PHENPROCOUMON TTS

Abstract

The present invention relates to a transdermal therapeutic system for the cutaneous administration of phenprocoumon, comprising an active-substance-impermeable backing layer, an adhesive matrix layer and optionally a removable protective layer, the adhesive matrix layer containing phenprocoumon and at least one matrix polymer, and the content of phenprocoumon in the matrix polymer being ≤7.5 wt. %. By virtue of the low load, it is ensured that the system releases the active ingredient substantially in high release rates, because high thermodynamic activity of the active ingredient is achieved. The present invention also relates to a method for producing a corresponding transdermal therapeutic system.

Claims

1. A transdermal therapeutic system for the cutaneous administration of phenprocoumon, comprising an active-substance-impermeable backing layer, an adhesive matrix layer and optionally a removable protective layer, characterised in that the adhesive matrix layer contains phenprocoumon with a content ≤12% by weight and at least one matrix polymer.

2-15. (canceled)

16. A transdermal therapeutic system for the cutaneous administration of phenprocoumon, comprising an active-substance-impermeable backing layer, an adhesive matrix layer and optionally a removable protective layer, characterised in that the adhesive matrix layer contains phenprocoumon with a content of 0.5 to ≤12% by weight and at least one matrix polymer, and in that the matrix polymer consists of neutral polymers.

17. The transdermal therapeutic system according to claim 16, characterised in that the content of phenprocoumon in the matrix polymer is 0.5 to 7.5% by weight.

18. The transdermal therapeutic system according to claim 16, characterised in that the phenprocoumon is present dissolved in the matrix polymer.

19. The transdermal therapeutic system according to claim 16, characterised in that the matrix polymer comprises or consists of linear styrene-butadiene-styrene block copolymer or styrene-isoprene-styrene block copolymer.

20. The transdermal therapeutic system according to claim 16, characterised in that the matrix polymer contains or consists of self-crosslinking or non-self-crosslinking acrylate copolymer.

21. The transdermal therapeutic system according to claim 16, characterised in that the matrix polymer contains or consists of polyisobutylene or polybutylene and polyisobutylene.

22. The transdermal therapeutic system according to claim 16, characterised in that the matrix polymer contains or consists of polyvinylpyrrolidone or polyvinyl alcohol.

23. The transdermal therapeutic system according to claim 16, characterised in that the matrix polymer contains or consists of polysiloxane.

24. The transdermal therapeutic system according to claim 16, characterised in that the active-substance-impermeable backing layer is constructed from a composite material and comprises an aluminised film.

25. The transdermal therapeutic system according to claim 16, characterised in that it is designed for an application time of at least 24 hours.

26. The transdermal therapeutic system according to claim 16, characterised in that it is designed to deliver a daily dose of phenprocoumon of about 0.5 to 10 mg.

27. The transdermal therapeutic system according to claim 16 for therapeutic or preventive treatment of vaso-occlusive blood clots, thrombosis or atrial fibrillation.

28. The transdermal therapeutic system according to claim 16 for therapeutic or preventive treatment of patients after implantation of artificial heart valves and/or heart support systems and/or artificial vascular bypasses.

29. A method for producing a transdermal therapeutic system according to claim 16, characterised by the following steps: applying a solution comprising the matrix polymer, phenprocoumon and at least one pharmaceutically acceptable solvent to a removable protective layer, drying the solution with formation of an adhesive matrix layer, and applying an active-substance-impermeable backing layer to the adhesive matrix layer.

30. The transdermal therapeutic system according to claim 16, characterised in that the content of phenprocoumon in the matrix polymer is 2.5 to 7.3% by weight.

31. The transdermal therapeutic system according to claim 16, characterised in that the matrix polymer contains or consists of a terpolymer of 2-ethylhexyl acrylate, vinyl acetate and 2-hydroxyl ethyl acrylate.

32. The transdermal therapeutic system according to claim 16, characterised in that it is designed to deliver a daily dose of phenprocoumon of about 1 to 5 mg.

33. The transdermal therapeutic system according to claim 16 for therapeutic or preventive treatment of long-term thrombosis prophylaxis.

Description

EXAMPLE 1: DETERMINATION OF THE SATURATION CONCENTRATION C.SUB.S .OF PHENPROCOUMON IN VARIOUS POLYMERS

[0054] The saturation concentration C.sub.s of phenprocoumon was determined in various polymer matrices according to the method of Liu (Liu, P., Gargiulo, P., Wong, J., and Novartis (1997). A Novel Method for Measuring Solubility of a Drug in an Adhesive. Pharmaceutical Research 14, p. 317).

[0055] In this method, known among experts as the “sandwich” method, the saturation concentration is determined as follows:

[0056] A laminate is built up with the following sequence of layers: protective film—donor layer with active substance (dissolved and undissolved)—active-substance-permeable membrane—acceptor layer without active substance—protective film. The two protective films consist of identical material; the matrix material of the donor layer and acceptor layer is also identical.

[0057] The donor layer is prepared by dissolving the active substance in a solution of the polymer in organic solvent. In this process, the concentration of the active substance must be chosen to be high enough that an undissolved residue is visible in the polymer matrix, so that the saturation concentration C.sub.s in the donor layer is safely exceeded. This solution is spread on the protective film and the process solvent is evaporated. Then, the adhesive surface of the donor layer is covered with the membrane. The membrane used is a dialysis tube made of regenerated cellulose (ZelluTrans, from Roth, 46 mm flat width), which has been cut open lengthwise. The acceptor layer is produced analogously to the donor layer without active substance and is applied to the other side of the membrane.

[0058] The laminates produced in this way are then stored at room temperature for 7 days, during which diffusion of the active substance through the membrane into the acceptor layer occurs. Subsequently, the active substance concentration in the donor layer is determined. For this purpose, aliquots of approx. 1 cm.sup.2 are punched using a punching tool with a standardised surface area. The membrane is then removed, the punched pieces without membrane are weighed, and their weight is documented (m.sub.1). Then, the punched pieces are placed in organic solvent to dissolve the matrices. The backing layers are removed, washed and dried and their weight (m.sub.2) is determined. From both measured values, the weight of the polymer portion of the acceptor layer m.sub.3 is obtained as follows:

m.sub.3=m.sub.1−m.sub.2

[0059] Subsequently, the concentration of phenprocoumon is determined in the solution using HPLC, and its concentration in the donor layer is calculated. The saturation concentrations of phenprocoumon in different polymer matrices determined according to this experimental approach are summarised in Table 1:

TABLE-US-00001 TABLE 1 C.sub.s of phenprocoumon in different polymer matrices Polymer C.sub.s of Solvent used phenprocoumon to dissolve [%] the polymer Polyisobutylene 2.8 Toluene Styrene-isoprene-styrene block copolymer 3.9 Toluene Acrylate copolymer of 2-ethylhexyl 6.11 Ethyl acetate acrylate, vinyl acetate and 2-hydroxyl ethyl acrylate Acrylic copolymer of 2- 7.26 Ethyl acetate ethylhexyl acrylate, butyl acrylate, vinyl acetate, acrylic acid Polysiloxane 0.3 Ethyl acetate

[0060] Table 1 shows that the saturation concentration C.sub.s of phenprocoumon in neutral polymers is about >5%. Slightly higher saturation concentrations were determined in acidic polymers, which can be explained by the vinylogous acid group of the active substance. A especially low C.sub.s of phenprocoumon was measured in polysiloxane.

EXAMPLE 2: PRODUCTION OF PHENPROCOUMON TTS

[0061] Transdermal therapeutic systems based on different base polymers were produced:

[0062] a) TTS with Polyisobutylene (PIB)

[0063] Production of Polyisobutylene Solution

[0064] 50 g each of Oppanol B 10 and Oppanol B 100 are dissolved in 250 g toluene with stirring for several days. 350 g of a solution with 28.6% solids are obtained.

[0065] Production of Samples 1, 2 and 3

[0066] In each 100 g of the produced polyisobutylene solution, 0.6 g, 0.9 g and 1.2 g phenprocoumon, respectively, are sprinkled in with stirring; stirring is continued for several hours until the solids are completely dissolved. These three solutions are spread using an Erikson squeegee onto a siliconised 100 μm PET film (Mitsubishi RN 100). After evaporation of the toluene, the basis weight is about 90 g/m.sup.2. The phenprocoumon concentration in sample 1 is about 2%, that in sample 2 is about 3%, and that in sample 3 is about 4%.

[0067] b) TTS with Styrene-Isoprene-Styrene (SIS)

[0068] Production of Styrene-Isoprene-Styrene Block Copolymer Solution

[0069] 95 g styrene-isoprene-styrene block copolymer and 5 g abietyl alcohol are dissolved in 250 g toluene by stirring for several days. 350 g of a solution with 28.6% solids are obtained. Since styrene-isoprene-styrene block copolymer is not adhesive, abietyl alcohol is added as a tackifying resin.

[0070] Production of Samples 4, 5 and 6

[0071] In each 100 g of the produced styrene-isoprene-styrene block copolymer solution, 0.8 g, 1.2 g and 1.5 g phenprocoumon, respectively, are sprinkled with stirring; stirring is continued for several hours until the solids are completely dissolved. These three solutions are spread using an Erikson squeegee onto a siliconised 100 μm PET film (Mitsubishi RN 100). After evaporation of the toluene, the basis weight is about 90 g/m.sup.2. The phenprocoumon concentration in sample 4 is about 2.7%, that in sample 5 is about 4%, and that in sample 6 is about 5%.

[0072] c) TTS with Polyacrylates

[0073] Polyacrylates used as medical adhesives can be obtained commercially as solutions in organic solvents. For samples 7 to 9, the trade products from Henkel, Durotak 87-4287—a neutral acrylate copolymer of 2-ethylhexyl acrylate, vinyl acetate and 2-hydroxyl ethyl acrylate in ethyl acetate (39% solids content)—and Durotak 387-2051, an acidic acrylate copolymer of 2-ethylhexyl acrylate, butyl acrylate, vinyl acetate, acrylic acid in ethyl acetate/n-heptane (51.5% solids content) was used as a reference.

[0074] TTS in Neutral Polyacrylate Samples 7, 8 and 9

[0075] In each 100 g of Durotak 87-4287, 2 g, 3 g and 4 g phenprocoumon, respectively, are sprinkled with stirring; stirring is continued for several hours until the solids are completely dissolved. These three solutions are spread using an Erikson squeegee onto a siliconised 100 μm PET film (Mitsubishi RN 100). After evaporation of the solvent, the basis weight is about 60 g/m.sup.2. The phenprocoumon concentration in sample 7 is about 4.9%, that in sample 8 is about 7.1%, and that in sample 9 is about 9.3%.

[0076] TTS in Acid Polyacrylate Samples 10, 11 and 12

[0077] In each 100 g of Durotak 387-2051, 2 g, 4 g and 6 g phenprocoumon, respectively, are sprinkled with stirring; stirring is continued for several hours until the solids are completely dissolved. These three solutions are spread using an Erikson squeegee onto a siliconised 100 μm PET film (Mitsubishi RN 100). After evaporation of the solvent, the basis weight is about 90 g/m.sup.2. The phenprocoumon concentration in sample 7 is about 3.8%, that in sample 11 is about 7.2%, and that in sample 12 is about 10.4%.

[0078] d) TTS in Polysiloxane

[0079] Production of the Solution of Polysiloxane in Toluene

[0080] Phenprocoumon is sufficiently soluble in aromatic hydrocarbons, but not in n-heptane. Since toluene polysiloxane solution is not commercially available, BIO PSA 4201 from Dow Chemicals (polysiloxane in n-heptane) was used as starting material. The solvent was evaporated off and the rubbery polymeric residue was dissolved with enough toluene to obtain a solution with approx. 75% solids.

[0081] Production of Samples 13, 14 and 15

[0082] In each 100 g of the produced polysiloxane solution, 0.25 g, 0.5 g and 1 g phenprocoumon, respectively, are sprinkled with stirring; stirring is continued for several hours until the solids are completely dissolved. These three solutions are spread using an Erikson squeegee onto a siliconised 100 μm PET film (Mitsubishi RN 100). After evaporation of the toluene, the basis weight is about 90 g/m.sup.2. The phenprocoumon concentration in sample 13 is about 0.33%, that in sample 14 is about 0.66%, and that in sample 15 is about 1.3%.

[0083] Crystallisation of the active substance occurred in samples 14 and 15.

[0084] Permeation Results

[0085] Permeation experiments were carried out with samples 1 to 15 in a Franz cell with human skin. The experimental parameters are summarised in Table 2.

TABLE-US-00002 TABLE 2 Test parameters for in vitro permeation Permeation time Permeation Punched Acceptor Water bath Thickness of the area part area medium temperature skin About 1.6 cm.sup.2 1.16 10 ml 32° C. 24 hours/ physiological Approx. 500 μm saline solution

[0086] Table 3 shows the results of the permeation studies, the absolute contents of phenprocoumon and the active substance utilisation.

TABLE-US-00003 TABLE 3 Mean (x out of n = 6) phenprocoumon flux, measured on human skin 500 pm in Franz cells over 24 hours. Content of Sample phenprocouman Cumulative flux in 24 h Active substance No./Polymer [mg/1.16 cm.sup.2] [mg/24] utilisation [%] 1 PIB 0.14 0.006 4.3 2* PIB 0.21 0.063 30 3 PIB 0.28 0.071 25 4 SIS 0.19 0.003 1.6 5* SIS 0.28 0.057 20 6 SIS 0.35 0.066 19 7 neutral PA 0.34 0.008 2.4 8* neutral PA 0.49 0.073 14.9 9 neutral PA 0.68 0.086 12.6 10 acidic PA 0.4 0.008 2 11 * acidic PA 0.75 0.054 7.2 12 acidic PA 1.09 0.063 5.8 13*Polysiloxane 0.04 0.009 22.5 14 Polysiloxane 0.07 0.026 37.1 15 Polysiloxane 0.13 0.039 36.2 * Phenprocoumon concentration close to the saturation concentration C.sub.s Flux rates around about 0.065 mg/1.16 × 24 h enable TTS with an area of about 40 cm.sup.2, which is of significant advantage for patient compliance.

[0087] Table 3 shows that the use of neutral polymer TTS with active areas around 40 cm.sup.2 makes phenprocoumon available transdermally, with the application of one TTS/day, in daily doses corresponding to the oral daily doses. Patterns 2, 3, 5, 6, 8 and 9 are especially suitable.

[0088] With sample 12, a TTS with an area of about 40 cm.sup.2 can indeed also be obtained, but the active substance utilisation is low at just <6%.