CA2012123C - Transdermal system exhibiting graduated drug release and its use for the local or systemic administration of active substances - Google Patents
Transdermal system exhibiting graduated drug release and its use for the local or systemic administration of active substancesInfo
- Publication number
- CA2012123C CA2012123C CA002012123A CA2012123A CA2012123C CA 2012123 C CA2012123 C CA 2012123C CA 002012123 A CA002012123 A CA 002012123A CA 2012123 A CA2012123 A CA 2012123A CA 2012123 C CA2012123 C CA 2012123C
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- Canada
- Prior art keywords
- active substance
- reservoir
- membrane
- transdermal system
- skin
- 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.)
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Classifications
-
- 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
- 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)
- Dermatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Biomedical Technology (AREA)
- Anesthesiology (AREA)
- Medical Informatics (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Media Introduction/Drainage Providing Device (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Adhesives Or Adhesive Processes (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- External Artificial Organs (AREA)
Abstract
The present invention relates to a transdermal system with graduated drug release and to its use for the local or systemic dermal drug administration in human and veterin-ary medicine, or in cosmetics.
Description
201212~
D E S C R I P T I O N
The present invention relates to a transdermal system with graduated drug release and to its use for the local or systemic dermal drug administration in human and veterinary medicine, or in cosmetics.
Transdermal therapeutic systems have become well-estab-lished in the treatment of various diseases. Their major advantage is the fact that the active substance after per-meation through the skin is immediately systemically effec-tive, thereby avoiding the primary liver passage which always occurs in the case of orally administered active substances, and that very constant plasma levels can be achieved, if the system is adequately prepared. This is of special importance for active substances which exhibit short half-lives and therefore make necessary a constant fresh delivery of the drug.
Since the system is applied externally, the intended func-tion can thus be performed for a very long period of time -some of the commercially available systems may remain on the site of application for up to one week. This effect can virtually not be achieved with oral systems, since they leave the organism after one day at the latest due to diges-2~2123 tion.
Such transdermal systems usually consist of a backing layerwhich is impermeable to the active substance, an active substance reservoir, a fixing device for anchoring the system to the skin, and a removable protective foil for the skin side of the system. In a preferred embodiment of the fixing device the skin side is rendered at least partially self-adhesive.
In those systems the reservoir may have the form of a bag containing the liquid or dissolved active substance, or it may be a foil-like article comprising the active substance as a polymer containing preparation.
The latter systems are also called matrix systems, and the following statements relate to those kinds of systems.
If the reservoir of such a matrix system consists of only one homogeneous layer and no further layers controlling the active substance release are present between the side facing the skin after application and the skin itself, the system controls the active substance release; if the matrix is supersaturated this is performed according to equation 1, if this is not the case according to equation 2.
2012~23 Q = ( DDR [CDR-cSDR~ * CSDR * t ) equation 1 Q = 2 * CDR * ( DDR t / 3.14 ) equation 2 Q : amount of active substance released at time t t : time DDR : diffusion coefficient of active substance in the matrix CDR : active substance concentration in the reservoir CSDR : saturation solubility of the active substance in the reservoir Since Q is directly proportional the square root of time, these equations are also called the root-t-law.
The active substance release is not constant in these systems and rapidly decreases in the course of time.
If a more constant active substance release is desired, this can be achieved by the use of so-called controlling membranes.
Such a system consists of a backing layer, an active sub-stance reservoir, a controlling membrane, a pressure-sensi-tive adhesive layer for securing the system to the skinand a removable protective foil.
-D /1 * t Q = Co * e equation 3 Co = initial concentration of active substance D = diffusion coefficient of active substance in the mem-brane 1 = thickness of membrane For some groups of active substances constant release rates and constant plasma levels may be undesired. For example, in the case of blood pressure and circulation influencing agents, calmatives and soporifics, psycho-pharmacological agents, anodynes, angina pectoris agents, antiasthmatics, and agents facilitating the curing of drug addiction, e.g., nicotine.
In case of these substances it is advantageous to achieve plasma levels adapted to the indiviual need.
In addition, some drugs are not administered constantly, but only when need arises at probably very large inter-vals. Such a substance which is already on the market as transdermal system, e.g., is scopolamine against motion sickness.
Other active substances suitable for such a temporary administration, e.g., are anodynes, psychopharmacological agents, calmatives, soporifics, or appetite-suppressing agents.
In the case of a transdermal application of such sub-stances, the transdermal system has to effect a variable active substance flux through the skin during the period of application, whereby an initial dosage provides for a rapid commencement of effect, and a maintenance dosage provides for a sufficiently long constancy or a prepro-grammed decrease of plasma levels.
A transdermal therapeutic system to solve this problem has been described in EP-A O 227 252. In this case, the active substance in a reservoir is brought into contact with an amount of penetration accelerator merely sufficient to maintain the accelerated penetration only during a defined initial phase of application. It is of disadvantage in this case that each active substance has to assigned a suitable penetration accelerator.
Another solution to this problem has been proposed in DE-OS 36 42 931. In this case, at least two plaster cham-bers lying side by side and being separate from each other are provided with different active substance concentra-tions so that in the first application phase the release of active substance from all chambers effects a high initi-al dosage, while after evacuation of the chambers with low active substance concentration only those chambers with higher active substance concentration contribute to the release and thus effect a lower maintenance dosage. This system is expensive merely because of this chamber con-struction, and requires special measures with respect to the different adjustments of concentration in the cham-bers.
It is accordingly the object of the present invention to provide a plaster used as therapeutic system with graduat-ed drug release for the administration of active sub-stances to the skin, which avoids the compelling presence of a penetration accelerator and - in excess of the prior art - offers additional possiblities to control the active substance release, and which furthermore can be manufac-tured in a simple manner.
According to the present invention, this object is surpris-ingly achieved in that the active substance containing reservoir comprises at least one membrane located parallel to the releasing surface, the surface of said membrane being smaller in its dimension than the releasing area.
According to one aspect of the present invention there is provided a transdermal system for the controlled, graduated admlnlstratlon of an actlve substance to the skln, for the release of a high initial dosage and a lower maintenance dosage which consists of a backing layer averted from the skin and impermeable to the active substance, an active substance reservoir adiacent to said backlng layer the reservoir having a releasing surface, the reservolr integrating at least one membrane located parallel to the releasing surface, said membrane being less permeable to the active substance than the reservolr and having a surface area smaller than said releasing surface, ad~acent to the skin, a pressure-sensitive adhesive for securing the system to the skin, and a removable protective layer optionally covering the surface of the system facing the skin.
In this connection, a membrane means an areal flexible article whose permeability to components of the active substance reservoir can also equal nil. Thus, for example a thin metal foil is also comprised by the term membrane. Usually the thickness of such a membrane rarely exceeds 50 ~, however, thicker membranes are not excluded for ' 1 specla cases.
Normal membrane thlcknesses are from 20 to 100 ~m.
The membrane may elther be incorporated or embedded in the membrane, or adjoin the reservoir on the skin side.
According to an embodiment of the present invention, the membrane is impermeable to the active substance or sub-stances to be released. According to a further embodiment, the membrane exhibits a limited permeability to the active substance or active substances. According to the present invention it is also possible to combine two membranes having different permeabilities to the substances to be released. In this connection, at least one of these membra-nes has a smaller surface than that of the releasing area of the system. In this case it is of advantage that said smaller membrane is impermeable to the substance or sub-stances to be released, and incorporated in the reservoir.
The active substance or substances may be present in the reservoir at a concentration below the saturation concen-tration or at a concentration exceeding the saturation concentration.
The reservoir itself may consist of several layers of different composition.
In principle, the same materials as described for common systems can be used for all components of such a system.
These materials are known to the man skilled in the art.
The backing layer may consist of flexible or inflexible material, and may be constructed single or multi-layered.
Substances suitable for its production are polymeric sub-stances, such as, e.g., polyethylene, polypropylene, poly-ethylene terephthalate, polyurethane, or polyamide. As further materials metal foils, e.g., an aluminum foil alone or coated with a polymeric substrate may be used.
Textile fabrics may be used, too, if the components of the reservoir cannot leave the reservoir via the gas phase due to their physical properties.
In principle, the same materials may be used for the remov-able protective foil, however, they must additionally be rendered dehesive.
This dehesive preparation can be achieved by a special siliconization.
The reservoir or the layers of the reservoir, respective-ly, consist of a polymeric matrix and the active substance or substances, whereby the polymeric matrix exhibits such a self-adhesiveness that the coherence in case of a multi--layer construction is guaranteed. The polymeric material of the matrix may, e.g., be built up of polymers, such as rubber, rubber-like synthetic homo-, co-, or blockpoly-mers, polyacrylic acid esters and their copolymers, poly-urethanes, copolymers of ethylene and polysiloxanes. In principle, all polymers are suitable which are used in the manufacture of pressure-sensitive adhesives and are physio-logically acceptable. Additives may also be used, their nature depends on the polymer used and the active sub-stance or substances. Depending on their function they can be divided into softeners, tackifiers, resorption agents, stabilizers, or fillers. Substances suitable for this purpose and physiologically acceptable are known to the man skilled in the art.
All physiologically acceptable foil-like materials having the adequate permeability to the active substance or sub-stances or auxiliary agents, respectively, are suitable for the manufacture of the membranes. Membranes on the basis of polyethylene, polyamide, ethylene-vinyl ace-tate-copolymers, and polysiloxanes are particularly suit-able.
In the following, the invention is further illustrated but not limited by the drawings:
igure 1 shows a section through a system provided with a controlling membrane according to the prior art, igure 2 shows an embodiment of a system according to the present invention, igure 3 shows another view of the matrix of figure 2 with a membrane incorporated into the matrix, igure 4 shows different embodiments of the membrane, igure 5a shows a section through an embodiment of the present invention exhibiting a combination of an impermeable membrane with a membrane of higher permeability, igure 5b shows a top view on the embodiment of Figure 5a, igure 6 shows diagrammatically the release behaviour of an embodiment with a membrane incorporated in the reservoir and impermeable to the active substance in the form as shown in Figure 4, whereby the cumulated released amount of active substance is shown as function of time, igure 7 shows the release behaviour of the same system as shown in Figure 6, however, diagram-matically the active substance release rate per system and hour as function of time, Figure 8 shows in a diagram the release behaviour of a system according to the present invention with a membrane of limited permeability to the active substance, whereby the cumula-tive active substance release is plotted versus time, Figure 9 shows diagrammatically the release rate of the same system as shown in Figure 8 per sys-tem and hour as function of time.
The system described in Figure 1 consists of a backing layer (11), the active substance containing reservoir (12), the controlling membrane (13), a pressure-sensitive adhesive layer for securing the system to the skin (14), and a removable protective foil (15).
In some cases the pressure-sensitive adhesive layer (14) has the same formulation as the reservoir (12) so that the membrane is actually incorporated in the reservoir, and thus one can imagine the reservoir being built up of two parts.
If the active substance is present in the reservoir at an oversaturated concentration, a release according to a kinetic O is achieved by the membrane. Order, i.e., a constant release within the application period; and if the active substance is present below this concentration, a release according to a kinetic 1 is achieved.
Order according to equation 3.
Figure 2 shows the general construction of a system accord-ing to the present invention. It consists of a backing layer (21), a reservoir (22), a membrane (23), a self-ad-hesive skin coat (24), and a removable protective foil (25).
Membrane (23) is smaller than the reservoir surface, since the membrane has a central, circular recess.
In Figure 3 a membrane (31) is incorporated in the reser-voir (32) which for this reason is divided into two halves (33 and 34). If the reservoir formulation is self-adhe-sive, the self-adhesive skin coat (24) of Figure 2 can naturally be omitted. Due to the fact that the surface of the membrane is always smaller than the total area of the reservoir, reservoir and skin, or reservoir and pressure-2012~23 -sensitive adhesive layer, or both parts of the reservoir, respectively, are in direct contact with each other on that surface which is not covered by the membrane.
Figure 4 shows some examples of geometric forms of such membranes according to the present invention, in which either the hatched areas or the areas without hatches are membranes.
The embodiments according to the present invention as shown in Figures 3 and 4 are particularly suitable for systems with only one membrane being impermeable to the active substance, e.g., such as is shown in Figure 4.1 and integrated into the reservoir according to Figure 3.
At first, this system behaves like a common matrix system, i.e., the active substance is released over the whole releasing surface according to the so-called root-t-law.
However, as soon as the reservoir member, which is posi-tioned below the membrane area, is emptied so far that the depletion zone has reached the membrane, the behaviour of the reservoir compared to a common matrix system changes drastically. The active substance release decreases rapid-ly on the surface having the same dimension as the membra-ne, while on the partial surface which is not covered by the membrane the release continues undiminishedly accord-~012123 ing to the root-t-law until the depletion zone reaches the backing layer. Thus, the additional initial dosage origi-nates from the area lying below the membrane. By way of changing the absolute area sizes and the relation between membrane surface and total surface of the reservoir, the amount of initial dosage and maintenance dosage can be influenced within wide ranges.
As a matter of fact, such a release behaviour can also be achieved in that the reservoir is given a steplike geo-metry. However, this bears the disadvantage that such a system is more difficult to produce, and that due to the plastic deformability of usual reservoir formulations such a system does not maintain its steplike shape.
Embodiment 4.5 is particularly advantageous, since there are no problems concerning positioning due to the variety of holes within the membrane.
By way of changing the ratio of membrane surface to the total surface, and the choice of membranes of different permeabilities to the active substance, the release be-haviour of the system can be influenced in wide ranges, as is stated below. It is particularly possible administer very high initial dosages.
201~23 Figures 5a and 5b show in sectional view and in top view an embodiment of the present invention which is provided with a combination of tow different membranes.
The combination of a membrane having permeability "O" with a membrane of higher permeability is particularly suit-able. Such a system is shown in Figure 5a. It consists of the impermeable backing layer (51), the reservoir (52), a membrane of permeability O to the active substance or substances (53), a membrane of a higher permeability than O to the active substance or substances (54), and a remov-able protective layer (55).
Both membranes are once more shown in Figure 5b in top view. As a matter of fact, the membrane having permeabil-ity O must be smaller than the total releasing surface of the system, thus limiting the maximum active substance release on that partial area of the total releasing sur-face corresponding to the membrane size, since that por-tion of active substance lying above the membrane cannot pass it.
The membrane having the permeability higher than O effects an active substance release according to a kinetic of order O or 1 on that partial area of the total releasing surface corresponding to its size.
2012:123 _ 17 Both membranes need not necessarily lie in the same plane within the system. Their exact position depends on the individual requirements, and it is an additional means to achieve the desired release behaviour.
If the membrane having permeability O lies closer to the releasing surface, the other membrane may be as large as the total releasing surface without changing the release behaviour, since said membrane is of no effect, if it lies above the impermeable membrane.
Figures 6 and 7 show the release behaviour of those systems having a membrane which is impermeable to the active substance, as example a scopolamine plaster is chosen. The following indications apply to all samples described in the following: the active substance content amounts to 450 ,ug/cm2 and the weight per unit area of the self-adhesive reservoir amounts to 12.5 mg/cm2.
Figure 6 shows the cumulated released amount of scopol-amine as function of time.
Curve I corresponds to a normal system of 2 cm2 size with-out membrane, and serves as comparison.
Curve II corresponds to a system of a total size of 3 cm2;
~012~23 _ 18 an impermeable membrane is incorporated into the reser-voir. The membrane has an area of 1 cm2 and divides the reservoir into one layer having an area weight of 10.4 mg/cm2 and one having an area weight of 2.1 mg/cm2.
Curve III corresponds to a system of a total area of 4 cm2 and a membrane surface of 2 cm2.
It can clearly be recognized that on the whole the active substance release of the systems provided with membrane is higher. However, in Figure 7 it can be recognized more clearly that this increased active substance release only applies to the initial phase of release. Figure 7 shows the release rate per system and hour as function of time, i.e., the flux is indicated.
Thus, this system is particularly useful, if relatively high initial dosages shall be combined with a maintenance dosage which is not necessarily constant.
Figures 8 and 9 show an embodiment according to the pres-ent invention having a membrane of limited permeability to the active substance; as example a scopolamine plaster was used under the same conditions as described for Figures 6 and 7.
_. 19 The cumulative release is shown in Figure 8, the flux is shown in Figure 9. Curve I or flux I, respectively, corres-ponds to a system of 2 cm2 having a membrane of the same size (comparison), curve II or flux II, respectively, correspond to a system of 2.5 cm2 having a membrane of 2 cm2, and curve III or flux III, respectively, correspond to a system of 3 cm2 size having a membrane of 2 cm2.
Even the system according to curve I and flux I is able to release a certain initial dosage. This initial dosage corresponds to a release according to the root-t-law ac-cording to equation 1 and 2, which takes place until the depletion zone of the active substance has reached the membrane.
The other two systems provided with membrane, which are of smaller dimension than the releasing surface of the system the initial dosage can be increased very easily. In this case, the intitial dosage is followed by a constant main-tenance dosage the amount of which depends on the permeability and the surface of the membrane.
Production of the systems according to the present invention used in Figures 6 to 9 (samples) _ 20 230 g polyacrylate resin adhesive (50 % in acetic ester) 6 g scopolamine base 10 g Cetiol S
50 g methanol were mixed and the mixture homogenized.
A siliconized polyester foil of 100 ~ thickness was coated with this mixture as films of 400 ~ (film I) and 100 ~
(film II), the films were dried at 50C for 15 minutes.
After drying, film I had a weight per unit area of 103 g/mZ and film II one of 21 g/m2.
The membrane having circular recesses of adequate size was laminated on film II, and film I in turn was laminated thereon. The siliconized polyester foil of film I was removed and substituted for an unsiliconized foil of 15 thickness.
The individual samples were punched in such a way that the adequate total area resulted and the recess became posi-tioned centrally.
Performance of the in vitro-release - 2012~3 The release was carried out at 32C according to the paddle-over-disk-method using 50 ml physiological saline.
In order to determine the samples the total release medium was changed completely and the content determined accord-ing to a HPLC-method.
D E S C R I P T I O N
The present invention relates to a transdermal system with graduated drug release and to its use for the local or systemic dermal drug administration in human and veterinary medicine, or in cosmetics.
Transdermal therapeutic systems have become well-estab-lished in the treatment of various diseases. Their major advantage is the fact that the active substance after per-meation through the skin is immediately systemically effec-tive, thereby avoiding the primary liver passage which always occurs in the case of orally administered active substances, and that very constant plasma levels can be achieved, if the system is adequately prepared. This is of special importance for active substances which exhibit short half-lives and therefore make necessary a constant fresh delivery of the drug.
Since the system is applied externally, the intended func-tion can thus be performed for a very long period of time -some of the commercially available systems may remain on the site of application for up to one week. This effect can virtually not be achieved with oral systems, since they leave the organism after one day at the latest due to diges-2~2123 tion.
Such transdermal systems usually consist of a backing layerwhich is impermeable to the active substance, an active substance reservoir, a fixing device for anchoring the system to the skin, and a removable protective foil for the skin side of the system. In a preferred embodiment of the fixing device the skin side is rendered at least partially self-adhesive.
In those systems the reservoir may have the form of a bag containing the liquid or dissolved active substance, or it may be a foil-like article comprising the active substance as a polymer containing preparation.
The latter systems are also called matrix systems, and the following statements relate to those kinds of systems.
If the reservoir of such a matrix system consists of only one homogeneous layer and no further layers controlling the active substance release are present between the side facing the skin after application and the skin itself, the system controls the active substance release; if the matrix is supersaturated this is performed according to equation 1, if this is not the case according to equation 2.
2012~23 Q = ( DDR [CDR-cSDR~ * CSDR * t ) equation 1 Q = 2 * CDR * ( DDR t / 3.14 ) equation 2 Q : amount of active substance released at time t t : time DDR : diffusion coefficient of active substance in the matrix CDR : active substance concentration in the reservoir CSDR : saturation solubility of the active substance in the reservoir Since Q is directly proportional the square root of time, these equations are also called the root-t-law.
The active substance release is not constant in these systems and rapidly decreases in the course of time.
If a more constant active substance release is desired, this can be achieved by the use of so-called controlling membranes.
Such a system consists of a backing layer, an active sub-stance reservoir, a controlling membrane, a pressure-sensi-tive adhesive layer for securing the system to the skinand a removable protective foil.
-D /1 * t Q = Co * e equation 3 Co = initial concentration of active substance D = diffusion coefficient of active substance in the mem-brane 1 = thickness of membrane For some groups of active substances constant release rates and constant plasma levels may be undesired. For example, in the case of blood pressure and circulation influencing agents, calmatives and soporifics, psycho-pharmacological agents, anodynes, angina pectoris agents, antiasthmatics, and agents facilitating the curing of drug addiction, e.g., nicotine.
In case of these substances it is advantageous to achieve plasma levels adapted to the indiviual need.
In addition, some drugs are not administered constantly, but only when need arises at probably very large inter-vals. Such a substance which is already on the market as transdermal system, e.g., is scopolamine against motion sickness.
Other active substances suitable for such a temporary administration, e.g., are anodynes, psychopharmacological agents, calmatives, soporifics, or appetite-suppressing agents.
In the case of a transdermal application of such sub-stances, the transdermal system has to effect a variable active substance flux through the skin during the period of application, whereby an initial dosage provides for a rapid commencement of effect, and a maintenance dosage provides for a sufficiently long constancy or a prepro-grammed decrease of plasma levels.
A transdermal therapeutic system to solve this problem has been described in EP-A O 227 252. In this case, the active substance in a reservoir is brought into contact with an amount of penetration accelerator merely sufficient to maintain the accelerated penetration only during a defined initial phase of application. It is of disadvantage in this case that each active substance has to assigned a suitable penetration accelerator.
Another solution to this problem has been proposed in DE-OS 36 42 931. In this case, at least two plaster cham-bers lying side by side and being separate from each other are provided with different active substance concentra-tions so that in the first application phase the release of active substance from all chambers effects a high initi-al dosage, while after evacuation of the chambers with low active substance concentration only those chambers with higher active substance concentration contribute to the release and thus effect a lower maintenance dosage. This system is expensive merely because of this chamber con-struction, and requires special measures with respect to the different adjustments of concentration in the cham-bers.
It is accordingly the object of the present invention to provide a plaster used as therapeutic system with graduat-ed drug release for the administration of active sub-stances to the skin, which avoids the compelling presence of a penetration accelerator and - in excess of the prior art - offers additional possiblities to control the active substance release, and which furthermore can be manufac-tured in a simple manner.
According to the present invention, this object is surpris-ingly achieved in that the active substance containing reservoir comprises at least one membrane located parallel to the releasing surface, the surface of said membrane being smaller in its dimension than the releasing area.
According to one aspect of the present invention there is provided a transdermal system for the controlled, graduated admlnlstratlon of an actlve substance to the skln, for the release of a high initial dosage and a lower maintenance dosage which consists of a backing layer averted from the skin and impermeable to the active substance, an active substance reservoir adiacent to said backlng layer the reservoir having a releasing surface, the reservolr integrating at least one membrane located parallel to the releasing surface, said membrane being less permeable to the active substance than the reservolr and having a surface area smaller than said releasing surface, ad~acent to the skin, a pressure-sensitive adhesive for securing the system to the skin, and a removable protective layer optionally covering the surface of the system facing the skin.
In this connection, a membrane means an areal flexible article whose permeability to components of the active substance reservoir can also equal nil. Thus, for example a thin metal foil is also comprised by the term membrane. Usually the thickness of such a membrane rarely exceeds 50 ~, however, thicker membranes are not excluded for ' 1 specla cases.
Normal membrane thlcknesses are from 20 to 100 ~m.
The membrane may elther be incorporated or embedded in the membrane, or adjoin the reservoir on the skin side.
According to an embodiment of the present invention, the membrane is impermeable to the active substance or sub-stances to be released. According to a further embodiment, the membrane exhibits a limited permeability to the active substance or active substances. According to the present invention it is also possible to combine two membranes having different permeabilities to the substances to be released. In this connection, at least one of these membra-nes has a smaller surface than that of the releasing area of the system. In this case it is of advantage that said smaller membrane is impermeable to the substance or sub-stances to be released, and incorporated in the reservoir.
The active substance or substances may be present in the reservoir at a concentration below the saturation concen-tration or at a concentration exceeding the saturation concentration.
The reservoir itself may consist of several layers of different composition.
In principle, the same materials as described for common systems can be used for all components of such a system.
These materials are known to the man skilled in the art.
The backing layer may consist of flexible or inflexible material, and may be constructed single or multi-layered.
Substances suitable for its production are polymeric sub-stances, such as, e.g., polyethylene, polypropylene, poly-ethylene terephthalate, polyurethane, or polyamide. As further materials metal foils, e.g., an aluminum foil alone or coated with a polymeric substrate may be used.
Textile fabrics may be used, too, if the components of the reservoir cannot leave the reservoir via the gas phase due to their physical properties.
In principle, the same materials may be used for the remov-able protective foil, however, they must additionally be rendered dehesive.
This dehesive preparation can be achieved by a special siliconization.
The reservoir or the layers of the reservoir, respective-ly, consist of a polymeric matrix and the active substance or substances, whereby the polymeric matrix exhibits such a self-adhesiveness that the coherence in case of a multi--layer construction is guaranteed. The polymeric material of the matrix may, e.g., be built up of polymers, such as rubber, rubber-like synthetic homo-, co-, or blockpoly-mers, polyacrylic acid esters and their copolymers, poly-urethanes, copolymers of ethylene and polysiloxanes. In principle, all polymers are suitable which are used in the manufacture of pressure-sensitive adhesives and are physio-logically acceptable. Additives may also be used, their nature depends on the polymer used and the active sub-stance or substances. Depending on their function they can be divided into softeners, tackifiers, resorption agents, stabilizers, or fillers. Substances suitable for this purpose and physiologically acceptable are known to the man skilled in the art.
All physiologically acceptable foil-like materials having the adequate permeability to the active substance or sub-stances or auxiliary agents, respectively, are suitable for the manufacture of the membranes. Membranes on the basis of polyethylene, polyamide, ethylene-vinyl ace-tate-copolymers, and polysiloxanes are particularly suit-able.
In the following, the invention is further illustrated but not limited by the drawings:
igure 1 shows a section through a system provided with a controlling membrane according to the prior art, igure 2 shows an embodiment of a system according to the present invention, igure 3 shows another view of the matrix of figure 2 with a membrane incorporated into the matrix, igure 4 shows different embodiments of the membrane, igure 5a shows a section through an embodiment of the present invention exhibiting a combination of an impermeable membrane with a membrane of higher permeability, igure 5b shows a top view on the embodiment of Figure 5a, igure 6 shows diagrammatically the release behaviour of an embodiment with a membrane incorporated in the reservoir and impermeable to the active substance in the form as shown in Figure 4, whereby the cumulated released amount of active substance is shown as function of time, igure 7 shows the release behaviour of the same system as shown in Figure 6, however, diagram-matically the active substance release rate per system and hour as function of time, Figure 8 shows in a diagram the release behaviour of a system according to the present invention with a membrane of limited permeability to the active substance, whereby the cumula-tive active substance release is plotted versus time, Figure 9 shows diagrammatically the release rate of the same system as shown in Figure 8 per sys-tem and hour as function of time.
The system described in Figure 1 consists of a backing layer (11), the active substance containing reservoir (12), the controlling membrane (13), a pressure-sensitive adhesive layer for securing the system to the skin (14), and a removable protective foil (15).
In some cases the pressure-sensitive adhesive layer (14) has the same formulation as the reservoir (12) so that the membrane is actually incorporated in the reservoir, and thus one can imagine the reservoir being built up of two parts.
If the active substance is present in the reservoir at an oversaturated concentration, a release according to a kinetic O is achieved by the membrane. Order, i.e., a constant release within the application period; and if the active substance is present below this concentration, a release according to a kinetic 1 is achieved.
Order according to equation 3.
Figure 2 shows the general construction of a system accord-ing to the present invention. It consists of a backing layer (21), a reservoir (22), a membrane (23), a self-ad-hesive skin coat (24), and a removable protective foil (25).
Membrane (23) is smaller than the reservoir surface, since the membrane has a central, circular recess.
In Figure 3 a membrane (31) is incorporated in the reser-voir (32) which for this reason is divided into two halves (33 and 34). If the reservoir formulation is self-adhe-sive, the self-adhesive skin coat (24) of Figure 2 can naturally be omitted. Due to the fact that the surface of the membrane is always smaller than the total area of the reservoir, reservoir and skin, or reservoir and pressure-2012~23 -sensitive adhesive layer, or both parts of the reservoir, respectively, are in direct contact with each other on that surface which is not covered by the membrane.
Figure 4 shows some examples of geometric forms of such membranes according to the present invention, in which either the hatched areas or the areas without hatches are membranes.
The embodiments according to the present invention as shown in Figures 3 and 4 are particularly suitable for systems with only one membrane being impermeable to the active substance, e.g., such as is shown in Figure 4.1 and integrated into the reservoir according to Figure 3.
At first, this system behaves like a common matrix system, i.e., the active substance is released over the whole releasing surface according to the so-called root-t-law.
However, as soon as the reservoir member, which is posi-tioned below the membrane area, is emptied so far that the depletion zone has reached the membrane, the behaviour of the reservoir compared to a common matrix system changes drastically. The active substance release decreases rapid-ly on the surface having the same dimension as the membra-ne, while on the partial surface which is not covered by the membrane the release continues undiminishedly accord-~012123 ing to the root-t-law until the depletion zone reaches the backing layer. Thus, the additional initial dosage origi-nates from the area lying below the membrane. By way of changing the absolute area sizes and the relation between membrane surface and total surface of the reservoir, the amount of initial dosage and maintenance dosage can be influenced within wide ranges.
As a matter of fact, such a release behaviour can also be achieved in that the reservoir is given a steplike geo-metry. However, this bears the disadvantage that such a system is more difficult to produce, and that due to the plastic deformability of usual reservoir formulations such a system does not maintain its steplike shape.
Embodiment 4.5 is particularly advantageous, since there are no problems concerning positioning due to the variety of holes within the membrane.
By way of changing the ratio of membrane surface to the total surface, and the choice of membranes of different permeabilities to the active substance, the release be-haviour of the system can be influenced in wide ranges, as is stated below. It is particularly possible administer very high initial dosages.
201~23 Figures 5a and 5b show in sectional view and in top view an embodiment of the present invention which is provided with a combination of tow different membranes.
The combination of a membrane having permeability "O" with a membrane of higher permeability is particularly suit-able. Such a system is shown in Figure 5a. It consists of the impermeable backing layer (51), the reservoir (52), a membrane of permeability O to the active substance or substances (53), a membrane of a higher permeability than O to the active substance or substances (54), and a remov-able protective layer (55).
Both membranes are once more shown in Figure 5b in top view. As a matter of fact, the membrane having permeabil-ity O must be smaller than the total releasing surface of the system, thus limiting the maximum active substance release on that partial area of the total releasing sur-face corresponding to the membrane size, since that por-tion of active substance lying above the membrane cannot pass it.
The membrane having the permeability higher than O effects an active substance release according to a kinetic of order O or 1 on that partial area of the total releasing surface corresponding to its size.
2012:123 _ 17 Both membranes need not necessarily lie in the same plane within the system. Their exact position depends on the individual requirements, and it is an additional means to achieve the desired release behaviour.
If the membrane having permeability O lies closer to the releasing surface, the other membrane may be as large as the total releasing surface without changing the release behaviour, since said membrane is of no effect, if it lies above the impermeable membrane.
Figures 6 and 7 show the release behaviour of those systems having a membrane which is impermeable to the active substance, as example a scopolamine plaster is chosen. The following indications apply to all samples described in the following: the active substance content amounts to 450 ,ug/cm2 and the weight per unit area of the self-adhesive reservoir amounts to 12.5 mg/cm2.
Figure 6 shows the cumulated released amount of scopol-amine as function of time.
Curve I corresponds to a normal system of 2 cm2 size with-out membrane, and serves as comparison.
Curve II corresponds to a system of a total size of 3 cm2;
~012~23 _ 18 an impermeable membrane is incorporated into the reser-voir. The membrane has an area of 1 cm2 and divides the reservoir into one layer having an area weight of 10.4 mg/cm2 and one having an area weight of 2.1 mg/cm2.
Curve III corresponds to a system of a total area of 4 cm2 and a membrane surface of 2 cm2.
It can clearly be recognized that on the whole the active substance release of the systems provided with membrane is higher. However, in Figure 7 it can be recognized more clearly that this increased active substance release only applies to the initial phase of release. Figure 7 shows the release rate per system and hour as function of time, i.e., the flux is indicated.
Thus, this system is particularly useful, if relatively high initial dosages shall be combined with a maintenance dosage which is not necessarily constant.
Figures 8 and 9 show an embodiment according to the pres-ent invention having a membrane of limited permeability to the active substance; as example a scopolamine plaster was used under the same conditions as described for Figures 6 and 7.
_. 19 The cumulative release is shown in Figure 8, the flux is shown in Figure 9. Curve I or flux I, respectively, corres-ponds to a system of 2 cm2 having a membrane of the same size (comparison), curve II or flux II, respectively, correspond to a system of 2.5 cm2 having a membrane of 2 cm2, and curve III or flux III, respectively, correspond to a system of 3 cm2 size having a membrane of 2 cm2.
Even the system according to curve I and flux I is able to release a certain initial dosage. This initial dosage corresponds to a release according to the root-t-law ac-cording to equation 1 and 2, which takes place until the depletion zone of the active substance has reached the membrane.
The other two systems provided with membrane, which are of smaller dimension than the releasing surface of the system the initial dosage can be increased very easily. In this case, the intitial dosage is followed by a constant main-tenance dosage the amount of which depends on the permeability and the surface of the membrane.
Production of the systems according to the present invention used in Figures 6 to 9 (samples) _ 20 230 g polyacrylate resin adhesive (50 % in acetic ester) 6 g scopolamine base 10 g Cetiol S
50 g methanol were mixed and the mixture homogenized.
A siliconized polyester foil of 100 ~ thickness was coated with this mixture as films of 400 ~ (film I) and 100 ~
(film II), the films were dried at 50C for 15 minutes.
After drying, film I had a weight per unit area of 103 g/mZ and film II one of 21 g/m2.
The membrane having circular recesses of adequate size was laminated on film II, and film I in turn was laminated thereon. The siliconized polyester foil of film I was removed and substituted for an unsiliconized foil of 15 thickness.
The individual samples were punched in such a way that the adequate total area resulted and the recess became posi-tioned centrally.
Performance of the in vitro-release - 2012~3 The release was carried out at 32C according to the paddle-over-disk-method using 50 ml physiological saline.
In order to determine the samples the total release medium was changed completely and the content determined accord-ing to a HPLC-method.
Claims (10)
1. A transdermal system for the controlled, graduated administration of an active substance to the skin, for the release of a high initial dosage and a lower maintenance dosage which consists of a backing layer averted from the skin and impermeable to the active substance, an active substance reservoir adjacent to said backing layer the reservoir having a releasing surface, the reservoir integrating at least one membrane located parallel to the releasing surface, said membrane being less permeable to the active substance than the reservoir and having a surface area smaller than said releasing surface, adjacent to the skin, a pressure-sensitive adhesive for securing the system to the skin, and a removable protective layer optionally covering the surface of the system facing the skin.
2. The transdermal system according to claim 1, wherein the membrane is either incorporated into the reservoir or adjoins the reservoir at the skin side.
3. The transdermal system according to claim 1 or 2, wherein the membrane is impermeable to the active substance.
4. The transdermal system according to claim 1 or 2, wherein the membrane is of limited permeability to the active substance.
5. The transdermal system according to claim 1, having at least 2 membranes exhibiting different permeabilities to the active substance, wherein at least one of said membranes has a surface which is smaller than the releasing surface of the system.
6. The transdermal system according to claim 5, wherein the membrane is smaller than the releasing surface of the system, is impermeable to the active substance and is incorporated into the reservoir.
7. The transdermal system according to any one of the claims 1, 2, 5 or 6, wherein the reservoir comprises the active substance at a concentration below the saturation concentration.
8. The transdermal system according to any one of claims 1, 2, 5 or 6, wherein the reservoir comprises the active substance at a concentration exceeding the saturation concentration.
9. The transdermal system according to any one of claims 1, 2, 5 or 6, wherein the reservoir is at least two layers of active substance of different composition.
10. A use of a transdermal system as defined in any one of claims 1, 2, 5 or 6 for the local and systemic dermal administration of an active substance in human or veterinary medicine, or in cosmetics.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3908431A DE3908431A1 (en) | 1989-03-15 | 1989-03-15 | TRANSDERMAL SYSTEM WITH STAGE SUBSTANCE DELIVERY AND USE FOR LOCAL OR SYSTEMIC DISPENSER |
| DEP3908431.0-45 | 1989-03-15 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2012123A1 CA2012123A1 (en) | 1990-09-15 |
| CA2012123C true CA2012123C (en) | 1997-05-20 |
Family
ID=6376396
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002012123A Expired - Fee Related CA2012123C (en) | 1989-03-15 | 1990-03-14 | Transdermal system exhibiting graduated drug release and its use for the local or systemic administration of active substances |
Country Status (26)
| Country | Link |
|---|---|
| EP (1) | EP0387693B1 (en) |
| JP (1) | JPH0693921B2 (en) |
| KR (1) | KR960005148B1 (en) |
| AT (1) | ATE143276T1 (en) |
| AU (1) | AU625402B2 (en) |
| CA (1) | CA2012123C (en) |
| CZ (1) | CZ284770B6 (en) |
| DD (1) | DD292383A5 (en) |
| DE (2) | DE3908431A1 (en) |
| DK (1) | DK0387693T3 (en) |
| ES (1) | ES2095216T3 (en) |
| FI (1) | FI901290A7 (en) |
| GR (1) | GR3022033T3 (en) |
| HR (1) | HRP930662A2 (en) |
| HU (1) | HU206991B (en) |
| IL (1) | IL93678A (en) |
| MY (1) | MY107420A (en) |
| NO (1) | NO300087B1 (en) |
| NZ (1) | NZ232895A (en) |
| PH (1) | PH26276A (en) |
| PL (1) | PL162693B1 (en) |
| PT (1) | PT93430B (en) |
| SI (1) | SI9010493B (en) |
| SK (1) | SK279357B6 (en) |
| YU (1) | YU48228B (en) |
| ZA (1) | ZA901941B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9428719B2 (en) | 2011-08-15 | 2016-08-30 | The Procter & Gamble Company | Personal care articles having multiple zones with compliant personal care compositions |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4341444C2 (en) * | 1993-12-04 | 1996-03-14 | Lohmann Therapie Syst Lts | Active substance-containing plaster and process for its production |
| US5714162A (en) * | 1994-09-16 | 1998-02-03 | Lts Lohmann Therapie-Systeme Gmbh & Co. Kg | Scopolamine patch |
| DE4438989C2 (en) * | 1994-09-16 | 1999-02-25 | Lohmann Therapie Syst Lts | Scopolamine patches |
| DE19705138A1 (en) * | 1997-02-11 | 1998-08-13 | Lohmann Therapie Syst Lts | Stretchy transdermal therapeutic system |
| DE19733981A1 (en) * | 1997-08-06 | 1999-02-11 | Lohmann Therapie Syst Lts | Transdermal therapeutic system (TTS) for the delivery of active ingredient through the skin to an organism and method for application to the skin |
| DE19738643C2 (en) * | 1997-09-04 | 2001-10-04 | Lohmann Therapie Syst Lts | Transdermal therapeutic system with the active ingredient scopolamine base and process for its preparation |
| DE10056012A1 (en) * | 2000-11-11 | 2002-05-16 | Beiersdorf Ag | Carrier material for medical applications, preferably for transdermal therapeutic system, has aluminum film between carrier and self-adhesive coating |
| DE10056014A1 (en) * | 2000-11-11 | 2002-05-16 | Beiersdorf Ag | Laminated plaster with active substance, used as transdermal therapeutic system, has impermeable barrier layer on side away from skin and separable carrier layer with adhesive on side towards skin |
| DE102004020463A1 (en) * | 2004-04-26 | 2005-11-10 | Grünenthal GmbH | Drug delivery system consisting of a drug-containing patch and at least one Wirkstoffabgaberegulierungsmittel |
| WO2012138685A1 (en) | 2011-04-04 | 2012-10-11 | The Procter & Gamble Company | Personal care article |
| CN104202987B (en) | 2011-08-15 | 2017-09-01 | 宝洁公司 | Personal nursing method |
| US9554978B2 (en) | 2013-06-27 | 2017-01-31 | The Procter & Gamble Company | Personal care articles |
| DE102018216244A1 (en) | 2018-09-24 | 2020-03-26 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system with barrier layer |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5755157A (en) * | 1980-09-19 | 1982-04-01 | Nitto Electric Ind Co | Drug member having transcataneous absorbing property |
| IE53703B1 (en) * | 1982-12-13 | 1989-01-18 | Elan Corp Plc | Drug delivery device |
| US4698062A (en) * | 1985-10-30 | 1987-10-06 | Alza Corporation | Medical device for pulsatile transdermal delivery of biologically active agents |
| US4666441A (en) * | 1985-12-17 | 1987-05-19 | Ciba-Geigy Corporation | Multicompartmentalized transdermal patches |
| DE3634016A1 (en) * | 1986-04-17 | 1987-10-29 | Lohmann Gmbh & Co Kg | AREA-BASED THERAPEUTIC SYSTEM, METHOD FOR THE PRODUCTION THEREOF AND ITS USE |
| EP0249343B1 (en) * | 1986-06-13 | 1992-01-08 | Alza Corporation | Moisture activation of transdermal drug delivery system |
| US4781924A (en) * | 1987-11-09 | 1988-11-01 | Alza Corporation | Transdermal drug delivery device |
-
1989
- 1989-03-15 DE DE3908431A patent/DE3908431A1/en active Granted
-
1990
- 1990-03-07 PH PH40155A patent/PH26276A/en unknown
- 1990-03-07 MY MYPI90000358A patent/MY107420A/en unknown
- 1990-03-07 AU AU50765/90A patent/AU625402B2/en not_active Ceased
- 1990-03-08 AT AT90104406T patent/ATE143276T1/en not_active IP Right Cessation
- 1990-03-08 CZ CS901136A patent/CZ284770B6/en unknown
- 1990-03-08 IL IL9367890A patent/IL93678A/en not_active IP Right Cessation
- 1990-03-08 ES ES90104406T patent/ES2095216T3/en not_active Expired - Lifetime
- 1990-03-08 DE DE59010514T patent/DE59010514D1/en not_active Expired - Fee Related
- 1990-03-08 DK DK90104406.5T patent/DK0387693T3/en active
- 1990-03-08 SK SK1136-90A patent/SK279357B6/en unknown
- 1990-03-08 EP EP90104406A patent/EP0387693B1/en not_active Expired - Lifetime
- 1990-03-09 NO NO901128A patent/NO300087B1/en not_active IP Right Cessation
- 1990-03-12 JP JP2058241A patent/JPH0693921B2/en not_active Expired - Fee Related
- 1990-03-13 NZ NZ232895A patent/NZ232895A/en unknown
- 1990-03-13 HU HU901422A patent/HU206991B/en not_active IP Right Cessation
- 1990-03-13 DD DD90338650A patent/DD292383A5/en unknown
- 1990-03-14 SI SI9010493A patent/SI9010493B/en unknown
- 1990-03-14 PT PT93430A patent/PT93430B/en not_active IP Right Cessation
- 1990-03-14 CA CA002012123A patent/CA2012123C/en not_active Expired - Fee Related
- 1990-03-14 YU YU49390A patent/YU48228B/en unknown
- 1990-03-14 ZA ZA901941A patent/ZA901941B/en unknown
- 1990-03-14 PL PL28430190A patent/PL162693B1/en unknown
- 1990-03-14 KR KR1019900003563A patent/KR960005148B1/en not_active Expired - Fee Related
- 1990-03-15 FI FI901290A patent/FI901290A7/en not_active Application Discontinuation
-
1993
- 1993-04-01 HR HR930662A patent/HRP930662A2/en not_active Application Discontinuation
-
1996
- 1996-12-13 GR GR960403458T patent/GR3022033T3/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9428719B2 (en) | 2011-08-15 | 2016-08-30 | The Procter & Gamble Company | Personal care articles having multiple zones with compliant personal care compositions |
| US9540602B2 (en) | 2011-08-15 | 2017-01-10 | The Procter & Gamble Company | Conformable personal care articles |
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