MXPA99004893A - Method for the low-waste manufacture of diskoid moulded bodies containing active ingredients, and transdermal therapeutic systems containing same - Google Patents

Abstract

The invention relates to laminate bodies or disks containing active ingredients, which are especially suitable as active ingredient reservoirs for transdermal therapeutic systems and are obtained on the basis of an oblong moulded shape whose outer surface area corresponds to the contours of the laminate bodies to be manufactured and whose cross-sectional structure corresponds to the structure of the laminate bodies, by slicing off sections at right angle to the lengthways direction of the oblong moulded body. In the simplest case, the moulded body consists of a homogeneous mass of active ingredient and has the form of a full cylinder, which is sliced perpendicular to its axis at equal intervals in such a way as to obtain identical, round, single-compartment disks. The moulded body may, however, present any other external form and internal structure;notably it may consist of a consolidated bundle of strands containing different active ingredients or active ingredient concentrations, which when divided yield disks having several compartments at one level. The"active ingredients"include not only therapeutic drugs and their precursors and activators but also any type of reagent, additive, test substance, etc.

Description

PROCEDURE FOR MANUFACTURING WITH SOME LOSSES STRATIFIED BODIES IN DISC FORM CONTAINING ACTIVE SUBSTANCES AND TRANSDERMAL THERAPEUTIC SYSTEMS CONTAINING THOSE DISTRIBUTORS DESCRIPTION OF THE INVENTION The invention relates to a method for producing flat bodies or sheets containing active substances, of uniform or partially different composition within the layer as well as to transdermal therapeutic systems using the laminated bodies produced according to the invention. Laminates or layered bodies containing active substances can be used in the most diverse fields and for various purposes, although it is especially interesting to use such sheet-shaped bodies as reservoirs of active substances in transdermal therapeutic systems (TTS). It should be understood by systems containing active substances those that come into contact with the surface of the skin or mucosa of people or mammals for a certain period of time.

REF .: 30027 The TTS can be equipped in a self-adhesive way in all or in part of its surface or can acquire autoadive character in the conditions that exist in the place of the application. The TTS serve to deliver to the adjacent organism one or more active substances in an amount that over time is determined either by the release of the TTS or by the capacity of absorption of the organism in the place of application. This release of active substance into the body can be kept limited to a local area or can also lead to its distribution throughout the body. The individual bodies in the form of a sheet can also be applied in the field of the diagnostics of application to the, for example for test systems or series of immunological tests. Systems for the transdermal determination of the concentration of certain substances in body fluids, such as blood glucose, can also be considered. According to the current level of technology, TTS are usually manufactured with flat structures. The manufacture of these flat structures is mainly carried out by cutting out the individual individual forms of the medicament starting from a flat material in the form of a band, on which a pharmaceutical preparation containing the active substance has previously been applied, and which can generally flow thanks to the addition of solvent or an increase in temperature, or a stratified body containing the active substance is applied. This individualization by die cutting or cutting is often linked to large quantities of wasted material, on the one hand for technical needs and on the other hand for the more or less suitable geometry of the individual form. The typical structure of a TTS further comprises various active or activating components in a multi-layer system in the form of an arrangement of individual components by layers, stacked together in a single direction of space. Different layers do not have to present the same shape or extension, but p.e. they can overlap each other. Generally, only one or a maximum of two layers that are in direct contact with the application site are obtained in this way, while for all others the connection is only mediated. The active substance may be contained in one or more of the TTS layers. The amount of the active substance that can be delivered may be limited by the circumstances by the usual procedures according to the current level of the art. The continuous processes with application of mass layers containing the active substance and containing solvents on web-like support materials therefore require a drying operation, while the application of the solvent-free masses using the process hot melt needs the corresponding cooling. In batch processes, the active substance or its appropriate preparation is dosed in a cyclic manner to the properly prepared TTS. The admission of the active substance is carried out in this case in suitable cavities or by using support materials which have absorption capacity. The object of the invention is therefore a process by means of which improvements can be achieved or the possibilities in the structure and manufacture of the TTS can be extended in three problematic aspects. This process consists of a new form of production of laminated bodies containing active substances and is essentially characterized in that a body of elongated shape with a wrapping surface corresponding to the contour of the laminated bodies which is attached to the sheet axis separates in the transverse direction. try to produce and with a composition of the section that corresponds to the composition of the stratified bodies, unitary or variable by zones. Other features of the invention can be deduced from the claims of the patent and from the description that follows. The process object of the invention offers the following possibilities: 1. With it the part of the substances and starting materials necessary for the preparation of the TTS with a very high yield can be incorporated into the finished products. This is especially desirable when dealing with very expensive active substances or those whose disposal of waste requires very high safety requirements or a high cost. 2. By means of the new method, large quantities of active substance can easily be introduced into a TTS since the mass containing the active substance can be produced and incorporated in the form of a semi-solid or solid body, in sheet form. The thickness of layers that this body can have is almost unlimited in terms of the process technique, unlike stratified bodies containing active substances that are prepared by a coating process. The stratified bodies prepared by this new system can also be transformed into vinas conditions of stability of form. Therefore, it is not necessary to wait for a distribution or absorption time co or in the case of incorporating the dosage of liquid preparations of active substances, or this does not suppose a factor that limits the amount that can be dosed »3. The procedure object of the invention offers especially great advantages or extensions of the technical possibilities when it comes to the preparation of special systems of multiple compartments: In this case it is understood by compartment a defined space having a unitary physical-chemical composition, and which can act especially in a TTS as a distribution camera. A compartment comprises the totality of all the volume elements of a TTS that are homogeneous with each other and have the same structure with each other. In a multilayer TTS according to the current level of technique, the different layers can also represent different compartments.

According to the invention, special multi-compartment systems can now be prepared in order to accommodate several compartments side by side in the same plane of the TTS, e.g. to simultaneously place several compartments in immediate contact with the application site without it being necessary to fear that there is some influence or mutual disturbance of the different active substances, and where the release or penetration velocity can be adjusted individually. Until now, when it was a question of simultaneously administering several active substances in the same place of application, it was always necessary to take into account the possibility that there were incompatibilities of these active substances within the same compartment. On the other hand, the conditions of solubility, release and absorption of different active substances within the same compartment are hardly ever optimal at the same time. In these cases it seems reasonable to house the different active substances in separate compartments. The same active substance can also be housed in different compartments (with different shape or concentration), e.g. to be able to release an initial dose regardless of the maintenance dose.

In advantageous embodiments, it is provided that the shape body section has two or more zones with different active substances and / or different release rates of the active substances and / or different concentration of active substances. The systems of multiple compartments also have special importance in the field of electro-oresis. Here, electrochemical processes are used to increase the rate of release of active substances from a TTS, to accelerate them to control them, to regulate them in some other suitable way. The application site can be a part of the electric current circuit. The systems in question often have a complex internal structure with separate compartments electrochemically, which can now be easily foreseen in the same application plane. The products of the invention can be used for the preparation of medicaments in a flat form as well as flat deposits of active substances of all kinds that must be delivered to the environment, e.g. to water or to the atmosphere. The products can also be used for galvanic thin-film elements, batteries or accumulators »According to the current level of technology, the simultaneous accommodation of several compartments in the same plane of a TTS with structured construction, on the other hand, is difficult and presents limitations , and on the one hand accommodation can be provided in a layer that allows direct contact with the next layer, and on the other hand there can be different layers that overlap each other due to increasing size. In any case this union of several layers of very different size and shape is very difficult according to the current level of the technique and can only be done at a high cost. On the other hand, the process object of the invention allows the preparation of bodies in the form of a sheet which, on its surface, can have a large number of compartments. These compartments are also exactly in a single plane and therefore can easily be brought into direct contact at the same time with a flat application site. Among the various compartments containing the active substance there may be compartments or zones free of active substance, for example for the purpose of an electrochemical or co-or diffusion barrier.

The thickness of the bodies in the sheet is preferably located in the region of 1G-2,000 μm. The laminated bodies or sheets according to the invention containing the active substance are obtained from a longitudinally shaped body with the corresponding content of active substance, separating it into sheets in the direction transverse to its longitudinal axis. By active substance, biologically active substances are not only understood here, or especially drugs, including inactive precursors and activators., but also reorders, inhibitors, permeation accelerators, drying agents, etc. or also substances for testing © systems for testing, reagents, etc. The invention has a very general utility thanks to the simple production of shaped bodies containing optionally active substance, as well as its preparation to obtain a multitude of individual forms that are suitable for the supply or reception of substances or groups of substances. These individual forms will preferably have a sheet form. In the simplest case they can have an outer round to oval contour. * In addition to this, practically any form of imaginable contour can be realized. The sheets may have a continuous surface or have necklines. They can be equal to each other, if they are produced from a longitudinal body of constant section, separating it in a direction perpendicular to the axis or also with a constant inclination with respect to the axis, at uniform intervals. But it is also perfectly possible to use longitudinal bodies of variable section and / or by varying the separation between the cuts and / or the slope with respect to the longitudinal e-beam when effecting the separation, obtaining from a longitudinal body, stratified bodies different from each other. The separation is carried out using suitable procedures such as brushing, cutting, sawing, crushing, splitting, etc. The separation can also be carried out using high energy radiation (for example laser beam) or by particle beams. The shape can be brought to a state in which an optimum separation is achieved according to the chosen separation process, by adjusting the pressure, the temperature and / or the chemical composition in the gas space. it surrounds it. In certain circumstances, the body of form only presents a state of solid or semi-solid aggregation under the conditions of transformation, while at room temperature it passes to the liquid state or passes from the solid to the semi-solid state (or eventually it can only be separated). easily under the conditions in which separation is effected). The shape body will preferably have an outer geometry and an inner structure such and is transformed in a direction in the space such that it allows the almost integral individualization of the sheet-like elements, which together have all the same exterior geometry and the same interior structure. In the case of the manufacture of the TTS, the apparatuses are ideally prepared in such a way that the individual elements in the form of a sheet that are separated can arrive by the shortest possible way on a support material that is fed continuously or discontinuous For the process object of the invention, it is essential to prepare the body in such a way that it contains the active substance as the starting material of the process: In the simplest case, this body has the shape of a solid cylinder and separates in the longitudinal and perpendicular direction to the shaft in individual round discs. This form of execution should only be understood as an example; it is obvious that by varying the proportions of a cylinder the shape body can present practically any geometry on the surface of its section (eg ellipse, polygon, or a contour that can be described by a Bézier function). What keeps it characteristic is the longitudinal shape with a configuration of the section surface that is preferably kept constant along the longitudinal axis. If this body represents only one compartment it can be prepared by melting a suitable mass in a suitable mold and then letting it solidify. Alternatively, the preparation of the shaped bodies can be carried out by pressing individual bulk elements into a suitable mold. Another important procedure is constituted by the extrusion where the surface of the section of the longitudinal product is determined by the shape of the nozzle. Likewise, a shaped body can be obtained by winding a previous product in the form of a band or yarn. In all these processes, special pressure and temperature values may be additionally selected, possibly resulting in variants. Of special interest is the preparation of longitudinally shaped bodies that give rise to stratified bodies with several compartments: For this purpose, several of the single-compartment longitudinal bodies prepared in accordance with the above procedures can be combined in a common beam. thus forming the starting material to divide it into stratified bodies. This union or consolidation can be achieved in a suitable way by gluing or melting or adhering the different bodies to one another, housing them within a melt or by any other form of consolidation that allows such bundles to be joined together. Within the framework of an extrusion process, a series of different masses can be directly brought together simultaneously from several nozzles to form a common beam. If a melting process is used, a suitable multi-chamber mold can be used which also makes it possible to produce a longitudinally multi-compartment body. It is also possible to obtain a bundle of multiple compartments by winding simultaneously or successively different starting materials in the form of a band or yarn. For the manufacture of the longitudinally shaped bodies of one or several compartments, an unlimited number of materials can be used, among them mainly polymers and preparations containing polymers. But they can also contain metals such as aluminum, copper, silver, tin, gold and platinum. The materials or their mixtures may have sticky structure in the final product or they may become sticky upon contact with an application site. An example of a simple process for the preparation of layered bodies or sheets containing the active substance, starting from the shape bodies produced in the manner described above, as well as variants useful for a production of TTS, are described by the attached drawings: The longitudinally-shaped body 1 is inside a suitable hollow body 2 from which it can be ejected by means of a precision feed system 3. This precision feed acts, for example, through a punch that is moved by means of a threaded spindle or by hydraulic force. The dosing precision of the active substance (the thickness of the sheet) depends mainly on the accuracy of this advancement mechanism. The different shaped sheets are separated from the piece of body in a way that comes out by means of a cyclically approaching device 4 carrying a rotary blade 5. The cutting process is eventually facilitated by cooling or heating the body in a way by means of a sleeve 6 (or also of the blade 5). The various shape sheets 7 fall in the shortest way on a support material 8 that is fed. The external geometry of the sheets 7 depends on the external geometry of the body of form 1 and in plan can present for example, sections A through D. The same applies to the internal structure in the case of multiple compartment systems. Some of these examples can be seen in the diagrams U to Z. Of these, the U and V differ mainly due to the fact that in V the two main compartments are separated by a thin intermediate compartment, which can form for example a barrier of diffusion or an electrochemical barrier.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims (5)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. Process for the production of stratified bodies © discs containing active substance, with different qualities unique to the field of application, inside the layer, wherein a body of longitudinal shape with a surrounding surface corresponding to the contour of the bodies of The layer to be manufactured and the unique quality or different field of action of the layer body is unified in cross-sectional quality, transverse to the axis in the disc, characterized in that the discs have a thickness of 10 to 2000 microns.

2. Method according to claim 1, characterized in that a shape body with a constant section surface is divided.

3. Method according to claim 1 or 2, characterized in that the shape body has a core that contains the active ingredient. 4, Process for the production of laminated bodies © discs containing active substance, with different unique qualities or application field, within the layer, wherein a longitudinally shaped body with a wrapping surface corresponding to the contour of the bodies of The layer to be manufactured and the unique quality or different field of action of the layer body is unified in cross-sectional quality, transverse to the axis on the disc, characterized because the body of the obtained -fetched together in a make cords of different composition. Method according to one of the preceding claims, characterized in that the longitudinally-shaped body, which lies within open paths in which it progresses in a controlled manner, cyclically separates sheets that fall onto a support or moving support band. throughout the guide. Method according to one of the preceding claims, characterized in that the solid or semi-solid consistency of the body longitudinally, suitable for carrying out the separation, is adjusted by choosing the appropriate temperature. I. Method according to one of the preceding claims, characterized in that the separation is carried out by means of a cutting process. 8-. Method according to one of the preceding claims, characterized in that the production of the laminated bodies forms part of the preparation of transdermal therapy systems. 9-. Method according to one of the preceding claims, characterized in that the shape body section has two or more zones with different active substances. 10. Process for the production of stratified bodies or discs containing active substance, with different unique qualities or field of application, within the layer, wherein a body of longitudinal shape with a wrapping surface corresponding to the contour of the layer bodies which are to be manufactured and the single quality or different field of action of the layer body is unified in cross-sectional quality, transverse to the axis in the disc, characterized in that the section of the body of form has two or more zones with different speed of release of the active substance. II. Method according to one of the preceding claims, characterized in that the shape body section has two or more zones of different concentration of active substance »12. • Method according to one of the preceding claims, characterized in that the body section of This form has one or several zones with a concentration of active substance for a high initial dose and one or more zones for the maintenance dose (s). Method according to one of the preceding claims, characterized in that the section of the shaped body has one or more zones possibly containing different substances or concentrations for testing. 1

4. Procedure according to one of the preceding claims, characterized in that the section of the body of form has anodic and cathodic areas isolated from each other. 1

5. Transverse therapy system containing at least one of the laminated bodies produced according to one of claims 4 to 12, with a unitary or different zone composition, as a reservoir layer containing the active substance. SUMMARY OF THE INVENTION Layered bodies or sheets containing active substance, which are especially suitable as active substance reservoirs for transdermal therapy systems, obtained starting from a longitudinally shaped body with a wrapping surface corresponding to the contour of the stratified bodies that are It attempts to produce and a composition of the section corresponding to the internal structure of the laminated bodies, separating by layers in the direction transverse to the longitudinal direction of the body longitudinally. In the simplest case this shape body is composed of a uniform mass that contains the active substance and forms a solid cylinder that is divided at equal distances perpendicular to the axis, thus obtaining round sheets of a single compartment equal to each other. The shape body, however, can also have any other external shape and internal structure, being formed especially by a consolidated bundle of strands of different active substances or concentrations of active substances, which upon separation give rise to sheets having several compartments in one piece. same plane. As "active substances" are considered not only drugs and their previous and activating materials but also any other reagents, auxiliary substances, test substances, etc.