of the invention that the particles suspended within the hydrophilic vehicle should be lipophilic, i.e. tending to dissolve in lipids or fats rather than water-based media, and therefore will not dissolve when stored within the hydrophilic phase of the topical composition according to the invention. In this way, non-polar particles suspended in the hydrophilic phase provide a granular, or lightly abrasive texture.

An important aspect of the invention is combination of the hydrophilic phase containing a lipophilic particle, and the lipophilic phase during topical administration. These two vehicles will mix when the composition containing the two phases is applied topically, for example by rubbing into the skin. This aspect of the invention serves the dual purpose of delivering a pleasant sensation of scratching an itch, while at the same time performing a manual mixing process allowing medicaments contained in the granules to be absorbed into skin when the lipophilic particles dissolve in the lipophilic phase. This aspect of the invention is also important for the topical composition to be non-occlusive, providing acute relief without needed to be wiped away.

In certain embodiments of the invention, the lipophilic phase of the topical composition comprises, or in some cases, also contains particles, allowing additional textural or medicinal components to be included in the formulation.

In certain embodiments of the invention, the particles suspended within the hydrophilic phase of the topical composition comprise, or may essentially consist of menthol. Menthol has the advantages of providing, in addition to the textural quality, a pharmaceutical quality in that it has analgesic properties and provides a sensation of cooling due to its interaction with temperature sensitive receptors on skin cells.

In certain particular embodiments, the particles suspended within either phase of the topical composition are characterized by a mean particle size of 200 - 2000 pm.

In certain particular embodiments, the particles suspended within either phase of the topical composition are characterized by a mean particle size of 800 - 2000 pm.

In certain particular embodiments, the particles suspended within either phase of the topical composition are characterized by a mean particle size of 200 - 1000 pm. In certain particular embodiments, the particles suspended within either phase of the topical composition are characterized by a mean particle size of 400 to 1200 pm.

In certain particular embodiments, the particles suspended within either phase of the topical composition are characterized by a mean particle size of more particularly by a particle size of 400 to 800 pm.

In certain particular embodiments, the particles suspended within either phase of the topical composition are characterized by a mean particle size of 500 - 750 pm.

The data presented in the examples demonstrates that menthol crystals with the particle size 500-710 pm (with reference to the approximate diameter of each granule of menthol, also known as grain size), had the desired texture and did not dissolve when mixed with a hydrophilic gel. This means that granules of menthol were retained by sieves that have a mesh size of 500 pm, and passed through a sieve with a mesh size of 710 pm.

In certain embodiments of the topical composition according to the invention, the second particles suspended in the lipophilic phase comprise, or in certain embodiments essentially consist of a water soluble particle, which will not dissolve in the lipophilic vehicle and can therefore add an additional scratching sensation during application to the skin, until the point at which it dissolves when mixed with the hydrophilic phase. In certain particular embodiments, the water soluble particle is a water soluble salt, more particularly a water soluble salt of a first or second group (alkali, earth alkali) element.

In particular embodiments, the lipophilic phase of the topical composition according to the invention contains, or in certain embodiments comprises sodium chloride (NaCI), potassium chloride (KCI), magnesium chloride (MgCh), calcium hydrogen phosphate CahfePO^ or CaH(P04)2, or another water soluble salt with the desired particle size and non-irritant qualities that suit topical administration.

The data in the examples demonstrates that the water soluble salt NaCI persists as granules when stored in the lyophilic media, and dissolves on coming into contact with the hydrophilic phase during topical administration, providing additional textural stimulation during the process of application.

In a particular embodiment of the topical composition according to the invention, menthol particles for addition to the hydrophilic phase are characterized by a mean particle size of 500 - 750 pm.

In certain embodiments of the topical composition according to the invention, the first particles are characterized by a mean particle size of 200 - 1000 pm. In certain embodiments of the topical composition according to the invention, the second particles are characterized by a mean particle size of 200 - 1000 pm.

In certain embodiments of the topical composition according to the invention, the first particles are characterized by a mean particle size of 400 to 800 pm, particularly by a particle size of 500 - 750 pm.

In certain embodiments of the topical composition according to the invention, the second particles are characterized by a mean particle size of 400 to 800 pm, particularly by a particle size of 500 - 750 pm.

In certain embodiments of the topical composition according to the invention, the first particles are menthol particles characterized by a mean particle size of 500 - 750 pm.

In certain embodiments of the topical composition according to the invention, the lipophilic phase which may or may not contain additional particles, comprises, or in some cases essentially consists of long chain waxy esters. A particularly desirable embodiment of the topical composition is one in which the lipophilic phase comprises or essentially consists of lanolin.

The term lanolin as used here is meant to encompass high-purity, acetylated lanolin as commonly used in formulations for topical administration, sometimes referred to in the description as “Wollwachsalkoholsalbe”. It should be understood that other hydrophobic gels for topical administration would be equally effective, such as acetate, silicone or oil-based gels.

The data in the examples show that acetylated lanolin is an effective vehicle for the suspension of NaCI particles, in order to deliver a scratching sensation during administration, while at the same time effectively dissolved the lipophilic menthol particles contained in the composition.

In certain embodiments, the hydrophilic phase comprises a hydrogel forming polymer, and may further comprise a buffer system, chelating agents for preservation, and excipients suitable for dermal application.

In certain particular embodiments, the hydrogel forming polymer is selected from galactomannan, kappa-carrageenan, alginate, alginate sulfate, cellulose, methylcellulose, ethylcellulose, bacterial cellulose, carrageenan, carrageenan sulfate, cellulose acetate, chitosan, chondroitin sulfate, dextran, hydroxypropyl dextran, fucan sulfate, gelatin, gellan gum, acylated and/or sulfated gellan gum, guar gum, gellan sulfate, cassia gum, konjac gum, Arabic gum, ghatti gum, locust bean gum, heparin, heparan sulfate, hyaluronan, hyaluronan sulfate, mannuronan, pectin, starch, hydroxypropyl starch, ulvan (sulfated xylorhamnoglucuronan), xanthan gum and xanthan gum sulfate. In certain particular embodiments, the hydrogel forming polymer is selected from alginate, hyaluronic acid, cellulose, chitosan, polyethylene glycol, gellan gum, caarageenan, and polyacrylate.

In certain embodiments of the topical composition according to invention, the hydrophilic phase is a hydrogel which comprises the polymer carbomer (polyacrylate), particularly carbomer 35 000, and in addition may comprise one or more of trometamol (Tris), sodium EDTA (edetate disodium), and/or propylene glycol. Carbomer 35000 is an example of a 2-propenoic acid homopolymer which can be used in the manufacture of a hydrogel with desirable hydrophilic features. Carmellose sodium, hydroxypropylcellulose and other cellulose derivatives are further examples of well-known polymers that can form hydrogels.

It is understood that the hydrogel as described in the in examples could be substituted by any similar hydrophilic media for topical administration. A hydrogel is a network of hydrophilic polymers that can incorporate large amounts of water: Examples of hydrogels currently available for use in gels for topical administration include Hypan (Hymedix International, USA), Smart Hydrogel (MedLogic Global, UK), Aquamere and Aquatrix II (Hydromer, USA).

In certain particular embodiments of the topical composition according to the invention an anaesthetic and/or antihistamine is included as part of the formulation, to assist in the relief of itching. One particular anaesthetic that is desirable for incorporation into the composition according to the invention is polidocanol. In similar alternatives or additional embodiments, the additional medicament incorporated into the formulation could be lidocaine, benzocaine, capsaicin, or other medicaments that are used for topical treatment of pruritus.

In the data in the examples, the hydrophilic phase used as vehicle for menthol particles is a hydrogel, such as “carbomagel” made by combining carbomer 35000, trometamol, sodium EDTA, and propylene glycol, combined with polidocanol at an appropriate dose to deliver topical anaesthesia. This composition successfully incorporated menthol particles without dissolving until mixed with the additional lipophilic phase.

In an alternative embodiment of the topical composition according to the invention, a different antipruritic medication is incorporated into the formulation, for example it includes one or more of a corticosteroid, camphor, mint oil, etheric oils, and/or crotamiton. An example of a mild corticosteroid that may be desirable for addition to the topical administration is hydrocortisone acetate. An example of an anti-itching crotamiton (CAS No 483-63-6) medication is Eurax (GSK, UK).

In certain particular embodiments, the anti-pruritus formulation according to the invention comprises a non-steroidal anti-inflammatory agent, particularly diclofenac particles. In certain embodiments, the topical composition according to the invention is used as a treatment for a subject who suffers from pruritus.

In one embodiment of the invention, the different phases of the topical composition according to the invention are stored in, and/or applied from separate tubes, in order to keep the lipophilic and hydrophilic components separate.

In another aspect of the invention, the topical composition is applied from a vessel containing separated chambers, where the lipophilic phase is stored in a first chamber and the hydrophilic phase is stored in a second chamber of, for example, a tube separated with one or several dividers. During application using the multi-chambered vessel, or tube, the phases emit from separate nozzles from their respective chambers, and are combined once administered to the skin.

In a related embodiment of the topical composition according to the invention, the composition is administered from a dual-chambered, squeezable tube, or a dual chambered tube. Different designs have been proposed for dual chamber administration systems for pharmaceutical or cosmetic formulations; these include designs described by US2004173632 (A1 ), US7435027B2, US8413845B1 , all of which are incorporated herein by reference.

The pharmaceutical composition is formulated in a way that is suitable for topical administration such as aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g., for delivery by aerosol or the like, comprising the active ingredient together with one or more of solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives that are known to those skilled in the art.

The following items are further encompassed by the invention:

Item 1. A topical composition comprising

- a lipophilic phase and

- a hydrophilic phase, wherein the hydrophilic phase comprises first particles.

Item 2. The topical composition according to item 1 , wherein the lipophilic phase comprises second particles.

Item 3. The topical composition according to item 1 or 2, wherein the first particles comprise or essentially consist of menthol.

Item 4. The topical composition according to any one of the preceding items, wherein the first and/or second particles are characterized by a mean particle size of 200 - 1000 pm, particularly 400 to 800 pm, more particularly by a particle size of 500 - 750 pm. Item 5. The topical composition according to any one of the preceding items, wherein the first particles are menthol particles characterized by a mean particle size of 500 - 750 pm.

Item 6. The topical composition according to any one of the preceding items, wherein the second particles comprise or essentially consist of a water soluble salt.

Item 7. The topical composition according to item 6, wherein the water soluble salt is selected from: NaCI, MgCh, KCI, NaHCOs, CahbPC , CaH(P04)2.

Item 8. The topical composition according to any one of the preceding items, wherein the lipophilic phase comprises or essentially consists of, in addition to the second particles, long chain waxy esters, particularly wherein the long chain waxy esters comprise or essentially consist of lanolin.

Item 9. The topical composition according to any one of the preceding items, wherein the hydrophilic phase comprises one or more of: carbomer 35000, trometamol, sodium EDTA, propylene glycol. Item 10. The topical composition according to any one of the preceding items, comprising an anaesthetic and/or antihistamine.

Item 11. The topical composition according to any one of the preceding items, wherein the anaesthetic is polidocanol.

Item 12. The topical composition according to any one of the preceding items, comprising one or more of: a corticosteroid, camphor, mint oil, etheric oils, or crotamiton.

Item 13. An administration form comprising a topical composition according to any one of the preceding items, wherein the lipophilic phase is disposed in a first chamber and the hydrophilic phase is disposed in a second chamber.

Item 14. The administration form according to item 14, wherein the administration form is arranged as a dual set of squeeze tubes, or a dual chamber tube.

Item 15. The topical composition or the administration form according to any one of the preceding items for use in treatment of pruritus. The invention is further illustrated by the following examples, from which further embodiments and advantages can be drawn. These examples are meant to illustrate the invention but not to limit its scope.

Examples

Materials

All substances were obtained at Hanseler by the Klus Apotheke AG and have precisely defined purity according to the European Pharmacopoeia Ph. Eur. The wollwachsalkoholsalbe, or acetylated lanolin was produced according to the regulations of the German Pharmacopoeia.

• Carbomer 35 000, Ph. Eur.

• Trometamol, Ph. Eur.

• Natriumedetat, Ph. Eur.

• Propylenglycol, Ph. Eur.

• Menthol, Ph. Eur.

• Polidocanol, Ph. Eur.

• NaCI, Ph. Eur.

• Wollwachsalkoholsalbe, DAB

• Amitryptilin Capsules

Example 1: Hydrophilic composition containing menthol Hydrophilic phase vehicle

In order to obtain a vehicle capable of bearing granular particles to deliver a non-abrasive and scratching effect, while having a slow rate of absorption into skin to prolong the textural benefits of application, a carbomergeral of pH 5 was prepared according to the DAC NRF (Deutscher Arzneimittel codex, neues rezeptur formularium, or German codex of pharmaceutical formulations) with the following components:

100g Carbomergel pH 5

- 1 0g Carbomer 35000,

- 0.5g Trometamol, (CAS No. 77-86-1)

- 0.1g Edetate disodium

- 10g Propylenglycol, Ph. Eur.

- Distilled water to 10Og. In brief, Carbomer 35000 was mixed in a mortar to obtain a uniform powder. The liquid reagants, propylenglycol and distilled water were mixed thouroghly to obtain a gel, which can contain lumps or air bubbles at this stage. The powered mixture was added to the gel with stirring, until a uniformly clear and colourless gel was obtained. The weight of the mixture was monitored during stirring, and weight loss was compensated for with the addition of more distilled water.

Hydrophilic phase particles

Menthol crystals were chosen as the particle to deliver a rough texture to the hydrophilic vehicle, as they have well-described antipruritic and confer a cooling, soothing sensation. The menthol was provided in the form of large, elongate crystals, which were considered inappropriate for the formulation due to their sharp ends which could abrade the skin. The menthol particles were crushed to smaller particles, and those within the range of 500-710 micrometres were isolated by filtration with mesh filters.

Hydrophilic phase

In order to obtain a hydrophilic gel with an appropriate dose of menthol for topical administration, the following ingredients were mixed until a uniform gel was formed:

50g Hydrophilic phase with menthol

- 2g Menthol crystals of 500-710 micrometres

- 43g Carbomergel pH 5

The hydrophobic menthol particles did not dissolve in the hydrophilic vehicle, successfully forming a gel with suspended menthol particles, capable of provided a texture supporting a scratching sensation.

Example 2 Hydrophilic composition containing menthol and an antipruritic medication.

In order to increase the antipruritic efficacy of the preparation, further medication was considered to deliver medicinal properties to provide further relief from itching sensations.

Amitryptilin in a granulated form derived from capsule dosage was first considered as an additional component of the formulation. Upon addition of amitryptilin granules to the Hydrophilic phase with menthol from example 1 , amitryptilin proved to have desirable hydrophobic qualities which led to the formation of a suspension containing particles capable of providing a scratching sensation when applied to skin. However, dissolving the amitryptilin to deliver a medical dose to the subject requires a high alkaline pH. This was incompatible with topical administration to the current application for human skin due to the acidity of the carbomergel pH 5 preparation. In addition, latest guidelines no longer recommend topical application of antihistamines for pruritus treatment. After some consideration, amitriptyline, a substance with antihistaminic properties, was deprioritized for the development of the formulation.

A second medication, polidocanol was then considered for addition to the hydrophilic phase. This surfactant can deliver moisturizing and anaesthetic properties, which have been found to significantly reduce pruritus when applied topically (Freitag G. et al. 1997, Curr. Med. Res. and Op. 13(9):529.37). It is mostly prescribed in sclerotherapy, but can also be applied externally. In an open drug monitoring survey of 1611 patients with a number of skin disorders such as eczema or psoriasis, polidocanol 3% combined with urea 5% was found to significantly reduce pruritus (Freitag G. ibid.). When treating larger skin areas, the European Guideline on Chronic Pruritus recommends the use of polidocanol at 2-10% (Weisshaar E. et al. Acta Dermato- venereologica 2012. 92(5):508-14). The composition was formed by adding polidocanol liquid to the hydrophilic phase with menthol, with mixing, in a mortar and pestle to provide a homogenous gel in the following proportions:

50g Hydrophilic phase with menthol and polidocanol

- 2g Menthol crystals of 500-710 micrometres

- 43g Carbomergel pH 5

- 5g Polidocanol

Example 3: Hydrophobic phase with particles

The amount of menthol crystals for the preparation of a hydrophilic composition containing menthol in Example 1 , was limited to the chosen dosage in order to avoid the possibility of skin irritation at high menthol concentrations. However, this amount of menthol failed to provide a sufficiently granular texture to provide the sensation of scratching when applied to skin. NaCI was tested as an additional non-irritant, particle ingredient. As sodium chloride is hydrophilic, acetylated lanolin was tested as a hydrophobic media, with additional moisturizing qualities. As a basic therapy, especially in xerosis and inflammatory skin disease, the use of mild non- alkaline soaps, emollients, and moisturizers should be established as they improve skin-barrier function and prevent trans-epidermal water loss. Extensive scratching may trigger or exacerbate pruritus by damaging the epidermal layer of the skin, facilitating the entry of pathogens and irritants. On that account, basic therapy with barrier protection and repair creams is indicated in all forms of general pruritus, regardless of aetiology.

NaCI powder formed a uniform paste when combined with acetylated lanolin, and the particles did not dissolve.

50 g Hydrophobic phase

- Wollwachsalkoholsalbe 45,0 g

- NaCI crystals 5,0 g Example 4: A two phase formulation to provide a topical scratching effect.

The chosen particles, one of which being menthol, an antipruritic agent itself, were stored in a septum divided tube, containing a hydrophobic and a hydrophilic vehicle. Only when applied to the skin, do the individual components mix, initializing a scratch effect until the individual particles dissolve in the respective opposite phase without harming the skin.

100 g Two phase emulgel

50 g Hydrophilic phase of the emulgel:

- Menthol crystals 2,0 g

- Polidocanol 5,0 g

- Carbomergel 43,0 g

50 g Hydrophobic phase of the emulgel:

- Wollwachsalkoholsalbe 45,0 g

- NaCI crystals 5,0 g

The result is an anti-pruritic emulgel containing two particle types of a dull, non-damaging, granular structure, which prevents skin excoriation, but at the same time mimics the instantaneous feeling of relief brought about by scratching.

This substance is a novel topical treatment strategy to break the itch-scratch cycle. It offers an alternative approach to the already existing manifold, yet deficient topical treatment in chronic pruritus.

Methods

In topical formulations for itch relief, methanol is a key feature. Methanol, which is contained in the formulation in particle form and, after application, first provides relief through a mechanical effect of blunt friction, followed by a direct anti-pruritic effect of the menthol after dissolution of the menthol crystals.

To achieve this, a two-phase formulation approach has been developed. One phase contained menthol crystals in stable suspension, the other phase is an emulsion that causes dissolution of the menthol after mixing. For selected formulations good stability was demonstrated in 24 weeks stability studies.

To further enhance the efficacy of the product, the University Hospital of Basel is now interested in including sodium chloride (NaCI) particles in the oil-containing phase. In order to avoid dissolution or crystal growth of the particles, it was assumed that a water-free formulation approach is necessary. In order to provide better cosmetic properties than for example a petrolatum-based ointment, oleogels containing triglycerides were suggested. After successful development, a 6-weeks short-term stability study including stress conditions should be performed.

Development ofoleoael base formulations

Medium chain triglycerides were identified as the preferred solvent for menthol after mixing of both phases. This finding is based on the good solubilization properties for menthol and favorable cosmetic properties. For this reason, it was also selected as solvent for the oleogels.

Oleogels are lipophilic, typically water-free, bi-coherent systems consisting of an oil phase and a coherent structure-building phase that may consist of polymers or network structures formed from low molecular weight consistency agents. A typical polymer is ethyl cellulose, however, it needs to be used in concentrations of several percent and leaves a water-insoluble film on the skin rendering it cosmetically unfavorable.

Low molecular weight consistency agents include monoacyl glycerides, in particular glycerol monostearate, fatty acids and fatty alcohols, aluminium stearate, or lecithin. Also, inorganic materials like fused silica or bentonites are used. The inorganic materials are typically cosmetically less favorable, and lecithin requires the presence of a certain amount of water. Therefore, glycerol monostearate was selected as the primary consistency agent. For the latter purpose, the lanolin substitute Softisan 649 (bis- diglyceryl polyacyladipate-2) was investigated. A further benefit of this excipient, which is frequently used in cosmetic formulations, is its ability to take up water which makes it favorable for the mixing with the water phase.

In order to allow an emulsification after mixing with the water phase, different emulsifiers were incorporated in the formulations.

Table 1 shows the composition of the initial oleogel base formulations. All ingredients are INCI listed and frequently used in cosmetics. Oleogels were characterized macroscopically, microscopically and by shear rheometry 14 days after manufacturing (stored at room temperature).

Table 1: Composition of oleogel base formulations F001 to F003 (percentage)

All three formulations showed a smooth homogeneous appearance both immediately after manufacturing and after 14 days at room temperature. Under the microscope, they all also showed a homogeneous structure and the typical polarized structures resulting from the emulsifier/consistency agents.

Zero shear viscosity was high which is positive for long-term physical stability and the ability to avoid sedimentation of incorporated suspended particles. All formulations showed the desired shear thinning which allows pumping and good spreading on the skin and. The viscosity at shear rates of 100 1/s was between 1.5 and 2.3 Pa ^* s (Table 2). This is comparable with the value of 1 to 2 Pa ^* s found for the reference gels (Nivea Men Deep Control and Eucerin Anti Pigment) which are provided in pump dispensers. Therefore, the base formulations were considered well suitable for incorporation of NaCI crystals.

As after application the oleogels will be mixed with the aqueous gel phase, the mixture should ideally result in a cosmetically pleasant emulsion. As emulsifiers would (partially) dissolve the menthol in the water phase, they needed to be integrated in the oil phase. The mixing behavior of all three oleogel base formulations with the gel phases F006 and F007 was investigated. As shown for F006 and the oleogels in all cases an emulsion was easily achieved (also when mixed with F007). F001 with the hydrophilic O/W emulsifier will form an O/W emulsion as soon as a high enough ratio of water is provided. During mixing, a phase transition from an initial W/O emulsion to a O/W emulsion occurs. O/W emulsions can more easily be washed off and appear less greasy than W/O emulsions. F002 and F003 will form W/O emulsions. Here, phase transition will not occur, unless a huge excess of water is provided.

Based on the cosmetic properties, F001 and F002 were selected for the development of the suspension formulations. In addition, it was decided to include a suspension in a Pharm. Eur. petrolatum base for comparison.

Table 2: Zero shear and high shear viscosity of oleogel base formulations F001 to F003

Aqueous ael formulations

Manufacturing and characterization of gels with increased menthol concentration 16% menthol was suspended in the gel matrix resulting in the final formulations described in Table 1. For the more viscous gel base F007 also a 24% suspension will be prepared when the necessary supply of menthol becomes available.

The resulting gels were homogenous suspension with a pH of 5.7 (F006) and 5.5 (F007), respectively. As the gel matrix is isotropic, only the menthol crystals could be observed Table 3: Composition of aqueous gels with increased menthol concentration

Development of Nad containing oleoael suspensions

Selection of sodium chloride type

It was previously discovered that the ideal particle size for blunt friction to relief itching sensations is between 500 pm and 700 pm. As no sodium chloride with tailor-made particle size in this range was available, it was agreed that RaDes should microscopically assess several commercially available types of table salt to select the best suited one for the purpose of the current feasibility study.

For that, four different table salts (two sea salts and two “regular” table salts) were purchased in supermarkets. In addition, an analytical quality available in the RaDes labs was characterized for comparison. The average diameter was estimated based on microscopic measurement of three or more representative crystals. The determined diameters are shown in table 4. As none of the salts was exactly in the optimal range, salt suspensions in oleogels were tested on the skin and it was noticed that the two table salts with diameters in the range of 300 pm to 400 pm resulted in a noticeable but pleasant sensation whereas the sea salts with average diameters of 800 pm to 900 pm were slightly irritating. In addition to the particle size, also the shape may have contributed to the difference: whereas the regular table salts did not show edges, the sea salts were sharp-edged. Therefore, the table salt “Tafelsalz feinkbrnig, Edeka” with an average particle diameter of around 350 pm was selected. Table 4: Microscopically estimated average diameters of NaCI from different sources.

Manufacturing, characterization, and stability of NaCI-containina oleoaels One oleogel suspension with O/W emulsifier (F001 NaCI), one with W/O emulsifier (F002 NaCI) and one petrolatum-based ointment (F004 NaCI) were manufactured. The compositions are shown in Table 5.

Also, with incorporated NaCI, the oleogels showed a homogeneous appearance which was confirmed in the microscopic image. Here, the appearance in the polarized mode was slightly different to the NaCI-free base formulations (As the crystal sizes are larger than the images sections, crystal-free parts of the formulations were selected). The petrolatum-based ointment showed a coarser structure.

The physical stability of the formulations was investigated in a short-term stability study for 6 weeks at 5°C, 25°C and cycling conditions (from -5°C to 40°C in 24h cycles). In the macroscopic examination, no signs of instability were observed at any condition, especially no signs of sedimentation or phase separation. Also, in the microscopic image no significant changes occurred. As the cycling test represents a strong stress to formulations, these results are encouraging for long-term stability.

For the presence of the relatively large salt crystals, rheological investigations were not foreseen as the currently available methods cannot be used in presence of such large particles.

Table 5: Composition of NaCI oleogel base formulations F001 to F003 (percentage)

Conclusion

Manufacturing of homogenous suspensions of aqueous gels with 16% menthol was possible. The stability study is ongoing. A 24% aqueous gel will be also manufactured and investigated for stability.

Furthermore, two variants of oleogel NaCI suspensions as oil phase of the itch relief product were successfully developed. The rheological profile was favorable and the selected oleogels F001 and F002 mix well with the aqueous gel phase to form an emulsion. A 6-weeks stability showed good stability, even at stress conditions so that it is likely that long-term stability could be confirmed in a respective study. Overall, the developed oleogels appear to be well suited for the purpose of the itch relief product.