Transdermal therapeutic system for the transdermal administration of rivastigmine
11389421 · 2022-07-19
Assignee
Inventors
- Marco Emgenbroich (Rheinbach, DE)
- Nico REUM (Mendig, DE)
- Jessica Verstraelen (Wolfsburg, DE)
- Regine Kaufmann (Neuwied, DE)
Cpc classification
A61K9/7069
HUMAN NECESSITIES
A61P25/28
HUMAN NECESSITIES
A61K31/27
HUMAN NECESSITIES
International classification
Abstract
The present invention relates to a transdermal therapeutic system (TTS) for the transdermal administration of rivastigmine comprising a rivastigmine-containing layer structure, said rivastigmine-containing layer structure comprising: A) a backing layer; and B) a rivastigmine-containing layer.
Claims
1. A transdermal therapeutic system for the transdermal administration of rivastigmine comprising a rivastigmine-containing layer structure, said rivastigmine-containing layer structure comprising: A) a backing layer; and B) a rivastigmine-containing layer; wherein the transdermal therapeutic system comprises a silicone acrylic hybrid polymer comprising repeating units of a silicone sub-species and an acrylate-sub species, wherein the silicone acrylic hybrid polymer is a silicone acrylic hybrid pressure-sensitive adhesive comprising the reaction product of: (a) a silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality; (b) an ethylenically unsaturated monomer; and (c) an initiator, and wherein the transdermal therapeutic system provides a permeated amount of rivastigmine as measured in a Franz diffusion cell with EVA-membrane of: 0 μg/cm.sup.2 to 240 μg/cm.sup.2 in hours 0 to 3; 80 μg/cm.sup.2 to 350 μg/cm.sup.2 from hour 3 to hour 8; and 210 μg/cm.sup.2 to 560 μg/cm.sup.2 from hour 8 to hour 24.
2. The transdermal therapeutic system according to claim 1, wherein the rivastigmine-containing layer is a rivastigmine-containing matrix layer comprising: (i) rivastigmine; and (ii) the silicone acrylic hybrid polymer.
3. The transdermal therapeutic system according to claim 1, wherein the rivastigmine-containing layer structure is a rivastigmine-containing self-adhesive layer structure.
4. The transdermal therapeutic system according to claim 1, wherein the silicone acrylic hybrid polymer is a silicone acrylic hybrid pressure-sensitive adhesive.
5. The transdermal therapeutic system according to claim 1, wherein the rivastigmine-containing layer structure contains from 0.5 to 5 mg/cm.sup.2 rivastigmine.
6. The transdermal therapeutic system according to claim 1, wherein the rivastigmine-containing layer comprises at least one or more of: (a) from 5 to 30% rivastigmine by weight of the rivastigmine-containing layer; and (b) from 35 to 95% silicone acrylic hybrid polymer by weight of the rivastigmine-containing layer.
7. The transdermal therapeutic system according to claim 1, wherein the silicone acrylic hybrid polymer comprises a reaction product of a silicone polymer, a silicone resin and an acrylic polymer, wherein the acrylic polymer is covalently self-crosslinked and covalently bound to the silicone polymer, the silicone resin, or both the silicone polymer and the silicone resin.
8. The transdermal therapeutic system according to claim 1, wherein the reaction product of (a) the silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality; (b) the ethylenically unsaturated monomer; and (c) the initiator; contains a continuous, silicone external phase and a discontinuous, acrylic internal phase; or contains a continuous, acrylic external phase and a discontinuous, silicone internal phase.
9. The transdermal therapeutic system according to claim 1, wherein the silicone acrylic hybrid polymer in the rivastigmine-containing layer contains a continuous, silicone external phase and a discontinuous, acrylic internal phase; or a continuous, acrylic external phase and a discontinuous, silicone internal phase, and wherein the rivastigmine-containing layer comprises from 15 to 25% rivastigmine by weight of the rivastigmine-containing layer.
10. The transdermal therapeutic system according to claim 1, wherein the rivastigmine-containing layer further comprises a non-hybrid polymer selected from the group consisting of polysiloxanes, acrylates, and polyisobutylenes.
11. The transdermal therapeutic system according to claim 10, wherein the non-hybrid polymer comprises from 5 to 40% by weight of the rivastigmine-containing layer, and wherein the weight ratio of the silicone acrylic hybrid polymer to the non-hybrid polymer is from 8:1 to 1:2.
12. The transdermal therapeutic system according to claim 1, wherein the rivastigmine-containing layer has an area weight ranging from 40 to 250 g/m.sup.2, and an area of release ranging from 1 to 30 cm.sup.2.
13. The transdermal therapeutic system according to claim 1, wherein the transdermal therapeutic system provides by transdermal delivery a mean release rate of from 150 to 3500 μg/cm.sup.2 rivastigmine over about 24 hours of administration.
14. The transdermal therapeutic system according to claim 1, wherein the transdermal therapeutic system provides by transdermal delivery at steady state at least one pharmacokinetic parameter selected from the group consisting of: a plasma concentration of rivastigmine of from 1 to 25 ng/ml; an AUC.sub.24h of about 10 to 450 ng*h/ml after repeated once daily administration; a C.sub.max of about 0.5 to 30 ng/ml after applying the transdermal therapeutic system on the skin of the patient; and a t.sub.max of about 3 to 15 hours after applying the transdermal therapeutic system on the skin of the patient.
15. A process for manufacturing a rivastigmine-containing layer for use in the transdermal therapeutic system according to claim 1 comprising: combining at least the components a. rivastigmine in an amount from 10 to 25% by weight of the resulting rivastigmine-containing layer; b. a silicone acrylic hybrid polymer; and c. optionally at least one additional non-hybrid polymer and/or additive; to obtain a coating composition; coating the coating composition onto the backing layer or release liner; and drying the coated coating composition to form the rivastigmine-containing layer.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
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(2)
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DETAILED DESCRIPTION
TTS Structure
(8) The present invention relates to a transdermal therapeutic system for the transdermal administration of rivastigmine comprising a rivastigmine-containing layer structure, said rivastigmine-containing layer structure comprising a) a backing layer, and b) a rivastigmine-containing layer, wherein the transdermal therapeutic system comprises a silicone acrylic hybrid polymer. This rivastigmine-containing layer structure is preferably a rivastigmine-containing self-adhesive layer structure and preferably does not comprise an additional skin contact layer. In particular, the silicone acrylic hybrid polymer, which is present in the transdermal therapeutic system, is present in the self-adhesive layer structure and provides the adhesive properties.
(9) The TTS according to the present invention may be a matrix-type TTS or a reservoir-type TTS, and preferably is a matrix-type TTS.
(10) In a matrix-type TTS according to the invention, the rivastigmine is homogeneously dissolved and/or dispersed within a polymeric carrier, i.e. the matrix, which forms with the rivastigmine and optionally remaining ingredients a matrix layer. Accordingly, the rivastigmine-containing layer may in one embodiment of the invention be a rivastigmine-containing matrix layer, wherein the rivastigmine is homogeneously distributed within a polymer matrix. The polymer matrix preferably comprises the silicone acrylic hybrid polymer. Thus, it is preferred according to the invention that the rivastigmine-containing matrix layer comprises rivastigmine and the silicone acrylic hybrid polymer, which is present in the TTS. In this connection, it is also preferred that the rivastigmine-containing matrix layer is self-adhesive, so that no additional skin contact layer is present. If a rivastigmine-containing matrix layer is prepared by laminating together two rivastigmine-containing matrix layers, which are of substantially the same composition, the resulting double layer is to be regarded as one rivastigmine-containing matrix layer.
(11) In a reservoir-type TTS according to the present invention, the rivastigmine-containing layer is a rivastigmine-containing reservoir layer, which preferably comprises a liquid reservoir comprising the rivastigmine. The reservoir-type TTS typically additionally comprises a skin contact layer, wherein the reservoir layer and the skin contact layer are preferably separated by the rate-controlling membrane. The silicone acrylic hybrid polymer then provides the adhesive properties. Preferably, the skin contact layer is manufactured such that it is rivastigmine-free.
(12) In a preferred embodiment of the invention, the rivastigmine-containing layer is a rivastigmine-containing matrix layer comprising 1. rivastigmine, and 2. the silicone acrylic hybrid polymer.
(13) Thus, according to one embodiment of the invention, the transdermal therapeutic system for the transdermal administration of rivastigmine comprises a rivastigmine-containing layer structure comprising: A) a backing layer; and B) a rivastigmine-containing layer, which is preferably a rivastigmine-containing matrix layer, comprising: 1. rivastigmine, and 2. a silicone acrylic hybrid polymer.
(14) The rivastigmine-containing layer structure is preferably a rivastigmine-containing self-adhesive layer structure. In this connection, it is also preferred that the rivastigmine-containing layer structure does not comprise an additional skin contact layer. Instead, it is preferred that the rivastigmine-containing layer, which is preferably a rivastigmine-containing matrix layer, is self-adhesive. Thus, in a preferred embodiment, the rivastigmine-containing layer structure is a rivastigmine-containing self-adhesive layer structure and does not comprise an additional skin contact layer. Alternatively or additionally, it is preferred that the rivastigmine-containing layer is directly attached to the backing layer, so that there is no additional layer between the backing layer and the rivastigmine-containing layer. Consequently, a layer structure of low complexity is obtained, which is advantageous, e.g., in terms of the costs for the manufacture.
(15) In particular, it is preferred that the rivastigmine-containing layer structure comprises not more than 3, preferably 2 layers, i.e. preferably only the backing layer and the rivastigmine-containing layer. Sufficient adhesion between the rivastigmine-containing self-adhesive layer structure and the skin of the patient during administration is then provided by the rivastigmine-containing layer, which is preferably a rivastigmine-containing matrix layer. If an additional skin contact layer is present, e.g., as the third layer of the rivastigmine-containing layer structure, the adhesive properties may be provided by the additional skin contact layer. However, it is preferred according to the invention that no additional skin contact layer is present.
(16) The self-adhesive properties of the rivastigmine-containing layer structure are preferably provided by the silicone acrylic hybrid polymer, which is present in the TTS, preferably in the rivastigmine-containing layer, more preferably in the rivastigmine-containing matrix layer. Thus, in a preferred embodiment of the invention, the silicone acrylic hybrid polymer is a silicone acrylic hybrid pressure sensitive adhesive. Further details regarding the silicone acrylic hybrid polymer according to the invention are provided further below.
(17) It is to be understood that the TTS according to the invention contains a therapeutically effective amount of rivastigmine. Thus, in a preferred embodiment of the invention, the rivastigmine-containing layer structure contains a therapeutically effective amount of rivastigmine. The rivastigmine in the rivastigmine-containing layer structure is preferably present in the form of the free base. Preferred embodiments regarding the rivastigmine in the TTS according to the invention are provided further below.
(18) It is preferred according to the invention that the area of release of the TTS is rather small. According to one specific embodiment of the invention, the area of release ranges from 1 to 30 cm.sup.2, preferably from 2 to 22 cm.sup.2.
(19) In a preferred embodiment of the invention, the backing layer is substantially rivastigmine impermeable. Furthermore, it is preferred that the backing layer is occlusive as outlined above.
(20) According to certain embodiments of the invention, the TTS may further comprise an adhesive overlay. This adhesive overlay is in particular larger in area than the rivastigmine-containing structure and is attached thereto for enhancing the adhesive properties of the overall transdermal therapeutic system. Said adhesive overlay comprises a backing layer and an adhesive layer. The adhesive overlay provides additional area adhering to the skin but does not add to the area of release of the rivastigmine. The adhesive overlay comprises a self-adhesive polymer or a self-adhesive polymer mixture selected from the group consisting of silicone acrylic hybrid polymers, acrylic polymers, polysiloxanes, polyisobutylenes, styrene-isoprene-styrene copolymers, and mixtures thereof, which may be identical to or different from any polymer or polymer mixture included in the rivastigmine-containing layer structure.
(21) The rivastigmine-containing layer structure according to the invention, such as a rivastigmine-containing self-adhesive layer structure, is normally located on a detachable protective layer (release liner), from which it is removed immediately before application to the surface of the patient's skin. Thus, the TTS may further comprise a release liner. A TTS protected this way is usually stored in a blister pack or a seam-sealed pouch. The packaging may be child resistant and/or senior friendly.
Rivastigmine-Containing Layer
(22) As outlined in more detail above, the TTS according to the present invention comprises a rivastigmine-containing layer structure comprising a rivastigmine-containing layer. Preferably, the rivastigmine-containing layer structure is a rivastigmine-containing self-adhesive layer structure. Accordingly, it is also preferred that the rivastigmine-containing layer is a self-adhesive rivastigmine-containing layer, more preferably a self-adhesive rivastigmine-containing matrix layer. In a preferred embodiment, the rivastigmine-containing layer comprises a therapeutically affective amount of the rivastigmine.
(23) In one embodiment of the invention, the rivastigmine-containing layer is a rivastigmine-containing matrix layer. In another embodiment, the rivastigmine-containing layer is a rivastigmine-containing reservoir layer. It is preferred that the rivastigmine-containing layer is a rivastigmine-containing matrix layer.
(24) In one embodiment, the rivastigmine-containing layer comprises: 1. rivastigmine, preferably in the form of the free base; and 2. a silicone acrylic hybrid polymer.
(25) In a preferred embodiment, the rivastigmine-containing layer is a rivastigmine-containing matrix layer comprising 1. rivastigmine, preferably in the form of the free base; and 2. a silicone acrylic hybrid polymer.
(26) In a preferred embodiment, the invention relates to a rivastigmine-containing layer structure, wherein the silicone acrylic hybrid polymer is a silicone acrylic hybrid pressure-sensitive adhesive.
(27) In one embodiment of the invention, the rivastigmine-containing layer is obtainable by dissolving, dispersing, or partly dissolving and partly dispersing the rivastigmine, preferably in the form of the free base. As a result, the rivastigmine-containing layer of the TTS according to the invention typically comprises rivastigmine in the form of the free base. In addition, the rivastigmine may, in certain embodiments of the invention, partly be present in protonated form. However, it is preferred that at least 50 mol %, preferably at least 75 mol % of the rivastigmine in the rivastigmine-containing layer are present in the form of the free base. In a particular preferred embodiment, at least 90 mol %, preferably at least 95 mol %, more preferably at least 99 mol % of the rivastigmine in the rivastigmine-containing layer are present in the form of the free base.
(28) In one embodiment of the invention, the amount of rivastigmine contained in the rivastigmine-containing layer structure ranges from 0.5 to 5 mg/cm.sup.2, preferably from 1 to 3 mg/cm.sup.2. The total amount of rivastigmine in the rivastigmine-containing layer structure ranges from 1 to 45, preferably from 3 to 40 mg/TTS.
(29) In one embodiment of the invention, the rivastigmine-containing layer comprises rivastigmine in an amount of from 5 to 30% by weight, preferably from 7 to 28% by weight, most preferably from 10 to 25% by weight, based on the total weight of the rivastigmine-containing layer.
(30) In one embodiment of to the invention, the silicone acrylic hybrid polymer in the rivastigmine-containing layer contains a continuous, silicone external phase and a discontinuous, acrylic internal phase, or a continuous, acrylic external phase and a discontinuous, silicone internal phase, and wherein preferably the rivastigmine is present in the rivastigmine-containing layer in an amount of from 15 to 25% by weight based on the total weight of the rivastigmine-containing layer.
(31) In one embodiment, the rivastigmine-containing layer structure is a rivastigmine-containing self-adhesive layer structure and does not comprise an additional skin contact layer. In yet another embodiment, the silicone acrylic hybrid polymer is a silicon acrylic hybrid pressure-sensitive adhesive. When no additional skin contact layer is needed, the rivastigmine-containing layer is preferably a rivastigmine-containing matrix layer, which has adhesive properties. The rivastigmine-containing matrix layer composition may comprise a second polymer or may comprise two or more further polymers.
(32) In one embodiment of the invention, the amount of the silicone acrylic hybrid polymer ranges from 35 to 95% by weight, preferably from 40 to 93% by weight or from 45 to 90% by weight, based on the total weight of the rivastigmine-containing layer.
(33) It is to be understood that the TTS according to the present invention may also comprise one or more non-hybrid polymers (e.g. non-hybrid pressure-sensitive adhesives) in addition to the silicone acrylic hybrid polymer. Exemplarily, non-hybrid polymers (e.g. non-hybrid pressure-sensitive adhesives) based on polysiloxanes, acrylates, polyisobutylenes, or styrene-isoprene-styrene block copolymers may be used. In one embodiment of the invention, the non-hybrid polymer is a pressure-sensitive adhesive based on polysiloxanes, acrylates, or polyisobutylene, in particular based on polysiloxanes or acrylates. Additional polymers may also be added to enhance cohesion and/or adhesion. In yet another preferred embodiment, the invention relates to a transdermal therapeutic system, wherein the rivastigmine-containing layer does not comprise a permeation enhancer or solubilizer.
(34) In certain embodiments of the invention, the non-hybrid polymer is contained in the rivastigmine-containing layer in an amount of from 5 to 40%, preferably from 8 to 35% by weight based on the total weight of the rivastigmine-containing layer. In another embodiment of the invention, the weight ratio of the silicone acrylic hybrid polymer to the non-hybrid polymer is from 8:1 to 1:2, preferably from 7:1 to 1:1.
(35) In one embodiment of the invention, the area weight of the rivastigmine-containing layer ranges from 40 to 250 g/m.sup.2, preferably from 50 to 200 g/m.sup.2. In certain preferred embodiments, the area weight ranges from 60 to 180 g/m.sup.2.
(36) In certain embodiments of the invention, the TTS for the transdermal administration of rivastigmine comprises a rivastigmine-containing layer structure, said rivastigmine-containing layer structure comprising:
(37) A) a backing layer; and
(38) B) a rivastigmine-containing layer comprising: 1. rivastigmine in an amount of from 10 to 25% by weight based on the total weight of the rivastigmine-containing layer; 2. a silicone acrylic hybrid polymer containing a continuous, silicone external phase and a discontinuous, acrylic internal phase, in an amount of from 45 to 90% by weight based on the total weight of the rivastigmine-containing layer; and 3. optionally a pressure-sensitive adhesive based on polysiloxanes in an amount of from 10 to 30% by weight based on the total weight of the rivastigmine-containing layer;
wherein said rivastigmine-containing layer is the skin contact layer;
and wherein the area weight of said rivastigmine-containing layer ranges from 60 to 180 g/m.sup.2.
(39) In certain embodiments of the invention, the TTS for the transdermal administration of rivastigmine comprising a rivastigmine-containing layer structure, said rivastigmine-containing layer structure comprising:
(40) A) a backing layer; and
(41) B) a rivastigmine-containing layer comprising: 1. rivastigmine in an amount of from 10 to 25% by weight based on the total weight of the rivastigmine-containing layer; 2. a silicone acrylic hybrid polymer containing a continuous, acrylic external phase and a discontinuous, silicone internal phase, in an amount of from 40 to 90% by weight based on the total weight of the rivastigmine-containing layer; and 3. optionally a pressure-sensitive adhesive based on acrylates in an amount of from 5 to 40% by weight based on the total weight of the rivastigmine-containing layer;
wherein said rivastigmine-containing layer is the skin contact layer;
and wherein the area weight of said rivastigmine-containing layer ranges from 60 to 180 g/m.sup.2.
Rivastigmine
(42) The TTS according to the invention comprises a rivastigmine-containing layer structure, said rivastigmine containing layer structure comprising A) a backing layer; and B) a rivastigmine containing layer; wherein the transdermal therapeutic system comprises a silicone acrylic hybrid polymer.
(43) In one embodiment of the invention, the amount of rivastigmine contained in the rivastigmine-containing layer structure ranges from 0.5 to 5 mg/cm.sup.2, preferably from 1 to 3 mg/cm.sup.2.
(44) In one embodiment of the invention, the rivastigmine-containing layer structure preferably contains a therapeutically effective amount of rivastigmine. More preferably, the therapeutically effective amount of rivastigmine is present in the rivastigmine-containing layer of the rivastigmine-containing layer structure. Preferably, the rivastigmine in the rivastigmine-containing layer structure is present in the form of the free base.
(45) In one embodiment of the invention, at least 50 mol %, preferably at least 75 mol % of the total amount of rivastigmine in the TTS are present in the form of the free base. In a particular preferred embodiment, at least 90 mol %, preferably at least 95 mol %, more preferably at least 99 mol % of the total amount of rivastigmine in the TTS are present in the form of the free base. Thus, it is preferred that at least 50 mol %, preferably at least 75 mol % of the rivastigmine in the rivastigmine-containing layer are present in the form of the free base. In a particular preferred embodiment, at least 90 mol %, preferably at least 95 mol %, more preferably at least 99 mol % of the rivastigmine in the rivastigmine-containing layer are present in the form of the free base. In certain embodiments, the rivastigmine-containing layer is free of rivastigmine salts.
(46) In certain embodiments, the amount of rivastigmine in the rivastigmine-containing layer ranges from 5 to 30% by weight, preferably from 7 to 28% by weight, most preferably from 10 to 25% by weight, based on the total weight of the rivastigmine-containing layer.
(47) In certain embodiments, the amount of rivastigmine contained in the rivastigmine-containing layer ranges from 1 to 45 mg, preferably from 3 to 40 mg/TTS, depending on the patch size. In a patch of the size of e.g. 5 cm.sup.2, the amount of rivastigmine contained in the rivastigmine-containing layer ranges from 5 to 15 mg, preferably from 7 to 12 mg.
(48) In one embodiment of the invention, the rivastigmine-containing layer is obtainable by dissolving or dispersing the rivastigmine in the form of the free base. If the rivastigmine-containing layer is a rivastigmine-containing matrix layer, said layer is preferably obtainable by dissolving or dispersing the rivastigmine in the form of the free base in the polymeric carrier, which particularly preferably comprises the silicone acrylic hybrid polymer.
(49) In one embodiment, the rivastigmine-containing layer comprises a pharmaceutically acceptable salt of rivastigmine, such as rivastigmine hydrochloride or rivastigmine tartrate, preferably rivastigmine tartrate. However, it is preferred according to the invention that the rivastigmine in the rivastigmine-containing layer is present in the form of the free base.
(50) In certain embodiments, the rivastigmine has a purity of at least 95%, preferably of at least 98%, and more preferably of at least 99% as determined by quantitative HPLC. Quantitative HPLC may be performed with Reversed-Phase-HPLC with UV detection.
Silicone Acrylic Hybrid Polymer
(51) The TTS according to the present invention comprises a silicone acrylic hybrid polymer. The silicone acrylic hybrid polymer comprises a polymerized hybrid species that includes silicone-based sub-species and acrylate-based sub-species that have been polymerized together. The silicone acrylic hybrid polymer thus comprises a silicone phase and an acrylic phase. Preferably, the silicone acrylic hybrid polymer is a silicone acrylic hybrid pressure-sensitive adhesive.
(52) The silicone acrylic hybrid pressure-sensitive adhesives are usually supplied and used in solvents like n-heptane and ethyl acetate. The solids content of the pressure-sensitive adhesives is usually between 30% and 80%. The skilled person is aware that the solids content may be modified by adding a suitable amount of solvent.
(53) Preferably, the weight ratio of silicone to acrylate in the silicone acrylic hybrid pressure-sensitive adhesive is from 5:95 to 95:5, or from 20:80 to 80:20, more preferably from 40:60 to 60:40, and most preferably the ratio of silicone to acrylate is about 50:50. Suitable silicone acrylic hybrid pressure-sensitive adhesives having a weight ratio of silicone to acrylate of 50:50 are, for example, the commercially available silicone acrylic hybrid pressure-sensitive adhesives 7-6102, Silicone/Acrylate Ratio 50/50, and 7-6302, Silicone/Acrylate Ratio 50/50, supplied in ethyl acetate by Dow Corning.
(54) The preferred silicone acrylic hybrid pressure-sensitive adhesives in accordance with the invention are characterized by a solution viscosity at 25° C. and about 50% solids content in ethyl acetate of more than about 400 cP, or from about 500 cP to about 3,500 cP, in particular from about 1,000 cP to about 3,000 cP, more preferred from about 1,200 cP to about 1,800, or most preferred of about 1,500 cP or alternatively more preferred from about 2,200 cP to about 2,800 cP, or most preferred of about 2,500 cP, preferably as measured using a Brookfield RVT viscometer equipped with a spindle number 5 at 50 RPM.
(55) These silicone acrylic hybrid pressure-sensitive adhesives may also be characterized by a complex viscosity at 0.1 rad/s at 30° C. of less than about 1.0e9 Poise, or from about 1.0e5 Poise to about 9.0e8 Poise, or more preferred from about 9.0e5 Poise to about 1.0e7 Poise, or most preferred about 4.0e6 Poise, or alternatively more preferred from about 2.0e6 Poise to about 9.0e7 Poise, or most preferred about 1.0e7 Poise, preferably as measured using a Rheometrics ARES rheometer, wherein the rheometer is equipped with 8 mm plates and the gap zeroed.
(56) To prepare samples for measuring the rheological behavior using a Rheometrics ARES rheometer, between 2 and 3 grams of adhesive solution can be poured onto a SCOTCH-PAK 1022 fluoropolymer release liner and allow to sit for 60 minutes under ambient conditions. To achieve essentially solvent-free films of the adhesive, they can be placed in an oven at 110° C.+/−10° C. for 60 minutes. After removing from the oven and letting equilibrate to room temperature. The films can be removed from the release liner and folded over to form a square. To eliminate air bubbles the films can be compressed using a Carver press. The samples can then be loaded between the plates and are compressed to 1.5+/−0.1 mm at 30° C. The excess adhesive is trimmed and the final gap recorded. A frequency sweep between 0.01 to 100 rad/s can be performed with the following settings: Temperature=30° C.; strain=0.5-1% and data collected at 3 points/decade.
(57) Suitable silicone acrylic hybrid pressure-sensitive adhesives which are commercially available include the PSA series 7-6100 and 7-6300 manufactured and supplied in n-heptane or ethyl acetate by Dow Corning (7-610X and 7-630X; X=1 n-heptane-based/X=2 ethyl acetate-based). For example, the 7-6102 silicone acrylic hybrid PSA having a silicone/acrylate ratio of 50/50 is characterized by a solution viscosity at 25° C. and about 50% solids content in ethyl acetate of 2,500 cP and a complex viscosity at 0.1 rad/s at 30° C. of 1.0e7 Poise. The 7-6302 silicone acrylic hybrid PSA having a silicone/acrylate ratio of 50/50 has a solution viscosity at 25° C. and about 50% solids content in ethyl acetate of 1,500 cP and a complex viscosity at 0.1 rad/s at 30° C. of 4.0e6 Poise.
(58) Depending on the solvent in which the silicone acrylic hybrid pressure-sensitive adhesive is supplied, the arrangement of the silicone phase and the acrylic phase providing a silicone or acrylic continuous external phase and a corresponding discontinuous internal phase is different. If the silicone acrylic hybrid pressure-sensitive adhesive is provided in n-heptane, the composition contains a continuous, silicone external phase and a discontinuous, acrylic internal phase. If the silicone acrylic hybrid pressure-sensitive adhesive is provided in ethyl acetate, the composition contains a continuous, acrylic external phase and a discontinuous, silicone internal phase. After evaporating the solvent in which the silicone acrylic hybrid pressure-sensitive adhesive is provided, the phase arrangement of the resulting pressure-sensitive adhesive film or layer corresponds to the phase arrangement of the solvent-containing adhesive coating composition. For example, in the absence of any substance that may induce an inversion of the phase arrangement in a silicone acrylic hybrid pressure sensitive adhesive composition, a pressure-sensitive adhesive layer prepared from a silicone acrylic hybrid pressure-sensitive adhesive in n-heptane provides a continuous, silicone external phase and a discontinuous, acrylic internal phase, a pressure-sensitive adhesive layer prepared from a silicone acrylic hybrid pressure-sensitive adhesive in ethyl acetate provides a continuous, acrylic external phase and a discontinuous, silicone internal phase. The phase arrangement of the compositions can, for example, be determined in peel force tests with pressure-sensitive adhesive films or layers prepared from the silicone acrylic hybrid PSA compositions which are attached to a siliconized release liner. The pressure-sensitive adhesive film contains a continuous, silicone external phase if the siliconized release liner cannot or can only hardly be removed from the pressure-sensitive adhesive film (laminated to a backing film) due to the blocking of the two silicone surfaces. Blocking results from the adherence of two silicone layers which comprise a similar surface energy. The silicone adhesive shows a good spreading on the siliconized liner and therefore can create a good adhesion to the liner. If the siliconized release liner can easily be removed the pressure-sensitive adhesive film contains a continuous, acrylic external phase. The acrylic adhesive has no good spreading due to the different surface energies and thus has a low or almost no adhesion to the siliconized liner.
(59) According to a preferred embodiment of the invention the silicone acrylic hybrid polymer is a silicone acrylic hybrid pressure-sensitive adhesive obtainable from a silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality. It is to be understood that the silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality can include only acrylate functionality, only methacrylate functionality, or both acrylate functionality and methacrylate functionality.
(60) According to certain embodiments of the invention the silicone acrylic hybrid pressure-sensitive adhesive comprises the reaction product of (a) a silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality, (b) an ethylenically unsaturated monomer, and (c) an initiator. That is, the silicone acrylic hybrid pressure-sensitive adhesive is the product of the chemical reaction between these reactants ((a), (b), and (c)). In particular, the silicone acrylic hybrid pressure-sensitive adhesive includes the reaction product of (a) a silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality, (b) a (meth)acrylate monomer, and (c) an initiator (i.e., in the presence of the initiator). That is, the silicone acrylic hybrid pressure-sensitive adhesive includes the product of the chemical reaction between these reactants ((a), (b), and (c)).
(61) The reaction product of (a) a silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality, (b) an ethylenically unsaturated monomer, and (c) an initiator may contain a continuous, silicone external phase and a discontinuous, acrylic internal phase or the reaction product of (a), (b), and (c) may contain a continuous, acrylic external phase and a discontinuous, silicone internal phase.
(62) The silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality (a) is typically present in the silicone acrylic hybrid pressure-sensitive adhesive in an amount of from 5 to 95, more typically 25 to 75, parts by weight based on 100 parts by weight of the hybrid pressure-sensitive adhesive.
(63) The ethylenically unsaturated monomer (b) is typically present in the silicone acrylic hybrid pressure-sensitive adhesive in an amount of from 5 to 95, more typically 25 to 75, parts by weight based on 100 parts by weight of the hybrid pressure-sensitive adhesive.
(64) The initiator (c) is typically present in the silicone acrylic hybrid pressure-sensitive adhesive in an amount of from 0.005 to 3, more typically from 0.01 to 2, parts by weight based on 100 parts by weight of the hybrid pressure-sensitive adhesive.
(65) According to certain embodiments of the invention the silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality (a) comprises the condensation reaction product of (a1) a silicone resin, (a2) a silicone polymer, and (a3) a silicon-containing capping agent which provides said acrylate or methacrylate functionality. The silicone resin (a1) may also be referred to as silicate resin or silica resin. Preferably, the silicone polymer (a2) is a polysiloxane, preferably polydimethylsiloxane. It is to be understood that (a1) and (a2) form a silicone-based pressure sensitive adhesive by polycondensation, and that the acrylate or methacrylate functionality is introduced by reaction with (a3).
(66) According to certain embodiments of the invention the silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality (a) comprises the condensation reaction product of: (a1) a silicone resin, (a2) a silicone polymer, and (a3) a silicon-containing capping agent which provides said acrylate or methacrylate functionality, wherein said silicon-containing capping agent is of the general formula XYR′.sub.bSiZ.sub.3-b, wherein X is a monovalent radical of the general formula AE- where E is —O— or —NH— and A is an acryl group or a methacryl group, Y is a divalent alkylene radical having from 1 to 6 carbon atoms, R′ is a methyl or a phenyl radical, Z is a monovalent hydrolyzable organic radical or a halogen, and b is 0 or 1; wherein the silicone resin and silicone polymer are reacted to form a pressure-sensitive adhesive, wherein the silicon-containing capping agent is introduced prior to, during, or after the silicone resin and silicone polymer are reacted, and wherein: the silicon-containing capping agent reacts with the pressure-sensitive adhesive after the silicone resin and silicone polymer have been condensation reacted to form the pressure-sensitive adhesive; or the silicon-containing capping agent reacts in-situ with the silicone resin and silicone polymer.
(67) According to certain embodiments of the invention the silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality comprises the condensation reaction product of a pressure sensitive adhesive and a silicon-containing capping agent which provides said acrylate or methacrylate functionality. That is, the silicon-containing pressure sensitive adhesive composition comprising acrylate or methacrylate functionality is essentially a pressure sensitive adhesive that has been capped or end blocked with the silicon-containing capping agent which provides said acrylate or methacrylate functionality, wherein the pressure sensitive adhesive comprises the condensation reaction product of the silicone resin and the silicone polymer. Preferably, the silicone resin reacts in an amount of from 30 to 80 parts by weight to form the pressure sensitive adhesive, and the silicone polymer reacts in an amount of from 20 to 70 parts by weight to form the pressure sensitive adhesive. Both of these parts by weight are based on 100 parts by weight of the pressure sensitive adhesive. Although not required, the pressure sensitive adhesive may comprise a catalytic amount of a condensation catalyst. A wide array of silicone resins and silicone polymers are suitable to make up the pressure sensitive adhesive.
(68) According to certain embodiments of the invention the silicone acrylic hybrid pressure-sensitive adhesive is the reaction product of:
(69) (a) a silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality that comprises the condensation reaction product of:
(70) (a1) a silicone resin, (a2) a silicone polymer, and (a3) a silicon-containing capping agent which provides said acrylate or methacrylate functionality, wherein said silicon-containing capping agent is of the general formula XYR′.sub.bSiZ.sub.3-b, wherein X is a monovalent radical of the general formula AE- where E is —O— or —NH— and A is an acryl group or a methacryl group, Y is a divalent alkylene radical having from 1 to 6 carbon atoms, R′ is a methyl or a phenyl radical, Z is a monovalent hydrolyzable organic radical or a halogen, and b is 0 or 1; wherein the silicone resin and silicone polymer are reacted to form a pressure-sensitive adhesive, wherein the silicon-containing capping agent is introduced prior to, during, or after the silicone resin and silicone polymer are reacted, and wherein: the silicon-containing capping agent reacts with the pressure-sensitive adhesive after the silicone resin and silicone polymer have been condensation reacted to form the pressure-sensitive adhesive; or the silicon-containing capping agent reacts in-situ with the silicone resin and silicone polymer;
(b) an ethylenically unsaturated monomer; and
(c) an initiator.
(71) The silicone acrylic hybrid composition used in the present invention may be described by being prepared by a method comprising the steps of:
(72) (i) providing a silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality that comprises the condensation reaction product of:
(73) a silicone resin, a silicone polymer, and a silicon-containing capping agent which provides said acrylate or methacrylate functionality, wherein said silicon-containing capping agent is of the general formula XYR′.sub.bSiZ.sub.3-b, wherein X is a monovalent radical of the general formula AE- where E is —O— or —NH— and A is an acryl group or a methacryl group, Y is a divalent alkylene radical having from 1 to 6 carbon atoms, R′ is a methyl or a phenyl radical, Z is a monovalent hydrolyzable organic radical or a halogen, and b is 0 or 1; wherein the silicone resin and silicone polymer are reacted to form a pressure-sensitive adhesive, wherein the silicon-containing capping agent is introduced prior to, during, or after the silicone resin and silicone polymer are reacted, and wherein: the silicon-containing capping agent reacts with the pressure-sensitive adhesive after the silicone resin and silicone polymer have been condensation reacted to form the pressure-sensitive adhesive; or the silicon-containing capping agent reacts in-situ with the silicone resin and silicone polymer;
(ii) polymerizing an ethylenically unsaturated monomer and the silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality of step (i) in the presence of an initiator to form a silicone acrylic hybrid composition, optionally at a temperature of from 50° C. to 100° C., or from 65° C. to 90° C.
(74) During the polymerization of the ethylenically unsaturated monomer and the silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality, the silicone to acrylic ratio can be controlled and optimized as desired. The silicone to acrylic ratio can be controlled by a wide variety of mechanisms in and during the method. An illustrative example of one such mechanism is the rate controlled addition of the ethylenically unsaturated monomer or monomers to the silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality. In certain applications, it may be desirable to have the silicone-based sub-species, or the overall silicone content, to exceed the acrylate-based sub-species, or the overall acrylic content. In other applications, it may be desirable for the opposite to be true. Independent of the end application, it is generally preferred, as already described above, that the silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality is preferably present in the silicone acrylic hybrid composition in an amount of from about 5 to about 95 parts by weight, more preferably from about 25 to about 75 parts by weight, and still more preferably from about 40 to about 60 parts by weight based on 100 parts by weight of the silicone acrylic hybrid composition.
(75) According to a certain embodiment of the invention, the silicone acrylic hybrid composition used in the present invention may be described by being prepared by a method comprising the steps of:
(76) (i) providing a silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality that comprises the condensation reaction product of:
(77) a silicone resin, a silicone polymer, and a silicon-containing capping agent which provides said acrylate or methacrylate functionality, wherein said silicon-containing capping agent is of the general formula XYR′.sub.bSiZ.sub.3-b, wherein X is a monovalent radical of the general formula AE- where E is —O— or —NH— and A is an acryl group or a methacryl group, Y is a divalent alkylene radical having from 1 to 6 carbon atoms, R′ is a methyl or a phenyl radical, Z is a monovalent hydrolyzable organic radical or a halogen, and b is 0 or 1; wherein the silicone resin and silicone polymer are reacted to form a pressure-sensitive adhesive, wherein the silicon-containing capping agent is introduced prior to, during, or after the silicone resin and silicone polymer are reacted, and wherein: the silicon-containing capping agent reacts with the pressure-sensitive adhesive after the silicone resin and silicone polymer have been condensation reacted to form the pressure-sensitive adhesive; or the silicon-containing capping agent reacts in-situ with the silicone resin and silicone polymer;
(ii) polymerizing an ethylenically unsaturated monomer and the silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality of step (i) in a first solvent in the presence of an initiator at a temperature of from 50° C. to 100° C. to form a silicone acrylic hybrid composition;
(iii) removing the first solvent; and
(iv) adding a second solvent to form the silicone acrylic hybrid composition, wherein the phase arrangement of the silicone acrylic hybrid composition is selectively controlled by selection of the second solvent.
(78) The silicone acrylic hybrid PSA composition used in the present invention may also be described by being prepared by a method comprising the steps of:
(79) (i) providing a silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality that comprises the condensation reaction product of:
(80) a silicone resin, a silicone polymer, and a silicon-containing capping agent which provides said acrylate or methacrylate functionality, wherein said silicon-containing capping agent is of the general formula XYR′.sub.bSiZ.sub.3-b, wherein X is a monovalent radical of the general formula AE- where E is —O— or —NH— and A is an acryl group or a methacryl group, Y is a divalent alkylene radical having from 1 to 6 carbon atoms, R′ is a methyl or a phenyl radical, Z is a monovalent hydrolyzable organic radical or a halogen, and b is 0 or 1; wherein the silicone resin and silicone polymer are reacted to form a pressure-sensitive adhesive, wherein the silicon-containing capping agent is introduced prior to, during, or after the silicone resin and silicone polymer are reacted, and wherein: the silicon-containing capping agent reacts with the pressure-sensitive adhesive after the silicone resin and silicone polymer have been condensation reacted to form the pressure-sensitive adhesive; or the silicon-containing capping agent reacts in-situ with the silicone resin and silicone polymer;
(ii) polymerizing an ethylenically unsaturated monomer and the silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality of step (i) in a first solvent in the presence of an initiator at a temperature of from 50° C. to 100° C. to form a silicone acrylic hybrid composition;
(iii) adding a processing solvent, wherein the processing solvent has a higher boiling point than the first solvent, and
(iv) applying heat at a temperature of from 70° C. to 150° C. such that a majority of the first solvent is selectively removed;
(v) removing the processing solvent; and.
(vi) adding a second solvent to form the silicone acrylic hybrid composition, wherein the phase arrangement of the silicone acrylic hybrid composition is selectively controlled by selection of the second solvent.
(81) The silicone resin according to the previous paragraphs may contain a copolymer comprising triorganosiloxy units of the formula R.sup.X.sub.3SiO.sub.1/2 and tetrafunctional siloxy units of the formula SiO.sub.4/2 in a ratio of from 0.1 to 0.9, preferably of about 0.6 to 0.9, triorganosiloxy units for each tetrafunctional siloxy unit. Preferably, each R.sup.X independently denotes a monovalent hydrocarbon radical having from 1 to 6 carbon atoms, vinyl, hydroxyl or phenyl groups.
(82) The silicone polymer according to the previous paragraphs may comprise at least one polydiorganosiloxane and is preferably end-capped (end-blocked) with a functional group selected from the group consisting of hydroxyl groups, alkoxy groups, hydride groups, vinyl groups, or mixtures thereof. The diorganosubstituent may be selected from the group consisting of dimethyl, methylvinyl, methylphenyl, diphenyl, methylethyl, (3,3,3-trifluoropropyl)methyl and mixtures thereof. Preferably, the diorganosubstituents contain only methyl groups. The molecular weight of polydiorganosiloxane will typically range from about 50,000 to about 1,000,000, preferably, from about 80,000 to about 300,000. Preferably, the polydiorganosiloxane comprises AR.sup.XSiO units terminated with endblocking TR.sup.XASiO.sub.1/2 units, wherein the polydiorganosiloxane has a viscosity of from about 100 centipoise to about 30,000,000 centipoise at 25° C., each A radical is independently selected from R.sup.X or halohydrocarbon radicals having from 1 to 6 carbon atoms, each T radical is independently selected from the group consisting of R.sup.X, OH, H or OR.sup.Y, and each R.sup.Y is independently an alkyl radical having from 1 to 4 carbon atoms.
(83) As an example using forms of the preferred silicone resin and the preferred silicone polymer, one type of pressure sensitive adhesive is made by:
(84) mixing (1) from 30 to 80 inclusive parts by weight of at least one resin copolymer containing silicon-bonded hydroxyl radicals and consisting essentially of R.sup.X.sub.3SiO.sub.1/2 units and SiO.sub.4/2 units in a mole ratio of 0.6 to 0.9 R.sup.X.sub.3SiO.sub.1/2 units for each SiO.sub.4/2 unit present, (ii) between about 20 and about 70 parts by weight of at least one polydiorganosiloxane comprising AR.sup.XSiO units terminated with endblocking TR.sup.XASiO.sub.1/2 units, wherein the polydiorganosiloxane has a viscosity of from about 100 centipoise to about 30,000,000 centipoise at 25° C. and each R.sup.X is a monovalent organic radical selected from the group consisting of hydrocarbon radicals of from 1 to 6 inclusive carbon atoms, each A radical is independently selected from R.sup.X or halohydrocarbon radicals having from 1 to 6 inclusive carbon atoms, each T radical is independently selected from the group consisting of R.sup.X, OH, H or OR.sup.Y, and each R.sup.Y is independently an alkyl radical of from 1 to 4 inclusive carbon atoms; a sufficient amount of (iii) at least one of the silicon-containing capping agents, also referred to throughout as endblocking agents, described below and capable of providing a silanol content, or concentration, in the range of 5,000 to 15,000, more typically 8,000 to 13,000, ppm, when desirable an additional catalytic amount of (iv) a mild silanol condensation catalyst in the event that none is provided by (ii), and when necessary, an effective amount of (v) an organic solvent which is inert with respect to (i), (ii), (iii) and (iv) to reduce the viscosity of a mixture of (i), (ii), (iii), and (iv), and condensing the mixture of (1), (ii), (iii) and (iv) at least until a substantial amount of the silicon-containing capping agent or agents have reacted with the silicon-bonded hydroxyl radicals and T radicals of (i) and (ii). Additional organosilicon endblocking agents can be used in conjunction with the silicon-containing capping agent or agents (iii) of the present invention.
(85) The silicon-containing capping agent according to the previous paragraphs may be selected from the group of acrylate functional silanes, acrylate functional silazanes, acrylate functional disilazanes, acrylate functional disiloxanes, methacrylate functional silanes, methacrylate functional silazanes, methacrylate functional disilazanes, meth-acrylate functional disiloxanes, and combinations thereof and may be described as to be of the general formula XYR′.sub.bSiZ.sub.3-b, wherein X is a monovalent radical of the general formula AE- where E is —O— or —NH— and A is an acryl group or a methacryl group, Y is a divalent alkylene radical having from 1 to 6 carbon atoms, R′ is a methyl or a phenyl radical, Z is a monovalent hydrolyzable organic radical or a halogen, and b is 0, 1 or 2. Preferably, the monovalent hydrolyzable organic radical is of the general formula R″0—where R″ is an alkylene radical. Most preferably, this particular endblocking agent is selected from the group of 3-methacryloxypropyldimethylchlorosilane, 3-methacryloxypropyldichlorosilane, 3-methacryloxypropyltrichlorosilane, 3-methacryloxypropyldimethylmethoxysilane, 3-methacryloxypropylmethyldimethoxysilane, 3-meth-acryloxypropyltrimethoxysilane, 3-methacryloxypropyldimethylethoxysilane, 3-methacryloxypropylmethyldiethoxysilane, 3-methacryloxypropyltriethoxysilane, (methacryloxymethyl)dimethylmethoxysilane, (methacryloxymethyl)methyldimethoxysilane, (methacryloxymethyl)trimethoxysilane, (methacryloxymethyl)dimethylethoxysilane, (methacryloxymethyl)methyldiethoxysilane, methacryloxymethyltriethoxysilane, methacryloxy-propyltriisopropoxysilane, 3-methacryloxypropyldimethylsilazane, 3-acryloxy-propyldimethylchlorosilane, 3-acryloxypropyldichlorosilane, 3-acryloxypropyl-trichlorosilane, 3-acryloxypropyldimethylmethoxysilane, 3-acryloxy-propylmethyldimethoxysilane, 3-acryloxypropyltrimethoxysilane, 3-acryloxypropyl-dimethylsilazane, and combinations thereof.
(86) The ethylenically unsaturated monomer according to the previous paragraphs can be any monomer having at least one carbon-carbon double bond. Preferably, the ethylenically unsaturated monomer according to the previous paragraphs may be a compound selected from the group consisting of aliphatic acrylates, aliphatic methacrylates, cycloaliphatic acrylates, cycloaliphatic methacrylates, and combinations thereof. It is to be understood that each of the compounds, the aliphatic acrylates, the aliphatic methacrylates, the cycloaliphatic acrylates, and the cycloaliphatic methacrylates, include an alkyl radical. The alkyl radicals of these compounds can include up to 20 carbon atoms. The aliphatic acrylates that may be selected as one of the ethylenically unsaturated monomers are selected from the group consisting of methyl acrylate, ethyl acrylate, propyl acrylate, n-butyl acrylate, iso-butyl acrylate, tert-butyl acrylate, hexyl acrylate, 2-ethylhexyl acrylate, iso-octyl acrylate, iso-nonyl acrylate, iso-pentyl acrylate, tridecyl acrylate, stearyl acrylate, lauryl acrylate, and mixtures thereof. The aliphatic methacrylates that may be selected as one of the ethylenically unsaturated monomers are selected from the group consisting of methyl methacrylate, ethyl methacrylate, propyl methacrylate, n-butyl methacrylate, iso-butyl meth-acrylate, tert-butyl methacrylate, hexyl methacrylate, 2-eth-ylhexyl methacrylate, iso-octyl methacrylate, iso-nonyl methacrylate, iso-pentyl methacrylate, tridecyl methacrylate, stearyl methacrylate, lauryl methacrylate, and mixtures thereof. The cycloaliphatic acrylate that may be selected as one of the ethylenically unsaturated monomers is cyclohexyl acrylate, and the cycloaliphatic methacrylate that may be selected as one of the ethylenically unsaturated monomers is cyclohexyl methacrylate.
(87) It is to be understood that the ethylenically unsaturated monomer used for preparing the silicone acrylic hybrid pressure sensitive adhesive may be more than one ethylenically unsaturated monomer. That is, a combination of ethylenically unsaturated monomers may be polymerized, more specifically co-polymerized, along with the silicon-containing pressure sensitive adhesive composition comprising acrylate or methacrylate functionality and the initiator. According to a certain embodiment of the invention, the silicone acrylic hybrid pressure-sensitive adhesive is prepared by using at least two different ethylenically unsaturated monomers, preferably selected from the group of 2-ethylhexyl acrylate and methyl acrylate, more preferably in a ratio of 50% 2-ethylhexyl acrylate and 50% methyl acrylate, or in a ratio of 60% 2-ethylhexyl acrylate and 40% methyl acrylate as the acrylic monomer.
(88) The initiator according to the previous paragraphs may be any substance that is suitable to initiate the polymerization of the silicon-containing pressure sensitive adhesive composition comprising acrylate or methacrylate functionality and the ethylenically unsaturated monomer to form the silicone acrylic hybrid. For example, free radical initiators selected from the group of peroxides, azo compounds, redox initiators, and photo-initiators may be used.
(89) Further suitable silicone resins, silicone polymers, silicon-containing capping agents, ethylenically unsaturated monomers, and initiators that can be used in accordance with the previous paragraphs are detailed in WO 2007/145996, EP 2 599 847 A1, and WO 2016/130408.
(90) According to a certain embodiment of the invention, the silicone acrylic hybrid polymer comprises a reaction product of a silicone polymer, a silicone resin and an acrylic polymer, wherein the acrylic polymer is covalently self-crosslinked and covalently bound to the silicone polymer and/or the silicone resin.
(91) According to a certain other embodiment of the invention, the silicone acrylic hybrid polymer comprises a reaction product of a silicone polymer, a silicone resin and an acrylic polymer, wherein the silicone resin contains triorganosiloxy units R.sub.3SiO.sub.1/2 where R is an organic group, and tetrafunctional siloxy units SiO.sub.4/2 in a mole ratio of from 0.1 to 0.9 R.sub.3SiO.sub.1/2 units for each SiO.sub.4/2.
(92) The acrylic polymer may comprise at least an alkoxysilyl functional monomer, polysiloxane-containing monomer, halosilyl functional monomer or alkoxy halosilyl functional monomer. Preferably, the acrylic polymer is prepared from alkoxysilyl functional monomers selected from the group consisting of trialkoxylsilyl (meth)acrylates, dialkoxyalkylsilyl (meth)acrylates, and mixtures thereof, or comprises end-capped alkoxysilyl functional groups. The alkoxysilyl functional groups may preferably be selected from the group consisting of trimethoxylsilyl groups, dimethoxymethylsilyl groups, triethoxylsilyl, diethoxymethylsilyl groups and mixtures thereof.
(93) The acrylic polymer may also be prepared from a mixture comprising polysiloxane-containing monomers, preferably from a mixture comprising polydimethylsiloxane mono (meth)acrylate.
(94) The silyl functional monomers will typically be used in amounts of from 0.2 to 20% by weight of the acrylic polymer, more preferably the amount of silyl functional monomers will range from about 1.5 to about 5% by weight of the acrylic polymer.
(95) The amount of polysiloxane-containing monomer will typically be used in amounts of from 1.5 to 50% by weight of the acrylic polymer, more preferably the amount of polysiloxane-containing monomers will range from 5 to 15% by weight of the acrylic polymer.
(96) Alternatively, the acrylic polymer comprises a block or grafted copolymer of acrylic and polysiloxane. An example of a polysiloxane block copolymer is polydimethylsiloxane-acrylic block copolymer. The preferred amount of siloxane block is 10 to 50% weight of the whole block polymer.
(97) The acrylic polymer comprises alkyl (meth)acrylate monomers. Preferred alkyl (meth)acrylates which may be used have up to about 18 carbon atoms in the alkyl group, preferably from 1 to about 12 carbon atoms in the alkyl group. Preferred low glass transition temperature (Tg) alkyl acrylate with a homopolymer Tg of less than about 0° C. have from about 4 to about 10 carbon atoms in the alkyl group and include butyl acrylate, amyl acrylate, hexyl acrylate, 2-ethylhexyl acrylate, octyl acrylate, isooctyl acrylate, decyl acrylate, isomers thereof, and combinations thereof. Particularly preferred are butyl acrylate, 2-ethylhexyl acrylate and isooctyl acrylate. The acrylic polymer components may further comprise (meth)acrylate monomers having a high Tg such as methyl acrylate, ethyl acrylate, methyl methacrylate and isobutyl methacrylate.
(98) The acrylic polymer component may further comprise a polyisobutylene group to improve cold flow properties of the resultant adhesive.
(99) The acrylic polymer components may comprise nitrogen-containing polar monomers. Examples include N-vinyl pyrrolidone, N-vinyl caprolactam, N-tertiary octyl acrylamide, dimethyl acrylamide, diacetone acrylamide, N-tertiary butyl acrylamide, N-isopropyl acrylamide, cyanoethylacrylate, N-vinyl acetamide and N-vinyl formamide.
(100) The acrylic polymer component may comprise one or more hydroxyl containing monomers such as 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, hydroxypropyl acrylate and/or hydroxypropyl methacrylate.
(101) The acrylic polymer components may, if desired, comprise carboxylic acid containing monomers. Useful carboxylic acids preferably contain from about 3 to about 6 carbon atoms and include, among others, acrylic acid, methacrylic acid, itaconic acid, β-carboxyethyl acrylate and the like. Acrylic acid is particularly preferred.
(102) Other useful, well known co-monomers include vinyl acetate, styrene, cyclohexyl acrylate, alkyl di(meth)acrylates, glycidyl methacrylate and allyl glycidyl ether, as well as macromers such as, for example, poly(styryl)methacrylate.
(103) One acrylic polymer component that can be used in the practice of the invention is an acrylic polymer that comprises from about 90 to about 99.5% by weight of butyl acrylate and from about 0.5 to about 10% by weight dimethoxymethylsilyl methacrylate.
(104) According to a certain embodiment of the invention the silicone acrylic hybrid polymer may be prepared by a) reacting silicone polymer with silicone resin to form a resultant product, b) reacting the resultant product of a) with an acrylic polymer containing reactive functionality, wherein the components are reacted in an organic solvent.
(105) According to a certain embodiment of the invention the silicone acrylic hybrid polymer may be prepared by a) reacting a silicone resin with an acrylic polymer containing reactive functionality to form a resultant product, b) reacting the resultant product of a) with silicone polymer, wherein the components are reacted in an organic solvent.
(106) According to a certain embodiment of the invention the silicone acrylic hybrid polymer may be prepared by a) reacting a silicone polymer with an acrylic polymer containing reactive functionality to form a resultant product, b) reacting the resultant product of a) with silicone resin, wherein the components are reacted in an organic solvent.
(107) Further suitable acrylic polymers, silicone resins, and silicone polymers that can be used for chemically reacting together a silicone polymer, a silicone resin and an acrylic polymer to provide a silicone acrylic hybrid polymer in accordance with the previous paragraphs are detailed in WO 2010/124187.
(108) According to certain embodiments of the invention, the silicone acrylic hybrid polymer used in the TTS is blended with one or more non-hybrid polymers, preferably the silicone acrylic hybrid polymer is blended with one or more non-hybrid pressure sensitive adhesives (e.g. pressure-sensitive adhesives based on polysiloxane or acrylates).
Non-Hybrid Polymers
(109) According to a certain embodiment of the invention, the TTS comprises one or more non-hybrid polymers (e.g. non-hybrid pressure-sensitive adhesives) in addition to the silicone acrylic hybrid polymer. Non-hybrid polymers (e.g. non-hybrid pressure-sensitive adhesives) are polymers (e.g. polymer-based pressure-sensitive adhesives) which do not include a hybrid species. Preferred are non-hybrid polymers (e.g. non-hybrid pressure-sensitive adhesives) based on polysiloxanes, acrylates, polyisobutylenes, or styrene-isoprene-styrene block copolymers.
(110) The non-hybrid polymers (e.g. the non-hybrid pressure-sensitive adhesives) may be contained in the active agent-containing layer structure and/or in the adhesive overlay.
(111) Non-hybrid pressure-sensitive adhesives are usually supplied and used in solvents like n-heptane and ethyl acetate. The solids content of the pressure-sensitive adhesives is usually between 30% and 80%.
(112) Suitable non-hybrid polymers according to the invention are commercially available e.g. under the brand names BIO-PSAs (pressure sensitive adhesives based on polysiloxanes), Oppanol™ (polyisobutylenes), JSR-SIS (a styrene-isoprene-styrene copolymer) or Duro-Tak™ (acrylic polymers).
(113) Polymers based on polysiloxanes may also be referred to as silicone-based polymers. These polymers based on polysiloxanes are preferably pressure sensitive adhesives based on polysiloxanes. Pressure-sensitive adhesives based on polysiloxanes may also be referred to as silicone-based pressure-sensitive adhesives, or silicone pressure-sensitive adhesives. These pressure-sensitive adhesives based on polysiloxanes provide for suitable tack and for quick bonding to various skin types, including wet skin, suitable adhesive and cohesive qualities, long lasting adhesion to the skin, a high degree of flexibility, a permeability to moisture, and compatibility to many actives and film-substrates. It is possible to provide them with sufficient amine resistance and therefore enhanced stability in the presence of amines. Such pressure-sensitive adhesives are based on a resin-in-polymer concept wherein, by condensation reaction of silanol end blocked polydimethylsiloxane with a silica resin (also referred to as silicate resin), a pressure-sensitive adhesive based on polysiloxane is prepared wherein for amine stability the residual silanol functionality is additionally capped with trimethylsiloxy groups. The silanol end blocked polydimethylsiloxane content contributes to the viscous component of the visco-elastic behavior, and impacts the wetting and the spreadability properties of the adhesive. The resin acts as a tackifying and reinforcing agent, and participates in the elastic component. The correct balance between silanol end blocked polydimethylsiloxane and resin provides for the correct adhesive properties.
(114) In view of the above, silicone-based polymers, and in particular silicone-based pressure sensitive adhesives, are generally obtainable by polycondensation of silanol endblocked polydimethylsiloxane with a silicate resin. Amine-compatible silicone-based polymers, and in particular amine-compatible silicone-based pressure sensitive adhesives, can be obtained by reacting the silicone-based polymer, in particular the silicone-based pressure sensitive adhesive, with trimethylsilyl (e.g. hexamethyldisilazane) in order to reduce the silanol content of the polymer. As a result, the residual silanol functionality is at least partly, preferably mostly or fully capped with trimethylsiloxy groups.
(115) As indicated above, the tackiness of the silicone-based polymer may be modified by the resin-to-polymer ratio, i.e. the ratio of the silanol endblocked polydimethylsiloxane to the silicate resin, which is preferably in the range of from 70:30 to 50:50, preferably from 65:35 to 55:45. The tackiness will be increased with increasing amounts of the polydimethylsiloxane relative to the resin. High tack silicone-based polymers preferably have a resin-to-polymer ratio of 55:45, medium tack silicone-based polymers preferably have a resin-to-polymer ratio of 60:40, and low tack silicone-based polymers preferably have a resin-to-polymer ratio of 65:35. High tack silicone-based polymers preferably have a complex viscosity at 0.01 rad/s and 30° C. of about 5×10.sup.6 Poise, medium tack silicone-based polymers preferably have a complex viscosity at 0.01 rad/s and 30° C. of about 5×10.sup.7 Poise, and low tack silicone-based polymers preferably have a complex viscosity at 0.01 rad/s and 30° C. of about 5×10.sup.8 Poise. High tack amine-compatible silicone-based polymers preferably have a complex viscosity at 0.01 rad/s and 30° C. of about 5×10.sup.6 Poise, medium tack amine-compatible silicone-based polymers preferably have a complex viscosity at 0.01 rad/s and 30° C. of about 5×10.sup.8 Poise, and low tack amine-compatible silicone-based polymers preferably have a complex viscosity at 0.01 rad/s and 30° C. of about 5×10.sup.9 Poise.
(116) Examples of silicone-based PSA compositions which are commercially available include the standard BIO-PSA series (7-4400, 7-4500 and 7-4600 series), the amine compatible (endcapped) BIO-PSA series (7-4100, 7-4200 and 7-4300 series) and the Soft Skin Adhesives series (7-9800) manufactured and typically supplied in n-heptane or ethyl acetate by Dow Corning. For example, BIO-PSA 7-4201 is characterized by a solution viscosity at 25° C. and about 60% solids content in heptane of 450 mPa s and a complex viscosity at 0.01 rad/s at 30° C. of 1×10.sup.8 Poise. BIO-PSA 7-4301 has a solution viscosity at 25° C. and about 60% solids content in heptane of 500 mPa s and a complex viscosity at 0.01 rad/s at 30° C. of 5×10.sup.6 Poise.
(117) The pressure-sensitive adhesives based on polysiloxanes are supplied and used in solvents like n-heptane, ethyl acetate or other volatile silicone fluids. The solids content of pressure-sensitive adhesives based on polysiloxanes in solvents is usually between 60 and 85%, preferably between 70 and 80% or between 60 and 75%. The skilled person is aware that the solids content may be modified by adding a suitable amount of solvent.
(118) Pressure-sensitive adhesives based on polysiloxanes, which are, e.g., available from Dow Corning, may be obtained according to the following scheme:
(119) ##STR00002##
Such pressure-sensitive adhesives based on polysiloxanes are available from Dow Corning, e.g., under the tradenames BIO-PSA 7-4401, BIO-PSA-7-4501, or BIO-PSA 7-4601, which are provided in the solvent n-heptane (indicated by the code “01”), or under the tradenames BIO-PSA 7-4402, BIO-PSA 7-4502, and BIO 7-4602, which are provided in the solvent ethyl acetate (indicated by the code “02”). Typical solids contents in the solvent are in the range of from 60 to 75%. The code “44” indicates a resin-to-polymer ratio of 65:35 resulting in a low tackiness, the code “45” indicates a resin-to-polymer ratio of 60:40 resulting in medium tackiness, the code “46” indicates a resin-to-polymer ratio of 55:45 resulting in high tackiness.
(120) Amine-compatible pressure-sensitive adhesives based on polysiloxanes, which are, e.g., available from Dow Corning may be obtained according to the following scheme:
(121) ##STR00003##
Such amine-compatible pressure-sensitive adhesives based on polysiloxanes are available from Dow Corning, e.g., under the tradenames BIO-PSA 7-4101, BIO-PSA-7-4201, or BIO-PSA 7-4301, which are provided in the solvent n-heptane (indicated by the code “01”), or under the tradenames BIO-PSA 7-4102, BIO-PSA 7-4202, and BIO 7-4302, which are provided in the solvent ethyl acetate (indicated by the code “02”). Typical solids contents in the solvent are in the range of from 60 to 75%. The code “41” indicates a resin-to-polymer ratio of 65:35 resulting in a low tackiness, the code “42” indicates a resin-to-polymer ratio of 60:40 resulting in medium tackiness, the code “43” indicates a resin-to-polymer ratio of 55:45 resulting in high tackiness.
(122) The preferred pressure-sensitive adhesives based on polysiloxanes in accordance with the invention are characterized by a solution viscosity at 25° C. and 60% solids content in n-heptane of more than about 150 mPa s, or from about 200 mPa s to about 700 mPa s, preferably as measured using a Brookfield RVT viscometer equipped with a spindle number 5 at 50 rpm. Theses may also be characterized by a complex viscosity at 0.01 rad/s at 30° C. of less than about 1×10.sup.9 Poise or from about 1×10.sup.5 to about 9×10.sup.8 Poise.
(123) Suitable polyisobutylenes according to the invention are available under the tradename Oppanol®. Combinations of high-molecular weight polyisobutylenes (B100/B80) and low-molecular weight polyisobutylenes (B10, B11, B12, B13) may be used. Suitable ratios of low-molecular weight polyisobutylene to high-molecular weight polyisobutylene are in the range of from 100:1 to 1:100, preferably from 95:5 to 40:60, more preferably from 90:10 to 80:20. A preferred example for a polyisobutylene combination is B10/B100 in a ratio of 85/15. Oppanol® B100 has a viscosity average molecular weight M.sub.v of 1,110,000, and a weight average molecular weight M.sub.w of 1,550,000, and an average molecular weight distribution M.sub.w/M.sub.n of 2.9. Oppanol® B10 has a viscosity average molecular weight M.sub.v of 40,000, and a weight average molecular weight M.sub.w of 53,000, and an average molecular weight distribution M.sub.w/M.sub.n of 3.2. In certain embodiments, polybutene may be added to the polyisobutylenes. The solids content of polyisobutylenes in solvents is usually between 30 and 50%, preferably between 35 and 40%. The skilled person is aware that the solids content may be modified by adding a suitable amount of solvent.
(124) Pressure-sensitive adhesives based on acrylates may also be referred to as acrylate-based pressure-sensitive adhesives, or acrylate pressure-sensitive adhesives. Pressure-sensitive adhesives based on acrylates may have a solids content preferably between 30% and 60%. Such acrylate-based pressure-sensitive adhesives may or may not comprise functional groups such as hydroxy groups, carboxylic acid groups, neutralized carboxylic acid groups and mixtures thereof. Thus, the term “functional groups” in particular refers to hydroxy- and carboxylic acid groups, and deprotonated carboxylic acid groups.
(125) Corresponding commercial products are available e.g. from Henkel under the tradename Duro Tak®. Such acrylate-based pressure-sensitive adhesives are based on monomers selected from one or more of acrylic acid, butylacrylate, 2-ethylhexylacrylate, glycidylmethacrylate, 2-hydroxyethylacrylate, methylacrylate, methylmethacrylate, t-octylacrylamide and vinylacetate, and are provided in ethyl acetate, heptanes, n-heptane, hexane, methanol, ethanol, isopropanol, 2,4-pentanedione, toluene or xylene or mixtures thereof.
(126) Specific acrylate-based pressure-sensitive adhesives are available as: Duro-Tak™ 387-2287 or Duro-Tak™ 87-2287 (a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylate provided as a solution in ethyl acetate without cross-linking agent), Duro-Tak™ 387-2516 or Duro-Tak™ 87-2516 (a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylate provided as a solution in ethyl acetate, ethanol, n-heptane and methanol with a titanium cross-linking agent), Duro-Tak™ 387-2051 or Duro-Tak™ 87-2051 (a copolymer based on acrylic acid, butylacrylate, 2-ethylhexylacrylate and vinyl acetate, provided as a solution in ethyl acetate and heptane), Duro-Tak™ 387-2353 or Duro-Tak™ 87-2353 (a copolymer based on acrylic acid, 2-ethylhexylacrylate, glycidylmethacrylate and methylacrylate, provided as a solution in ethyl acetate and hexane), Duro-Tak™ 87-4098 (a copolymer based on 2-ethylhexyl-acrylate and vinyl acetate, provided as a solution in ethyl acetate).
(127) Additional polymers may also be added to enhance cohesion and/or adhesion.
(128) Certain polymers in particular reduce the cold flow and are thus in particular suitable as additional polymer. A polymeric matrix may show a cold flow, since such polymer compositions often exhibit, despite a very high viscosity, the ability to flow very slowly. Thus, during storage, the matrix may flow to a certain extent over the edges of the backing layer. This is a problem with storage stability and can be prevented by the addition of certain polymers. A basic acrylate polymer (e.g. Eudragit® E100) may e.g. be used to reduce the cold flow. Thus, in certain embodiments, the matrix layer composition comprises additionally a basic polymer, in particular an amine-functional acrylate as e.g. Eudragit® E100. Eudragit® E100 is a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate with a ratio of 2:1:1. The monomers are randomly distributed along the copolymer chain. Based on SEC method, the weight average molar mass (Mw) of Eudragit® E100 is approximately 47,000 g/mol. Further, polymers such as Plastoid B, acrylic polymers such as Eudragits, Chitosan, celluloses and derivatives thereof, and polystyrene may be useful to increase the dryness of the adhesive (e.g. the matrix layer).
Further Additives
(129) The TTS according to the invention, and in particular the rivastigmine-containing layer may further comprise at least one additive or excipient. Said additives or excipients are preferably selected from the group consisting of crystallization inhibitors, solubilizers, fillers, substances for skincare, pH regulators, preservatives, tackifiers, softeners, stabilizers, and permeation enhancers, in particular from crystallization inhibitors, substances for skincare, tackifiers, softeners, stabilizers, and permeation enhancers. More preferably, said additives are selected from the group consisting of crystallization inhibitors, solubilizers, fillers, substances for skincare, pH regulators, preservatives, tackifiers, softeners, stabilizers, and permeation enhancers, in particular from substances for skincare, tackifiers, softeners, and stabilizers. Such additives may be present in the rivastigmine-containing layer in an amount of from 0.001% to 15% by weight, e.g. from 1 to 10% by weight or from 0.01 to 5% by weight, based on the total weight of the rivastigmine-containing layer.
(130) It should be noted that in pharmaceutical formulations, the formulation components are categorized according to their physicochemical and physiological properties, and in accordance with their function. This means in particular that a substance or a compound falling into one category is not excluded from falling into another category of formulation component. E.g. a certain polymer can be a crystallization inhibitor but also a tackifier. Some substances may e.g. be a typical softener but at the same time act as a permeation enhancer. The skilled person is able to determine based on his general knowledge in which category or categories of formulation component a certain substance or compound belongs to. In the following, details on the excipients and additives are provided which are, however, not to be understood as being exclusive. Other substances not explicitly listed in the present description may be as well used in accordance with the present invention, and substances and/or compounds explicitly listed for one category of formulation component are not excluded from being used as another formulation component in the sense of the present invention.
(131) In one embodiment, the rivastigmine-containing layer further comprises a crystallization inhibitor. In some embodiments, the crystallization inhibitor can be present in an amount of from 0.5 to 10% by weight based on the total weight of the rivastigmine-containing layer. Suitable examples of crystallization inhibitors include polyvinylpyrrolidone, vinyl acetate/vinylpyrrolidone copolymer and cellulose derivatives. The crystallization inhibitor is preferably polyvinylpyrrolidone, more preferably soluble polyvinylpyrrolidone. The crystallization inhibitor may increase the solubility of the active agent or inhibit the crystallization of the active agent, e.g., if the active agent is used in the form of a salt.
(132) In one embodiment, the rivastigmine-containing layer further comprises a stabilizer, wherein the stabilizer is preferably selected from tocopherol and ester derivatives thereof and ascorbic acid and ester derivatives thereof. In some embodiments, the stabilizer can be present in an amount of from 0.001 to 2.0%, preferably from 0.01 to 1.0%, by weight based on the total weight of the rivastigmine-containing layer. In some embodiments, preferred stabilizers include sodium metabisulfite, ascorbyl esters of fatty acids such as ascorbyl palmitate, ascorbic acid, butylated hydroxytoluene, tocopherol, tocopheryl acetate and tocopheryl linoleate. Preferred stabilizers include ascorbyl esters of fatty acids, ascorbic acid, tocopherol, tocopheryl acetate and tocopheryl linoleate. Particularly preferred is tocopherol. Also particularly preferred is a combination of tocopherol and ascorbyl palmitate.
(133) In one embodiment, the rivastigmine-containing layer further comprises a softener/plasticizer. Exemplary softeners/plasticizers include linear or branched, saturated or unsaturated alcohols having 6 to 20 carbon atoms, triglycerides and polyethylene glycols.
(134) In one embodiment, the rivastigmine-containing layer further comprises a solubilizer. The solubilizer preferably improves the solubility of the rivastigmine in the rivastigmine-containing layer. Preferred solubilizers include, e.g., glycerol-, polyglycerol-, propylene glycol- and polyoxyethylene-esters of medium chain and/or long chain fatty acids, such as glyceryl monolinoleate, medium chain glycerides and medium chain triglycerides, non-ionic solubilisers made by reacting castor oil with ethylene oxide, and any mixtures thereof which may further contain fatty acids or fatty alcohols; cellulose and methylcellulose and derivatives thereof such as hydroxypropylcellulose and hypromellose acetate succinate; various cyclodextrins and derivatives thereof; non-ionic tri-block copolymers having a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene known as poloxamers; water-soluble derivatives of vitamin E; pharmaceutical graded or agglomerated spherical isomalt; a polyethylene glycol, polyvinyl acetate and polyvinylcaprolactame-based graft copolymer, also abbreviated as PVAc-PVCap-PEG and known as Soluplus®; purified grades of naturally derived castor oil, of polyethylene glycol 400, of polyoxyethylene sorbitan monooleate (such as polysorbate 80) or of propylene glycols; diethylene glycol monoethyl ether; glucono-delta-lactone; maize and potato starch; as well as any of the below mentioned soluble polyvinylpyrrolidones, but also insoluble/cross-linked polyvinylpyrrolidones such as crospovidones.
(135) However, also the permeation enhancers mentioned below can act as solubilizers. Furthermore, also crystallization inhibitors may act as solubilizers.
(136) In one embodiment, the rivastigmine-containing layer further comprises a pH regulator. Suitable pH regulators include mild acids and bases including amine derivatives, inorganic alkali derivatives, and polymers with basic or acidic functionality.
(137) In one embodiment, the rivastigmine-containing layer further comprises a preservative. Suitable preservatives include parabens, formaldehyde releasers, isothiazolinones, phenoxyethanol, and organic acids such as benzoic acid, sorbic acid, levulinic acid and anisic acid.
(138) In one embodiment, the rivastigmine-containing layer further comprises a substance for skincare. Such substances may be used to avoid or reduce skin irritation as detectable by the dermal response score. Suitable substances for skincare include sterol compounds such as cholesterol, dexpanthenol, alpha-bisabolol, and antihistamines. Substances for skincare are preferably used in amounts of from 1 to 10% by weight based on the total weight of the rivastigmine-containing layer.
(139) If the rivastigmine-containing layer is required to have self-adhesive properties and one or more polymers is/are selected, which does/do not provide sufficient self-adhesive properties, a tackifier is added. Preferred tackifiers include Miglyol, which is a liquid wax ester based on long-chain, unsaturated, even-numbered fatty acids and long-chain, unsaturated, even-numbered fatty alcohols of vegetable origin, and polyethyleneglycols. In particular, the tackifier may be selected from polyvinylpyrrolidone (which, due to its ability to absorb water, is able to maintain the adhesive properties of the matrix layer and thus can be regarded as a tackifier in a broad sense), triglycerides, polyethylene glycols, dipropylene glycol, resins, resin esters, terpenes and derivatives thereof, ethylene vinyl acetate adhesives, dimethylpolysiloxanes and polybutenes, preferably polyvinylpyrrolidone and more preferably soluble polyvinylpyrrolidone. Preferably, the tackifier may be selected from polyvinylpyrrolidone, triglycerides, dipropylene glycol, resins, resin esters, terpenes and derivatives thereof, ethylene vinyl acetate adhesives, dimethylpolysiloxanes and polybutenes, preferably polyvinylpyrrolidone and more preferably soluble polyvinylpyrrolidone. In some embodiments, the tackifier can be present in an amount of from 5 to 15% by weight based on the total weight of the rivastigmine-containing layer.
(140) The term “soluble polyvinylpyrrolidone” refers to polyvinylpyrrolidone, also known as povidone, which is soluble with more than 10% in at least ethanol, preferably also in water, diethylene glycol, methanol, n-propanol, 2 propanol, n-butanol, chloroform, methylene chloride, 2-pyrrolidone, macrogol 400, 1,2 propylene glycol, 1,4 butanediol, glycerol, triethanolamine, propionic acid and acetic acid. Examples of polyvinylpyrrolidones which are commercially available include Kollidon® 12 PF, Kollidon® 17 PF, Kollidon® 25, Kollidon® 30 and Kollidon® 90 F supplied by BASF, or povidone K90F. The different grades of Kollidon® are defined in terms of the K-Value reflecting the average molecular weight of the polyvinylpyrrolidone grades. Kollidon® 12 PF is characterized by a K-Value range of 10.2 to 13.8, corresponding to a nominal K-Value of 12. Kollidon® 17 PF is characterized by a K-Value range of 15.3 to 18.4, corresponding to a nominal K-Value of 17. Kollidon® 25 is characterized by a K-Value range of 22.5 to 27.0, corresponding to a nominal K-Value of 25, Kollidon® 30 is characterized by a K-Value range of 27.0 to 32.4, corresponding to a nominal K-Value of 30. Kollidon® 90 F is characterized by a K-Value range of 81.0 to 97.2, corresponding to a nominal K-Value of 90. Preferred Kollidon® grades are Kollidon® 12 PF, Kollidon® 30 and Kollidon® 90 F.
(141) Within the meaning of this invention, the term “K-Value” refers to a value calculated from the relative viscosity of polyvinylpyrrolidone in water according to the European Pharmacopoeia (Ph.Eur.) and USP monographs for “Povidone”.
(142) Fillers such as silica gels, titanium dioxide and zinc oxide may be used in conjunction with the polymer in order to influence certain physical parameters, such as cohesion and bond strength, in the desired way.
(143) In one embodiment, the rivastigmine-containing layer further comprises a permeation enhancer. Permeation enhancers are substances, which influence the barrier properties of the stratum corneum in the sense of increasing the active agent permeability. Some examples of permeation enhancers are polyhydric alcohols such as dipropylene glycol, propylene glycol, and polyethylene glycol; oils such as olive oil, squalene, and lanolin; fatty ethers such as cetyl ether and oleyl ether; fatty acid esters such as isopropyl myristate; urea and urea derivatives such as allantoin; polar solvents such as dimethyldecylphosphoxide, methylcetylsulfoxide, dimethylaurylamine, dodecyl pyrrolidone, isosorbitol, dimethylacetonide, dimethylsulfoxide, decylmethylsulfoxide, and dimethylformamide; salicylic acid; amino acids; benzyl nicotinate; and higher molecular weight aliphatic surfactants such as lauryl sulfate salts. Other agents include oleic and linoleic acids, ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol, tocopheryl acetate, tocopheryl linoleate, propyl oleate, and isopropyl palmitate.
(144) If the rivastigmine-containing layer further comprises a permeation enhancer, the permeation enhancer is preferably selected from diethylene glycol monoethyl ether (transcutol), diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lauryl lactate, and dimethylpropylene urea.
(145) It has been found that the TTS provides sufficient permeability of the active agent even if no permeation enhancer is present. Therefore, in certain embodiments of the invention, the rivastigmine-containing layer does not comprise a permeation enhancer or solubilizer.
Release Characteristics
(146) The TTS in accordance with the invention are designed for transdermally administering rivastigmine to the systemic circulation for a predefined extended period of time, preferably for 24 hours.
(147) In one embodiment, the TTS according to the invention provides by transdermal delivery a mean release rate of from 150 to 3500 μg/cm.sup.2*day, preferably from 200 to 3000 μg/cm.sup.2*day rivastigmine over about 24 hours of administration.
(148) In one embodiment, the TTS according to the invention provides by transdermal delivery from 2 to 20 mg of rivastigmine at an approximately constant rate, during an administration period of the TTS to the skin of the patient for about 24 hours.
(149) In one embodiment, the TTS according to the invention provides by transdermal delivery at steady state a plasma concentration of rivastigmine of from 1 to 25 ng/ml, preferably from 1 to 20 ng/ml.
(150) Preferably, the TTS provides therapeutically effective plasma concentrations of rivastigmine within less than 8 hours, preferably less than 6 hours, more preferably less than 4 hours after application of the TTS to the skin.
(151) Preferably, the TTS provides, after a steady state of the plasma concentration is reached, a therapeutically effective steady state plasma concentration of rivastigmine for at least 12 hours, preferably at least 18 hours, more preferably at least 20 hours, provided that the TTS is administered to the skin for a sufficient time, e.g., for at least 24 hours, so that the steady state can be reached and maintained. In particular, the TTS ensures that a plasma concentration of rivastigmine of from 1 ng/ml to 25 ng/ml is reached within less than 8 hours, preferably less than 6 hours, more preferably less than 4 hours, and that this plasma concentrations is maintained for at least 12 hours, preferably at least 18 hours, more preferably at least 20 hours, if the TTS is administered to the skin of the patient for about 24 hours.
(152) In one embodiment, the TTS according to the invention provides an AUC.sub.24h of about 10 to 450 ng*h/ml, preferably of about 20 to 340 ng*h/ml, after repeated once daily administration. In another embodiment, the TTS according to the invention provides, a C.sub.max of about 0.5 to 30 ng/ml, preferably of about 1 to 25 ng/ml, after applying the transdermal therapeutic system on the skin of the patient. In yet another embodiment, the TTS according to the invention provides a t.sub.max of about 3 to 15 hours, preferably of about 5 to 10 hours, after applying the transdermal therapeutic system on the skin of the patient.
(153) In one embodiment, the TTS according to the invention provides a plasma concentration of rivastigmine as analyzed using LC-MS/MS with a lower limit of quantification (LLOQ) of 0.1 ng/ml of
(154) 0 ng/ml to 15 ng/ml in the first 4 hours,
(155) 1 ng/ml to 22 ng/ml from hour 4 to hour 12,
(156) 0.5 ng/ml to 14 ng/ml from hour 12 to hour 24.
(157) In one embodiment, the transdermal therapeutic system according to the invention provides a cumulative permeated amount of rivastigmine as measured in a Franz diffusion cell with an EVA membrane of about 300 μg/cm.sup.2 to 1200 μg/cm.sup.2 over a time period of 24 hours.
(158) In one embodiment, the transdermal therapeutic system according to the invention provides a permeated amount of rivastigmine as measured in a Franz diffusion cell with EVA-membrane (9% vinyl acetate Cotran 9702 von 3M) of
(159) 0 μg/cm.sup.2 to 240 μg/cm.sup.2 in the first 3 hours,
(160) 80 μg/cm.sup.2 to 350 μg/cm.sup.2 from hour 3 to hour 8,
(161) 210 μg/cm.sup.2 to 560 mg/cm.sup.2 from hour 8 to hour 24.
Method of Treatment/Medical Use
(162) In accordance with a specific aspect of the present invention, the TTS according to the invention is for use in a method of treating a human patient, preferably for use in a method of preventing, treating, or delaying of progression of Alzheimer's disease, dementia associated with Parkinson's disease, and/or symptoms of traumatic brain injury. According to another specific aspect of the present invention, the TTS is for use in a method of treating a human patient, preferably for use in a method of treating mild to moderate dementia caused by Alzheimer's or Parkinson's disease.
(163) In one embodiment, the TTS according to the invention is for use in a method of treating a human patient, preferably for use in a method of treating a human patient, preferably for use in a method of preventing, treating, or delaying of progression of Alzheimer's disease, dementia associated with Parkinson's disease, and/or symptoms of traumatic brain injury, or for use in a method of treating a human patient, preferably for use in a method of treating mild to moderate dementia caused by Alzheimer's or Parkinson's disease, wherein the transdermal therapeutic system is applied to the skin of the patient for a dosing interval of at least 24 hours, preferably about 24 hours.
(164) In one embodiment, the TTS according to the invention is for use in a method of treating a human patient, preferably for use in a method of treating a human patient, preferably for use in a method of preventing, treating, or delaying of progression of Alzheimer's disease, dementia associated with Parkinson's disease, and/or symptoms of traumatic brain injury, or for use in a method of treating a human patient, preferably for use in a method of treating mild to moderate dementia caused by Alzheimer's or Parkinson's disease, wherein the transdermal therapeutic system is applied to the skin of the patient for a dosing interval of at least 72 hours, preferably about 84 hours.
(165) In certain embodiments, the present invention relates to a method of treating a human patient, in particular preventing, treating, or delaying of progression of Alzheimer's disease, dementia associated with Parkinson's disease, and/or symptoms of traumatic brain injury, by applying a transdermal therapeutic system as defined within the invention to the skin of the patient. In another certain embodiment, the present invention relates to a method of treating a human patient, in particular treating a mild to moderate dementia caused by Alzheimer's and Parkinson's disease, by applying a transdermal therapeutic system as defined within the invention to the skin of the patient.
(166) In one embodiment, the present invention relates to a method of treating a human patient, in particular preventing, treating, or delaying of progression of Alzheimer's disease, dementia associated with Parkinson's disease, and/or symptoms of traumatic brain injury, or a method of treating a human patient, in particular treating a mild to moderate dementia caused by Alzheimer's and Parkinson's disease, wherein the transdermal therapeutic system is applied to the skin of the patient for a dosing interval of at least 24 hours, preferably about 24 hours.
(167) In one embodiment, the present invention relates to a method of treating a human patient, in particular preventing, treating, or delaying of progression of Alzheimer's disease, dementia associated with Parkinson's disease, and/or symptoms of traumatic brain injury, or a method of treating a human patient, in particular treating a mild to moderate dementia caused by Alzheimer's and Parkinson's disease, wherein the transdermal therapeutic system is applied to the skin of the patient for a dosing interval of at least 72 hours, preferably about 84 hours.
(168) In connection with the above uses and methods of treatment, the TTS according to the invention is preferably applied to at least one body surface on the subject selected from the upper outer art, upper chest, upper back or the side of the chest for the defined dosing intervals.
(169) The preferred application time of a TTS according to the invention is at least 24 hours, preferably about 24 hours (1 day) or about 84 hours (3.5 days), particularly preferably about 24 hours. After this time, the TTS may be removed, and optionally a new TTS may be applied, so as to allow an around-the-clock treatment.
Process of Manufacture
(170) The invention further relates to a process of manufacture of a rivastigmine-containing layer, preferably a rivastigmine-containing matrix layer, for use in a transdermal therapeutic system.
(171) In accordance with the invention, the process for manufacturing a rivastigmine-containing layer for use in a transdermal therapeutic system according to the invention comprises the steps of:
(172) 1) combining at least the components 1. rivastigmine in an amount such that the amount of rivastigmine in the resulting rivastigmine-containing layer is from 10 to 25% by weight based on the total weight of the rivastigmine-containing layer; 2. a silicone acrylic hybrid polymer; and 3. optionally at least one additional non-hybrid polymer and/or additive; to obtain a coating composition;
(173) 2) coating the coating composition onto the backing layer or release liner; and
(174) 3) drying the coated coating composition to form the rivastigmine-containing layer.
(175) In step 1) of the above process of manufacture, the rivastigmine is preferably dissolved or dispersed to obtain a homogenous coating composition.
(176) In the above described process, the solvent is preferably selected from alcoholic solvents, in particular methanol, ethanol, isopropanol and mixtures thereof, and from non-alcoholic solvents, in particular ethyl acetate, hexane, heptane, petroleum ether, toluene, and mixtures thereof, and is more preferably selected from non-alcoholic solvents, and is most preferably ethyl acetate or n-heptane.
(177) In certain embodiments of the present invention, the silicone acrylic hybrid polymer is provided as a solution, wherein the solvent is ethyl acetate or n-heptane. Preferably ethyl acetate is used. Preferably, the silicone acrylic hybrid polymer has a solids content of from 40 to 60% by weight.
(178) In step 3) of the above process of manufacture, drying is performed preferably at a temperature of from 20 to 90° C., more preferably from 40 to 70° C.
EXAMPLES
(179) The present invention will now be more fully described with reference to the accompanying examples. It should be understood, however, that the following description is illustrative only and should not be taken in any way as a restriction of the invention. Numerical values provided in the examples regarding the amount of ingredients in the composition or the area weight may vary slightly due to manufacturing variability.
Comparative Example 1
(180) Comparative Example 1 (Comp. 1) is the commercially available rivastigmine-containing TTS product Exelon®, having a rivastigmine-containing acrylic based layer (60 g/m.sup.2) and a rivastigmine-free silicone based skin contact layer (30 g/m.sup.2), provided by Novartis Pharma.
(181) The permeated amount of the commercially available Exelon® TTS was determined in accordance to Examples 1 to 7 and the corresponding cumulated amount at 24 hours was calculated.
(182) The results are shown in Tables 2.2, 4.2, 5.2, and 6.2 and in
Example 1a-d
(183) Coating Composition
(184) The formulation of the rivastigmine-containing coating composition of Examples 1a-d are summarized in Table 1.1a and 1.1b below. The %-values refer to the amounts in % by weight.
(185) TABLE-US-00001 TABLE 1.1 Ex. 1a Ex. 1b Amt Solids Amt Solids Ingredient (Trade Name) [g] [%] [g] [%] Rivastigmine base 4.01 20.02 4.22 20.86 Silicone acrylic hybrid pressure 31.98 79.98 23.97 59.35 sensitive adhesive in ethyl acetate Solids content of 50.1% by weight (PSA SilAc 7-6102 from Dow Corning Healthcare) Silicone adhesive in n-heptane — — 6.47 19.79 Solids content of 61.9% by weight (DOW CORNING ® BIO-PSA Q7-4202) Total 35.99 100.0 34.66 100.0 Area Weight [g/m.sup.2] 98.0 92.4 Loading API [μg/cm.sup.2] 1962 1927 Ex. 1c Ex. 1d Amt Solids Amt Solids Ingredient (Trade Name) [g] [%] [g] [%] Rivastigmine base 4.02 20.07 4.00 19.98 Silicone acrylic hybrid pressure 31.76 79.93 23.81 59.95 sensitive adhesive in n-heptane Solids content of 50.4% by weight (PSA SilAc 7-6301 from Dow Corning Healthcare) Acrylate adhesive in ethyl acetate — — 10.46 20.07 Solids content of 38.4% by weight (DURO-TAK ® 387-4098) Total 35.78 100.0 38.27 100.0 Area Weight [g/m.sup.2] 91.8 84.7 Loading API [μg/cm.sup.2] 1842 1692
Preparation of the Coating Composition
(186) A beaker was loaded with the silicone acrylic hybrid pressure-sensitive adhesive having a solids content of about 50% by weight (PSA SilAc 7-6102 from Dow Corning Healthcare for Ex. 1a and 1b or PSA SilAc 7-6301 from Dow Corning Healthcare for Ex. 1c and 1d). The rivastigmine base and, if applicable (Ex. 1b and 1d), the additional adhesive was added under stirring. The mixture was stirred at about 800 rpm until a homogenous mixture was obtained (at least 20 min).
(187) Coating of the Coating Composition
(188) The resulting rivastigmine-containing coating composition was coated within less than 24 h after the rivastigmine-containing mixture was finished on an adhesively equipped foil (Scotchpak 9755 AB1F) using hand over knife lab coating equipment, using an erichson coater. The solvent was removed by drying in a first step at about room temperature (23±2° C.) for about 10 min, followed by a second drying step at about 60° C. (about 70° C. for Ex. 1a) for about 20 min (about 10 min for Ex. 1a).
(189) The coating thickness was chosen such that removal of the solution results in an area weight of the rivastigmine-containing layer of about 98.0 (Ex. 1a), 92.4 (Ex. 1b), 91.8 (Ex. 1c), and 84.7 (Ex. 1d) g/m.sup.2. The dried film was then laminated with a backing layer (FO PET 23 μm transparent).
(190) Preparation of the TTS (Concerning all Examples)
(191) The individual systems (TTS) were punched out from the rivastigmine-containing self-adhesive layer structure obtained as described above. Then, the TTS were sealed into pouches of the primary packaging material.
(192) Measurement of Permeated Amount
(193) The permeated amount of TTS prepared according to Examples 1a-d was determined by experiments in accordance with the EMA Guideline on quality of transdermal patches (adopted Oct. 23, 2014) carried out with a 10.0 ml Franz diffusion cell, wherein EVA-membrane (9% vinyl acetate; Scotchpak Cotran 9702 from 3M) having a thickness of 50 μm was used. Diecuts with an area of release of 1.156 cm.sup.2 were punched from the TTS. The TTS was applied to the EVA-membrane by using an adhesive overly. The rivastigmine permeated amount in the receptor medium of the Franz diffusion cell (phosphate buffer solution pH 5.5 with 0.1% sodium azide as antibacteriological agent) at a temperature of 32±1° C. was measured and the corresponding cumulated amount at 24 hours was calculated.
(194) The results are shown in Table 1.2 and
(195) TABLE-US-00002 TABLE 1.2 permeated amount with SD [μg/cm.sup.2] Elapsed Ex. 1a (n = 3) Ex. 1b (n = 3) Ex. 1c (n = 3) Ex. 1d (n = 3) time [h] Amount SD Amount SD Amount SD Amount SD 3 100.91 1.96 118.85 2.35 120.82 1.72 98.06 3.61 6 101.18 1.67 122.72 6.31 129.56 3.92 104.45 3.24 8 65.93 4.36 80.6 3.72 85.53 2.81 67.88 4.83 24 430.58 20.61 482.19 26.37 509.03 26.13 438.11 4.33 Cum. at 24 h 698.6 23.8 804.36 36.4 844.94 31.4 708.5 15.2
Coating Composition
(196) The formulation of the rivastigmine-containing coating composition of Examples 2a-c are summarized in Table 2.1 below. The %-values refer to the amounts in % by weight.
(197) TABLE-US-00003 TABLE 2.1 Ex. 2a Ex. 2b Ex. 2c Amt Solids Amt Solids Amt Solids Ingredient (Trade Name) [g] [%] [g] [%] [g] [%] Rivastigmine base 4.00 20.02 5.00 23.81 4.00 19.96 Silicone acrylic hybrid pressure 19.64 50.04 19.65 47.63 23.57 59.88 sensitive adhesive in ethyl acetate Solids content of 50.9% by weight (PSA SilAc 7-6302 from Dow Corning Healthcare) Acrylate adhesive in ethyl acetate 15.58 29.94 15.62 28.56 — — Solids content of 38.4% by weight (DURO-TAK ® 387-4098) Acrylate polymer in ethyl acetate — — — — 9.95 20.16 Solids content of 40.6% by weight (Eudragit E100) Total 39.22 100.0 40.27 100.0 37.52 100.0 Area Weight [g/m.sup.2] 82.3 110.3 98.9 Loading API [μg/cm.sup.2] 1648 2626 1974
Preparation of the Coating Composition
(198) The coating composition was prepared as described in Example 1, wherein the respective silicone acrylic hybrid pressure sensitive adhesive (PSA SilAc 7-6302 from Dow Corning Healthcare) and the respective additional adhesive DURO-TAKO 387-4098 for Ex. 2a and 2b and polymer Eudragit E100 for Ex. 2c, was used.
(199) Coating of the Coating Composition
(200) See Example 1b-d for the coating process. The coating thickness gave an area weight of the rivastigmine-containing layer of 82.3 (Ex. 2a), 110.3 (Ex. 2b), and 98.9 (Ex. 2c) g/m.sup.2. The dried film was laminated with a polyethylene terephthalate backing layer (FO PET 23 μm transparent) to provide a rivastigmine-containing self-adhesive layer structure.
(201) Preparation of the TTS
(202) See Example 1.
(203) Measurement of Permeated Amount
(204) The permeated amount of TTS prepared according to Examples 2a-c as well as the commercially available Exelon® was determined as described for Examples 1a-d above.
(205) The results are shown in Tables 2.2 and
(206) TABLE-US-00004 TABLE 2.2 Permeated amount with SD [μg/cm.sup.2] Elapsed Ex. 2a (n = 3) Ex. 2b (n = 3) Ex. 2c (n = 3) Exelon ® (n = 3) time [h] Amount SD Amount SD Amount SD Amount SD 3 91.5 3.56 98.11 2.19 91.74 2.3 87.97 2.44 6 92.83 6 103.43 0.25 96.98 4.67 80.67 4.05 8 61.2 4 65.75 0.73 62.34 3.94 57.2 4.11 24 367.38 32.9 403.58 18.53 402.79 14.23 338.51 15.64 Cum. at 24 h 612.91 48.5 670.87 18.1 653.85 20.1 564.35 20.5
Example 3a, 3b
(207) The formulation of the rivastigmine-containing coating composition of Examples 3a and 3b are summarized in Table 3.1 below. The %-values refer to the amounts in % by weight.
(208) TABLE-US-00005 TABLE 3.1 Ex. 3a Ex. 3b Amt Solids Amt Solids Ingredient (Trade Name) [g] [%] [g] [%] Rivastigmine base 3.03 15.13 3.00 15.00 Silicone acrylic hybrid pressure 33.92 84.87 — — sensitive adhesive in ethyl acetate Solids content of 50.1% by weight (PSA SilAc 7-6102 from Dow Corning Healthcare) Silicone acrylic hybrid pressure — — 33.39 85.00 sensitive adhesive in ethyl acetate Solids content of 50.9% by weight (PSA SilAc 7-6302 from Dow Corning Healthcare) Total 36.95 100.0 36.39 100.0 Area Weight [g/m.sup.2] 92.1 93.3 Loading API [μg/cm.sup.2] 1393 1400
Preparation of the Coating Composition
(209) The coating composition was prepared as described in Example 1, wherein the respective silicone acrylic hybrid pressure sensitive adhesive PSA SilAc 7-6102 from Dow Corning Healthcare (Ex. 3a) or PSA SilAc 7-6302 from Dow Corning Healthcare (Ex. 3b), was used.
(210) Coating of the Coating Composition
(211) See Example 1a for the coating process. The coating thickness gave an area weight of the rivastigmine-containing layer of 92.1 (Ex. 3a) and 93.3 (Ex. 2b) g/m.sup.2. The dried film was laminated with a polyethylene terephthalate backing layer (FO PET 23 μm transparent) to provide a rivastigmine-containing self-adhesive layer structure.
(212) Preparation of the TTS
(213) See Example 1.
(214) Measurement of Permeated Amount
(215) The permeated amount of TTS prepared according to Examples 3a and 3b was determined as described for Examples 1a-d above.
(216) The results are shown in Table 3.2 and
(217) TABLE-US-00006 TABLE 3.2 Permeated amount with SD [μg/cm.sup.2] Elapsed 3a (n = 3) 3b (n = 3) time [h] Amount SD Amount SD 3 88.82 5.57 77.12 4.6 6 87.74 3.63 81.89 1.08 8 59.19 2.79 53.31 2.66 24 359.27 1.12 308.35 17.35 Cum. at 24 h 595.02 11.0 520.67 16.4
Example 4a-d
(218) Coating Composition
(219) The formulation of the rivastigmine-containing coating composition of Examples 4a-d are summarized in Table 4.1a and 4.1b below. The %-values refer to the amounts in % by weight.
(220) TABLE-US-00007 TABLE 4.1 Ex. 4a Ex. 4b Amt Solids Amt Solids Ingredient (Trade Name) [g] [%] [g] [%] Rivastigmine base 4.03 20.11 4.08 20.29 Silicone acrylic hybrid pressure 32.20 79.89 24.19 59.79 sensitive adhesive in n-heptane; Solids content of 49.7% by weight (PSA SilAc 7-6101 from Dow Corning Healthcare) Silicone adhesive in n-heptane — — 5.50 19.91 Solids content of 72.8% by weight (DOW CORNING ® BIO-PSA Q7-4201) Total 36.23 100.0 33.77 100.0 Area Weight [g/m.sup.2] 70.8 76.8 Loading API [μg/cm.sup.2] 1424 1558 Ex. 4c (0084) Ex. 4d (0085) Amt Solids Amt Solids Ingredient (Trade Name) [g] [%] [g] [%] Rivastigmine base 4.00 20.00 3.99 19.91 Silicone acrylic hybrid pressure 23.57 60.00 23.58 59.90 sensitive adhesive in ethyl acetate Solids content of 50.9% by weight (PSA SilAc 7-6302 from Dow Corning Healthcare) Acrylate adhesive in ethyl acetate 11.11 20.00 — — Solids content of 36% by weight (DURO-TAK ® 387-2353) Acrylate adhesive in ethyl acetate — — 10.48 20.19 Solids content of 38.6% by weight (DURO-TAK ® 387-4098) Ethyl acetate 10.22 — — — Total 48.9 100.0 38.05 100.0 Area Weight [g/m.sup.2] 77.5 84.2 Loading API [μg/cm.sup.2] 1550 1676
Preparation of the Coating Composition
(221) A beaker was loaded with the silicone acrylic hybrid pressure-sensitive adhesive having a solids content of about 50% by weight (PSA SilAc 7-6101 from Dow Corning Healthcare for Ex. 4a and 4b or PSA SilAc 7-6302 from Dow Corning Healthcare Ex. 4c and 4d). The rivastigmine base and, if applicable (Ex. 4b, 4c, and 4d), the additional adhesive was added under stirring. If applicable, the solvent (ethyl acetate for Ex. 4c) was added. The mixture was stirred at about 800 rpm until a homogenous mixture was obtained (at least 20 min).
(222) Coating of the Coating Composition
(223) The resulting rivastigmine-containing coating composition was coated within less than 24 h after the rivastigmine-containing mixture was finished on an adhesively equipped foil (Scotchpak 9755 AB1F) using hand over knife lab coating equipment, using an erichson coater. The solvent was removed by drying in a first step at about room temperature (23±2° C.) for about 10 min, followed by a second drying step at about 70° C. for about 10 min.
(224) The coating thickness was chosen such that removal of the solution results in an area weight of the rivastigmine-containing layer of about 70.8 (Ex. 4a), 76.8 (Ex. 4b), 77.5 (Ex. 4c), and 84.2 (Ex. 4d) g/m.sup.2. The dried film was then laminated with a backing layer (FO PET 23 μm transparent).
(225) Preparation of the TTS (Concerning all Examples)
(226) See Example 1.
(227) Measurement of Permeated Amount
(228) The permeated amount of TTS prepared according to Examples 4a-d and of the commercially available Exelon® TTS was determined by experiments in accordance with the EMA Guideline on quality of transdermal patches (adopted Oct. 23, 2014) carried out with a 10.0 ml Franz diffusion cell, wherein EVA-membrane (9% vinyl acetate; Scotchpak Cotran 9702 from 3M) having a thickness of 50 μm was used. Diecuts with an area of release of 1.156 cm.sup.2 were punched from the TTS. The rivastigmine permeated amount in the receptor medium of the Franz diffusion cell (phosphate buffer solution pH 5.5 with 0.1% sodium azide as antibacteriological agent) at a temperature of 32±1° C. was measured and the corresponding cumulated amount at 24 hours was calculated.
(229) The results are shown in Tables 4.2 and
(230) TABLE-US-00008 TABLE 4.2 Permeated amount with SD [μg/cm.sup.2] Ex. 4a Ex. 4b Ex. 4c Ex. 4d Exelon ® Elapsed (n = 3) (n = 3) (n = 3) (n = 3) (n = 3) time [h] Amt SD Amt SD Amt SD Amot SD Amt SD 3 100.07 1.22 112.04 2.67 73 0.96 86.37 3.26 79.12 2.25 6 112.76 2.4 128.22 1.66 82.51 6.5 91.85 5.12 83.54 1.64 8 61.94 11.02 61.72 6.65 41.79 0.7 51.51 4.43 48.4 2.05 24 416.55 25.15 488.2 39.78 247.65 65.29 333.26 6.16 304.26 19.61 Cum. at 24 h 691.32 32.8 790.18 36.6 444.95 72.2 562.99 4.4 515.32 22.8
Example 5a-d
(231) Coating Composition
(232) The formulation of the rivastigmine-containing coating composition of Examples 5a-d are summarized in Table 5.1a and 5.1b below. The %-values refer to the amounts in % by weight.
(233) TABLE-US-00009 TABLE 5.1 Ex. 5a Ex. 5b Amt Solids Amt Solids Ingredient (Trade Name) [g] [%] [g] [%] Rivastigmine base 4.00 19.84 3.50 17.50 Silicone acrylic hybrid pressure 27.53 69.50 32.80 82.50 sensitive adhesive in ethyl acetate Solids content of 50.9% (Ex. 5a) or 50.3% (Ex. 5b) by weight (PSA SilAc 7-6302 from Dow Corning Healthcare) Acrylate adhesive in ethyl acetate 5.60 10.66 — — Solids content of 38.4% by weight (DURO-TAK ® 387-4098) Total 37.13 100.0 36.30 100.0 Area Weight [g/m.sup.2] 93.1 107.7 Loading API [μg/cm.sup.2] 1847 1885 Ex. 5c Ex. 5d Amt Solids Amt Solids Ingredient (Trade Name) [g] [%] [g] [%] Rivastigmine base 3.51 17.53 3.54 17.67 Silicone acrylic hybrid pressure 35.37 82.47 — — sensitive adhesive in n-heptane Solids content of 46.7% by weight (PSA SilAc 7-6101 from Dow Corning Healthcare) Silicone acrylic hybrid pressure — — 32.67 82.33 sensitive adhesive in ethyl acetate Solids content of 50.5% by weight (PSA SilAc 7-6102 from Dow Corning Healthcare) Total 38.88 100.0 36.21 100.0 Area Weight [g/m.sup.2] 102.0 100.5 Loading API [μg/cm.sup.2] 1788 1776
Preparation of the Coating Composition
(234) A beaker was loaded with the silicone acrylic hybrid pressure-sensitive adhesive having a solids content of about 50% by weight (PSA SilAc 7-6302 from Dow Corning Healthcare for Ex. 5a and 5b, PSA SilAc 7-6101 from Dow Corning Healthcare Ex. 5c, or PSA SilAc 7-6102 from Dow Corning Healthcare 5d). The rivastigmine base and, if applicable (Ex. 5a), the additional adhesive was added under stirring. The mixture was stirred at about 800 rpm (about 900 rpm for Ex. 5b to 5d) until a homogenous mixture was obtained (at least 20 min).
(235) Coating of the Coating Composition
(236) The resulting rivastigmine-containing coating composition was coated within less than 24 h after the rivastigmine-containing mixture was finished on an adhesively equipped foil (Scotchpak 9755 AB1F) using hand over knife lab coating equipment, using an erichson coater. The solvent was removed by drying in a first step at about room temperature (23±2° C.) for about 10 min, followed by a second drying step at about 60° C. for about 20 min.
(237) The coating thickness was chosen such that removal of the solution results in an area weight of the rivastigmine-containing layer of about 93.1 (Ex. 5a), 107.7 (Ex. 5b), 102.0 (Ex. 5c), and 100.5 (Ex. 5d) g/m.sup.2. The dried film was then laminated with a backing layer (FO PET 23 μm transparent).
(238) Preparation of the TTS (Concerning all Examples)
(239) See Example 1.
(240) Measurement of Permeated Amount
(241) The permeated amount of TTS prepared according to Examples 5a-d and of the commercially available Exelon® TTS was determined by experiments in accordance with the EMA Guideline on quality of transdermal patches (adopted Oct. 23, 2014) carried out with a 10.0 ml Franz diffusion cell, wherein EVA-membrane (9% vinyl acetate; Scotchpak Cotran 9702 from 3M) having a thickness of 50 μm was used. Diecuts with an area of release of 1.156 cm.sup.2 were punched from the TTS. The rivastigmine permeated amount in the receptor medium of the Franz diffusion cell (phosphate buffer solution pH 5.5 with 0.1% sodium azide as antibacteriological agent) at a temperature of 32±1° C. was measured and the corresponding cumulated amount at 24 hours was calculated.
(242) The results are shown in Tables 5.2 and
(243) TABLE-US-00010 TABLE 5.2 Permeated amount with SD [μg/cm.sup.2] Ex. 5a Ex. 5b Ex. 5c Ex. 5d Exelon ® Elapsed (n = 3) (n = 3) (n = 3) (n = 3) (n = 3) time [h] Amt SD Amt SD Amt SD Amot SD Amt SD 3 97.14 1.56 94.9 8.8 114.09 3.45 93.71 3.69 78.02 0.68 6 105.68 1.73 107.26 7.12 124.93 9.12 104.83 6.52 83.76 0.77 8 77.13 0.76 82.5 4.58 97.92 3.81 81.65 3.69 52.75 11.25 24 343.11 36.25 400.3 26.75 476.69 9.66 415.22 11.53 333.42 3.95 Cum. at 24 h 623.06 35.4 684.96 39.9 813.63 15.4 695.41 20.3 547.95 11.7
Example 6a-d
(244) Coating Composition
(245) The formulation of the rivastigmine-containing coating composition of Examples 6a-d are summarized in Table 6.1a and 6.1b below. The %-values refer to the amounts in % by weight.
(246) TABLE-US-00011 TABLE 6.1 Ex. 6a Ex. 6b Amt Solids Amt Solids Ingredient (Trade Name) [g] [%] [g] [%] Rivastigmine base 10.03 20.04 6.00 19.94 Silicone acrylic hybrid pressure 85.67 79.96 38.54 59.83 sensitive adhesive in n-heptane; Solids content of 46.7% by weight (PSA SilAc 7-6101 from Dow Corning Healthcare) Silicone adhesive in n-heptane — — 8.36 20.23 Solids content of 72.8% by weight (DOW CORNING ® BIO-PSA Q7-4201) Total 95.7 100.0 52.9 100.0 Area Weight [g/m.sup.2] 90.9 90.0 Loading API [μg/cm.sup.2] 1822 1795 Ex. 6c Ex. 6d Amt Solids Amt Solids Ingredient (Trade Name) [g] [%] [g] [%] Rivastigmine base 10.00 20.00 10.00 19.80 Silicone acrylic hybrid pressure 59.64 60.00 59.68 59.45 sensitive adhesive in ethyl acetate Solids content of 50.3% by weight (PSA SilAc 7-6302 from Dow Corning Healthcare) Acrylate adhesive in ethyl acetate 27.85 20.00 — — Solids content of 35.9% by weight (DURO-TAK ® 387-2353) Acrylate adhesive in ethyl acetate — — 26.80 20.75 Solids content of 39.1% by weight (DURO-TAK ® 387-4098) Total 97.49 100.0 96.48 100.0 Area Weight [g/m.sup.2] 98.7 91.4 Loading API [μg/cm.sup.2] 1973 1810
Preparation of the Coating Composition
(247) A beaker was loaded with the silicone acrylic hybrid pressure-sensitive adhesive having a solids content of about 50% by weight (PSA SilAc 7-6101 from Dow Corning Healthcare for Ex. 6a and 6b or PSA SilAc 7-6302 from Dow Corning Healthcare for Ex. 6c and 6d) and, if applicable (Ex. 6b, 6c, and 6d) the additional adhesive and homogenized for about 20 min. The rivastigmine base was added under stirring and under nitrogen flush (Ex. 6a and 6b). The mixture was stirred at about 500 rpm (Ex. 4a to 6c) or about 800 rpm (Ex. 6d) until a homogenous mixture was obtained (at least 20 min).
(248) Coating of the Coating Composition
(249) The resulting rivastigmine-containing coating composition was coated within less than 24 h after the rivastigmine-containing mixture was finished on an adhesively equipped foil (Scotchpak 9755 AB1F) using hand over knife lab coating equipment, using an erichson coater. The solvent was removed by drying in a first step at about room temperature (23±2° C.) for about 10 min, followed by a second drying step at about 60° C. (Ex 6a, 6c, and 6d) or 70° C. (Ex. 6b) for about 10 min (Ex. 6a to 6c) or for about 20 min (Ex. 6d).
(250) The coating thickness was chosen such that removal of the solution results in an area weight of the rivastigmine-containing layer of about 90.9 (Ex. 6a), 90.0 (Ex. 6b), 98.7 (Ex. 6c), and 91.4 (Ex. 6d) g/m.sup.2. The dried film was then laminated with a backing layer (FO PET 23 μm beige).
(251) Preparation of the TTS (Concerning all Examples)
(252) See Example 1.
(253) Measurement of Permeated Amount
(254) The permeated amount of TTS prepared according to Examples 6a-d and of the commercially available Exelon® TTS was determined by experiments in accordance with the EMA Guideline on quality of transdermal patches (adopted Oct. 23, 2014) carried out with a 10.0 ml Franz diffusion cell, wherein EVA-membrane (9% vinyl acetate; Nitroderm TTS K-Membrane 343 mm from PetroplastVinora AG) having a thickness of 50 μm was used. Diecuts with an area of release of 1.118 cm.sup.2 were punched from the TTS. The rivastigmine permeated amount in the receptor medium of the Franz diffusion cell (phosphate buffer solution pH 5.5 with 0.1% sodium azide as antibacteriological agent) at a temperature of 32±1° C. was measured and the corresponding cumulated amount at 24 hours was calculated.
(255) The results are shown in Tables 6.2 and
(256) TABLE-US-00012 TABLE 6.2 Permeated amount with SD [μg/cm.sup.2] Ex. 6a Ex. 6b Ex. 6c Ex. 6d Exelon ® Elapsed (n = 3) (n = 3) (n = 3) (n = 3) (n = 3) time [h] Amt SD Amt SD Amt SD Arnot SD Amt SD 3 178.59 4.84 192.61 2.36 143.63 4.09 174.06 5.4 141.32 7.77 6 173.35 1.43 187.99 2.01 138.2 1.45 166.44 4.81 132.31 3.54 8 117.09 2.37 128.68 1.69 93.37 1.71 115.32 2.87 86.78 1.38 24 499.49 0.86 505.02 4.55 424.02 6.86 484.43 3.74 409.43 5.86 Cum. at 24 h 968.52 9.14 1014.3 5.26 799.22 12.9 940.25 15.6 769.84 16.0
Example 7a-d
(257) Coating Composition
(258) The formulation of the rivastigmine-containing coating composition of Examples 7a-d are summarized in Table 7.1a and 7.1b below. The %-values refer to the amounts in % by weight.
(259) TABLE-US-00013 TABLE 7.1a Ex. 7a Ex. 7b Amt Solids Amt Solids Ingredient (Trade Name) [g] [%] [g] [%] Rivastigmine base 10.00 19.99 10.02 20.04 Silicone acrylic hybrid pressure 79.25 80.01 59.4 60.01 sensitive adhesive in ethyl acetate Solids content of 50.5% by weight (PSA SilAc 7-6102 from Dow Corning Healthcare) Silicone adhesive in n-heptane — — 16.11 19.95 Solids content of 61.9% by weight (DOW CORNING ® BIO-PSA Q7-4202) Total 89.25 100.0 85.53 100.0 Area Weight [g/m.sup.2] 97.8 93.9 Loading API [μg/cm.sup.2] 1955 1882
(260) TABLE-US-00014 TABLE 7.1b Ex. 7c Ex. 7d Amt Solids Amt Solids Ingredient (Trade Name) [g] [%] [g] [%] Rivastigmine base 10.00 20.00 8.78 17.54 Silicone acrylic hybrid pressure 79.68 80.00 — — sensitive adhesive in n-heptane Solids content of 50.2% by weight (PSA Sil Ac 7-6301 from Dow Corning Healthcare) Silicone acrylic hybrid pressure — — 88.38 82.46 sensitive adhesive in ethyl acetate Solids content of 46.7% by weight (PSA SilAc 7-6101 from Dow Corning Healthcare) Total 89.68 100.0 97.16 100.0 Area Weight [g/m.sup.2] 88.1 105.8 Loading API [μg/cm.sup.2] 1762 1856
Preparation of the Coating Composition
(261) A beaker was loaded with the silicone acrylic hybrid pressure-sensitive adhesive having a solids content of about 50% by weight (PSA SilAc 7-6102 from Dow Corning Healthcare for Ex. 7a and 7b, PSA SilAc 7-6301 from Dow Corning Healthcare Ex. 7c, or PSA SilAc 7-6101 from Dow Corning Healthcare 7d) and, if applicable (Ex. 7b) the additional adhesive was added and the mixture was homogenized. The rivastigmine base was added under stirring and, if applicable under nitrogen flush (Ex. 7c and 7d). The mixture was stirred at about 500 rpm (about 800 rpm for Ex. 7c) until a homogenous mixture was obtained (at least 20 min).
(262) Coating of the Coating Composition
(263) The resulting rivastigmine-containing coating composition was coated within less than 24 h after the rivastigmine-containing mixture was finished on an adhesively equipped foil (Scotchpak 9755 AB1F for Ex. 7a to 7c; Scotchpak 1022 TEPA for Ex. 7d) using hand over knife lab coating equipment, using an erichson coater. The solvent was removed by drying in a first step at about room temperature (23±2° C.) for about 10 min, followed by a second drying step at about 60° C. for about 10 min.
(264) The coating thickness was chosen such that removal of the solution results in an area weight of the rivastigmine-containing layer of about 97.8 (Ex. 7a), 93.9 (Ex. 7b), 88.1 (Ex. 7c), and 105.8 (Ex. 7d) g/m.sup.2. The dried film was then laminated with a backing layer (FO PET 23 μm beige).
(265) Preparation of the TTS (Concerning all Examples)
(266) See Example 1.
(267) Measurement of Permeated Amount
(268) The permeated amount of TTS prepared according to Examples 7a-d and of the commercially available Exelon® TTS was determined by experiments in accordance with the EMA Guideline on quality of transdermal patches (adopted Oct. 23, 2014) carried out with a 10.0 ml Franz diffusion cell, wherein EVA-membrane (9% vinyl acetate; Nitroderm TTS K-Membrane 343 mm from PetroplastVinora AG) having a thickness of 50 μm was used. Diecuts with an area of release of 1.118 cm.sup.2 were punched from the TTS. The rivastigmine permeated amount in the receptor medium of the Franz diffusion cell (phosphate buffer solution pH 5.5 with 0.1% sodium azide as antibacteriological agent) at a temperature of 32±1° C. was measured and the corresponding cumulated amount at 24 hours was calculated.
(269) The results are shown in Tables 7.2 and
(270) TABLE-US-00015 TABLE 7.2 permeated amount with SD [μg/cm.sup.2] Ex. 7a Ex. 7b Ex. 7c Ex. 7d Elapsed (n = 3) (n = 3) (n = 3) (n = 3) time [h] Amt SD Amt SD Amt SD Amt SD 3 188.84 6.61 201.61 11.83 194.9 3.51 166.9 6.62 6 183.82 2.58 191.09 20.38 194.16 2.68 163.53 7.13 8 128.37 2.96 128.06 14.22 132.06 1.06 111.98 5.39 24 508.67 4.2 490.65 51.07 543.48 3.51 477.85 20.93 Cum. at 24 h 1009.4 3.73 1011.41 91.7 1064.6 5.06 920.26 38.9
The Invention Relates in Particular to the Following Further Items
(271) 1. Transdermal therapeutic system for the transdermal administration of rivastigmine comprising a rivastigmine-containing layer structure, said rivastigmine-containing layer structure comprising:
(272) A) a backing layer; and
(273) B) a rivastigmine-containing layer;
(274) wherein the transdermal therapeutic system comprises a silicone acrylic hybrid polymer.
(275) 2. Transdermal therapeutic system according to item 1,
(276) wherein the rivastigmine-containing layer is a rivastigmine-containing matrix layer comprising:
(277) 1. rivastigmine; and 2. the silicone acrylic hybrid polymer.
3. Transdermal therapeutic system according to any one of items 1 or 2,
wherein the rivastigmine-containing layer structure is a rivastigmine-containing self-adhesive layer structure and preferably does not comprise an additional skin contact layer.
4. Transdermal therapeutic system according to any one of items 1 to 3,
wherein the silicone acrylic hybrid polymer is a silicone acrylic hybrid pressure-sensitive adhesive.
5. Transdermal therapeutic system according to any one of items 1 to 4,
wherein the rivastigmine-containing layer structure contains a therapeutically effective amount of rivastigmine.
6. Transdermal therapeutic system according to any one of items 1 to 5,
wherein the rivastigmine in the rivastigmine-containing layer structure is present in the form of the free base.
7. Transdermal therapeutic system according to any one of items 1 to 6,
wherein the amount of rivastigmine contained in the rivastigmine-containing layer structure ranges from 0.5 to 5 mg/cm.sup.2, preferably from 1 to 3 mg/cm.sup.2.
8. Transdermal therapeutic system according to any one of items 1 to 7,
wherein the rivastigmine-containing layer comprises rivastigmine in an amount of from 5 to 30%, more preferably from 7 to 28%, most preferably from 10 to 25% by weight based on the total weight of the rivastigmine-containing layer.
9. Transdermal therapeutic system according to any one of items 1 to 8,
wherein the amount of the silicone acrylic hybrid polymer ranges from 35 to 95%, preferably from 40 to 93%, most preferably from 45 to 90% by weight based on the total weight of the rivastigmine-containing layer.
10. Transdermal therapeutic system according to any one of items 1 to 9,
wherein the silicone acrylic hybrid polymer comprises a reaction product of a silicone polymer, a silicone resin and an acrylic polymer, wherein the acrylic polymer is covalently self-crosslinked and covalently bound to the silicone polymer and/or the silicone resin.
11. Transdermal therapeutic system according to any one of items 1 to 9,
wherein the silicone acrylic hybrid polymer is a silicone acrylic hybrid pressure-sensitive adhesive obtainable from (a) a silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality.
12. Transdermal therapeutic system according to any one of items 1 to 9 or 11,
wherein the silicone acrylic hybrid polymer is a silicone acrylic hybrid pressure-sensitive adhesive comprising the reaction product of (a) a silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality; (b) an ethylenically unsaturated monomer; and (c) an initiator.
13. Transdermal therapeutic system according to any one of items 11 or 12,
wherein the silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality comprises the condensation reaction product of
(a1) a silicone resin, and
(a2) a silicone polymer, and
(a3) a silicon-containing capping agent comprising acrylate or methacrylate functionality.
14. Transdermal therapeutic system according to any one of items 11 to 13,
wherein the silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality comprises the condensation reaction product of
(a1) a silicone resin, and
(a2) a silicone polymer, and
(a3) a silicon-containing capping agent comprising acrylate or methacrylate functionality,
wherein said silicon-containing capping agent is of the general formula XYR′.sub.bSiZ.sub.3-b, wherein X is a monovalent radical of the general formula AE, where E is —O— or —NH— and A is an acryl group or methacryl group, Y is a divalent alkylene radical having from 1 to 6 carbon atoms, R′ is a methyl or a phenyl radical, Z is a monovalent hydrolysable organic radical or halogen, and b is 0 or 1;
wherein the silicone resin and silicone polymer are reacted to form a pressure-sensitive adhesive, wherein the silicon-containing capping agent is introduced prior to, during, or after the silicone resin and silicone polymer are reacted,
and wherein the silicon-containing capping agent reacts with the pressure-sensitive adhesive after the silicone resin and silicone polymer have been condensation reacted to form the pressure-sensitive adhesive, or the silicon-containing capping agent reacts in situ with the silicone resin and silicone polymer.
15. Transdermal therapeutic system according to any one of items 12 to 14,
wherein the ethylenically unsaturated monomer is selected from the group consisting of aliphatic acrylates, aliphatic methacrylates, cycloaliphatic acrylates, cycloaliphatic methacrylates, and combinations thereof, each of said compounds having up to 20 carbon atoms in the alkyl radical.
16. Transdermal therapeutic system according to any one of items 12 to 15,
wherein the reaction product of
(a) the silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality;
(b) the ethylenically unsaturated monomer; and
(c) the initiator
contains a continuous, silicone external phase and a discontinuous, acrylic internal phase.
17. Transdermal therapeutic system according to any one of items 12 to 15,
wherein the reaction product of
(a) the silicon-containing pressure-sensitive adhesive composition comprising acrylate or methacrylate functionality;
(b) the ethylenically unsaturated monomer; and
(c) the initiator
contains a continuous, acrylic external phase and a discontinuous, silicone internal phase.
18. Transdermal therapeutic system according to any one of items 1 to 16,
wherein the silicone acrylic hybrid polymer in the rivastigmine-containing layer contains a continuous, silicone external phase and a discontinuous, acrylic internal phase, or a continuous, acrylic external phase and a discontinuous, silicone internal phase,
and wherein preferably the rivastigmine is present in the rivastigmine-containing layer in an amount of from 15 to 25% by weight based on the total weight of the rivastigmine-containing layer.
19. Transdermal therapeutic system according to any one of items 1 to 18,
wherein the rivastigmine-containing layer further comprises a non-hybrid polymer.
20. Transdermal therapeutic system according to item 19,
wherein the non-hybrid polymer is a pressure-sensitive adhesive based on polysiloxanes, acrylates, or polyisobutylenes, preferably based on polysiloxanes or acrylates.
21. Transdermal therapeutic system according to any one of items 19 or 20,
wherein the non-hybrid polymer is contained in the rivastigmine-containing layer in an amount of from 5 to 40%, preferably from 8 to 35% by weight based on the total weight of the rivastigmine-containing layer.
22. Transdermal therapeutic system according to any one of items 19 to 21,
wherein the weight ratio of the silicone acrylic hybrid polymer to the non-hybrid polymer is from 8:1 to 1:2, preferably from 7:1 to 1:1.
23. Transdermal therapeutic system according to any one of items 1 to 22,
wherein the rivastigmine-containing layer does not comprise a permeation enhancer or solubilizer.
24. Transdermal therapeutic system according to any one of items 1 to 23,
wherein the area weight of the rivastigmine-containing layer ranges from 40 to 250 g/m.sup.2, preferably from 50 to 200 g/m.sup.2.
25. Transdermal therapeutic system according to any one of items 1 to 24,
wherein the area of release ranges from 1 to 30 cm.sup.2, preferably from 2 to 22 cm.sup.2.
26. Transdermal therapeutic system according to any one of items 1 to 25,
wherein the transdermal therapeutic system provides by transdermal delivery a mean release rate of from 150 to 3500 μg/cm.sup.2*day, preferably from 200 to 3000 μg/cm.sup.2*day rivastigmine over about 24 hours of administration.
27. Transdermal therapeutic system according to any one of items 1 to 26,
wherein the transdermal therapeutic system provides by transdermal delivery at steady state a plasma concentration of rivastigmine of from 1 to 25 ng/ml, preferably from 1 to 20 ng/ml.
28. Transdermal therapeutic system according to any one of items 1 to 27,
having an AUC.sub.24h of about 10 to 450 ng*h/ml, preferably of about 20 to 340 ng*h/ml, after repeated once daily administration.
29. Transdermal therapeutic system according to any one of items 1 to 28,
having a C.sub.max of about 0.5 to 30 ng/ml, preferably of about 1 to 25 ng/ml, after applying the transdermal therapeutic system on the skin of the patient.
30. Transdermal therapeutic system according to any one of items 1 to 29,
having a t.sub.max of about 3 to 15 hours, preferably of about 5 to 10 hours, after applying the transdermal therapeutic system on the skin of the patient.
31. Transdermal therapeutic system according to any one of items 1 to 30,
providing a cumulative permeated amount of rivastigmine as measured in a Franz diffusion cell with an EVA membrane of about 300 to 1200 μg/cm.sup.2 over a time period of about 24 hours.
32. Transdermal therapeutic system according to any one of items 1 to 31 for use in a method of treating a human patient, preferably for use in a method of preventing, treating, or delaying of progression of Alzheimer's disease, dementia associated with Parkinson's disease, and/or symptoms of traumatic brain injury.
33. Transdermal therapeutic system according to any one of items 1 to 31 for use in a method of treating a human patient, preferably for use in a method of treating mild to moderate dementia caused by Alzheimer's or Parkinson's disease.
34. Transdermal therapeutic system for use according to any one of items 32 or 33, wherein the transdermal therapeutic system is applied to the skin of the patient for a dosing interval of at least 24 hours, preferably about 24 hours.
35. Method of treating a human patient, in particular preventing, treating, or delaying of progression of Alzheimer's disease, dementia associated with Parkinson's disease, and/or symptoms of traumatic brain injury, by applying a transdermal therapeutic system as defined in any one of items 1 to 31 to the skin of the patient.
36. Method of treating a human patient, in particular treating a mild to moderate dementia caused by Alzheimer's and Parkinson's disease, by applying a transdermal therapeutic system as defined in any one of items 1 to 31 to the skin of the patient.
37. Method of treating a human patient according to any one of items 35 or 36, wherein the transdermal therapeutic system is applied to the skin of the patient for a dosing interval of at least 24 hours, preferably about 24 hours.
38. A process for manufacturing a rivastigmine-containing layer for use in a transdermal therapeutic system according to any one of items 1 to 31 comprising the steps of:
(278) 1) combining at least the components 1. rivastigmine in an amount such that the amount of rivastigmine in the resulting rivastigmine-containing layer is from 10 to 25% by weight based on the total weight of the rivastigmine-containing layer; 2. a silicone acrylic hybrid polymer; and 3. optionally at least one additional non-hybrid polymer and/or additive; to obtain a coating composition;
(279) 2) coating the coating composition onto the backing layer or release liner; and
(280) 3) drying the coated coating composition to form the rivastigmine-containing layer.
(281) 39. Process for manufacturing a rivastigmine-containing layer according to item 38, wherein the silicone acrylic hybrid polymer is provided as a solution, wherein the solvent is ethyl acetate or n-heptane.
(282) 40. Transdermal therapeutic system obtainable by a process in accordance with any one of items 38 or 39.
(283) 41. Transdermal therapeutic system for the transdermal administration of rivastigmine comprising a rivastigmine-containing layer structure, said rivastigmine-containing layer structure comprising:
(284) A) a backing layer; and
(285) B) a rivastigmine-containing layer comprising: 1. rivastigmine in an amount of from 10 to 25% by weight based on the total weight of the rivastigmine-containing layer; 2. a silicone acrylic hybrid polymer containing a continuous, silicone external phase and a discontinuous, acrylic internal phase, in an amount of from 45 to 90% by weight based on the total weight of the rivastigmine-containing layer; and 3. optionally a pressure-sensitive adhesive based on polysiloxanes in an amount of from 10 to 30% by weight based on the total weight of the rivastigmine-containing layer;
wherein said rivastigmine-containing layer is the skin contact layer;
and wherein the area weight of said rivastigmine-containing layer ranges from 60 to 180 g/m.sup.2.
42. Transdermal therapeutic system for the transdermal administration of rivastigmine comprising a rivastigmine-containing layer structure, said rivastigmine-containing layer structure comprising:
(286) A) a backing layer; and
(287) B) a rivastigmine-containing layer comprising: 1. rivastigmine in an amount of from 10 to 25% by weight based on the total weight of the rivastigmine-containing layer; 2. a silicone acrylic hybrid polymer containing a continuous, acrylic external phase and a discontinuous, silicone internal phase, in an amount of from 40 to 90% by weight based on the total weight of the rivastigmine-containing layer; and 3. optionally a pressure-sensitive adhesive based on acrylates in an amount of from 5 to 40% by weight based on the total weight of the rivastigmine-containing layer;
wherein said rivastigmine-containing layer is the skin contact layer;
and wherein the area weight of said rivastigmine-containing layer ranges from 60 to 180 g/m.sup.2.