OVER-PATCH HAVING IMPROVED COMPATIBILITY AND A LONG ADHESION DURATION AND METHOD FOR PRODUCING SAID OVER-PATCH

Abstract

The invention relates to a medical product for a fastening duration of at least 7 days having good skin compatibility. The medical product includes a central adhesive compartment (3) and an over-patch. The over-patch is free of active ingredients and is formed from a water-vapor-permeable back layer (1) and an adhesive polymer layer (2) that is free of active ingredients. The invention further relates to a method for the production of the foregoing medical product, and to kits of parts containing laminates of layers 1 and 2.

Claims

1. A transdermal therapeutic system (TTS) comprising (1) a central compartment and (2) a pressure-sensitive, active-ingredient-free overplaster, wherein said central compartment is pressure-sensitively adhered to a releasable release liner such that said central compartment can be applied directly to the skin after removal of said releasable release liner, wherein said central compartment comprises a) at least one pressure-sensitive, active-ingredient-containing polymer layer which can be applied directly to the skin after removal of the releasable release liner, and (b) a separating layer which covers the active-ingredient-containing polymer layer such that said separating layer is in contact with said active-ingredient-containing polymer layer on one side and in contact with said pressure-sensitive, active-ingredient-free polymer layer on its opposite side; and wherein said overplaster comprises a) a water vapor-permeable backing layer and b) a pressure-sensitive, active-ingredient-free polymer layer, and the overplaster fixes the central compartment and overhangs the central compartment on all sides and the active-ingredient-free polymer layer comprises non-amine-resistant, highly water vapor-permeable polysiloxanes, polyacrylates or vinyl acetate-acrylate copolymers without free acid groups or with an acid number of less than 1, styrene-isoprene-styrene block copolymers present in combination with at least one of hydrogenated hydrocarbon resins and oils, or styrene-butadiene-styrene block copolymers present in combination with at least one of hydrogenated hydrocarbon resins and oils.

2. The transdermal therapeutic system as claimed in claim 1, wherein the active-ingredient-free polymer layer further comprises at least 0.16% (w/w) of a neutral oil as compatibilizer, based on the layer dry weight.

3. The transdermal therapeutic system as claimed in claim 1, wherein the active-ingredient-free polymer layer comprises 0.5 to 5% (w/w) of dexpanthenol, based on the layer dry weight.

4. The transdermal therapeutic system as claimed in claim 1, wherein the active-ingredient-free polymer layer comprises non-amine-resistant polysiloxane polymers in which, after polycondensation of a resin fraction and polydimethylsiloxanol groups, remaining silanol groups that are still free have not been capped by methyl groups.

5. The transdermal therapeutic system as claimed in claim 1, wherein the active-ingredient-free polymer layer further comprises silicone oil, and the concentration of said silicone oil is 0 to 4% (w/w) based on the layer dry weight.

6. The transdermal therapeutic system as claimed in claim 1, wherein the backing layer comprises a bidirectional elastic fabric permeable to water vapor.

7. The transdermal therapeutic system as claimed in claim 6, wherein the fabric is a polyester fabric.

8. The transdermal therapeutic system as claimed in claim 1, wherein said transdermal therapeutic system further comprises said active-ingredient-free overplaster placed next to said active-ingredient-containing polymer layer thereby preventing the crystallization of the active ingredient/ingredients in the active-ingredient-containing polymer layer.

9. The transdermal therapeutic system as claimed in claim 1, wherein said transdermal therapeutic system further comprises said active-ingredient-free overplaster placed next to said active-ingredient-containing polymer layer such that said active-ingredient-free overplaster reduces the cold flow of the transdermal therapeutic system.

10. The transdermal therapeutic system as claimed in claim 1, wherein the oil is liquid paraffin.

11. A method for producing a transdermal therapeutic system as claimed in claim 1, said method comprising producing the central compartment and lining a skin-side adhesive face of said central compartment with a releasable release liner which protrudes on all sides by at least 4 mm, selecting a polymer from the group consisting of non-amine-resistant, highly water vapor-permeable polysiloxanes, polyacrylates, vinyl acetate-acrylate copolymers without free acid groups, vinyl acetate-acrylate copolymers with an acid number of less than 1, styrene-isoprene-styrene block copolymers present in combination with at least one of hydrogenated hydrocarbon resins and oils, or styrene-butadiene-styrene block copolymers present in combination with at least one of hydrogenated hydrocarbon resins and oils thereof and adding additions necessary for the medical product to be utilized for a fixing time of at least 7 days while meeting requirements for good skin compatibility, producing coating material from said polymer and optional additions and coating said coating material onto an intermediate carrier and drying the coated material to form an active-ingredient-free polymer layer/intermediate carrier laminate, laminating the backing layer onto the active-ingredient-free polymer layer/intermediate carrier laminate, and punching out an overplaster from the foregoing laminate in a size and shape which overhangs the central compartment on all sides by at least 4 mm, and adhering the overplaster, after removing the intermediate carrier, to a side of the central compartment that is facing away from the skin-side adhesive face, such that said overplaster overhangs the central compartment on all sides by at least 4 mm.

12. A kit-of-parts comprising a first part and a second part, wherein the first part comprises a central compartment that includes a) at least one pressure-sensitive, active-ingredient-containing polymer layer which can be applied directly to the skin after removal of a releasable release liner, and (b) a separating layer which covers the active-ingredient-containing polymer layer such that said separating layer is in contact with said active-ingredient-containing polymer layer, and wherein a second part comprises at least one active-ingredient-free overplaster laminated to an intermediate carrier and is comprised of a) a water vapor-permeable backing layer; and b) a pressure-sensitive, active-ingredient-free polymer layer comprising non-amine-resistant, highly water vapor-permeable polysiloxanes, polyacrylates or vinyl acetate-acrylate copolymers without free acid groups or with an acid number of less than 1, styrene-isoprene-styrene block copolymers present in combination with at least one of hydrogenated hydrocarbon resins and oils, or styrene-butadiene-styrene block copolymers present in combination with at least one of hydrogenated hydrocarbon resins and oils thereof, the overplaster being large enough to overhang the central compartment on all sides, wherein said first part is capable of being attached to said second part following removal of said intermediate carrier such that the active-ingredient-free overplaster is adhered to said central compartment and overhangs said central compartment on all sides.

13. The kit-of-parts as claimed in claim 12, comprising at least two active-ingredient-free overplasters as claimed in claim 8 that are laminated onto intermediate carriers, said overplasters differing in composition of their active-ingredient-free polymer layers, their size and/or their shape.

14. The kit-of-parts as claimed in claim 12, wherein the active-ingredient-free polymer layer further comprises a neutral oil as compatibilizer, and the concentration of said neutral oil is 0 to 5% (w/w) based on the layer dry weight.

15. A method of using the kit-of-part as claimed in claim 12, wherein a user combines said first part, manufactured in a standardized process and meeting pharmaceutical stipulations, with a suitable said second part that allows the transdermal therapeutic system to be used in accordance with the requirements for a fixing time of at least seven days and meeting the requirement for good skin compatibility Which is facilitated by the user removing said intermediate carrier to adhere said active-ingredient-free overplaster to said central compartment.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0063] FIG. 1 shows a section through the medical product of the invention.

[0064] FIG. 2 shows a section through the preferred TTS of the invention.

[0065] In FIGS. 1 and 2 the layer thicknesses have been exaggerated for clarity. In FIG. 1 the pressure-sensitively adhering central compartment (3) is shown schematically with a rectangular cross section. The actual cross section may differ from this.

[0066] As can be seen in FIG. 1, compartment 3 rests on the redetachable protective layer (6) and is covered by the overplaster, which is formed from the water vapor-permeable backing layer (1) and the pressure-sensitively adhering, active-ingredient-free polymer layer (2). It can be seen that compartment 3 is overhung on all sides by the backing layer 1 and the polymer layer 2.

[0067] As can be seen in FIG. 2, the TTS comprises a pressure-sensitively adhering, active-ingredient-containing polymer layer (5), which rests on the redetachable protective layer (6) and is covered by the overplaster, which is formed from the water vapor-permeable backing layer (1) and the pressure-sensitively adhering, active-ingredient-free polymer layer (2). The separating layer (4) here separates the active-ingredient-containing layer 5 from the pressure-sensitively adhering, active-ingredient-free polymer layer (2). It can be seen that laminate formed from the layers 4 and 5 is overhung on all sides by the backing layer 1 and the polymer layer 2.

[0068] In preferred embodiments, the highly skin-compatible, active-ingredient-free polymer layer (2) comprises (percentage quantities indicated here and below are mass fractions [w/w]):

[0069] a standard PSA non-amine-resistant polysiloxane adhesive with an optional silicone oil fraction (e.g., silicone oil 12500 cST) for increasing the tack of <4% and a basis weight of <80 g/m.sup.2;

[0070] a polyacrylate adhesive without free acid groups, with a neutral oil fraction (e.g., Miglyol) of <5% and a basis weight of <80 g/m.sup.2;

[0071] a polyacrylate adhesive without free acid groups, with a dexpanthenol fraction of <5% and a basis weight of <80 g/m.sup.2;

[0072] a polyisobutylene-polybutylene adhesive optionally with a neutral oil fraction or silicone oil fraction (e.g., Miglyol or silicone oil 12500 cST) of <5% and a basis weight of <80 g/m.sup.2; or

[0073] an adhesive based on styrene-isoprene (alternatively: butadiene)-styrene (SIS) block copolymer (these are often used for increasing the bonding performance with hydrogenated hydrocarbon resins and/or oils such as liquid paraffin in combination. The styrene-isoprene (alternatively to isoprene: butadiene)-styrene block copolymer fraction may amount to between 15-100%, the resin fraction to up to 70%, the oil fraction to up to 50%. The basis weight is <90 g/m.sup.2.)

[0074] In particularly preferred embodiments, the highly skin-compatible, active-ingredient-free polymer layer (2) comprises:

[0075] a standard PSA non-amine-resistant polysiloxane adhesive with an optional silicone oil fraction (e.g., silicone oil 12500 cST) for increasing the tack of 1% and a basis weight of 70 g/m.sup.2;

[0076] a polyacrylate adhesive without free acid groups, with a neutral oil fraction (e.g., Miglyol) of 2% and a basis weight of <75 g/m.sup.2;

[0077] a polyacrylate adhesive without free acid groups, with a dexpanthenol fraction of 2.5% and a basis weight of <75 g/m.sup.2;

[0078] a polyisobutylene-polybutylene adhesive optionally with a neutral oil fraction or silicone oil fraction (e.g., Miglyol or silicone oil) of 2% and a basis weight of <70 g/m.sup.2; or

[0079] an adhesive based on styrene-isoprene (alternatively to isoprene: butadiene)-styrene block copolymer. (These are often used for increasing the bonding performance with hydrogenated hydrocarbon resins and/or oils such as liquid paraffin in combination. The styrene-isoprene (alternatively to isoprene: butadiene)-styrene block copolymer fraction may amount to between 25-100%, the resin fraction to up to 55%, the oil fraction to up to 38%. The basis weight is <75 g/m.sup.2.)

[0080] The separation layer (4) between active ingredient delivery unit 5 and the overplaster formed from layers 1 and 2 consists preferably of polyethylene terephthalate (PET) with a thickness of 19-23 m. Where polysiloxane adhesives are utilized in layers 2 or 5, this layer (4) may be siliconized.

Production Examples

Examples 1-5a (DoE1) with Polyacrylate Adhesive+Neutral Oil

Preparation of the Composition for the Active-Ingredient-Free Overplaster With Polyacrylate Adhesive+Neutral Oil

[0081] A vinyl acetate-acrylate copolymer solution in ethyl acetate/ethanol/heptane with a solids fraction of 40-43% [w/w] is admixed with a solution of neutral oil (Miglyol), and the total solids fraction of the solution is adjusted with ethanol to 40%.

[0082] Stirring then takes place until the solution is homogeneous.

[0083] This adhesive solution (composition) is utilized for producing the active-ingredient-free, skin-facing side (layer 2) of the overplaster.

[0084] Coating and drying the composition on intermediate carriers:

[0085] The composition is coated onto a siliconized PE paper in such a way that, following evaporation of the solvents in a drying cabinet or drying tunnel at not more than 100 C., a layer of adhesive is formed which has a basis weight of 50-100 g/m.sup.2.

[0086] The compositions of the adhesive solutions used for the overplaster per formulation which follows in the DoE1 (Design of Experiment) trials were:

TABLE-US-00001 TABLE 1 Vinyl acetate- acrylate Coating weight copolymer after drying at solution 42.1% about (e.g., Neutral oil 10-12 min DURO-TAK (MIGLYOL Ethanol at 60 C. Example 387-2515) [g] 812) [g] [g] [g/m.sup.2] Example 1 181.6 1.6 11.9 81.1 Example 2 368.5 0.82 30.6 52.5 Example 3 368.5 0.82 30.6 114.4 Example 4 352.2 7.8 30.2 49 Example 5 352.2 7.8 30.2 114.1 Example 5a 181.6 0.8 11.9 75

Examples 6-10 (DoE2) With Polyacrylate Adhesive+Dexpanthenol

Preparation of the Composition for the Active-Ingredient-Free Overplaster With Polyacrylate Adhesive+Dexpanthenol

[0087] A vinyl acetate-acrylate copolymer solution in ethyl acetate/ethanol/heptane with a solids fraction of 40-43% [w/w] is admixed with dexpanthenol, and the total solids fraction of the solid is adjusted with ethanol to 40%.

[0088] Stirring then takes place until the solution is homogeneous.

[0089] This adhesive solution (composition) is utilized for producing the active-ingredient-free, skin-facing side (layer 2) of the overplaster.

[0090] Coating and drying the composition on intermediate carriers:

[0091] The composition is coated onto a siliconized PE paper in such a way that, following evaporation of the solvents in a drying cabinet or drying tunnel at not more than 100 C., a layer of adhesive is formed which has a basis weight of 50-110 g/m.sup.2.

[0092] The compositions of the adhesive solutions used for the overplaster per formulation which follows in the DoE2 (Design of Experiment) trials (examples 6-10) were:

TABLE-US-00002 TABLE 2 Vinyl acetate- acrylate copolymer Coating weight solution 42.1% after drying at (e.g., Dex- about 10-12 min DURO-TAK panthenol Ethanol at 60 C. Example 387-2515) [g] [g] [g] [g/m.sup.2] Example 6 180.4 2.1 12.5 80.7 Example 7 368.8 0.8 20.5 47.8 Example 8 368.8 0.8 20.5 119.2 Example 9 352.9 7.9 30.2 50.6 Example 10 352.9 7.9 30.2 113.5

Examples 11-15 (DoE3) and 16-20 (DoE4) With Non-Amine-Resistant Polysiloxane Adhesive+Silicone Oil

Preparation of the Composition for the Active-Ingredient-Free Overplaster With Non-Amine-Resistant Polysiloxane Adhesive+Silicone Oil

[0093] A non-amine-resistant polysiloxane adhesive solution in heptane (alternatively ethyl acetate) with a solids content of 50-70% [w/w] is admixed with silicone oil, optionally diluted to 60-70% with n-heptane (or with ethyl acetate in the case of non-amine-resistant polysiloxane adhesives in solution in ethyl acetate), and then stirred until a homogeneous solution is formed.

[0094] This adhesive solution (composition) is utilized for producing the active-ingredient-free, skin-facing side (layer 2) of the overplaster.

[0095] Coating and Drying the Composition on Intermediate Carriers

[0096] The composition is to a fluoropolymer-coated PET film (protective layer and/or intermediate carrier) in such a way that, after evaporation of the solvents in a drying cabinet or drying tunnel at not more than 100 C., a layer of adhesive having a basis weight of 50-80 g/m.sup.2 is formed.

[0097] The compositions of the adhesive solutions used for the overplaster per formulation which follows in the DoE3 (Design of Experiment) trials were:

TABLE-US-00003 TABLE 3 Non-amine-resistant polysiloxane Coating weight adhesive solution at Silicone after drying at 60% (e.g., BIO- oil n-heptane about 10 min at Example PSA 7-4501) [g] [g] [g] 50 C. [g/m.sup.2] Example 11 323.1 1.0 0.6 54.4 Example 12 323.1 1.0 0.6 85.9 Example 13 310.9 7.9 5.2 51.9 Example 14 310.9 7.9 5.2 81.6 Example 15 160.5 1.0 0.7 65.9

[0098] The compositions of the adhesive solutions used for the overplaster per formulation which follows in the DoE4 (Design of Experiment) trials were:

TABLE-US-00004 TABLE 4 Coating weight Non-amine-resistant after drying at polysiloxane about 10 min at adhesive solution at 50 C. [g/m.sup.2] 61% (e.g., BIO- (viscosity of PSA 7-4601) [g] Silicone the coating (possibly different oil n-heptane composition in Example solids content) [g] [g] dPas) Example 16 311.5 1.0 3.0 59.5 Example 17 311.5 1.0 3.0 85.6 Example 18 306.4 7.9 10.2 59.2 Example 19 306.4 7.9 10.2 84.2 Example 20 167.4 1.0 3.4 72.6 Example 21 160.5 (60%) 0.7 0.7 69 (5 dPas) Example 22 160.5 (65%) 0.7 0.7 70 (8 dPas) Example 23 160.5 (67%) 0.7 0.7 70 (9.5 dPas) Example 24 160.5 (69%) 0.7 0.7 70 (15 dPas)

[0099] The dried adhesive surface is lined elastically with a water vapor-permeable backing layer 1, e.g. polyester fabric. This is, for example, a bidirectionally elastic polyethylene-terephthalate fabric which can be stretched in warp and weft directions and whose stretchability is about 50% in lengthwise direction, 35% in transverse direction (measured according to DIN 61632), and whose basis weight is about 130 g/m.sup.2 (manufacturer: Karl Otto Braun GmbH & Co. KG (KOB)).

[0100] From the resultant laminates, consisting of intermediate carrier, dry polymer layer 2, and backing layer 1, overplasters of suitable size are then punched out, in order for these to be adhered to the separating layer 4 in the case, for example, of use in combination with an active ingredient delivery layer 5. The punching of the overplaster laminate takes place in such a way that all of the layers are severed apart from the intermediate carrier. The size of the overplaster in comparison to the active ingredient delivery unit, including the separating layer, is a critical determinant here of the size of the overlapping edge region which allows fixing in direct skin contact. The width of the overlapping edge region ought not to be less than 0.4 cm, in order to ensure adequate fixing over 7 days.

Storage Tests

[0101] In order to produce a TTS for the storage tests, a vinyl acetate-acrylate copolymer matrix, with a size of 16 cm.sup.2 and a thickness of 0.1 mm, containing 3.2 mg of estradiol-hemihydrate and 11.2 mg of norethisterol, was lined with an overplaster protruding on all sides, this overplaster being comprised of acylate adhesive and bidirectionally elastic PES fabric. The plasters thus produced were packaged in Surlyn or PET/AL/PAN (Barex) sealed edge pouches.

[0102] The packaged plasters were then stored for 1.5, 3, 4.5 or 6 months at 40 C. and standard atmospheric humidity or at 40 C. and increased atmospheric humidity. They were subsequently removed from the sealed edge pouches. Assessments were made of the sticking to the pouch material and of the cold flow. In addition, the plasters were investigated by microscope for crystals.

Results and Discussion

[0103]

TABLE-US-00005 TABLE 5 40 C. and 40 C. and increased increased 40 C. 40 C. humidity humidity Surlyn pouch Barex pouch Surlyn pouch Barex pouch 0 mon. no crystals no crystals no crystals no crystals visible visible visible visible 1.5 mon. (n = 3) easily easily easily easily removable; no removable; no removable; no removable; no crystals crystals crystals crystals visible visible visible visible 3 mon. (n = 3) easily easily easily easily removable; no removable; no removable; no removable; no crystals crystals crystals crystals visible visible visible visible 4.5 mon. easily easily easily easily (n = 3) removable; no removable; no removable; no removable; no crystals crystals crystals crystals visible visible visible visible 6 mon. (n = 6) easily easily easily easily removable; in removable; no removable; no removable; no one of the six crystals crystals crystals pouches, one visible visible visible round crystal was visible

CONCLUSION

[0104] 1. By means of the overplaster, the cold flow can be stopped successfully.
2. The crystallization of the active ingredients can be largely prevented by the overplaster. After 6 months at 40 C. and standard atmospheric humidity, a crystal was found only in one case after 6 months. In plasters stored at 40 C. and increased atmospheric humidity, no crystals at all were detectable.