DOSAGE OF TRANSDERMAL DELIVERY SYSTEMS

Abstract: The invention relates to a process for the individual dosage and discharge of matrix-controlled transdermal delivery systems as well as devices and delivery systems that are suitable for such a process.

Description: Dosage of transdermal delivery systems The invention relates to a process for the individual dosage and discharge of matrix- controlled transdermal delivery systems (also referred to hereinafter as matrix systems) as well as devices and drug systems, which are suitable for such a process. Non-invasive applications of substance preparations, which are suitable for the penetration of a permeability barrier, such as the skin, are of advantage with many courses of therapy. Transdermal delivery systems have been in use for this purpose for about twenty years . The epidermis constitutes a natural barrier against penetrating substances. Consequently, for transdermal applications, consideration is given to substances small quantities of which suffice for obtaining therapeutic effects; where transport is possible through the skin so that an adequate amount reaches the blood circulation (good water and lipid solubility); where long-term therapy is planned and skin tolerability is good or combination with enhancer substances which allow high amounts of substances to penetrate or with the help of concentration gradients which increase diffusion properties. Transdermal drug systems, also known as transdermal therapeutic systems (TTS), generally incorporate patches which vary in padding type, form and size, which are adhered to areas of the skin and remain there, for up to several days. The active substance is stored in the patch and is discharged therefrom into the skin. For the deli- very of the substance, it is necessary that the patch be in direct contact with the skin. The best known active substance in TTS is glycerol trinitrate (GTN), which is used to treat coronary cardiac disease. When orally administered and because of its early breakdown due to its pronounced "first pass" effect, it only reaches the targeted organ to a minor degree. The second most common therapy target focuses on people giving up smoking and includes several nicotine TTS with which a constant nicotine plasma level is achieved. Also on the market are TTS that continuously discharge synthetic opiates for the treatment of chronic pain. Here too a constant plasma level is achieved that lasts for several days. The delivery of the drug substance takes place under controlled permeation conditions from a reservoir through a membrane or by diffusion from a matrix. This is why the TTS patches are also known as medicaments with a controlled substance delivery and have been broken down into two main groups: reservoir systems (membrane-controlled TTS) and matrix-controlled TTS. With reservoir systems, the patch comprises, from the outside inwards, e.g. colored or a skin-colored, impermeable covering sheet (support carrier coating), a semi-solid substance suspension in silicon oil or polyisobutylene (reservoir), a control polymer membrane, an adhesive layer (adhesive coating) with or without the initial dose, and strip-off sheeting. The delivery of the substance is continuous and is controlled by the membrane that has a specific permeability for the substance in question. The disadvantage of the reservoir system is that if the membrane is damaged, the entire dose can be discharged at once (precipitated discharge). Matrix-controlled TTS contain a homogenous dispersion of solid and/or dissolved substance particles in a lipophilic or hydrophilic polymer matrix mainly made up of acryl resin as a drug reservoir. Delivery is controlled by the polymer matrix and/or the adhesive layer. Many matrix patches can be cut up, for example with a pair of scissors. Matrix systems do not discharge the active substance in a steady state. Precipitated discharge of the entire dose, as with membrane systems, is not possible, for which reason these matrix-controlled TTS are considered safer for highly potent pharmaceutical substances (more tamper resistant). In modern matrix patches, control mechanisms have been developed to assure a practically constant delivery of the pharmaceutical substance. With depot-effect patches in the form of a mono-layered matrix, the substance is bound in a hydrophilic polymer matrix that contains water, in particular a gel system. In this case, delivery depends on a defined swelling performance of the matrix. With systems in the form of a multi-layered matrix (for example formed by multi-layered laminas) the pharmaceutical substance is fixed depot-like to a carrier, such as lactose, and embedded, partially dissolved, in a self-adhesive resin compound. With micro-reservoir systems, the silicon elastomer matrix contains many substance-bearing micro- compartments, of the order of 10 to 200 μm in size. The substance is delivered from these microparticles by controlled dissolution. Compared to conventional pharmaceutical forms, a TTS has the following advantages: 1) Avoids initially passing through the liver (averts a "first pass" effect). 2) Level of active substance is largely constant and hence no underdose or overdose of substances with a narrow therapeutic spectrum of required effect. 3) Improvement of application compliance because the effect lasts several days to weeks and there are fewer side-effects. 4) With incompatibility reactions or when no longer required, the action can be interrupted by removal of the patch. (Cave: the subcutaneous reservoir) 5) No gastro-intestinal incompatibility reactions. With the matrix systems, the substance is applied either directly on the underside of the patch and diffused over the entire surface into the system, or is mixed with the adhesive agent, i.e. with an adhesive, and diffused from this adhesive agent into the biological system. Whereas with a reservoir system, the overall dose of substance is specified by the appropriately defined volume of the reservoir, with matrix systems, the quantity of the diffused substance can be determined by the size of the applied matrix, i.e. patch. With an even layering of the patch, the dose of the active substance is proportional to the area of the patch. Conventional transdermal patches are usually packed singly in sealed bags. The user instruction particularly relates to the dose of the substance or substances and to the dose, which is to be delivered within a certain period of time. The conventional TTS detail a defined size and hence an appropriate strength of action. With transdermal systems, which in the broadest sense have a matrix formulation, the dose is thus equivalent to the given size, for example in cm 2 , of the patch. The patch is usually coated in whole and apportioned into sections with a suitable cutting tool, and is then packaged. Consequently different package sizes provide different strengths of action. A disadvantage is that the transdermal delivery systems available on the market give specified dosages which always provide only approximations to the individual requirements - a fact which is true, for example, for tablets, suppositories and other oral application forms as well. It is not infrequent for dosage steps to be at intervals of 50 to 100%. It would hence be desirable if the substance or substances of transdermal delivery systems could be individually and precisely adjusted to each specific dose for the respective therapeutic purpose, such as is possible for example, with injectable agents and orally liquid forms that are phased over in their application or specified in numbers of drops. This invention is thus directed at enabling dosage and application in transdermal delivery systems as individually adjusted to each patient. This invention is further directed at providing devices which in the interest of guaranteeing swift and low-cost health care, enable such dosage and application to be effected where required, such as in hospitals. Other objects of this invention are notable from the following description. The features defined in the separate claims serve to attain these objects. Advantageous embodiments are described in the sub-claims. The invention attains the objects of the present invention by providing a portable or stationary device for the individual dosage and dispensing of matrix-controlled transdermal delivery systems, which comprises a matrix system of specified width provided with at least one pharmaceutically active agent, a carriage means for the matrix system and a separating device for the matrix system. A pertinent feature of the current invention relates to a unit i.e. a module that specifies the dosage of the substance and serves to convert a required dosage into an appropriate length of the matrix system that is to be dispensed. Hence said unit appliance enables an individual dosage of the substance to be administered by means of separating a length of the matrix system corresponding to the desired dosage, using the separating device. In a preferred form, the unit for specifying the substance dosage enables continuous selection of the required dosage within the adjustment range of the device as constituted by the invention. Another particular feature of the device in accordance with the invention is that it is portable. In the context of the present invention, portable means that the device can, for example, be operated as a hand-held device, or can be set up on an ordinary table. Hence the device of the invention can be used where it is required, for example in hospitals, pharmacies, doctors' offices and such like for the dosage and discharge of matrix-controlled transdermal delivery systems. The device in accordance with the invention proves to be highly advantageous, since it enables individually adjusted dosages outside the fixed specified regular dose of a prefabricated transdermal patch, such as regularly available on the market, to be applied to the patient. The invention's carriage means required for the matrix system and the separating device for the matrix system may conform with the means normally used for such purposes and are known per se to the skilled person. The carriage means for the matrix system is preferably a rotatable reel. The separating device for the matrix system is preferably a cutting device or a rip-off appliance. Preferably the matrix system is a patch evenly coated with active substance, with the active substance or substances directly places on the underside of the patch. The side of the matrix system coated with active substance is protected until application, for example by a pull-off sheeting that serves the same purpose as in conventional patches. Furthermore, the matrix systems can be available in the form of a mono-coated matrix or in the form of a multi-coated matrix. Preferred substances that can penetrate the skin are glycerol trinitrate, nicotine, and opiates and opioids, such as buprenorphine, hydromorphone, fentanyl, isofentanyl, afentanyl, and other substances, which can be formulated in a transdermal system with or without enhancer substances. Specification of the dosage by way of a mechanism equivalent to the dose quantity/patch length proceeds, in the invention's device, by way of a mechanical unit and/or an electronic unit. This unit serves to transpose a given desired dose into a quantitative measurement of the area of the patch to be detached or separated. With a specified width of the matrix system, the area of the TTS to be separated is determined by the length thereof. For this purpose, the unit for the specification of the dosage causes the advance of a length of material equivalent to the required substance quantity, which is then separated by the separating device of the invention. The advancing of the required length is preferably caused automatically by the electronic unit, however it can alternatively also be carried out manually, for example, by pulling the matrix system out, to the length required, up to the separating point. Preferably the device constituted by the invention comprises an electronic unit for dosage specification, enabling a particular dosage to be fixed by entering the requirement by means of a keyboard similar to that of a calculator, whereupon the advancement of appropriate amount of the matrix system is electronically actuated and the transdermal delivery patch is appropriately divided into sections. The amount of the matrix system thus advanced is then detached preferably cut off by the separating device of the invention. Alternatively, the inventive device incorporates a mechanical unit for specification of the dosage, which transposes the required dosage into an appropriate length of the matrix system over two wheels that are connected to each other. The one wheel is turned until the required dosage is set and the appropriate length of the matrix system to be detached is indicated on the second wheel. Since drug products subject to the Narcotics Act, such as the aforementioned opiates and opioids, are also applied by transdermal route, another embodiment of the inventive device effects additional protection from drug misuse under the Narcotics Act. The device additionally incorporates a mechanism, which can prevent the appliance being operated. Such a blocking mechanism can be activated or deactiva- ted by an individual user code such as a number code, a chip or magnet strip, fingerprint retina check and others. Preferably the device additionally incorporates a printing unit to produce a delivery slip on which the quantity of substance from the matrix system delivered, the time of delivery, such as date and hour, as well as the prescribing physician of the substance and the user of the device, identified, for example, by the user code, are recorded. With the above-mentioned printing unit, the documentation required under the Narcotics Act can be provided, the respective delivery slips detailing minimum details as required in one or several copies. Coding can be effected over a combination of keys, if the particular dose specification is entered over a keyboard, but it can also be effected by user voice coding or by a chip card or magnet strip reader, fingerprint retina check and others. Finally the inventive device can incorporate, in addition to or integrated with the electronic unit, a calculation system for the amount of substance delivered over a specific period of time. The calculating system can serve to keep the entire amount of substance consumed on store and make this available on appropriate data carriers for hospital pharmacies or the Federal Narcotics Registration Authority. In another preferred embodiment, the device of the invention is so designed that throughout the entire dosage process, including the pre-use storage of the matrix system, the advancement of the matrix system length to be detached and (in case) the packaging of the matrix system length ultimately detached, the system is kept under sterile conditions. The device constituted by the invention is suitable for use in pharmacies or hospitals, as well as for the requirements of a practitioner. Another major aspect of the present invention relates to a process for the dosage and dispensing of matrix-controlled transdermal delivery systems, in case under sterile conditions, and incorporates the following steps: application of a matrix system of a specified width and coated with at least one active agent on a carriage means, preferably a reel; - specification of a required dose; transposition of the required dose into a corresponding length of the matrix system; - separation of a length of the matrix system corresponding to the dose required; in case, packaging of the separated matrix system length; in case, production of a delivery slip e.g. for the amount of active agent comprised by the dispensed matrix system length, the time of delivery, and the user and in case, calculation of the amount of active agent dispensed over a specified period of time. The conversion of the required dose into an appropriate length of the matrix system can be effected mechanically by the process of the invention. Preferably, however, the conversion of the required dosage is effected electronically. With the process of the invention, a locking mechanism may, in case, have to be deactivated prior to using the device, by entering an individual user code. Furthermore, the present invention provides matrix-controlled transdermal delivery systems, which are suitable for use in the above-described portable device for individual dosage and dispensing. The drug systems of the invention are marked for separation at intervals of length corresponding to a certain dose unit. By selecting the number of dose units, the substance amount can be precisely adjusted to the requirements of the individual patient. In order to effect adjustments as individual as possible, the markings are preferably at short intervals. The marking is, for example, an imprint on the drug system or a perforation, so that the drug delivery system can be separated at the required length. With electronically relayed dosage and discharge of the drug delivery system, the marking is preferably readable by the above- mentioned inventive device, so that the matrix system is detached automatically at the marking. Example: A patch roll (matrix patch) of a width of 7 cm and a length of 70 cm is inserted into a table top device for the individual dosage and dispensing of matrix-controlled transdermal delivery systems. The matrix system is evenly coated with the substance Buprenorphine. In each 1 cm length of a matrix patch of a width of 7 cm, a discharge rate of 10 μg/h Buprenorphine is provided. Integral multiples of 1 cm length thus correspond to discrete steps of 10 μg/h, whereas decimal multiples correspond to steps of 1 μg/h. Any required dosage is set by operating the keys on a keyboard. An electronic unit automatically advances the matrix patch to a length corresponding to the required dosage. The matrix patch is then separated into portions by cutting off the amount of the matrix patch thus advanced. A dispensed length of 7 cm, at a width of 7 cm, corresponds to a Buprenorphine patch ordinarily obtainable on the market with a discharge rate of 70 μg/h.

Claims: Claims 1. Portable or stationary device for individual dosage and dispensing of matrix- controlled transdermal delivery systems (matrix systems) incorporating a matrix system of a specified width and coated with at least one active agent, a carriage means for the matrix system, a separating device for the matrix system and a unit to specify the substance dose, which transposes a required dose into an appropriate length of the matrix system to be dispensed. I 2. Device according to Claim 1 characterized in that the unit for specification of the substance dosage is operable to continuously set the dosage required, within a given setting range. 3. Device according to Claim 1 or 2 characterized in that the matrix system is a patch coated evenly with active agent. 4. Device according to Claim 3 characterized in that the active agent is directly applied to the underside of the patch. 5. Device according to Claim 3 characterized in that the active agent is combined with the adhesive composition of the patch. 6. Device according to one of the previous Claims characterized in that the matrix system is provided in the form of a mono-layered matrix. 7. Device according to one of the Claims 1 to 5 characterized in that the matrix system is provided in the form of a multi-layered matrix. 8. Device according to one of the previous Claims characterized in that the active agent is selected from glycerol trinitrate, nicotine, opiates and opioids and others which can be formulated in a transdermal system with or without enhancer substances. 9. Device according to one of the previous Claims characterized in that it incorporates a mechanical unit for dosage setting. 10. Device according to one of the Claims 1 to 8 characterized in that it incorporates an electronic unit for dosage setting. 11. Device according to one of the previous Claims characterized in that it additionally incorporates a locking mechanism for preventing operation of the device. 12. Device according to Claim 11 characterized in that the locking mechanism can be activated or deactivated by an individual user code. 13. Device according to one of the above Claims characterized in that it additionally incorporates a printing unit for the production of a delivery slip. 14. Device according to one of the previous Claims characterized in that it additionally incorporates a unit for calculating the amount of substance dispensed over a specified period of time 15. Device according to one of the previous Claims characterized in that throughout the entire dosage process, including the storage of the matrix system, the preliminary advancement of the matrix system material length that is to be separated, and (in case) the packaging of the separated length of matrix system, the matrix system is kept under sterile conditions. 16. Process for the dosage and discharge of matrix controlled transdermal delivery systems (matrix systems), in case under sterile conditions, that incorporates the following steps: - application of a matrix system of a specified width and coated with at least one active agent on a carriage means, preferably a reel; specification of a required dose; - transposition of the required dose into a corresponding length of the matrix system; separation of a length of the matrix system corresponding to the dose required; in case, packaging of the separated matrix system length; in case, production of a delivery slip e.g. for the amount of active agent dispensed from the matrix system, the time of delivery, and the user and in case, calculation of the amount of active agent dispensed over a specified period of time. 17. Process according to Claim 16 characterized in that the matrix system is a patch evenly coated with active agent. 18. Process according to Claim 17 characterized in that the active agent is applied directly to the underside of the patch. 19. Process according to Claim 17 characterized in that the active agent is combined with the adhesive composition of the patch. 20. Process according to one of the Claims 16 to 19 characterized in that the transposition of the required dose into the appropriate length of the matrix system is effected mechanically. 21. Process according to one of the Claims 16 to 19 characterized in that the transposition of the required dose into an appropriate length of the matrix system is effected electronically. 22. Process according to one of the Claims 16 to 21 characterized in that prior to dosage specification, a locking mechanism is deactivated by an individual user code. 23. Use of a device according to one of the Claims 1 to 15 for the individual dosage of matrix-controlled transdermal delivery systems. 24. Matrix-controlled transdermal delivery system for use in a portable or stationary device for the individual dosage and delivery as described in one of the Claims 1 to 15 with markings provided at intervals of length which correspond to particular dose units. 25. Delivery system according to Claim 24 characterized in that the marking is an imprint or a perforation. 26. Delivery system according to Claim 24 or 25 characterized in that the marking can be read by the device constituted by one of the Claims 1 to 15. 27. Delivery system according to one of the Claims 24 to 26 characterized in that the matrix system is a patch evenly coated with active agent. 28. Delivery system according to Claim 27 characterized in that the active agent is applied directly on the underside of the patch. 29. Delivery system according to Claim 27 characterized in that the active agent is combined with the adhesive composition of the patch. 30. Delivery system according to one of the Claims 24 to 29 characterized in that the matrix system is provided in the form of a mono-layered matrix. 31. Delivery system according to one of the Claims 24 to 29 characterized in that the matrix system is provided in the form of a multi-layered matrix. 32. Delivery system according to one of the Claims 24 to 31 characterized in that the active agent is selected from glycerol trinitrate, nicotine, opiates and opioids and others, which can be formulated in a transdermal system with or without enhancer substances.

Inventors: FLEISCHER WOLFGANG, FLEISCHER, WOLFGANG
Applicants: EURO CELTIQUE SA, FLEISCHER WOLFGANG, EUROCELTIQUE S.A., FLEISCHER, WOLFGANG
Application year: 2001
Main classification: A61K9
IPC codes: A61K9, A61K31, A61K45, A61M37, A61P9, A61P25