AU627422B2 - Plaster containing active ingredients for controlled administration of active ingredients to the skin - Google Patents
Plaster containing active ingredients for controlled administration of active ingredients to the skin Download PDFInfo
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- AU627422B2 AU627422B2 AU14894/88A AU1489488A AU627422B2 AU 627422 B2 AU627422 B2 AU 627422B2 AU 14894/88 A AU14894/88 A AU 14894/88A AU 1489488 A AU1489488 A AU 1489488A AU 627422 B2 AU627422 B2 AU 627422B2
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- Australia
- Prior art keywords
- active substance
- skin
- plaster
- substance reservoir
- reservoir
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
- A61H37/00—Accessories for massage
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
- A61K9/7061—Polyacrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7092—Transdermal patches having multiple drug layers or reservoirs, e.g. for obtaining a specific release pattern, or for combining different drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Anesthesiology (AREA)
- Biomedical Technology (AREA)
- Medical Informatics (AREA)
- Hematology (AREA)
- Pain & Pain Management (AREA)
- Physical Education & Sports Medicine (AREA)
- Rehabilitation Therapy (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Media Introduction/Drainage Providing Device (AREA)
- Medicines Containing Plant Substances (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Materials For Medical Uses (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Cosmetics (AREA)
- Medical Preparation Storing Or Oral Administration Devices (AREA)
Abstract
A plaster containing active ingredients for controlled administration of active ingredients to the skin and possessing a rear side and a skin side, has a rear layer, an active ingredient reservoir containing one or more active ingredients arranged essentially perpendicular to the surface of the plaster in contact with the skin, and an adhesive device on the skin side and possibly a covering layer which is detached before application of the plaster. At least one active ingredient reservoir part (12) can be detached on to the skin while one or more active ingredient reservoir parts remain. For this purpose, the part (13) of the active ingredient reservoir remaining on the skin adheres more strongly to the skin than to the rear side (11).
Description
14,894/88 g~~7~99 LTORGAN[SATION FOR GEISTIGES EIGENTLJM 2 7 c4 2 2E Internadionales BHro INTERNATIONALE ANMELDUNG VEROFFENTLICHT NACH DEM VERTRAG OBER DIE INTERNATIONALE ZUSAMMENARBEIT AUF DEM GEBIET DES PATENTWESENS (PCT) (51) Internationale Paten tklassifikation 4: (11) Internationale Veroffentlichungstulmmer: WO088/ 08318 A61M 37/00, A61L 15/06 Al (43) Internationales Veroffentlichungsdatum: 3. November 1988 (03.11.88) (21) Internationales Aktenzeichen: PCT/DE88/00180 (74) Anwalt: NEIDL-STIPPLER, Cornelia; Rauchstrage 2, D-8000 Mfinchen 80 (22) Internationales Anmeldedatumn: 22. Miirz 1988 (22.03.88) (81) Bestimmungsstaaten: AU, DK, FL, HU, JP, KR, NO, (31) Priori tNitsaktenzeichen: P 37 14 140.6 us.
(32) Priori titsd atumr: 28. April 1987 (28.04.87) Verdiffentlicht (33) Prioritatsland: D E Mit internationalem Recherchenbericlu.
(71) Antnelder (fair alle Bestimmungssmtaien ausser US): LTS LOHMANN THERAPIE-SYSTEME GMBH CO KG [DE/DE]; Irlicher Stralle 55, D-5450 Neuwied 12 5JN 18 A. ID. J. P. 5JN18 (72) Erfinder;und Erfinder/Anmelder (nurfiir US) HOFFMANN, Hans, Rainer [DE/DE]; Burghofstra~e 123, D-5450 Neuwied
ASRLA
22 WOLTER, Karin [DE/DE]; Altwieder Str. ASRLA 46, D-5451 Meisbach SIMON, Gflnter [DE/ EC18 DE]; Tulpenweg 1, D-5533 Hillesheim BARTH, 2DC18 Peter [DE/DE]; Johan n-Gottfried- Herder-Strage 6, D- 5450 Neuwied 12 PATENT OFFICE (54) Title: PLASTER CONTAINING ACTIVE INGREDIENTS FOR CONTROLLED ADMINISTRATION OF AC- TIVE INGREDIENTS TO THE SKIN (54) Bezeichnung: WIRKSTOFFHALTIGES PFLASTER ZUR KONTROLLIERTEN VERABREICHUNG VON WIRKSTOFFEN AN DIE HAUT 11 12 14.
e"0 11 1 1.-J l 11 1 1 i1 (57) Abstract A plaster containing active ingredients for controlled administration of active ingredients to the skin and possessing a rear side and a skin side, has a rear layer, an active ingredient reservoir containing one or more active ingredients arranged essentially perpendicular to the surface of the plaster in contact with the skin, and an adhesive device on the skin side and possibly a covering layer which is detached before application of the plaster. At least one active ingredient reservoir part (12) can be detached on to the skin while one or more active ingredient reservoir parts remain. For this purpose, the part (13) of the active ingredient reservoir remaining on the skin adheres more strongly to the skin than to the rear side (11).
(57) Zusammenfassung Die Erfindung betrifft emn wirkstoffhaltiges Pflaster zur kontrollierten Verabreichung von Wirkstoffen an die Haut, das eine Riickseite und eine Hautseite besitzt, mit einer Riickschicht, einem im wesentlichen senkrecht zur Hautkontaktfliche des Pflasters geteilten, einen oder mehrere Wirkstoffe aufweisenden Wirkstoffreservoir, einer Haftklebeeinrichtung auf der Hautseite sowie ggf. einer vor Appiikation des Pflasters abl6sbare Abdeckschicht, wobei mindestens emn Wirkstoffreservoirteil (12) unter Verbleiben eines oder mehrerer Wirkstoffreservoirteile (13) auf der Haut ablbsbar ist. Dazu ist vorgesehen, dass der auf der Haut verbleibende Teil (13) des Wirkstoffreservoirteils eine bessere Haftung an der H-aut als an der Riickschicht (11) aufweist.
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Active substance-containifg::phaster...for .the c6ntrolledtadministration of active substances to.the skin SThe invention relates to an active substance-containing plaster for the controlled administration of active substances to the skin, which has a back and a skin side, with a back layer, an active substance reservoir subdivided substantially perpendicularly to the skin contact surface of the plaster and having one or more active substances, a contact adhesive device on the skin side and optionally a cover layer detachable prior to the application of the plaster, it being possible Sto reduce the size of the active substance release surface of the plaster by a predetermined amount by removing part of the active substance reservoir, as well as the use thereof and a process for .the controlled administration of active substances to the skin.
SThe invention more particularly relates to those plaster used as transdermal therapeutic systems for the controlled administration of medical active substances or also cosmetically active substances to the human Sor animal skin. A therapeutic system is a medicamet or active substance-containing means or administration form, which delivers one or more active substances in continuous manner, at a predetermined rate and over a given time interval to a predetermined application point. These systems are therapeutic precision.,instruments, whose construction requires extraordinary measures in order to ensure continuous active substance release.
Plaster-like therapeutic systems have already been developed for the most varied uses and, apart from a topical effect, a systemic effect can also be obtained. The multiplicity of active substances applicable in this way and their different chemical, physical and pharmacological characteristics make it impossible to cover all therapeutic problems with a single system.
Numerous therapeutic systems for the administration of medical active substances to the skin are known, a summary being e.g. provided in Klaus Heilmann "Therapeutische Systeme", Ferdinand Enke Verlag,
I-
-2- Stuttgart, 1977. The prior art systems were not able to provide a completely satisfactory action in all cases.
In the conventional structure of a transdermal plaster-like therapeutic system there is an active substance reservoir, which contains the active substance in solid, liquid or dissolved form and a pressuresensitive adhesion layer (contact adhesive), through which the system is closely linked with the skin. It is important that a whole-area contact is ensured between the active substance release surfaces to the skin throughout the application of the system, in order to make sure of the active substance release kinetics. This can be achieved not only. through an uninterrupted adhesion layer, but also by restricted adhesion areas in the skin contact layer of the plaster.
Although the hitherto known plaster-like therapeutic systems permit a uniform or continuously decreasing application of an active substance over a predetermined time, they do not permit specific active substance release kinetics, such as a planned reduction of the active substance release after a predetermined time, or a graduated active substance release quantity, per unit of time.
This measure is e.g. necessary if the active substance dose has to be reduced in a planned manner during the application period for therapeutic reasons. The same problem arises if, during the application of a combination product, one active substance in the combination must be interrupted after a predetermined time. In such cases, it is in principle possible to solve the problem by using two transdermal plasters, whereof one is removed at the given time. However, this leads to problems for patients, particularly if they are aged. Therefore it is easy to forget to apply the second plaster. In a combination of two plasters with different active substance release surfaces, there is also a risk of choosing the incorrect combination (two identical plasters), or the removal of the wrong plaster. The same complications occur if plasters with different active substances have to be combined and there is in this case also the problem of double 0A' O 3 -3storage. Thus, the use of two plasters leads to numerous disadvantages and the avoidance thereof forms an objective of the invention.
The proposal of combing two plasters, whereby part thereof can be detached with the aid of a predetermined breaking line, admittedly improves compliance, but leads to handling problems. Thus, the part to be detached can only be handled by raising from the skin and in undesired manner at least a part of the plaster still remaining on the skin is raised and must be firmly held during detachment. Thus, pressure is exerted on the sensitive transdermal system, which can negatively influence the active substance release rate.
US Patent 4 297 995 describes a manipulatable active substance plaster, in which the active substance reservoir is subdivided, but is integrated into a single plaster. The active substance reservoir parts are arranged in concentric rings about a disk-like central portion. The overall construction of the plaster with a mechanical fixing of the reservoir of the back layer only makes it possible to change the active substance release surface prior to the application of the plaster, i.e. prior to plaster application the doctor/patient can choose which dose is to be administered, but for changing the active substance release during plaster application, the plaster must be raised from the skin, whilst interrupting therapy and this can also lead to damage and contamination to the plaster support surface.
As yet no satisfactory solution has been found for the associated problems of repositioning 20 and the permanent refixing of the system to the skin.
"•Therefore the problem of the present invention is to provide an improved therapeutic transdermal system, which makes it possible to realize more complicated changes to the active substance release than have hitherto been possible.
The invention provides an active substance-containing plaster for the controlled 25 administration of active substances onto the skin, which has a backing side and a skin side, a backing layer, with an active substance reservoir which is divided essentially at right angles to the skin contact area of the plaster and has one or more active substances, with an adhesive device on the skin side and, where appropriate, with a covering layer which can be detached before application of the plaster, where the active substance delivery area 30 of the plaster can be reduced in size by a predetermined area by removing a part of the active substance reservoir, characterised in that at least one active substance reservoir part can be detached while leaving one or more active substance reservoir parts on the skin, where the part of the active substance reservoir part remaining on the skin has better adhesion to the skin than to the backing layer.
rn-SPEV7ILT h. 15, IM i a- -4- The invention also provides a process for the controlled administration of one or more active substances to the skin by means of a plaster according to any one of the preceding claims, characterised by adhesion to the skin of a plaster, said plaster having several active substances or the same active substance in different active substance reservoir parts, which active substance reservoir parts can be separated from one another, and removal of at least one plaster part with in each case one or more active substance reservoir parts after a predetermined time, leaving behind a plaster residue with at least one active substance reservoir part on the skin.
Due to the fact that, according to the invention, the active substance reservoir is partly detachable whereby the part of the active substance reservoir which is not to be detached has a greater adhesion to the skin than to the back layer, after removing a predetermined plaster part with the active substance reservoir part adhering thereto, there is left behind a predetermined active substance reservoir part on the skin, which can e.g.
be alone removed following the desired application period. Advantageously the active substance reservoir of the inventive plaster is in two parts.
In the case of given therapies with varying or marked concentration-fluctuating active substance administrations, it can also be advantageous for the active substance reservoir to be in three parts. The active substance release surfaces of the active substance reservoir parts can be geometrically identical or different. The active substance release 20 surfaces can be juxtaposed, or one active substance reservoir part can completely surround one or more other active substance reservoir parts, considered in a flat or surface-based manner. The subdivision of the partial surfaces is dependent on the therapeutic requirements. Thus, e.g. one active substance reservoir part can circularly surround one or more other active substance reservoir parts.
25 The release surface size ratio of one active substance reservoir part to another is preferably in the range between approximately 1:1 and 1:10. The same active substance or the same active substance combination can be present in all the active substance reservoir parts.
S•Particularly preferred products are plasters with the following active substances, but it is also possible to process random other transdermally administrable active substance combinations known to the medical Expert: asthma/bronchodilators, such as e.g.
clenbuterol, proctaterol and salbutamol and vasodilators, such as e.g. bencyclane and cinnarizine.
@-spE 1! T 0 s c/NrO' f 5 Thus, with the aid of the inventive plaster, in such cases it is S possible to reduce the administration dose in planned and controlled .manner during application.
However, the active substance reservoir parts can also contain different active substances or different active substance combinations, so that during application it is possible to interrupt or stop one active substance.or active substance combination. Examples for different active substances in the active substance reservoir parts are: oestrogen/gestagen (contraceptives), dexamethasone/prednisolone (in the case of inflammatory, rheumatic muscle.and joint diseases), nitroglycerin/ p-blockers (for cardiac diseases), phenytoin/phenobarbital/ caffeine (for epilepsy) and amitriptyline/chlordiazepoxide (psychopharmaceuticals).
All suitable active substances belong to the;groups having either a topical or systemic action. In at least one.active substance reservoir part there can 'be different active substance/active substance combinations as compared with the other active substance reservoir part or parts.
The preferred use of the inventive plasters is 'in local and systemic, transdermal active substance administration in human or animal medicine or in cosmetics.
The invention is described in greater detail hereinafter relative to non-limitative embodiments and with reference to the attached drawings, which are not true to scale and wherein show: Fig. I a cross-section through a first embodiment of an inventive plaster with a two-part active substance reservoir.
Fig. 2 a plan view of the skin side of a second embodiment of the inventive plaster without a protective layer.
Fig. 3 a cross-section along line I-I of fig. 2.
0 i ^C~jy^ s -6- Fig. 4 a plan view of the skin side of a third inventive embodiment without protective layer Fig. 5 a cross-section through the embodiment of Fig. 4 along line II-II on a larger scale.
Fig. 6 a plan view of the skin side of a fourth embodiment of the invention without a protective layer.
Fig. 7 a cross-section through the embodiment of Fig. 6 along line III-III.
Fig. 8 a cross-section through a fifth embodiment of the invention.
Fig. 9 a cross section through a sixth embodiment of the invention.
Fig. 10 a plan view of the skin side of another embodiment of an inventive plaster with a three-part active substance reservoir and without a protective layer.
Fig. 11 a larger scale cross-section along line IV-IV of Fig. The preferred embodiments of the invention shown in the individual drawings will now be described. The active substance reservoir part left last on the skin is referred to as the first active substance reservoir part, whilst the second and third active substance reservoir parts are those which are detached with the back layer.
The 'skin side' of the plaster is that which in use lies on the skin, that is, the side closest to the skin, whereas the back side is the other side thereof.
Fig. 1 shows a preferred embodiment, in cross-section, of an inventive, optionally 20 circular or angular plaster with a two-part, contact adhesive active substance reservoir.
The second active substance reservoir part 12 directly adheres to the backing layer (or back layer) 11 and is separated from the first contact adhesive active substance reservoir part 13 i by a reservoir separating layer 14, which can be constructed as a gap or space between the active substance reservoir parts, or can be filled by an inert separating material. Active 2. 5 substance reservoir parts 12,13 have different adhesive strengths, and are covered by a peel-off layer 11. The peel-off layer 15 can e.g. be a polymer or metal film or foil, a textile fabric or a laminate i k AI-SPEUX. I- 5. 1992 1-.f T4 4 .4 -7thereof and following the removal of the back layer 11 with the second active substance reservoir part 12 forms a protective layer for the first active substance reservoir part 13 left on the skin in order to protect the latter. The adhesion of the first active substance reservoir part 13 to the skin must.be greater than the adhesion between the peel-off layer 15 and the back layer 11. The protective layer 16 is removed prior to the application of the plaster. By the use of the same dotting system for the surfaces representing the active substance reservoir parts 12,13 in fig. 1, it.is made clear that in both active substance reservoir parts 12,13 there is the same active substance or active substance combination, so that with the plaster according to fig. 1 it is possible to bring about a gradual decrease of the active substance release to the skin.
Fig. 2 is a plan view of the skin side of a further inventive angular plaster with a two-part, non-contact adhesive active substance reservoir, from which the protective layer has already been removed. -Thus, on the skin side, the plaster has contact adhesive layers 21,22, which are separated from one another by the inert reservoir separating layer 23, which can once again be a simple gap or an inert material.
Fig. 3 is a cross-section through the embodiment shown in fig. 2 along line I-I thereof. The non-adhesive active substance reservoir parts 24,25 are fixed at the back by a contact adhesive layer 27 to the back layer 28, the first active substance reservoir part 24 adhering to the back layer by means of a peel-off layer 26 located between the first contact adhesive layer 27 and the first active substance reservoir part 24. Peel-off layer 26 is designed in such a way that its adhesion to the first active substance reservoir part 24 is greater than to the contact adhesive layer 27. Thus, on detaching the back layer 28 and the second active substance reservoir part 25 fixed by means of the contact adhesive layer 27 to the back layer 28, peeloff layer 26 together with the first active substance reservoir part- 24'remains on the skin and assumes for said remaining part 24 the function of a protective layer protecting the reservoir material from F I 8 -8contamination and damage from the outside or also against the escape of e.g. volatile active substance components.
The skin side contact adhesive layers 21,22 on the non-adhesive active substance reservoir parts 24,25 are so adjusted that the adhesion of the contact adhesive layer 22 of the first active substance reservoir part 24 to the skin is greater than the adhesion between peeloff layer 26 and contact adhesive layer 27. The differently represented surfaces in the drawing are intended to show that there are different active substances or active substance combinations in both active substance reservoir parts 24,25.
Fig. 4 shows another preferred embodiment of an inventive plaster in plan view on the skin side thereof. The oval plaster has a twopart active substance reservoir and a contact adhesive layer 41 responsible for the fixing of the active substance'reservoir parts 42,43 to the back layer 45 also forms the fastening to the skin of the therapeutic system.
i Fig. 5 shows a larger scale cross-section along line II-II of fig.
4. The contact adhesive active substance reservoir parts 42,43, which are separated from one another by an inert reservoir separating layer 46, in this case in the form of a gap, are surrounded in bag-like manner by the back layer 45 carrying a contact adhesive layer 41.
Here again a separating layer 44 ensures that the adhesion of the first active substance reservoir part 42 to the skin is greater than the adhesion between the peel-off layer 44 and the contact adhesive, layer 41 and also ensures that the first active substance reservoir part 42 left on the skin after detaching the second active substance reservoir part 43 and the back layer 45 is protected by a layer.
The two active substance reservoir parts 42,43 contain different active substances or active substance combinations, as is made clear by the arrangement of the surfaces.
Fig. 6 sh6ws another inventive plaster with a two-part active substance ,i 1 1V i.
-9reservoir, in which one active substance reservoir part 61 concentrically surrouLlds the other active substance reservoir part 63, the representation being from the skin side and with the protective layer removed. The contact adhesive, first circular active.substance reservoir 63 is separated from the circular second active substance reservoir 61 by an inert reservoir separating layer 62, which can also be in the form of a gap. This embodiment has the advantage that on reducing the active substance release surface by removing part of the plaster with the second active substance reservoir part 61 and together with the back layer 65, it is possible to freely choose the plaster removal direction.: Fig. 7 shows a cross-section through the embodiment of fig. 6 represented along line III-III thereof. -The circular, second active substance reservoir part 61 is directly adjacent to the back layer whilst the peel-off layer 64 is arranged between the circular, first active substance reservoir part.63 and the back layer 65.. The adhesion of the first active substance reservoir part 63 to the skin and that between the peel-off layer 64 and the back layer 65 is greater than the adhesion between the peel-off layer 64 and active substance reservoir part 63, so that on removing the back layer 65 the second active substance reservoir part 61 is removed, whilst leaving the first active substance reservoir part 63 on the skin and which is now covered by the peel-off layer 64. The inert reservoir separating layer 62 separates active substance reservoir parts 61,63. In this embodiment, the active substance is the same in both active substance reservoir parts 61,63.
SFig. 8 shows another preferred embodiment of the invention in crosssection, in which the two parts of a non-adhesive active substance reservoir are once again constructed as a circular disk 82 with a surrounding ring 81. They are separated from one another by an inert reservoir separating layer 83. Back layer 88 is covered by a contact adhesive layer 87, which is directly in contact with the second active substance reservoir part 81.
14'.
A
f
I
S- Between the contact adhesive layer 87 and the first active substance reservoir part 82 is provided an inert peel-off layer 86, which is so designed that its adhesion to the contact adhesive layer 87 is less than the adhesion between the contact adhesive layer 85 and the skin. The remaining adhesion values on the boundary layers of said plaster part must naturally be above the adhesion value to the skin.
The skin side contact adhesive layers 84,85 of the active substance reservoir parts 81,82 ensure contact with the skin and prior to the application of the inventive plaster are advantageously covered by a protective layer 89.
In this embodiment, both active substance reservoir parts 81,82 have different active substances or active substance combinations.
Fig. 9 shows a-cross-section through another embodiment of the invention, in which the back layer 95 surrounds the concentric arrangement of the contact adhesive active substance reservoir parts 91,92 to Sthe skin side. For fixing the overall plaster and the active substance reservoir parts to the skin, the whole surface of back layer 95 is covered with a contact adhesive layer 93. To the latter adheres the second active substance., reservoir part 91 in a direct manner, whilst the first active substance reservoir part 92 is fixed via a peel-off' layer 94. The adhesion of peel-off layer 94 to the active substance reservoir part 92 is above and the adhesion of layer 94 to contact adhesive layer 93 is below the adhesion between the first active substance reservoir part 92 and the skin. This permits a selective removal of back layer 95 together with the second active substance reservoir part 91. Through a corresponding change to the structure, it is also possible to bring about a selective removal of the first active substance reservoir part 92. Reference numeral 96 designates the inert reservoir separating layer or the gap between the active substance reservoir parts 91,92. Up to application, the overall arrangement is covered by a detachable protective layer 97. The active substances or active substance combinations are different in both reservoir parts 91,92 in this embodiment.
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11 Another preferred embodiment of the invention with a three-part active substance reservoir is shown in fig. 10. The latter is a plan view of the skin side of an inventive plaster without the protective layer.
A first, circular, contact adhesive active substance reservoir part 105 is surrounded by a second, circular, contact adhesive active substance reservoir part 103 and is separated therefrom by an inert reservoir separating layer 104. The third contact adhesive active substance reservoir part 101 surrounds the second active substance reservoir part 103 in concentric ring form. Between the second and third active substance reservoir parts 101,103 is provided a further inert reservoir separating layer 102. Fig. 11 is a larger scale crosssection along line IV-IV.
Active substance reservoir part 101 adheres directly to back layer 108. A first peel-off layer 106 connected to back layer 108 covers the active substance reservoir parts 103,105. The adhesion thereof to the back layer 108 is less than the adhesion of the active substance reservoir parts 103,105 to the skin, so that active substance reservoir parts 103,105 remain on the skin on removing the back layer 108 with active substance reservoir part 101. Thus, the first peel-off layer 106 then forms a protective, new layer for the remaining parts of the plaster. The contact adhesive active substance reservoir part 103 adheres directly to the first peel-off layer 106 and can be removed together with the latter in a further removal step, whilst leaving behind on the skin the first active substance reservoir part 105, Sthis being made possible by the second peel-off layer 107 between the first active substance reservoir part 105 and the first peel-off layer 106. The adhesion of the second peel-off layer 107 to the first layer 106 is less than the adhesion of the first active substance o••o S• reservoir part 105 to the skin. The inert reservoir separating layers 102,104, which can also be formed by gaps, are located between active substance reservoir parts 101,103 or 102,105. The chosen example shows for active substance reservoir parts 103,105 the same active substance or active substance combination, indicated by the identical dotting in fig. 11, whilst the active substance reservoir part 101
V.T
1-
L
i lr 12 has a different active substance or active substance combination.
The drawings which merely illustrate the invention in an exemplified manner, are not intended to restrict the invention either as regards geometrical shape, the association of specific individual components, or as regards the size of the active substance release surfaces.
As is well known to the Expert in this field, all these quantities can be adapted to the therapeutic requirements and obviously account must be taken of rational production. The part of the active substance reservoir part to be detached can also have a peel-off layer, which then has a greater adhesion to the back layer than the peel-off layer of the reservoir part remaining on the skin. This construction is advantageous if the active substance reservoir parts are to have the same thickness. The contact adhesive layers, particularly those on the skin side, can have contact adhesive-free areas for improved active substance permeability, or can be constructed solely as individual contact adhesive surfaces, e.g. can be embedded in the active substance reservoir material. The release of the active substances from the active substance reservoir parts can optionally be regulated by control membranes, which are embedded in per se known manner in the reservoir mass in one or more active substance reservoir parts, or can be located between the active substance reservoir and the skin side contact adhesive layer, or within the skin side contact adhesive layer.
For the construction of an active substance reservoir, as used according to the invention, it is possible to use the standard measures and materials. The basic materials can be constituted by low and high molecular weight, natural and/or synthetic substances, whose choice is a function of the characteristics of the active substances ooooo S to be administered and the therapeutic requirements. Apart from the basic material, the active substance reservoir can also contain further suitable additives known or obvious to the Expert on the basis of his knowledge, such as e.g. solubilizers, softeners, plasticizers, tackifiers, stabilizers, fillers and enhancers. The composition in the reservoir parts can be the same or different, which is once again dependent on the active substances to be administered and the desired T 0 -13 release rates or kinetics. In the case of an identical reservoir composition and only one active substance to be administered, it can be appropriate to have a graduated concentration setting of .the active substance in the different reservoir parts. Suitable active substances for the inventive plasters are all those which alone or with adjuvants are able to migrate into the skin.
The back layer covering the active substance reservoir on the skin S remote side can be permeable or impermeable. It must be flexible and, as a result of the mechanical stabilization of the plaster, serves S to remove part of the active substance reservoir. If components of the reservoir or the incorporated active substances are volatile, then the back layer must be impermeable to these substances. It can be in one or:multi-layer form. Suitable materials for the production thereof are e.g. polymeric substances, such as polyethylene, polyp opylene, polyesters and polyamides. Further materials can be metal foils, such as e.g. aluminium foil, either alone or coated-with a polymeric substrate. Permeable back layers are e.g. textile fabrics, such as non-woven fabrics and the'like, but also porous polymer materials. The back layer can optionally carry a marking for indicating the optimum plaster removal direction. Optionally p.-al-off layers are provided between the active substance reservoir parts in S place of a gap. They can be constituted by the same materials as described hereinbefore for the separating layer between the active substance reservoir parts and the back layer. The protective layer detachable prior to application and which covers the skin side contact adhesive surfaces can be made from the same material as used for'making the back layer, provided that they can be made detachable, e.g. by applying a silicone layer. Other detachable protective layers, as known to the Expert in the field of plasters and in particular plasterlike therapeutic systems are e.g. polytetrafluoroethylene, treated paper, cellophane, polyvinylchloride, etc. To facilitate detachability, the protective layer can be provided with removal aids in per se known manner. The protective layer can also be larger than the plaster, e.g. if several plasters are arranged on an uninterrupted Sl Ai T o -1, 14 web of the protective layer material.
Contact adhesive layers used for the inventive plasters can be constituted by all physiologically unobjectionable contact adhesives which are inert to active substances other active substance reservoir components, e.g. can be based 'orirbber, rubber-like, synthetic homoco- or block polymers, polyacrylates and their copolymers, polyurethanes and silicones.
The inventive plaster can be produced by all known plaster technology methods. This is demonstrated:i' ''the following production example for a plaster with a two-part active substance reservoir.
Production Example.
In a roller application process to a film or foil given a repelling finish by siliconizing and which serves as an intermediate covering, is applied an active substance--containing reservoir material solution and which, after drying at 650C, forms a contact adhesive layer of g/m 2 and having the following composition: 1.
2.
3.
4.
Acrylate'copolymer I Acrylate copolymer II POE-(lO)-oleyl alcohol Active substance 68.86 parts by weight 10.39 parts by weight 5.20 parts by weight 15.56 parts by weight Acrylate copolymer I is Durotac 280-2516 of National Starch Chemical Netherlands; Acrylate copolymer II is Eudragit E100 of R6hm Pharma, Germany; POE-(10)-oleyl alcohol is Brij 97 of Atlas Chemical Industries, GB.
Onto one half of the active substance-containing contact adhesive layer is applied a non-siliconized polyester film (thickness 0.036 mm) and to the other half the non-siliconized side of a one-sided, siliconized polyester film (thickness 0.036 mm). After removing the intermediat 'ecovering ring-like active substance reservoir parts are punched otit of the first half and are applied with the contact adhesive side to a: siliconized, a.7uminium vapo'ur-deposited polyester fiim .(pr~otective layer).; From the second half are punched disk-like active st'bstac roi pjarts with* a slightly smaller dia.meter than ;the internal diEiieter of. the rings-into which they are centrally inserted with th cohtact adhesive, side 'directed towards the protective layer.
The .open s ideof the thus obtaine'd union is' by a polyesterbased,- corft~ct*.adhesively finished'0.015 mm thick back layer (Du'rotac 280-2516, '30 g/n 2 dry).
-7, f~TR< I
Claims (16)
1. An active substance-containing plaster for the controlled administration of active substances onto the skin, which has a backing side and a skin side, with a backing layer, with an active substance reservoir which is divided essentially at right angles to the skin contact area of the plaster and hat one or more active substances, with an adhesive device on the skin side and, where appropriate, with a covering layer which can be detached before application of the plaster, where the active substance delivery area of the plaster can be reduced in size by a predetermined area by removing a part of the active substance reservoir, characterised in that at least one active substance reservoir part can be detached while leaving one or more active substance reservoir parts on the skin, where the part of the active substance reservoir part remaining on the skin has better adhesion to the skin than to the backing layer.
2. An active substance-containing plaster according to claim 1, characterised in that the active substance reservoir is in two parts.
3. An active substance-containing plaster according to claim 1, characterized in that the active substance reservoir is in three parts.
4. An active substance-containing plaster according to any one of the preceding claims, characterised in that the active substance delivery areas of the active substance reservoir parts are geometrically identical or different.
5. An active substance-containing plaster according to any one of the preceding claims, charcterised in that an active substance reservoir part completely surrounds one other or several other active substance reservoir part(s) viewed in surface terms.
6. An active substance-containing plaster according to claim 4 or claim characterised in that an active substance reservoir part surrounds in the form of a ring one or more other active substance reservoir part(s).
7. An active substance-containing plaster according to any one of claims 1 to characterised in that the delivery area/size ratio of one active substance reservoir part to another is between about 1:1 to 1:10.
8. An active substance-containing plaster according to any one of the preceding claims, characrterised in that the same active substance or the same active substance combination is present in all active substance reservoir parts.
9. An active substance-containing plaster according to any one of claims 1 to 7, characterised in that a different active substance or active substance combination is present in at least one active substance reservoir part than in the other active substance reservoir r o L PIt -sIE7/LTs 15, 1992 4 17 part.
An active substance-containing plaster according to any one of the preceding claims, characterised in that the active substances have a topical or systemic action.
11. A process for the controlled administration of one or more active substances to the skin by means of a plaster according to any one of the preceding claims, characterised by adhesion to the skin of a plaster, said plaster having several active substances or the same active substance in different active substance reservoir parts, which active substance reservoir parts can be separated from one another, and removal of at least one plaster part with in each case one or more active substance reservoir parts, after a predetermined time, leaving behind a plaster residue with at least one active substance reservoir part on the skin.
12. A process according to claim 11, characterised therein that the active substance or active substances al,; present in the reservoir parts in different concentrations.
13. A process according to claim 11 or claim 12, characterised by repeating the last stage after a predetermined period of time.
14. A process according to claim 11, substantially as herein described with reference to the accompany drawings.
15. Use of the active substance-containing plaster according to any one of claims 1 to 10, for local transdermal, systemic transdermal, or a combination of local and systemic e 20 transdermal, administration in cosmetics.
16. An active substance-containing plaster, substantially as herein described with reference to the accompanying drawings. DATED this June 18, 1992 CARTER SMITH BEADLE 25 Fellows Institute of Patent Attorneys of Australia A Patent Attorneys for the Applicant: LTS LOHMANN THERAPIE-SYSTEME GMBH CO. KG AV T
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19873714140 DE3714140A1 (en) | 1987-04-28 | 1987-04-28 | ACTIVE SUBSTANCE PLASTER FOR THE CONTROLLED ADMINISTRATION OF ACTIVE SUBSTANCES TO THE SKIN, ITS USE AND METHOD FOR THE CONTROLLED ADMINISTRATION OF ACTIVE SUBSTANCES TO THE SKIN |
DE3714140 | 1987-04-28 |
Publications (2)
Publication Number | Publication Date |
---|---|
AU1489488A AU1489488A (en) | 1988-12-02 |
AU627422B2 true AU627422B2 (en) | 1992-08-27 |
Family
ID=6326433
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU14894/88A Ceased AU627422B2 (en) | 1987-04-28 | 1988-03-22 | Plaster containing active ingredients for controlled administration of active ingredients to the skin |
Country Status (28)
Country | Link |
---|---|
EP (1) | EP0288734B1 (en) |
JP (1) | JP2683264B2 (en) |
KR (1) | KR910002250B1 (en) |
AT (1) | ATE69962T1 (en) |
AU (1) | AU627422B2 (en) |
CA (1) | CA1316062C (en) |
CZ (1) | CZ278969B6 (en) |
DD (1) | DD281349A5 (en) |
DE (2) | DE3714140A1 (en) |
DK (1) | DK166193C (en) |
ES (1) | ES2027720T3 (en) |
FI (1) | FI91599C (en) |
GR (1) | GR3003289T3 (en) |
HR (1) | HRP920828B1 (en) |
HU (1) | HU204203B (en) |
IE (1) | IE61005B1 (en) |
IL (1) | IL85859A (en) |
MY (1) | MY103355A (en) |
NO (1) | NO172278C (en) |
NZ (1) | NZ223894A (en) |
PH (1) | PH25091A (en) |
PL (1) | PL161617B1 (en) |
PT (1) | PT87345B (en) |
SI (1) | SI8810781B (en) |
SK (1) | SK288388A3 (en) |
WO (1) | WO1988008318A1 (en) |
YU (1) | YU47056B (en) |
ZA (1) | ZA881739B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU631167B2 (en) * | 1989-01-20 | 1992-11-19 | Lts Lohmann Therapie-Systeme Gmbh & Co. Kg | Superficial therapeutic system comprising an anti-neoplastic active substance, particularly 5-fluorouracil |
Families Citing this family (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0725669B2 (en) * | 1988-12-23 | 1995-03-22 | 日東電工株式会社 | Pharmaceutical formulation for transdermal administration |
DE3844247A1 (en) * | 1988-12-29 | 1990-07-12 | Minnesota Mining & Mfg | DEVICE, IN PARTICULAR PLASTER FOR TRANSDERMAL ADMINISTRATION OF A MEDICINAL PRODUCT |
DE4020144A1 (en) * | 1990-06-25 | 1992-01-09 | Lohmann Therapie Syst Lts | Patches for topical or transdermal drug delivery - with adhesive layer contg. polyacrylate adhesive and film former |
DE4110027C2 (en) * | 1991-03-27 | 1996-08-29 | Lohmann Therapie Syst Lts | Process for packaging transdermal therapeutic patches |
GB2273044B (en) * | 1992-12-02 | 1997-04-09 | Pacific Chem Co Ltd | Medicinal patches for percutaneous administration |
DE4405898A1 (en) * | 1994-02-18 | 1995-08-24 | Schering Ag | Transdermal therapeutic systems containing sex steroids |
FR2728463A1 (en) * | 1994-12-21 | 1996-06-28 | Lhd Lab Hygiene Dietetique | TRANSDERMIC SYSTEM FOR SIMULTANEOUS DELIVERY OF SEVERAL ACTIVE PRINCIPLES |
DE29514849U1 (en) * | 1995-09-15 | 1995-11-16 | Weyergans, Rudolf, 52355 Düren | Cellulite patch |
FR2749514B1 (en) * | 1996-06-11 | 1998-08-07 | Hoechst Marion Roussel | TRANSDERMAL SYSTEMS CONTAINING 2 ACTIVE INGREDIENTS IN SEPARATE COMPARTMENTS, THEIR PREPARATION METHOD AND THEIR APPLICATION AS A MEDICAMENT |
DE19820999A1 (en) * | 1998-05-11 | 1999-11-18 | Lohmann Therapie Syst Lts | Layered medicinal adhesive plaster with high holding power and flexibility |
DE19911262C2 (en) * | 1999-03-13 | 2003-04-10 | Scs Skin Care Systems Gmbh | Device for dispensing cosmetic active ingredients |
DE19923427A1 (en) | 1999-05-21 | 2000-11-23 | Lohmann Therapie Syst Lts | Device for improved delivery of active agents to skin, useful e.g. for administering opiates, contains agent that increases local skin temperature or blood flow |
DE10042412B4 (en) * | 2000-08-30 | 2005-12-22 | Lts Lohmann Therapie-Systeme Ag | Transceiver for bus subscriber of bus system of building system engineering, has two wires, where microcontroller is connected with receiver unit over connection on one hand, which is connected to two wires of bus system |
GB2383282B (en) | 2002-04-02 | 2004-06-16 | Crane Electronics | Torque sensing tool |
DE102004009903A1 (en) | 2004-02-26 | 2005-09-22 | Grünenthal GmbH | Patch with reduced skin irritation |
EP2000119A1 (en) * | 2007-06-08 | 2008-12-10 | Royal College of Surgeons in Ireland | Wound dressings |
HU227970B1 (en) | 2007-07-10 | 2012-07-30 | Egis Gyogyszergyar Nyrt | Pharmaceutical compositions containing silicones of high volatility |
JP5386205B2 (en) * | 2009-03-19 | 2014-01-15 | リンテック株式会社 | Transdermal patch |
US11154535B2 (en) | 2012-07-31 | 2021-10-26 | Egis Pharmaceuticals Plc | Transdermal formulation containing COX inhibitors |
US10045935B2 (en) | 2012-07-31 | 2018-08-14 | Egis Pharmaceuticals Plc | Transdermal formulation containing COX inhibitors |
CN108697655B (en) | 2015-12-30 | 2021-12-10 | 考里安公司 | Systems and methods for long-term transdermal administration |
WO2017223402A1 (en) | 2016-06-23 | 2017-12-28 | Corium International, Inc. | Adhesive matrix with hydrophilic and hydrophobic domains and a therapeutic agent |
DE102023107257A1 (en) | 2023-03-22 | 2024-09-26 | Xeno Patch GmbH | Flexible plaster |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4297995A (en) * | 1980-06-03 | 1981-11-03 | Key Pharmaceuticals, Inc. | Bandage containing attachment post |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4622031A (en) * | 1983-08-18 | 1986-11-11 | Drug Delivery Systems Inc. | Indicator for electrophoretic transcutaneous drug delivery device |
-
1987
- 1987-04-28 DE DE19873714140 patent/DE3714140A1/en active Granted
-
1988
- 1988-03-11 ZA ZA881739A patent/ZA881739B/xx unknown
- 1988-03-14 PH PH36635A patent/PH25091A/en unknown
- 1988-03-15 NZ NZ223894A patent/NZ223894A/en unknown
- 1988-03-18 MY MYPI88000275A patent/MY103355A/en unknown
- 1988-03-22 AU AU14894/88A patent/AU627422B2/en not_active Ceased
- 1988-03-22 DE DE8888104580T patent/DE3866582D1/en not_active Expired - Lifetime
- 1988-03-22 EP EP88104580A patent/EP0288734B1/en not_active Expired - Lifetime
- 1988-03-22 IE IE83488A patent/IE61005B1/en not_active IP Right Cessation
- 1988-03-22 KR KR1019880701436A patent/KR910002250B1/en not_active IP Right Cessation
- 1988-03-22 WO PCT/DE1988/000180 patent/WO1988008318A1/en active IP Right Grant
- 1988-03-22 HU HU882152A patent/HU204203B/en not_active IP Right Cessation
- 1988-03-22 JP JP63502541A patent/JP2683264B2/en not_active Expired - Lifetime
- 1988-03-22 ES ES198888104580T patent/ES2027720T3/en not_active Expired - Lifetime
- 1988-03-22 PL PL88272134A patent/PL161617B1/en unknown
- 1988-03-22 AT AT88104580T patent/ATE69962T1/en not_active IP Right Cessation
- 1988-03-24 IL IL85859A patent/IL85859A/en not_active IP Right Cessation
- 1988-03-25 CA CA000562578A patent/CA1316062C/en not_active Expired - Fee Related
- 1988-04-19 SI SI8810781A patent/SI8810781B/en unknown
- 1988-04-19 YU YU78188A patent/YU47056B/en unknown
- 1988-04-26 DD DD88315094A patent/DD281349A5/en not_active IP Right Cessation
- 1988-04-28 CZ CS882883A patent/CZ278969B6/en not_active IP Right Cessation
- 1988-04-28 SK SK2883-88A patent/SK288388A3/en unknown
- 1988-04-28 PT PT87345A patent/PT87345B/en active IP Right Grant
- 1988-10-11 NO NO884530A patent/NO172278C/en not_active IP Right Cessation
- 1988-12-23 DK DK722888A patent/DK166193C/en not_active IP Right Cessation
- 1988-12-28 FI FI886019A patent/FI91599C/en not_active IP Right Cessation
-
1991
- 1991-12-05 GR GR91401871T patent/GR3003289T3/en unknown
-
1992
- 1992-10-02 HR HRP-781/88A patent/HRP920828B1/en not_active IP Right Cessation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4297995A (en) * | 1980-06-03 | 1981-11-03 | Key Pharmaceuticals, Inc. | Bandage containing attachment post |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU631167B2 (en) * | 1989-01-20 | 1992-11-19 | Lts Lohmann Therapie-Systeme Gmbh & Co. Kg | Superficial therapeutic system comprising an anti-neoplastic active substance, particularly 5-fluorouracil |
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MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |