Use of polyalkylkene oxide-containing graft copolymers as...

Details Use of polyalkylkene oxide-containing graft copolymers as... Use of polyalkylkene oxide-containing graft copolymers as...

1999-04-01

2001-08-07

Nutter, Nathan M. (Department: 1711)

Synthetic resins or natural rubbers -- part of the class 520 ser

Synthetic resins

Mixing of two or more solid polymers; mixing of solid...

C525S194000, C525S298000, C525S303000, C525S307000, C525S309000, C524S561000, C424S487000, C424S070310, C426S069000, C426S090000

Reexamination Certificate

active

06271307

ABSTRACT:

The invention relates to the use of polyalkylene oxide-containing graft copolymers as solubilizers.
The solubilization of hydrophobic substances has become of very great practical importance in the production of homogeneous pharmaceutical or cosmetic preparations.
Solubilization means improving the solubility by using amphiphilic compounds able to convert substances which are insoluble or are of low solubility in water into clear, or at most opalescent, aqueous solutions without this involving an alteration in the chemical structure of these substances.
The solubilisates which are produced contain the substance which is insoluble or of low solubility in water dissolved in the aggregates of molecules of the amphiphilic compounds formed in the aqueous solution, which are called micelles. The resulting solutions are stable single-phase systems which appear optically clear or opalescent and can be produced without input of energy.
Solubilizers are able, for example, to improve the appearance of cosmetic formulations and of food products by making the formulations transparent. In addition, in the case of pharmaceutical preparations, the bioavailability and thus the effect of drugs can be increased by using solubilizers.
The solubilizers employed for pharmaceutical substances and cosmetic ingredients are mainly the following products:
ethoxylated (hydrogenated) castor oil (e.g. Cremophor® types supplied by BASF);
ethoxylated sorbitan fatty acid esters (e.g. Tween® types supplied by ICI);
ethoxylated hydroxystearic acid (e.g. Solutol® HS 15 supplied by BASF).
However, the solubilizers described above and employed to date have a number of technical disadvantages on use.
Thus, for example, parenteral administration thereof is associated with release of histamine and a resulting fall in blood pressure (Lorenz et al., Agents and Actions, Vol. 12, 1/2, 1982).
Known solubilizers have only a low solubilizing action for some medicinal substances of low solubility, such as clotrimazole.
Surface-active compounds often have high hemolytic activity which prevents use in the pharmaceuticals sector, especially in parenteral products.
EP-A-0 219 048 describes the use of graft copolymers of polyalkylene oxides and vinyl acetate as antiredeposition agents in the washing and after-treatment of synthetic fiber-containing textile materials.
It is an object of the present invention to provide novel solubilizers without the abovementioned disadvantages for pharmaceutical, cosmetic and foodstuff applications.
We have found that this object is achieved by using graft copolymers obtained by grafting
a) polyalkylene oxides with
b) at least one monomer selected from the group of
b
1
) C
1
-C
30
-alkyl esters of monoethylenically unsaturated C
3
-C
8
-carboxylic acids;
b
2
) vinyl esters of aliphatic C
1
-C
30
-carboxylic acids;
b
3
) C
1
-C
30
-alkyl vinyl ethers;
b
4
) N—C
1
-C
30
-alkyl-substituted amides of monoethylenically unsaturated C
3
-C
8
-carboxylic acids;
b
5
) N,N—C
-C
30
-dialkyl-substituted amides of monoethylenically unsaturated C
3
-C
8
-carboxylic acids as solubilizer.
It is possible to use as grafting base a) in general polyalkylene oxides, in particular those having an average molecular weight of from 300 to 100,000 g/mol and based on ethylene oxide, propylene oxide and/or butylene oxide.
Homopolymers of ethylene oxide or copolymers with an ethylene oxide content of from 40 to 99% by weight are preferably used. Thus, for the ethylene oxide polymers which are preferably to be employed, the content of ethylene oxide units is from 40 to 100 mol %. Suitable comonomers for these copolymers are propylene oxide, butylene oxide and/or isobutylene oxide. Suitable examples are copolymers of ethylene oxide and propylene oxide, copolymers of ethylene oxide and butylene oxide, and copolymers of ethylene oxide, propylene oxide and at least one butylene oxide. The ethylene oxide content in the copolymers is preferably from 40 to 99 mol %, the propylene oxide content is from 1 to 60 mol %, and the butylene oxide content in the copolymers is from 1 to 30 mol %. It is possible to use not only straight-chain but also branched homo- or copolymers as grafting base.
Branched copolymers can be produced by, for example, adding ethylene oxide and, where appropriate, propylene oxide and/or butylene oxides onto polyhydric low molecular weight alcohols, e.g. trimethylolpropane, pentoses or hexoses. The alkylene oxide units can be randomly distributed in the polymer or be present in the form of blocks.
The component a) which is particularly preferably used comprises polyethylene oxides with a human average molecular weight of from 500 to 20,000, in particular 800 to 10,000 g/mol.
However, it is also possible to use polyesters of polyalkylene oxides and aliphatic or aromatic dicarboxylic acids, e.g. oxalic acid, succinic acid or adipic acid, with molecular weights of from 1500 to 25,000, described in EP-A-0 743 962, as grafting base.
As component b) for grafting onto the polyalkylene oxides, mention may be made of the following copolymerizable monomers:
C
1
-C
30
-alkyl esters of monoethylenically unsaturated carboxylic acids with 3 to 8 C atoms, e.g. acrylic acid, methacrylic acid, dimethylacrylic acid, ethacrylic acid, maleic acid, citraconic acid, methylenemalonic acid, allylacetic acid, vinylacetic acid, crotonic acid, fumaric acid, mesaconic acid and itaconic acid.
C
1
-C
30
-Alcohols, preferably C
1
-C
12
-alcohols, particularly preferably C
1
-C
6
-alcohols may be mentioned as alcohol component in the abovementioned esters.
The monoethylenically unsaturated carboxylic acids preferably used are acrylic acid, methacrylic acid, maleic acid or mixtures of said carboxylic acids.
Particularly important in this connection are the acrylic, methacrylic and maleic esters with alcohols having a chain length of from 1 to 12, preferably 1 to 6, carbon atoms.
Particular mention may be made here of: methyl acrylate, ethyl acrylate, n-propyl acrylate, isopropyl acrylate, n-butyl acrylate, 1-methylpropyl acrylate, 2-methylpropyl acrylate, n-hexyl acrylate, n-heptyl acrylate, n-octyl acrylate, 2-ethylhexyl acrylate, nonyl acrylate, decyl acrylate, lauryl acrylate, methyl methacrylate, ethyl methacrylate, n-propyl methacrylate, isopropyl methacrylate, n-butyl methacrylate, 1-methylpropyl methacrylate, 2-methylpropyl methacrylate, n-hexyl methacrylate, n-heptyl methacrylate, n-octyl methacrylate, 2-ethylhexyl methacrylate, nonyl methacrylate, decyl methacrylate and lauryl methacrylate.
It is possible to employ as further component b) vinyl esters of aliphatic, saturated or unsaturated C
1
-C
30
-carboxylic acids, e.g. formic acid, acetic acid, propionic acid, butyric acid, valeric acid, isovaleric acid, caproic acid, caprylic acid, capric acid, undecylenic acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, arachic acid, behenic acid, lignoceric acid, cerotic acid and melissic acid.
Preference is given to using vinyl esters of the abovementioned C
1
-C
12
-carboxylic acids, in particular C
1
-C
6
-carboxylic acids.
It is also possible for C
1
-C
30
-alkyl vinyl ethers, preferably C
1
-C
12
-alkyl vinyl ethers, particularly preferably C
1
-C
6
-alkyl vinyl ethers, to be used for the graft copolymerization.
Alkyl radicals which may be mentioned as preferred in the vinyl ethers are branched or unbranched C
1
-C
6
-alkyl chains such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, 1-methylpropyl, n-pentyl and n-hexyl.
It is also possible to use as component b) N—C
1
-C
30
-alkyl- or N,N—C
1
-C
30
-dialkyl-substituted amides of monoethylenically unsaturated C
3
-C
8
-carboxylic acids, where the alkyl radicals are aliphatic or cycloaliphatic alkyl radicals having 1 to 30, preferably 1 to 12, particularly preferably 1 to 6, carbon atoms.
The monoethylenically unsaturated carboxylic acids having 3 to 8 C atoms likewise mean the abovementioned acids, preferably acrylic acid, methacrylic acid, dimethylacrylic acid, ethacrylic acid, maleic acid, citraconic acid, methylenemalonic acid, al

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