ACRYLATE COPOLYMERS FOR GALENIC APPLICATIONS

Abstract

The invention relates to a copolymer for galenic applications, having an acrylate backbone and sidearms, containing α-hydroxycarboxylic acid groups. The invention further relates to the process of preparing the foregoing copolymer for galenic applications and its use thereof.

Claims

1. A copolymer comprising the following structure: poly(MA.sub.x-co-[AS—(O—R).sub.n—OH].sub.y-co-[AS—OH].sub.z), poly(MMA.sub.x-co-[AS—(O—R).sub.n—OH].sub.y-co-[AS—OH].sub.z), poly(EA.sub.x-co-[AS—(O—R).sub.n—OH].sub.y-co-[AS—OH].sub.z), poly(EMA.sub.x-co-[AS—(O—R).sub.n—OH].sub.y-co-[AS—OH].sub.z), poly(MA.sub.x-co-[AS—(O—R).sub.n—OH].sub.y-co-[MAS—OH].sub.z), poly(MMA.sub.x-co-[AS—(O—R).sub.n—OH].sub.y-co-[MAS—OH].sub.z), poly(EA.sub.x-co-[AS—(O—R).sub.n—OH].sub.y-co-[MAS—OH].sub.z), poly(EMA.sub.x-co-[AS—(O—R).sub.n—OH].sub.y-co-[MAS—OH].sub.z), poly(MA.sub.x-co-[MAS—(O—R).sub.n—OH].sub.y-co-[AS—OH].sub.z), poly(MMA.sub.x-co-[MAS—(O—R).sub.n—OH].sub.y-co-[AS—OH].sub.z), poly(EA.sub.x-co-[MAS—(O—R).sub.n—OH].sub.y-co-[AS—OH].sub.z), poly(EMA.sub.x-co-[MAS—(O—R).sub.n—OH].sub.y-co-[AS—OH].sub.z), poly(MA.sub.x-co-[MAS—(O—R).sub.n—OH].sub.y-co-[MAS—OH].sub.z), poly(MMA.sub.x-co-[MAS—(O—R).sub.n—OH].sub.y-co-[MAS—OH].sub.z), poly(EA.sub.x-co-[MAS—(O—R).sub.n—OH].sub.y-co-[MAS—OH].sub.z), or poly(EMA.sub.x-co-[MAS—(O—R).sub.n—OH].sub.y-co-[MAS—OH].sub.z); wherein MA=methyl acrylate residue (—CH[(C═O)OCH.sub.3]CH.sub.2—), MMA=methyl methacrylate residue (—C(CH.sub.3)[(C═O)OCH.sub.3]CH.sub.2—), EA=ethyl acrylate residue (—CH[(C═O)OCH.sub.2CH.sub.3]CH.sub.2—), EMA=ethyl methacrylate residue (—C(CH.sub.3)[(C═O)OCH.sub.2CH.sub.3]CH.sub.2—); AS=acrylic acid residue (—CH[(C═O)—]CH.sub.2—), MAS=methacrylic acid residue (—C(CH.sub.3)[(C═O)—]CH.sub.2—); and wherein R=—CH.sub.2(C═O)—, R=—CH(CH.sub.3)(C═O)—, R=—CH(CH.sub.2CH.sub.3)(C═O)—, R=—C(CH.sub.3).sub.2(C═O)—, R=—C(CH.sub.3)(COCH.sub.3)(C═O)—, R=—CH(Ph)(C═O)—, R=—CH[(CH.sub.2).sub.2SCH.sub.3](C═O)—, R=—CH(CH.sub.2COOH)(C═O)—, R=—CH(COOH)(C═O)—, R=—C(CH.sub.2COOH).sub.2(C═O)—, R=—CH(COOH)CH(CH.sub.2COOH)(C═O)— or R=—CH(COOH)(CHOH)(C═O)—; and wherein n is an integer with 1≤n≤20 and x, y, z denote the relative molar proportions of the monomer units with 1≤x≤20, 1≤y≤20 and 0≤z≤20.

2. A copolymer as claimed in claim 1, wherein it has the structure: poly(MA.sub.x-co-[AS—O—R—OH].sub.y-co-[AS—OH].sub.z), poly(MA.sub.x-co-[MAS—O—R—OH].sub.y-co-[MAS—OH].sub.z), poly(MMA.sub.x-co-[AS—O—R—OH].sub.y-co-[AS—OH].sub.z), poly(MMA.sub.x-co-[MAS—O—R—OH].sub.y-co-[MAS—OH].sub.z), poly(EA.sub.x-co-[AS—O—R—OH].sub.y-co-[AS—OH].sub.z), poly(EA.sub.x-co-[MAS—O—R—OH].sub.y-co-[MAS—OH].sub.z), poly(EMA.sub.x-co-[AS—O—R—OH].sub.y-co-[AS—OH].sub.z) or poly(EMA.sub.x-co-[MAS—O—R—OH].sub.y-co-[MAS—OH].sub.z).

3. A copolymer as claimed in claim 1, wherein it has the structure: poly(MA.sub.1-co-[MAS—O—R—OH].sub.1), poly(MA.sub.2-co-[MAS—O—R—OH].sub.1), poly(MA.sub.1-co-[MAS—O—R—OH].sub.2), poly(MMA.sub.1-co-[MAS—O—R—OH].sub.1), poly(MMA.sub.2-co-[MAS—O—R—OH].sub.1) or poly(MMA.sub.1-co-[MAS—O—R—OH].sub.2).

4. A copolymer as claimed in claim 1, wherein R=—CH.sub.2(C═O)— or R=—CH(CH.sub.3)(C═O)—.

5. A copolymer as claimed in claim 1, wherein it has a molar mass M.sub.w with 4000 g.Math.mol.sup.−1≤M.sub.w<500 000 g.Math.mol.sup.−.

6. A copolymer as claimed in claim 1, wherein it has a polydispersity M.sub.w/M.sub.n≤3, M.sub.w/M.sub.n≤2.5, M.sub.w/M.sub.n≤2, M.sub.w/M.sub.n≤1.8 or M.sub.w/M.sub.n≤1.6.

7. The use of a copolymer as claimed in claim 1 in a pharmaceutical formulation or for coating of tablets or capsules.

8. A process for preparing a copolymer, comprising the steps of (a) esterifying: an α-hydroxycarboxylic acid selected from the group consisting of: hydroxyethanoic acid, 2-hydroxypropanoic acid, 2-hydroxybutanoic acid, 2-hydroxyisobutanoic acid, 2-hydroxy-2-methyl-3-oxobutanoic acid, phenylhydroxyethanoic acid, 2-hydroxy-4-methylthiobutanoic acid, 2-hydroxybutane-1,4-dioic acid, 2-hydroxypropanedioic acid, 2-hydroxypropane-1,2,3-tricarboxylic acid, hydroxypropane-1,2,3-tricarboxylic acid and 2,3-dihydroxybutanedioic acid having the structure
OH—R—OH wherein R=—CH.sub.2(C═O)—, R=—CH(CH.sub.3)(C═O)—, R=—CH(CH.sub.2CH.sub.3)(C═O)—, R=—C(CH.sub.3).sub.2(C═O)—, R=—C(CH.sub.3)(COCH.sub.3)(C═O)—, R=—CH(Ph)(C═O)—, R=—CH[(CH.sub.2).sub.2SCH.sub.3](C═O)—, R=—CH(CH.sub.2COOH)(C═O)—, R=—CH(COOH)(C═O)—, R=—C(CH.sub.2COOH).sub.2(C═O)—, R=—CH(COOH)CH(CH.sub.2COOH)(C═O)— or R=—CH(COOH)(CHOH)(C═O)—; with acrylic acid ((CH.sub.2)HC—COOH) or methacrylic acid ((CH.sub.2)(CH.sub.3)C—COOH); to give a compound having the structure
Ayl-O—R—OH   (Ia) or
MAyl-O—R—OH   (IIa) wherein “Ayl”=acryloyl ((CH.sub.2)HC—CO—) and “MAyl”=methacryloyl ((CH.sub.2)(CH.sub.3)C—CO—); (b) optionally mono- or polyesterifying the compound (Ia) or (IIa) obtained in step (a) with an α-hydroxycarboxylic acid, in order to obtain a compound of the structure
Ayl-(O—R).sub.m—OH   (Ib) or
MAyl-(O—R).sub.m—OH   (IIb) wherein 2≤m≤20; (c) conjugating the compound (Ia), (Ib), (IIa) or (IIb) obtained in step (a) or (b) with a protecting group P, in order to obtain a compound of the structure
Ayl-(O—R).sub.n—OP   (Ic) or
MAyl-(O—R).sub.n—OP   (IIc) with wherein 1≤n≤20; (d) optionally conjugating acrylic acid or methacrylic acid with the protecting group P in order to obtain protected acrylic acid ((CH.sub.2)HC—COOP) or protected methacrylic acid ((CH.sub.2)(CH.sub.3)C—COOP); (e) polymerizing the compound (Ic) or (IIc) in a relative molar proportion y with an acrylate selected from the group consisting of: methyl acrylate, methyl methacrylate, ethyl acrylate and ethyl methacrylate, in a relative molar proportion x and optionally with protected acrylic acid or protected methacrylic acid in a relative molar proportion z to give a copolymer of the following type: poly(MA.sub.x-co-[AS—(O—R).sub.n—OP].sub.y-co-[AS—OP].sub.z), poly(MMA.sub.x-co-[AS—(O—R).sub.n—OP].sub.y-co-[AS—OP].sub.z), poly(EA.sub.x-co-[AS—(O—R).sub.n—OP].sub.y-co-[AS—OP].sub.z), poly(EMA.sub.x-co-[AS—(O—R).sub.n—OP].sub.y-co-[AS—OP].sub.z), poly(MA.sub.x-co-[AS—(O—R).sub.n—OP].sub.y-co-[MAS—OP].sub.z), poly(MMA.sub.x-co-[AS—(O—R).sub.n—OP].sub.y-co-[MAS—OP].sub.z), poly(EA.sub.x-co-[AS—(O—R).sub.n—OP].sub.y-co-[MAS—OP].sub.z), poly(EMA.sub.x-co-[AS—(O—R).sub.n—OP].sub.y-co-[MAS—OP].sub.z), poly(MA.sub.x-co-[MAS—(O—R).sub.n—OP].sub.y-co-[AS—OP].sub.z), poly(MMA.sub.x-co-[MAS—(O—R).sub.n—OP].sub.y-co-[AS—OP].sub.z), poly(EA.sub.x-co-[MAS—(O—R).sub.n—OP].sub.y-co[AS—OP].sub.z), poly(EMA.sub.x-co-[MAS—(O—R).sub.n—OP].sub.y-co[AS—OP].sub.z), poly(MA.sub.x-co-[MAS—(O—R).sub.n—OP].sub.y-co-[MAS—OP].sub.z), poly(MMA.sub.x-co-[MAS—(O—R).sub.n—OP].sub.y-co[MAS—OP].sub.z), poly(EA.sub.x-co-[MAS—(O—R).sub.n—OP].sub.y-co-[MAS—OP].sub.z), or poly(EMA.sub.x-co-[MAS—(O—R).sub.n—OP].sub.y-co-[MAS—OP].sub.z), wherein MA=methyl acrylate residue (—CH[(C═O)OCH.sub.3]CH.sub.2—), MMA=methyl methacrylate residue (—C(CH.sub.3)[(C═O)OCH.sub.3]CH.sub.2—), EA=ethyl acrylate residue (—CH[(C═O)OCH.sub.2CH.sub.3]CH.sub.2—), EMA=ethyl methacrylate residue (—C(CH.sub.3)[(C═O)OCH.sub.2CH.sub.3]CH.sub.2—); AS=acrylic acid residue (—CH[(C═O)—]CH.sub.2—), MAS=methacrylic acid residue (—C(CH.sub.3)[(C═O)—]CH.sub.2—); 1≤x≤20, 1≤y≤20 and 0≤z≤20;and (f) deprotecting and hydrolyzing the copolymer obtained in step (e) in order to obtain a copolymer of the following type: poly(MA.sub.x-co-[AS—(O—R).sub.n—OH].sub.y-co-[AS—OH].sub.z), poly(MMA.sub.x-co-[AS—(O—R).sub.n—OH].sub.y-co-[AS—OH].sub.z), poly(EA.sub.x-co-[AS—(O—R).sub.n—OH].sub.y-co-[AS—OH].sub.z), poly(EMA.sub.x-co-[AS—(O—R).sub.n—OH].sub.y-co-[AS—OH].sub.z), poly(MA.sub.x-co-[AS—(O—R).sub.n—OH].sub.y-co-[MAS—OH].sub.z), poly(MMA.sub.x-co-[AS—(O—R).sub.n—OH].sub.y-co-[MAS—OH].sub.z), poly(EA.sub.x-co-[AS—(O—R).sub.n—OH].sub.y-co-[MAS—OH].sub.z), poly(EMA.sub.x-co-[AS—(O—R).sub.n—OH].sub.y-co-[MAS—OH].sub.z), poly(MA.sub.x-co-[MAS—(O—R).sub.n—OH].sub.y-co-[AS—OH].sub.z), poly(MMA.sub.x-co-[MAS—(O—R).sub.n—OH].sub.y-co-[AS—OH].sub.z), poly(EA.sub.x-co-[MAS—(O—R).sub.n—OH].sub.y-co-[AS—OH].sub.z), poly(EMA.sub.x-co-[MAS—(O—R).sub.n—OH].sub.y-co-[AS—OH].sub.z) poly(MA.sub.x-co-[MAS—(O—R).sub.n—OH].sub.y-co-[MAS—OH].sub.z), poly(MMA.sub.x-co-[MAS—(O—R).sub.n—OH].sub.y-co-[MAS—OH].sub.z), poly(EA.sub.x-co-[MAS—(O—R).sub.n—OH].sub.y-co-[MAS—OH].sub.z), or poly(EMA.sub.x-co-[MAS—(O—R).sub.n—OH].sub.y-co-[MAS—OH].sub.z).

9. The process as claimed in claim 8, wherein a free-radical polymerization is performed in step (e).

10. The process as claimed in claim 8, wherein a RAFT polymerization (reversible addition fragmentation chain transfer polymerization) using a chain transfer reagent is performed in step (e).

11. The process as claimed in claim 8, wherein the deprotection and hydrolysis in step (f) is performed using a catalyst.

12. A copolymer preparable by a process as claimed in claim 8.

Description

[0392] In addition, the invention is elucidated in detail by figures. The specific figures show:

[0393] FIG. 1 an apparatus for determination of the solubility of polymers as a function of pH;

[0394] FIG. 2 the result of solubility measurements on Eudragit® L 100 and analogous polymers of the invention in diagram form;

[0395] FIG. 3 the result of solubility measurements on Eudragit® L 100-55 and analogous polymers of the invention in diagram form;

[0396] FIG. 4 the release of paracetamol from capsules coated with Eudragit® L 100 and analogous polymers;

[0397] FIG. 5 the release of paracetamol from capsules coated with Eudragit® L 100-55 and analogous polymers.

[0398] EXAMPLE 24

Solubility

[0399] FIGS. 2 and 3 show the measurement results for solubility of polymers of the Eudragit® L 100 and Eudragit® L 100-55 type by comparison with polymers of the invention in the form of diagrams. As well as the measurements represented as dots, diagrams show fitted curves that are each based on a pH-dependent function of the following type:

[00001]$f\left(pH\right)=a.Math.\left[2+\tanh \left(\frac{pH-p{K}_{1/2}}{c}\right)\right]$

[0400] with the parameters of a, pK.sub.1/2 and c to be fitted. pK.sub.1/2 corresponds here to the pH at which about 50% of the respective polymer is solvated. The diagrams further state a standard error o for each fitted curve, which is calculated as the square root of the mean square between the fitted curve and the measurements, according to the following relationship:

[00002]$\sigma =\sqrt{\frac{1}{2}\underset{i=1}{\overset{n}{.Math.}}{\left[T\left(p{H}_i\right)-f\left(p{H}_i\right)\right]}^2}$

[0401] in which T(pH.sub.i) denotes the transmission measured at pH, and n the number of measurements.

[0402] It is apparent from the measurement results for solubility that are reproduced in FIGS. 2 and 3 that the polymers of the invention are solvated at lower pH compared to Eudragit® polymers of the L 100 and L 100-55 type. For instance, at a pH of 4.5, the light transmittance of a Eudragit® L 100 suspension is less than 20%, compared to 90% to 100% for inventive polymers of the MAylO-Gly-co-MMA, MAylO-L-La-co-MMA and MAylO-D,L-La-co-MMA type. The situation is similar for Eudragit® L 100-55 and inventive polymers of the MAylO-Gly-co-EA, MAylO-L-La-co-EA and MAylO-D,L-La-co-EA type.

[0403] For comparative purposes, the inventors also synthesized, by means of free-radical polymerization, polymers analogous to Eudragit® L 100 and Eudragit® L 100-55, referred to as “L 100 analog” and “L 100-55 analog” respectively, and examined the solubility thereof. The polymers of the “L 100 analog” and “L 100-55 analog” type dissolve at slightly lower pH than the Eudragit® polymers prepared by means of anionic polymerization. The dissolution characteristics of the “L 100 analog” and “L 100-55 analog” polymers are likely to be attributable to a lower molecular weight.

EXAMPLE 25

Release of Paracetamol

[0404] FIGS. 4 and 5 show measurement results for the release of the active ingredient paracetamol from coated capsules under physiological conditions, i.e. at a temperature of 37° C., pH 2, within a time interval of 0-60 min, and pH 6.5 for the time interval of >60 min. The diagrams show discrete measurements or measurement points and fitted curves. The fitted curves are based on a function of the same type as described above in example 24, using time rather than the pH as the independent variable.

[0405] It is apparent from FIGS. 4 and 5 that paracetamol is not released at a pH of 2 within the first 60 minutes for any of the capsule coatings tested. Moreover, the measurement results show that the active ingredient paracetamol is respectively released from the capsules coated with the inventive polymers about 60 minutes and about 25 minutes earlier compared to Eudragit® L 100 and Eudragit® L 100-55. The smaller time difference of about 25 minutes in the case of release from capsules coated with MAylO-Gly-co-EA, MAylO-L-La-co-EA and MAylO-D,L-La-co-EA compared to Eudragit® L 100-55 is attributable to the fact that the polymers in question dissolve at a pH in the range from 4.0 to 4.7 (cf. example 24). By contrast, the polymers of the MAylO-Gly-co-MMA, MAylO-L-La-co-MMA and MAylO-D,L-La-co-MMA type already dissolve at a pH in the range from 3.5 to 3.7.

List of Abbreviations

[0406] The abbreviations used in the context of the present description have the meaning given below, with some of the abbreviations for copolymers between parentheses preceded by the word “poly”; for example, the abbreviations “MAylO-Gly-Bn-co-EA” and “poly(MAylO-Gly-Bn-co-EA)” refer to the same copolymer: [0407] AlBN . . . azoisobutyronitrile [0408] ATRP . . . atom transfer radical polymerization [0409] Eq. . . . equivalents [0410] AS . . . acrylic acid residue (—CH[(C═O)—]CH.sub.2—) [0411] Ayl . . . acryloyl group (CH.sub.2═CH—(C═O)—) [0412] AylO . . . acryloyloxy group (CH.sub.2═CH—(C═O)—O—) [0413] AylO-Gly-Bn . . . 2-acryloyloxyethanoate benzyl ester [0414] AylO-L-La-Bn . . . (S)-2-acryloyloxypropionate benzyl ester [0415] AylO-D,L-La-Bn . . . 2-acryloyloxypropionate benzyl ester [0416] AylO-Gly-Bn-co-EA . . . 2-acryloyloxyethanoate benzyl-ethyl acrylate copolymer [0417] AylO-L-La-Bn-co-EA . . . (S)-2-acryloyloxypropionate benzyl-ethyl acrylate copolymer [0418] AylO-D,L-La-Bn-co-EA . . . 2-acryloyloxypropionate benzyl-ethyl acrylate copolymer [0419] AylO-Gly-Bn-co-MMA . . . 2-acryloyloxyethanoate benzyl-methyl methacrylate copolymer [0420] AylO-L-La-Bn-co-MMA . . . (S)-2-acryloyloxypropionate benzyl-methyl methacrylate copolymer [0421] AylO-DfL-La-Bn-co-MMA 2-acryloyloxypropionate benzyl-methyl methacrylate copolymer [0422] BHT . . . butylhydroxytoluene [0423] CFRP . . . controlled free radical polymerization [0424] DBU . . . 1,8-diazabicyclo[5.4.0]undec-7-ene [0425] DIPC . . . diisopropylcarbodiimide [0426] D,L-La-Bn . . . 2-hydroxypropionate benzyl ester [0427] DMAP . . . 4-(N,N-dimethylamino)pyridine) [0428] DMF . . . N,N-dimethylformamide [0429] DMPA . . . 2,2-dimethoxy-2-phenylacetophenone [0430] DMSO . . . dimethyl sulfoxide [0431] EA . . . .ethyl acrylate residue (—CH[(C═O)OCH.sub.2CH.sub.3]CH.sub.2—) [0432] EMA . . . ethyl methacrylate residue (—C(CH.sub.3)[(C═0)0CH.sub.2CH.sub.3]CH.sub.2—) [0433] EtAc . . . ethyl acetate [0434] Gly-Bn . . . hydroxyethanoate benzyl ester [0435] GPC . . . gel permeation chromatography [0436] L-La-Bn . . . (S)-2-hydroxypropionate benzyl ester [0437] MA . . . .methyl aerylate residue (—CH[(C═O)OCH.sub.3]CH.sub.2—) [0438] MA-co-MMA . . . methacrylica cid-methyl methacrylate copolymer [0439] MA-co-EA . . . methacrylica cid-ethyl acrylate copolymer [0440] MAS . . . methacrylie acid residue (—C(CH.sub.3)[(C═O)—]CH.sub.2—) [0441] MAyl . . . methacryloyl-group ( CH.sub.2═C(CH.sub.3)—(C═O)—) [0442] MAylO . . . methacryloyloxy group ( CH.sub.2═C(CH.sub.3)—(C═O)—O—) [0443] MAylO-Gly-Bn . . . 2-methacryloyloxyethanoate benzyl ester [0444] MAylO-L-La-Bn . . . (S)-2-methacryloyloxypropionate benzyl ester [0445] MAylO-D,L-La-Bn . . . 2-methacryloyloxypropionate benzyl ester [0446] MAylO-Gly-Bn-co-EA . . . 2-methacryloyloxyethanoate benzyl-ethyl acrylate copolymer [0447] MAylO-L-La-Bn-co-EA . . . (S)-2-methacryloyloxypropionate benzyl-ethyl acrylate copolymer [0448] MAylO-D,L-La-Bn-co-EA . . . 2-methacryloyloxypropionate benzyl-ethyl acrylate copolymer [0449] MAylO-Gly-Bn-co-MMA . . . 2-methacryloyloxyethanoate benzyl-methyl methacrylate copolymer [0450] MAylO-L-La-Bn-co-MMA (S)-2-methacryloyloxypropionate benzyl-methyl methacrylate copolymer [0451] MAylO-D,L-La-Bn-co-MMA . . . 2-methacryloyloxypropionate benzyl-methyl methacrylate copolymer [0452] MMA . . . methyl methacrylate residue (—C(CH.sub.3)[(C═O)OCH.sub.3]CH.sub.2—) [0453] RAFT . . . reversible addition fragmentation chain transfer polymerization

[0454] In the context of the present invention, the term “radical polymerization” encompasses methods such as free-radical polymerization, controlled free radical polymerization (CFRP), reversible addition fragmentation chain transfer polymerization (RAFT) and atom transfer radical polymerization (ATRP).

[0455] The copolymers of the invention may be either random copolymers or block copolymers. Accordingly, the IUPAC-conformant term “-co-” in the polymer structural formulae of the present invention includes the IUPAC-conformant terms “-stat-” and “-block-”.

Test Methods

[0456] In the context of the present invention, weights and weight distributions of the copolymers produced are determined by means of gel permeation chromatography (GPC or SEC) in dimethylformamide (DMF) at a temperature in the range from 25 to 30° C., standard pressure (985-1010 hPa) and typical humidity (40-100% rH) (source: measurement station of the Institute for Atmospheric Physics, Johannes Gutenberg University of Mainz).

[0457] All chemicals and solvents, unless stated otherwise, were sourced from commercial suppliers (Acros, Sigma-Aldrich, Fisher Scientific, Fluka, Riedel-de-Haën, Roth) and—apart from the drying of the solvents and monomers—used without further purification. Deuterated solvents were sourced from Deutero GmbH (Kastellaun, Germany).

Gel Permeation Chromatography (GPC or SEC)

[0458] GPC or SEC measurements were conducted according to DIN 55672-3 2016-01 at a temperature of 25 to 30° C. on an Agilent 1100 HPLC system with refractive index detector (Agilent 2160 Infinity RI detector), UV detector (275 nm), online viscometer and an SDV column set (SDV 103, SDV 105, SDV 106) from Polymer Standard Service GmbH (referred to hereinafter as PSS). Dimethylformamide (DMF) was used as solvent for the polymers to be analyzed and as eluent at a volume flow rate of 1 mL.Math.min.sup.−1. The polymers to be analyzed, having been dissolved in DMF, were injected into the GPC column by means of a Waters 717 plus autosampler. Calibration was effected using polystyrene standards from PSS. The elugrams were evaluated with the aid of the PSS WinGPC Unity software from PSS.

NMR Spectroscopy

[0459] .sup.1H and .sup.13C NMR spectra were recorded on an Avance II 400 (400 MHz, 5 mm BBFO head with z gradient and ATM) from Bruker, with a frequency of 400 MHz (.sup.1H) or 101 MHz (.sup.13C). For kinetic in situ .sup.1H NMR measurements, a Bruker Avance III HD 400 spectrometer equipped with a 5 mm BBFO SmartProbe sensor (Z gradient probe), ATM and SampleXPress 60 autosampler was used. Chemical shifts are reported in ppm and are based on the proton signal of the deuterated solvent.

Solubility and Active Ingredient Release

[0460] The solubility of inventive and known polymers of the Eudragit® class is determined by means of optical transmittance measurements at a temperature of 37° C. For this purpose, the polymer to be examined in each case is dissolved or suspended in a concentration of 5 mg/mL in a basic NaOH-buffered bath, and the pH is lowered stepwise by means of titration of 0.1 M HCl solution. As the pH is lowered, the polymer is protonated and precipitates out, which scatters and attenuates the light.

[0461] The apparatus used for the measurement of solubility is shown in schematic form in FIG. 1. The polymer solution or suspension is in a glass vessel closed with a lid and heated to 37° C. by means of Peltier elements. A magnetic stirrer is disposed in the glass vessel, i.e. in the polymer suspension, which is rotated by means of a magnetic drive. A light beam emitted by a light source passes through the walls of the glass vessel and the polymer suspension between them, and hits a photoelectric sensor, for example a photodiode, with which the intensity of the light beam transmitted is measured. The apparatus further comprises a reservoir vessel (not shown in FIG. 1) for HCl, which is connected via a conduit to the interior of the glass vessel. Disposed in the conduit is a metering or titration valve (not shown in FIG. 1) with which the amount of HCl supplied to the polymer suspension per unit time is controlled. The optical measurement of transmittance is conducted with the aid of a Jasco V-640 spectrophotometer.

[0462] In addition, paracetamol-containing capsules are coated with inventive polymers and Eudragit® L 100 and Eudragit® L 100-55, and the release of paracetamol is examined with simulation of the physiological conditions in the gastrointestinal tract. The apparatus used for the simulation—as obtainable, for example, from Erweka GmbH—corresponds to apparatus 1 in the European Pharmacopoeia. At given times, fixed, negligibly small amounts of liquid compared to the contents of the test vessel are withdrawn, and the paracetamol concentration is determined photometrically at a wavelength of 243 nm.

[0463] Multiple paracetamol-containing capsules of identical form are respectively coated with a coating of Eudragit® L 100 and Eudragit® L 100-55 and the inventive polymers of the MAylO-Gly-co-MMA, MAylO-L-La-co-MMA, MAylO-D,L-La-co-MMA, MAylO-Gly-co-EA, MAylO-L-La-co-EA and MAylO-D,L-La-co-EA type. In the course of a test series, the viscosity of the respective polymer solution is adjusted such that the weight per unit area of the coating or the increase in weight of the capsules as a result of the coating conforms to an accuracy of ±3 %.

[0464] 3 to 4 capsules coated with one of the polymers to be examined in each case are introduced into 900 mL of a test solution having a pH of 2. Over a period of 60 minutes, the test solution containing the capsules is stirred while retaining the pH of 2 and a temperature of 37° C., in order to simulate the acidic environment of the stomach. Subsequently, the pH is raised to 6.5 by replacing the test solution with phosphate buffer.