CA1316062C - Active substance-containing plaster for the controlled administration of active substances to the skin, the use thereof and a process for the controlled administration of active substances to the skin - Google Patents
Active substance-containing plaster for the controlled administration of active substances to the skin, the use thereof and a process for the controlled administration of active substances to the skinInfo
- Publication number
- CA1316062C CA1316062C CA000562578A CA562578A CA1316062C CA 1316062 C CA1316062 C CA 1316062C CA 000562578 A CA000562578 A CA 000562578A CA 562578 A CA562578 A CA 562578A CA 1316062 C CA1316062 C CA 1316062C
- Authority
- CA
- Canada
- Prior art keywords
- active substance
- skin
- reservoir
- substance reservoir
- active
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- 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
Abstract
Abstract of the Disclosure An active substance-containing plaster for the controlled administration of active substances to the skin has a back and a skin side and a back layer. An active substance reservoir is divided substantially perpendicularly to the skin contact surface of the plaster and has 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, in which it is possible to reduce the active substance release surface of the plaster by a predetermined amount through the removal of part of the active substance reservoir. At least one active substance reservoir part is detachable from the skin, whilst leaving behind one or more active substance reservoir parts, the part of the active substance reservoir remaining on the skin having a better adhesion to the skin than to the back layer.
Description
DESCRIPTION
The 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, wlth a back layer, an active substance reservoir subdivided substantially perpendicularly to the ækin contact surface of the plaster and having one or more active substances, &
contact adhe~i~e device on the skin side and optionally a cover layer detachable prior to the application of the plaster, it being posslble to reduce the size of ~he active substance release surface of the plaster by a predetermined amount by removing part of the active substance reservoir, as well as the use thereoP and a process for the controlled administration of active substances to the skin.
The invention more partlcularly relates to those plaster used as trans-dermal therapeutic systems for the controlled administration of medical active substances or also cosmetically actiYe substances to the human or animal skin. A therapeutic system is a medicament or active substance-containing means or administration form, which delivers one or more active 6ubstances 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 t opical effect, a systemic effect can also be obtained. The multiplicity of active substances applicable in this way and their different chemical, physical and pharmacological characteristlcs make it impo6sible 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 bein8 e.g. provided in Klaus Heilmann "Therapeutische Systeme", Ferdinand Enke Verlag~
~.~
131 ~2 Stuttgart, 1~77. The prior art systems were not able to provlde a completely satisfactory action in all cases.
In the conventional structure of a transdermal plaster-like ~herapeutic system there is an active substance reservoir, which contains the active substance in solid, liquid or dissolved form and a pressure-sensitive adhesion layer (contact adhesive), through which the system is closely linked with the skinO It is important that a whole-area contact is ensured be~ween the active substsnce re:Lease ~urfaces to the skin throughout the application oE the system, in order to make sure of the active substance release kinetics. This can be achieved not only through an uninterrupted adheslon layer, but also by rest-ricted adhesion areas in the skin contact layer of ~he plaster.
Although the hitherto known plaster-like therapeutic system permit a uniform or continuously decreasing application of an active 6ubstance over a predetermined timet they do not permit specific active substance release kinetics, such as a plsnned reduction of the active substance release after a predetermined time, or a graduated active substance release quantit~ per unit of ti~e.
This messure is e.g. necessary if the active substance dose has to be reduced in a planned manner dllring the application period for ther-apeutic reasons. The same problem arises if, during the application of a combination product, one active substance in the combi~ation must be interrupted after a predetermined time. In such cases, it is in principle possible to solve the problem by using two transdermal plasters, ~hereof one is removed at the given time. However, this leads to problems for patients, particularly if they are aged. There-fore it is easy to forge~ to appl~ the second plaster. In a combin-ation of two plasters wi~h different active substance release surfaces, there is also a risk of choo6ing the incorrect combina~ion (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 proble~ of double ~ 3 ~
storage. Thus, the use of two plasters leads ~o numerous disadvantages and the aYoidance thereof forms an objective of th~e lnvention.
The proposal of combinlng 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 th~ skin i9 raised snd must be firmly held during detachment. Thus, pressure is exerted on the sensitlvs transdermal s~stem, which can negatively influence the active substance release rate.
US Patent 4 297 995 describeæ a manipulatable active sub~tance plaster,in which the active substance reservoir i9 subdivided, but i5 in~e-grated into a single plaster. I'he 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 to the back layer onl~ makes it possible to change the active substance release surface prior to the applicatio~ 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 rsised from the skin9 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 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 ha~e hltherto been possible.
This problem is solved by a plaster of the aforementioned type, which is characterized in that at least part of the active substance reservoir ~3~ 2 cnn be detachedl whilst leaving one or more parts of said reservoir on the skin and the part of the acti~e substance reservoir left behind on the skin has a better adhesion to the skin than to the back layer.
Due to the fact that9 according to ~he inYentiOn, the act-lve substancereservo-lr is partly detachable whereby the part of the ac~ive substance reservoir which is not to be detached has a greater adhesion to the skln than to the back layer, after removing a predetermined plaster part with the active subst&nce reservoir part adherlng thercto, there is left behind a predetermlned acti~e substance reservoir part on the skin, which can e.g. be alone removed following the desi~ed appli-cation perlod. Advantageou61y 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, lt can also be advAn-tageous for the ac~ive substance reservoir to be in three parts.
The active substAnce release surfAces of the actlve substance reservcir parts can be geometrically identical or different. The actire sub-stance release surface~ can be ~uxtaposed, or one active substance reservoir part can completely surround one or more other active sub-stance reservoir parts, considered in a flat or surfsce-based manner.
The subdivision of the partial surfaces i~ dependent on the therapeutic requirements. Thus, e.g. one active substance reservoir part can circularly surround one or more other active substance reservoir parts.
.
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 ln all the active sub6tance reservoir parts.
Particularly preferred products sre plasters with the following active substances, b~t it is also possible to process random other trans-dermally administrsble active substance combinations known to the medical Expert: asthma/bronchodilators, such as e.g. clenbuterol, proctaterol and salbutamol and vasodilatorsl such as e.~. bencyclane and clnnarizlne.
~316~6~
Thus, with the aid of the inventive plaster, in such cases it i8 possible to reduce the admlnistration dose in planned and controlled manne} durlng application.
However, the active subs~ance reservoir parts can also contain diff-erent active substances or different active substance co~binations, 80 that during application it is possible to interrupt or stop one active substance or ac~ive substance combination. Example~ for di~f~
erent active substances in the active substance reservoir parts are:
oestrogen/gestagen (contraceptives), dexamethasone/prednisolone (in the case of inflammatory, rheumatic muscle and jOillt diseases), nitro-glycerin/ ~-blockers (for cardiac diseases)9 phenytoin/phenobarbital/
caffeine (for epilepsy) and amitriptyline/chlordiazepoxlde (psycho-pharmaceuticals).
.
All suitable active substances belong to the groups having either a topical or systemic sction. In at least one active substance reser-voir part there csn be different active substance/active substance combinations as compared with the other sctiYe substance reservoir part or parts.
The preferred use of the inventive plasters is in local and systemic, transdermal acti~e substance administration in humaa or animal medicine or in cosmetics.
The invention is described in greater detail hereinafter relative to non-l~mitative embodiments and with reference to the attached drswings, which are not true to scale and whereln show:
ig. 1 a cross-section through a first embodiment of an inventive plaster with a two-part active substance reservolr.
ig. 2 a plan view of the skin side of a second embodiment of the inventive plaster without a protective layer.
ig. 3 a cross-section along line I-I of fig. 2.
~ 3~ 62 ig. 4 a plsn vlew of the skin side of a third inventive embodiment without protectlve layer Fig. S a cross-sectiQn through the e~bodiment Df flg. 4 along line II-II on a larger scale.
Fig. 6 a plan view of the skin side of a four~h embodiment of the invention without a protective la~er.
Fig. 7 a ~ross-section through the e~bodiment of fig. 6 along line III~III.
Fig. 8 a cross~sec~lon through a flfth embodiment of the invention.
Fig. 9 a cross-section through a sixth embodlment of the invention.
ig. 10 a plan view of the skin ~ide of another embodiment of an inventive plaster ~ith a three-part active substance reser-voir and without a protective layer.
Fig. 11 a larger scale cross-sec~ion along line IV-IV of fig. 10.
The preferred embodi~ents of the invention shown in the individual drawingR 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 lsyer.
Fig. 1 shows a preferred emb~diment of an inventive, optionally circ-ular or angular plaster with 8 two part, contact ~dhesive active substance reser~oir ln cross-section. The second active substance reservoir pzrt 12 directly adheres to the back layer 11 and i8 separ-ated from the first contact adhesi~e active subs~ance reservoir par~
13 br a reserroir separatlng layer 14, which can be constructed as a gap or space between the active substance reservoir parts, or can be fill~d by an inert s~parating material. Active substance reservoir part 13 sdheres to the back layer 11 by ~eans of a peel-off layer 15, which brings about a gradual adhesion of the two active substance reservoir parts 12,13 to the back layer. The peel-off layer 15 can e.g. be a polymer or ~etal film or foil, a textlle fabric or a la~inate ~ 3 ~
thereof 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 ækin must be greater than the adhesion between the peel-of layer 15 end the back layer 11. The protective layer 16 is removed prior to the application oE the plaster. By the use of the same dotting system for the surfaces representing the açtive substance reservolr parts 12,13 ln fig. 1, it is ~ade clear that in both active substance reservoir parts 12,13 there is the same active subst~nce or active substance combination, so that with the plaster according to fig. 1 it is possible to brin8 about a gradual decrease of the ~ctive substance release to the skin.
.
Fig, 2 is a plan view of the skin side o a further inventive angular plaster wlth a two-part, non-contact adhesive active substance reser-voir, from which the protective layer has already been removed. Thus, on the skin side; the plaster has contact adhesive la~ers 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 materlal.
Fig. 3 is a cros6-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 loca~ed between the first eontact 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, peel-off 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 ~3~6~
contamination and damage from the outside or also against the escape of ¢.g. volatile active 6ubstance components.
The skin side contact adhesive layers 21,22 on the non-adhesive active substanc~ reser~oir parts 24,25 are so sd~usted that the adheslon of the con~act adhesive layer 22 of the first active substance reser-voir part 24 to the skin i8 grea~er than the adhesion between peel-off layer 26 and contact adhesive layer 27. The differently repreæ-ented 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.
Fi8. 4 æhows another preferred embodiment of an inventive plaster in plan view on the skin side thereof. The oval plaster has a two-part active substance reservoir and a contact adhesive lsyer 41 respon-sible for the fi~ing of the active substance reservoir parts 42,43 to the back layer 45 also forms the fastening to the skin of the therapeutic system.
Fig. 5 shows a lsrger scale cross-section along line II-II of fig.
4. The contac~ 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.
~ere 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 adhesi~e 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 actlve substance reservoir parts 42,43 contain different active substances or actlve substance combinatlons, as is ~ade clear by the arrangement of the surfaceæ.
Fig. 6 shows another inventive plaster with a two-part active substance ~ 3 ~ 2 .
re~erroir, in which one active substance reservoir part 61 concentric-811y surrounds the other actlve substance reservoir part 637 the representntion being from the skin side and with the protective layer removed. The contact adhesive, first circular active substance reser-voir 63 is separated from the circular second act:ive substance reser-voir 61 by an inert reserroir ~eparating layer 62, whlch can also be in the orm of a gap. This embodiment has the advantage that on reducing the active substance release surface b~ removing part of the plas~er with ~he second active substance reservoir p~rt 61 and together ~ith the back layer 65, it is possible to freel~ choose the plas~er removal direction.
Fig. 7 shows a cross-section through the embodiment of fig. 6 repres-ented along line III-III thereof. The circular, second sctive sub-stance reservoir part 61 is directly adjacent to the back layer 65, whilst the peel-off layer 64 is arranged between the clrcular, first active substance reservoir part 63 and the back layer 65. The adhe~ion of the first sctive substance reservoir par~ 63 to the skin and that between the peel-off layer 64 a~d the back layer S5 is greater than the adhesion between the peel-off layer 64 and active subs~ance reser-voir part 63, so that on removing the back layer 65 the ~econd acti~e subs~ance reservoir part 6I is removed, whilst leaving the first actlve substance reservoir part 63 on the skin and which is now covered by the peel-of la~er 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.
Fig. 8 shows snother preferred embodimen~ of the inventlon in cross-section, in which the two parts o~ a non-adhesive active substance reservoir are once again cons~ructed as a circular disk 82 with 8 surroundi~g ring 81. The~ are separated from one another by an inert reservoir separating layer 83. Back layer 88 is covered by a contact adhesive layer 87, whlch is directly in contact wlth the second active substance reservoir part 81.
~ 3 ~ 2 .
Between the contact adhesive la~er 87 and the first actlve substance reservoir part 82 is provided an inert peel-off layer 86~ whieh is so designed that its adhesion to the contact adhesive la~er 87 iB
le~s 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 advantageousl~ covered by a protective layer 89.
In this embodLment, both active substance reservoir parts 81,82 have diferent active substances or active substance combination~.
Fig. 9 shows a cross-sectiorl through another embodiment of the in~en-tion, in which the back la~er 95 6urrounds the coneentric arrangement of the contact adheslve active substance reservoir parts 91,92 to the skin side. For fixlng the overall plsster and the active ~ubstance reser~sir parts to the skin, the whole surface of back layer 95 is covered wlth a co~tact 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 la~er g4 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 sub-stance 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 actlve s~bstance reservoir part 92. Reference numeral 96 designates he inert reservoir Reparating layer or the gap between the active substance reser~oir parts 91,92. Up to application, the overall arrangement i6 covered by a detachable protective layer 97. The acti~e substances or active substance combinations are different in both reservoir parts 91,92 in this embodiment.
~31~62 ~ 11 --Another preferred embodiment of the invention wi~h a three-part active substance reservoir is shown in fig. 10. The latter is a plan view of the skin side of nn inventive plaster withollt the protective layer.
A firs~, circular, con~act adhesive active substance reservolr part 105 is surrounded by a second, circular, contact adhesive active sub-stance reservoir part 103 and is separated therefrom by an inert reservoir separating layer 104. The third contact adhesive sctive substance reservoir part 101 surrounds the second active substance reservoir part 103 in concentric ring form. Bet~een the second and third active substance reservoir parts 101,103 ls provided a further inert reservoir separating layer 102. Fig. 11 is a larger scale cross-section along line IY-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 reserroir parts 103,105 to the ækin, so that active substance reservoir parts 103,105 remain on the skin on removing the back layer 108 wi~h active substance reservoir part 101. Thus, the first peel-off layer 106 then orms a protective, new layer for the rema~ning parts of the plaster. The contact adhesive active substance reservoir part 103 adheres directly to the first peel-off layer 106 and can be re~oved together with the latter in a further removal step, whilst leaving behind on the skin the first active substance reservoir part 105, this being made possible by the second peel-off layer 107 between the first actire substance reservoir part 105 and the flrst 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 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 ex~mple shows for active substance reservoir parts 103,105 the same actire substance or active substance combination, indicated by the identical dotting in flg. 11~ whilst the active substance reservoir part 101 ~ 3 ~
hss a different actlYe substance or active substance comblnation.
The drawings which merely lllustrate the invention in an e~emplified manner, are not lntended to restrict the invention ei~her as regards geometrical shape, the association of speciflc indi~idual components, or aæ regards the size of tlle active substance release surfsces.
As is well known to the Expert in this field, al.L these quantities can be adapted to the therapeutic requirements and obviously account must be taken oE rational production. The part of the active substance reservoir part to be detached can also have a peel-off layerD 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, particularl~ those on the skin side, can have contact adhesive-free areas for improved active substance permeability, or can be constructed solel~ as individual contact adhesive surfaces, e.g. can be embedded in the active substance reservoir material. The release of the active substances fro~ the active substance reservoir parts can optionally be regulated b~ control membranes, which are embedded in per se known manner in th~ 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 adhesi~e layer.
:
For the construction of an active substance reservoir, as used accord-ing to the invention, it is possible to use the standard measures and materials. The basic materials csn be conetituted by low and high molecular weight, natsral and/or synthetic substances, whose choice is a function of the characteristics of the active substances 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 ~xpert on the basis of his knowledge, such as e.g. solubilizers, softeners, plastlcizers, 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 ~ 3 ~ 2 release rates or kinetics. In the case of an identical reservoir oomposition and only one active substance to be adminlstered, it can be approprlate to have a graduated concentration setting of the actlve substance in the different reservoir parts. Sultable active substances for the inventive plasters are all those which alone or with adjuvants are able to mi8rate into the skin.
The back layer covering the actire substance reservoir on the skln remote side can be permeable or impermeable. It must be flexible and, as a result of the mechanical stabilization of the plaster, serves to remove part of the a~tive substance reservoir. If components of the reservoir or the incorporated active substances are volat~le, then the back layer must be impermeable to these substances. It can be in one or ~ulti-layer form. Suitable materials for the production thereof are e.8. polymeric substances, such as polyethylene, polyprop-ylene, polyesters and polyamldes. Further materlals 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 indic-ating the optimum plaster remoYal direction. Optionally peel-off layers are provided between the active substance reservoir parts ln 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 materlal as used for making the back layer, provided that they can be made detachable, e.g. by applylng a silicone layer. Other detachable protective layers, as known to the Expert in the field of plasters and in particular plaster-like therapeutic systems are e~g. polytetrafluoroethylene, treated paper, cellophsne, polyvinylchloride, etc. To facilltate detach-ability, 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 1 3 ~
.
web of the pro~ective layer material.
Contact adhesive layers used for the inventive plasters can be cons-tituted by all physiologically unob~ectiollable contact adhesives which are inert to active substances and other active subs~snce reservoir componen~s, e.g. can be based on rubber, rubber-llke, synthetic homo-co- or block polymers, polyacrylstes and their copolrmers, poly-urethanes and silicones.
The inventive plaster can be produced by all known plaster technology methods. This is demonstrated in the following production e~ample for a plaster with a two-part actiYe substance reserYoir.
Production Example.
~, .
In a roller application process to a film or foil given a repelling ~inish b7 siliconizing and which serves as an intermediate co~ering, is spplied an active substance-containing reservoir material solution and which, after drying at 65C, forms a contact adhesl~e layer of 55 g/m2 and having the following composition:
~, .
1. Acrylate copolymer I 68.86 parts by weight 2. Acrylate copolymer II 10.39 parts by weight 3. POE-(10)-oleyl slcohol 5.20 parts by weight 4. Active substance 15.56 parts by weight Acrylste copolymer I i9 Durotac 280-2516 of National Starch & Chemicsl B.V., Netherlands; Acrylate copolymer II i9 Eudragit E100 of Rohm Pharma, Germany; POE-(10)-oleyl alcohol is Bri; 97 of Atlas Chemical Industries, GB.
~nto one half of the actlve substance-contsining contact adhesive layer is applied a non-siliconized polyester film (~hickneæ~ 0.036 mm~ and to the other hal~ the non-siliconized slde of a one-sided, siliconized polyester film (thickness 0.036 mm). After removing the 1 3 ~ 2 intermediate covering ring-like active ~ubstance reservoir parts ars punched out of the first half and are applied Wit}l the contact adhesive side to a slliconized, aluminium vapour-deposited polyester film (prot-ective layer). From the second half are punched disk-like actlve substance reservoir parts with a slightly smatler diame~er than the internal diameter o~ the rings into which they sre centrally inserted with the contsct adhesive side directed towards the protective layer.
The open side of the thus obtained union is covered by a polyester-based, contact adhesively finished 0.015 mm thick back layer (Durotac 280-2516, 30 g/m2 dry), the outwardly directed side being adhesive-free. The distance between ~he actlve substance reservoir units is approximately 14 mm, so that the back layer i9 in contact with the protective layer between the units. The thus obtained laminate is then supplied to a production process, in which by circular punching at a distance of approximately 7 mm from the outer edge of the rings, all-round closed disk-like plasters are obtained, one or more of which are packed in sealed bags.
The 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, wlth a back layer, an active substance reservoir subdivided substantially perpendicularly to the ækin contact surface of the plaster and having one or more active substances, &
contact adhe~i~e device on the skin side and optionally a cover layer detachable prior to the application of the plaster, it being posslble to reduce the size of ~he active substance release surface of the plaster by a predetermined amount by removing part of the active substance reservoir, as well as the use thereoP and a process for the controlled administration of active substances to the skin.
The invention more partlcularly relates to those plaster used as trans-dermal therapeutic systems for the controlled administration of medical active substances or also cosmetically actiYe substances to the human or animal skin. A therapeutic system is a medicament or active substance-containing means or administration form, which delivers one or more active 6ubstances 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 t opical effect, a systemic effect can also be obtained. The multiplicity of active substances applicable in this way and their different chemical, physical and pharmacological characteristlcs make it impo6sible 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 bein8 e.g. provided in Klaus Heilmann "Therapeutische Systeme", Ferdinand Enke Verlag~
~.~
131 ~2 Stuttgart, 1~77. The prior art systems were not able to provlde a completely satisfactory action in all cases.
In the conventional structure of a transdermal plaster-like ~herapeutic system there is an active substance reservoir, which contains the active substance in solid, liquid or dissolved form and a pressure-sensitive adhesion layer (contact adhesive), through which the system is closely linked with the skinO It is important that a whole-area contact is ensured be~ween the active substsnce re:Lease ~urfaces to the skin throughout the application oE the system, in order to make sure of the active substance release kinetics. This can be achieved not only through an uninterrupted adheslon layer, but also by rest-ricted adhesion areas in the skin contact layer of ~he plaster.
Although the hitherto known plaster-like therapeutic system permit a uniform or continuously decreasing application of an active 6ubstance over a predetermined timet they do not permit specific active substance release kinetics, such as a plsnned reduction of the active substance release after a predetermined time, or a graduated active substance release quantit~ per unit of ti~e.
This messure is e.g. necessary if the active substance dose has to be reduced in a planned manner dllring the application period for ther-apeutic reasons. The same problem arises if, during the application of a combination product, one active substance in the combi~ation must be interrupted after a predetermined time. In such cases, it is in principle possible to solve the problem by using two transdermal plasters, ~hereof one is removed at the given time. However, this leads to problems for patients, particularly if they are aged. There-fore it is easy to forge~ to appl~ the second plaster. In a combin-ation of two plasters wi~h different active substance release surfaces, there is also a risk of choo6ing the incorrect combina~ion (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 proble~ of double ~ 3 ~
storage. Thus, the use of two plasters leads ~o numerous disadvantages and the aYoidance thereof forms an objective of th~e lnvention.
The proposal of combinlng 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 th~ skin i9 raised snd must be firmly held during detachment. Thus, pressure is exerted on the sensitlvs transdermal s~stem, which can negatively influence the active substance release rate.
US Patent 4 297 995 describeæ a manipulatable active sub~tance plaster,in which the active substance reservoir i9 subdivided, but i5 in~e-grated into a single plaster. I'he 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 to the back layer onl~ makes it possible to change the active substance release surface prior to the applicatio~ 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 rsised from the skin9 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 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 ha~e hltherto been possible.
This problem is solved by a plaster of the aforementioned type, which is characterized in that at least part of the active substance reservoir ~3~ 2 cnn be detachedl whilst leaving one or more parts of said reservoir on the skin and the part of the acti~e substance reservoir left behind on the skin has a better adhesion to the skin than to the back layer.
Due to the fact that9 according to ~he inYentiOn, the act-lve substancereservo-lr is partly detachable whereby the part of the ac~ive substance reservoir which is not to be detached has a greater adhesion to the skln than to the back layer, after removing a predetermined plaster part with the active subst&nce reservoir part adherlng thercto, there is left behind a predetermlned acti~e substance reservoir part on the skin, which can e.g. be alone removed following the desi~ed appli-cation perlod. Advantageou61y 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, lt can also be advAn-tageous for the ac~ive substance reservoir to be in three parts.
The active substAnce release surfAces of the actlve substance reservcir parts can be geometrically identical or different. The actire sub-stance release surface~ can be ~uxtaposed, or one active substance reservoir part can completely surround one or more other active sub-stance reservoir parts, considered in a flat or surfsce-based manner.
The subdivision of the partial surfaces i~ dependent on the therapeutic requirements. Thus, e.g. one active substance reservoir part can circularly surround one or more other active substance reservoir parts.
.
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 ln all the active sub6tance reservoir parts.
Particularly preferred products sre plasters with the following active substances, b~t it is also possible to process random other trans-dermally administrsble active substance combinations known to the medical Expert: asthma/bronchodilators, such as e.g. clenbuterol, proctaterol and salbutamol and vasodilatorsl such as e.~. bencyclane and clnnarizlne.
~316~6~
Thus, with the aid of the inventive plaster, in such cases it i8 possible to reduce the admlnistration dose in planned and controlled manne} durlng application.
However, the active subs~ance reservoir parts can also contain diff-erent active substances or different active substance co~binations, 80 that during application it is possible to interrupt or stop one active substance or ac~ive substance combination. Example~ for di~f~
erent active substances in the active substance reservoir parts are:
oestrogen/gestagen (contraceptives), dexamethasone/prednisolone (in the case of inflammatory, rheumatic muscle and jOillt diseases), nitro-glycerin/ ~-blockers (for cardiac diseases)9 phenytoin/phenobarbital/
caffeine (for epilepsy) and amitriptyline/chlordiazepoxlde (psycho-pharmaceuticals).
.
All suitable active substances belong to the groups having either a topical or systemic sction. In at least one active substance reser-voir part there csn be different active substance/active substance combinations as compared with the other sctiYe substance reservoir part or parts.
The preferred use of the inventive plasters is in local and systemic, transdermal acti~e substance administration in humaa or animal medicine or in cosmetics.
The invention is described in greater detail hereinafter relative to non-l~mitative embodiments and with reference to the attached drswings, which are not true to scale and whereln show:
ig. 1 a cross-section through a first embodiment of an inventive plaster with a two-part active substance reservolr.
ig. 2 a plan view of the skin side of a second embodiment of the inventive plaster without a protective layer.
ig. 3 a cross-section along line I-I of fig. 2.
~ 3~ 62 ig. 4 a plsn vlew of the skin side of a third inventive embodiment without protectlve layer Fig. S a cross-sectiQn through the e~bodiment Df flg. 4 along line II-II on a larger scale.
Fig. 6 a plan view of the skin side of a four~h embodiment of the invention without a protective la~er.
Fig. 7 a ~ross-section through the e~bodiment of fig. 6 along line III~III.
Fig. 8 a cross~sec~lon through a flfth embodiment of the invention.
Fig. 9 a cross-section through a sixth embodlment of the invention.
ig. 10 a plan view of the skin ~ide of another embodiment of an inventive plaster ~ith a three-part active substance reser-voir and without a protective layer.
Fig. 11 a larger scale cross-sec~ion along line IV-IV of fig. 10.
The preferred embodi~ents of the invention shown in the individual drawingR 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 lsyer.
Fig. 1 shows a preferred emb~diment of an inventive, optionally circ-ular or angular plaster with 8 two part, contact ~dhesive active substance reser~oir ln cross-section. The second active substance reservoir pzrt 12 directly adheres to the back layer 11 and i8 separ-ated from the first contact adhesi~e active subs~ance reservoir par~
13 br a reserroir separatlng layer 14, which can be constructed as a gap or space between the active substance reservoir parts, or can be fill~d by an inert s~parating material. Active substance reservoir part 13 sdheres to the back layer 11 by ~eans of a peel-off layer 15, which brings about a gradual adhesion of the two active substance reservoir parts 12,13 to the back layer. The peel-off layer 15 can e.g. be a polymer or ~etal film or foil, a textlle fabric or a la~inate ~ 3 ~
thereof 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 ækin must be greater than the adhesion between the peel-of layer 15 end the back layer 11. The protective layer 16 is removed prior to the application oE the plaster. By the use of the same dotting system for the surfaces representing the açtive substance reservolr parts 12,13 ln fig. 1, it is ~ade clear that in both active substance reservoir parts 12,13 there is the same active subst~nce or active substance combination, so that with the plaster according to fig. 1 it is possible to brin8 about a gradual decrease of the ~ctive substance release to the skin.
.
Fig, 2 is a plan view of the skin side o a further inventive angular plaster wlth a two-part, non-contact adhesive active substance reser-voir, from which the protective layer has already been removed. Thus, on the skin side; the plaster has contact adhesive la~ers 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 materlal.
Fig. 3 is a cros6-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 loca~ed between the first eontact 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, peel-off 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 ~3~6~
contamination and damage from the outside or also against the escape of ¢.g. volatile active 6ubstance components.
The skin side contact adhesive layers 21,22 on the non-adhesive active substanc~ reser~oir parts 24,25 are so sd~usted that the adheslon of the con~act adhesive layer 22 of the first active substance reser-voir part 24 to the skin i8 grea~er than the adhesion between peel-off layer 26 and contact adhesive layer 27. The differently repreæ-ented 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.
Fi8. 4 æhows another preferred embodiment of an inventive plaster in plan view on the skin side thereof. The oval plaster has a two-part active substance reservoir and a contact adhesive lsyer 41 respon-sible for the fi~ing of the active substance reservoir parts 42,43 to the back layer 45 also forms the fastening to the skin of the therapeutic system.
Fig. 5 shows a lsrger scale cross-section along line II-II of fig.
4. The contac~ 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.
~ere 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 adhesi~e 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 actlve substance reservoir parts 42,43 contain different active substances or actlve substance combinatlons, as is ~ade clear by the arrangement of the surfaceæ.
Fig. 6 shows another inventive plaster with a two-part active substance ~ 3 ~ 2 .
re~erroir, in which one active substance reservoir part 61 concentric-811y surrounds the other actlve substance reservoir part 637 the representntion being from the skin side and with the protective layer removed. The contact adhesive, first circular active substance reser-voir 63 is separated from the circular second act:ive substance reser-voir 61 by an inert reserroir ~eparating layer 62, whlch can also be in the orm of a gap. This embodiment has the advantage that on reducing the active substance release surface b~ removing part of the plas~er with ~he second active substance reservoir p~rt 61 and together ~ith the back layer 65, it is possible to freel~ choose the plas~er removal direction.
Fig. 7 shows a cross-section through the embodiment of fig. 6 repres-ented along line III-III thereof. The circular, second sctive sub-stance reservoir part 61 is directly adjacent to the back layer 65, whilst the peel-off layer 64 is arranged between the clrcular, first active substance reservoir part 63 and the back layer 65. The adhe~ion of the first sctive substance reservoir par~ 63 to the skin and that between the peel-off layer 64 a~d the back layer S5 is greater than the adhesion between the peel-off layer 64 and active subs~ance reser-voir part 63, so that on removing the back layer 65 the ~econd acti~e subs~ance reservoir part 6I is removed, whilst leaving the first actlve substance reservoir part 63 on the skin and which is now covered by the peel-of la~er 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.
Fig. 8 shows snother preferred embodimen~ of the inventlon in cross-section, in which the two parts o~ a non-adhesive active substance reservoir are once again cons~ructed as a circular disk 82 with 8 surroundi~g ring 81. The~ are separated from one another by an inert reservoir separating layer 83. Back layer 88 is covered by a contact adhesive layer 87, whlch is directly in contact wlth the second active substance reservoir part 81.
~ 3 ~ 2 .
Between the contact adhesive la~er 87 and the first actlve substance reservoir part 82 is provided an inert peel-off layer 86~ whieh is so designed that its adhesion to the contact adhesive la~er 87 iB
le~s 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 advantageousl~ covered by a protective layer 89.
In this embodLment, both active substance reservoir parts 81,82 have diferent active substances or active substance combination~.
Fig. 9 shows a cross-sectiorl through another embodiment of the in~en-tion, in which the back la~er 95 6urrounds the coneentric arrangement of the contact adheslve active substance reservoir parts 91,92 to the skin side. For fixlng the overall plsster and the active ~ubstance reser~sir parts to the skin, the whole surface of back layer 95 is covered wlth a co~tact 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 la~er g4 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 sub-stance 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 actlve s~bstance reservoir part 92. Reference numeral 96 designates he inert reservoir Reparating layer or the gap between the active substance reser~oir parts 91,92. Up to application, the overall arrangement i6 covered by a detachable protective layer 97. The acti~e substances or active substance combinations are different in both reservoir parts 91,92 in this embodiment.
~31~62 ~ 11 --Another preferred embodiment of the invention wi~h a three-part active substance reservoir is shown in fig. 10. The latter is a plan view of the skin side of nn inventive plaster withollt the protective layer.
A firs~, circular, con~act adhesive active substance reservolr part 105 is surrounded by a second, circular, contact adhesive active sub-stance reservoir part 103 and is separated therefrom by an inert reservoir separating layer 104. The third contact adhesive sctive substance reservoir part 101 surrounds the second active substance reservoir part 103 in concentric ring form. Bet~een the second and third active substance reservoir parts 101,103 ls provided a further inert reservoir separating layer 102. Fig. 11 is a larger scale cross-section along line IY-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 reserroir parts 103,105 to the ækin, so that active substance reservoir parts 103,105 remain on the skin on removing the back layer 108 wi~h active substance reservoir part 101. Thus, the first peel-off layer 106 then orms a protective, new layer for the rema~ning parts of the plaster. The contact adhesive active substance reservoir part 103 adheres directly to the first peel-off layer 106 and can be re~oved together with the latter in a further removal step, whilst leaving behind on the skin the first active substance reservoir part 105, this being made possible by the second peel-off layer 107 between the first actire substance reservoir part 105 and the flrst 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 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 ex~mple shows for active substance reservoir parts 103,105 the same actire substance or active substance combination, indicated by the identical dotting in flg. 11~ whilst the active substance reservoir part 101 ~ 3 ~
hss a different actlYe substance or active substance comblnation.
The drawings which merely lllustrate the invention in an e~emplified manner, are not lntended to restrict the invention ei~her as regards geometrical shape, the association of speciflc indi~idual components, or aæ regards the size of tlle active substance release surfsces.
As is well known to the Expert in this field, al.L these quantities can be adapted to the therapeutic requirements and obviously account must be taken oE rational production. The part of the active substance reservoir part to be detached can also have a peel-off layerD 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, particularl~ those on the skin side, can have contact adhesive-free areas for improved active substance permeability, or can be constructed solel~ as individual contact adhesive surfaces, e.g. can be embedded in the active substance reservoir material. The release of the active substances fro~ the active substance reservoir parts can optionally be regulated b~ control membranes, which are embedded in per se known manner in th~ 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 adhesi~e layer.
:
For the construction of an active substance reservoir, as used accord-ing to the invention, it is possible to use the standard measures and materials. The basic materials csn be conetituted by low and high molecular weight, natsral and/or synthetic substances, whose choice is a function of the characteristics of the active substances 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 ~xpert on the basis of his knowledge, such as e.g. solubilizers, softeners, plastlcizers, 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 ~ 3 ~ 2 release rates or kinetics. In the case of an identical reservoir oomposition and only one active substance to be adminlstered, it can be approprlate to have a graduated concentration setting of the actlve substance in the different reservoir parts. Sultable active substances for the inventive plasters are all those which alone or with adjuvants are able to mi8rate into the skin.
The back layer covering the actire substance reservoir on the skln remote side can be permeable or impermeable. It must be flexible and, as a result of the mechanical stabilization of the plaster, serves to remove part of the a~tive substance reservoir. If components of the reservoir or the incorporated active substances are volat~le, then the back layer must be impermeable to these substances. It can be in one or ~ulti-layer form. Suitable materials for the production thereof are e.8. polymeric substances, such as polyethylene, polyprop-ylene, polyesters and polyamldes. Further materlals 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 indic-ating the optimum plaster remoYal direction. Optionally peel-off layers are provided between the active substance reservoir parts ln 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 materlal as used for making the back layer, provided that they can be made detachable, e.g. by applylng a silicone layer. Other detachable protective layers, as known to the Expert in the field of plasters and in particular plaster-like therapeutic systems are e~g. polytetrafluoroethylene, treated paper, cellophsne, polyvinylchloride, etc. To facilltate detach-ability, 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 1 3 ~
.
web of the pro~ective layer material.
Contact adhesive layers used for the inventive plasters can be cons-tituted by all physiologically unob~ectiollable contact adhesives which are inert to active substances and other active subs~snce reservoir componen~s, e.g. can be based on rubber, rubber-llke, synthetic homo-co- or block polymers, polyacrylstes and their copolrmers, poly-urethanes and silicones.
The inventive plaster can be produced by all known plaster technology methods. This is demonstrated in the following production e~ample for a plaster with a two-part actiYe substance reserYoir.
Production Example.
~, .
In a roller application process to a film or foil given a repelling ~inish b7 siliconizing and which serves as an intermediate co~ering, is spplied an active substance-containing reservoir material solution and which, after drying at 65C, forms a contact adhesl~e layer of 55 g/m2 and having the following composition:
~, .
1. Acrylate copolymer I 68.86 parts by weight 2. Acrylate copolymer II 10.39 parts by weight 3. POE-(10)-oleyl slcohol 5.20 parts by weight 4. Active substance 15.56 parts by weight Acrylste copolymer I i9 Durotac 280-2516 of National Starch & Chemicsl B.V., Netherlands; Acrylate copolymer II i9 Eudragit E100 of Rohm Pharma, Germany; POE-(10)-oleyl alcohol is Bri; 97 of Atlas Chemical Industries, GB.
~nto one half of the actlve substance-contsining contact adhesive layer is applied a non-siliconized polyester film (~hickneæ~ 0.036 mm~ and to the other hal~ the non-siliconized slde of a one-sided, siliconized polyester film (thickness 0.036 mm). After removing the 1 3 ~ 2 intermediate covering ring-like active ~ubstance reservoir parts ars punched out of the first half and are applied Wit}l the contact adhesive side to a slliconized, aluminium vapour-deposited polyester film (prot-ective layer). From the second half are punched disk-like actlve substance reservoir parts with a slightly smatler diame~er than the internal diameter o~ the rings into which they sre centrally inserted with the contsct adhesive side directed towards the protective layer.
The open side of the thus obtained union is covered by a polyester-based, contact adhesively finished 0.015 mm thick back layer (Durotac 280-2516, 30 g/m2 dry), the outwardly directed side being adhesive-free. The distance between ~he actlve substance reservoir units is approximately 14 mm, so that the back layer i9 in contact with the protective layer between the units. The thus obtained laminate is then supplied to a production process, in which by circular punching at a distance of approximately 7 mm from the outer edge of the rings, all-round closed disk-like plasters are obtained, one or more of which are packed in sealed bags.
Claims (10)
1. Active substance-containing plaster for the controlled admin-istration of active substances to the skin, which has a back and a skin side, with a back layer, an active substance reservoir divided 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, in which it is possible to reduce the active substance release surface of the plaster by a predetermined amount through the removal of part of the active substance reservoir, characterized in that at least one active substance reservoir part (12,25,43,61,81,91, 101,103) is detachable from the skin, whilst leaving behind one or more active substance reservoir parts (13,24,42,63,82,92,105), the part of the active substance reservoir remaining on the skin having a better adhesion to the skin than to the back layer (11,28,45,65,88,95,108).
2. Active substance-containing plaster according to claim 1, char-acterized in that the active substance reservoir is in two parts.
3. Active substance-containing plaster according to claim 1, char-acterized in that the active substance reservoir is in three parts.
4. Active substance-containing plaster according to claim 1, characterized in that the active substance release surfaces of the active substance reservoir parts are geometrically identical or different.
5. Active substance-containing plaster according to claim 1, characterized in that one active substance reservoir part (61,81,91,101,103) completely surrounds one or more other active substance reservoir parts (63,82,92,103,105), considered in a flat or surface manner.
6. Active substance-containing plaster according to claim 4 or 5, characterized in that one active substance reservoir part (61, 81, 91, 101, 103) annularly surrounds one or more other active substance reservoir parts (63, 82, 92, 103, 105).
7. Active substance-containing plaster according to any one of claims 1, 2 or 3 characterized in that the release surface-size ratio of one active substance reservoir part to another is between approximately 1:1 and 1:10.
8. Active substance-containing plaster according to any one of claims 1, 2 or 3 characterized in that the same active substance or same active substance combination is present in all the active substance reservoir parts.
9. Active substance-containing plaster according to any one of claims 1, 2 or 3 characterized in that in at least one active substance reservoir part there is a different active substance-active substance combination as compared with the other active substance reservoir part.
10. Active substance-containing plaster according to one of claims 1, 2 or 3 characterized in that the active substances have a topical or systemic action.
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 |
| DEP3714140.6 | 1987-04-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1316062C true CA1316062C (en) | 1993-04-13 |
Family
ID=6326433
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000562578A Expired - Fee Related CA1316062C (en) | 1987-04-28 | 1988-03-25 | Active substance-containing plaster for the controlled administration of active substances to the skin, the use thereof and a process for the controlled administration of active substances 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) |
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 |
| DE3901551A1 (en) * | 1989-01-20 | 1990-07-26 | Lohmann Therapie Syst Lts | SUPERFICIAL THERAPEUTIC SYSTEM WITH AN ANTINEOPLASTIC ACTIVE SUBSTANCE, IN PARTICULAR 5-FLUORURACIL |
| 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 | 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 |
| US10045935B2 (en) | 2012-07-31 | 2018-08-14 | Egis Pharmaceuticals Plc | Transdermal formulation containing COX inhibitors |
| US11154535B2 (en) | 2012-07-31 | 2021-10-26 | Egis Pharmaceuticals Plc | Transdermal formulation containing COX inhibitors |
| KR20180127315A (en) * | 2015-12-30 | 2018-11-28 | 코리움 인터네셔널, 인크. | System and method for transdermal transdermal administration |
| CN109922796B (en) | 2016-06-23 | 2023-04-07 | 考里安有限责任公司 | Adhesive matrix with hydrophilic and hydrophobic domains and therapeutic agents |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4297995A (en) * | 1980-06-03 | 1981-11-03 | Key Pharmaceuticals, Inc. | Bandage containing attachment post |
| 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 PL PL88272134A patent/PL161617B1/en unknown
- 1988-03-22 IE IE83488A patent/IE61005B1/en not_active IP Right Cessation
- 1988-03-22 HU HU882152A patent/HU204203B/en not_active IP Right Cessation
- 1988-03-22 EP EP88104580A patent/EP0288734B1/en not_active Expired - Lifetime
- 1988-03-22 DE DE8888104580T patent/DE3866582D1/en not_active Expired - Lifetime
- 1988-03-22 WO PCT/DE1988/000180 patent/WO1988008318A1/en active IP Right Grant
- 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 AU AU14894/88A patent/AU627422B2/en not_active Ceased
- 1988-03-22 AT AT88104580T patent/ATE69962T1/en not_active IP Right Cessation
- 1988-03-22 KR KR1019880701436A patent/KR910002250B1/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 YU YU78188A patent/YU47056B/en unknown
- 1988-04-19 SI SI8810781A patent/SI8810781B/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 PT PT87345A patent/PT87345B/en active IP Right Grant
- 1988-04-28 SK SK2883-88A patent/SK288388A3/en unknown
- 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
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| Date | Code | Title | Description |
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| MKLA | Lapsed |