AQUEOUS FORMULATIONS COMPRISING BUFFERED TIOTROPIUM BROMIDE FOR TOPICAL TREATMENT OF HYPERHIDROSIS

TECHNICAL FIELD OF THE INVENTION

The present invention relates to the field of topical aqueous formulations comprising tiotropium for therapeutically or cosmetically treating a skin disease.

BACKGROUND OF THE INVENTION

Sweating, or perspiring, is an essential and natural biological process for the thermoregulation of the human body. Sweating occurs in response to the body’s temperature increase due to physical exertion or environmental conditions, but may be also triggered by emotions. Two types of sweat glands can be identified: eccrine glands producing odorless water-like sweat and apocrine glands producing fluid with sebum which can be altered by cutaneous bacteria in sulfur containing compounds resulting in unpleasant odors. Although odorless, the sweat produced by the sweat glands may be acted on by cutaneous bacteria resulting in the production of unpleasant odors, due to for example, sulfur containing compounds.

Hyperhidrosis is a clinical condition and may be described as focal or generalized hyperhidrosis. Focal hyperhidrosis is characterized by excessive sweating, occurs typically during puberty or adult life localised mainly at underarms, hand and feet. Excessive sweating can severely effect a person’s self-esteem. The affected individuals may become stigmatized and it can even lead to social isolation since the presence of excessive sweat (and its resulting odor) may be seen as evidence of insecurity and/or insufficient hygiene. It is estimated that one in every hundred people suffers from excessive sweating that has a significant impact on daily life.

Deodorants and antiperspirant compositions are available to keep the skin (especially underarms) dry and odorless. Most of the compositions available in the market comprise astringent salts of aluminium and/or zirconium, such as aluminium ch loro hydrate. These materials function by blocking the sweat ducts thereby reducing the production of perspiration. Current treatments are not effective at treating the symptoms of hyperhidrosis, in particular focal hyperhidrosis. In addition many treatments give rise to irritation leading to discontinuation of use. There is a need for a pharmaceutical composition that is effective in the treatment of hyperhidrosis that has enhanced stability (increasing shelf-life for products). In particular, there is a need for easy to apply formulations that are devoid of unpleasant side effects such as irritation, rash and burning sensation. Furthermore there is a need for formulations that have a pleasant odour.

It is therefore desirable to provide tiotropium formulations that are efficacious yet devoid of unpleasant side effects. It is also desirable to provide tiotropium formulations that are stable at room temperature, easy to apply, and do not have a malodour.

SUMMARY OF THE INVENTION

In a first aspect, the present invention relates to an aqueous formulation for use in the treatment of a skin disease, the treatment comprising topically administering to a human patient an aqueous formulation comprising, by weight of the total formulation:

• 0.0001- 1.5 wt.% tiotropium equivalent;

• 70-99.9 wt.% aqueous phase;

• dermatologically acceptable pH adjusting agent comprising citrate, wherein the formulation has a pH in the range of 3.0 to 6.0, preferably 3.5 to 5.5, at 21 °C.

It was unexpectedly found that the aqueous formulation of the present invention can be administered topically to provide instant relief of a skin disease, for example, hyperhidrosis symptoms, notably excessive perspiration. Without wishing to be bound by theory, the inventors postulate that the pH in the range of 3.0 to 6.0 facilitates rapid and effective binding of tiotropium bromide to the muscarinic receptors within the skin, e.g. the muscarinic receptors located on the sweat glands.

The therapeutic or cosmetic treatment using the aqueous formulations according to the invention is advantageously cheaper due to the low amounts of tiotropium, less allergenic since the anti-perspiration effect does not depend on aluminium-derived components and other known skin irritating compounds, yet showing an excellent efficacy.

The present invention further relates to a skin applicator comprising the aqueous formulation of the invention, method of preparing the aqueous formulation of the invention and to a cosmetic treatment using the aqueous formulation of the invention. DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the present invention relates to an aqueous formulation for use in the treatment of a skin disease, the treatment comprising topically administering to a human patient an aqueous formulation comprising, by weight of the total formulation:

• 0.0001 - 1.5 wt.% tiotropium equivalent;

• 70-99.9 wt.% aqueous phase;

• dermatologically acceptable pH adjusting agent comprising citrate, wherein the formulation has a pH in the range of 3.0 to 6.0, preferably 3.5 to 5.5 at 21 °C.

The term “treatment” as used herein encompasses both therapeutic and palliative treatment of a human patient. In other words, by “treatment” is meant that at least an amelioration of the symptoms or characteristics associated with a condition afflicting the subject is achieved.

The term “hyperhidrosis” as used herein refers to a skin disease characterized by excessive perspiration in localized parts of the body or generalized excessive perspiration as diagnosed by a medical practitioner or reported by a subject.

Excessive perspiration may be quantitatively determined by gravimetric assessments, on the Hyperhidrosis Disease Severity Scale (HDSS), by measurement by transdermal epidural water vapor loss (e.g., Vapometer, Delfin Technologies, Kuopio Finland), on the Hyperhidrosis Visual Quantification Scale (HHVQS, e.g., HHVQSa or HHVQSp), on the Hyperhidrosis Visual Analog Scale (HHVAS) or any combination thereof.

The term “topical administration” as used herein refers to both epicutaneous administration (i.e., the route of topical drug administration by which tiotropium is taken into the body via direct skin application) and local pharmacodynamic effect. In other words, the formulation of the invention is meant to be applied directly to or on the skin for local absorption and action of tiotropium equivalent. Accordingly, the “topical administration” used herein does not represent a significant route for systemic delivery of tiotropium equivalent.

“Tiotropium equivalent” as used herein refers to the substance (1a, 2b, 4b, 5a, 7b)-7- [(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azonia tricyclo[3.3.1.0 ² ' ⁴ ]nonane and salts thereof. Suitable salts are fluoride, chloride, bromide, iodide, C C4alkyl sulfate, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, nitrate, maleate, acetate, trifluoroacetate, citrate, fumarate, tartrate, oxalate, succinate and benzoate. Preferably, tiotropium as used herein refers to anhydrous or monohydrate tiotropium bromide. The term “aqueous phase” as used herein refers to an aqueous phase comprising water or pharmaceutically acceptable water-soluble components, such as ethanol, propylene glycol, glycerol, and conventional water-soluble components.

The “aqueous phase” is in the liquid state or in the semi-solid state at 20 °C, preferably the liquid state.

The term “dermatologically acceptable pH adjustment agent” as used herein refers to buffering agents comprising citrate. Typical citrate buffers are comprised of citric and sodium or potassium citrate, or citric acid and Na2HPC>4.

All “wt.%” referred to herein are based on weight of total aqueous formulation, unless otherwise indicated.

The pH of the aqueous formulation according to the invention is measured at 21 °C using conventional techniques known to the skilled person.

Suitable examples of aqueous formulations according to the invention comprise solutions, lotions, dispersions, suspensions, emulsions, foamable liquids, foams, aqueous gels, and the like.

The terms “sweating” and “perspiring” are used herein as synonyms and refer to the biological act of fluid secretion by the eccrine and/or apocrine glands in a patient in response to nerve stimulation, emotional state, environmental conditions (/.e., hot air temperature), and/or exercise.

The term “dry touch” as used herein refers to the cosmetic aspect of the skin such as a dry feel and an aesthetics sensation perceived by the subject upon alleviation or prevention of sweating or perspiration in normal subjects, /.e., not in subjects suffering from hyperhidrosis.

The term “deodorant”, as used herein, relates to personal care products that are applied topically to minimize the odor caused by the bacterial breakdown of perspiration. The term “antiperspirant”, as used herein, refers to the subclass of deodorant products whose primary function is to inhibit perspiration, and normally act to the sweat glands level.

The term “water soluble” as used herein, unless indicated otherwise, refers to materials having a solubility in demineralized water of 21 °C of more than 20 g/l. Tiotropium equivalent, preferably tiotropium bromide is present in the aqueous formulation in an amount of 0.0001 to 1.5 wt.%, preferably in an amount of 0.001 to 1.0 wt.%, more preferably 0.01 to 1.0 wt.%, even more preferably 0.025 to 1.0 wt.%, yet more preferably 0.05 to 0.5 wt.%. Preferably, the aqueous formulation comprises 0.001 to 1.0 wt.% tiotropium equivalent, more preferably 0.01 to 1.0 wt.%, even more preferably 0.025 to 0.05 wt.% tiotropium equivalent, preferably tiotropium bromide.

Typically, tiotropium equivalent is present in the aqueous formulation in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salt is selected from the group consisting of fluoride, chloride, bromide, iodide, C1-C4alkyl sulfate, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, nitrate, maleate, acetate, trifluoroacetate, citrate, fumarate, tartrate, oxalate, succinate and benzoate. The tiotropium equivalent maybe anhydrous or a monohydrate. Preferably, the tiotropium equivalent is a monohydrate. More preferably, the tiotropium equivalent is tiotropium bromide monohydrate, or tiotropium chloride monohydrate, most preferably tiotropium bromide monohydrate.

The aqueous formulation comprises 70-99.9 wt.% aqueous phase, by weight of the total formulation, preferably 80-99.7 wt.%, even more preferably 85-99.5, most preferably 90-99.25 wt.% aqueous phase by weight of the total formulation.

According to a preferred embodiment, the aqueous phase comprises, based on the weight of the aqueous phase, at least 50 wt.% water, preferably at least 60 wt.% water, more preferably at least 75 wt.% water, even more preferably at least 80 wt.% water, most preferably at least 90 wt.% water.

In a preferred embodiment, the aqueous formulation is a liquid formulation selected from a lotion or a solution.

Tiotropium equivalent is substantially water-soluble in the aqueous phase of the aqueous formulations. Substantially water-soluble as used herein refers to a solubility of at least 90% in water when tiotropium equivalent in a concentration of 20 mg/ml is added to a buffered aqueous solution, having a pH preferably in the range of 3.0 to 6.0 at 20 ^° C. Accordingly, in a most preferred embodiment, the tiotropium equivalent is preferably substantially soluble in the aqueous formulation. The aqueous formulation has a pH in the range of 3.5 to 6.0, preferably 3.5 to 5.5, more preferably 3.75 to 5.0, even more preferably 3.75 to 4.50, most preferably 3.75 to 4.25. Advantageously, in the pH range of 3.5 to 5.0 the risk of irritation and smelling is reduced when applied to the skin, whilst presenting excellent stability and efficacy.

Preferably, the pH adjustment agent comprises sodium citrate or potassium citrate, preferably sodium citrate.

Preferably, the formulation comprises 0.01-1.0 wt.% pH adjustment agent, by weight of the total formulation, preferably 0.05-0.5 wt.%, pH adjustment agent.

If necessary, the pH of the final solution may be adjusted by adding suitable amounts of pH agents such as a neutralizing agent or an acidifying agent. Neutralizing agents are, for example, amines such as monoethanolamine, diethanolamine, triethanolamine, tromethamine, tetrahydroxypropylethylendiamine, aminomethyl propanol, diisopropanolamine, or an inorganic alkali such as NaOH solution, KOH solution, or NH ₄ OH solution. Acidifying agents are, for example, HCI solution, hydroxyacids solutions, such as lactic acid solution, citric acid solution, phosphoric acid solutions, and the like.

The skilled person will appreciate that the concentration of dermatologically acceptable pH adjustment agent in the aqueous formulation may be adjusted without difficulty to provide an aqueous formulation having a pH in the range of 3.0 to 5.0, in view of the optional components present in the composition.

The aqueous formulation may suitably comprise 0.001 to 20 wt.% of dermatologically acceptable excipients. Typically, the excipients are selected from bactericides, preservatives, antioxidants, humectants, sequestering agents, moisturizers, emollients, surfactant, drying agents, fragrances and the like. More preferably, the aqueous formulation comprises 0.01 to 15 wt.%, even more preferably 0.05 to 10 wt.%, most preferably 0.5 to 5 wt.% of dermatologically acceptable excipients.

Preferably the formulation comprises 0 to 1.0 wt.% of one or more bactericides selected from benzalkonium chloride, triclosan, sorbic acid, citric acid or combinations thereof. In a particularly preferred embodiment, the formulation comprises less than 0.01 wt.% benzalkonium chloride or sorbic acid, more preferably the formulation does not contain benzalkonium chloride or sorbic acid. The aqueous formulations of the present invention preferably contains 0.1 to 30 wt.%, more preferably 0.5 to 20 wt.%, most preferably 1 to 10 wt.% of at least one cationic or non-ionic surfactant.

The aqueous formulation may comprise at least one gelling agent. In a preferred embodiment, at least one gelling agent is present in an amount of at most 20 wt.%, more preferably 0.5 to 10 wt.%, even more preferably 1 to 5 wt.%. In a further preferred embodiment, at least one gelling agent is present in an amount of at most 1 wt.%, more preferably at most 0.8 wt.%, even more preferably at most 0.5 wt.% by weight of the aqueous formulation

Preferably, the aqueous formulation comprises less than 15 wt.% propylene glycol, preferably less than 10 wt.%, more preferably less than 5 wt.% propylene glycol, even more preferably less than 3 wt.% propylene glycol by weight of the aqueous formulation. In a most preferred embodiment, the aqueous formulation does not comprise propylene glycol.

Suitable gelling agents to be used in the aqueous formulation are cationic or non-ionic gelling agents, e.g., polyethylene glycol (PEG). Accordingly, the gelling agent preferably is not an anionic component, such as polyacrylate.

The aqueous formulation of the present invention preferably comprises a drying agent to provide improved dry skin feel in a concentration from about 0.1 % to about 5%, more preferably from about 0.3% to about 3%, even more preferably from about 0.5% to about 2%, by weight of the composition. Suitable drying agents are typically in the form of inert solid particulates, and include materials such as talc, microthene, silicates, colloidal silicas, and mixtures thereof. These materials provide benefits such as dry feel and aesthetics, especially dry feel benefits.

Preferably, the aqueous formulation comprises, by weight of the total formulation,:

• 0.02 to 0.05 wt.% tiotropium bromide,

• 0.18 to 0.25 wt.% dermatologically acceptable pH adjustment agent comprising citrate, preferably citric acid and sodium citrate,

• 99.1 to 99.8 wt.% water, wherein the formulation has a pH in the range of 3.75 to 4.75.

Preferably, the aqueous formulation consists of, by weight of the total formulation:

• 0.02 to 0.05 wt.% tiotropium bromide

• 0.18 to 0.25 wt.% dermatologically acceptable pH adjustment agent comprising citrate, preferably citric acid and sodium citrate, • 99.1 to 99.8 wt.% water wherein the formulation has a pH in the range of 3.75 to 4.75.

Preferably, the aqueous formulation according to the invention is for use in the treatment of primary hyperhidrosis or secondary hyperhidrosis, i.e., in consequence of the use of certain medicaments or resulting from other diseases or conditions.

Primary hyperhidrosis usually develops during childhood and tends to persist throughout adult life. The main affected areas are the axilla, the palms of the hands, the soles of the feet, and the face (in particular the forehead), the back, or the belly.

Causes of secondary hyperhidrosis include endocrine diseases such as diabetes mellitus, hyperthyroidism, and hyperpituitarism, or neurological diseases including peripheral nerve injury, Parkinson’s disease, reflex sympathetic dystrophy, spinal injury, and Arnold-Chiari malformation. Additional causes include are pheochromocytoma, respiratory diseases, and psychiatric diseases. The main affected areas are axilla, the palms of the hands, the soles of the feet, and the face (in particular the forehead), the back, or the belly.

Accordingly, the aqueous formulation according to the invention is preferably topically administered for the treatment of primary or secondary hyperhidrosis. More preferably, the primary or secondary hyperhidrosis is selected from palmar, plantar, axillary, facial, truncal, thigh or gustatory (lips, nose and forehead) hyperhidrosis or combinations thereof.

Preferably, the aqueous formulation according to the invention is preferably topically administered for the treatment of focal or generalized hyperhidrosis, more preferably focal hyperhidrosis. Accordingly, the aqueous formulation according to the invention is preferably topically administered for the treatment of focal primary or secondary hyperhidrosis.

In accordance with a particularly preferred embodiment, the treatment comprises topically administering the aqueous formulation according to the invention to the affected skin to provide tiotropium equivalent in a dosage of 0.0001 to 1.5 mg per cm ² , preferably at least 0.005 mg per cm ² of skin (such as 0.005 to 1.5 mg per cm ² of skin), preferably 0.01 to 1.0 mg per cm ² of skin, even more preferably 0.05 to 0.5 mg per cm ² of skin. Preferably the treatment comprises topically administering the aqueous formulation according to the invention to the affected skin to provide tiotropium equivalent in a dosage of 0.0001 to 0.5 mg per cm ² of skin, more preferably 0.005 to 0.5 mg per cm ² of skin. In one embodiment, the treatment comprises topically administering the aqueous formulation according to the invention to the affected skin to provide tiotropium equivalent in a dosage of 0.0001 to 0.02 mg per cm ² of skin, more preferably 0.0001 to 0.01 mg per cm ² of skin.

The aqueous formulation is topically applied to the affected area in an amount of 0.05 to 7 ml, more preferably 0.1 to 6 ml, even more preferably 0.3 to 3 ml and most preferably 0.5 to 1 ml.

In a preferred embodiment, the treatment comprises topically administering the aqueous formulation according to the invention to the affected skin at least once a day, more preferably at least twice a day, even more preferably at least three times a day. Preferably, the aqueous formulation according to the invention to the affected skin once a day.

In a second aspect, the present invention relates to a skin applicator comprising the aqueous formulation according to the invention, wherein the skin applicator comprises a dispenser or holder comprising the aqueous formulation, the dispenser or holder preferably being selected from a plastic flask, spray tube, a roll-on, aerosol can or soaked wipes or pads. Preferably, the skin applicator is a spray or an aerosol comprising the aqueous formulation.

The suitable holder or dispenser according to the invention efficiently enables the subject to apply the tiotropium formulation to the affected area of the skin, such as the underarm, hand palms, feet soles, neck, back, etc., where control of perspiration and/or deodorancy is desired.

In a third aspect, the present invention relates to a method of preparing an aqueous formulation according to the invention, the method comprising the steps of combining tiotropium equivalent with a dermatologically acceptable pH adjustment agent to produce an aqueous formulation having a pH in the range of 3.0 to 5.0.

In one embodiment of the invention, the pH adjustment agent is present in the aqueous phase before adding the tiotropium equivalent thereto. In another embodiment of the invention the pH adjustment agent is combined with the tiotropium equivalent in the solid form, followed by combining the mixture of solids to an aqueous solution.

A preferred method according to the invention comprises the steps of combining tiotropium equivalent with the pH adjustment agent (e.g. citric acid and sodium citrate) in the solid form, followed by combining (e.g. solubilising) the solids mixture with an aqueous solution. Preferably, the solubilisation step is performed at 21 °C, but not more than 30 °C. Optionally, the aqueous solution further comprises dermatologically acceptable excipients. The dermatologically acceptable excipients may be added to the aqueous solution before or after adding the tiotropium equivalent thereto.

If necessary, the pH of the final aqueous formulation can be adjusted by adding a pH neutralizer or acidifier until the pH in the range of 3.0 to 5.0 is achieved.

Preferred ingredients and amounts thereof described herein with regards to the aqueous formulation apply mutatis mutandis to the method of preparing the aqueous formulation.

A fourth aspect of the invention relates to a non-therapeutic method for cosmetically reducing sweating and/or skin odours, the method comprising applying the aqueous formulation according to the invention or obtainable by the method of the invention to the affected skin.

Preferably, the non-therapeutic method according to the invention comprises applying the aqueous formulation as a deodorant or antiperspirant, preferably in an affected area(s) selected from armpits, face, back, palm or feet soles.

In a particularly preferred embodiment, the non-therapeutic method according to the invention comprises applying the aqueous formulation to the affected area(s) at least once a day, preferably twice a day, even more preferred at least three times a day. Preferably, the non- therapeutic method according to the invention comprises applying the aqueous formulation to the affected skin once a day.

Accordingly, the present invention relates to a non-therapeutic method for cosmetically reducing sweating and/or skin odours, the method comprising applying an aqueous formulation to the affected skin, the formulation comprising, by weight of the total formulation,:

• 0.02 to 0.05 wt.% tiotropium bromide,

• 0.18 to 0.25 wt.% dermatologically acceptable pH adjustment agent comprising citrate, preferably citric acid and sodium citrate,

• 99.1 to 99.8 wt.% water, wherein the formulation has a pH in the range of 3.75 to 4.75, and the formulation is topically administered to the affected skin at least once a day, preferably twice a day.

Preferably, the non-therapeutic method according to the invention provides a dry touch on the skin of a subject suffering from excessive perspiration. The invention will now be illustrated by the following non-limiting examples

EXAMPLES

Formulations comprising tiotropium were prepared according to table 1.

Table 1 The formulations were prepared following the steps of: providing weighted amounts of tiotropium bromide, citric acid and sodium citrate in the powder form; dissolving powders in water under stirring; measuring the pH at 21 °C using pH measurement strips; - adjusting the final volume of the aqueous solution; and adjusting the pH of the final solution to pH 4.0 with HCI or NaOH solution, if necessary.

All solutions were kept in white polyethylene flacons with a suitable mechanical spraying device. The final formulations were stored for 6 weeks at 21 °C.

Example 2

The antiperspirant efficacy of the formulations prepared as described in Example 1 was examined by using patients clinically diagnosed with hyperhidrosis HDSS 3 and 4.

Each patient was subjected to 14 consecutive days of treatment for each of the test formulations. The subjects were asked to apply the 0.10 to 0.15 mL of formulation according to example 1 (0.025% solution of tiotropium) twice a day, by means of an applicator or spray. The applicator applied 1 x 0.10 mL of formulation (0.025% solution of tiotropium), the spray (1 x 0.15 L) of formulation (0.025% solution of tiotropium).

Each subject was asked to evaluate the sweat reduction with a sweat reduction score on a scale from 1 to 10, with 1 being no sweat reduction, 10 being maximum sweat reduction.

Table 2

Comparative Example 1

Formulations as per example 1 further comprising either 3 wt. % methyl cellulose or PEG where prepared. These formulations were difficult to apply and were found to leave an undesirable residue on the skin that had a “fatty” feel. These formulations do not provide a reduction in sweating.

Comparative Example 2

Formulation as Table 1 with pH 6.5. This comparative formulation had an unpleasant smell. The formulation does not provide a reduction in sweating.

Comparative Example 3

Three tiotropium containing formulations were tested in 8 subjects suffering from hyperhidrosis: • Formulation 1: tiotropium 0,025%, propylene glycol 15%, citrate buffer solution 10mM, pH=4, water

• Formulation 2: tiotropium 0,025%, propylene glycol 15%, lactic acid 10mM, water, pH=4 (adjusted with HCI)

• Formulation 3: tiotropium 0,0005%, ethanol 10%, water, pH=3,5 (adjusted with HCI)

Formulations 1 and 2 were prepared as described in Example 1. Formulation 3 was prepared as described in CN 106137955. Formulation 2 presents crystallization after several weeks in storage, and are reported to have unpleasant smell (data not shown).

A double-blind study was carried out to determine the antiperspirant efficacy of the above formulations in subjects clinically diagnosed with hyperhidrosis. Each patient was subjected to 7 consecutive days of treatment with each of the test formulations. The subjects were asked to apply 0.10 mL of the test formulation twice a day in both armpits.

Each subject was asked to evaluate the sweat reduction using a sweat reduction scale from 1 to 10, with 1 being no sweat reduction and 10 being maximum sweat reduction. HDSS is an international scale for quantification of hyperhidrosis (scale from 1 to 4, 4 being the most severe form of hyperhidrosis). Average sweat reduction scores and HDSS reduction are presented in Table 3:

Table 3