Abstract:
A stent holder for securely holding a drug eluting stent (DES) during a real-time or an accelerated in-vitro drug release test of a therapeutic substance contained in or on the DES. The holder has a retainer portion and a wire portion separable from the retainer. The holder has a narrowed or reduced profile resulting in less disruptive flow in and around the stent during the accelerated in-vitro drug release test.

Description:
FIELD OF THE INVENTION 
       [0001]    The present invention relates to implantable medical devices and more particularly medical device holders used during the real-time or accelerated drug-release testing. 
       BACKGROUND OF THE INVENTION 
       [0002]    The localized drug delivery from a drug-eluting stent (DES) has been shown to be quite effective and accepted as one of the most promising treatment methods for preventing restenosis after stenting procedures. For example, a polymeric coating on a DES is designed to sustain appropriate drug release kinetics in order to deliver the therapeutic dose of the drug for the required time interval at the treatment site. An estimation of the real-time release rate is critical for characterization of the DES dosage forms. 
         [0003]    With respect to testing drug elution properties of a DES, there are certain challenges to overcome. Most notably, when evaluating the sustained release of a candidate DES structure the test can consume significant time, spanning weeks or months for sustained release of these dosage forms. This is disadvantageous in early research, and therefore not conducive for efficient management of product development. An accelerated (short-term) in-vitro release method is helpful for achieving a more rapid assessment of the formulation and processing variables. Accelerated in-vitro drug release testing is also used as a quality control tool to (i) ensure the consistency of the product performance from batch-to-batch and (ii) assure the stability of the product during the established shelf life. 
         [0004]    Characterization of in-vitro drug release profiles for drug products and medical devices with therapeutic agents is routinely accomplished using commercially available automated or semi-automated equipment fitted with specialized holders to accommodate a variety of drug products or devices. Chapter 724 in the US Pharmacopeia (USP) lists several suitable release apparatus designs with the most common applications for each type. The Apparatus 7 (Reciprocating Holder) variety has been used to characterize the release profile of the drug substance used on a coated stent, e.g., Everolimus, when submersed in a release media, e.g., porcine serum. Apparatus 7 utilizes a reciprocating sample holder to dip the drug eluting device in a vessel, e.g., a test tube, containing release media. There are, however, only a limited number of commercially available Apparatus 7 sample holder designs to accommodate a wide variety of drug/device configurations. As a result, companies often design and build custom sample holders to suit specific needs since commercially available choices have limited usefulness. 
         [0005]    The most frequently used types of Apparatus 7 sample holder designs for holding a stent during dipping employ a pair of cylindrical or frustoconical bodies received over a mandrel. A pair of collets, at least one of which being capable of sliding along a carrying mandrel, engages each end of the stent. The arrangement secures a stent on the holder while the stent is dipped.  FIGS. 1A and 1B  illustrate in perspective examples of two such Apparatus 7-type reciprocating holders. Referring to  FIG. 1A , the stent holder, shown supporting a stent  10 , has two ends  3   a ,  3   b  received over a wire  5 . Each end  3   a ,  3   b  has opposed conical faces  6   a ,  6   b , or frustoconical bodies mated together at their respective frustums with a cylindrical portion  4  separating the frustums. The end  3   a  is movable along the mandrel  5  while the end  3   b  is fixed. End  3   a  has a collar  7 . Referring to  FIG. 1B , there is a second type of Apparatus 7-type reciprocating holder. It also has a pair of brackets  8   a ,  8   b  received over a mandrel. Each bracket has a frustoconical shape  9   b  arranged to face each other. Stent ends are placed against the conical surface. The sliding end  8   a  moves towards or away from the other end  8   b  according to the length of the stent. 
         [0006]    The design types in  FIGS. 1A and 1B  do not, generally speaking, produce an optimal flow profile of release medium over drug-containing surfaces of a medical device during the drug release testing, especially in the case of a stent with both exterior and interior surfaces coated. This conclusion was reached based on, e.g., inconsistencies seen between measured in-vivo vs. in-vitro release properties for the same product. As a result, it was concluded that the known Apparatus 7-type holders tend to cause significant variability in the amount of drug released at each dipping time point, compromising the precision and accuracy of the test. The concern is most serious for stents drug coated on both interior and exterior surfaces. 
         [0007]    Accordingly, there is a need to provide a stent or scaffold holder that reduces variability in a drug release profile measured during a real-time or an accelerated in-vitro drug release test of a medical device, such as a stent, where the variability is due to an undesirable flow profile over drug-eluting surfaces of the medical device caused by interfering surfaces of the medical device holder. An improved medical device holder should produce more accurate quality assurance from batch-to-batch of manufactured medical devices; provide better guidance during product development; and/or more accurate predictions of the in-vivo response (when an in vitro/in vivo correlation is established) when using an accelerated in-vitro drug release test method. 
       SUMMARY OF THE INVENTION 
       [0008]    The invention provides a medical device holder that satisfies one or more of these objectives. The holder is capable of securely holding a medical device, preferably a drug-eluting stent (DES), in a vertical alignment for dipping while avoiding the drawbacks of the prior art holders. 
         [0009]    The holder includes a narrow cross section or flow profile. In a preferred embodiment there is a triangle-shaped base and triangle-like and movable retainer (sized to receive a DES) that significantly reduces impedance of a free flow of release media to thereby expose interior or hidden surfaces, e.g., side and luminal surfaces or surfaces close to the holder supporting surfaces of a DES, during a real-time or an accelerated drug release test. The resulting free flow of release media to both interior and exterior surfaces will result in more reproducible and reliable drug release profile results. 
         [0010]    A preferred holder includes a shouldered design to better assure that a DES remains securely in place while letting release media freely drain off the holder when changing to a next dip interval. This shouldered feature can enhance the accuracy and precision of the drug release determination by minimizing carryover. The holder can also be used with a wide variety of DES sizes, both in length and diameter, as compared to existing holders, without detracting from the desirable low or minimal profile features. 
         [0011]    This preferred holder, which may be used with either a drug-eluting stent or scaffold, has two separable parts. The first part is a core wire with one end shaped as an isosceles or equilateral triangle (in two possible base widths of about 8 to 9 mm and about 12 to 13 mm for different outer diameter sizes of stents). The triangle shape (isosceles or equilateral) end of the core wire helps with stable seating of the stent at one end of the holder. The core wire can be in different lengths for different lengths of the stent. 
         [0012]    The second part is a metallic retainer, which slides over the core wire and brackets the stent so that the stent is held between the triangular-shaped end of the core wire and the retainer, thereby stabilizing the stent in place. The retainer has a flat surface (in two widths of about 8 to 9 mm and about 12 to 13 mm as needed for different stent diameter sizes). It also has a thin frontal profile of about 2 to 3 mm for both width sizes. 
         [0013]    The retainer also has a collar that discourages sliding movement along the wire during dipping yet provides very little increase in frontal profile or surfaces to interfere with the flow of release media or retention of the media when the holder is removed from the test container (thereby avoiding contamination with subsequent testing). Such a collar is sufficient to keep the retainer in its manually-positioned placed during the dipping of the stent and holder in a test container holding the release medium. 
         [0014]    There are two profile sizes for the holders, a small profile and a large profile. Either of these holders can come in various total length of core wire to compensate for different lengths of stents/scaffolds. A small profile holder: intended for stent/scaffold with an outer diameter (OD) of about 7 mm and lower (most of coronary stent/scaffold as well as small peripheral stent/scaffold). The base of the triangle-shaped end of the core wire and the width of the retainer are about 8 to 9 mm. The length of the core wire can be in the range of 70 mm to 150 mm (or longer) for different length stents. 
         [0015]    Large profile holder: for peripheral stent/scaffold with an outer diameter (OD) of about 8 mm and higher. The base of the triangle-shaped end of the core wire and the width of the retainer are about 12 to 13 mm. The length of the core wire can be in range of 100 mm to 150 mm (or longer) for different length peripheral stents. 
         [0016]    In accordance with the foregoing, there is a stent holder, medical device and holder, method of use, method for making, or method for assembly of holder having one or more, or any combination of the following things (1)-(19):
       (1) A core wire with one end shaped as an isosceles or equilateral triangle (in two possible base widths of about 8-9 mm or about 12-13 mm for different outer diameter sizes of stent).   (2) The core wire has a diameter of about 0.1 to 5.0 mm.   (3) A member which slides over a core wire. The retainer has flat surfaces (in two widths of about 8-9 mm and about 12-13 mm options for different outer diameter sizes of stents/scaffolds).   (4) The member is a retainer.   (5) The member has a thickness of about 2-3 mm.   (6) The member is made from a single piece of metal or metal alloy.   (7) The member has a width to thickness ratio (W/T) of about 2 to 7, or about 7, 6, 5, 4, 3 or 2.       
 
         [0024]    (8) The member has a front surface that slopes rearward by about 0, 5, 5-10, 20, 10, 30, or about 10-30 degrees.
       (9) The member has a rear surface that slopes forward by about 30, 45, 50, 60, or about 40-60 degrees.   (10) Increase in edge roundness front to back for a member.   (11) The member having a collar with a slot.   (12) Any dimension, or combination of the dimensions provided in TABLE 1.   (13) The member has a flat side surface, a width larger than a stent diameter; the member configured to hold the stent, and a thickness that is at least 2 times smaller than the stent diameter.   (14) A stent holder comprising a retainer having a forward end and rear end, the retainer including a collar having a bore and located at the forward end, a forward sloping surface proximal the rear end, a rearward sloping surface proximal the forward end, a maximum width (W) of the stent holder, viewable from a side view of the retainer, a maximum thickness (T) of the stent holder, viewable from a front view of the retainer which is perpendicular to the side view, and wherein the ratio W/T is more than 2.   (15) The apparatus of (14), (17) or (18), or method of (16), in combination with one of, more than one of, or any combination in any order of the following list of things: a holder holding a stent, comprising: a stent disposed between the second end of the wire and the forward sloping surface of the retainer according to the stent holder of (14); further including a mandrel comprising a wire having a first end received in the collar bore and a second end configured to support an end of the stent; wherein the collar includes a slot and the collar forcible receives a wire such that the wire elastically deforms the collar; wherein the retainer is integral with the collar and has a bore aligned with collar bore; wherein the retainer has a flat side surface such that a majority of the thickness of the retainer is T; and/or wherein the mandrel second end comprises the wire shaped into a triangle.   (16) A method for accelerated release testing, comprising the steps of: placing a stent on a stent holder according to (14); dipping the stent and stent holder into a container containing a release medium; removing the stent and holder from the container, and/or dipping the stent and holder into a different container containing a different release medium.   (17) A tubular medical device holder comprising: a wire having a first and second end, the wire extending in a direction perpendicular to a first plane and lying within a second plane; a collet having a bore and the wire first end extends through the bore, the collet further including: sloping surfaces configured to penetrate into a bore of the medical device, a maximum width (W) as measured in the first plane a maximum thickness (T) as measured in the second plane, and the ratio of W/T is about 2 to 7.   (18) An apparatus for holding a medical device, comprising a member having a first and second forwardly sloping surfaces that together form a tip capable of penetrating a bore of the medical device; the first and second forwardly sloping surfaces defining a maximum width (W) of the member, wherein width is measured in a first plane; and in a second plane perpendicular to the first plane the member has a maximum thickness (T); wherein W/T is greater than 2.   (19) The apparatus of (14), (17) or (18), or method of (16), in combination with one of, more than one of, or any combination in any order of the following list of things: wherein W/T is greater than 4 or 5; wherein each of the first and second forwardly sloping surfaces slopes forward by greater than 30, 40 or 50 degrees; further including first and second rearwardly sloping surfaces opposing the first and second forwardly facing surfaces; wherein each of the first and second rearwardly sloping surfaces slopes rearward by greater than 0, 5, 10, and 20 degrees; wherein a forward slope angle for the forwardly sloping surfaces is greater than a rearward slope angle for the rearwardly sloping surfaces; wherein the member defines a bore having a bore axis, the bore configured to receive a wire and the member is symmetric about the bore axis; further including a collar having a slot and defining a bore for forcible receiving a wire such that the wire elastically deforms the collar; and/or wherein the member is integral with the collar and has a bore aligned with collar bore.       
 
       INCORPORATION BY REFERENCE 
       [0036]    All publications and patent applications mentioned in the present specification are herein incorporated by reference in their entirety, to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference in its entirety, including any figures, herein. To the extent there is an inconsistent usage of a word and/or phrase between an incorporated publication or patent application and the present specification, this word and/or phrase will have a meaning consistent with only the manner that the word and/or phrase is used in the present specification. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0037]      FIG. 1A  is a perspective view of a first prior art stent holder. 
           [0038]      FIG. 1B  is a perspective view of a second prior art stent holder. 
           [0039]      FIGS. 2A and 2B  are side and top views, respectively, of a stent holder according to the disclosure. The stent holder includes a first portion and a second portion, which are assembled together in these views. There is also defined an X-Y-Z rectangular coordinate system as a reference for describing aspects of the stent holder. With respect to this reference, the stent holder viewed in the X-Y plane is a side view of the stent holder; the stent holder viewed in the Z-Y plane is a front or rear view of the stent holder; and the stent holder viewed in the X-Z plane is a top or bottom view of the stent holder. 
           [0040]      FIG. 3  is a perspective view of a retainer of the stent holder of  FIGS. 2A-2B . 
           [0041]      FIGS. 3A and 3B  are side and top views, respectively, of the  FIG. 3 . Retainer. 
           [0042]      FIG. 4  is a side view of a core wire or wire of the stent holder of  FIGS. 2A-2B . 
           [0043]      FIG. 5  shows a stent being held by the stent holder of  FIGS. 2A-2B  during a dipping process in a release medium. 
       
    
    
     DETAILED DESCRIPTION OF EMBODIMENTS 
       [0044]    For purposes of this disclosure, the following terms and definitions apply: 
         [0045]    The term “about” means 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1.5%, 1%, between 1-2%, 1-3%, 1-5%, or 0.5%-5% less or more than, less than, or more than a stated value, a range or each endpoint of a stated range, or a one-sigma, two-sigma, three-sigma variation from a stated mean or expected value (Gaussian distribution). It is understood that any numerical value, range, or either range endpoint (including, e.g., “about none”, “about all”, etc.) preceded by the word “about” in this disclosure also describes or discloses the same numerical value, range, or either range endpoint not preceded by the word “about”. 
         [0046]      FIGS. 2A-2B  show side and top views of a stent holder according to the disclosure. The stent holder includes a retainer  20  separable and capable of being forcibly slid along a mandrel, which in this example is a wire  30 . The wire  30  has a first end  30   b  that receives the retainer  20  and a second end  30   b  that forms a triangular-shaped base  40 . A stent holder is configured for securely holding a stent between the retainer  20  and base  40  during a dipping process for evaluating release rates of a DES.  FIG. 5  illustrates such a test. As shown, the stent  10  is held between the base  40  and retainer  20  during a dipping into release medium  14 . 
         [0047]      FIGS. 3 ,  3 A and  3 B show perspective, side and top views of the retainer  20  from  FIGS. 2 and 5 , separate from the wire  30 . The retainer  20  includes front sides  22  and  22 ′, rear sides  24  and  24 ′ and flat sides  26  and  26 ′. Together these six sides describe a triangular-like body  29  having a flat side surface  29   a . The retainer has a width B and a thickness C which produce an extremely narrow profile in the X-Y plane. 
         [0048]    Sides of retainer  20  are distinguished by a rearward slope (side  22  and  22 ′), forward slope (side  24  and  24 ′) and a relatively flat surface (side  26  and  26 ′). The retainer  20  is symmetric in the X-Y plane, as seen in  FIG. 3A . Thus the top, front and rear side descriptions referred to above have the same features and description, regardless of whether the retainer is viewed from the bottom or top; in other words, it is understood that any description for the sides  22 ,  26 ,  24  applies equally to the sides  22 ′,  26 ′, and  24 ′ of the retainer  20 . 
         [0049]    The retainer  20  forms a rear collar  27  and a front collar  25 . The front collar  25  is preferably made significantly longer than rear collar  25  and includes a narrow slot  25   a  formed in the collar  25  and extending over about the entire length of the collar  25 . The collar  25 , collar  27  and a bore through the triangular-like body  29  (not shown) of the retainer  20  are aligned with each other so as to provide a circular passage for the wire  30  to pass through the retainer  20  as shown in  FIGS. 1A ,  1 B and  5 . 
         [0050]    The inner diameter of the collar  25  is slightly less than the inner diameter of the triangular body  29  and rear collar  27 . The inner diameter of the collar  25  is also slightly less than the outer diameter of the wire  30 . With this configuration for collar  25  and the forming of the slot  25   a  there is provided a force fit of the retainer  20  onto the wire  30  which retains the retainer  20  in place by friction, essentially between the inner walls of collar  25  and outer surface of the wire  30 . As the wire is inserted into the bore of the retainer  20 , starting with the collar  27 , the wire  30  passes relatively easily until it reaches the collar  25 , whereupon the wire end  30   a  must be forced through the collar  25 , resulting in an elastic deflection radially outward of the collar  25  (the slot  25   a  permits this to happen). Thus, as a result of the elastic deflection radially outward of the collar  25  (caused by forcing the wire  30  through the collar  25  bore) and resulting radial inwardly directed restoring force imposed on the wire  30  surface, there is generated a holding force that prevents the retainer  20  from sliding about on the wire  30  during the dipping process. 
         [0051]    Edges that demarcate each of surfaces  22 ,  22 ′,  24 ,  24 ′,  26  and  26 ′ from surface  29   a  are generally rounded; with the degree of roundness increasing from front to back (the front of the retainer  20  is the left-most tip of the collar  25  in  FIG. 3 ). Thus, edges separating surfaces  22  and  22 ′ from surface  29   a  are more sharp or abrupt (or less rounded) than the edges separating surfaces  26  and  26 ′ from surface  29   a . And the edges separating surfaces  24 ,  24 ′ and  29   a  are more sharp or abrupt (or less rounded) than the edges separating surfaces  24 ,  24 ′ from surface  29   a.    
         [0052]    The portion of the triangular body  29  closest the collar  27  is almost circular, as depicted in  FIG. 3 . As can be appreciated from the illustrated increase in edge roundness form front to back, this tip of body  29  gradually transitions to a circular shape. This rounded surface is represented by surface  28 ,  28 ′ which gradually transitions from a relatively sharp edge (nearest surface  26   a ) to a rounded, almost circular edge adjacent collar  27 . In this way the transition, from the flat surface  29   a  providing the desired small or narrow, and minimally disruptive frontal profile of the retainer  20  to the circular surfaces of the collar  27 , is gradual, which tends to cause less disruptive flow in the vicinity of stent portions nearest the surface  26   a / 28 , which engage a stent end. Thus, drug loaded near the stent end will be more exposed to the release medium, which is desirable. 
         [0053]    Referring to  FIG. 3A , the top side  26  has a surface  26   a  that lies substantially within the Z-X plane. The surfaces  24  and  22  are oriented in planes rotated at angles θ1 and θ2, respectively, to the Z-Y plane. In other words, the side  22  is sloped rearward by an angle θ2 and the side  24  is sloped forward by an angle θ1 in  FIG. 3A . The angle θ1 is about 45, 50, 60, or about 40-60 degrees, and the angle θ2 is about 0, 5, 5-10, 20, 10, 30, or about 10-30 degrees. The angle θ2 may be chosen to be relatively small the requirement is essentially only that release medium easily fall off or away from the holder when removed from the test container, so that residual release medium and eluted drug does not contaminate the test results for a subsequent time point. As for angle θ1 its range can be as low as about 30 degrees. Its purpose is to securely hold the stent yet without damaging the stent when brought into engagement. 
         [0054]    Referring to  FIGS. 3A and 3B , the maximum thickness of the retainer  20  in the top (or bottom) view is C and the maximum width of the retainer  20  in the side view is B. According to the embodiments, the retainer  20  profile in the Z-Y plane is believed to contribute significantly to the results seen in testing. Thus, it is believed that a critical parameter for the retainer  20  is the ratio of B/C as this characterizes the slimness of the profile of the holder that minimizes interferences between the stent and release medium. The ratio of width to thickness of the retainer, or ratio of B/C can range from about 2 to 7, or about 7, 6, 5, 4, 3 or 2. 
         [0055]    In the preferred embodiment retainer  20  is made from a single piece of metal or metal alloy that was milled to the shape shown in  FIGS. 3 ,  3 A- 3 B. Given the dimensions of the bore for receiving the wire, the stent size and durability needed for the piece, it will be appreciated that a thickness of about 2 to 3 mm represents about the smallest dimension possible (given the functional demand on the retainer  20 ) using a conventional milling machine and material. 
         [0056]    Referring to  FIG. 4  there is shown the wire  30  portion of the stent holder. The end  30   a  of the wire  30  is inserted into the retainer  20 . The end  30   b  forms a triangular-shaped base  40 . Like the retainer  20  the base  40  is made narrow, as explained earlier. Also, the base  40  has a minimal amount of surfaces while still providing a base support for holding the end of the stent. The stent end is received on the surfaces  40   a  so that the tip of the triangle, which may be an isosceles or equilateral type, partially penetrates into the bore of the stent (similarly, the collar  27  and rounded tip of the body  29  penetrates into the stent bore when the stent is held on the stent holder. 
         [0057]    With reference to the drawings, TABLE 1, below, summarizes possible ranges of dimensions for a stent holder. 
         [0000]    
       
         
               
               
               
             
           
               
                   
               
               
                   
                 Preferred size 
                 Range of sizes 
               
               
                 Dimension 
                 (mm) 
                 (mm) 
               
               
                   
               
             
             
               
                 A 
                 0.8 
                  0.1 to 5.0 
               
               
                 B 
                 9.0 
                 0.5 to 20 
               
               
                 C 
                 2.5 
                 0.2 to 15 
               
               
                 D 
                 9.0 
                 0.5 to 20 
               
               
                 Thickness of base 40 
                 0.8 
                  0.1 to 5.0 
               
               
                   
               
             
          
         
       
     
         [0058]    Referring to  FIG. 5  there is shown the stent holder and a stent  10  securely held thereon. The stent holder is being held at end  30   a  of the wire  30  and shaken within a release medium  14 . As can be appreciated more from this view, the small Z-Y plane profile of the holder provided by the retainer and base  20 ,  40  which hold the stent in place for a holders according to the disclosure causes much less disruption to the flow of release medium in the vicinity of the hidden or interior surfaces of the stent  10 . 
         [0059]    The first end  30   a  of the wire is held in an actuator  12  that imparts an oscillating force “F” to the assembly. The actuator  12  causes the stent holder and stent  10  to move about in the release medium  14  of the test tube  13 , thereby producing a real-time or an accelerated release of the drug into the release medium. As the holder is moved up and down, the slim profile in the Z-Y plane reduces significantly the interference of the flow over, around, through and into the drug-coated crevices or interior surfaces of the stent during the accelerated test. The ratio of width to thickness for the retainer  20  can be up to 7, greater than 7, or greater than 2, 3, 4, 5, and 6. 
         [0060]    The above description of illustrated embodiments of the invention, including what is described in the Abstract, is not intended to be exhaustive or to limit the invention to the precise forms disclosed. While specific embodiments of, and examples for, the invention are described herein for illustrative purposes, various modifications are possible within the scope of the invention, as those skilled in the relevant art will recognize. 
         [0061]    These modifications can be made to the invention in light of the above detailed description. The terms used in the claims should not be construed to limit the invention to the specific embodiments disclosed in the specification. Rather, the scope of the invention is to be determined entirely by the claims, which are to be construed in accordance with established doctrines of claim interpretation.