STABILIZED TRANSDERMAL DELIVERY SYSTEM

Abstract

The present invention concerns a method for the production of a transdermal delivery system (TDS) comprising at least one active ingredient, wherein the method comprises temperature-conditioning. Furthermore, the present invention concerns a TDS which can be produced by means of the method in accordance with the invention, as well as the use of the TDS in accordance with the invention.

Claims

1. A method for the production of a transdermal delivery system, comprising the steps of: (i) providing at least one active ingredient-containing matrix, preferably an active ingredient-containing matrix on a non-aqueous basis, (ii) applying the at least one active ingredient-containing matrix to a film in order to obtain a laminate with an active ingredient-containing matrix, (iii) optionally, drying the laminate comprising the active ingredient-containing matrix, (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 non-aqueous basis and/or the laminate and/or the punched transdermal therapeutic systems and/or the packaged transdermal therapeutic systems, wherein the temperature-conditioning is carried out directly, preferably within 7 days, preferably within three days, particularly preferably within two days, in particular within 24 hours following application of the at least one active ingredient-containing matrix to the film.

2. The method for the production of a transdermal delivery system as claimed in claim 1, wherein the temperature-conditioning is carried out at a temperature of at least approximately 50 C., preferably at a temperature of at least approximately 60 C., particularly preferably at a temperature of at least approximately 70 C., and/or at a temperature of up to approximately 120 C., preferably at a temperature of up to approximately 100 C., particularly 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.

3. The method for the production of a transdermal delivery system as claimed in claim 1, wherein the temperature-conditioning is carried out over a time period of up to 12 hours, preferably over a time period of up to 6 hours, particularly preferably over a time period of up to 2.5 hours, in particular over a time period of up to approximately one hour, particularly preferably over a time period of up to approximately 30 minutes, more particularly preferably over a time period of up to approximately 15 minutes.

4. A transdermal delivery system, wherein the transdermal delivery system is obtainable by means of a method as claimed in claim 1.

5. The transdermal delivery system as claimed in claim 4, wherein the transdermal delivery system furthermore has an adhesive application layer which is free from active ingredient or contains an active ingredient.

6. The transdermal delivery system as claimed in claim 4, which has a control membrane between the matrix, preferably the matrix on a non-aqueous basis, and the adhesive application layer which is free from active ingredients or which contains an active ingredient.

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

8. The transdermal delivery system as claimed in claim 4, wherein at least one matrix, preferably the matrix on a non-aqueous basis, comprises a silicon dioxide.

9. The transdermal delivery system as claimed in claim 4, wherein the matrix, preferably 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.

10. The transdermal delivery system as claimed in claim 9, 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.

11. The transdermal delivery system as claimed in claim 4, which has an occlusive backing layer.

12. The transdermal delivery system as claimed in claim 4, for medical, veterinary or cosmetic use.

13. The transdermal delivery system as claimed in claim 4, comprising an antiemetic, a dopamine agonist, an analgesic, a sedative and/or an anti-dementivum.

14. The transdermal delivery system as claimed in claim 13, wherein the antiemetic is selected from a tropane alkaloid, in particular scopolamine, and wherein the dopamine agonist is selected from a D2 agonist, in particular rotigotine, and wherein the analgesic is selected from buprenorphine and/or fentanyl, and wherein the anti-dementivum is selected from rivastigmine.

15. A transdermal delivery system as claimed in claim 4, 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

[0127] Examples 1 and 2 below describe the production of transdermal therapeutic systems in accordance with the invention, as well as stability studies.

Example 1

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

[0128] A solution of 40.3% by weight of polyisobutylene (PIB) adhesive (Oppanol B80, from BASF), 25.8% by weight of PIB adhesive (Oppanol B10, from BASF), 20% 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 chloroform was coated onto a polyethylene terephthalate (PET) film siliconized on one side (Primeliner PET 75 m 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.

[0129] A solution of 33.8% by weight of PIB adhesive (Oppanol B80, from BASF), 21.6% by weight of PIB adhesive (Oppanol B10, from BASF), 36.3% 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 chloroform 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.

[0130] 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.

[0131] 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 0.24% by weight water content.

[0132] The TDS obtained in this manner was then treated as follows: [0133] T1: the punched and pouch-packaged TDSs were temperature-conditioned within 24 h following its production, for 24 h at 75 C.; [0134] T2: no temperature-conditioning of the punched and pouch-packaged TDSs was carried out;

[0135] The transdermal therapeutic systems were stored at room temperature (RT) and at 40 C./75% r.h. (relative humidity) respectively. The stability studies show that within the test period of six months in the TDS in accordance with the invention, which was temperature-conditioned 24 hours after its production, no crystals of active ingredient had formed. In contrast to this, in TDSs which had not been temperature-conditioned, crystals of active ingredient could be observed even after 1.5 weeks (see Table 1).

TABLE-US-00001 TABLE 1 Stability studies regarding the crystallization of active ingredient in temperature-conditioned (T1) and non-temperature-conditioned (T2) TDS. T1 (the pouch- packaged TDSs were Duration of storage temperature-conditioned T2 (the pouch- (respectively at within 24 h following packaged TDSs were room temperature production for 24 h not temperature- and at 40 C.) at 75 C.) conditioned) 1.5 Weeks No crystals Onset of crystallization 1 month No crystals Crystals 2 months No crystals Crystals 3 months No crystals Crystals 6 months No crystals Crystals

Example 2

[0136] A solution of 26.7% by weight of polyisobutylene (PIB) adhesive (Oppanol N80, from BASF), 33.3% 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), 8% 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 m 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 30 min at 75 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).

[0137] A solution of 24.3% by weight of PIB adhesive (Oppanol N80, from BASF), 30.4% by weight of PIB adhesive (Oppanol B10, from BASF), 37% 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.

[0138] Drying was carried out for 30 min at 75 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.

[0139] 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 0.24% by weight water content.

[0140] Studies on the Crystallization of the Active Ingredient Scopolamine:

[0141] The pouch-packaged TTSs obtained in this manner were temperature-conditioned for 30 minutes at 75 C. in a drying cabinet 24 hours following production and stored for a period of 6 months at a temperature of 25 C./60 r.h. Tests regarding the crystallization of the active ingredient scopolamine showed that within the test period of 6 months, no active ingredient crystals had formed in any of the TDSs in accordance with the invention.

[0142] Studies on the Chemical Stability of the Active Ingredient Scopolamine:

[0143] Furthermore, studies regarding the chemical stability of the active ingredient were carried out. In a first step, how the duration of temperature-conditioning at an exemplary temperature of 75 C. affected the chemical stability of the active ingredient or the formation of contaminants was tested.

[0144] In this regard, the pouch-packaged TDSs were temperature-conditioned for one hour, 5.5 hours, 13.5 hours or 24 hours at a temperature of 75 C. Next, the active ingredient-containing matrix was tested as regards contaminants which resulted from a degradation of the active ingredient. The results of the tests are shown in Table 2.

[0145] Table 2 shows that a temperature-conditioning duration of beyond approximately 13.5 hours caused an increase in the profile of the contaminants, in the present case of the contaminants B and C. A temperature-conditioning duration of approximately 1 hours and approximately 5.5 hours, on the other hand, exhibited only a small influence on the degradation of the active ingredient.

TABLE-US-00002 TABLE 2 Stability of active ingredient in pouch-packaged TDSs as a function of the duration of the temperature-conditioning. Temperature-conditioning (75 C.) 0 h 1 h 5.5 h 13.5 h 24 h Active ingre- 1.47 1.45 1.45 1.49 1.38 dient content (mg/TDS) Purity (%) VU A n.d. n.d. n.d. n.d. n.d. VU B n.d. n.d. n.d. 0.30 0.77 VU C 0.10 0.12 0.13 0.13 0.16 VU D n.d. n.d. n.d. n.d. n.d. VU = contaminants; n.d. = not detected;

[0146] In a subsequent step, TDSs which had been temperature-conditioned for 30 minutes or for 5 hours at a temperature of 75 C. were each stored for 6 months at a temperature of 25 C./60% r.h. The tests also showed that over the entire test period of 6 months, there was a slight degradation of the active ingredient when the TDS was temperature-conditioned at temperature for 30 minutes or for 5 hours at a temperature of 75 C. (see Tables 3A and 3B).

TABLE-US-00003 TABLE 3A Stability of active ingredient in temperature-conditioned TDSs after storage for 6 months at 25 C./60% r.h, with temperature-conditioning at 75 C. for 30 minutes. Temperature-conditioning (75 C. for 30 min.) Start 3 M 25 C. 6 M 25 C. Content % 106.0 100.7 100.0 Purity % VU A n.d. n.d. n.d. VU B n.d. <RL 0.22 VU C n.d. <RL <RL VU D n.d. n.d. n.d. VU = contaminants; RL = reporting level (0.1%); n.d. = not detected;

TABLE-US-00004 TABLE 3B Stability of active ingredient in temperature-conditioned TDSs after storage for 6 months at 25 C./60% r.h., with temperature-conditioning at 75 C. for 5 hours. Temperature-conditioning (75 C. for 5 hours) Start 3 M 25 C. 6 M 25 C. Content % 99.3 102.0 102.0 Purity % VU A n.d. n.d. n.d. VU B n.d. 0.14 0.23 VU C n.d. <RL <RL VU D n.d. n.d. n.d.

[0147] 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.