Use of esters or amides of hydroxylated carboxylic acids as...

Details Use of esters or amides of hydroxylated carboxylic acids as... Use of esters or amides of hydroxylated carboxylic acids as...

1999-11-04

2002-04-02

Killos, Paul J. (Department: 1823)

Drug, bio-affecting and body treating compositions

Dispersion or emulsion

Oil-water type

C560S185000, C560S187000, C560S189000, C424S401000

Reexamination Certificate

active

06365637

ABSTRACT:

The invention relates to the use of esters or amides of hydroxylated carboxylic acids as solubilizer.
In the manufacture of homogeneous pharmaceutical or cosmetic preparations, the solubilization of hydrophobic substances has achieved very great practical importance.
Solubilization is taken to mean an improvement in the solubility by virtue of surface-active compounds which can convert substances which are insoluble or virtually insoluble in water into clear, at most opalescent aqueous solutions without changing the chemical structure of these substances in the process.
The solubilizates formed are notable for the fact that the substance which is insoluble or virtually insoluble in water is present in dissolved form in the molecular associations of the surface-active compounds which form in aqueous solution, also called micelles. The resulting solutions are stable single-phase systems which appear optically clear to opalescent and can be prepared without the input of a great deal of energy.
Solubilizers can improve the appearance, for example, of cosmetic formulations and food preparations by making the formulations transparent. Furthermore, in the case of pharmaceutical preparations, the bioavailability and thus the activity of medicaments can also be increased by using solubilizers.
The principal solubilizers used for pharmaceutical medicaments and cosmetic active ingredients are the following products:
ethoxylated (hydrogenated) castor oil, (e.g. Cremophor® products, BASF);
ethoxylated sorbitan fatty acid esters, (e.g. Tween® products, ICI);
ethoxylated hydroxystearic acid, (e.g. Solutol® products, BASF).
The above-described hitherto used solubilizers do, however, exhibit a number of technical disadvantages.
For example, their parenteral application, is associated with the release of histamine and a consequent drop in blood pressure (Lorenz et al., Agents and Actions, Vol. 12, 1/2 , 1982).
The known solubilizers have only a low solubilizing action for some virtually insoluble medicaments, such as, for example, clotrimazole.
Surface-active compounds frequently have high hemolytic activity, which prevents use in the pharmaceutical field, in particular in substances administered parenterally.
EP-A-0 017 059 describes the preparation of alkoxylated fatty acids of the Solutol® type and their use as solubilizers. However, solubilizers having this type of structure display the above disadvantages.
DE-A-4 331 228 describes the reaction of polyethylene glycol with hydroxycarboxylic acids and the use of these reaction products as antifoams for aqueous systems.
J5 9069135 describes the use of polyoxyalkylene esters of ricinoleic acid as emulsifier. The compounds disclosed here have the disadvantage that they are either insufficiently soluble in water or, upon parenteral application, cause an undesirably high release of histamine.
FR 2056177 describes water-in-oil emulsions containing alkoxylated fatty acids as emulsifiers.
It is an object of the present invention to provide novel solubilizers for pharmaceutical, cosmetic and food preparations which do not have the abovementioned disadvantages.
We have found that this object is achieved by the use of esters or amides of hydroxylated carboxylic acids of the formula I
in which the substituents and variables independently of one another have the following meanings:
R
1
is hydrogen, C
1
-C
22
-acyl,
R
2
is hydrogen, C
1
-C
16
-alkyl, C
2
-C
12
-alkenyl;
R
3
is C
1
-C
16
-alkylene, C
2
-C
16
-alkenylene;
R
4
is C
1
-C
12
-alkyl, C
2
-C
12
-alkenyl, C
1
-C
12
-acyl;
A is —N(R
5
)—R
6
—;
B is —CH
2
—CH
2
—O—, —CH
2
—CH
2
—CH
2
—O— and/or —CH(CH
3
)—CH
2
—O—;
R
5
is hydrogen, C
1
-C
12
-alkyl, C
2
-C
12
-alkenyl, C
1
-C
12
-acyl, [B]
z
—R
4
;
R
6
is —CH
2
—CH
2
—, —CH
2
—CH
2
—CH
2
—, —CH(CH
3
)—CH
2
—;
R
7
is C
1
-C
16
-alkylene, C
2
-C
16
-alkenylene, radical of a dimerized fatty acid;
x is 1 to 6;
y is 0 or 1;
z is 8 to 18
as solubilizers.
Alkyl radicals R
2
which may be mentioned are branched or unbranched C
1
-C
16
-alkyl chains, for example methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl and n-hexadecyl.
Alkyl radicals R
4
and R
5
which may be mentioned are branched or unbranched C
1
-C
12
-alkyl chains, for example methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl.
Alkenyl radicals R
2
and also R
4
and R
5
which may be mentioned are branched or unbranched C
2
-C
12
-alkenyl chains, for example vinyl, propenyl, isopropenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-1-butenyl, 1-hexenyl, 2-hexenyl, 1-heptenyl, 2-heptenyl, 1-octenyl or 2-octenyl.
Alkylene radicals R
3
and R
7
which may be mentioned are branched or unbranched C
1
-C
16
-alkylene chains, preferably methylene, ethylene, n-propylene, 1-methylethylene, n-butylene, 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene, n-pentylene, 1-methylbutylene, 2-methylbutylene, 3-methylbutylene, 2,2-dimethylpropylene, 1-ethylpropylene, n-hexylene, 1,1-dimethylpropylene, 1,2-dimethylpropylene, 1-methylpentylene, 2-methylpentylene, 3-methylpentylene, 4-methylpentylene, 1,1-dimethylbutylene, 1,2-dimethylbutylene, 1,3-dimethylbutylene, 2,2-dimethylbutylene, 2,3-dimethylbutylene, 3,3-dimethylbutylene, 1-ethylbutylene, 2-ethylbutylene, 1,1,2-trimethylpropylene, 1,2,2-trimethylpropylene, 1-ethyl-1-methylpropylene, 1-ethyl-2-methylpropylene, n-heptylene, n-octylene, n-nonylene, n-decylene, n-undecylene, n-dodecylene, n-tridecylene, n-tetradecylene, n-pentadecylene and n-hexadecylene.
Alkenyl radicals R
3
and R
7
which may be mentioned are branched or unbranched C
2
-C
16
-alkenyl chains, for example vinylene, propenylene, isopropenylene, 1-butenylene, 2-butenylene, 1-pentenylene, 2-pentenylene, 2-methyl-1-butenylene, 2-methyl-2-butenylene, 3-methyl-1-butenylene, 1-hexenylene, 2-hexenylene, 1-heptenylene, 2-heptenylene, 1-octenylene, 2-octenylene, 1-nonenylene, 1-decenylene, 1-undecenylene, 1-dodecenylene, 1-tridecenylene, 1-tetradecenylene, 1-pentadecenylene or 1-hexadecenylene.
Acyl radicals R
1
which may be mentioned are branched or unbranched, saturated or unsaturated, optionally hydroxylated C
1
-C
22
-acyl radicals or C
1
-C
21
,-alkylcarbonyl radicals, for example formyl, methylcarbonyl (acetyl), hydroxymethylcarbonyl, ethylcarbonyl, 1-hydroxyethylcarbonyl, n-propylcarbonyl, 3-hydroxypropylcarbonyl, n-butylcarbonyl, 1-methylpropylcarbonyl, 2-methylpropylcarbonyl, 1,1-dimethylethylcarbonyl, n-pentylcarbonyl, 5-hydroxypentylcarbonyl, 3-methylbutylcarbonyl, 2,2-dimethylpropylcarbonyl, n-hexylcarbonyl, n-heptylcarbonyl, n-octylcarbonyl, 2-ethylhexylcarbonyl, n-nonylcarbonyl, n-decylcarbonyl, n-undecylcarbonyl, n-dodecylcarbonyl, n-tridecylcarbonyl, n-tetradecylcarbonyl, n-pentadecylcarbonyl, n-hexadecylcarbonyl, n-heptadecylcarbonyl, n-octadecylcarbonyl, n-nonadecylcarbonyl and n-eicosylcarbonyl.
Acyl radicals R
4
and R
5
which may be mentioned are branched or unbranched, saturated or unsa

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