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, 2 113, 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).
US2003/0171 391 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 11 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
HS1 5, 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(1 0): 984-7), fixed drug eruption (Vilaplana J. e 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 0.5:1 0 to 5:1 0.
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 HS1 5 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 LC201 0A 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;
- : 3 19 nm;
- injection volume: 10 m I;
- column: C 18 Gemini, 250 x 4.6 mm 5m i i ;
- column temperature: 40 °
- 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 1g 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/1 22/02, rev 1) ,
i.e. by maintaining the product in its container at a temperature of 40 °
± 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 11.067 99.8 10.758 100.6 11.042 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 (A' , B') 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 LC201 0A 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
H 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.
11. 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 11, 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.