Drug – bio-affecting and body treating compositions – Topical body preparation containing solid synthetic organic... – Skin cosmetic coating
Reexamination Certificate
1999-03-17
2001-12-18
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Topical body preparation containing solid synthetic organic...
Skin cosmetic coating
C424S401000, C424S078020
Reexamination Certificate
active
06331294
ABSTRACT:
The invention relates to the use of copolymers of mono-ethylenically unsaturated carboxylic acids as solubilizers.
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 energy.
Solubilizers can, for example, improve the appearance 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 only have a low solubilizing action for some virtually insoluble medicaments, such as, for example, clotrimazole.
Surface-active compounds frequently have high haemolytic activity, which prevents use in the pharmaceutical field, in particular in substances administered parenterally.
The dissertation by G. Eisenmann (Prof. Bauer, Freiburg University, 1994, page 44/45, 93 to 95) describes the polymer-analogous reaction of polyacrylic acid having a M
w
≈2000 with. linear alkylamines of chain length C
6
to C
8
with activation of the carboxyl groups using dicyclohexylcarbodiimide to give the corresponding amides. The proportion of amidated carboxyl groups is between 20% and 33%. However, the copolymers described here as solubilizers have the disadvantage that they are insufficiently soluble in water at concentrations >5% by weight.
C. Tribet et al. (Proc. Natl. Acad. Sci. 1996, 93, 15047-15050) describe polyacrylic acid reacted with octylamine and isopropylamine in a polymer-analogous manner which has a molecular weight of M
w
≈8000 to 34,000. Its profile of properties (insufficient solubility in water, too low a solubilizing action) indicates that these polymers are unsatisfactory for use as solubilizers in pharmaceutical and cosmetic preparations.
U.S. Pat. No. 4,432,881 describes hydrophobically modified polyacrylic acid having a molecular weight between 200,000 and 5,000,000, which are obtained by copolymerization of acrylic acid with the corresponding N-alkylacrylamides or acrylates. The resulting polymers are used as dispersible hydrophobic thickeners.
U.S. Pat. No. 4,395,524 describes the copolymerization of hydrophilic components (e.g. acrylamide, acrylic acid, N-vinylpyrrolidone etc.) with N-alkylacrylamides. The resulting polymers having a molecular weight of from 30,000 to 2,000,000 are used as thickeners, sedimentation stabilizers or dispersants.
EP-A-0 268 164 describes the use of copolymers of mono-olefinically unsaturated acids and alkyl esters of mono-olefinically unsaturated acids for the stabilization of O/W emulsions.
It is an object of the present invention to provide novel solublizers for pharmaceutical, cosmetic and food applications which do not have the abovementioned disadvantages.
We have found that this object is achieved by the use of copolymers comprising
a) 82 to 99.9 mol % of at least one monoethylenically unsaturated C
3
-C
8
-carboxylic acid;
b) 0.1 to 18 mol % of at least one monomer selected from the group
b
1
) N—C
8
-C
30
-alkyl-substituted amides of monoethylenically unsaturated C
3
-C
8
-carboxylic acids,
b
2
) N,N—C
8
-C
30
-dialkyl-substituted amides of monoethylenically unsaturated C
3
-C
8
-carboxylic acids,.
b
3
) C
8
-C
30
-alkyl esters of monoethylenically unsaturated C
3
-C
8
-carboxylic acids;
c) 0 to 17.9 mol % of at least one monomer selected from the group of
c
1
) vinyl esters of aliphatic C
8
-C
30
-carboxylic acids,
c
2
) C
8
-C
30
-alkylvinyl ethers,
the mol % data for the individual components adding up to 100%, as solubilizer.
As hydrophilic component a), the following copolymerizable monomers may be mentioned:
monoethylenically unsaturated carboxylic acids having from 3 to 8 carbon atoms, such as, for example, acrylic acid, methacrylic acid, dimethacrylic acid, ethacrylic acid, maleic acid, citraconic acid, methylenemalonic acid, allylacetic acid, vinylacetic acid, crotonic acid, fumaric acid, mesaconic acid and itaconic acid.
From this group of monomers, preference is given to using acrylic acid, methacrylic acid, maleic acid or mixtures of said carboxylic acids.
The monoethylenically unsaturated carboxylic acids can be used in the copolymerization as free acid, as anhydrides and also in partially or completely neutralized form.
For the neutralization of the abovementioned carboxylic acids, alkali metal or alkaline earth metal bases, ammonia or amines are advantageously used, preferably sodium hydroxide solution, potassium hydroxide solution, soda, potash, sodium hydrogencarbonate, magnesium oxide, calcium hydroxide, calcium oxide, gaseous or aqueous ammonia, triethylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, diethylenetriamine or tetraethylenepentamine.
Other comonomers which can be used are the following copolymerizable, hydrophilic monomers in amounts of from 0 to 17.9 mol %, preferably from 0 to 14.9 mol %, particularly preferably from 0 to 12.9 mol %:
acrylamidoglycolic acid, vinylsulfonic acid, allylsulfonic acid, methallylsulfonic acid, styrenesulfonic acid, 3-sulfopropyl acrylate, 3-sulfopropyl methacrylate and acrylamido methylpropanesulfonic acid;
monomers containing phosphonic acid groups, such as vinylphosphonic acid, allylphosphonic acid and acrylamidomethanepropanephosphonic acid;
N-vinylpyrrolidone, N-vinylcaprolactam, N-vinylimidazole, N-vinyl-2-methylimidazole and N-vinyl-4-methylimidazole.
It is of course also possible to use mixtures of said monomers.
The proportion of hydrophilic monomer units a) in the copolymer is in the range from 82 to 99.9 mol %, preferably from 85 to 95 mol %, particularly preferably in the range from 87 to 93 mol %.
As hydrophobic components b), the following polymerizable comonomers may be mentioned:
N—C
8
-C
30
-alkyl- or N,N—C
8
-C
30
-dialkyl-substituted amides of monoethylenically unsaturated C
3
-C
8
-carboxylic acids, the alkyl radicals being aliphatic or cycloaliphatic alkyl radicals having from 8 to 30, preferably from 8 to 18, carbon atoms.
The monoethylenically unsaturated carboxylic acids having from 3 to 8 carbon atoms are understood to include the acids already mentioned above, preferably acrylic acid, methacrylic acid, dimethacrylic acid, ethacrylic acid, maleic acid, citraconic acid, methylenemalonic acid, allylacetic acid, vinylacetic acid, crotonic acid, fumaric acid, mesaconic acid and itaconic acid.
From this group of monomers, acrylic acid, methacrylic acid, maleic acid or mixtures of said carboxylic acids are likewise used particularly preferably.
Preferred amidated comonomers are, for example, N-stearylacrylamide, N-stearylmethacrylamide, N-(1-methyl) undecylacrylamide, N-(1-methyl)undecylmethacrylamide, N-dodecylac
Bauer Kurt Heinz
Berndl Gunther
Kolter Karl
Meffert Helmut
Ruchatz Folker
BASF - Aktiengesellschaft
Keil & Weinkauf
Page Thurman K.
Seidleck Brian K.
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