Abstract:
A diffusion cell to facilitate the automatic or manual removal of test aliquots of liquid from a receptor chamber of the diffusion cell so as to determine percantaneous absorption through a membrane of a substance from a donor chamber into a receptor chamber of the diffusion cell. There is utilized a capillary port through which the test aliquot is to be removed. A refilling tube connects also with the receptor chamber to add receptor liquid into the receptor chamber as the test aliquot is being removed. A quick release clamping apparatus secures the donor housing which contains the donor chamber tightly to the main housing of the diffusion cell.

Description:
BACKGROUND OF THE INVENTION  
         [0001]    1. Field of the Invention  
           [0002]    The field of this invention relates to testing equipment and more particularly to an apparatus which is usable to determine the transfer of a substance through a membrane into a liquid placed in contact with the opposite side of the membrane.  
           [0003]    2. Description of the Related Art  
           [0004]    There are three ways to apply a medicine to the body of any animal. The most common way probably is to take the medicine orally. The second most common way is direct injection by using a syringe. The third way, which is becoming more common, is by permutation of the drug through the skin.  
           [0005]    It is well known to utilize a cream or ointment to be placed on one&#39;s skin for the treating of a disease of the skin. However, what is becoming more common is the use of a drug in the form of an ointment, cream or patch that is to be placed onto the skin for the purpose of the drug entering the human body for the treatment of a medical condition. Transdermal patches are being commonly used, at the present time, for the administration of nitroglycerine for heart patients as well as the applying of nicotine to individuals for the purpose of assisting individuals in stopping smoking.  
           [0006]    The usage by human beings and other animals of any topically applied medication depends on the specific knowledge of the transfer kinetics of the active ingredients of the medication on its ability to penetrate through the skin and be absorbed by the animal&#39;s body. It is necessary to know exactly the amount of active ingredients that will penetrate the animal&#39;s skin within a given amount of time. This information is essential to determine the amount of the dosage of medicine to be applied to the skin patch or the amount of ointment or cream that is to be applied to the animal&#39;s skin.  
           [0007]    In the past, it has been common to utilize a vertical diffusion cell which is commonly called a Franz cell, named by it&#39;s inventor. The Franz cell is in the form of a container with the upper half separated from the lower half by a porous membrane comprising a barrier. A donor material is placed against the membrane. A receptor fluid, such as a saline solution, is placed within a receptor chamber of the Franz cell container. At predetermined intervals, aliquots are withdrawn from the receptor fluid. Each aliquot is then tested to determine the amount of active medicine that has been absorbed by the receptor fluid.  
           [0008]    Generally, the testing of the receptor fluid occurs over a period of hours or days with each sample aliquot withdrawn at certain time intervals apart. Typically, a typical testing apparatus will utilize a plurality of the Franz cells from which there will be automatically removed aliquots from each Franz cell with the aliquot then being tested to determine the quantity of medicine that has been absorbed by the receptor fluid. The reason that a plurality of Franz cells are used is to provide a plurality of readings for the particular donor substance so then an overall average can be arrived at and make a determination of the transfer characteristics of the active ingredients of the donor substance into the receptor fluid. The donor substance could comprise a solid, semi-solid, cream, gel or liquid. Typical donor substances are creams, topical ointments, lotions, or transdermal patches. The active ingredient in the donor substance could comprise a medicine such as an antibiotic or an ophthalmic preparation, cosmetic, pesticide, paint or any potentially toxic substance that would have a tendency to penetrate an animals skin. The receptor fluid normally comprises a saline solution, water or buffered solution. The aliquots, which are to be removed from the receptor fluid, are defined as an exact sub-volume of the overall volume of the receptor fluid.  
           [0009]    Generally useful in the whole field of physical chemistry, Franz cells have become particularly useful in the health care field. Transfer kinetics of active substances through the animal skin are determined in order to determine the level of epidermal exposure to pesticides, chemicals, ointments, cosmetics, paints and other substances.  
           [0010]    The membrane that is used in conjunction with the Franz cell could comprise cadaver skin or some form of a synthetic membrane that is specifically constructed to essentially duplicate human skin.  
         SUMMARY OF THE INVENTION  
         [0011]    One of the objectives of the present invention is to construct a diffusion cell which provides for the withdrawal of aliquots in a manner that does not permit air to be added into the receptor chamber.  
           [0012]    Another objective of the present invention is to construct a diffusion cell which provides for accurate replacement in volume of fresh receptor fluid equal to what was withdrawn in each aliquot.  
           [0013]    Another objective of the present invention is to construct a diffusion cell which minimizes the volume of the aliquot that is contained within the sampling port thereby having minimal affect on the subsequent aliquot that is withdrawn.  
           [0014]    Another objective of the present invention is to incorporate luer fittings in conjunction with the sampling port and refilling port for the receptor fluid which provides for easy connection and disconnection with a withdrawing conduit and a refilling conduit at the same time achieving a leakage free connection.  
           [0015]    Another objective of the present invention is to utilize a quick disconnect clamping apparatus in conjunction with the diffusion cell to insure that the donor housing is tightly secured to the main housing of the diffusion cell.  
           [0016]    The basic embodiment of diffusion cell of the present invention utilizes a main housing of a container which has a receptor chamber. The receptor chamber has an open top and a closed bottom. A receptor liquid is to be located within the receptor chamber in a sufficient quantity so as to connect with the open top. A receptor liquid refilling port connects with the receptor chamber with this refilling port being located directly adjacent the closed bottom. A sampling port connects with the receptor chamber intermediate the open top and the closed bottom but nearer the open top. A thin membrane is mounted on the main housing extending across the open top effectively closing such. A donor housing has a donor chamber which connects with the membrane. A media is to be supplied to the donor chamber and in contact with the membrane. A quick release clamping apparatus engages with the donor housing function to tightly press the donor housing onto the membrane and the main housing.  
           [0017]    A further embodiment of the present invention comprises the main embodiment where the sampling port includes a capillary tube so as to minimize the volume of receptor fluid that is contained within the sampling port upon withdrawing of an aliquot.  
           [0018]    A further embodiment of the present invention is where the main embodiment is modified by the donor housing comprising a disc with a center opening which forms the donor chamber. A cover plate is designed to be located over the disc with a cap to be mounted over the cover plate.  
           [0019]    A further embodiment of the present invention is where the just previous embodiment is modified by the cap including a viewing port to facilitate visual observation of the receptor chamber in the area of the open top.  
           [0020]    A further embodiment of the present invention is where the basic embodiment is modified by the sampling port and the refilling port both having mounted thereon LUER fittings.  
           [0021]    A further embodiment of the present invention is where the clamping apparatus is utilized in conjunction with the diffusion cell comprises a pair of plates that define an internal cavity. The main housing is to be inserted within this cavity. One of the plates is mounted against the cap of the donor housing with the other of the plates being fixed to the main housing. A spring biasing arrangement connects between the plates of the clamp of the clamping apparatus therefore tending to maintain a tight connection by the clamping apparatus between the main housing and the donor housing. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0022]    For a better understanding of the present invention, reference is to be made to the accompanying drawings. It is to be understood that the present invention is not limited to the precise arrangement shown in the drawings.  
         [0023]    [0023]FIG. 1 is an exterior side view of the diffusion cell of the present invention;  
         [0024]    [0024]FIG. 2 is a top plan view of the diffusion cell of the present invention taken along line  2 - 2  of FIG. 1; and  
         [0025]    [0025]FIG. 3 is a longitudinal cross-sectional view through the diffusion cell of the present invention taken along line  3 - 3  of FIG. 2. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0026]    Referring particularly to the drawings, there is shown the diffusion cell  10  of this invention. The diffusion cell  10  includes a thin walled receptor container  12 . The container  12  will normally be constructed of glass. Located internally of the receptor container  12  is a receptor fluid chamber  14 . The upper portion  16  of the receptor fluid chamber  14  is expanded to be of a greater diameter than the lower portion of the chamber  14 . The diffusion cell  10  has a closed bottom  18  and an open top which is located at flat surface  20  which is formed on annular flange  22 . The receptor fluid chamber  14  is designed to be filled with receptor liquid  24 . The receptor liquid  24  will normally comprise water, saline or some other type of liquid solution.  
         [0027]    Liquid is to be supplied into the receptor fluid chamber by means of a refilling conduit  26  which connects by a refilling connector  28  through a refilling tube  30 . Refilling tube  30  has a LUER fitting  32 . The LUER fitting  32  is capable of quickly being disconnected and connected to the refilling connector  28 , and when it is connected to the refilling connector  28 , there is established a secure leakage free connection. The LUER fitting  32  is basically tapered and has an exterior roughened surface which facilitates the forming of the leakage free connection. Formed within the refilling tube  30  is a storage chamber  34 . From the storage chamber  34 , liquid is to be supplied through capillary passage  36  to the receptor fluid chamber  14 . The function of the storage chamber  34  is to provide an area for collection of any air bubble and to prevent that bubble from entering into the receptor fluid chamber  14 .  
         [0028]    It is to be noted that the refilling tube  30  connects to the receptor fluid container  14  directly adjacent the bottom  18 . This means that new receptor fluid  24  is always being supplied into the receptor fluid chamber  14  as far away from the open top as possible. The reason for this is so that the new receptor fluid  24  that is being supplied will not immediately intermix with the aliquot or sample of fluid that is being extracted from the upper portion  16  by the sample tube  38 . The sample tube  38  terminates in a LUER fitting  40  which connects with a sampling connector  42 . Sampling connector  42  connects with the a sampling conduit  44 . The sampling tube  38  has a capillary passage  46  through which the aliquot that is to be removed is to be conducted prior to entrance within the sampling conduit  44 .  
         [0029]    It is desirable that at the time each aliquot is removed that the liquid of the aliquot be representative of the precise percentage of the amount of active ingredient that is contained within the receptor liquid  24 . Inherently, because there will always be some small amount of residual aliquot liquid contained within the capillary passage  46  and also contained within the sampling conduit  44 , it is desirable to have the smallest amount of residual aliquot liquid contained within the passage  46  and the conduit  44 . Residual aliquot liquid contained within the passage  46  and the conduit  44  is not representative of the receptor liquid. Therefore, because there is a minimal amount of residual aliquot liquid, only a small waste volume is required to purge the residual volume and the reading that is taken on the particular selected aliquots should give a true representation of the amount of active ingredients within that aliquot since the volume of the previously obtained aliquot that is being added to the new aliquot constitutes only a minor amount of the total volume of the aliquot since the volume of the capillary passage  46  constitutes only a minor amount of the total volume of the aliquot. It is to be understood that the capillary passage  46  will not be completely filled as most of the liquid that remains within the capillary passage  46  will be drained back into the receptor fluid chamber  14 .  
         [0030]    Surrounding the receptor container  12  is a jacket  48 . The jacket  48  is also formed of glass and is to normally be constructed integral with the receptor container  12 . Between the receptor container  12  and the jacket  48  is located a jacket chamber  50 . Jacket chamber  50  is basically annular and totally surrounds the receptor container  12 . It is desirable, and actually necessary, for the receptor liquid  24  to be maintained at a known temperature. A temperature maintaining liquid  52  is to be supplied within the jacket chamber  50  and is intended to circulate through the jacket chamber  50  from an inlet tube  54  to an outlet tube  56 . An inlet conduit  58  is connected to the inlet tube  54 , and an outlet conduit  60  is connected to the outlet tube  56 . A flow of the liquid  52  is to constantly be supplied from the inlet conduit  58  to the jacket chamber  50 . A similar quantity of the liquid  52  will also be discharged through the outlet conduit  60 . It is to be understood that the inlet conduit  58  and outlet conduit  60  will be connected to a source of the liquid, which is not shown. Generally, at this source of liquid there will be located some type of a heater that will be designed to raise the temperature to a certain temperature to correspond to the temperature level of the particular animal for which the diffusion cell  10  is to be used. For example, in the case of a human, the temperature level of the liquid  52  should be thirty-two degrees centigrade. It can quickly be seen that the temperature of the liquid  52  will readily pass through the receptor container  12  with the result that the receptor liquid  24  will also be located at the same temperature as the liquid  52 .  
         [0031]    A membrane  62  is to be placed on the flat surface  20 . The function of the membrane  62  is to essentially duplicate human skin or the skin of whatever animal the diffusion cell  10  is being used. The membrane  62  could comprise cadaver skin, a synthetic material that essentially duplicates human skin, some form of a plastic membrane and even possibly a tightly woven cloth material. On the membrane  62  is located a donor plate  64 . The donor plate  64  is in the shape of a washer having a center opening  66 . Typically, the donor plate  64  will be constructed of glass, plastic or other rigid material. With the donor plate  64  located against the membrane  62 , the membrane  62  is clamped between the donor plate  64  and the flat surface  20  of the annular flange  22 . Within the opening  66  is to be located a quantity of donor material  68 . Typically, the donor material  68  will be in the form of an ointment or cream but could comprise a liquid and possibly even a solid material such as a gel. The donor material  68  will be in contact with the upper surface of the membrane  62 . The lower surface of the membrane  62  will be in continuous contact with the receptor liquid  24 . It can thus be seen that the active ingredients of the donor material  68  will penetrate the membrane  62  and become mixed within the receptor liquid  24  and extraction of aliquots over a period of time through the capillary passage  46 . The amount of active ingredients within the donor material  68  within each aliquot is to be measured by an appropriate measuring apparatus, which is not shown.  
         [0032]    A cover plate  70  is then to be placed on the donor plate  64 . Typically, the cover plate  70  will comprise a glass disc. One reason the cover plate  70  is made of glass as well as the receptor container  12  and the jacket  48  is so that a user can then readily observe the donor material  68 , membrane  62  and whether the receptor liquid  24  is in continuous contact with the membrane  62 . Also, if an air bubble happens to be resting against the membrane  62 , incorrect dissolvability readings will be ascertained within the aliquots. It is important to view the membrane  62 , and that is why transparent glass is used.  
         [0033]    A cap  72  is located on the cover plate  70 . Typically, the cap  72  will be constructed of a rigid metallic material with generally aluminum or stainless steel being preferred. The cap  72  includes an enlarged center hole  74 . The hole  74  will permit visual observance of the cover plate  70  which is transparent and therefore can readily observe the donor material  68  to make sure that an adequate quantity of the material  68  is contained within the center opening  66 . The cap  72  has a sidewall  76  that is to be positioned against the side of the annular flange  22 . Typically, the cap  72  will be in the shape of a cup. The sidewall  76  includes a cutout  78 . The cutout  78  is to function as a viewing port so that the user is able to observe the membrane  62  and ascertain whether there are any air bubbles located against the membrane  62 . If there is determined that there is an air bubble, a measure will have to be taken to remove that bubble. Typically, the measure to remove the air bubble will be to remove the cap  76 , the cover plate  70 , the donor plate  64  and the membrane  62  to permit the air bubble to escape. Then the membrane  62 , donor plate  64 , cover plate  70  and cap  72  are then reinstalled in position.  
         [0034]    It is desirable, and necessary, for the cap  62  to be tightly restrained in position on the annular flange  22 . In order to achieve this, there is utilized a quick disconnect clamping apparatus  80 . The clamping apparatus  80  comprises an upper plate  82  and a lower plate  84 . The upper plate  82  is basically U-shaped defining an internal cavity  86 . Similarly, the lower plate  84  is U-shaped and has an internal cavity  88 . The upper plate  82  is mounted relative to the lower plate  84  by means of a pair of bolt fasteners  90  and  92 . Surrounding the bolt fastener  90  is a spacer sleeve  94 . A similar spacer sleeve  96  surrounds the bolt fastener  92 . Spacer sleeves  94  and  96  are located between the upper plate  82  and the lower plate  84 . The spacer sleeves  94  and  96  function to define the minimum spacing between the upper plate  82  and lower plate  84 .  
         [0035]    Located about the bolt fastener  90  is a coil spring  98 . A similar coil spring  100  is located about the bolt fastener  92 . The coil springs  98  and  100  abut against the lower plate  84 . The outer end of the coil spring  98  abuts against a nut  102  that is threadably mounted on the bolt fastener  90 . The outer end of the coil spring  100  abuts against a nut  104  that is threadably mounted on the bolt fastener  92 . Loosening and tightening of the nuts  102  and  104  on their respective bolt fasteners  90  and  92  will control the amount of clamping force that is achieved by the clamping apparatus  80  of this invention.  
         [0036]    The length of the spacer sleeves  94  and  96 , which is identical, is preselected to be just slightly less than the distance from the bottom edge  106  of the annular flange  22  and the top of the cap  72 . The upper plate  82  has, in essence, a pair of legs located on each side of the internal cavity  86 . The outer end of these legs include upturn flanges  108  and  110 . The lower plate  84  includes a similar pair of legs located between the internal cavity  88 . Each of these legs include downturn flanges  112  and  114 .  
         [0037]    The use of the flanges  108 ,  110 ,  112  and  114  are to facilitate manual separating movement of the upper plate  82  from the lower plate  84  in order to permit its installation about the annular flange  22 . Manual pressure is to be applied to the flanges  108 ,  110 ,  112  and  114 . When installed, the upper plate  82  will abut against the upper surface of the cap  72  and the lower plate  84  will abut against the bottom edge  106 . The biasing of the springs  98  and  100  will cause a clamping force to be applied against the cap  72  holding the cap  72  tightly in position on the annular flange  22 .  
         [0038]    When it is desired to change the membrane  62 , it is only necessary to quickly grasp clamping apparatus  80  and disengage such from the annular flange  22  which will provide access to remove the cap  72 , cover plate  70  and donor plate  64  to gain access to the membrane  62 . Once the clamping apparatus  82  is then quickly installed back into position on the annular flange  22  and cap  72 , the cap  72  is then securely held in position on the annular flange  22 .