Abstract:
A getter system ( 20 ) is provided for the sorption of organic molecules on the inside of active systems ( 30 ) for the transdermal release of drugs. The getter system is suitable to avoid the corrosion of electrical parts of these systems, caused by these organic molecules in the presence of water.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a Section 371 of International Application No. PCT/IT2006/000507, filed Jun. 30, 2006, which was published in the English language on Jan. 25, 2007, under International Publication No. WO 2007/010576 A1 and the disclosure of which is incorporated herein by reference. 
     BACKGROUND OF THE INVENTION 
     The present invention relates to a getter device for active systems for the transdermal release of drugs. 
     Systems for the transdermal release of drugs are used in the treatment of conditions, dysfunctions or diseases requiring a regular administration of drugs to a patient, such as post-operative aches, cardiovascular diseases or diabetes. These systems essentially consist of an envelope of polymeric material having on the inside the drug to be dispensed, generally in form of suspension in a gel. A portion of the envelope surface is made of a plastic material permeable to the drug. By causing this portion of the envelope to adhere to the patient&#39;s skin (e.g., on an arm), the drug is released onto and absorbed by the skin itself, then entering the blood stream. 
     The first transdermal systems, appeared at the beginning of 1990s, were of the so-called passive type, wherein the drug release was determined only by the velocity of absorption by the skin. These systems have a number of drawbacks, such as the fact that it is impossible to control the drug flow (and consequently its dosing over a unit of time), as well as that it is impossible to have intermittent administrations, only for prefixed durations of time and at prefixed intervals or only upon the patient&#39;s request, which on the contrary are the more appropriate administration modes in some cases. 
     Therefore, more recently, active systems for releasing drugs have been introduced which are based on ionophoresis, i.e., transportation of drugs in ionic form under the effect of electrical fields. An example of this kind of apparatus is schematically shown in  FIG. 1 . The system T is formed of an envelope P on the inside of which there is a gel H, in which the drug is dispersed. The system also comprises a microcomputer MC, being fed by a battery B that controls the polarity of two electrodes E and E′. The battery is preferably of the lithium type. When the electrodes are not fed, there is no flow towards the skin of ions corresponding to the drug, whereas when the microcomputer feeds the electrodes, ions F + , corresponding to the drug, are forced to pass through the permeable parts of the envelope towards the skin. At the second electrode there is a passage of sodium ions Na +  from the skin towards a container of saline solution, in order to keep the system neutral. The Fig. refers to the case where the ion corresponding to the drug is positively charged, but the system operates with ions with negative charge F −  as well, in this case being balanced by the transportation of chlorine ions Cl −  from the skin to the transdermal system. The microcomputer can be programmed for a timed release of the drug. The system can also comprise a push-bottom for releasing the drug upon the patient&#39;s request (not shown in the drawing). 
     The problem that has been observed with active transdermal systems is that the battery releases dimethoxyethane (also indicated in the following as DME), an essential component of the process of manufacturing the batteries, which is kept partly trapped inside thereof. This compound together with water, always present in these systems, forms corrosive solutions attacking the electrical parts, thus leading in time to the loss of functionality of the system. Other acid components can be released by the polymeric material itself forming the envelope. For example, a material commonly employed to make the envelope is Surlyn® (Surlyn® is a registered trademark of the Du Pont company of Wilmington, Del., USA), a mixture of ethylene/(meth)acrylic acid copolymer, other polymers, such as polyesters or nylon, and including charges of metallic salts. It has been observed that in the working conditions of transdermal systems, Surlyn® releases small quantities of acetic acid, which in any case contributes to the problem of corrosion of the electrical parts. 
     The problem of organic components being released by batteries in general (not necessarily in field of the present application) is known, e.g., from European patent application publication EP 1 115 168 A1. According to the teaching of this document, the problem can be solved by introducing on the inside of the battery a material for the sorption of organic compounds, such as silica, alumina, titanium oxide, or porous solid particles of polymers. The problem of this solution is that, first of all, battery manufacturing is complicated. In addition, in order not to have a continuous removal of organic components of the electrolyte, such as DME or the like (necessary for the battery operation), the sorbing material in this case is coated with a layer of material impermeable to the organic compound, which material dissolves only as a consequence of malfunctions of the battery which cause its overheating. Thereby, this solution is inefficient to absorb the DME quantities, however small, which are released by the battery under normal operating conditions, i.e., when the temperature of the battery does not exceed the foreseen values. Consequently, a battery of the type described in the mentioned patent application would not solve the above-described problems of active systems for transdermal release of drugs. 
     BRIEF SUMMARY OF THE INVENTION 
     An object of the present invention is to provide a solution to the above-mentioned problems. 
     This and other objects are achieved according to the present invention with a getter device for active systems for the transdermal release of drugs, comprising activated charcoals and at least a first wall, permeable to organic molecules, but capable of retaining solid particles, the first wall being coupled to a second wall capable of retaining solid particles, so that the assembly resulting by the connection of the first wall and the second wall is suitable to contain the activated charcoals. 
    
    
     
       BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS 
       The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, there are shown in the drawings embodiments which are presently preferred. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities shown. In the drawings: 
         FIG. 1  is a schematic representation of an active system for the transdermal release of drugs according to the prior art; 
         FIG. 2  is a schematic, partially broken-away, perspective view of one embodiment of a getter device according to the present invention; 
         FIG. 3  is a schematic representation of a system similar to that of  FIG. 1 , including a getter device of the invention shown in  FIG. 2 ; and 
         FIG. 4  is a schematic representation of a transdermal system comprising an alternative embodiment of a getter device of the invention. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       FIG. 1  has been already described with reference to the prior art in the Background section above. 
       FIG. 2  shows a first possible embodiment of a getter device according to the invention. In this embodiment the device  20  comprises an envelope  21  formed of two sheets, the first one forming the first wall  22  permeable to the organic molecules but capable of retaining particles, the second one forming the second wall  23 . The two sheets are mutually coupled at the peripheral zone  24  identified by the hatched area in the  FIG. 2 . The activated charcoals  25  are contained within the envelope. The two sheets can be continuous polymers having a sufficient permeability with respect to small organic molecules, such as dimethoxyethane or organic acids. Preferably, however, the sheets are made with a fabric, either normal or nonwoven, of polymeric fibers. For example, it is possible to use two sheets of nonwoven fabric made with polyolefin fibers (e.g., polyethylene or polypropylene), of polyesters, such as PET, or Teflon® (Teflon® is a registered trademark of the Du Pont company). The joining of the two walls  22  and  23  in zone  24  can be obtained by glues, but preferably is obtained by heat sealing. In the latter case, to favor their welding, the two sheets are preferably made of the same material. 
     In an alternative embodiment (not shown in the drawings), the envelope can be formed by joining a wall permeable to the organic molecules (e.g., a sheet similar to that of wall  22 , as described above) and an impermeable wall, which can be a polymeric sheet of greater thickness than that of the permeable wall or a metallic sheet, such as of aluminum. In the latter case, the impermeable wall can be formed as a cup for housing the activated charcoals. 
     The activated charcoals useful for the present invention are the simple ones, not impregnated with additional substances. Charcoals of this type are sold, e.g., by the C*Chem company of Lafayette, Colo., USA, under the trademark Chemsorb 1000, or by the Chemviron Carbon company of Feluy, Belgium. 
     The amount of activated charcoals contained in the device depends upon the required life length of the transdermal system. For example, in order to ensure to the system a life of about 3 years, including the storage time between production and actual use, it has been observed with accelerated tests that at least 50 mg of activated charcoals are required. 
     The getter device of the invention can be located at any position inside the envelope of the transdermal system. However, the getter device is preferably fixed to the system envelope in a region remote from those parts where the ionic flow occurs from and toward the skin.  FIG. 3  shows this preferred embodiment. The transdermal system  30  comprises an envelope  31  having on the inside gel  32  in which the drug is suspended, and electronic parts, as already described with reference to  FIG. 1 . In addition, the system includes the getter device  20 , adhering to a portion of the internal surface of envelope  31  remote from the electrodes for the ionic species transportation, with at least wall  22 , permeable to organic molecules, in contact with gel  32 . 
     In view of manufacturing the system of  FIG. 3 , the getter device  20  is caused to adhere to the internal wall of envelope  31 , preferably by heat sealing. In the latter case, at least the sheet designed to be fixed to the internal wall of the envelope, among those forming envelope  21 , is made of a material chosen for the function of heat sealability with envelope  31 . For example, if envelope  31  is made with a Surlyn® containing a copolymer with ethylene, the sheet of wall  23  can be made with a polyolefin. 
     In an alternative embodiment of the transdermal system, shown in  FIG. 4 , the getter device is not a discrete component, but is integrated in the system itself and is manufactured in a production step of the final system. In this embodiment of the transdermal system  40 , the getter device  41  comprises a first wall  42 , permeable to organic molecules but capable of retaining solid particles, the perimeter of which is directly fixed to the internal surface of the envelope  43  of system  40 , such that in this case a portion of envelope  43  also forms the second wall of the getter device. In the pocket thus formed, there are housed the activated charcoals  44 . 
     This second embodiment can be manufactured, for example, by placing powders of activated charcoals on a small portion of the polymeric sheet intended to form the envelope  43  and by fixing the perimeter of a sheet designed to form wall  42 , having the required features described above, along a closed line completely encircling the area where the activated charcoals are present. Alternatively, it is possible to use a support (e.g., metallic) having in its top portion a recess of similar shape and size as those of the final getter device; to lay and cause the sheet, which will form wall  42 , to adhere within the recess; to pour the desired quantity of activated charcoals onto the sheet, in an area corresponding to the recess; to cause the peripheral portion of the sheet to adhere to a polymeric sheet intended to form the envelope  43 , fixing the two sheets by gluing or heat sealing; and finally, to remove the support. Other sequences of operations for obtaining the system shown in  FIG. 4  will be clear to those skilled in the art. The envelope  43  with an “integrated” getter device thus obtained is then employed for the subsequent steps of production of the transdermal system. Also in this case, the coupling between the sheet intended to form wall  42  and envelope  43  is preferably performed by heat sealing, and consequently the materials for envelope  43  and the sheet forming wall  42  will be chosen in a way suitable to the purpose, as described above. 
     It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the present invention as defined by the appended claims.