CA2340546C - Soft capsules comprising polymers of vinyl esters and polyethers, the use and production thereof - Google Patents

Abstract

The present invention relates to soft capsules comprising (a) polymers prepared by polymerization of vinyl esters in the presence of polyethers (b) where appropriate structure-improving auxiliaries and (c) where appropriate other conventional constituents, the use and production thereof.

Description

Soft capsules comprising polymers of vinyl esters and polyethersti the use arnd production thereof The present invention relates to soft capsules, for example for pharmaceutical applicatione, comprising polymers prepared by polymerization of vinyl esters in the presence of polyethers, and, where appropriate, in the presence of structure-improving auxiliaries and/or other conventional shell constituents, and to the use and production thereof.

Soft capsules are distinguished by the fact that the production of the shell and the filling take place virtually simultaneously in one step. The shell of such capsules ordinarily consists mainly of gelatin, which is why the capsules are often also referred to as soft gelatin capsules. Since gelatin is per se a brittle material of low fl.xibility, it must be plasticized appropriately, i.e. plasticizers must be added. Such plasticizore are low molecular weight compounds, ordinarily liquids such as, for example, glycerol, propyleae glycol, polyethylene glycol 400.
Such capsules often additionally contain dyes, opacifying agents and preservatives.

Although gelatin is frequently employed, it has numerous disadvantages. Thus, gelatin is a material of animal origin and thus not kosher. In addition, there is always a slight resi'dual risk of aBE, because gelatin from cattle is preferably used to produce it. Obtaining suitable gelatin is very complioated and requires strict supervision of the process. Despite this, differences between batches are larQe because of the animal origin, which is subject to a certain variability. Gelatin is very susceptible to microbias because it represents a good nutrient medium for microorgani.ams. tt is therefore necessary to take appropriate measures during the production as well as the use of such packaging materials. The use of preservatives is frequently indis8ensible.

Ths plasticizers which are absolutely necessary to produce gelatin capsules frequently miQrate from the shell into the filling and cause changes there. The shell loses plasticizers and becomes brittle and mechanically unstable during the course of storage. In addition, the shell of a soft gelatin capsule has a relatively high water content, which likewise has a plasticizing effect. On storage of such capsules with pure humidity there is evaporation of water from the shell, which likewise makes the capsule brittle. The eame thing happens when very hygroscopic materials are encapsulated. Particularly hygroscopic or hydrolysis-sensitive substances cannot.be encapsulated at all.
The rate of dissolution of gelatin is relatively slow. A higher rate of dissolution in gqast.ric or intestinal fluid would be desirable for rapid release of active ingredients.

Numerous substances lead to interactions with gelatin, such as, for example, aldehydes, polyphenols, reducing sugars, multiply charged cations, electrolytes, cationic or anionic polymers etc., with crosslinking frequently occurring and the capsule then disintegrating or dissolving only very slowly or not at all. Such changes are catastrophic for a drug product because efficacy is lost. Many drugs also lead to interactions with gelatin. xn some cases during storage there is formation of drug degradation products with, for example, an alc3ehyde structure, which lead to crosslinking of the gelatin. Since gelatin has both acidic and basic groups, it is clear that reactions easily occur with other charged molecules.
Gelatin can be cleaved by enzymes. Contamination by enzymes or bacteria which release enzymes may drastically alter the properties of gelatin.

Soft gelatin capsules very readily stick together under warm and moist conditions.

The adhesion of film coatings to soft gelatin capsules is extremely poor. For them it is frequently necessary first to apply a special subcoating, which is inconvenient.

Because of these many disadvantages, there has been no lack of attempts to replace gelatin wholly or partly in soft oapsules.
For example, polyvinyl alcohol has been described for this purpose. However, polyvinyl alcohol has a alow rate of dissolution, likewise requiree additional plasticizers, which in turn may migrate and which, as described above, may alter the properties of the filling, and it may moreover become extremely brittle as a consequence of internal crystallization. In particular, the flexibility decreases drastically during the course of storage if the ambient humidity is low.

us patent 5,342,626 describes a combination of gellan, carrageenan and mannan for;producing soft capsules or microcapsules. All these components are of natural origin and are subject to the natural variations in quality. Low molecular weight plasticizers are necessary and the products become brittle when the ambient humidity is low. Similar is true of the sof t or haxd capsules made of carrageenan which are described in the application WO 99/07347.
S
WO 91/19487 describes a combination of a cationic polymer and an anionic polymer. it is evident merely from the data given that the flexibility changes greatly with the ambient humidity; it decreases greatly when the humidity becomes less. This is understandable because the charges on the polymers greatly attract water. The line between polymer mixtures which are too tacky and too brittle is stated to be very narrow. The charges on the polymers may lead to interactions with the filling material and the drugs, especially since most drugs are likewise charged.
wo 99/40156 describes combinations of polyethylene glycols of various molecular weights which are suitable for producing f ilms or soft capsules. However, polyethylene glycols with a high molecular weight dissolve only slowly in water and are brittle.
Although combination with polyethylene glycols with a very low molecular weight makes them,somewhat more flexible, they also become more tacky. In addition, they may in turn migrate into the filling because of their low molecular weight.

The application WO 98/27151 describes a mixture of cellulose ethers and polysaccharides plus sequestnring agents, where the cellulose ether represents the main constituent (90 to 99.98%) for producing hard and soft. capsules. Because of the brittleness of the cellulose ethers, this preparation is suitable without plasticizers at the mo9t for hard gelatin capsules and, if plasticizers are added, the abovementioned disadvantages reappear. The rate of dissolution of sucn capsules is likewise unsatisfactory.

DE-A2 2 363 853 describes the use of partially hydrolyzed copolymers of vinyl acetate on polyethylene glycol for producing hard capsules for medicines. There are no references in this publication to the use of the copolysners for producing soft capsules.
However, the requirements to be met by hard capsules are quite different from those for soft capsules. Hard capsules require great strength, while flexibility is a priority with soft capsules. The production processes also differ entirely. In the case of hard capsules, firstly only the shell is produced in 2 separate parts, a cap and a body, by a dip process, whereas in the case of sof t capsules the shell and the fi.lling are produced virtually simultarseously.

In the case of hard capsules, af ter production of cap and body these are loosely fitted together so that the pharmaceutical manufacturer is able to separate the two parts again mechanically, introduce his powder and close the capsule.
Detailed examination of this processing makes it clear that the two capsule parts must be very mechanically stable, especially since the filling machines operate very rapidly and changes in shape would bring the entire process to a stop.

In the case of soft capsules, the shell must firstly be absolutely leakproof so that the filling, which is usua7.ly liquid, cannot escape, and secondly very flexible because the filling would otherwise escape through cracks or microfissures.
Par'ticularly high flexiblity is necessary for production because the polymer film is sucked into drilled cavities and is thus greatly deformed and stretched. The production of soft capsules is a technologically very d-manding process, which is why the polymer properties and the inachines must be harmonized and adjusted accurately.

The entirely different processes for producing hard aiad soft gelatin capsules are described in W. Fahrig and U. Hofer, Die Rapsel, wissenschaftliche vrsrl.agsgesellschaft mbH Stuttgart, 1983, pp. 58-82.

DE 1 077 430 describes a process for producing graft copolymers of vinyl esters on polyalky,lene glycols.

DE 1 094 457 and DE 1 081 229 describe processes for producing graft copolymers of polyvinyl alcohol on polyalkylene glycols by hydrolyzing the vinyl esters and the use thereof as protective colloids, water-soluble packaging films, as sizing and finishirxg agents for textilies and in cosmetics.

The application WO 97/35537 describes a special process for producing soft capsules using various materials, mainly polyvinyl alcohol. Before the encapsulation, a solvent is applied to the film to partly dissolve it so that better adhesion can be achieved. However, this is necessary only for films which are correspondingly difficult to process.

It is an object of the present invention to develop a material for soft capsules which is superior to gelatin and many substitute materials disclosed to date and, in particular, can be processed even without additional plasticizers.

we have found that this object is achieved by soft capsules comprising a) polymers prepared by polymerization of vinyl esters in the presence of polyethers b) where appropriate structure-improving auxiliaries and c) where appropriate other conventional constituents.
The polymers (a) are obtainable by free-radical polymerization of a) at least one vinyl ester in the presence of b) polyether-containing compounds and, where appropriate, one or more copolymerizable monomers c) and subsequent at least partial hydrolysis of the ester functions in the original monomers a). The soft capsules according to the inventioa are preferably used for producing pharmaceutical dosage forms.

During production of the polymers used according to the invention there may be during the polymerization a gxaftinq onto the polyether-containing compounos (b), which may lead te the advantageous properties of the polymers. However, mechanisms other than grafting are also conceivable.

Depending on the degree of grafting, the polymers used according to the invention comprise both pure graft copolymers and mixtures of the abovementioned graft copolymers with ungrafted polyether-containing compounds and homo- or copolymers of monomers a) and c).

Polyether-containing compounds (b) which can be used are both polyalkylene oxides based on ethylene oxide, propylene oxide, butylene oxide and other alkylene oxides, and polyglycerol.
Depending on the nature of the monomer building blocks, the polymers contain the following structural units.

- (CHZ) 2-0-, - (CHZ) 3-0-, - (CH2) 4-0-, -CH2-CH (R6) -0-, with R6 Cl,-C24-alkyl;

R7 hydrogen, Cl-C24-alkyl, R6-C(=O)-, R6-NH-C(=0)-.

It is moreover possibla for the structural units to be both homopolymers and random copolymers and block copolymers.

The polyethers (b) preferably used are polymers of the general formula I

RlkO- (R2-0) u(R3-0)v (Ra-0) W~A- (R2--0) X(R3-0) y(R4-O) xRS/
g in which the variables have, independently of one another, the following meaning:

Rl hydroge-n, Cl-C24-alkyl, R6-C (=0) -, R6-NH-C (=O) -, polyalcohol reaiduei RS hydrogen, C1-C24-alkyl, R6-C(-0)-, R6-NH-C(=0)-;
R2 to R4 - (CHZ) a-, - (CHZ) 3-, - (CHz) 4-, -CH2-CH (M) -, -CH2-CHOR7 -CH2-;
R6 Cl-CZd-alkyl;

R7 hydrogen, Cl-CZq-alkyl, R6-C (=O) -, R6-NX-G (=o) -;
A -C (=0) -0, -C (=0) -B-C (=0) -0, -C (=0) -NH-B-ISH-C (=0) -Os B -(CHy)t-, arylene, optionally substituted;
n 1 to 1000;
s 0 to 1000;
t 1 to 12;

u 1 to 5000;
v 0 to 50001 w 0 to 5000;

x 0 to 50001 y 0 to 5000;
z 0 to 5000.

The terminal primary hydroxyl groups of the polyethers produced on the basis of polyalkylene oxides, and the secondary OH groups of polyglycerol may moreover be present both free in unprotected form and etherifisd with alcohols with a Cl-C24 chain length or esterified with carboxylic acids with a C1-C24 chain length, or reacted with isocyanates to give urethanee.

AZkyl radicals which may be, mentioned for RI and Rg to R7 are branched or unbranched CI-C24-alkyl chains, preferably methyl, ethyl, n-propyl, 1-m thy7.ethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2, 2 -dime thylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1.2-Ciimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimeithylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dime:thylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-tri=nethylpropyl, 1,2,2-trimethyipropyl, 1-ethyl-l-methylpropyl, 1-athyl-2-methylpropyl, n-heptyl, 2'.-ethylhexyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodec:yl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl or n-eicosyl.
Pxef erred representativee of the abovementioned alkyl radicals which may be mentioned are branched or unbranched CI-C12-, particularly preferably Cl-C6-alkyl chains.

The number average molecular weight of the polyethers is in the range below 1000000, preferably in the range from 300 to 100000, particularly preferably in the range from 500 to 50000, very particularly preferably in the range from 800 to 40000.

=t is advantageous to use homopolymers of ethylene oxide or copolymere with an ethylen(a oxide content of from 40 to 9995 by weight. Thus, the content of ethylene oxide units in the ethylene oxide polymers to be pzeferably employed 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 ethylane oxidea and propylene oxide, copolymers of ethylene oxide and butylene oxide, and copolymers of ethylene oxide, propylene oxide and at least one butylena oxide. The ethylene oxide content of the copolymers is preferably from 40 to 99 mol%, the propylene oxidEa content is from 1 to 60 mol% and the content of butylene oxide in the copolymers is from 1 to 30 mol%.
Not only straight-chain but also branched homo- or copolymers can be used as polyether-containing compouds b).

Aranched polymers can be produced by, for example, adding ethylene oxide and, where appropriate, also propylene oxide and/or butylene oxides onto polyalcohol residues, for example onto pentaerythritol, glycerol or onto sugar alcohols such as D-sorbitol and D-mannitol, as well as polysaccharides such as cellulose and starch. The alkylene oxide units in the polymer may be randomly distributed or present in the form of blocks.
However, it is also possible to use polyesters of polyalkylene oxides and aliphatic or aromatic dicarboxylic acids, for example oxalic acid, succinic acid, adipic acid and terephthalic acid, with molecular weights of from 1500 to 25000 as described, for example, in EP-A-0 743 962, as polyether-containing compound. A
further possibility is also to use polycarbonates through reaction of polyalkylene oxides with phosgene or carbonates such as, for example, diphenyl carbonate, and polyurethanes through reaction of polyalkylene oxides with aliphatic and aromatic diisocyanates.

Particularly preferred polyethers (b) are polymers of the general formula I with a number average molecular weight of from 300 to 100,000, in which the variables have, independently of one another, the following meaning:

Ri hydrogen, Ci-C18-alkyl, R6-C(=0)-, R6-NH-C(=O)-, polyalcohol residue;

R5 hydrogen, C1-C12-alkyl, R6-C (-0) -, R6-NH-C (=0) -;
R2 to R4 - (CHz) 2-, - (CH2) 3-, - (CH2) 4', -CE2-CH (R6) -, -CH2-CHOR7-CH2-;
R6 Cl-CI2-alkyl;

R7 hydrogen, Cl-C12-alkyl, R6-C (=0) -, R6-NIi-C (=O) -;
n 1 to 6;

s 0;

u 2 to 2000;
v 0 to 2000;
w 0 to 2000.

Very particularly preferred polyethers b) are polymers of the general formula I with a nunber average molecular weight of from 500 to 50000, in which the variables have, independently of one another, the following meaziing:

Rl hydrogen, C2,-C6-alkyl, R6-C (=0) -, R6-NH-C (=0) -;
R5 hydrogen, C1-C6-alkyl, R6-C (=0) -, R6-N'FI-C (-O) -;
R2 to R4 - (CHa) Z-, - (CHZ) 3-, - (CH2) ry-, -CH2-CH (R6) -, -CH2-CHOR7 -CH2-;
R6 C1-C6-alkyl;

R7 hydrogen, C1-C6-alkyl, R6-C(=O)-, R6-NH-C(=0)-;
n 1;

s u 5 to 1000;
v 0 to 1000;

w 0 to 1000.

Further polyethers (b) which can be used are homo- and copolynmers of polyalkylene oxide-containing ethyleaically unsaturated monomers such as, for 2xample, polyalkylene oxide (meth)acrylates, polyalkyl.ene oxide vinyl ethers, polyalkylene oxide-(meth)acrylamides, polyalkylene oxide-allylamides or polyalkylena oxide-vinylamides. It is, of course, also possible 43 to employ copolymers of such monomers with other ethylenically unsaturated monomers.

The following monomers capable of free-radical polymerization may be mentioned as component a) for the polymerization in the presence of the polyethers b):

5 Vinyl eaters of aliphatic, saturated or unsaturated Cl-C24-carboxylic acids such as, for example, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, isovaleric acid, caproic acid, caprylic acid, capric acid, undecylanic acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid, 10 stearic acid, oleic acid, arachidic acid, behenic acid, lignocerie acid, cerotic acid and melissic acid.

it is preferred to use vinyl esters ot the abovementioned Cl-C12-carboxylic acids, in particular of the C1-C6-carboxylic acids. viny7, acetate is very particularly preferred.

it is, of course, also possible to copolymerize mixtures of the particular monomers from gx-oup a).

The vinyl esters (a) may also be employed in a mixture with one or more ethylenically unsaturated copolymerizable comonomera (c), in which case the proportion of these additional monomers should be restricted to a maximum of 50% by weight. Proportions of 0 and 20% by weight are preferred. The term ethylenically unsaturated means that the monomers have at least one carbon-carbon double bond which is capable of free-radical polymerization and which may be mono-, di-, tri- or tetrasu.bstituted.

The preferred additionally employed ethylenically unsaturated comonomers (c) can be described by the following general formula:
X-C (0) CR15_Cj.M14 where x is selected from the group of radicals -OH, -OM, -ORls, NHZ, -NIiR16, N (R"6) 2 ;

M is a cation selected from the group consisting of; Na*, it+, 110 Mg++, Ca**, 2ni'*, NH4+, alkylammonium, dialkylammonium, trialkylammonium and tetraalkylaaaanonium;

the R16 radicals can be identical or different and selected from the group consisting of -H, linear or branched-chain Cy-C40-alkyl radicals, N,N-dimethylaminoethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-ethoxyethyl, hydroxypropyl, methoxypropyl or ethoxypropyl.

7Z15 and R14 are, independently of one another, selected from the group consisting of: -H, linear or branched-chain Cl-CB-alkyl i:hains, methoxy, ethoxy, 2-hydroxyethoxy, 2-methoxyethoxy arLd :2-ethoxyethyl.
Representative but non-limiting examples of suitable monomers (c) are, for example, acrylic acid or methacrylic acid and their salts, esters and amides. The salts may be derived from any nontoxic metal, ammonium or 6ubstituted ammonium counter ions.
The esters may be derived from linear C1-C40, branched-chain C3-C40 or carbocyclic C3-C40 alcohols, from polyfunctional alcohols with 2 to about 8 hydroxyl groups, such as ethylene glycol, hexylene glycol, glycerol and 1,2,6-)iexanetriol, from amino alcohols or from alcohol ethers such as methoxyethaaol and ethoxyethanol, (alkyl)polyethylene glycols, (al7cyl)polypropylene glycols or ethoxylated fatty alcohols, for example C12-C24-fatty alcohols reacted with 1 to 200 ethylene oxide unita.

Also suitable are N,N-dialkylaminoalkyl acrylates and methacrylates and N,N-dialkylaminoalkylacrylaa-ides and -methaorylamides of the general formula (=xZ) R"
V 1e)q Z- FV9-- NR2Q Rzt (iiI) ~
with 3Ci R17 = H, alkyl with 1 to 8 C atoms, R1e = H, methyl, 315 R19 = alkylene with I to 24 C atoms, optionally substituted by alkyl, R20, R21 = Cl_CQo--alkyl radical, 40 Z = nitrogen for g= 1 or oxygen for g = 0.
The amides may be unsubstf.tuted., N-alkyl- or N-al.kylamino-monogubstituted or N,N-dialkyl-substituted=or N,N-dialkylarnino-disubstituted, in which the alkyl or alkylamino 45 groups are derived from linear C1-C40, branched-chain C3-C40 or 1.2 -aarbocyclic C3-C40 units. The alkylamino groups may additionally :be quaternized.

Preferred comonomers of formula III are N,N-dimethylaminomethyl (meth)acrylate, N,N-diethylaminomethyl (meth)acrylate, N,N-dimethylaminoethyl (meth)acrylate, N,N-diethylaminoethyl (meth)acrylate, N-[3-(dimethylamino)propyl]methacrylamide and N- [3- (dimethylamino)propyl) acx=ylamide.

Comonome.rs (c) which can likewise be used are substituted acrylic acids and salts, esters and amides thereof, where the substituents are located on the carbon atoms in position two or three of the acrylic acid, and are selected, independently of one another, from the group consisting of Cl-Ca-alkyl, CN, COOH, particularly preferably methacrylic acid, ethacrylic acid and 3-cyanoacrylic acid. These salts, esters and amides of these substituted acrylic acids may be selected as described above for the salts, esters and amides of acrylic acid.

Other euitable comonamers (c) are allyl esters of linear Ci-Cao, branched-chain C3-C40 or carbocyclic C3-C40 carboxylic acids, vinyi or allyl hal ides , preferably v7Lnyl chloride and allyl= chloride, vinyl ethers, preferably methyl, ethyl, butyl or dodecyl vinyl ether, vinylformataide, vinylmethylacetamide, vinylamine;
vinyllactams, preferably vinylpyrrolidone. and vinylcaprolactam, vinyl- or allyl-substituted heterocyclic compounds, preferably vinylpyrxdine, vinyloxazoline and allyl.pyridine.

Also suitable are N-vinylimidazoles of the general formula xV in 31D which R22 to R24 are, independently of one another, hydrogen, Cz-C&-a1kyl or phe.nyl:

rol W2 (Iv) Ff' 460 Further suitable comonomers (c) are diallylamines of the general formula (V) (V) FP

with R25 = C1- to C24-alkyl.

Further suitable comonomers, (c) are vinylidene chloride; and hydrocarbons having at least one carbon-carbon double bond, preferably styrene, alpha-methylstyrene, tert-butylstyreiie, butadi.ene, isoprene, cyclohexadiene, ethylene, propylene, 1-butene, 2-butene, isobutylene, vinyltoluene, and mixtures of these monomers.

Particularly suitable comonomers (c) are acrylic acid, methacrylic acid, ethacrylic acid, methyl acrylate, ethyl acrylate, propyl acxylate, n-butyl acrylate, isobutyl acrylate, t-butyl acrylate, 2-ethyl.hexyl acrylate, decyl acrylate, methyl methacrylate, ethyl methacrylate, propyl methacrylate, n-butyl methacrylate, a.sobutyl methacrylate, t-butyl methacrylate, 2-ethylhexyl methaczylate, decyl methaorylate, methyl ethacrylate, ethyl ethacrylate, n-butyl ethacrylate, isobutyl 2S ethacrylate, t-butyl ethac;rylate, 2-ethylhexyl ethacrylate, decyl ethacrylate, steary]. (meth)acrylate, 2,3-dihydroxypropyl acrylate, 2,3-dihydroxypropyl methacrylate, 2-hydroxyethyl acrylate, hydxoxypxopyl acrylates, 2-hydroxyethyl methacrylate, 2-hydroxyethyl ethacrylate, 2-methoxyethyl acrylate, Z4 2-methoxyethyl methacrylate, 2-methoxyethyl ethacrylate, 2-ethoxyethyl methacrylate, 2-ethoxyethyl ethacrylate, hydroxypropyl methaerylates, glyceryl monoacrylate, glyceryl monomethacrylate, polyalkylene glycol (meth)acryla,tes, unsaturated sulfonic acids such as, for example, 35 acrylamidopropanesulfonic acid;

acrylamide, methacrylamicie, ethacrylamide, N-methylacrylamide, N,N--dimethylacrylamide; N-ethylacrylamide, N-isopropylaczylamide, N-butylacrylamide, N-t-butylacrylama.de, N-octylacrylamide, 40 N-t-octylacrylamide, N-octadecylaerylamids, N-8henylacrylamide, N-methylmethacrylamide, N-ethylmethaczylainide, N-dodecylmothacrylamide, 1-vinylimidazole, 1-vinyl-2-methylvinylimidazole, N,N-dimethylaminomethyl (math)acrylate, iv,N-diethylaminotnethyl (meth)acrylate, 45 N,N-dimethylazninoethyl (meth)acrylate, N,N-diethylaminoethyl (meth)acrylate, N,N-dime.thylaminobutyl (meth)acrylate, N,N-diethylarninobutyl (meth)acrylate, N,N-dimethylaminohexyl i,meth)acrylate, N,N-di.methyl+aminooctyl (meth)acrylate, N,N-dimethy7.aminodode.cyl (meth)aerylate, 2i- [3- (dimethylamino) propyllmethacrylamide, 11- [3- (dimethylamino) propyll acrylamide, 1v- [3- (dimethylamito) butyl]me.thacrylamide, :v- (8- (dimethylamino) oc tyll methacrylamide, N- [).2-- (dimethylamino) dodecyl] methacrylamide, N- [3- (diethylamino) propyll methacryl.amide, N-[3-(diethylamino)propyl)ar,rylamide;
maleic acid, fumaric acid, male3.c anhydride and its monoesters, crotoaic acid, itaconic acid, diallyldimethylamntonium chloride, vinyl ethers (for example: methyl, ethyl, butyl or dodecyl vinyl ether), vinyltormamide, vinylmethylacetamide, vinylamine; methyl vinyl ketone, maleimide, vinylpyridine, vinylimidazole, vinylfuran, styrene, styrenesulfonate, allyl alkohol, and mixtures thereof. ' Of these, particular preference is given to acrylic acid, methacrylic acid, maleic acid, iumaric acid, crotonic acid, maleic anhydride and its manoesters, methyl acrylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate, n-butyl acry].ate, n-butyl methacrylate, t-butyl acrylate, t-butyl methacrylate, isobutyl acrylate, isobutyl methacrylate, 2-ethylhexyl acrylate, stearyl acrylate, stearyl methacrylate, N-t-butylacrylama.de, N-octylacrylamide, 2-hydroxyethyl acrylate, hydroxypropyl acrylates, 2-hydroxyethyl methacrylate, hydroxypropyl mothacrylates, alkylene glycol (meth)acrylates, styrene, unsaturated sulfonic acids such as, for example, acrylamidoPropanesulfonic acid, vinylpyrroli6.one, vinylcaprolaCtam, vinyl ethers (for example: methyl, ethyl, butyl or dodecyl vinyl ether), viny].formamide, vinylmethylacetamide, viny1amine, 1.-viriylimidazole, 1-vinyl-2-methylimidazole, N, N-dimethylamino=nethyl mathaorylate and N- [3- ( ditt:ethylamino) 25 propyl7methacrylamide; 3-methyl-l-vinylirtmidazolium chloride, 3-methyl-i-vinylimidazolium methyl sulfate, N,N-dimethylantinoethyl methacrylate, N- [3- (dimethylamino) propyll methacrylasnide quaternized with me.thyl chloride, methyl sulfate or diethyl sulfate.
Monomers with a basic nitrogen atom may moreover be quaternized in the following way:

Suitable for quaternizing the ama.nes are, for example, a1ky7.
halides with 1 to 24 C atoms in the alkyl group, for example methyl chloride, methyl bromide, methyl iodide, ethyl chloride, ethyl bromide, propyl chloride, hexyl chloride, dodecyl chloride, l~
7.auxyl chloride and benzyl halides, in particular benzyl chloride iind benzyl bromide. Further suitable quaternizing agents are dialkyl sulfates, in particular dimethyl sulfate or diethyl :sulfate. The quaternization of the basic amines can also be S(zarried out with alkylene oxf,des such as ethylene oxide or ipropylene oxide in the presence of acids. Preferred quaternizing agents are: methyl chloride, dimethyl sulfate or diethyl sulfate.
The quaternization can be carried out before the polymerization or after the polymerization.

it is additionally possible to employ the products of the reaction of unsaturated acids, such as, for example, aCryli.c acid or methacrylic acid, with a quaterzsized epichlorohy6xin of the general formula (VI) (R26 = C1- to C40-alkyl).
L-_" ~~+ (VI) ~V (FP)3 X-2a Examples thereof are:
(meth)acryloyloxyhydroxypropyl.trimethylammonium chloride and (meth)acryl.oyloxyhydroxypropyltriethylammonium chloride.
The basic monomers can also be cationized by neutralizing them with mineral acids such as, for example, sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid or nitric acid, or with organic acids such as, for example, formic acid, acetic acid, lactic acid or citric acid.

In addition to the abovementioned comonomers, it is possible to employ as comonomers (c) so-called macromonomers such as, for example, silicone-containing macromonorners with one or more groups capable of free-radical polyneerization, or alkyloxazoline macromonomers as described, for example, in EP 408 311.

zt is further possible to employ fluorine-containing monomers as described, for example, in EP 558423, and compounds which have a q40 crosalinki.ng action or regulate the molecular weight, in combination or alone.

Requlatora which can be used are the usual compounds known to the skilled worker, sueh as, for example, sulfur compounds (e.g.:
mercaptoethanol, 2-ethylhexyl thioglycolate, thioglycolic acid or dodecyl mercaptan), and t:ribromochloromethane or other compounds which have a regulating effect on the molecular weight of the i:esulting polymers.

:[t is also possible where appropriate to employ thiol-containinq silicone compounds.

Silicone-free reqqulators are preferably employed.

It is also possible to employ crosslinking monomers as additional monomers c). The term crosslinking means that the monomers have at least two unconjugated ethylenic double bonds. Examples of suitable compounds are esters of ethylenically uneaturated carboxylic acids such as acrylic acid or methacrylic acid and polyhydric alcohols, ethers of at least dihydric alcohols, such as, for example, vinyl ethers or allyl ethers.

Examples of the underlying alcohols are dihydric alcohols such as 1,2-ethanediol, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, 2,3-butanedioi, 1,4-butanediol, 2-butene-1,4-diol, 1,2-pentanediol, 1,5-pentanediol, 1,2-hexanediol, 1,6-hexaxiediol, 1,10-decanediol, 1,2-dodecanediol, 1,12-dodecanediol, neopentyl glycol, 3-methylpentane-1,5-diol, 2,5-c4s.methyl-1,3-hexanediol, 2,2,4-tXimethyl-l,3-peritaned.iol, 1,2-cyclohexanedi.ol, 1,4-cyclohexanediol, 1,4-bns(hydroxymethyl)cyclohexane, hydroxypivali.c acid neopentyl glycol monoester, 2,2-bis(4-hydroxyphenyl)propane, 2, 2-bis [4- (2-hydroxypropyl) phenyl] propane, diethylene glyco7., triethylene glycol, tetraethylene glycol, dipropylene glycol, 31) tripropylene glycol, tetrapropylene glycol, 3-thiapentane-1,5-diol, and polyethylene glycols, polypropylene glycols and polytetrahydrofurans with molecular weighte of, in each case, from 200 to 10 000. Apart from the homopolyiners of ethylene oxide or propylene oxide, it is also possible to employ block copolymers of ethylene oxide or propylene oxide or copolymers containirsg incorporated ethylene oxide and propylene oxide groups. Examples of underlying alcohols with more than two OH groups are trimethylolpropane- glycerol, pentaerythritol, 1,2,5-pentanetriol, 1,2,6-hexanetrxol, triethoxycyanuric acid, 460 sorbitan, sugars such as sucrose, glucose, mannose. It is, of course, also possible for the polyhydric al.cohols to be employed after reaction with ethylene oxide or propylene oxide as the corresponding ethoxylates or propoxylates. The polyhydric alcohols can also be firstly converted into the corresponding glycidyl ethers by reaction with epichlorohydrin.

:Further suitable crossl.inkers are the vinyl esters or the esters lDf monohydri.c unsaturated alcohols with ethylenically unsaturated C3- to C6-carboxylic aoids, for example acrylic acid, methacrylic acid, itaconic acid, maleic acid or fumaric acid. Examples of such alCohols are allyl alcohol, 1-buten-3-ol, 5-hexen-1-ol, 1-octen-3-ol, 9-decen-l-ol, dicyclopentenyl alcohol, 10-undecen-l-ol, cinnamyl alcohol, citronellol, crotyl alcohol or cis-9-octadecen-l-ol. However, the monohydric unsaturated alcohols can also be esterif:ied with polybasic carboxylic acids, for example malonic acid, tartaric acid, trimellitic acid, phthalic acid, terephthalic acid, citric acid or succinic acid.
Further suitable crosslinkers are esters of unsaturated carboxylic acids with the polyhydric alcohols described above, for example of oleic acid, crotonic acid, cinnamic acid or 10-undecenoic acid.

Also suitable are straight-chain or branched, linear or cyclic aliphatic or aromatic hydrocarbons which have at least two double bonds which, in the case of' the aliphatic hydrocarbons, must not be conjugated, for example divinylbenzene, diviny].toluene, 1,7-octadiene, 1,9-decadierae, 4-vinyl-l-cyclohexene, trivinyloyclohexane or polybutadienes with molecular weights of from 200 to 20000.
Also suitable are amides of unsaturated carboxylic acids such as, for example, acrylic and methacrylic acids, itaconic acid, maleic acid, and N--allylamines of at least difunctional amines, such as, for example, diaminomethane, 1,2-dianminoethane, 31) 1,3-diaminopropane, 1,4-diaminobutane, 1,6-diaminohexane, 1,12-dodecanediamine, piperazine, di.ethylenetriamine or isophoronediamine. Likewise suitable are the amides from allylamine and unsaturated carboxylic acids such as acrylic acid, methaczrylic acid, itaconic acid, maleic acid, or at least dibasic carboxylic acids like those desoribed above.

Further suitable crosslinkers are triallylamine or corresponding a.mmonium salts, for example triallylmethylainmonium chloride or methyl sulfate.

Yt is further possible to employ N-vinyl compounds of urea derivatives, at least difunctional amides, cyanurates or urethanes, for example of urea, ethyleneurea, propyleneurea or tartaramide, for example N,NI-divinylethyleneurea or c5 N,N'-divinyipropyleneurea.

Further suitable cross].inkers are divinyldioxane, tetraallylsilane and tetravinylsilane.

Examples of particularly preferred crosslinkers are methylenebisacxyiamide, div;inylben.zene, triallylamine and triallylanunonium salts, div;i.nylimidazole, N,N'-divinylethyleneurea, products of the reaction of polyhydric alcohols with acrylic acid or methacrylic acid, methacryl9.c esters and acrylic esters of polyalkylene oxides or polyhydric alcohols which have been reacted with ethylene oxide arnd/or propylene oxide and/or epichlorohydrin, and allyl or vinyl ethers of polyhydric alcohols, for example 1,2-etlhanediol, 1,4-butanediol, diethylene glycol, trimethylo7.propane, glycerol, pentaerythritol, sorbitan and sugars such as sucrose, glucose, maanose.

Very particularly preferred crosslinkers are pentaarythritol triallyl ether, allyl ethers of sugars such as sucrose, glucose, mannose, divinylbenzene, methylenebisacrylamide, N,N'-divinylethyleneurea, and (meth)acrylic esters of glycol, butaizediol, trimethylolpropane or glycerol or (meth)acrylic esters of glycol, butanediol, trimethyloipropane or glycerol reacted with ethylene oxide and/or epichlorohydrin.

The proportion of the monomers with a crosslinking action is from 0 to 10% by weight, preferably 0 to 5% by weight, very particularly preferably 0 to 2% by weight.

The comonomers (c) according to the invention can, if they contain ionizable groups, be partly or completely neutralized with acids or bases before or after tha polymerization, in order, for example, in this way to adjust the solubility or dispersibility in water to a desired extent.

Neutralizing agents which can be used for monomers with acidic groups are, for example, mineral bases such as sodium carbonate, alkali metal hydroxides, a.nd ammonia, organic bases such as amino alcohols, specifically 2-amino--2-methyl-l-propanol, mono ethano lamine, diethaaolamirne, triethanolamine, triisopropanolatnine, tri (2-hydroxy-l-propyl) amine, 2-amino-2-methyl-l,3-propanediol, 2-amino-2-hydroxymethyl-l.,3-propanediol, and diamines such as, for example, lysine.

To prepare the polymers, the monomers of component a) can be polyrnerized in the presence of the polyethers both with the aid of free radical-forming initiators and by exposure to high-energy radiation, which is intended to include the exposure to high-energy electrons.

The initiators which can be eMloyed for the free-radical polymerization are the peroxo and/or a:.o compounds customary for '~his purpose, for example al'kali metal or ammonium peroxodisulfates, diacetyl peroxide, dibenzoyl peroxide, succinyl peroxide, di-tert-butyl peroxide, tert-butyl perbeazoate, tert-butyl perpivalate, tert-butyl peroxy-2-ethylhexanoate, tert-butyl permaleate, cumen.e hydroperoxide, diisopropyl peroxydicarbonate, bis(o-toluyl) p2roxide, didecanoyl peroxide, dioctanoyl peroxide, dilauroyl peroxide, tert-butyl perisobutyrate, tert-butyl peracetate, di-tert-amyl peroxide, tert-butyl hydz'operoxicle, azobisisobutyronitriJ.e, azobis(2-amidinopropaae) dihydrochloride or 2,2'-azobis(2-rnethylbutyron:itrile). Also suitable are indicator mixtures of redox initiator syetems such as, for example, ascorbic acid/iron(II) sulfate/sodium peroxodisulfate, tert-butyl hydroperoxide/sodium disulfite, tert-butyl hydroperoxide/sodium hydroxymethanesulfinate.

organic peroxides are preferably employed.

The amounts of initiator or initiator mixtures used based on monomer employed are betweera 0.01 and 10% by weight, preferably between 0.1 and 5% by weight.

The polymerization takes place at a temperature in the raxnge from 40 to 200 C, preferably in the range from 50 to 140 C, 3Ci particularly preferably in the range from 60 to 110 C. It is normally carried out under atmospheric pressure, but can also take place under reduced or elevated pressure, preferably between i and 5 bar.

3!5 The polymerization can be carriad out, for example, as solution polymerization, bulk polymerization, emulsion polymerization, inverse emulsion polymerization, suspension polymerization, inverse suspension polymerization or precipitation polymerization without the methods which can be used being restricted thereto.
The procedure for bulk polymerization can be such that the polyether-containing compound b) is dissolved in at least one monomer of group a) and, where appropriate, one or more comonomers of group c) and, after= addition of a polymerization initiator, the mixture is completely polymerized. The polymerization can also be carried out semicontinuously by initially introducing part, for example 10% of the mixture of the lpo lyether -containing compound b), at least one monomer of group a), where appropriate one or more comonomers of group c) and initiator, heating the mixture to the polymerization teatperature and, after the polymerization has started, adding the remainder 5 of the mixture to be polymerized in accordance with the progress of the polymeri2ation. The polymers can also be obtained by introducing the polyether-containing compounds of group b) into a reactor and heating to the polymerization temperature, and adding at least one monomer of group a), where appropriate one or more 10 comonomera of group c) and polymerization initiator, either all at once, batchwi.se or, preferably, continuously, aild polymerizing.

If required, the polymer3.zation described above can also be 15 carried out in a solveat. Examples of suitable solvents are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-hexanol and cyclohexanol, and glycols such as ethylene glycol, propylene glycol and butylene glycol, and the methyl or ethyl ethers of the dihydric 20 alcohols, diethylene glycol, triethylene glycol, glycerol and dioxana. The polymerization can also be carried out in water as solvent. In this case, a solution is initially present, which is more or less soluble in water depending on the emount of t:he added monomers of component: a). In order to dissolve water-insoluble products which may be produced during the polymerization it is possible, for example, to add organic solvents such as monohydric alcohols with 1 to 3 carbon atoms, acetone or dimetlaylformamicle. However, the procedure for the polymerization in water can also be such that the water-inaoluble polymers are converted into a fine-particle dispersion by adding conventional emulsifiers or protective colloid.s, for example polyvinyl alcohol.

Examples of emulsifiers used are ionic or nonionic surf actants whose HLB is in the range from 3 to 13. For the definition of the HLS, reference is made to the publication by W.C. Griffin, J.
Soc. Cosmetic Chern., volume 5, 249 (1954).

The amount of surfactants is from 0.1 to 10% by weight, based on the polymer. Vee of water as solvent results in solutions or dispersions of the polymers. If solutions of the polymer are prepared in an organic solvent or in mixtures of an organic solvent and water, then f:rom 5 to 2000, preferably 10 to 500, parts by weight of the organic solvent or mixture of solvents are 4<5 used per 100 parts by weight of the polymer_ l?referred polymers are obtainable by f ree-radical polymerization of ,OL) 10 to 98% by weight of at least one vin.yl ester of C1-C24-carboxylic acids in the presence of b) 2 to 90% by weight of at least one polyether-containing compound and c) 0 to 50% by weight of one or more other copolymerizable monomers.
Particularly preferred polymers are obtainable by free-radical polymerization of a) 50 to 97% by weight of at least one vinyl ester of C1-C24-carboxylic acids in the presance of b) 3 to 5096 by weight of at least one polyether-containing compound and c) 0 to 20% by weight of one or more other copolymerizable monomers.
Vexyypaxticularly preferred polymers are obtainable by free-radical polymerization of a) 65 to 97% by weight of at least one vi.nyl ester of Cl-C24-carboXy].ic acids ir.- the presence of b) 3 to 35% by weight of at least one polyether-containing compound and c) 0 to 20% by weight of one or more other copolymeriza.ble monomers.
3E;
To prepare the polymers used according to the invention, the ester groups of the original monomers a) and, where appropriate, other monomers are cleaved after the polymerization by hydrolysis, alcoholysis or atninolysis. This process atep is 41) generally referred to as hydrolyis hereinafter. The hydrolysis takes place in a manner known per se by adding a base, pref erably by adding a sodium or potassium hydroxide solution in water and/or alcohol. Methanolic: sodium or potassium hydroxide solutions are particu].arly preferably employed. The hydrolysis is 45 carried out at temperatures in the range from 10 to 80 C, preferably in the range from 20 to 60 C. The degree of hydrolysis depends oa the amount of base employed, on the hydrolysis temperature, the hydrolysis time and the water content of the srolution.

7Che degree of hydrolysis of the polyvinyl ester groups is in the 53range from 1 to 100%, preferably in the range from 40 to 100%, 1?articularly preferably irn the range from 65 to 100%, very 3particularly preferably in the range from 80 to 100%.

The polymers prepared in this way can be subaequently cationizec9.
by reacting hyydroxyl and/or amino functions present in the polymer with epoxides of the formula VI (R26 = C1- to Cao- alkyl).

(VI) ~(F:fs)s X-it is possible and preferred for the hydrokyl groups of the polyvinyl alcohol units and vinylamine units produced by hydrolysis of vinylformamide to be reacted with the epoxides.
The epoxides of the formula VI can also be ge.nerated in situ by reacting the corresponding chlvrohydrins with bases, for example sodium hydroxide.

2,3-Epoxypropyltri.methylarnmonium chloride or 3-chloro-2-hydroxypropyltrimethylar=onium chloride is preferably employed.

The K values of the polymers should be in the range from 10 to 300, preferably 25 to 250, particularly preferably 25 to 200, very particularly preferably in the range Erom 30 to 150. The K
value required in each case can be adjusted in a manner known per se by the composition of the starting materials. The K values are determined by the method of Fikentscher, Cellu2osechemie, Vol.
13, pp. 58 to 64 and 71 to 74 (1932) in N-methylpyrrolidone at 25 C and polymer concentrations which are between 0.1% by weight and 5% by weight, depending on the K value range.

After the hydrolysis, the polymer solutions can be steam distilled to remove so].vents. The steam distillation results in aqueous solutions or dispersions, depending on the degree of hydrolysis and nature of the polyethers b), ot the vinyl estere a) and of the possibly employed monomers c).

The resulting polymers can also be subsequently crosslinked by reacting the hydroxyl groups or amino groups in the pol.yiuer with at least bifunctional reagents. Water-solu.ble products are obtained with low degrees of crosslixiking, while water-swellable or insoluble products are obtained with high degrees of crosslinking.

The polymers according to the invention can be reacted, for izxample, with dialdehydes and diketones, for example glyoxal, glutaraldebyde, succinaldehyda or teraphthalaldehyde. Also suitable are aliphatic or aromatic carboxylic acids, for example maleic acid, oxalic acid, malonic acid, succinic acid or citric acid, or carboxylic acid dex'ivatives such as carboxyli-c esters or aizhydrides or carbonyl halides. Polyfunctional epoxides are also suitable, for example epichlorohydrin, glycidyl methacrylate, ethylene glycol diglycidyl ether, 1,4-butanediol diglycidyl ether or 1,4-bis(glyci.dyloxy)benzene. Also suitable are diisocyanates, for example hexamethylene dl.isocyaaate, isophorone diisocyanate, methylenediphenyl diisocyanate, tolylene diisocyanate or divinyl sulfone.

Additionally suitable are inorganic compounds such as boric acid or boric acid salts, for example sodium metaborate, borax (disodium tetraborate), and salts of multiply charged cations, for example copper(II) salts such as copper(II) acetate or zinc, aluminum or titanium salts.

Boric acid or boric acid salts such as sodium metaborate or disodium tetraborate are suitable and preferred for the subsequent crosslinking. This may entail adding the boric acid or boric acid salts, preferably as salt solutions, to the solutions o the polymers according to the invention. The boric acid or boric acid salts are preferably added to the aqueous polymer solutions.
The boric acid or boric acid salts can be added to the polymer solutions i.mtttediately after preparation. Kowever, it is also possible for the boric aci.d or boric acid salts to be added subsequently to the polyme:rs according to the invention or during the soft capsule production process.

The proportion of boric acid or boric acid salts based on the polymers according to the invention is from 0 to 15% by weight, 4,0 preferably 0 to 10% by we:i.ght, particularly preferably 0 to 5% by weight.

The solutions and dispersions of the polymers according to the invention can be converted into powder form by various drying ,45 processes such as, for example, spray drying, flui.dized spray drying, drum drying or freeze drying. Spray drying is preferably employed as drying process. An aqueous solution or dispersion can be prepared again by dissolving or redispersing the dry polymer powder obtained in this way in water. The conversion into powder form has the advantage of better storability, simpler t:ransportability and less tendency to microbial attack.
:Gn place of the steazn-distilled polymer solutions, it is also possible to convert the alcoholic po7.ymer solutions directly into powder f orm.

The water-soluble or water-dispersible polymers according to the invention are outstandingly suitable for producing soft capsules, ia particular for pharmaceutical dosage forms.

The polymers according to the invention produced by free-radical polymerization of vinyl esters and, where appropriate, one or more polymerizable monomers in the presence of polyether-containing compounds and subsequent at least partial hydrolysis of the ester functions of the original vinyl esters are suitable for producing soft capsules.
The polymers can be produced with high reproducibility in the abovementioned processes. No materials of animal origin are used to produce them and, since no vegetable matarials are employed either, the problem of products of genetic engineering origin does not arise.

The polymers are not particularly microbi.ologically susceptible because they do not represent good nutrient media for microbes.
The polymer chains are not degraded either by enzymes or by hydrolysis. The preparation of solutions to produce films and for encapsulation is therefore no problem either.

The particular suitability of the descri.bed polymers for producing soft capsules derives from their flexibility and softness. This great flexibility usually means that it is unneceseary to employ low molecular weight plasticizers. Thus no change in the shell and the capsule contents occurs because of migration either.

9:0 Typical packaged materials are preferably pharmaeeutieal products such as solid and liquid active ingredients, but also vitamins, carotenoids, minerals, trace elements, food supplements, spices and sweeteners. The capsules can also be used for cosmetic active ingredients (personal care), such as, for example, hair and s'kin formulations, for oiils, perfumes, bath additives or proteins.
Further applications in the personal care sector, and further applications for water-soluble Qackagings are mentioned in WO
99/40156.

Further possible examples of such packaged materials are 5 cleaners, such as soaps, detergents, colorants and bleaches, agroehemical.s such as fertilizers (or eornbinations thereof), crop protection agents such as herbicides, fungicides or pesticides, and seeds.

10 Tt is possible in general to use the polymers according to the invention to package contents which are to be protected before they are brought into a wet environment.

Table 1 15 Flexibility of polymers (23 C / 54% r.h.) Composition Elongation at break 20 PEG 6 000 / polyvinyl acetate (15 : 85), 121%
hydrolyzed PEG b 000 / polyvinyl acetate 10 : 90 140%
PEG 6 000 / polyvi.nyl acetate 5 95 209%
25 The determination took place on pieces of fi1.m in a tensile tester (Texture Analyzer TA.XT 2; Winopal Forschungebadarf GmbH, 30161 Hannover) in accordance with DIN 53504.

Surprisingly, the flexibility changes only sli.ghtly when the ambient humidity changes. This means that on storage in a dry environment the soft capsules do not become brittle and retain their mechanical stability.

Table 2 Fle-cibility of polymers at different ambient humidities (23 C) Elongations at break [%] at various reZ. humidities 11% 3396 54% 65sk 75%
`iQ PEG 6 000 / polyvinyl acetate (1.5 : 85), hydrolyzed polyvinyl alcohol (Mowiol 4/88) 4 40 106 - -Gelatin 200 B1oom 0 - 0 Gelatin 200 Bloom + 5% glycerol 3 - 5 Gelatin 200 Bloom + 35% glycerol 31 - 157 * trademark The elasticity is retained even on encapsulation of substances with high hygroscopicity. The polymers are therefore particularly suitable for encapsulating water-sensitive substances.

The rate of dissolution of the polymers according to the invention and soft capsules produced therefrom is extremely high and markedly exceeds that of gelatin and polyvinyl alcohol. In addition, the polymers are soluble in cold water. Gelatin and polyvinyl alcohol dissolve only at higher temperatures. Since many drugs are intended to act quickly after intake, this dissolving behavior is a clear advantage in particular for this use.

Table 3 Rate of dissQlution of polymers Product 0.08 N HC1 Buffer pH 6.6 PEG 6 000 / polyvinyl acetate 58 s 1 tnin 00 s (15 : 85), hydrolyzed Gelatin 200 Bloom + 35% glycerol 1 min 20 1 min 31 (Hydroxypropylmethylcellulose) 6 min 21 s 6 rnin 31 s Pharmacoat 606*
Polyvinyl alcohol (Mowiol 8/88) 3 min 10 s 3 min 18 s The rate of dissolution was determined in a release apparatus (Pharmatest PTSI complying with USP 23 using a film 100 m thick clamped into a slide frame with an aperture of 3.5 x 2.5 cm, at 50 rpm and 37 C. The time in which the piece of film has dissolved is indicated.

in contrast to gelatin, it is also possible to encapsulate in the shells according to the invention substances prone to interactions, such as, for example, aldehydes or multiply charged cations. No crosslinking or slowing of the rate of dissolution is evident.

Soft capsules of the composition according to the invention can be coated extremely well using aqueous polymer solutions or polymer suspensions. Thus, a coating which is resistant to gastric fluid and adheres strongly to the surface a-*id, moreover, is stable on storage can be applied by spraying on Kollicoat MAE
30 DP (USP type C methacrylic acid copolymer) in a horizontal drum coater .

* trademarks To achieve resistance to gastric fluid it is additionally possible for the shell to cor-tain from 20 to 80%, preferably 30 to 70%, of a polymer resistazit to gastric fluid.

it is possible to add to the polymers structure-improving auxiliaries in order to modify the mechanical properties such as flexibility and strength. These structure-improving auxiliaries can be divided into 2 large groups.

A) Polymers with a molecular weight greater than 50000, preferably greater than 100000 B) substances which lead to crosslinking of the polymer chains, either of the polymers or of the substances mentioned under A), preferably aldehydes, boric acid and its salts, and, where appropriate, substances which lead to crosslinking of the polymer chains of the structure-improving auxiliaries, preferably alkaline earth metal ions, aminzs, tannins, and aldehydes and borates.

High molecular weight polymers which can be employed are substances from the following classes:

Polyamino acids such as qrelatin, zein, soybcan protein and derivatives thereof, polysaccharides such as starch, degraded starch, maltodextrins, carboxymethylstarch, cellulose, hydrox-ypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose, ethylcellulose, cellulose acetate, cellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, hydroxypropylcellulose acetate succinate, hemicellulose, galactomannans, pectins, alginates, carrageenans, xanthan, gellan, dextran, curdlan, pullulan, chitin, and derivatives thereof, synthetic polymers such as polyacrylic acid, polymethacrylic acid, copolymers of ac;.ylic esters and methacxylic esters, polyvinyl alcohols, polyvinyl acetate, polyethylene glycols, polyoxyethyleae/polyoxypropyle=e block copolymers, polyvinyl.pyrrolidones and derivatives thereof.
These high molecular weight polymers form a network with the polymers and thus increase the strength of the soft capsules. The f lexibility is usually not compromised as long as the 4:i concentrations used are not very high. Surprisingly, not only water-soluble but also water-insoluble polymers such as copolymers of acrylic esters and methacrylic esters are suitable f'or this purpose. The capsules still disintegrate as long as the c:oncentratl.on of these water-insoluble polymers remaiae below 50%.

5;3ubstances which lead to crosslinking either of the polymer (;hains of the polymers or of the added high molecular weight >>olymers act in a similar way.

!Besides the compouents mentioned, it is possible for the soft capsules according to r.he invention to contain other conventional constituents. These include fillers, release agents, flow aids, stabilizers and water-soluble or water-insoluble dyes, flavorings and sweeteners.

Examples of dyes are iron o};ides, titanium dioxide, which are added in an amount of about 0.001 to 10, preferably of 0.5 to 3, % by weight, triphenylmethaxie dyes, azo dyes, quinoline dyes, indigo dyes, carotenoids, in order to color the capsules, opacifying agents such as titanium dioxide or talc in order to decrease the transparency and save on dyes.

Flavorings and sweeteners are particularly important when an unpleasant odor or taste is to be masked and the capsule is chewed.
Preservatives are usually unnecessary.

Exampies of fillers are inorganic fillers such as oxides of magnesium, aluminum, silicon, titanium or calcium carbonate. The preferred concentration range for the fillers is about 1 to 50%
by weight, particularly preferably 2 to 30% by weight, based on the total weight of all the components.

Lubricants are stearates of aluminum, calcium, magnesium and tin, n and snagnesium silicate, si:Licones and the like. The preferred concentration range is about 0.1 to 5% by weight, particularly preferably about 0.1 to 3% by weight, based on the total weight of all the components.

41) Examples of flow aids are fine-particle or extremely fine-particle silicas, modified where appropriate. The preferred concentration range is 0.05 to 3% by weight, particularly preferably 0.1 to 1% by weight, based on the total weight of all the components.

The incorporation of active ingredients into the shell represents a special case. This may be advantageous for separating incompatible active ingredients from one another. The active ingredient with the smallest dose should then be incorporated into the shell.

The shell of the packaging materials according to the invention consists of 10 to 100%, preferably 20 to 98%, polymars, where appropriate 0 to 80%, preferably ], to 50%, structure-improving auxiliaries and, where appropriate, 0 to 30%, preferably 0.1 to 30%, other conventional constituents.

The packaging materials are produced by conventional processes, for example the rotary die process, the Accogel process, the Norton process, the drop or blow procass or by the Colton-Upjohn process. These processes are described in W. Fahrig and U. Hofer, Die Kapsel, Wissensehaf tliche Verlagsgesellschaft mbH Stuttgart, 1983.

Method for preparing the polymers:

The polyether-containing compound is introducsd into a polymerization vessel and heated to 80 C with stirring under a gentle stream of nitrogen. Vinyl acetate and the other monomer are metered in with stirring over the course of 3 h.
Simultaneously, a solution of 1,4 g of tert-butyl pexpivnlate in g of methanol is added, likewise over the course of 3 h. The mixture is then stirred at 80 C for 2 h. After cooling, the polymer is dissolved in 450 ml of methanol. For the hydrolysis, 30 50 ml of a 10% atrength methanolic sodium I-Lydroxide solution are added at 30 C. After about 40 min, the reaction is stopped by adding 750 ml of 1% strength acetic acid. The methanol is removed by distillation.

The K values were determined on 1% solutions in N--methylpyrrol idon e .

9:5 Table 4 Degree of pie Grafting base Vinyl ester Comonomer value hydrolysis 5 PEG %
5 Vinyl acetaEe, 47 > 95 P Q 4000 inyl 10 2 acetate, - 51 > 95 E 6000, tinyl 3 acetate, _ 54 > 95 15 PEG 6000, Vinyl 4 acetate, 49 > 95 E 6000, snyl 5 acetate _ 73 > 95 P , inyl 6 acetate 42 y 95 PEG 9000, iny ~ 7 acetate, 58 > 95 2.i Po yglycero 2200, Vinyl $ acetate, _ 66 >95 30 PEC3-PPG block copo ymcx V.myl 9 80002, acetate, 45 > 95 -72 410 g eth lpolyct ylcne g ycol Vmyl '5 10 2000~ acetate, _ 47 > 95 ~
72 410 g A lpo yethylcue glyco1,3500 tny 11 ecet8te' 48 >95 PPG 4 Vinyl 12 acetate 50 >95 E 0000 iny!

13 acetate, _ 69 > 95 E pl K De e Grafling base Vinyl ester Comonomer vglue %
hydrolysis P 2 ~nyl 14 acetate, _ 64 >95 PEO 20000 ny acetate, _ 59 > 95 10 pEd 200 Vinyl 16 acetate, - 55 86 PEG 35000 Vinyi 17 acetate, - 77 > 95 G35000 inyl 18 acetate, - so > 95 137g 410 (3 5000 Lnyl 30 19 acetate, - 65 97 ime icone copo yol , ix~yl acetate, _ 58 >95 Pol sodium metbacrylato-co-methylpol)- V'snyl 21 ethylene glycol metbacrylatep acetate, 43 >95 410 g 103 , visya 31) acetate, 22 ethoxylated polyethyieneimineg 52 > 95 'PFIQ 6000, n3'`=- Methyl 3 5 23 acetate, rnethacrylato, 24 47 >95 72 386 g P G 20000, my~
24 ace~.at, N-Viny~- 61 > 95 pyrrolidone, 82 g 40 PEG 20000, Vinyl 3--Methy~l--~ ace*.ate, ~vinyfimidazolium 53 > 95 methyl sulfate, 48 PEG 6000, myl N-.V'myl-acetate, formamsde, 57 > 95 Exam- Degree of ple Grafting base Vinyl ester Comonotner v~ue hydrolysis PE ooo, Vinyl rt--Vinyl- %
27 acetate, formamide, 67 > 95 72 326 a 82g PEG 35000, Vinyl 28 acetate, 59 96 270 410 g PEG 35000, Vinyl acetate, Pentaerythritol 29 triallyl ether, 71 95 270 410 , 1.6 g PEG 35000, Vinyl pentaerythritol 30 aeetate, tiallyl etber, 65 94 270 410 0'g g PEG 35000, Ylztyl N,TI`-DMny -31 ace:ate, cthyleneurea 73 95 270 410 = 0.7 PEG 12000, Ynyl Pentacrythritol 32 acetate, tria11y1 ether, 50 94 270 41 1.6 g 1 PEG x: PolyethyJ.ene glycol with average mqlecu].ar weight x 2 Lutrol F 68*supplied by BASF A!ctiengesellschaft (PPG:
polypropylene glycol) 3 Pluriol A 2000 E* supplied by BASF Aktiengesellechaf t 4 Lutensol AT 80*supplied by BnSF Aktiengesellschaft (c16-C1e-fatty alcohol + 80 E0) 5 Polypropylene gl{col with average molecular weight 4000 6 Belsil DMC 60312TM*supplied by wacker Chemie GmbH
7 Sodium methacrylate/methylpolyethylene glycol methacrylate molar ratio 4:1; methylpoXyethyiene glycol with molecular weight about 1000 8 Prepared from 12.5% polyethylenaimine (average molecular weight 1400) and 87.59s ethyleae oxide Example 33; Reaction with 3-chloro-2-hydroxypropyltrimethylammonium chloride 22 g of a 60% strength aqueous solution of 3--chloro-2-hydroxypropyltzimethylammonium chloride and 3.5 g of sodium hydroxide are added to 40C g of a 32.9% strength solunion froin Example 3. The mixture is stirred at 60 C for 3 hours and then at 90 C for a further two hours. A clear solution is obtained.

* trademarks E:xample 34: Reaction with 3-chloro-2-hydroxypropyltrimethylammonium chloride 46 g of a 60% strength aqueous solution of 3-chloro-2-hydroxypropyltrimethylammonium chloride and 6 g of sodium hydroxide are added to 400 g of a 15.3% strength solution from Example 26. The mixture is stirred at 60 C for 3 hours and then at 90 C for a further two hours. A clear solution is obtained.
E:xample 35: subeequent crossiinking with borax A 5% strength aqueous solution of disodium tetraborate (borax) is eLdded to a stirred 19.3% strength aqueous solution of the polymer i:rom ExaLtnple 28 at room temperature over the course of half an hour. An increase in viscosity is observed.

Amount of 5% borax Srook ield viscosity solution added (LVF, Spindle 2, 30 rpm, 23 C) [g] [mPas3 14.9 128 18.0 216 21.0 534 24.0 2228 26.9 75201 29.8 29190 1 Spindle 4, 30 rpm 2 Spindle 4, 6 rpm Example 36 1.0 kg of polymer of polyethylene glycol 6000 / polyvinyl acetate (15 : 85) hydrolyzed, was dissolved in 1.5 kg of demineralized water, and the solution was heated to 60 C and drawn out to a film 300 m thick, and dried at 60 C. Soft capsules filled with vitamin E (2 parts) and medium chain-length triglycerides (8 parts) were produced from this film by the rotary die process. The capsules were then dried at 35 C in a fluidized bed.

The dissolution time in simulated gastric fluid was 2 min 30 9.
During storage at 11% r.h. the capsules retained their flexibility and disintegration properties.

Example 37 0.66 kg of polymer of polyethylene glycol 6000 / polyvinyl acetate (15/85) hydrolyzed, 0.04 kg of pectin and 0.16 kg of polyvinyl alcohol (Mowiol 4/B81 ware dissolved with heating in 1,58 kg of demineralized water. A pigment suspension was prepared from 16 g of red iron oxide (Sicovit red 30, BASF Aktiengese7.lsChaft) and 33 g of titanium dioxide with 115 g of demineralized water and, after homogenization in a corundunm disk mill, added to the polymer solution with stirring. The suspension was drawn out to a film 400 rn thick. Soft capsules filled with ibuprofen (3 parts) and medium chain-length triglycerides (7 parts) were produced f-'rom this film by the rotary die process. The capsules were then dried at 35 C in a fluidized bed.

The dissolution time of the capsules iri simulated gastric fluid was 3 min 03 s. During storage at 11% r.h. for 3 months, the capsules retained their flexibility and disintegration properties.
Example,38 0.6 kg of polymer of polyethylene glycol 6000 / polyvinyl acetate (15/85) hydrolyzed, 0.5 kg of gelatin 200 Eloom and 10 g of 10%
beta-carotene dry powder (Lucarotin 10% CWD) were dissolved with heating in 1.4 kg of demineralized water and 0.10 kg of glycerol.
The solution was drawn out to a film 400 m thick.

Soft capsules tilled. with ibuprofen (3 parts) and medium chain-length triglycerides (7 parts) were pXoduced from this film by the rotary die process. The capsules were then dried at 35 C in a fluidized bed.

The dissolution time of the capsules in si-mulated gastric fluid was 4 min 30 s.

Example 39 0.175 kg of a copolymer of methacrylic acid and ethyl acrylate (Kollicoat MAE 100 Pl was dispersed in 1.625 kg of water and adjusted to pH 6.5 by adding 20% strength sodium hydroxide solution with stirring. Then 0.7 kg of polymer of methylpolyethylene glycol 6000 / polyvinyl acetate (15/85) 4S hydrolyzed was dissolved with stirring. This solution was drawn out to a film 350 m thick.

* trademarks Soft capsules filled with verapamil HC1 (3 parts), Cremophor*
RH 40 (1 part) and medium chain-length triglycerides (6 parts) were produced fronti this film by the rotary die process. The capsules were then dried at 35 C in a fluidized bed.

The dissolution time of the capsules in simulated gastric fluid was 3 min 45 s.

Exarnple 40 0.95 kg of polymer of polyethylene glycol 6000 / polyvinyl acetate (15/85) hydrolyzed, 0.1 kg of *
hydroxypropylmethylce].lulose (Pharrnacoat 606), 0.05 kg of carrageenan and 10 g of 10% beta-carotene dry powder (Lucarotin 1096..CWD)'and 0.l kg of polyethylene glycol 6000 were dissolved with heating in 1.4 kg of demineralized water. The solution was drawn out to a film 350 rn thick.

5oft capsules filled with theophylline (3 part.s), polysorbate 80 (0.5 part) and medium chain-length triglycerides (6 parts) were produced from this film by the Accogel process by dimpling the film, injecting the filling and closing with a second film. The capsules were then dr;ed at 35 C in a fluidized bed.
~= .
The dissolution time of the capsules in simulated gastric fluid was 2 min 55 s. No embrittlement was detectable even on storage at 11% ambient humidity.

Example 41 1.0 kg of"polymer of polyethylene glycvl 6000 / polyvinyl acetate (15/85) hydrolyzed was dissolved in 2.3 kg of demineralized water, and 10 g of sodium tetraborate were added. The solution was drawn out to a film 400 m thick. Soft capsules filled with tocopherol acetate (3 parts), polysorbate 80 (0.5 part) and medium chain-length triglycerides (6.5 parts) were produced from this film'by the Accogel process by dimpling the_film, injecting the filling and closing with a second film. The capsules were then dried at 35 C in a fluidized bed. The dissoluti.on time of the capsules in simulated gastric fluid was 4 m:.n 35 s. No embrittlernent was detectable even on storaga at 11% ambient humidity.

* trademarks C;omparati.ve example :;of t capsules could not be produced either with gelati= or with polyvinyl alcohol or hydroxypropylmethylcellulose without 513,fldition of plasticizer. The films ware too brittle and fragile.

4.0

Claims (26)

1. A soft capsule comprising:
(a) polymers prepared by polymerization of vinyl esters in the presence of polyethers having a member average molecular weight below 1,000,000;
(b) optionally structure-improving auxiliaries; and (c) optionally other conventional constituents.

2. A soft capsule as claimed in claim 1, wherein the polymers (a) are obtained by free-radical polymerization of:
a) at least one vinyl ester of C1-C24-carboxylic acids in the presence of:
b) polyether-containing compounds; and c) optionally one or more copolymerizable monomers and subsequent at least partial hydrolysis of the ester functions in the original monomers a).

3. A soft capsule as claimed in either of claims 1 or 2, wherein the polymers (a) are obtained by free-radical polymerization of:
a) at least one vinyl ester of C1-C24-carboxylic acids in the presence of:
b) polyether-containing compounds of the general formula (I):

R1-(-O-(R2-O)u-(R3-O)v-(R4-O)w-[-A-(R2-O)x-(R3-O)y-(R4-O)z-]-s R5)n in which the variables have, independently of one another, the following meaning:

R1 hydrogen, C1-C24-alkyl, R6-C(=O)-, R6-NH-C(=O)-, polyalcohol residue;

R5 hydrogen, C1-C24-alkyl, R6-C(=O)-, R6-NH-C(=O)-;

R2 to R4 -(CH2)2-, -(CH2)3-, -(CH2)4-, -CH2-CH(R6)-, -CH2-CHOR7-CH2-;
R6 C1-C24-alkyl;

R7 hydrogen, C1-C24-alkyl, R6-C(=O)-, R6-NH-C(=O)-;
A -C(=O)-O, -C(=O)-B-C(=O)-O, -C(=O)-NH-B-NH-C(=O)-O, B -(CH2)t-, arylene, optionally substituted;
n 1 to 1000;
s 0 to 1000;
t 1 to 12;
u 1 to 5000;
v 0 to 5000;
w 0 to 5000;
x 0 to 5000;
y 0 to 5000;
z 0 to 5000; and c) optionally one or more other copolymerizable monomers;
and subsequent at least partial hydrolysis of the ester functions in the original monomers a).

4. A soft capsule as claimed in any one of claims 1 to 3, wherein the polymers (a) are obtained by free-radical polymerization of:
a) at least one vinyl ester of C1-C24-carboxylic acids is the presence of:
b) polyether-containing compounds of the general formula I with a number average molecular weight of from 300 to 100000, in which the variables have, independently of one another, the following meaning:

R1 hydrogen, C1-C12-alkyl, R6-C(=O)-, R6-NH-C(=O)-, polyalcohol residues;

R5 hydrogen, C1-C12-alkyl, R6-C(=O)-, R6-NH-C(=O)-;
R2 to R4 -(CH2)2-, -(CH2)3-, -(CH2)4-, -CH2-CH(R6)-, -CH2-CHOR7-CH2-;
R6 C1-C12-alkyl;

R7 hydrogen, C1-C12-alkyl, R6-C(=O)-, R6-NH-C(=O)-;
n 1 to 8;
s 0;
u 2 to 2000;
v 0 to 2000;
w 0 to 2000;
and c) optionally one or more other copolymerizable monomers;
and subsequent at least partial hydrolysis of the ester functions is the original monomers a).

5. A soft capsule as claimed in any of claims 1 to 4, wherein the polymers (a) are obtained by free-radical polymerization of a) at least, one vinyl ester of C1-C24-carboxylic acids in the presence of:
b) polyether-containing compounds of the general formula (I) with a number average molecular weight of from 500 to 50000, in which the variables have, independently of one another, the following meaning:

R1 hydrogen, C1-C6-alkyl, R6-C(=O)-, R6-NH-C(=O)-;
R5 hydrogen, C1-C6-alkyl, R6-C(=O)-, R6-NH-C(=O)-;
R2 to R4 -(CH2)2-, -(CH2)3-, -(CH2)4-, -CH2-CH(R6)-, -CH2-CHOR7-CH2-;
R6 C1-C6-alkyl;

R7 hydrogen, C1-C6-alkyl, R6-C(=O)-, R6-NH-C(=O)-;

n 1;
s 0;
u 5 to 1000;
v 0 to 1000;
w 0 to 1000;
and c) optionally one or more other copolymerizable monomers;
and subsequent at least partial hydrolysis of the ester functions in the original monomers a).

6. A soft capsule as claimed in any one of claims 1 to 5, wherein the polymers (a) are obtained by free-radical polymerization of:
a) at least one vinyl ester of C1-C24-carboxylic acids in the presence of:
b) polyether-containing compounds; and c) optionally one or more other copolymerizable monomers;
and subsequent at least partial hydrolysis of the ester functions in the original monomers a), wherein the polyether-containing compounds b) have been prepared by polymerization of ethylenically unsaturated alkylene oxide-containing monomers and optionally, other copolymerizable monomers.

7. A soft capsule as claimed in claim 6, wherein the polyether-containing compounds b) have been prepared by polymerization of polyalkylene oxide vinyl ethers and optionally, other copolymerizable monomers.

8. A soft capsule as claimed in claim 6, wherein the polyether-containing compounds b) have been prepared by polymerization of polyalkylene oxide (meth)acrylates and optionally, other copolymerizable monomers.

9. A soft capsule as claimed in any one of claims 1 to 8, wherein the other copolymerizable monomer c) is selected from the group of:

acrylic acid, methacrylic acid, maleic acid, fumaric acid, crotonic acid, maleic anhydride and its monoesters, methyl acrylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate, n-butyl acrylate, n-butyl methacrylate, t-butyl acrylate, t-butyl methacrylate, isobutyl acrylate, isobutyl methacrylate, 2-ethylhexyl acrylate, stearyl acrylate, stearyl methacrylate, N-t-butylacrylamide, N-octylacrylamide, 2-hydroxyethyl acrylate, hydroxypropyl acrylates, 2-hydroxyethyl methacrylate, hydroxypropyl methacrylates, alkylene glycol (meth)acrylates, styrene, unsaturated sulfonic acids, vinylpyrrolidone, vinylcaprolactam, vinyl ethers, vinylformamide, vinylmethylacetamide, vinylamine, 1-vinylimidazole, 1-vinyl-2-methylimidazole, N,N-dimethylamino-methyl methacrylate and N-[3-(dimethylamino)propyl]methacrylamide; 3-methyl-1-vinylimidazolium chloride, 3-methyl-1-vinylimidazolium methyl sulfate, N,N-dimethylaminoethyl methacrylate, N-[3-(dimethylamino)-propyl]methacrylamide quaternized with methyl chloride, methyl sulfate and diethyl sulfate.

10. A soft capsule as claimed in any one of claims 1 to 9, wherein the ratios of amounts are:
a) 10 to 98% by weight, b) 2 to 90% by weight, and c) 0 to 50% by weight.

11. A soft capsule as claimed in any of claims 1 to 10, wherein the ratios of amounts are:
a) 50 to 97% by weight, b) 3 to 50% by weight, and c) 0 to 20% by weight.

12. A soft capsule as claimed in any one of claims 1 to 11, wherein the ratios of amounts are:
a) 65 to 97% by weight, b) 3 to 35% by weight, and c) 0 to 20% by weight.

13. A soft capsule as claimed in any one of claims 1 to 12, wherein the resulting polymers are subsequently crosslinked by a polymer-analogous reaction.

14. A soft capsule as claimed in any one of claims 1 to 13, wherein dialdehydes, diketones, dicarboxylic acids, boric acid, boric acid salts, and salts of multiply charged cations are employed for the subsequent crosslinking.

15. A soft capsule as claimed in any one of claims 1 to 14, wherein the structure-improving auxiliaries (b) employed are compounds from the following classes:
a) polymers with a molecular weight of more than 50000, b) substances leading to crosslinking of the polymer chains of the polymers, and c) optionally substances which lead to crosslinking of the polymer chains of the structure-improving auxiliaries.

16. A soft Capsule as claimed in any one of claims 1 to 15, wherein the structure-improving auxiliaries employed are polymers from the following classes of substances:
polyamino acids such as gelatin, zein, soybean protein and derivatives thereof, polysaccharides such as starch, degraded starch, maltodextrins, carboxy-methylstarch, cellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose, ethylcellulose.
cellulose acetate, cellulose acetate phthalate, hydroxypropyloellulose acetate phthalate, hydroxypropylcellulose acetate succinate, hemicellulose, galactomannans, pectins, alginates, carrageenans, xanthan, gellan, dextran, curdlan, pullulan, gum arabic, chitin, and derivatives thereof, synthetic polymers such as polyacrylic acid, polymethacrylic acid, copolymers of acrylic esters and methacrylio eaters, polyvinyl alcohols, polyvinyl acetate, polyethylene glycols, polyoxyethylene/polyoxypropylene block copolymers. polyvinylpyrrolidones and derivatives thereof.

17. A soft capsule as claimed in any one of claims 1 to 16, wherein other conventional constituents of the shell which are present are fillers, release agents, flow aids, dyes, pigments, opacifiers, flavorings, sweeteners, plasticizers, preservatives and/or active ingredients.

18. A soft capsule as claimed in any one of claims 1 to 17, wherein the shell consists of from 10 to 100% by weight of polymers of vinyl esters on polyether, optionally from 0 to 80% of structure-improving auxiliaries and, optionally from 0 to 30% of other conventional constituents.

19. A soft capsule as claimed in any one of claims 1 to 18, obtained by processes such as the rotary die process, Accogel process, Norton process, drop or blow process or the Colton-Upjohn process.

20. A soft capsule as claimed in any one of claims 1 to 19, which comprises one or more active pharmaceutical ingredients, vitamins, carotenoids, minerals, trace elements, food supplements, cosmetic active ingredients, crop protection agents, bath additives, perfume, flavoring, cleaner or detergent.

21. A soft capsule as claimed in any one of claims 1 to 20, wherein the shell comprises from 20 to 80% of a polymer resistant to gastric fluid.

22. A soft capsule as claimed in any one of claims 1 to 21, wherein resistance to gastric fluid is achieved by applying after production a coating resistant to gastric fluid by conventional pharmaceutical coating processes.

23. The use of a soft capsule as claimed in any one of claims 1 to 22 for a pharmaceutical application.

24. The use of a soft capsule as claimed is any one of claims 1 to 22 for a cosmetic application, application in crop protection, for cleaner or for food supplement.

25. The use of polymers obtained by free-radical polymerization of:
a) at least one vinyl ester of C1-C24-carboxylic acids in the presence of:
b) polyether-containing compounds, and c) optionally one or more copolymerizable monomers, and subsequent at least partial hydrolysis of the ester functions in the original monomers a) to produce soft capsules as claimed in any one of claims 1 to 22.

26. The use of polymers obtained by free-radical polymerization of:
a) at least one vinyl ester of C1-C24-carboxylic acids in the presence of:
b) polyether-containing compounds, and c) optionally one or more copolymerizable monomers, and subsequent at least partial hydrolysis of the ester functions in the original monomers a) wherein the polyether-containing compounds b) have been prepared by polymerization of ethylenically unsaturated alkylene oxide-containing monomers and optionally other copolymerizable monomers, for producing soft capsules as claimed in any one of claims 1 to 22.