WO2012085185A1

WO2012085185A1 - Aqueous solution of ambroxol

Info

Publication number: WO2012085185A1
Application number: PCT/EP2011/073754
Authority: WO
Inventors: Gianluigi PASSETTI
Original assignee: Advance Holdings Limited
Priority date: 2010-12-23
Filing date: 2011-12-22
Publication date: 2012-06-28
Also published as: NZ609742A; BR112013012815A2; JP2014503542A; CL2013001297A1; MX2013005500A; CN103269685A; AU2011347257A1; CA2817453A1; EA201300535A1; AR084537A1; EP2654719A1; KR20130140042A

Abstract

The present invention relates to an aqueous solution comprising an acid addition salt of ambroxol, wherein the ambroxol content is ranging from 0.1% to 7% (w/v), the total content of polyalcohols selected from polyols and polyalkyleneglycols is at least 20% (w/v), the total content of alcohols is lower than 1% (w/v), and said aqueous solution is free of benzoic acid and/or salts thereof with organic or inorganic bases.

Description

Aqueous solution of ambroxol

FIELD OF THE INVENTION

The present invention relates to an aqueous solution, comprising an acid addition salt of ambroxol.

More in particular, the aqueous solution of the present invention comprises an ambroxol content ranging from 0.1 % to 7% (w/v), a total content of polyalcohols selected from polyols and polyalkyleneglycols of at least 20% (w/v), an alcohol content lower than 1 % (w/v) and is free of benzoic acid and/or salts thereof with organic or inorganic bases, hereinbelow collectively referred to as "benzoates".

BACKGROUND OF THE INVENTION

Ambroxol hydrochloride [trans-4-(2-amino-3,5-dibromobenzyl amino)cyclohexanol hydrochloride] (Ph. Eur., Monograph 1489) is a well known mucolytic drug available in various compositions suitable for oral or parenteral administration. However, oral compositions are by far preferred.

The international patent application WO 01 /05378 discloses a tablet to be sucked for the treatment of sore throat symptoms.

Subsequently, two articles have been published (Deutsche Apotheker Zeitung; 17, 21 13, 2002; J. Fischer et al. Arzneim. Forsch.; 52, 256, 2002) relating to controlled studies versus placebo, randomised and statistically significant, which prove the effectiveness on sore throat symptoms of tablets containing 20 or 30 mg of ambroxol. However, the authors believe that liquid forms, such as mouth washes and sprays, do not allow ambroxol to exercise its effectiveness on sore throat symptoms due to its short time of persistence in the mouth. Moreover, currently available aqueous liquid forms could not exercise a sufficient action because the concentration of ambroxol is rather low due to the poor solubility in water of ambroxol hydrochloride, which is about 3% (w/v).

US2003/0171391 and US 2005/0014844 generally disclose a pharmaceutical composition containing ambroxol. Example G of both such patent applications discloses an oral solution comprising 1 .5% w/v of ambroxol, 6% w/v of a sorbitol solution at 70%, 2% w/v of glycerol, and minor amount of other additives and flavouring agents.

US 2005/0266058, US 2003/01 13377, and US 2005/0075403 generally disclose a pharmaceutical composition containing ambroxol, in particular in the form of gels, hydrophilic pastes, lotions, solutions, suppositories, hydrophobic pastes, ointments, creams, lotions, sticks, lozenges, tablets, pastilles, and sweets. Example 1 of US 2005/0266058 discloses an aqueous solution comprising 1 % w/w of ambroxol, 20% w/w of a glycerol solution at 85%, 5% w/w of ethanol solution at 96%, and minor amount of flavouring and colouring agents. Examples 1 1 and 15 of US 2003/01 13377 disclose an aqueous solution comprising about 2.3% w/w of ambroxol, about 47% w/w of propylene glycol, and 10% w/w of ethanol. Formulation 3 of US 2005/0075403 discloses an aqueous solution comprising 1 % w/w of ambroxol, 30% w/w of sorbitol, 10% w/w of glycerol, 5% w/w of ethanol, and minor amount of flavouring agents.

EP 1 543 826 describes an oral liquid formulation of ambroxol, characterized by high concentration (about 4-7% w/v) of the active ingredient. Example 1 of EP 1 543 826 discloses an aqueous solution comprising 5% w/v of ambroxol, 20% w/v of xylitol, 10% w/v of Solutol HS15, 2.9% w/v of glycerol, 0.50% w/v of sodium benzoate, and minor amount of flavouring agents. Such formulation is said to be stable for at least 12 months if it is stored in an amber glass bottle at 25 °C.

The use of preservatives, like alcohols, benzoates, sorbates, and parabens is common in liquid formulations. Preservatives are effective in controlling mold, inhibiting yeast growth and protecting against bacterial proliferation, thus, finally, to allow compliance with the European Pharmacopoeia microbiological specifications (Ph. Eur. 6.7, § 5.1 .4) for "aqueous preparations for oral use" or "aqueous preparations for oromucosal use". The use of preservatives is particularly recommended in aqueous compositions, wherein microorganisms can find favourable conditions for their propagation.

SUMMARY OF THE INVENTION

The Applicant has found that a drawback of the formulations containing ambroxol, both at low and at high concentration, is the formation of several degradation impurities, both during storage and stability studies. This drawback is more evident with high concentration formulations, as they reach more quickly non-acceptance levels.

One of the main impurities produced during the storage of the product, according to EP 1 543 826, is the impurity B [trans-4-(6,8- dibromo-1 ,4-dihydroquinazolin-3(2H)-yl)cyclohexanol]. This is a well known compound, reported on European Pharmacopoeia as possible impurity of the active ingredient, due to the interaction between ambroxol with formaldehyde. Other possible impurities due to oxidation reactions are impurity A [(2-amino-3,5-dibromophenyl)methanol] and impurity E (2-amino-3,5-dibromobenzaldeyde), but both can be controlled by operating in nitrogen atmosphere.

The Applicant has found that another drawback is that the formulation according to EP 1 543 826, during storage, put in evidence some unknown degradation products with a trend to increase more than impurities A, B and E.

The formation of both known and unknown impurities originated by degradation of the active ingredient is a common problem of drug products and in particular of liquid forms. Of course, it must be regarded as a negative aspect which may limit the stability of the product. The rules in force (e.g. "Note For Guidance On Impurities In New Drug Products" CPMP/ICH/2738/99, issued by EMEA, European Medicines Agency) provide strict limitations for this kind of impurities, nevertheless it is better to prevent or reduce as possible the degradation to avoid the exposure of patients to substances whose toxicological properties are not always known (especially for unknown impurities).

The Applicant has noticed that the aqueous oral ambroxol formulations known in the art, both with low and high active ingredient concentration, contain benzoates or other specific antimicrobial preservatives.

Benzoates are known to induce adverse reactions, both in adults and children, for example in asthmatic persons (see Petrus M. et al., Arch. Pediatr., 1996; 3(10): 984-7), fixed drug eruption (Vilaplana J. ei al., Contact Dermatitis, 2003; 49(6):290-1 ) and episodes of acute urticaria/angio-oedema. (Nettis E. et al., Br. J. Dermatol., 2004; 151 (4): 898-902). Further, recent studies have reported serious side effects associated with potassium sorbate and methyl hydroxybenzoate (methyl-paraben). Skin reactions, such as rash, urticaria, and contact dermatitis have been reported after topical application. Allergic potential and estrogenic potential have been reported after ingestion (C. Boukarim et al., The Journal of Applied Research, Vol. 9. No. 1 & 2, 2009). Further, the Applicant has realized that formulations comprising alcohols, such as those described in US 2005/0266058, US 2003/01 13377, and US 2005/0075403, in spite of being very stable from the point of view of microbiological specifications, are not generally well accepted by consumers which are reluctant to drink alcoholics for health, ethic, moral or legal reasons, and are not allowed for pediatric uses.

Now, the Applicant has surprisingly found a solution to overcome the aforesaid drawbacks.

Investigating on product prepared according to EP 1 543 826, the Applicant has surprisingly found that removing sodium benzoate from the composition, the formulation is strongly improved in terms of stability and exhibits a slower increase of impurity B and a much slower increase of unknown degradation products.

Moreover, the absence of benzoates permits to overcome the tolerability problems related to the use of this preservative.

Furthermore, the Applicant has found that, despite the absence of sodium benzoate and the very low, if any, amount of alcohols, when the total content of polyols and polyalkyleneoxides is at least 20% w/v. the "efficacy of antimicrobial preservation" (Eur. Ph. 6.6 Ed. § 5.1 .3) test in different severe conditions is maintained, so that the presence of additional preservatives, together with the side effects thereof, can be optionally avoided.

DETAILED DESCRIPTION OF THE INVENTION

It is therefore an object of this invention to provide an aqueous solution comprising an acid addition salt of ambroxol, wherein the ambroxol content is ranging from 0.1 % to 7% (w/v), the total content of polyalcohols selected from polyols and/or polyalkyleneglycols is at least 20% (w/v), the total content of alcohols is lower than 1 % (w/v), and said aqueous solution is free of benzoates.

For the purpose of the present invention, the term "benzoates" shall refer to both the benzoic acid and the salt thereof with organic or inorganic bases. For the purpose of the present invention, the term "free of" referred to the amount of "benzoates" as defined herein shall mean that the amount of benzoates is below 0.001 % (w/v).

For the purpose of the present invention, the term "alcohols" shall refer to any of a class of pharmaceutically acceptable organic compounds bearing only one hydroxy (-OH) group attached to a carbon atom of an alkyl group (hydrocarbon chain). Specific examples of alcohols within the above mentioned definition are: ethanol, propanol and isopropanol.

Typically, the acid addition salt of ambroxol is hydrochloride salt. Preferably, the ambroxol content is from 0.2 to 6% (w/v), more preferably is from 0.3 to 5% (w/v), and most preferably from 1 .0% to 4.0% (w/v).

Advantageously, the formulation comprises polyalcohols selected from polyols and/or polyalkyleneglycols having solubilising, surfactant and sweetening properties as main functions.

Preferably, said polyols are selected from glycols, such as ethylene glycol, propylene glycol, 1 ,3-propanediol, trimethylene glycol, 1 ,2- butanediol, 1 ,3-butanediol, 1 ,4-butanediol, 1 ,2-pentanediol, 1 ,4- pentanediol, 1 ,5-pentanediol, 1 ,6-hexanediol, 1 ,7-heptanediol, diethylene glycol, dipropylene glycol, glycerol, 1 , 1 , 1 -trimethylolpropane, 1 ,1 ,1 -trimethylolethane, 1 ,2,6 hexanetriol, etohexadiol, 2-methyl-2,4- pentanediol, 1 ,8-octanediol, and glycerol; sugar alcohols, such as threitol, arabitol, ribitol, dulcitol, iditol, lactitol, pentaerythritol, maltitol, sorbitol, mannitol, xylitol, erythritol, isomalt; and sugars, such as ribose, arabinose, xylose, lyxose, deoxyribose, fructose, sorbose, glucose, mannose, galactose, gulose, sucrose, lactose, lactulose, maltose, trehalose, turanose, cellobiose, and mixture thereof.

More preferably, the polyols useful in the present invention are selected from glycerol, propylene glycol, xylitol, sorbitol, sucrose, glucose, and mixture thereof.

Preferably, said polyalkylene glycols are selected from polyethylene glycol, polypropylene glycol, esters thereof with organic acids, or ethers thereof with alcohols, and mixture thereof.

More preferably, the polyalkylene glycols useful in the present invention are selected from esters of polyethylene glycols having a molecular weight ranging from 200 to 1500 (PEG 200, PEG 300, PEG 400, PEG 600, PEG 660, PEG 1000, PEG 1500) with hydroxy fatty acids, such as, for example hydroxylauric acid, hydroxymyristic acid, hydroxypalmitic acid, hydroxystearic acid, and hydroxyarachidic acid.

Advantageously, the polyalkylene glycol ester useful in the present invention is Solutol™ HS 15 (Macrogol 15 hydroxystearate, Ph. Eur., Monograph 2052), a polyethylene glycol 660 hydroxystearate manufactured by BASF (Parsippany, N.J.).

The total content of the above described polyols and polyalkylene glycols amounts to at least 20% by weight based on the total volume of the aqueous solution (w/v). Preferably, the total content of the above described polyols and polyalkylene glycols ranges from 25% to 75% w/v, more preferably from 30% to 70% w/v, and most preferably from 35% to 65% w/v. Particularly, the total content of alcohols is lower than 0.7% (w/v), and more particularly, the presence of alcohols can also be totally avoided.

Advantageously, the aqueous solution is preferably free of additional preservatives represented by sorbic acid, sorbates (salts of sorbic acid) and parabens (esters of para-hydroxybenzoic acid). For the purpose of the present invention, the term "free of" referred to the amount of "additional preservatives" as defined herein shall mean that the amount of any of such preservatives is below 0.001 % (w/v).

Preferably, the pH value of the formulation is from 6 to 7 and more preferably it is about 6.4.

Advantageously, a pH value of from 6 to 7 is obtained by adding an inorganic or organic base, such as sodium or potassium hydroxide, sodium or potassium bicarbonate, triethanolamine, tris [tris(hydroxy methyl)aminomethane], N-methylglucosamine, lysine, arginine and the like.

In general, the aqueous solution of this invention may comprise further pharmacologically active ingredients whose concurrent administration is useful, provided they do not interfere with the solubility of the acid addition salt of ambroxol in the solution of this invention.

Preferably, however, an acid addition salt of ambroxol is the sole pharmacologically active ingredient in the aqueous solution of this invention.

As it is well known, ambroxol is characterised by a particularly bitter aftertaste which is increasingly difficult to mask as concentration increases. Therefore, it is particularly difficult to mask the aftertaste of ambroxol even when the excipients present in the solution of this invention do not have an unpleasant taste. Accordingly, the solution of this invention preferably comprises a taste masking agent.

Preferably, the taste masking agent is an ammonium salt of glycyrrhizic acid.

Advantageously, the preferred salt is ammonium monoglycyrrhizinate.

For this purpose, the combined action of ammonium monoglycyrrhizinate with menthol has been found to be particularly effective.

Anyway, the Applicant has found that, in general, the palatability of formulations free of benzoates is improved when compared to the same formulation comprising benzoates.

The preferred ammonium monoglycyrrhizinate:menthol weight ratio is of from 0.5:10 to 5:10.

In turn, the preferred ammonium monoglycyrrhizinate:ambroxol weight ratio is of from 0.001 :1 to 0.1 :1 . More preferably, said weight ratio is of from 0.01 :1 to 0.05:1 and even more preferably, it is of from 0.01 1 :1 to 0.025:1 .

The solution of this invention is suitable for mucolytic therapy in place of known ambroxol-based compositions. Moreover, the most concentrated (> 5%) solutions of this invention are also effective in the treatment of sore throat symptoms when administered in the form of sprays or mouth washes.

Preferably, the solution of the present invention is for oral use. Preferred dosage forms of the solution of this invention are, therefore, syrups, drops, sprays and mouthwashes. The following examples further illustrate the invention, without limiting it.

EXAMPLES

Example 1 - Compositions

Formulation 1 : 5% ambroxol solution, comparative formulation according to EP 1 543 826 (100 mL).

Formulation 2: 5% ambroxol solution, formulation according to the present invention (100 mL).

Table 1

Ingredients Formulation 1 (^*) Formulation 2

Ambroxol- HCI g 5.000 g 5.000

Tromethamine g 0.360 g 0.360

Sodium benzoate g 0.500 —

Solutol HS15 g 10.000 g 10.000

Glycerol g 2.900 g 2.900

Xylitol g 20.000 g 20.000

K Acesulfame g 1 .500 g 1 .500

Levomenthol g 0.500 g 0.500

Ammmonium

g 0.063 g 0.063 Glycyrrhizate

Ethanol mL 0.625 mL 0.625

Sodium Hydroxide

mL 0.625 mL 0.625 0.001 N

Purified water q.s. to mL 100 q.s. to mL 100 pH 6.4 6.4

(^*) Comparative

Example 2 - HPLC analysis

An HPLC analysis was performed to quantify ambroxol HCI, impurity B and the others unknown degradation products in the formulations 1 and 2 prepared as described in previous Example 1 .

Method

The analysis was performed with a Shimadzu LC2010A instrument with UV detector in the following conditions:

- mobile phase: mixture of ammonium phosphate buffer (0.02M pH 7.50)/acetonitrile in a ratio of 51 /49;

- flow: 1 mL/min;

- A: 319 nm;

- injection volume: 10 μΙ;

- column: C18 Gemini, 250 x 4.6 mm 5μιτι ;

- column temperature: 40 °C;

- run Time: 30 minutes.

Standard solutions

A standard solution of impurity B was prepared by weighing exactly 10 mg of the product, in a 100 mL volumetric flask. The product was dissolved with acetonitrile and the solution thus obtained was brought to volume (100 mL) with acetonitrile.

A standard solution of ambroxol HCI was prepared by weighing exactly 50 mg of the product, in a 25 mL volumetric flask. The product was then dissolved with 10 mL of acetonitrile and then, 0.5 ml of the standard solution of impurity B, prepared as described above, was added. The solution thus obtained was brought to volume (25 ml_) with acetonitrile.

Sample solutions

Two sample solutions were prepared for both Formulations 1 and 2. The sample solutions to be used in the HPLC analysis were prepared by transferring 1 g of each Formulation 1 and Formulation 2, into two 25 ml_ volumetric flasks. The solutions thus obtained were brought to volume (25 ml_) with acetonitrile.

Batches A and B were obtained from Formulation 1 and batches A' and B' were obtained from Formulation 2.

The HPLC analysis was performed shortly after the preparation of the solutions (T=0) by injecting once the sample solutions and six times the standard solution of impurity B and ambroxol HCI (the standard is the average of the six measures).

The results are summarized in the following Table 2. The results are expressed as follows: (i) ambroxol hydrochloride as relative percentage (%) with respect to the nominal concentration (50 mg/mL); (ii) impurity B as relative concentration with respect to ambroxol hydrochloride; (iii) unknown Impurity as relative concentration with respect to ambroxol hydrochloride assuming that it has the same analytical response of impurity B.

Table 2

Assay (%) at T=0

Formulation 1 (^*) Formulation 2

Peak Rt Batch Rt Batch Rt Batch Rt Batch

(min) A (%) (min) B (%) (min) A' (%) (min) B' (%)

Ambroxol 10.567 100.2 10.592 99 10.542 101 .4 10.625 99.8

Impurity B 8.392 0.01 8.400 0.01 8.358 0.01 8.417 0.01 Unknown

6.450 0.010 6.450 0.013 6.417 0.009 6.458 0.008

Impurity

(^*) Comparative

Rt (min.) = retention time in minutes

The results demonstrated that at time 0 in Formulation 2, according to the present invention, the amount of Unknown Impurity was a little bit lower when compared with the Formulation 1 , according to EP 1 543 286, but the difference involved only the third decimal digit.

Example 3 - Accelerated stability test

Accelerated stability tests are performed by storing a product in stress conditions.

These tests allow to predict the shelf life of the product over the years when it will be stored in normal storage conditions.

The accelerated stability test in this case was performed according to the EMEA Guideline on Stability Testing (CPMP/QWP/122/02, rev 1 ), i.e. by maintaining the product in its container at a temperature of 40 °C ± 2°C and 75% + 5 %RH (Relative Humidity) for six months.

The HPLC analyses on the samples obtained after 6 month storage under stress conditions were performed as described in Example 2. The results are summarized in the following Table 3 and they are expressed as described for Table 2.

Table 3

I Assay (%) at T=6 months Formulation 1 (^*) Formulation 2

Peak Rt Batch Rt Batch Rt Batch Rt Batch

(min) A (%) (min) B (%) (min) A' (%) (min) B' (%)

Ambroxol 10.758 99.7 1 1 .067 99.8 10.758 100.6 1 1 .042 98

Impurity B 8.425 0.26 8.792 0.22 8.425 0.06 8.767 0.06

Unknown

6.483 1 .51 6.742 1 .13 6.483 0.32 6.717 0.35 Impurity

(^*) Comparative

Rt (min.) = retention time in minutes The comparison between batches (A, B) and (Α', Β') showed that during six months of storage in stress conditions, in formulation 2, according to the present invention, the Impurity B and Unknown Impurity increased much less than in Formulation 1 , according to EP 1 543 286. In fact, both impurities in Formulation 2 reached levels between 1 /3 and 1 /4 of that present in Formulation 1 .

These results demonstrated that the absence of sodium benzoate improved stability of the formulation and slowed the increase of the concerned impurities.

Example 4 - Compositions

Formulation 3: 0.3% ambroxol solution, comparative formulation prepared in substantial agreement with that of Mucosolvan (100 ml_).

Formulation 4: 0.3% ambroxol solution, as Formulation 3, modified according to the present invention (100 ml_). Table 4

(^*) Comparative

Example 5 - HPLC analysis

An HPLC analysis was performed to quantify ambroxol HCI, impurity B and the Unknown Degradation product in the Formulations 3 and 4 prepared as in previous Example 4.

The analysis was performed with a Shimadzu LC2010A instrument with UV detector under the same conditions of previous Example 2. The standard solutions of impurity B and of ambroxol HCI were prepared as described in previous Example 2.

The sample solutions to be used in the HPLC analysis were prepared by transferring 10 mL of each Formulation 3 and 4 in two 15 mL volumetric flasks. The solutions thus obtained were brought to volume (15 mL) with acetonitrile. One batch for each of Formulation 3 and 4 was prepared. The HPLC analysis was performed shortly after the preparation of the solutions (T=0).

The results are summarized in the following Table 5 and they are expressed as described for Table 2.

Table 5

(^*) Comparative

Rt (min.) = retention time in minutes The results demonstrated that in Formulation 4, according to the present invention, the amount of Impurity B was very similar to that of the comparative Formulation 3, while the Unknown Impurity was substantially lower.

Example 6 -Accelerated stability test

The accelerated stability test was performed in the same conditions reported in previous Example 3; the stored samples were analyzed after six months (T=6 months) from their preparations The results are summarised in the following Table 6 and they are expressed as described for Table 2.

Table 6

(^*) Comparative

Rt (min.) = retention time in minutes

The results demonstrated that in Formulation 4, according to the present invention, after 6 months, the amount of Impurity B, although lower, was rather close to that present in the comparative Formulation 3, while the amount of Unknown Impurity was about 20% lower.

The differences observed between Formulation 3 and Formulation 4, were less marked than those observed between Formulation 1 and Formulation 2. This was the consequence of the much lower concentration of ambroxol in Formulations 3 and 4.

Considering that the new Formulations 2 and 4 and their corresponding comparative Formulations 1 and 3 were prepared at the same time and with active ingredient and excipients of the same batches, the observed differences in the impurity formation were significant to confirm the unexpectedly negative effect of benzoates on the ambroxol stability in aqueous formulations characterized by completely different compositions and a wide range of concentrations.

Example 7 - Anti-microbial test

Three formulations in accordance with the present invention with different concentrations of ambroxol were prepared. Formulation A and B correspond to Formulations 2 and 4. Formulation C has the composition of the following Table 7.

TABLE 7

Ingredients Formulation C

Ambroxol- HCI g 2.500

Tromethamine g 0.360

Solutol HS15 g 10.000

Glycerol g 2.900

Xylitol g 20.000

K Acesulfame g 1 .500

Levomenthol g 0.500

Ammmonium Glycyrrhizate g 0.063

Ethanol ml 0.625

Sodium Hydroxide 0.001 N ml 0.625

Purified water q.s. to mL 100

pH 6.4 Formulations A to C were subjected to a test to verify the preservative properties.

The test for efficacy of anti-microbial preservation was performed in accordance with the EU Ph. 6.6, § 5.1 .3. In particular, the test verified that the limits related to the concentration of bacteria and fungi in oral preparations were in accordance with Table 5.1 .3-3 of the European Pharmacopoeia.

Formulations A to C demonstrated that the preservative properties of the preparations were maintained, although the absence of a specific excipient acting as preservative agent.

Claims

1 . An aqueous solution comprising an acid addition salt of ambroxol, wherein the ambroxol content is ranging from 0.1 % to 7% (w/v), the total content of polyalcohols selected from polyols and polyalkyleneglycols is at least 20% (w/v), the total content of alcohols is lower than 1 % (w/v), and said aqueous solution is free of benzoic acid and/or salts thereof with organic or inorganic bases.

2. The aqueous solution according to claim 1 , wherein the ambroxol content is ranging from 0.2% to 6% (w/v).

3. The aqueous solution according to claim 2, wherein the ambroxol content is ranging from 0.3% to 5% (w/v).

4. The aqueous solution according to claim 3, wherein the ambroxol content is ranging from 1 .0% to 4.0% (w/v).

5. The aqueous solution according to any one of the preceding claims, wherein the total content of said polyalcohols ranges from 25% to 75% (w/v).

6. The aqueous solution according to claim 5, wherein the total content of said polyalcohols ranges from 30% to 70% (w/v).

7. The aqueous solution according to claim 6, wherein the total content of said polyalcohols ranges from 35% to 65% (w/v).

8. The aqueous solution according to claim 1 , wherein the total content of alcohols is lower than 0.7 (w/v).

9. The aqueous solution according to claim 1 , wherein said aqueous solution is free of sorbic acid and sorbates.

10. The aqueous solution according to claim 1 , wherein said aqueous solution is free of parabens.

1 1 . The aqueous solution according to any one of the preceding claims, wherein said polyols are selected from glycols, such as ethylene glycol, propylene glycol, 1 ,3-propanediol, trimethylene glycol, 1 ,2- butanediol, 1 ,3-butanediol, 1 ,4-butanediol, 1 ,2-pentanediol, 1 ,4- pentanediol, 1 ,5-pentanediol, 1 ,6-hexanediol, 1 ,7-heptanediol, diethylene glycol, dipropylene glycol, glycerol, 1 , 1 , 1 -trimethylolpropane, 1 ,1 ,1 -trimethylolethane, 1 ,2,6 hexanetriol, etohexadiol, 2-methyl-2,4- pentanediol, 1 ,8-octanediol, and glycerol; sugar alcohols, such as threitol, arabitol, ribitol, dulcitol, iditol, lactitol, pentaerythritol, maltitol, sorbitol, mannitol, xylitol, erythritol, isomalt; and sugars, such as ribose, arabinose, xylose, lyxose, deoxyribose, fructose, sorbose, glucose, mannose, galactose, gulose, sucrose, lactose, lactulose, maltose, trehalose, turanose, and cellobiose; and mixture thereof.

12. The aqueous solution according to claim 1 1 , wherein said polyols are selected from glycerol, propylene glycol, xylitol, sorbitol, sucrose, glucose, and mixture thereof.

13. The aqueous solution according to any one of the preceding claims, wherein said polyalkylene glycols are selected from polyethylene glycol, polypropylene glycol, esters thereof with organic acids, ethers thereof with alcohols, and mixture thereof.

14. The aqueous solution according to claim 13, wherein said polyalkylene glycols are selected from esters of polyethylene glycols having a molecular weight ranging from 200 to 1500 with hydroxy fatty acids.