NL2023160A

NL2023160A - Aqueous formulations comprising oxybutynin for topical treatment of skin diseases

Info

Publication number: NL2023160A
Application number: NL2023160A
Authority: NL
Inventors: Venema Wim; Homan Ben
Original assignee: Notoxins Ip B V
Priority date: 2018-05-17
Filing date: 2019-05-17
Publication date: 2019-11-21
Also published as: NL2023160B1

Abstract

The present invention relates to a topical aqueous formulation comprising oxybutynin that is particularly effective in topical treatment of a skin disease, e.g. hyperhidrosis.

Description

FIELD OF THE INVENTION

The present invention relates to a topical aqueous formulation comprising oxybutynin, more particularly a topical aqueous formulation comprising oxybutynin that is particularly effective in topical treatment of e.g. hyperhidrosis.

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. Although odorless, the sweat produced by the sweat glands may become beyond inconvenient due to its breakdown by bacteria living on the skin which results in the production of unpleasant odours.

Focal or generalized hyperhidrosis, a clinical condition characterized by excessive sweating, occurs typically during puberty or adult life. Excessive sweating makes unpleasant odours formation more difficult to control. The affected individuals may become stigmatized and even be led to social isolation since the presence of excessive sweat (and its resulting odor) may be seen as evidence of insecurity and/or insufficient hygiene.

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. However, skin inflammation or allergy to such components is often reported.

Oxybutynin is a known anticholinergic agent known for the treatment of overactive bladder or hyperhidrosis per oral administration. Patients orally treated with oxybutynin are nevertheless heavily affected by its adverse effects, namely xerostomia and constipation. It is believed that N-desethyloxybutynin (N-DEO), a compound resulting from oxybutynin first pass metabolism, is the responsible for its undesirable side effects.

Topical oxybutynin-containing formulations are therefore of interest and have been investigated.

Bakshi et al. developed a spray for transdermal administration of oxybutynin. The tested formulations comprise 10% (w/w) oxybutynin and were reported to be useful in the treatment of overactive bladder (Bakshi et al. “A Novel Metered Dose Transdermal Spray Formulation for Oxybutynin”, Indian Journal of Pharmaceutical Sciences, 70.6(2008):733-739).

WO 2007/046102 A2 describes the use of anti-cholinergic and substituted benzamide therapeutic agents in topical compositions for treating hyperhidrosis, perspiration and apocrine sweating. Example 1 describes a lotion comprising 12.5 mg oxybutynin, 0.25 g hydroxyethylcellulose and 25 mL purified water. Example 4 describes foam compositions in aerosol cans, the compositions comprising, in weight per volume of the pressurized liquid:

• 0.01 - 5% oxybutynin;

• 0.2% xantham gum;

• 0.3% EDTA;

• 4% polysorbate 20;

• 4% polyglycol 300 isostearate;

• 80.5 - 86.4% purified water; and • 5-10% propellant.

WO 2016/062583 A1 and WO2016/062586 A1 describe products comprising an antiperspirant composition and a dispenser therefor, the composition comprising a non-pore blocking inhibitor of perspiration. The composition is described to be in the form of a cream, gel or soft solid and may comprise from 1-5 wt.% of the non-pore blocking inhibitor of perspiration. The non-pore blocking inhibitor of perspiration is an anticholinergic agent, such as oxybutynin.

US 2014/0037713 A1 describes formulations for transdermal administration of anti-cholinergic agents for treating hyperhidrosis, the formulations containing (i) 0.1 to 10% by weight of the anti-cholinergic agent and (ii) a delivery vehicle of a C2 to C4 alkanol present in the delivery system in an amount of about 20 to no more than 65%, a polyalcohol of propylene glycol, dipropylene glycol, polyethylene glycol, glycerin, or mixtures thereof present in the delivery system in an amount of 0.5 to 10%, a monoalkyl ether of diethylene glycol present in the delivery system in an amount of 0.5 to 20%, and water in the delivery system in an amount of about 10 to about 25%. The examples describe oxybutynin-containing gels having a pH in the range of 4 to 9.

There is a need for a pharmaceutical composition that is more effective in the treatment of hyperhidrosis. In particular, there is a need for a simple treatment that provides instant relief of hyperhidrosis symptoms.

It is therefore desirable to provide oxybutynin dosage forms that can be administrated topically and provide instant relief of hyperhidrosis symptoms.

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, said treatment comprising topically administering to a human patient an aqueous formulation comprising, by weight of the total formulation:

• 1.0-8 wt.% oxybutynin equivalent;

• 70-98 wt.% aqueous phase, preferably 70-95 wt.% aqueous phase;

• less than 10 wt.% propylene glycol;

• dermatologically acceptable pH adjustment agent to provide the formulation with a pH in the range of 3.0 to 5.0 at 21 °C.

It was unexpectedly found that the aqueous formulation of the present invention can be administered topically to provide instant relieve of hyperhidrosis symptoms, notably excessive perspiration. Without wishing to be bound by theory, the inventors postulate that the acidic pH of the formulation facilitates rapid and effective binding of oxybutynin to the muscarinic receptors within the skin, e.g. the muscarinic receptors located on the sweat glands.

The present invention further relates to a skin applicator comprising the aqueous formulation of the invention and a method of preparing 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 disease, said treatment comprising topically administering to a human patient an aqueous formulation comprising, by weight of the total formulation:

• 1.0-8 wt.% oxybutynin equivalent;

• 70-98 wt.% aqueous phase, preferably 70-95 wt.% aqueous phase;

• less than 10 wt.% propylene glycol;

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 “topical administration” as used herein refers to the route of oxybutynin administration by which oxybutynin is taken into the body via direct application to the intact skin (epicutaneous administration). Administration to the skin may be used for both local and systemic effects. In the context of this application, the topical administration is used to achieve local effect. Accordingly, the “topical administration” used herein does not represent a significant route for systemic delivery of oxybutynin.

“Oxybutynin equivalent” as used herein refers to oxybutynin free base or a dermatologically acceptable salt of oxybutynin, such as oxybutynin hydrochloride (C22H31NO3.HCI; 4diethylaminobut-2-ynylalpha-cyclohexylmandelate hydrochloride), or mixtures thereof. Oxybutynin as used herein refers to the (R) and (S) stereoisomers of oxybutynin, and mixtures of the stereoisomers.

Typically, oxybutynin hydrochloride presents a solubility in water of 50 mg/mL at 20 °C.

The term “aqueous phase” as used herein refers to an aqueous phase comprising water or pharmaceutically acceptable water-soluble components.

The “aqueous phase” is in the liquid state at 20 °C.

The term “dermatologically acceptable pH adjustment agent” as used herein refers to buffering agents, salts of weak organic or inorganic acids, or organic or inorganic acids or bases.

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, and the like.

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 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 (i.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, i.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.

According to an embodiment of the invention, oxybutynin is present in an aqueous formulation in an amount of 1.5 - 6.0 wt.%, preferably in an amount of 2.0 - 5.0, more preferably 2.5 to

4.5 wt.%, based on total weight of the aqueous formulation.

Suitable oxybutynin salts are selected from the group consisting of, but not limited to, acetate, bitartrate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, hydrobromide, hydrochloride, lactate, malate, maleate, mandelate, mesylate, methylnitrate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate, salicylate, stearate, succinate, sulfate, tarmate, tartrate, xinafoate, palmitate, pamoic salt, a resonate salt, a laurate salt and others. Pharmaceutical derivatives of oxybutynin which are closely related to oxybutynin are also understood to fall within the scope of the present invention. Preferably, oxybutynin is oxybutynin hydrochloride or used in equivalent amount thereof.

The aqueous phase may suitably consist of water, water-soluble components, or mixtures thereof.

In a preferred embodiment, the aqueous phase comprises, based on the weight of the aqueous phase, at least 50 wt.% water, preferably at least 55 wt.% water, more preferably at least 60 wt.% water, even more preferably at least 70 wt.% water.

Preferably, the aqueous phase comprises an alkanol selected from ethanol, isopropanol, npropanol, and mixtures thereof. More preferably, the alkanol is ethanol.

The aqueous phase may comprise polyalcohols. The polyalcohol may be polyethylene glycols having general formula CH2OH(CH2OH)_nCH2OH wherein the number of oxyethylene groups represented by n is between 4 to 200, propylene dipropylene butylene glycol, hexylene glycol, glycerin, and mixtures thereof. Preferably, the polyalcohol is propylene glycol.

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

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

It has been found that due to the lower pH range of the aqueous formulations according to the invention, oxybutynin is substantially water-soluble in the aqueous phase. Substantially watersoluble as used herein refers to a solubility of at least 90% when oxybutynin in a concentration of 50 mg/ml is added to a buffered aqueous solution having pH 4 at 21 °C. Accordingly, in a most preferred embodiment, the oxybutynin is substantially soluble in the liquid formulation.

In a particularly preferred embodiment, the aqueous formulation has a pH in the range of 3.2 to 4.8, more preferably 3.5 to 4.5, even more preferably 3.7 to 4.0.

The pH of the formulation is suitably adjusted by adding a dermatologically acceptable pH adjustment agent selected from buffering systems or salts of weak organic or inorganic acids, such as carbonate buffers, citrate buffers, phosphate buffers, acetate buffers, hydrochloric acid, lactic acid, tartric acid, diethylamine, triethylamine, diisopropylamine, aminomethylamine, or the like. Preferably, the buffer is citrate.

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, a ternary amine such as monoethanolamine, diethanolamine, triethanolamine, tromethamine, tetrahydroxypropylethylendiamine, aminomethyl propanol, diisopropanolamine, or an inorganic alkali such as NaOH solution, KOH solution, or NH4OH solution. Acidifying agents are, for example, hydroxyacids solutions, such as a HCI solution, 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 suitable comprise 0.001 to 20 wt.% of dermatologically acceptable excipients. Typically, the excipients are selected from gelling agents, bactericides, preservatives, antibiotics, 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.

In a preferred embodiment, the formulation comprises 0.001 wt.% to 1 wt.% of one or more bactericides and/or preservatives selected from benzalkonium chloride, triclosan, sorbic acid, citric acid or combinations thereof. In a particularly preferred embodiment, the formulation comprises 0.01 - 0.08 wt.%, more preferably 0.03 - 0.05 wt.% of benzalkonium chloride. The inventors have found that an aqueous formulation of oxybutynin at an acidic pH is advantageously stable at 21°C for over 16 weeks in the presence of a preservative like 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 inventors have further discovered that propylene glycol may adversely affect the stability and efficacy of the formulation if high amounts thereof is present. Accordingly, in a particularly preferred embodiment, the aqueous formulation comprises 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.

The aqueous formulation may comprise at least one gelling agent. In a preferred embodiment, the at least one gelling agent is present in an amount of at most 20.00 wt.%, more preferably 0.5 to 10 wt.%, even more preferably 1 to 5 wt.%. In a further preferred embodiment, the at least one gelling agent is present in an amount of at most 1.00 wt.%, more preferably at most 0.8 wt.%, even more preferably at most 0.5 wt.% by weight of the aqueous formulation.

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 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 to consider 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.

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 oxybutynin in a dosage of 0.015 to 1.5 mg per cm² of skin, preferably 0.01 to 1.0 mg per cm²of skin, even more preferably 0.005 to 0.5 mg per cm² of skin.

The aqueous formulation is topically applied to the affected area in an amount of 0.1 to 6 ml, 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.

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 tube comprising the aqueous formulation.

The suitable holder or dispenser according to the invention efficiently enables the subject to apply the oxybutynin 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 oxybutynin 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 oxybutynin thereto. In another embodiment of the invention the pH adjustment agent is combined with the oxybutynin in the solid form, followed by combining the mixture of solids to an aqueous solution.

A preferred method according to the invention comprising combining oxybutynin 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 oxybutynin 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.

A forth aspect of the invention relates to the use of an aqueous formulation for providing a dry touch on the skin of a subject suffering from excessive perspiration, the use comprising topically applying to the skin area in need of a an aqueous formulation comprising:

• 1.0-8 wt.% oxybutynin;

• 70-98 wt.% aqueous phase, preferably 70-95 wt.% aqueous phase;

• less than 10 wt.% propylene glycol;

It has been found that application of an aqueous solution of oxybutynin having a pH between 3.0 and 5.0 provides instant relief from, for example, sweaty hands or underarms, and other discomforting symptoms associated with hyperhidrosis.

In a preferred embodiment, the use comprises applying the aqueous formulation as a deodorant or antiperspirant, preferably in an affected area selected from armpits, face, back, palm or feet soles.

In a particularly preferred embodiment, the comprises applying the aqueous formulation to the affected area at least once a day, preferably twice a day, even more preferred at least three times a day.

The embodiments of the aqueous formulation described herein before in the context of its use in the treatment of a disease correspondingly apply to the aqueous formulation used o for providing a dry touch on the skin of the invention.

The invention will now be illustrated by the following non-limiting examples

EXAMPLES

Example 1

Two aqueous formulations according to the invention and comparative oxybutynin-containing formulations were prepared according to the compositions shown in Table 1 (based on weight of the total composition):

Table 1

Component	Formulation 1 (% w/v)	Formulation 2 (% w/v)	Comparative Formulation A (% w/v)	Comparative Formulation B (% w/v)	Placebo Formulation P (% w/v)
Oxybutynin hydrochloride¹	2	4	2	2	-
Benzalkonium chloride²	0.01	0.01	-	0.01	-
Propylene glycol³	-	-	15	-	-
Citric acid⁴	0.12	0.12	0.12	0.03	0.07
Sodium citrate⁵	0.11	0.11	0.11	0.29	0.19
Demineralized water	q.s. 100 mL	q.s. 100 mL	q.s. 100 mL	q.s. 100 mL	q.s. 100 mL
pH	pH 4	pH 4	pH 4	pH 7	pH 4

¹ 02881 Sigma-Aldrich >98% TLC, powder. Solubility >50 mg/ml in a citrate buffer solution at pH 4.

² 234427 Sigma-Aldrich.

³ Propylene glycol USP/EP >99.8% - Dow.

⁴ Anhydrous, free-flowing, Redi-Dri™, ACS reagent, >99.5% (Sigma-Aldrich).

⁵ W302600 >99%, Aldrich.

The formulations were prepared following the steps of:

combining 0,01% benzalkonium chloride with demineralized water to provide an aqueous solution of 0.1 %(w/v) benzalkonium chloride;

Providing weighted amounts of oxybutynin HCI, citric acid and sodium citrate in the powder form;

dissolving powders into the benzalkonium solution under stirring;

measuring the pH at 21 °C using a pH meter;

adjusting the final volume of the aqueous solution; and adjusting the pH of the final solution 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 transparent solutions stored for 12 weeks at 21 °C.

Formulations 1 and 2 were stable in the storage conditions for at least 12 weeks without visual changes.

Comparative formulation A exhibited precipitation formation after 7 days when left undisturbed under storage conditions (room light and temperature). Comparative formulation B exhibited precipitation formation after 2 days when left undisturbed under storage conditions (room light and temperature).

Example 2

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

Each patient was subjected to a double-blind placebo controlled test for a period of 7 consecutive days for each of the test formulations. The subjects were asked to apply the formulation twice a day , two sprays each armpit (1 spray = about 0,15 ml solution).

Each patient was asked to evaluate the axillary odor and sweating reduction in a scale from 1 to 4 following the Hyperhidrosis Disease Severity Scale (HDSS) as determined by the International Hyperhidrosis Society (https ://www.sweathelp.ürg/paf/HpSS.pdf):

How would you rate the severity of your hyperhidrosis?

1. My sweating is never noticeable and never interferes with my daily activities

2. My sweating is tolerable but sometimes interferes with my daily activities

3. My sweating is barely tolerable and frequently interferes with my daily activities

4. My sweating is intolerable and always interferes with my daily activities

The results were measured as a reduction in HDSS score (in percentage), i.e., HDSS for a certain solution and a certain volunteer in relation to a basic HDSS score of the same volunteer when nothing was used.

All subjects treated with formulations 1 and 2 reported reduction in the excessive sweating during the test period.

All subjects treated with formulation 1 reported a significant amelioration (>50%) in the excessive sweating and odour formation. Reduction in sweating was seen within 30 minutes. An average reduction in the HDSS of 56% was reported by the tested subjects using Formulation 2.

100% of the tested subjects reported 0% amelioration of the condition during the period using formulations A and P.

Example 3

A comparison between oxybutynin compositions with different salts (citrate, lactate, acetate) and ethanol content were tested. Compositions with 4% oxybutynin and 40% ethanol were refused by the human subjects due to the strong alcoholic smell. Compositions with 4% oxybutynin and 1% sodium acetate were also refused by subjects due to the unpleasant smell. The test including these compositions was discontinued.

The followed-up study involved the comparison between three compositions, as described in Table 2.

Table 2

	Invention	Solution A	Solution B
Oxybutynin HCI	40 g	40g	40g
Sodium citrate	1.11 g	1.11 g	-
Sodium lactate	-	-	10g
Citric acid	1.12g	1.12g	-
Benzalkonium chloride	100mg	-	-
Propylene glycol	-	150 g	150g
Ethanol	-	200g	200g
Purified water ad	1000ml	1000ml	1000ml
pH	4	4	5.5

Raw materials used as specified in Table 1

The daily dosage of all tested compositions was: 2-3 times daily using 1-2 sprays per armpit (1 spray equals about 0,15 ml) during 2 weeks. Subjects were asked to evaluate the reducing of sweating on a scale from 0-10 (0: completely dry; 10: permanently wet). The average results of all tested are disclosed in table 3:

	Sweating reduction scale (average)
Control (no composition)	5.9
Invention	3.2
Solution A	4
Solution B	3.8

The subjects testing the composition according to the invention observed a better relief of the symptoms of hyperhidrosis (drier skin).

Claims

• 1.0-8 wt.% oxybutynin;

• 70-98 wt.% aqueous phase;

• dermatologically acceptable pH adjustment agent to provide the formulation with a pH in the range of 3.0 to 5.0 at 21 °C.

• 1.0-8 wt.% of oxybutynin equivalent;

• less than 10 wt.% propylene glycol;

• 70-98 wt.% of aqueous phase; and • dermatologically acceptable pH adjustment agent to provide the formulation with a pH in the range of 3.0 to 5.0 at 21 °C.

1. An aqueous formulation for use in the treatment of a skin disease, said treatment comprising topically administering to a human patient an aqueous formulation comprising, by weight of the total formulation:
2. Aqueous formulation for use according to claim 1, wherein the oxybutynin is present in an amount of 1.5 - 5 wt.%, preferably 2-4 wt.%.
3. Aqueous formulation for use according to anyone of the preceding claims, wherein the aqueous phase comprises, based on weight of the aqueous phase, at least 50 wt.% water.
4. Aqueous formulation for use according anyone of the preceding claims, wherein the formulation has a pH in the range of 3.2 to 4.8.
5. Aqueous formulation for use according to anyone of the preceding claims, wherein the dermatologically acceptable pH adjustment agent being selected from the group comprising buffering systems, preferably a citrate buffering system, and salts of weak organic or inorganic acids.
6. Aqueous formulation for use according to anyone of the preceding claims, wherein the formulation comprises less than 5 wt.% propylene glycol.
7. Aqueous formulation for use according to anyone of the preceding claims, wherein the formulation comprises less than 5 wt.%, preferably less than 2.5 wt.%, even more preferably less than 1 wt.% of hydroxypropylcellulose.
8. Aqueous formulation for use according to anyone of the preceding claims, wherein the aqueous formulation is topically administered to the affected skin at least once a day.
9. Aqueous formulation for use according to anyone of the preceding claims, wherein the aqueous formulation is administered in an amount of at least 0.015 mL per cm² of skin.
10. Aqueous formulation for use according to anyone of claims 1 to 9, wherein the skin disease is primary or secondary hyperhidrosis.
11. A skin applicator comprising the aqueous formulation for use according to claims 1 to 10, 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.
12. A method of preparing an aqueous formulation according to claims 1 to 10, the method comprising the steps of combining oxybutynin with a dermatologically acceptable pH adjustment agent to produce an aqueous formulation having a pH in the range of 3.0 to 5.0 at 21 °C.
13. Use of an aqueous formulation for providing a dry touch on the skin of a subject suffering from excessive perspiration, the use comprising topically applying to the skin area in need of a an aqueous formulation comprising:
14. Use of aqueous formulation according to claim 13, wherein the aqueous formulation comprises less than 15 wt.% propylene glycol.