CA2114537A1

CA2114537A1 - Transdermal therapeutic systems

Info

Publication number: CA2114537A1
Application number: CA002114537A
Authority: CA
Inventors: Jutta Riedl; Ralph Lipp; Matthias Hartisch
Original assignee: Individual
Current assignee: Bayer Pharma AG
Priority date: 1991-07-30
Filing date: 1992-07-07
Publication date: 1993-02-18
Also published as: EP0596903A1; DE4210165A1; DK0596903T3; PT100737A; FI940427A7; GR3024097T3; HUT66125A; HU9400253D0; ATE151985T1; FI940427L; JPH06509346A; PT100737B; DE59208408D1; AU676826B2; NO307736B1; NO940313L; ES2103952T3; WO1993002669A1; HU217215B; AU2229892A

Abstract

ABSTRACT

Described are transdermal therapuetic systems characterized in that they contain, in an adhesive matrix containing an active substance, a polar penetration enhancer and a non-polar penetration enhancer which is insoluble in the polar penetration enhancer.

Description

~ 1 211~-~37 ~ ~:

Tra~sdermal Therapeutic ~ystems The invention relates to transdermal therapeutic systems, Which are characterized in that they contain a polar penetration enhancer in an adhesive matrix containing an active ingredient and a nonpolar penetration enhancer insoluble in the polar enhancer.
As is known, transdermal therapeutic systems (TTS) are patche~ containing an active ingredient built up in multiple layers, which are attached to the skin and which continuously deliver their active ingredient percutaneously over a longer period. To reach a therapeutically sufficient penetration rate of the active ingredient through the skin, it is necessary in most case~ to provide the transdermal therapeutic systems with penetration enhancers in addition to the active ingredient.
Transdermal therapeutic systems, which contain a combination of a polar penetration enhancer and a nonpolar penetration enhancer, are previously known. ;
But according to the known prior art, the combination ¢apability of the different penetration enhancers required that they either can be mixed with one another or that they are processed separately (for example, by layers in different matrices). (W0-A 90/~4397; EP-A 0305026 and EP-A 0272987).
It has now been found that it is surprisingly possible to produce transdermal therapeutic systems, which contain a polar penetration enhancer in an adhesive matrix containing an active ingredient and a nonpolar penetration enhancer insoluble in the 21~ j3~ :
polar enhancer, without a separation of the components resulting during the production process.
The thus produced transdermal therapeutic systems according to the invention have several advantages relative to comparable systems, which in a matrix contain either only one polar penetration enhancer or only one nonpolar penetration enhancer:
l. The use of combined penetration enhancers often produces an unexpectedly great increase of the penetration rate of the active ingredient.

2. The use of the special combination often results in that the upper load limits of the individual penetration enhancers can be exceeded.

3. Poor adhesion of the system to the skin, as it is observed in transdermal systems which are loaded with a polar penetration enhancer to the upper load limit, is not observed in the systems according to the invention.

4. Patch residues, as they are often observed after the administration of systems that contain nonpolar penetration enhancers, do not occur.
Overall, the adhesive properties of the transdermal systems are improved by the combination according to the invention and their wearing comfort increases by buffering of the moisture during the wearing.
As the adhesive forming the matrix, the system according to the invention preferably contains a commercially available adhesive (Pharmaceutical Technology, 1989, pp. 126-138). Such adhesives are, for example, polyacrylate adhesives of the ~ 3 ~1t~ 7 Durotak~R) type (National Starch Company), Sichello~R) type (Sichelwerke [Sickle Factory]3 or Gelva~R) type (Monsanto Company), synthetic rubber adhesive of Adhesin~R) type (Henkel KG) or silicone adhesive of X7 type (Dow Corning Corp.) As polar penetration enhancers, the transdermal systems according to the invention contain urea or a multivalent alcohol with preferably 2 to 6 carbon atoms. Such polyols are, for example, 1,2-ethanediol, 1,3-propanediol, glycerol, sorbitol, mannitol, dulcitol or especially 1,2-propanediol. In the finished matrix, the concentration of polar penetration enhancer is preferably 5 to 25% by weight relative to the total weight of the matrix.
As nonpolar penetration enhancers, the transdermal system according to the invention preferably contains a fatty acid ester with at least 8 carbon atoms.
Fatty acid esters, which are suitable for the process according to the invention are, for example, those of lauric acid, myristic acid, palmitic acid, isopalmitic acid, stearic acid and isostearic acid, CUch as, for example, methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, sec-butyl ester, isobutyl ester, tert-butyl ester or glycerol ester.
Such pharmaceutically common fatty acid esters are, for example, methyl myristate, ethyl myristate, propyl myristate, methyl laurate, ethyl laurate, propyl laurate, isopropyl laurate, methyl oleate, ethyl oleate, propyl oleate, isopropyl oleate and isopropyl palmitate and especially isopropyl myristate.
Certainly, high-boiling liquid hydrocarbons with at least ~ ;

4 ~ 37 ~ ~

carbon atoms and mixtures of these hydrocarbons, such as liquid paraffin or terpenoid hydrocarbons, such as ~-pinene, d-limonene, 3-carene, myrcene, camphene, bisabolene or squalene, alcohols with at least 8 carbon atoms, such as, for example, alkanols, myristyl alcohol or stearyl alcohol or sterines, such as -cholesterol and also fatty acids with at least 8 carbon atoms, such as stearic acid, palmitic acid, oleic acid, should also be suita~le for the production of the transdermal systems according to the invention. There are not yet any attempts that relate to ;~
this.
~ he nonpolar penetration enhancer is preferably metered so that its concentration in the ~inished matrix is 1 to 15% by weight relative to the latter.
Active ingredients which are suitable for the production of the transdermal systems according to the invention are preferably those that are poorly soluble in water or insoluble. Suitable, for example, are steroid hormones, such as:
Progestationally active steroid hormones, such as, for example, 13-ethyl-17~-hydroxy-18,19-dinor-17a-pregn-4-en-20yl-3-one (clevonorgestrel), 13-ethyl-17~-hydroxy-18,19-dinor-17a-pregna-4~15-dien-20yn-3-one (=gestodene) or 13-ethyl-17~-hydroxy- -11-methylene-18,19-dinor-17~-pregn-4-en-20yn (=desorgestrel), estrogenically active steroid hormones, 3-hydroxy-1,3,5-(10)-estrat~ien-17-one (=estrone), 1,3,5(10)-estratriene-3,17~-diol (=estradiol) or 1,9-nor-17~-pregna-1,3,5(10)-trien-20yn-3,17 diol (=ethinylestradiol).

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21~ 37 Androgenically active steroid hormones, such as 17~-hydroxy-4 androsten-3-one (=testosterone) and its esters~or 17~-hydroxy-l~-methyl-5~-androsten-3-one (=mesterolone).
Antiandrogenically active steroid hormones, such as 17 acetoxy-6-chloro-l~r2~-dihydro-3H-cyclopropa[l~2]-pregna-l~4~6 triene-3,20-dione (=cypoterone acetate).
Corticoids, such as 11~,17a,21-trihydroxy-4-pregnene-3,20-dione (chydrocortisone), 11~,17~,21-trihydroxy-1,4-pregnadiene-3,20-dione (=prednisolone), 11~,17~,21-trihydroxy-6~-methyl-1,4-pregnatriene-3,20-dione (=methyl prednisolone) and 6~-fluoro-11~,21-dihydroxy-16~-methyl-1,4-pregnadiene-3,20-dione (~diflucortolone) and its esters.
Suitable active ingredients are further~
Ergoline derivatives, such as lisuride [=3-(9,10-didehydro-6-methyl-8a-ergolinyl)-1,1-diethylurea], bromolisuride t=3-(2-bromo-9~lo-dehydro-6-methyl-8a-ergolinyl-l~l-diethylurea]~
terguride t=3-(6-methyl-8~-ergolinyl~ diethylurea] and proterguride t=3-(6-propyl-8~-ergolinyl)-1,1-diethylurea].
Antihypertensive agents, such as 7~-acetylthio-17-hydroxy-3-oxo-4-pregnene-21-carboxylic acid-~-lactone (=spironolactone) and 7~-acetylthio-15~,16~-methylene-3-oxo-17~-pregna-1,4-diene-21,17-carbolactone (=mespirenone).
Anticoagulants, such as 5~[hexahydro-5-hydroxy-4-(3-hydroxy-4-methyl-1-octen-6-ynyl)-2(lH)-pentalenylidene)]-pentanoic acid (~iloprost) or (Z)-7-[(lR,2R,3R,5R)-5-chloro-3-hydroxy-2-[(E)-(3R)-3-hydroxy-4,4-dimethyl-l-octenyl]-cyclopentyl]-5-heptenoic acid (=nocloprost).

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2 ~ 3 7 Psychopharmaceutical agents, such as 4-(3-cyclopentyloxy-4-methoxy-phenyl-2-pyrrolidone (=rolipram) and 7-chloro-1,3-dihydro-l-methyl-s-phenyl-2H-1,4-benzodiazepin-2-one (=diazepam).
Organic nitro compounds, such as nitroglycerine or isosorbide dinitrate t=l,4,3,6-dianhydro-D-glucitol-dinitrate].
Beta-blockers, such as propanolol ~ [(l-methylethyl)-amino]-3-~l-naphthyloxy-2-propanolol}r mepindolol ~=i-[(l-methylethyl)-amino]-3-~(2-methyl-lH-inol-4-yl)-oxy]-2-propanol~
and carazolol ~=2-(sH-carbazol-4-yloxy)-3-t(l-methethyl)-amino]
2-propanol}.
Carotenoids, such as ~-carotene and ~-carotene.
~-Carbolines are another group, as they are described, for ; ;~
example, in European Patent Applications 234,173 and 239,667. As ~-carbolines, there can be mentioned, for example, 6-benzoyloxy-4-methoxymethyl-~-carboline-3-carboxylic acid-isopropylester . . .
~-becarnil) and 5-(4-chlorophenoxy)-4-methoxymethyl-~-carboline-3-carboxylic acid-isopropylester (=Cl-PHOCIP~.
Also worth mentioning are analgesics, such as, for example, salicylic acid, glycol salicylate, methyl salicylate, 7,8-didehydro-4,5-epoxy-17-methyl-morphinan-3,6-diol (=morphine), 4,5-epoxy-14-hydroxy-3-methoxy-17-methyl-morphinan-6-one (oxycodone), (-)-(R)-6-(dimethylaminol-4,4-diphenyl-3-heptanone (=levomethadone) or 3,4,5,6-tetrahydro-5-methyl-1-phenyl-lH-2,5-benzoxacin (=nefopam).
Finally, nicotine, clonidine and scopolamine can be mentioned as suitable active ingredients.

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3~1 It is plausible that ~he transdermal systems according to -the invention can also contain mixtures of these-active ingredients.
The optimal concentration of the active ingredient in the transdermal therapeutic systems according to the invention is, of course, dependent on the type of active ingredient, its effectiveness, the type of penetration enhancer, the adhesive used, etc., and must be determined in the individual case by the preliminary tests familiar to the galenic specialist. Usually, he will proportion the active ingredient so that its concentration in the finished matrix is 0.1 to 10% by weight ~ `
relative to the latter.
The transdermal therapeutic systems according to the invention are pre*erably constituted so that they consist of a top coating impermeable to the penetration enhancer and optlonally also to water, an adhesive matrix containing an active ingredient adhering to the top coating, which contains polar and nonpolar penetration enhancers, and a removable protective layer.
This simplest form of a transdermal therapeutic system, which i5 designated as an adhesive matrix-TTS, can be produced in the way that a solution of adhesive is mixed in a low-boiling solvent with the active ingredient or active ingredient mixture, the polar and the nonpolar penetration enhancer, the mixture is applied in sheets to a top coating impermeable to the penetration enhancer and optionally also to water, the volatile solvent is removed by heating and the obtained product is covered with a removable protective layer.

--~ 8 211~1~37 Suitable solvents for dissolving the adhesive are, for example, low-boiling alcohols, such as methanol~ ethanol or isopropanol, low-boiling ketones, such as acetone, low-boiling hydrocarbons, such as hexane, or low-boiling esters, such as ethyl acetate as well as their mixtures.
This process can be performed in the way that a solution or : .
suspension of the active ingredient, the penetration enhancer and -~
the adhesive in a volatile solvent are spread on a flat, impermeable top coating and after the drying at about 60C to 90C are provided with a removable protective layer.
As protective layers, all films are suitable which are usually used with adhesive in transdermal therapeutic systems.
Such films are, for example, siliconized or coated with fluoropolymer.
As a top coating, for example, 10 to 100 ~m thick films made oP polyethylene, PVC, PVDC or their copolymers or polyesters can be used alternatively pigmented or metallized. The pharmaceutical agent layer applied upon this preferably has a thickness of 20 to 500 ~m. The active ingredients are delivered preferably over an area of 5 to 100 cm2.
It is obvious to one skilled in the art that the transdermal therapeutic systems according to the invention can also be con~igured significantly more complex than the already mentioned simple matrix systems. (Yie W. Chien: "Transdermal Controlled Systemic Medications," Marcel Dekker, Inc., New York and Basel, 1987, Dr. Richard Baker: "Analysis of Transdermal Drug Delivery Patents 1934 to 1984" and "Analysis of Recent Transdermal ,. .. .

2 ~ 3 7 Delivery Patents, 1984-1986 and Enhancers," Membrane Technology Research, 1030 Hamilton Court, Menlo Park, CA 94025 (415) 328-2228). But this should generally provide no significant ~.
advantages of the systems whatsoever, which warrant the increased ~ ~:
expense in their production.
The following embodiment is used to explain the invention in -more detail:

~ ~ 10 2 ~ 3 r~ :

Example 1 -To 100 g of a 50% by weight solution of silicone adhesive X7-4~02 (manufacturer: Dow Corning Comp.) in hexane are added in succession 3.00 g of 17~-estradiol 6.00 g of 1,2-propanediol and ~ `
1.00 g of isopropyl myristate.
The cloudy mass which forms is then rolled in a high-grade steel vessel to remove existing gas bubbles.
The mass that is largely free of gas bubbles is applied to a fluoropolymer-coated polyester film (Scotchpack~R) 1022 of the 3M
company, Minneapolis) or a siliconized film (Akrosil Silox B 54 of the Akrosil company, Comp.) by a knife-over-roll coating device in the way that after the removal of the volatile solvent at 65-75C over 2 to 3 minutes, a uniform film of 50 g/m2 results. Then, it is laminated with a polyester cover film ~Hytrel 6108 film 30 ~m -- of the Bertek company, Vermont/USA).
The thus obtained laminate is divided by a punching device into individual patche6 of 5 cm2, 10 cm2 and 20 cm2 areas and packed in ;~`
aluminized bags. After removal of the protective film, the patches adhere to the skin and can be used for hormone replacement.

Exam~le 2 To 100 g of a 50% by weight solution of acrylate adhesive Gelva~R) (manufacturer: Monsanto Comp.) in ethyl acetate are added ' i"' 2 1 ~ 7 ~ ~
in succession 3.00 g of 17~-estradiol -6.00 g of micronized urea, dispersed in hexane and -3.00 g of isopropyl myristate.
The cloudy mass which forms is then rolled in a high-grade steel vessel to remove existing gas bubbles.
The mass that is largely free of gas bubbles is applied to a fluoropolymer-coated polyester film (Scotchpack~R) 1022 of the 3M
company, Minneapolis) or a siliconized film (Akrosil Silox B 54 of the Akrosil company, Comp.) by a knife-over~roll coating device ln the way that after the removal of the volatile solvent at 65-75C over 2 to 3 minutes, a uniform film of 50 g/m2 results. ~hen, it is laminated with a polyester cover film (Hytrel 6108 film 30 ~m -- of the Bertek company, Vermont/USA).
The thus obtained laminate is divided by a punching device into individual patches of 5 cm2, 10 cm2 and 20 cm2 area and packed in aluminized bags. After removal of the protective film, the patches adhere to the skin and can be used for hormone replacement.

Example 3 To 100 g of a 50% by weight solution of silicone adhesive X7-4502 (manufacturer: Dow Corning Comp.) in hexane are added in succession 3.00 g of 17~-estradiol 5.00 g of micronized urea, dispersed in hexane and 2.00 g of isopropyl myristate.
- ' ~

~-` 2 1 t ~ 7 ~ .
The cloudy mass which forms is then rolled in a high-grade steel ~ ;
vessel to remove existing gas bubbles. -The mass that is largely free of gas bubbles is applied to a -. .
fluoropolymer-coated polyester film (Scotchpack~R) 1022 of the 3M
company, Minneapolis) or a siliconized film (Akrosil Silox B 54 of the Akrosil company, Comp.) by a knife-over-roll coating -device in the way that after the removal of the volatile solvent at 65-75C over 2 to 3 minutes, a uniform film of 50 g/m2 results. Then, it is laminated with a polyester cover film (Hytrel 6108 film 30 ~m -- of the Bertek company, Vermont/USA).
The thus obtained laminate is divided by a punching device into individual patches of 5 cm2, lO cm2 and 20 cm2 areas and packed in --aluminized bags. After removal of the protective film, the patches adhere to the skin and can be used for hormone replacement.
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Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. Transdermal therapeutic systems, wherein they contain a polar penetration enhancer in an adhesive matrix containing an active ingredient and a nonpolar penetration enhancer insoluble in the polar enhancer.

2. Transdermal therapeutic systems according to claim 1, wherein they contain a multivalent alcohol or urea as polar penetration enhancer.

3. Transdermal therapeutic systems according to claim 2, wherein they contain 1,2-propanediol, glycerol, sorbitol, mannitol or dulcitol as multivalent alcohol.

4. Transdermal therapeutic systems according to claims 1 to 3, wherein they contain a hydrocarbon, an alcohol, a fatty acid or a fatty acid ester with at least 8 carbon atoms each as nonpolar penetration enhancer.

5. Transdermal therapeutic systems according to claim 4, wherein they contain isopropyl myristate as fatty acid ester.

6. Transdermal therapeutic systems according to claims 1 to 5, wherein they consist of a top coating impermeable to the penetration enhancer and optionally also to water, an adhesive matrix containing an active ingredient adhering to the top coating, which contains polar and nonpolar penetration enhancers, and a removable protective layer.

7. Process for the production of transdermal therapeutic systems according to claim 6, wherein a solution of adhesive is mixed in a low-boiling solvent with the active ingredient or active ingredient mixture, the polar and the nonpolar penetration enhancer, the mixture is applied in sheets to a top coating impermeable to the penetration enhancer and optionally also to water, the volatile solvent is removed by heating and the obtained product is covered with a removable protective layer.