PROCESS FOR PREPARING PRESSURE SENSITIVE ADHESIVE COMPOUNDS FOR USE IN A TRANSDERMAL THERAPEUTIC SYSTEM

Abstract

The invention relates to a process for preparing an active-principle-containing adhesive formulation for use in a transdermal therapeutic system, comprising the following steps: a) providing an adhesive formulation containing a carboxylic acid ester-based solvent and a self-adhesive polymer matrix containing monomers of the compounds on which the polymer matrix is based, b) removing the carboxylic acid ester-based solvent and the monomers from the adhesive formulation, c) re-dissolving the compound obtained in step b) in an organic solvent that does not contain any ester groups, and adding a pharmacologically active principle having at least one hydroxyl group, carboxyl group, amino group and/or ester group so that the active-principle-containing adhesive formulation is obtained. The invention also relates to a transdermal therapeutic system containing the active-principle-containing adhesive formulation. The invention further relates to the use of said transdermal therapeutic system and to a kit containing the transdermal therapeutic system.

Claims

1. A process for producing an active-ingredient-containing adhesive formulation for use in a transdermal therapeutic system, comprising the following steps: a) providing an adhesive formulation comprising a carboxylic ester-based solvent and a pressure-sensitive adhesive polymer matrix which comprises monomers of the compounds on which the polymer matrix is based, b) removing the carboxylic ester-based solvent and the monomers from the adhesive formulation to obtain a composition, and c) redissolving the composition obtained in step b) in an organic solvent which contains no ester groups, and adding a pharmacologically active ingredient which has at least one hydroxyl group, carboxyl group, amino group and/or ester group, to give the active-ingredient-containing adhesive formulation.

2. The process as claimed in claim 1, wherein the carboxylic ester-based solvent is selected from methyl acetate, ethyl acetate or butyl acetate.

3. The process as claimed in claim 1, wherein residual contents of the carboxylic ester-based solvent and/or of the monomers after this-step b) independently of one another are each <1.0 wt %, based on the composition obtained in step b), preferably <0.5 wt %.

4. The process as claimed in claim 1, wherein the organic solvent is tetrahydrofuran, methanol, isopropanol, n-heptane, hexane, toluene, methyl ethyl ketone, or ethanol.

5. The process as claimed in claim 1, wherein the polymer matrix is selected from acrylates, pressure-sensitive silicone adhesives, polyisobutylene, SIS copolymers, silicone-acrylate hybrid systems, or mixtures thereof.

6. The process as claimed in claim 5, wherein the polymer matrix has side chains with hydroxyl and/or carboxyl groups.

7. The process as claimed in claim 1, wherein the pharmacologically active ingredient is selected from fingolimod, ozanimod, teriflunomide, baclofen, or cladribine.

8. The process as claimed in claim 1, wherein at least one additive is added in step c).

9. The process as claimed in claim 8, which further comprises adding a solubilizer for the active ingredient, wherein the solubilizer for the active ingredient is a polymer different from the polymer matrix.

10. A transdermal therapeutic system comprising a carrier coated over very largely its full area with an active-ingredient-containing adhesive formulation produced by a process as claimed in claim 1, and optionally a protective film which, after the organic solvent has been removed from the layer of the active-ingredient-containing adhesive formulation, is applied over very largely the full area of this layer.

11. A process for producing a transdermal therapeutic system, comprising the steps of a) applying an active-ingredient-containing adhesive formulation produced by a process as claimed in claim 1 to a carrier, to give a layer covering very largely the full area of the carrier, b) removing the organic solvent, and c) optionally applying a protective film on a side of the layer applied in step a) that is remote from the carrier, with the protective film covering very largely the full area of the layer.

12. A method for the purpose of treatment of hypogonadism, for hormone replacement therapy, for the treatment of Alzheimer's, of Parkinson's, of Multiple Sclerosis, of bipolar disorders, of muscle strains, of pain, of hypertension, or for contraception, in a patient in need thereof, said method comprising (A) providing a transdermal therapeutic system as claimed in claim 10, wherein the pharmacologically active ingredient is effective for said purpose, and (B) applying said transdermal therapeutic system to the skin of said patient.

13. The method as claimed in claim 12, wherein fingolimod is the pharmacologically active ingredient and the transdermal therapeutic system is applied for the purpose of treatment of Multiple Sclerosis or of diseases treated by immunosuppression.

14. A kit comprising a transdermal therapeutic system as claimed in claim 10 in an outer packaging and optionally usage instructions for the use of the transdermal therapeutic system.

15. The process as claimed in claim 2, wherein the carboxylic ester-based solvent is ethyl acetate.

16. The process as claimed in claim 3, wherein residual contents of the carboxylic ester-based solvent and/or of the monomers after this step b) independently of one another are each <0.5 wt %, based on the composition obtained in step b).

17. The process as claimed in claim 5, wherein the polymer matrix comprises a copolymer of 2-ethylhexyl acrylate, glycidyl methacrylate, 2-hydroxyethyl acrylate and/or vinyl acetate.

18. The process as claimed in claim 7, wherein the pharmacologically active ingredient is fingolimod.

19. The process as claimed in claim 8, wherein the additive comprises a solubilizer for the active ingredient in the polymer matrix, a penetration enhancer, an antioxidant, a plasticizer, a bond strength enhancer, crosslinkers, or a mixture of these.

20. The process as claimed in claim 9, wherein the polymer different from the polymer matrix is polyvinylpyrrolidone.

Description

EXAMPLES

[0055] The present invention is elucidated further by means of the examples below, but without being limited to them.

[0056] Various adhesive formulations were produced, using different commercially available pressure-sensitive adhesives (PSAs).

TABLE-US-00001 TABLE 1 Commercially available PSAs used Polymer Contains Trade- containing Functional vinyl Solvent in PSA name as monomers groups acetate the PSA 1 Durotak 2-ethylhexyl acrylate, OH groups Yes Ethyl 387-2287 vinyl acrylate acetate 2-hydroxyethyl acrylate glycidyl methacrylate 2 Durotak 2-ethylhexyl acrylate, OH groups Yes Ethyl 87-4287 vinyl acrylate acetate 2-hydroxyethyl acrylate

[0057] PSAs 1 and 2 are suitable for TTS which are worn on the skin for at least 7 days.

[0058] Production of the Adhesive Formulations of the Invention

[0059] The commercially available PSAs stated above were coated out onto siliconized films and the resulting laminates were dried at room temperature for 15 minutes and thereafter at 60° C. for 10 minutes. After drying, the dried PSAs were removed from the films and redissolved in an organic solvent which contains no ester groups, and 3 wt %, based on the total mass of the dried PSA, of pharmacologically active ingredient, and also, optionally, 10 wt % of polyvinylpyrrolidone, were added. After the resulting compositions had been homogenized, they were coated out onto siliconized films to give a laminate. The laminates were dried at room temperature for 15 minutes and thereafter at 60° C. for 10 minutes, to give an adhesive formulation. The respective composition of the TTS of the invention is reported in table 2.

TABLE-US-00002 TABLE 2 Composition of the adhesive formulations of the invention Solvent for the Inventive Pharm. act. Polyvinyl- redissolution ex. PSA Ingredient pyrrolidone after drying 1 1 Fingolimod No Ethanol 2 1 Fingolimod Yes Tetrahydrofuran 3 2 Fingolimod Yes Tetrahydrofuran

TABLE-US-00003 TABLE 3 Visual assessment of the compositions of the invention after addition of the active ingredient and second drying Appearance of the Inventive composition before Appearance of ex. coating out Viscosity the laminate 1 Homogeneous, cloudy, Highly viscous Homogeneous, cloudy milky 2 Homogenous, cloudy Moderately Crystals perceptible, viscous cloudy 3 Homogenous, cloudy Highly viscous Crystals perceptible, cloudy

[0060] Production of the Reference Examples

[0061] The commercially available PSAs were admixed with in each case 3 wt %, based on the total mass of the PSA, of pharmacologically active ingredient, and also, in some cases, 10 wt % of polyvinylpyrrolidone. Following homogenization of the resultant compositions, they were coated out onto siliconized films to give a laminate. The laminates were dried at room temperature for 15 minutes and thereafter at 60° C. for 10 minutes, to give an adhesive formulation.

TABLE-US-00004 TABLE 4 Composition of reference examples Reference Pharm. act. Polyvinyl- ex. PSA ingredient pyrrolidone 2a 1 Fingolimod No 3a 1 Fingolimod Yes 4a 2 Fingolimod Yes

[0062] Investigation of the Adhesive Formulations Obtained

[0063] The fraction of pharmacologically active ingredient in the laminates obtained was extracted using an acidified methanol (1 vol % of conc. nitric acid in methanol). The extracts were diluted with a phosphate buffer, pH 2.5, and then analyzed by means of HPLC gradient elution on a C8 phase with diode array detection at 220 nm. The eluents used were the following mixtures:

[0064] Eluent A: 0.01-M KH.sub.2PO.sub.4:acetonitrile (80:20, v/v), 0.1% triethylamine, pH 2.5

[0065] Eluent B: 0.01-M KH.sub.2PO.sub.4:acetonitrile (20:80, v/v), 0.05% triethylamine, pH 2.5

[0066] Gradient profile: t[min]/B[%]: 0/35, 6/37, 8/40, 12/55, 18/100, 22/100, 24/35, 28/35

[0067] Quantification took place on a calibration plot drawn up using fingolimod reference material (external standard).

[0068] Table 5 below reports the fraction of fingolimod and any degradation products or byproducts of the fingolimod found in the adhesive formulations. Byproducts reported were degradation products and byproducts of the active ingredient whose UV spectrum is similar to that of fingolimod. To identify the byproducts, LC/MS and LCMS/MS were carried out on 1:1 mixtures of fingolimod with ethyl acetate and, respectively, with vinyl acetate in solution in methanol, and structural resolutions were conducted, resulting in the following byproducts: [0069] acetamide of fingolimod, or acetyl-fingolimod (both have the same molar mass of M=350, it therefore not being known which of the two reaction products is present), [0070] vinyl-fingolimod, M=334, and [0071] reaction product of fingolimod with 2 vinyl groups, M=360.

[0072] The percentages >100% derive firstly from a measurement inaccuracy of ±2% and secondly from the fact that inaccuracies of 1-2% in relation to the amount of fingolimod may occur when the adhesive formulations are produced on the laboratory scale.

TABLE-US-00005 TABLE 5 Fraction of fingolimod and any degradation products or byproducts of fingolimod in the adhesive formulations obtained Fraction of Byproducts of fingolimod fingolimod [%] [%] Inventive 1 102 0.3 Reference 1a 98 2.0 Inventive 2 99 0.7 Reference 2a 98 2.0 Inventive 3 103 0.4 Reference 3a 97 1.2 [%] based on amounts of fingolimod added

[0073] The adhesive formulations of the invention had a higher fraction of fingolimod than those of the reference examples. Furthermore, the fraction of byproducts resulting from reactions of fingolimod with solvents or residual monomers from the commercially available PSAs is significantly reduced for the adhesive formulations of the invention. From the results, therefore, it is apparent that the removal of the residual monomers, in this case vinyl acetate, and of the solvent, in this case ethyl acetate, from the commercially available adhesives means that these compounds are no longer available as reaction partners for the active ingredient, presently fingolimod, and therefore that a higher recovery rate of the active ingredient in the adhesive formulations, and also a smaller fraction of byproducts, are detectable. The results thus show that in the case of the adhesive formulations of the invention, the availability of the ingredient is higher than with commercially available, known PSAs.

[0074] Aging Behavior of PSAs Containing Ethyl Acetate and Vinyl Acetate

[0075] In order to show that the residual monomers and solvents contained in the commercially available PSAs react with the active ingredient fingolimod and contribute to a reduced availability of the active ingredient after storage, LC/MS and LCMS/MS were carried out on 1:1 mixtures of fingolimod with ethyl acetate, or with vinyl acetate, in solution in methanol, and the formulation of reaction products of fingolimod with ethyl acetate and vinyl acetate, and also of the decomposition products of fingolimod, was investigated. Storage took place under laboratory conditions at room temperature.

TABLE-US-00006 TABLE 6 Reaction products of the active ingredient with residual monomers or solvent after storage Number of byproducts with a Fingolimod Age of fraction > 0.2% Sum total of with sample in the solution all byproducts Vinyl acetate 2 days 8 around 57% Vinyl acetate 1 month 16 around 44% Ethyl acetate 2 days 3 around 15%

[0076] Just 2 days after production, a multiplicity of decomposition products and reaction products of fingolimod with the compounds contained as residual monomers or solvents in commercially available PSAs were perceptible. In particular the concentration of a number of reaction products, at >0.2%, was very high.

[0077] The results of investigation on the fingolimod/vinyl acetate solution showed that further byproducts form after one month, but with no rise in the overall concentration of byproducts. When interpreting the test results after 1 month of storage, however, it should be borne in mind that probably not all of the compounds could be detected, since their structure is possibly not known to the HPLC-FLD detector.