PREVENTING CRYSTALLIZATION OF ACTIVE INGREDIENTS IN TRANSDERMAL DELIVERY SYSTEMS

Abstract

The present invention concerns a transdermal delivery system (TDS) comprising at least one active ingredient, wherein the active ingredient is in a non-aqueous matrix, and wherein the non-aqueous matrix has a reduced moisture content. Furthermore, the present invention concerns a method for the production of the TDS in accordance with the invention, as well as the use of the TDS in accordance with the invention.

Claims

1. A transdermal therapeutic system comprising: (i) at least one active ingredient in at least one matrix on a non-aqueous basis, (ii) a backing layer, and (iii) an optional protective film, wherein at least one active ingredient-containing matrix on a non-aqueous basis has a water content of less than 2% by weight, in particular of less than 1% by weight.

2. The transdermal delivery system as claimed in claim 1, wherein the transdermal delivery system furthermore has an adhesive application layer which is free from active ingredient or contains an active ingredient.

3. The transdermal delivery system as claimed in claim 2, which has a control membrane between the matrix on a non-aqueous basis and the adhesive application layer which is free from active ingredients or which contains an active ingredient.

4. The transdermal delivery system as claimed in claim 1, wherein at least one matrix on a non-aqueous basis comprises a mineral oil.

5. The transdermal delivery system as claimed in claim 1, wherein at least one matrix on a non-aqueous basis comprises a silicon dioxide.

6. The transdermal delivery system as claimed in claim 1, wherein the matrix on a non-aqueous basis comprises at least one polymer, preferably at least two polymers, which are selected from the group formed by polybutylenes, in particular by polyisobutylenes.

7. The transdermal delivery system as claimed in claim 6, wherein one of the at least two polybutylenes, in particular polyisobutylenes, has a molecular weight of at least approximately 20,000 g/mol and/or at most approximately 100,000 g/mol, and/or a second polybutylene, in particular a polyisobutylene, has a molecular weight of at least approximately 500,000 g/mol and/or at most approximately 3,500,000 g/mol.

8. The transdermal delivery system as claimed in claim 1, which has an occlusive backing layer.

9. A method for the production of a transdermal delivery system, comprising the following steps: (i) providing at least one active ingredient-containing matrix on a non-aqueous basis, (ii) optionally, applying the at least one active ingredient-containing matrix on a non-aqueous basis to a film in order to obtain a laminate with an active ingredient-containing matrix on a non-aqueous basis, (iii) optionally, drying the laminate comprising the active ingredient-containing matrix on a non-aqueous basis, (iv) optionally, punching out transdermal therapeutic systems in order to obtain laminar active ingredient cores, (v) optionally, packaging transdermal therapeutic systems, (vi) temperature-conditioning the active ingredient-containing matrix on a nonaqueous basis and/or the laminate and/or the punched transdermal therapeutic systems and/or the packaged transdermal therapeutic systems.

10. The method for the production of a transdermal delivery system as claimed in claim 9, wherein the temperature-conditioning is carried out at a temperature of at least approximately 30° C., preferably at a temperature of at least approximately 50° C., in particular at a temperature of at least approximately 60° C., and/or at a temperature of up to approximately 100° C., preferably at a temperature of up to approximately 90° C., in particular at a temperature of up to approximately 80° C., particularly preferably at a temperature of approximately 75° C.

11. The method for the production of a transdermal delivery system as claimed in claim 9, wherein the temperature-conditioning is carried out over a time period of up to one week, preferably over a time period of up to 24 hours, particularly preferably over a time period of up to twelve hours, in particular over a time period of up to approximately 1 hour, particularly preferably over a time period of up to approximately one hour, particularly preferably over a time period of up to approximately 30 minutes.

12. The transdermal delivery system as claimed in claim 1, wherein the transdermal delivery system is obtained by a method comprising: (i) providing at least one active ingredient-containing matrix on a non-aqueous basis, (ii) optionally, applying the at least one active ingredient-containing matrix on a non-aqueous basis to a film in order to obtain a laminate with an active ingredient-containing matrix on a non-aqueous basis, (iii) optionally, drying the laminate comprising the active ingredient-containing matrix on a non-aqueous basis, (iv) optionally, punching out transdermal therapeutic systems in order to obtain laminar active ingredient cores, (v) optionally, packaging transdermal therapeutic systems, (vi) temperature-conditioning the active ingredient-containing matrix on a nonaqueous basis and/or the laminate and/or the punched transdermal therapeutic systems and/or the packaged transdermal therapeutic systems.

13. The transdermal delivery system as claimed in claim 1, for medical, veterinary or cosmetic use.

14. The transdermal delivery system as claimed in claim 1, comprising an antiemetic, a dopamine agonist, an analgesic, a sedative and/or an anti-dementivum.

15. The transdermal delivery system as claimed in claim 14, wherein the antiemetic is selected from a tropane alkaloid, in particular scopolamine, and wherein the dopamine agonist is selected from a D.sub.2 agonist, in particular rotigotine, and wherein the analgesic is selected from buprenorphine and/or fentanyl, and wherein the anti-dementivum is selected from rivastigmine.

16. A transdermal delivery system as claimed in claim 1, for use in the treatment of travel sickness, Parkinson's disease and/or restless leg syndrome, pain, in particular cancer-related pain, and Alzheimer's disease.

Description

EXAMPLES

[0126] Examples 1 and 2 below describe the production of transdermal therapeutic systems in accordance with the invention, including a stability study.

Example 1

Exemplary Embodiment Concerning Production, and Stability Study of a Scopolamine TDS in Accordance with the Invention

[0127] A solution of 26% by weight of polyisobutylene (PIB) adhesive (Oppanol B80, from BASF), 33% by weight of PIB adhesive (Oppanol B10, from BASF), 32% by weight of mineral oil (paraffin Ph. Eur., Klearol, from Sonneborn), 9% by weight of scopolamine base (hyoscine, from Alkaloids Private Limited) and a suitable quantity of 2-propanol and heptane was coated onto a polyethylene terephthalate (PET) film siliconized on one side (Primeliner PET 75 μm 1S, from Loparex) in a manner such that after drying, a matrix layer with a basis weight of approximately 56 g/m.sup.2 was produced. In order to remove the solvent, drying was carried out at 60° C. for 15 min. The matrix layer was laminated with a polyester protective film (from Mitsubishi) siliconized on one side.

[0128] A solution of 24.5% by weight of PIB adhesive (Oppanol B80, from BASF), 31% by weight of PIB adhesive (Oppanol B10, from BASF), 41% by weight of mineral oil (paraffin Ph. Eur., Klearol, from Sonneborn), 3.3% by weight of scopolamine base (hyoscine, from Alkaloids Private Limited) and a suitable quantity of 2-propanol and heptane was coated onto a polyethylene terephthalate (PET) film siliconized on one side in a manner such that after drying, an application layer (=adhesive layer) with a basis weight of approximately 45 g/m.sup.2 was produced. In order to remove the solvent, drying was carried out at 60° C. for 15 min.

[0129] A microporous polypropylene membrane (thickness 25 □m; microporous (porosity 41%), from Celgard) soaked with mineral oil (paraffin Ph. Eur., Klearol, from Sonneborn) was laminated onto an application layer. The PET film was removed from the matrix layer and the matrix layer was applied to the laminate formed by the application layer and membrane.

[0130] The laminate obtained in this manner was temperature-conditioned for 24 hours at 75° C. in a drying cabinet immediately following production. The determination of the water content of the active ingredient-containing matrix on a non-aqueous basis was carried out using Karl Fischer titration and yielded a value of 0.18% by weight of water.

[0131] The transdermal therapeutic system in accordance with the invention was stored at temperatures of 5° C., 25° C./60% r.h. (relative humidity) and 40° C./75% r.h. The stability studies showed that within the test period of three months, no crystals of active ingredient had been formed.

Example 2

[0132] A solution of 26% by weight of polyisobutylene (PIB) adhesive (Oppanol N80, from BASF), 33% by weight of PIB adhesive (Oppanol B10, from BASF), 27% by weight of mineral oil (paraffin Ph. Eur., Klearol, from Sonneborn), 5% by weight of silicon dioxide (silicon dioxide Ph. Eur., high purity and amorphous high dispersity silicic acid, hydrophilic, Aerosil 200 Pharma, from Evonik), 9% by weight of scopolamine base (hyoscine, from Alkaloids Private Limited) and a suitable quantity of 2-propanol and heptane was coated onto a polyethylene terephthalate (PET) film siliconized on one side (Primeliner PET 75 μm 1S, from Loparex) in a manner such that after drying, a matrix layer with a basis weight of approximately 56 g/m.sup.2 was produced. Drying was carried out for 15 min at 60° C. in order to remove the solvent. The matrix layer was laminated with a polyester protective film siliconized on one side (polyester film from Mitsubishi).

[0133] A solution of 24.5% by weight of PIB adhesive (Oppanol N80, from BASF), 31% by weight of PIB adhesive (Oppanol B10, from BASF), 36% by weight of mineral oil (paraffin Ph. Eur., Klearol, from Sonneborn), 5% by weight of silicon dioxide (silicon dioxide Ph. Eur., high purity and amorphous high dispersity silicic acid, hydrophilic, Aerosil 200 Pharma, from Evonik), 3.3% by weight of scopolamine base (hyoscine, from Alkaloids Private Limited) and a suitable quantity of 2-propanol and heptane was coated onto a polyethylene terephthalate (PET) siliconized on one side in a manner such that after drying, an application layer (=adhesive layer) with a basis weight of approximately 45 g/m.sup.2 was produced.

[0134] Drying was carried out for 15 min at 60° C. in order to remove the solvent. A microporous polypropylene membrane (thickness 25 □m; microporous (porosity 41%) from Celgard) soaked with mineral oil (paraffin Ph. Eur., Klearol, from Sonneborn) was laminated onto the application layer. The PET film was removed from the matrix layer and the matrix layer was applied to the laminate formed by the application layer and membrane. Next, the laminate was punched in order to obtain transdermal therapeutic systems (TTS) which were subsequently packaged into pouches.

[0135] The pouch-packaged TTSs obtained in this manner were temperature-conditioned at 75° C. for 30 minutes as well as at 75° C. for 24 hours in a drying cabinet immediately following production. The determination of the water content of the active ingredient-containing matrix on a non-aqueous basis was carried out using Karl Fischer titration and yielded a value of 0.26% by weight of water.

[0136] The transdermal therapeutic system in accordance with the invention was stored at temperatures of 25° C./60% r.h. (relative humidity) and of 40° C./75% r.h. The stability studies showed that within the test period of 3 months or 6 months, no crystals of active ingredient had been formed.

[0137] Finally, it should be pointed out once again that the examples described above in detail relate solely to exemplary embodiments which can be modified by the person skilled in the art in a wide variety of manners without departing from the scope of the invention. Furthermore, the use of the indefinite article “a” or “an” does not exclude that the features concerned could also be present as a plurality thereof.