CA2012124A1

CA2012124A1 - Plaster used as therapeutic system for the administration of active substances to the skin, which exhibits a graduated active substance release, process for the production of the plaster and the use thereof

Info

Publication number: CA2012124A1
Application number: CA002012124A
Authority: CA
Inventors: Annegrete Hoffmann
Original assignee: Individual
Current assignee: LTS Lohmann Therapie Systeme AG
Priority date: 1989-03-14
Filing date: 1990-03-14
Publication date: 1990-09-15
Also published as: HUT53814A; SI9010494A; PH26277A; EP0387694B1; ATE133569T1; EP0387694A2; AU5076690A; CZ113790A3; DE3908432C2; PT93431A; PT93431B; YU48229B; AU622775B2; ES2085293T3; DK0387694T3; JP2588039B2; SK280996B6; PL162638B1; NZ232896A; SI9010494B

Abstract

A B S T R A C T

The present invention relates to a plaster used as therapeu-tic system for the administration of active substances to the skin exhibiting an graduated active substance release, to the process for the production of such a plaster, and to the use for the local or systemic dermal adminstration of active substances in the human or veterinary medicine, or in cosmetics.

Description

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D E S C R I P T I O N

The present invention relates to a plaster used as therapeu-tic system for the administration of active substances to the skin, said plaster exhibiting graduated active sub-stance release, to the process for the production of such a therapeutic system, and to its use for the local or system-ic dermal administration of active substances in the human or veterinary medicine, or in cosmetics.

Therapeutic devices for the controlled administration of -drugs are called therapeutic systems (K. Heilmann, Therapeu-tische Systeme, page 26, publishers F. Enke, Stuttgart, 1984). According to this publication such a system is an :
active substance containing device or form of adminstra-tlon, respectively, which continuously releases one or more pharmaceuticals at a predetermined rate over a fixed period -of t$me to a fixed place of application.

Such systems may have topical as well as a systemic effects - -when applied to the skin, and the variety of active sub-stances applicable by way of these systems and the differ-ent chemical, physical, and pharmacological properties of the drugs always demand for new requirements in the produc-tion of such systems. For example, in the case of dermal --: -'~ " '. '' ' ,' ', '' ' ' , ,. ' ' . . ' . ': ,. " ' . - .
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application, solutions for many active substances have been found in which a continuous, substantially constant release over the desired period of application has been achieved.

However, there are also therapeutical requirements accord-ing to which the release profile of the drug has to exhibit a high initial dosage followed by a lower maintenance dosage. For example, in case of soporifics, high delivery of active substance for sleep induction, and a lower dosage to prevent awakening over a longer period of time after sleep induction is desired. In the case of appetite-sup-pressing agents, too, higher blood levels of active sub-stance shall be adjustable during the day compared to those during the night. The same applies to the administration of nicotine in the curing of smokers. Not least the treatment of pain attacks is mentioned, where after a high initial dosage a lower maintenance dosage is desirable.

A transdermal therapeutic system to solve this problem has been described in EP-A O 227 252. In this case, the active substance in a reservoir is brought into contact with an amount of penetration accelerator merely sufficient to maintain the accelerated penetration only during a defined initial phase of application. It is of disadvantage in this case that each active substance has to assigned a suitable penetration accelerator, and that in the choice of the "

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2~12~24 reservoir matrix in addition to considering the diffusivity of the active substance that of the penetration accelerator has to be taken into consideration, too.
In the latter case, an expensive additional controlling membrane is frequently required.

Another solution to this problem has been proposed in DE-OS
36 42 931. In this case, at least two plaster chambers being separate from each other are provided with different active substance concentrations so that in the first appli- -cation phase the release of active substance from all cham-bers effects a high initial dosage, while after evacuation of the chambers with low active substance concentration only those chambers with higher active substance concentra-tion contribute to the release, and thus effect a lowered maintenance dosage. This system is expensive merely because of this chamber construction, and requires special measures with respect to the different concentration adjustments in the chambers.

It is accordingly the object of the present invention to provide a plaster as therapeutic system with graduated drug release for the administration of active substances to the skln, which avoids the compelling presence of a penetration accelerator and can be manufactured in a simple manner.

.

2nl2l24 According to the present invention, this object is sur-prisingly achieved by a plaster with a high initial dosage and a lower maintenance dosage, which is provided with a backing layer averted from the skin, at least one active substance deposit contacting a matrix, which controls the active substance release, and a pressure-sensitive adhesive fixing device for securing the plaster to the skin. In this connection, the whole matrix contains active substances at the time of application, and the dimension of the active substance containing deposit or deposits compared to that of the matrix, as well as the position of the active sub-stance deposit or deposits in contact with the matrix are chosen is such a way that, at least in one direction, the space between deposit and edge of matrix, which contacts the releasing surface, is larger than the diffusion path of at least one active substance from the deposit into the matrix during the period of application.

Thus the subject matter of the present invention is a plaster used as therapeutic system for the controlled and graduated administration of active substances to the skin, with a high initial dosage and lower maintenance dosage comprising a backing layer averted from the skin, at least one active substance deposit in contact with a matrix controlling the active substance release, and a pressure--8ensitive adhesive fixing device to secure the plaster to ,. , , , , " , . . . .
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the skin, whereby the complete matrix at the beginning of the application comprises active substances, wherein the dimension and position of the active substance deposit or deposits in contact with the matrix are chosen in such a way that, at least in one direction, the space between deposit and a matrix edge, which contacts the releasing surface, is larger than the diffusion path from the deposit into the matrix during the course of application of at least one active substance.

The general design of the plaster according to the present invention is known from DE-OS 21 35 533, however, without having recognized the constructional features of the intend-ed change in release profile according to the present inven-tion. -An important feature of the plaster according to the pres-ent invention is that the matrix comprises active substance at the time of application. This can be achieved by two methods. On the one hand, the matrix may be loaded with active substances already during the manufacture of the plaster, or, on the other hand, the matrix is loaded with active substance after production of the plaster by diffu-sion of active substance from the active substance deposit -~
into the matrix which up to then had been empty. The last mentloned process can be accelerated by temperature in- -', .'' ,' ', ' ,, ', ', ",' ' ' ' ',, ;,' '~',',' ':; ':,.,'", "". ,'. ;" ', '.',,.; ~, ' ,, '' ''- , ' ' ~., ,, ",, , , , , , , ", , . , " " :. , ,; . ;;, ,, ,,', " ', "' ,' , ' , " ' ,, ,', ', '' ",' ', ,', ' '' ' ,,~,' ''~','','; ',i ',''' ' ' '", ' , - 2~12124 crease, and may last for hours or days. Thus, during the initial phase of application, active substance may issue over the whole releasing surface of the matrix (corresponds to high initial dosage) which results in a depletion of active substance in the bordering layers. This depletion can only be compensated by additional delivery of active substances from the active substance deposit. If the space between deposit and emptying zones is so large that it cannot be overcome during application due to the diffusitiv-ity of the active substance, the active substance release comes to a standstill in these regions. Only those portions of the releasing surface of the matrix are still releasing active substances, which can be delivered by subsequent diffusion from the deposit (corresponding to a lower main-tenance dosage). Thus, the geometric relations within the plaster are mainly determined by the desired release pro-file, the active substance to be administered, the choice of matrix, as well as the dimension and position of the deposit. - -The active substance deposit containing one or more active substances may consist of pure active substance which may solid or flowable, however, said deposit may also contain --inert auxiliaries. The term "inert" is to be understood in thi~ connection in that the active substance and the auxi-liary agent do not react with one another. Inert auxili-,, , ,, ,, ;, , ,, , " ,, " " , , , ,, . ,-.
,, ,,,, ~ , ,,,,, ,, ",~ . , ,, , ,, '. , , ~ -2~2~2~

aries known to those skilled in the art, e.g., are sol-vents, fillers, stabilizers, supporting materials, carriers, and optionally as well additives regulating diffu-sion and penetration.

All transdermally applicable active substances for the application of which high initial dosages are indicated can be used as active substances. Active substances selected from the group consisting of analgesics, antiemetics, anti-adipogenics, antiphlogistics, antispasmolytics, and anti-angina-agents, are mentioned as examples. Nicotine employed as active substance for curing smokers does also belong to this group.

Advantageously the sum of active substances in the deposit and the matrix amounts to up to 20 times the therapeutical-ly required amount.

The matrix is preferably built up in layers and/or as a laminate, whereby the layers can be the same or different.
The matrix may be pressure-sensitive adhesive, this can be achieved by the use of adequate polymeric materials, e.g., rubber, rubber-like synthetic homo-, co-, or blockpolymers, poly(meth)acrylates and their copolymers, polyurethanes, and silicones. In principle, all polymers are suitable which are employed in the manufacture of pressure-sensitive 2~1212~

adhesives and are physiologically acceptable. It may be advantageous, if the matrix is pressure-sensitive adh2sive, since the necessity for a separate pressure-sensitive adhe-sive fixing device can be omitted. In case of a matrix not being pressure-sensitive adhesive, suitable polymeric mate-rials are used, e.g., those selected from the group consist-ing of poly(meth)acrylates, polyvinylpyrrolidones, ethyl-cellulose, hydroxypropylcelluloses, hydroxypropylmethyl-cellulosephthalates, polyvinyl alcohols or their copolymers with vinyl laurate or maleic acid, respectively, vinyl acetates or their copolymers with vinyl laurate or maleic acid, respectively, polyvinyl ether, butyl rubbers, and polycaprolactames.

The active substance deposit may be composed of a single layer and/or of multiple layers in itself. The form of a layer of the active substance deposit is always preferred from the production standpoint, in cases where it can be achieved to adjust the active substance concentration in the layer in correspondence with the requirements and to maintain the necessary space to the matrix edge. The lami-nated construction of the substance deposit is preferred, if a direct mixture of drug-containing deposit portions with requlred or desired inert auxiliaries is impossible, or if advantages with respect to its production result; in this connection the deposit itself need not be in the form ... . .............. .. . ..
.. ,, , , , . , , . , ,~ , .

,, ' ', ' ', ', :', ' ,", ,', ", ~, , , ' ,. ' : ' of a laminate.

In the construction of the plaster, for example, at least one active substance deposit may be inserted between a back side matrix layer and a matrix layer on the skin side, whereby the thickness ratio of the matrix layers preferably is in the range of 1:1 to 1:20, particularly preferred in the range of 1:1 to 1:5.

In another advantageous embodiment of the plaster according to the present invention, the active substance deposit may be located between matrix and backing layer, this is partic-ularly suitable in case of solid active substance deposits which are applicable in the form of matter.

If the matrix is not self-adhesive, a pressure-sensitive adhesive layer may be provided for on that surface of the device facing the skin. In this case, the inner coherence of the device can also be managed by additional pressure--sensitive adhesive intermediate layers. According to a preferred embodiment of the present invention the fixing device may be built by pressure-sensitive adhesive sections embedded in the matrix, or by pressure-sensitive adhesive -edges surrounding the releasing surface. The pressure-sensi-tive adheslve layers may also contain active substances -thus contrlbutlng to the increase of the initial dosage.

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The backing layer serves for the protection and/or mechan-ical stabilization of the device. It may consist of flex-ible or inflexible material and may be single or multi--layered.

Substances suitable for its production are polymeric sub-stances, such as, e.g., polyethylene, polypropylene, poly-ester, and polyamides. As further materials metal foils, e.g., an aluminum foil alone or coated with a polymeric substrate, may be used, too. Textile fabrics may also be used, if they are able to prevent the components of the device from escaping. Polymer foils vapourized with metal have proved particularly successful.

It i8 possible in a usual manner to provide for a removable protective layer on those surfaces of the plaster facing the skin, this protective layer prevents an undesirable contamination and premature release of the plaster compo-nents. This layer is removed only immediately prior to application. In principle, the same materials as used for the backing layer may be used for the manufacture of the protective layer, provided that they are removable, e.g., by way of a silicone treatment. Other removable protective layers, for example, are polytetrafluoroethylene, treated paper, cellophane, and polyvinyl chloride. As a matter of , '',, ' ''' , ', ' ', :,,', ' ': " , :;.'', ., , ,' ',:, ' ,, j , ,-, , , : ,: , ., ~ ", .
,, ,, ,, ; , ,, . " ,,, ; , ,, :, ;'":: ' . ', . , :

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fact, the protective layer may be provided with a touch aid in order to facilitate stripping it off the plaster.

A preferred process for the production of the plaster ac-cording to the present invention is the in situ-production of the active substance deposit. In this connection, the deposit is built of the deposit components directly at the contact point to the matrix. As for the rest, the layers of the device are joined by applying pressure and/or heat. The deposit may also be integrated into the matrix by pressure, for example, by in~ection of a predetermined amount, or by pressing a deposit body into a soft matrix. According to a preferred process of the present invention, the active substance deposit is incorporated between two matrix layers which can be the same or different.

Advantageously at least one part of the plaster is produced of a solution, a dispersion, a melt, or by sprinkling par-ticles. The areal intermediate products thus obtained are -distributed to smaller units, the dimension and shape of -, which are determined by the therapeutical requirements.

The plaster according to the present invention is particu-larly suitable for the local and systemic dermal administra-tion of active substances in the human or veterinary medi- -cine, and can be used in cosmetics, too.

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In the following, the present invention shall be illustrat-ed but not limited by the figures which, amongst others, show the schematic, not true to scale construction of the plasters according to the present invention:

Figure la shows a section through a plaster according to the prior art, Figure lb shows a diagram of the in vivo-release profile of the plaster according to Figure la, Figure 2a shows a section through an embodiment of the plaster according to the present inven- :
tion, Figure 2b shows a diagram of the in vivo-release profile -of the plaster according to Figure 2a, Figure 3a shows a section through a further embodiment of the plaster according to the present inven-tion, Figure 3b shows a diagram of the in vivo-release profile of the plaster according to Figure 3a, . ~ . ~ - , , , ,:

,, , " ,,, , ~ , , ", .. ..

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Figure 4 shows a section through another preferred embodi-ment of the plaster according to the pres-ent invention, igure 5 show~ a section through yet another preferred embodiment of the plaster according to the present invention, igure 6 shows a section through an embodiment of the plaster according to the present invention provided with several active substance ..
deposits, and .
igure 7 shows a section through an embodiment of the plaster according to the present inventlon provided with a variety of active sub- . -stance deposits. ' Figure la represents the schematic section through a plaster according to the prior art, in which an active substance deposit (13) is embedded in a pressure-sensitive --adhesive matrix (12) which is covered by a backing layer -(11). The space of the active substance deposit (13) from :

the edge of matrix (14) is so small that those regions of the matrlx which are emptying during application can be -refilled with active substance by diffusion. Thus active 20~2~2~

substance is released over the complete releasing surface during the whole period of application.
Figure lb shows the in vivo-release profile corresponding to this plaster, whereby the flux is indicated versus time.
It can be seen that after achieving the maximum the flux mainly remains at the same level without gradation, for the rest of the time. Thus, according to this prior art, a substantially constant flux is maintained during the de- -sired period of time.

The schematic section through an embodiment of the plaster according to the present invention with backing layer (21), pressure-sensitive adhesive matrix (22), embedded deposit (23), and edge of matrix (24) as shown in Figure 2a shows a -considerably extended space between deposit (23) and edge of matrix (24) compared to that of the plaster according to Figure la. If the matrix (22) ~s correctly adapted to the individual active substance, the active substance, during the course of further application, is no longer able to -afterdiffuse into those regions of matrix (22) which are more distant from the deposit (23), once the originally contained actlve substance in the matrix has been released, due to the geometric conditions. As is shown by the corres-ponding in vivo-release profile according to Figure 2b, the flux decreases to a substanstially constant, lower value, after exceeding a certain maximum. Thus, in general, lower ,, ,, ,, , ,,, , , ;,, ,,,",. .. . ...

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maintenance dosages are adjustable after an increased ini-tial dosage.

Figure 3a shows a schematic section through a further em-bodiment of the plaster according to the present invention with backing layer (31), pressure-sensitive adhesive matrix -(32), embedded deposit (33), and edge of matrix (34). In -this figure the distance between deposit (33) and edge of matrix (34) is further extended compared to that of embodi-ment according to Figure 2a so that even larger regions of the matrix (32) cannot be provided with active substance -during application. However, since the total releasing surface is clearly larger than that shown in Figure 2a, a higher initial maximum is obtained according to Figure 3b, in which the corresponding flux is indicated, said initial flux, in the course of application then decreases to ap-proximately the same value as that of Figure 2b. ~

The deposit within the matrix may be positioned symmetrical- -ly or asymmetrically, whereby it must always be assured that the space between deposit and releasing surface can be ~
bridged in the sense of an intented release by diffusion of the active substances. As a matter of fact, the desired release profile is of significant importance in this connec-tion. The most favourable space can be calculated in some cases, or must experimentally be determined in many cases.

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Figure 4 represents a schematic section through another embodiment of the plaster according to the present inven-tion. Here, the remarkable feature is the position of depo-sit (43) which is only partially embedded into the pressure--sensitive adhesive matrix (42) and contacts backing layer (41) at one side. The distance of deposit (43) to edge of matrix (44) corresponds to that shown in Figure 3a, how-ever, the larger distance between deposit (43) and releas-ing surface influences the choice of suitable active sub-stances for this embodiment. This embodiment may have advan-tages from the production standpoint.

As can be seen from Figure 5, which represents a section through yet another embodiment of the plaster according to the present invention, deposit (53) may also be mounted on pressure-sensitive adhesive matrix (52), whereby for the --rest it is surrounded by backing layer (51). The statements made for Figure 4 apply to the space between deposit (53) and edge of matrix (54) and that between deposit and releas-ing surface. Here, too, advantages with respect to produc- -tion may be decisive for chosing this embodiment.

Figure 6 schematically represents a section through an embodiment of the plaster according to the present inven-tion in which three deposits (64) which are separated from ,,, . ,, ,', ' '. ", ,,,, ", - '"'"'';: ;'"' "','''' ', '~; ' ' ' ' '::

" ,, , ,, , , ~:, , , , , , ,: , . .

2~12~24 each other are embedded in a non-adhesive matrix (63).
Matrix (63) is connected with backing layer (61) via a pressure-sensitive adhesive intermediate layer (62), where-by backing layer (61) as well covers the edge (65) of the matrix, and builds an edge extending parallely to the skin.
Fixing the plaster to the skin is effected by a pressure--sensitive adhesive layer (62a) which in permeable to the active substance and extends over the whole free surface of --matrix (63) as well as over extending edges of backing layer (61).

The design of the plaster with several deposits points out another possibility to influence the release profile. The spacial isolation of deposit portions of the same total volume allows fresh delivery of active substances by diffu- -sion into larger regions of the matrix, compared to a single deposit exhibiting the same volume. However, the condition according to the present invention with respect to the space of deposit to the plaster edge has to remain fulfilled. As a matter of fact, the space between at least two deposit members may be such large that it exceeds the posslble diffusion path from the deposit part into the matrix during the application period of at least one active substance.

Figure 7 is an example with respect to the further division .. , , ........... , ,., , v, ., ,, ~ . -, , , - - , , , , ,: , : -,, , ~ , :, ............... .
- ,. ;. , : , , .~ ' ','," ' '",' ,', "' " ,'' ~ '' '' " "',' ' ' """ ''' ~", ' .'' ' ' , , ' , ' ' ~ , ' ' , :, ' " ,, , , , , , ~, , ~ ,.

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of the deposit. Figure 7 represents a schematic section through a further embodiment of the plaster according to the present invention. The non-adhesive matrix (73) is interspersed with several small deposits (74) in its mid-dle, whereby these deposits may be solid or flowable bodies or as well microcapsules. Matrix (73) is connected with backing layer (71), except for that surface facing the skin, via a pressure-sensitive adhesive layer (72); edge (75) of the matrix is covered, too. Pressure-sensitive adhesive layer (72) also spreads the extending edges of backing layer (71), thereby forming the fixing device to the skin, since that surface of matrix (73) which is in direct contact with the skin is non-adhesive.

For the sake of clarity, the protective layers for those surfaces facing the skin have not been drawn in all figures showing sections through plaster embodiments. As a matter of fact, they constitute an important component of the plasters according to the present invention. The dimension of the plasters may widely be varied with respect to out-lines and sizes; in this connection, the therapeutic re- -quirements as well as those determined by the site of appli-cation have to be considered principally, aspects concern-lng handling have to be considered, too.

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It is understood that the specification and examples are illustrative but not limitative of the present invention and that other embodiments within the spirit and scope of the invention will suggest themselves to those skilled in the art.

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Claims

1. A plaster used as therapeutic system for the controlled and graduated administration of active substances to the skin, with a high initial dosage and lower maintenance dosage comprising a backing layer averted from the skin, at least one active substance deposit in contact with a matrix controlling the active substance release, and a pressure--sensitive adhesive fixing device to secure the plaster to the skin, whereby the complete matrix at the beginning of the application comprises active substances, characterized in that the dimension and position of the active substance deposit or deposits in contact with the matrix are chosen in such a way that, at least in one direction, the space between deposit and a matrix edge, which contacts the re-leasing surface, is larger than the diffusion path from the deposit into the matrix during the course of application of at least one active substance.

2. The plaster according to claim 1, characterized in that at least one active substance deposit exclusively comprises active substance or substances.

3. The plaster according to claim 1, characterized in that at least one active substance deposit comprises at least one inert auxiliary agent.

4. The plaster according to claims 1 to 3, characterized in that at least one active substance deposit is present in solid or flowable form.

5. The plaster according to any one of the preceeding claims, characterized in that it is built up at least partially in layers and/or as a laminate.

6. The plaster according to claim 5, characterized in that the matrix consists of at least two layers, whereby prefer-ably at least one active substance deposit is incorporated between a back-side matrix layer and a matrix layer facing the skin, and that the thickness ratio of the matrix layers preferably is in the range of 1:1 to 1:20, particularly preferred in the range of 1:1 to 1:5.

7. The plaster according to claim 5, characterized in that at least one active substance deposit is formed in layers and/or in the form of a laminate.

8. The plaster according to any one of the preceeding claims, characterized in that the matrix is pressure-sensi-tive adhesive.

9. The plaster according to claims 1 to 7, characterized in that the matrix or at least one matrix layer exhibits pres-sure-sensitive adhesive devices on at least one side.

10. The plaster according to claims 1 to 7 and 9, character-ized in that pressure-sensitive adhesive portions embedded in the matrix form the fixing device.

11. The plaster according to claims 1 to 5 and 7 to 10, characterized in that at least one active substance deposit is positioned between matrix and backing layer.

12. The plaster according to any one of the preceeding claims, characterized in that it exhibits a removable pro-tective layer for those surfaces facing the skin.

13. The plaster according to any one of the preceeding claims, characterized in that it comprises an amount of active substance amounting to up to 20 times the therapeu-tically required amount.

14. A process for the production of a plaster as defined in claims 1 to 13, characterized in that the active substance deposit is manufactured in situ by combining the deposit components during the production of the plaster.

15. A process according to claims 5, 6, and 7, character-ized in that the layers are joined by application of pres-sure and/or heat.

16. A process according to any one of the preceeding claims, characterized in that the active substance deposit is inserted into the matrix by the application of pressure.

17. A process according to any one of the preceeding claims, characterized in that the active substance is incor-porated into the matrix during the production of the plaster.

18. A process according to claims 1 to 16, characterized in that the amount of active substance within the matrix is adjusted by diffusion of the active substance from the active substance deposit or deposits after production of the plaster.

19. A process according to any one of the preceeding claims, characterized in that at least one part of the plaster is produced of a solution, a dispersion, a melt or by sprinkling particles thereon.

20. The use of the plaster according to claims 1 to 12 for the local or systemic dermal adminstration of active sub-stances in the human or veterinary medicine, or in cos-metics..