Preservatives of formulations for topical use

Details Preservatives of formulations for topical use Preservatives of formulations for topical use

2001-04-09

2003-04-01

Dees, Jose′ G. (Department: 1616)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Biocides; animal or insect repellents or attractants

C252S380000, C252S384000, C514S129000

Reexamination Certificate

active

06541019

ABSTRACT:

The present invention relates to the use of functionalized (per) fluoropolyethers as preservatives of compositions for topical use, specifically cosmetic compositions.
The maintenance in the time of the homogeneity, of the appearance and of the organoleptic properties of cosmetic formulations, as well as of the dermatological and pharmaceutical ones, is an essential requirement for the marketing of these compounds. For these reasons the use of preservatives is in many cases indispensable.
Preservatives are regulated through proper lists with indications of no use and of the allowed maximum doses. The preservative often has a local irritating and allergenic potential activity and therefore the use is limited to the minimum doses necessary to assure the compound protection from the biological contamination for the validity time of the formulation. The compositions containing water are those sensitive to the bacteria, moulds and yeasts contamination, in a proportional way to the water content. Said compositions are for example gels and emulsions and among the latter in particular oil-in-water emulsions.
The preservative must be a subsantially water-soluble compound at the concentrations at which it is used, and it must be active on a wide spectrum of microorganisms (gram-positive bacteria, gram-negative bacteria, yeasts and moulds). In general a preservative is effective only towards some kinds of microorganisms but not towards all. Therefore the activity spectrum towards the various kinds of microrganisms is enlarged by using mixtures of preservatives. Alternatively only one preservative could be used, but in this case its concentration should be increased so that the compound is B effective towards a wider spectrum of microorganisms. The drawback is that these high concentrations are generally not allowed from the rules of the various countries.
It is known that it is possible to reduce the preservative amount by adding to the formulation a surfactant amount of about 5-10% by weight. The use of surfactants has however the drawback to substantially modify the formulation and the application properties since surfactants are aggressive substances. It is well known that in cosmetic compositions the surfactants confer detergent properties wherefor for example the protective creams become detergent creams, and therefore rinsing products.
It is possible to avoid the addition of preservatives by using formulations containing high concentrations of some excipients, for example water-soluble substances, such as for example polyols, sugars, salts, etc. In these cases a partial protection is obtained, for example from bacteria but not from fungi (yeasts and moulds).
Alcohols and glycols, at high concentrations, higher than 15% by weight, can also be used. Ethanol is for example used at concentrations higher than 20% by weight. The production cost of these formulations is often high and contra-indications as for the local skin tolerability is concerned can occur.
In the prior art it is therefore known how to reduce or eliminate preservatives from the formulations of the products for topical use, in connection with their undesired local irritating or allergenic properties, by using to excipients which however have the drawback, as said, to be less effective than preservatives and to impose some restrictions as regards the formulation, or to cause in their turn skin tolerability problems.
The need was felt to formulate compositions for topical use without preservatives, in order to avoid undesired side effects at local skin level, maintaining the protection from contamination both of gram-positive and gram-negative bacteria and of yeasts and moulds, which typically requires the use of preservatives.
The Applicant has surpirisngly and unexpectedly found that it is possible to solve this technical problem by adding to said formulations for topical use containing water a well defined compound as indicated hereunder.
An object of the present invention is the use as preservative, in formulations for topical use containing water, of a component A): (per)fluoropolyether phosphate of general formula:
R
f
—[CF
2
CH
2
—O—L—P(O) (OZ
1
) (OZ
2
)]
l
  (I)
wherein l=1 o 2;
L is a bivalent linking group, preferably of the type (CHR
1
CHR
2
O)
n
wherein R
1
, R
2
equal to or different from each other are selected from H, CH
3
; n is an integer in the range 1-50, preferably 1-6;
Z
1
equal to or different from Z
2
selected from H, alkaline or ammonium cation, di- or tri-alkanolammonium cation wherein alkanol comprises from 1 to 20 C atoms, preferably 1-4 C atoms, di- or tri- or tetra-alkylammonium cation wherein alkyl comprises from 1 to 20 C atoms, preferably 1-4 C atoms, or R
f
—CF
2
CH
2
—O—L—;
R
f
represents a (per)fluoropolyether chain having number average molecular weight in the range from about 400 to about 1,800, preferably from 500 to 1,300, said (per)fluoropolyether chain comprising repeating units selected from one or more of the following:
a)—(C
3
F
6
O)—;
b)—(CF
2
CF
2
O)—;
c)—(CFL
0
O)—, wherein L
0
=—F, —CF
3
;
d)—CF
2
(CF
2
)
z
,CF
2
O—, wherein z′ is an integer 1 or 2;
e)—CH
2
CF
2
CF
2
O—.
The preferred formulations comprise also:
component B): a solvent selected from linear or branched when possible alcohols, from 2 to 3 carbon atoms and ethers thereof, preferably methyl; linear or branched glycols from 2 to 6 carbon atoms or linear or branched mono alkyletherified glycols wherein the alkyl group ranges from 1 to 4 carbon atoms; dimethoxymethane, acetone.
When R
f
is monofunctional (l=1), an end group is of the perfluoroalkyl type such as for example CF
3
O, C
2
F
5
O, C
3
F
7
O; optionally in perfluoroalkyl end groups one fluorine atom can be replaced by one chlorine or hydrogen atom; examples of these end groups are Cl (C
3
F
6
O), H (C
3
F
6
O).
The preferred compound of general formula (I) is the one in which Z
1
and Z
2
are different from R
f
—CF
2
CH
2
—O—L—; preferably Z
1
═Z
2
═H and in the formula (I) l=2.
In particular R
f
is of the bifunctional (per) fluoropolyether type and it has preferably one of the following structures:
1)—(CF
2
O)
a
—(CF
2
CF
2
O)
b
—
with b/a comprised between 0.3 and 10, extremes included, a being an integer different from 0;
2)—(CF
2
—(CF
2
)
z′
—CF
2
O)
b′—
wherein z′ is an integer equal to 1 or 2;
3)—(C
3
F
6
O)
r
—(C
2
F
4
O)
b
—(CFL
0
O)
t
—,
with r/b =0.5-2.0 (r+b)/t =10-30, b and t being integers different from 0;
4)—(OC
3
F
6
)
r
—(CFL
0
O)
t
—OCF
2
—R′
f
—CF
2
O—(C
3
F
6
O)
r
—(CFLO
0
O)
t
—
5)—(CF
2
CF
2
CH
2
O)
q′
—R′
f
—O—(CH
2
CF
2
CF
2
O)
q′—
wherein:
R′
f
is a fluoroalkylene group from 1 to 4 carbon atoms;
L
0
is selected between F, CF
3
;
6)—(C
3
F
6
O)
r
—OCF
2
—R′
f
—CF
2
O—(C
3
F
6
O)
r
—
wherein in said formulas:
—(C
3
F
6
O)— can represent units of formula:
—(CF(CF
3
) CF
2
O)— and/or —(CF
2
—CF (CF
3
)O)—
a, b, b′,q′, r, t, are integers, the sum of which is such that R
f
shows values of number average molecular weight {overscore (M)}
n
in the range from about 400 to about 1,800, preferably 500 to 1,500.
The preferred (per)fluoropolyether chain R
f
is selected from the following structures:
from the bifunctional ones (1=2):
—(CF
2
O)
a
—(CF
2
CF
2
O)
b
—;
—(C
3
F
6
O)
r
—(C
2
F
4
O)
b
—(CFL
0
O
t
—;
from the monofunctional ones (l=1):
—(C
3
F
6
O)
r
—(CFL
0
O)
t
—;
wherein L
0
and the a,b,r,t indexes have the above indicated value, still more preferably —(CF
2
O)
a
—(CF
2
CF
2
O)
b
—, wherein the a and b indexes have the above indicated values.
The compounds of formula (I) preferably used according to the present invention are those wherein L=(CH
2
-CH
2
O)
n
n being an integer from 1 to 3; Z
1
equal to or different from Z
2
is selected from H, NH
4
, or an alkaline metal cation; l=2.
The compounds, according to the general formula (I), having the following formulas, are still more preferred:
CF
3
—O(CF
2
CF(CF
3
)O)
r
(CF
2
O)
a
—CF
2
—CH
2

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