WO2012007150A1

WO2012007150A1 - Transdermal therapeutic system with a choline esterase inhibitor

Info

Publication number: WO2012007150A1
Application number: PCT/EP2011/003473
Authority: WO
Inventors: Katalin Tisa Bostedt; Tobias Pfaller; Wolf-Dieter Vogel; Susanne Lang
Original assignee: Amw Gmbh
Priority date: 2010-07-12
Filing date: 2011-07-12
Publication date: 2012-01-19
Also published as: DE102010026903A1

Abstract

The invention relates to a transdermal therapeutic system with a choline esterase inhibitor for the treatment of slight to medium-severe dementia of the Alzheimer disease type.

Description

Transdermal therapeutic system with a cholinesterase inhibitor

The invention relates to a transdermal therapeutic system (TDS) containing a carbamate-type cholinesterase inhibitor as active ingredient, for example with

Rivastigmine.

To administer rivastigmine via a transdermal system (TDS), according to the prior art, an antioxidant is necessary, otherwise the active substance remains chemically unstable. EP 1 047 409 B1, WO 99/34 782 and the Exelon® patch provide, for example, alpha-tocopherol. The antioxidant alpha-tocopherol is described in the literature as causing allergic contact dermatitis. For example, refer to Dermatitis 2010 June 21 (3): 148-53 (Kosari, P., Alikhan, A., Sockolov, M. & Feldman, SR.: Vitamin E and allergic dermatitis), Dermatitis 2010 August 21 (4 ): 199-202 (Adams, AK & Connolly, SM .: Allergic contact dermatitis from vitamin E: the experience at Mayo Clinic Arizona, 1987 to 2007) and Dermatitis 2008 May-June 19 (3): 154-6 (Ramirez Santos, A., Fernandez-Redondo, V., Perez Perez, L., Concheiro Cao, J. & Toribio, J .: Contact allergy from vitamins in cosmetic products).

In addition, a silicone adhesive layer is required in the prior art to achieve a sufficiently strong adhesion to the skin. Thus, in WO2007 / 064407 AI

described that the reservoir layer (as Exelon) too low adhesive force and it is therefore necessary to laminate a silicone adhesive layer.

Furthermore, DE 38 05 744 C2 and DE 38 44 992 B4 describe the use of the S - (-) - enantiomer of rivastigmine and one of its salts for systemic transdermal

Administration for the treatment of dementia and Alzheimer's disease.

EP 1 171 104 B1 and WO 00/64 418 describe a transdermal therapeutic matrix or a reservoir system with a basic or neutral active substance, for example

CONFIRMATION COPY Rivastigmine, as well as a fully or partially neutralized acidic pressure-sensitive polyacrylate adhesive.

EP 2 292 219 A1, EP 1 959 937 and EP 2 286 802 describe a transdermal

Therapeutic system with rivastigmine for AUC24h from 25 to 450 ng * h / mL with repeated single daily dose.

Furthermore, WO 2011/076 621 A2 describes a transdermal therapeutic system with rivastigmine as the active ingredient in a reservoir with a polymer matrix which has neither hydroxyl nor carboxyl groups.

The use of avocado oil for dermal and transdermal applications is already known.

Thus, DE 698 30 095 T2 (priority 11. 04. 1997) describes a cosmetic or dermo-pharmaceutical patch for releasing a present in the form of particles water-soluble drug and additionally dissolved in an oil fat-soluble drug in the epidermis [0001]. As an oil in a large list of oils including avocado oil is proposed. Avocado oil is also proposed by DE 198 82 916 Tl (priority 28. 12. 1997) (page 7) also in a list of oils for skin care and skin protection, but here in a gel composition. The device for dispensing cosmetic active ingredients described in DE 199 11 262 A1 (filing date 13. 03. 1999) can also use the avocado oil, which in turn is listed in a large list of oils. Lastly, DE 600 28 642 T2 (priority: 03/31/1999) discloses avocado oil in a comprehensive list of oils for incorporation of a solubilized active substance, namely for a plaster containing magnetic particles, which inhibits the penetration of the active ingredient into the Promote skin [0009], wherein the plaster on the skin to achieve a cosmetic effect and / or a pharmaceutical treatment is to be performed [0001].

The use of avocado oil has also been mentioned for TDSe, but has not been taken up for a long time for TDSe. Thus, DE 33 47 278 AI (filing 28. 12. 1983) and DE 34 09 079 AI (filing 13. 03. 1984) described anti-inflammatory

medicated plaster for which avocado oil has been listed in a list of oils as an entrainment agent (page 12 or page 9). Furthermore, DE 42 37 453 Cl (filing date 06. 11. 1992) a TDS for the delivery of a special active substance, namely 17-.beta.-estradiol, wherein avocado oil is listed in an extensive list of possible solubility-improving additives or skin permeation enhancers (page 2 line 64 to page 3 line 13 ).

The object of the invention is a transdermal therapeutic system for the treatment of mild to moderate dementia of the type of Alzheimer's disease and containing a carbamate-type cholinesterase inhibitor such as rivastigmine for the treatment of mild-to-moderate dementia of the Alzheimer's type Disease.

The transdermal therapeutic system should (1) circumvent the frequent to very common side effects associated with oral administration, especially nausea, diarrhea, and vomiting. (2) Also, the transdermal therapeutic system should have better compliance than oral dosage forms. (3) Thus, the transdermal therapeutic system should allow a comfortable application to the skin and (4) provide good skin compatibility with good comfort and sufficient adhesive power. In addition, it should provide (5) high storage stability and (6) reliable performance. (7) The transdermal therapeutic system should be inexpensive to manufacture. (8) It should be usable for prolonged continuous release of active substances, in particular 1 to 7 days. (9) Finally, the transdermal therapeutic system without antioxidant should be provided.

The subject of the invention is now a transdermal therapeutic system

with an active substance-impermeable covering layer,

- With a drug reservoir with

a content of a carbamate-type cholinesterase inhibitor,

a pressure sensitive polymer as well

an optional avocado oil and / or palm oil content,

- with an optional skin-facing active substance-free adhesive layer and

- with a peel-off layer.

The term polymer can also be understood as meaning a polymer mixture. A drug-free adhesive layer is a layer that has not been loaded with active ingredient during manufacture. According to one embodiment of the invention, its underlying object is achieved by a transdermal therapeutic system (TDS) with an optional avocado oil content. The above-mentioned prior art has not expected that with avocado oil for a carbamate-type cholinesterase inhibitor such as rivastigmine a skin permeation can be achieved with which plasma levels can be achieved, the one

Treatment of mild to moderate dementia of the type Alzheimer's disease permit.

It is conceivable that the avocado oil and / or the palm oil act as cohesive, solubilizer and / or skin compatibility improver.

According to the invention for the transdermal therapeutic system rivastigmine as

Be provided carbamate-type cholinesterase inhibitors. The active ingredient may also be provided as a physiologically acceptable salt, hydrate, solvate or derivative.

Furthermore, according to the invention, rivastigmine and / or at least one other carbamate-type cholinesterase inhibitor may be provided for the transdermal therapeutic system. The transdermal therapeutic system of the invention may comprise one or more carbamate-type cholinesterase inhibitors, rivastigmine being that active agent or one of these agents.

The active ingredients can be dissolved in the active substance reservoir or homogeneously dispersed.

According to the invention for the transdermal therapeutic system, an active ingredient concentration of 0.1 to 40 and especially to 50 wt .-% and preferably 0.1 to 40 wt .-% (based on the total weight of the drug reservoir) may be provided.

Furthermore, according to the invention for the transdermal therapeutic system an active compound concentration of 15 to 35 wt .-% and in particular about 30 wt .-% (based on the total weight of the drug reservoir) may be provided.

In the transdermal therapeutic system of the present invention, the at least one carbamate-type cholinesterase inhibitor may be dissolved in the drug reservoir or dispersed homogeneously. For the transdermal therapeutic system according to the invention, avocado oil and / or palm oil (based on the total weight of the oil) may contain from 0 to 15% by weight

Drug reservoirs) may be provided.

Also, the transdermal therapeutic system according to the invention may have a content of avocado oil and / or palm oil and an additional content of at least one further optional adjuvant, which contributes, for example, to ohäsionsverbesserung or to solubility improvement, in particular to improved solubility of the active ingredient.

In the transdermal therapeutic system according to the invention, the avocado oil and / or palm oil and the optional additional adjuvant can be dissolved in the active substance reservoir or homogeneously dispersed.

In the transdermal therapeutic system according to the invention, the active substance reservoir and / or the optional adhesive layer may comprise a pressure-sensitive polymer, in particular from the group of polyacrylates, silicones, block copolymers, polyisobutylenes, acrylate-hydrocarbon graft copolymers, in particular acrylate rubber graft copolymers, or comprise or consist of a pressure-sensitive mixture of several of these polymers. The polyacrylate may, for example, be uncrosslinked polyacrylate and, in particular, uncrosslinked polyacrylate having carboxyl groups, such as DuroTak DT 87-235A. Such uncrosslinked polyacrylate may be present, for example, in admixture with an uncrosslinked acrylate copolymer, for example a

Butyl methacrylate / methyl methacrylate copolymer such as Plastoid B.

Thus, in the transdermal therapeutic system of the present invention, the drug reservoir and / or the optional adhesive layer can be an acrylate [poly (ethylene butylene)] graft copolymer, acrylate [poly (ethylene propylene)] graft copolymer or acrylate- [poly (ethylene-butylene-propylene)] graft copolymer as acrylate-hydrocarbon graft copolymer or styrene-butadiene-styrene as block copolymer or consist thereof. Acrylate hydrocarbon graft copolymers or acrylate rubber graft copolymers are known, for example, from US 5 625 005, US 6 642 298, US 6 670 417 and US 2020/0 068 515 Al.

Thus, in the transdermal therapeutic system of the invention for the

Active agent reservoir and / or the optional adhesive layer

a hydroxyl-functionalized acrylate polymer as the grafting base of the grafted hydrocarbon of the graft copolymer and or

a poly (ethylene-butylene) -macromer as a grafted hydrocarbon, in particular a Mw of about 4000 to 7200 (weight average),

be provided.

Further, in the transdermal therapeutic system of the invention for the drug reservoir and / or the optional adhesive layer

the poly (ethylene-butylene) macromers have terminal acrylic or acrylate groups and / or

- The hydroxyl groups of the acrylate polymer crosslinked, in particular by aluminum tris-acetylacetonate.

Examples of acrylate hydrocarbon graft copolymers to be used according to the invention are an acrylate polymer having hydroxyl functional groups

Grafting base with grafted ethylene-butylene macromer terminated

Methacrylate groups (weight average Mw of macromolecular weight about 4000 to 7200), in particular an acrylate-hydrocarbon graft copolymer (hybrid adhesive) according to US 2010/0 068 515 AI Example 2 Sample B (weight average Mw of macromolecular weight about 4000 to 7200).

Further, in the transdermal therapeutic system of the present invention, the acrylate-hydrocarbon graft copolymer may be modified with a natural or synthetic hydrocarbon-based tackifier. Examples of adhesives include EP 0 836 506 B1 (eg [0016]), WO 95/018 603 A (eg pages 30-31) and US 2010/0 068 515 A1 (eg [0038] to [0039]). The disclosure of this prior art is incorporated by reference. Furthermore, the transdermal therapeutic system of the invention may have a content of a solubilizer, in particular a content of 1, 2-propanediol, dimethylacetamide and / or N-methylpyrrolidone.

Furthermore, the transdermal therapeutic system according to the invention may have a content of cohesion promoter, in particular a content of polysiloxane.

Furthermore, the transdermal therapeutic system according to the invention may have a content of adhesion promoter, in particular a content of one or more resins of natural or synthetic origin.

Furthermore, the transdermal therapeutic system according to the invention may have a content of a permeation enhancer.

However, the transdermal therapeutic system of the present invention need not have an antioxidant content, and thus may be free thereof, for example, when the drug reservoir comprises or consists of a carboxyl-containing uncrosslinked polyacrylate such as DuroTak DT 87-235A.

Further, the transdermal therapeutic system of the present invention can be adjusted for drug skin permeation in vitro from 10 μg (micrograms) / (hr and system) to 5 mg / hr and system.

Further, in the transdermal therapeutic system of the present invention, the level of active ingredient may be adjusted to a continuous release of active ingredient for a period of whole days ranging from 1 to 7 days.

Finally, the transdermal therapeutic system according to the invention can be provided with an active ingredient-containing basis weight or with a weight of the active substance-containing surface or a weight per unit area of the active substance reservoir of 30 to 150 g / m ² .

Furthermore, the transdermal therapeutic system according to the invention may have a skin-facing active substance-free layer, which may be provided with a basis weight of 10 to 40 g / m ² and in particular 10 to 30 g / m ² . This layer may consist of an acrylate Vinyl acetate adhesive, which is preferably uncrosslinked, such as DuroTak DT 87- 4287. This drug-free layer can improve the adhesive properties of the system. This layer has therefore not been loaded with active substance during production.

The stripping layer may be an active-substance-impermeable protective layer, for example a siliconized polyester film, which is peeled off before application to the skin

The invention will be explained in more detail by examples.

example 1

Rivastigmine was diluted in ethyl acetate. To the resulting solution was added an acrylate-hydrocarbon graft copolymer (hybrid adhesive), followed by

was homogenized. Avocado oil was added to the obtained homogenate, followed by mixing to homogeneity. The resulting mixture was spread on a polyester film to a weight of 60 g homogenate / m. After that it became

Solvent by the film was spread with coated homogenizer for 15 min at 60 ° C. On the dried adhesive film was a siliconized

Laminated polyester film. The following table gives quantities.

Component wet [g] dry [% m / m]

Rivastigmine 0.7 10.0

Ethyl acetate 2.5 0.0

Hybrid adhesive 14.0 80.0

(Solids content 40.07% m / m)

Avocado oil 0.7 10.0

In order to prevent the excessive flooding of the active ingredient, a thin film of a surface weight of 10 to a maximum of 40 g / m ^{2 is} applied to the skin side, which is a polymer from the group of polyacrylates, silicones, block copolymers, polyisobutylenes, acrylate Rubber hybrids or a pressure-sensitive mixture comprises or consists of a plurality of these polymers.

Example 2 to 3

For these examples, the acrylate-hydrocarbon graft copolymer (hybrid adhesive) was an acrylate polymer having functional hydroxyl groups as a graft base with grafted ethylene-butylene macromer terminated with methacrylate groups

(Weight average Mw of macromolecular weight about 4000), wherein the graft copolymer in Example 3 was crosslinked. Incidentally, reference can be made to Example 1.

Example 4

For this example, an acrylate-hydrocarbon graft copolymer (hybrid adhesive) according to US 2010/0 068 515 AI Example 2 Sample B (weight average Mw of macromolecular weight about 4000) was used. Incidentally, reference can be made to Example 1.

Example 5

Rivastigmine was dissolved in ethyl acetate. To this solution, a polymer mixture, namely non-crosslinked acidic acrylate adhesive (eg DuroTak DT 87-235A) with a butyl methacrylate / methyl methacrylate copolymer (eg Plastoid B), was added and homogenized. Thereafter, the obtained mixture was spread on a polyester film to a weight of 60 g / m ² . The solvent was removed by drying the laminate at 60 ° C for 15 minutes. On the dried adhesive film, a likewise dried acrylate-vinyl acetate film (eg DuroTak DT 87-4287) with a basis weight of 17 g / m ^{2 was} laminated. On the two-layer adhesive laminate, a siliconized polyester film was laminated. Reservoir layer:

Adhesive layer:

DT 87-235 A cf. e.g. US 2010/0 087 768 AI DT 87-4287 cf. e.g. US 2010/0 087 768 A1 Plastoid B cf. e.g. WO 2007/064407

Claims

claims

1. Transdermal therapeutic system

with an active substance-impermeable covering layer,

- With a drug reservoir containing

at least one carbamate-type cholinesterase inhibitor as active ingredient,

- a pressure-sensitive polymer as well

- optionally avocado oil and / or palm oil,

- with an optional skin-facing active substance-free adhesive layer and

- with a peel-off layer.

2. Transdermal therapeutic system according to claim 1 with rivastigmine as

Carbamate-type cholinesterase inhibitors.

3. Transdermal therapeutic system according to claim 1 with rivastigmine and at least one further cholinesterase inhibitor of the carbamate type.

4. Transdermal therapeutic system according to claim 2 or 3 with an active compound concentration of 0.1 to 40 and in particular to 50 wt .-%, preferably 15 to 35% by weight and in particular of about 30 wt .-% (based on the total weight of the

Drug reservoir).

5. Transdermal therapeutic system according to at least one of the preceding

Claims in which the at least one carbamate-type cholinesterase inhibitor is dissolved in the active substance reservoir or homogeneously dispersed.

6. Transdermal therapeutic system according to at least one of the preceding

Claims with up to 15 wt .-% avocado oil and / or palm oil (based on the

Total weight of the drug reservoir).

7. Transdermal therapeutic system according to at least one of the preceding

Claims containing avocado oil and / or palm oil and an additional content of at least one adjuvant, in particular for improving cohesion and / or

Solubility.

8. Transdermal therapeutic system according to at least one of the preceding

Claims in which the avocado oil and / or palm oil and the optional additional active ingredient are dissolved in the active substance reservoir or homogeneously dispersed.

9. Transdermal therapeutic system according to at least one of the preceding

Claims in which the active ingredient reservoir and / or the optional skin-facing active ingredient-free layer, a pressure-sensitive polymer, in particular from the group of polyacrylates, silicones, block copolymers, polyisobutylenes, acrylate hydrocarbon graft copolymers, in particular acrylate-ouchch-graft copolymers, or a

includes or consists of pressure-sensitive mixture of several of these polymers.

10. Transdermal therapeutic system according to claim 9, wherein the drug reservoir and / or the optional skin-facing drug-free layer of an acrylate [poly (ethylene butylene)] - graft copolymer as acrylate hydrocarbon graft copolymer or a styrene Butadiene-styrene comprises or consists of a block copolymer.

11. Transdermal therapeutic system according to claim 9 and / or 10 with

a hydroxyl-functionalized acrylate polymer as the grafting base of the grafted hydrocarbon of the graft copolymer and / or

a poly (ethylene-butylene) -macromer as a grafted hydrocarbon, in particular a Mw of about 4000 to 7200 (weight average).

12. Transdermal therapeutic system according to claim 9 and / or 10 and / or 11, wherein

the poly (ethylene-butylene) macromer has terminal acrylic or acrylate groups.

13. Transdermal therapeutic system according to at least one of claims 9 to 12, wherein the acrylate hydrocarbon graft copolymer is modified with a tackifier on natural or synthetic hydrocarbon-based.

14. Transdermal therapeutic system according to at least one of the preceding claims, wherein the drug reservoir uncrosslinked polyacrylate and in particular Comprising uncrosslinked polyacrylate having carboxyl groups, preferably DuroTak DT 87-235 A, or consisting thereof

The transdermal therapeutic system of claim 14, wherein the system, and in particular the drug reservoir, is free of antioxidant.

16. Transdermal therapeutic system according to at least one of the preceding claims with a content

to a solubilizer, in particular containing 1,2-propanediol,

Dimethylacetamide and / or N-methylpyrrolidone, and / or

- To cohesion, in particular with a content of polysiloxane, and / or

- To adhesive force, in particular with a content of one or more resins of natural or synthetic origin.

17. Transdermal therapeutic system according to at least one of the preceding claims, characterized in that the system is adjusted to a drug skin permeation in vitro of 10 micrograms (micrograms) / (h and system) to 5 mg / (h and system).

18. Transdermal therapeutic system according to at least one of the preceding claims, characterized in that the content of active ingredient is adjusted to a continuous active ingredient release for a duration of whole days of the range of 1 to 7 days.

19. Transdermal therapeutic system according to at least one of the preceding claims with a basis weight of the active substance reservoir of 30 to 150 g / m and / or a basis weight of the optional skin-facing drug-free adhesive layer of 10 to 40 g / m ² .