Patent Publication Number: US-2003225451-A1

Title: Stent delivery system, device, and method for coating

Description:
PRIORITY  
     [0001] This application claims priority to U.S. patent application Ser. No. 10/050,219 filed Jan. 14, 2002, which is incorporated herein by reference. 
    
    
     
       TECHNICAL FIELD OF THE INVENTION  
       [0002] The present invention relates generally to the field of implantable medical devices. More particularly, the invention relates to a stent delivery system and device having a coating, and a method for coating the same.  
       BACKGROUND OF THE INVENTION  
       [0003] Balloon angioplasty has been used for the treatment of narrowed and occluded blood vessels. A frequent complication associated with the procedure is restenosis, or vessel re-narrowing. Within 3-6 months of angioplasty, restenosis occurs in almost 50 percent of patients. In order to reduce the incidence of re-narrowing, several strategies have been developed. Implantable devices, such as stents, have been used to reduce the rate of angioplasty related restenosis by about half. The use of such devices has greatly improved the prognosis of these patients. Nevertheless, restenosis remains a formidable problem associated with the treatment of narrowed blood vessels.  
       [0004] Restenosis associated with interventional procedures such as balloon angioplasty may occur by two mechanisms: thrombosis and intimal hyperplasia. During angioplasty, a balloon is inflated within an affected vessel thereby compressing the blockage and imparting a significant force, and subsequent trauma, upon the vessel wall. The natural antithrombogenic lining of the vessel lumen may become damaged thereby exposing thrombogenic cellular components, such as matrix proteins. The cellular components, along with the generally antithrombogenic nature of any implanted materials (e.g., a stent), may lead to the formation of a thrombus, or blood clot. The risk of thrombosis is generally greatest immediately after the angioplasty.  
       [0005] The second mechanism of restenosis is intimal hyperplasia, or excessive tissue re-growth. The trauma imparted upon the vessel wall from the angioplasty is generally believed to be an important factor contributing to hyperplasia. This exuberant cellular growth may lead to vessel “scarring” and significant restenosis. The risk of hyperplasia associated restenosis is usually greatest 3 to 6 months after the procedure.  
       [0006] Prosthetic devices, such as stents or grafts, may be implanted during interventional procedures such as balloon angioplasty to reduce the incidence of vessel restenosis. To improve device effectiveness, stents may be coated with one or more therapeutic agents providing a mode of localized drug delivery. The therapeutic agents are typically intended to limit or prevent the aforementioned mechanisms of restenosis. For example, antithrombogenic agents such as heparin or clotting cascade IIb/IIIa inhibitors (e.g., abciximab and eptifibatide) may be coated on the stent thereby diminishing thrombus formation. Such agents may effectively limit clot formation at or near the implanted device. Some antithrombogenic agents, however, may not be effective against intimal hyperplasia. Therefore, the stent may also be coated with antiproliferative agents or other compounds to reduce excessive endothelial re-growth. Therapeutic agents provided as coatings on implantable medical devices may effectively limit restenosis and reduce the need for repeated treatments.  
       [0007] Several considerations should be made when devising a strategy for coating implantable prosthetic devices, such as stents or grafts. One consideration in coating strategy relates to surface uniformity. Ideally, coatings should be evenly applied with limited surface imperfections. Some coating strategies, however, may produce pooling of the coating material and/or dry spots. Failure to control surface uniformity may lead to inaccurate, non-uniform drug dose delivery and therapeutic variability from device to device. Therefore, it would be desirable to provide a uniform stent coating.  
       [0008] Another consideration in coating strategy relates to topography. It may be desirable for the coating to be disposed on certain areas of the stent. For example, stents typically have a wire mesh with open spaces formed between. Some coating strategies may leave ‘bridged’ material within the open spaces. Such coating bridges may break off causing complications or may prevent the device from expanding or functioning properly. As another example, only certain portions of the stent may require coating, or several coating layers may be required. As yet another example, a rough irregular coating will increase variability in drug elution and stent tracking, and increase thrombogenicity and the chance of coating damage during use. As such, it would be desirable to control the stent coating topography.  
       [0009] Another consideration in coating strategy relates to efficiency. It may be desirable to effectively coat the implantable device in relatively short time, with a minimal amount of coating material. Some coating strategies require lengthy steps, thereby reducing the amount of devices that can be coating within a certain period. In addition, some strategies do not utilize coating material in a complete manner thereby increasing cost. For example, coating material that is vaporized may get dispersed on areas other than the stent surface. Therefore, it would be desirable to efficiently coat the stent.  
       [0010] Accordingly, it would be desirable to provide a strategy for coating a stent that would overcome the aforementioned and other disadvantages.  
       SUMMARY OF THE INVENTION  
       [0011] One aspect of the present invention provides a stent delivery system. The system includes a catheter, a balloon operably attached to the catheter, and a stent disposed on the balloon. The stent includes at least one coating, the coating having an average surface roughness of less than 75 nanometers. The coating may include a therapeutic agent and may be substantially on an outer surface of the stent. The coating may be about 1 to 150 microns thick. The coating may have an average surface roughness of about 1 to 30 nanometers.  
       [0012] Another aspect of the invention provides a stent device. The stent device includes a body, and at least one coating, the coating having an average surface roughness of less than 75 nanometers. The coating may include a therapeutic agent and may be substantially on an outer surface of the body. The coating may be about 1 to 150 microns thick. The coating may have an average surface roughness of about 1 to 30 nanometers.  
       [0013] Another aspect of the invention provides a method for coating a stent. The method includes immersing a portion of the stent into a coating liquid, and withdrawing the immersed portion of the stent from the coating liquid. The method further includes simultaneously rotating the stent with respect to the coating liquid while the stent is being immersed and withdrawn. The method further includes drying the coating liquid adhering to the stent to form a coating, the coating having an average surface roughness of less than 75 nanometers. The rotation may force the coating liquid to an outer portion of the stent. Multiple layered coatings may be applied. Immersing the stent may include controlling a stent wetting characteristic. The stent may be immersed at a rate of about 0.1 to 60.0 millimeters per second, and for a time period of about 5 seconds to 10 minutes. The stent may be rotated at a rate of about 100 to 3,500 rotations per minute during immersion. Withdrawing the stent may include controlling a stent coating thickness, wherein the coating may be about 1 to 150 microns thick. The stent may be withdrawn at a rate of about 0.1 to 60.0 millimeters per second, and rotated at a rate of about 100 to 25,000 rotations per minute. The method may further include withdrawing the immersed portion of the stent from the coating liquid at a first withdrawal rate and withdrawing the immersed portion of the stent from the coating liquid at a second withdrawal rate. The method may further include programming a control sequence, and controlling at least one of the immersion, withdrawal, and rotation based on the control sequence. The coating may have an average surface roughness of about 1 to 30 nanometers.  
       [0014] Another aspect of the invention provides a stent device. The stent devices includes means for immersing a portion of the stent into a coating liquid, and means for withdrawing the immersed portion of the stent from the coating liquid. The stent device further includes means for simultaneously rotating the stent with respect to the coating liquid while the stent is being immersed and withdrawn. The stent device further includes means for drying the coating liquid adhering to the stent to form a coating, the coating having an average surface roughness of less than 75 nanometers. The stent device may further include a control sequence, and means for controlling at least one of the immersion, withdrawal, and rotation based on the control sequence.  
       [0015] The foregoing and other features and advantages of the invention will become further apparent from the following detailed description of the presently preferred embodiments, read in conjunction with the accompanying drawings. The detailed description and drawings are merely illustrative of the invention, rather than limiting the scope of the invention being defined by the appended claims and equivalents thereof. 
     
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
     [0016]FIG. 1 is a perspective view of a stent delivery system made in accordance with the present invention;  
     [0017]FIG. 2 is a perspective view of a prior art stent compatible with the disclosed coating process of the present invention;  
     [0018]FIG. 3 is a magnified view of two W-shaped elements of the stent in FIG. 2; and  
     [0019]FIG. 4 is a diagram of a stent coating process made in accordance with the present invention.  
     [0020] FIGS.  5 A- 5 D show stent surfaces for stents prepared by spraying and by the stent coating process of the present invention.  
    
    
     DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS  
     [0021] Referring to the drawings, wherein like reference numerals refer to like elements, FIG. 1 is a perspective view of a stent delivery system made in accordance with the present invention and shown generally by numeral  100 . The stent delivery system  100  includes a catheter  105 , a balloon  110  operably attached to the catheter  105 , and a stent  120  disposed on the balloon  110 . The balloon  110 , shown in a collapsed state, may be any variety of balloons capable of expanding the stent  120 . The balloon  110  may be manufactured from any suitable material such as polyethylene, polyethylene terephthalate (PET), nylon, or the like. In one embodiment, the balloon  110  may include retention means  111 , such as mechanical or adhesive structures, for retaining the stent  120  until it is deployed. The catheter  105  may be any variety of balloon catheters, such as a PTCA balloon catheter, capable of supporting a balloon during angioplasty.  
     [0022] The stent  120  may be any variety of implantable prosthetic devices capable of carrying a coating known in the art. In one embodiment, the stent  120  may have a plurality of identical cylindrical stent segments placed end to end. Four stent segments  121 ,  122 ,  123 , and  124  are shown, and it will be recognized by those skilled in the art that an alternate number of stent segments may be used. The stent  120  includes at least one coating applied dipping a portion of the stent  120  into a coating liquid while simultaneously rotating the stent  120 . In one embodiment, three coating layers  125 ,  126 , and  127  may be applied by a dip-spin coating process on various segments  121 ,  122 , and  124 . Segment  121  is shown having two coating layers  125 , and  126 . Segment  122  and segment  124  are shown each having one coating layer  125 , and  127 , respectively. Segment  123  is shown having no coating. The coating layers  125 ,  126 , and  127  are merely exemplary, and it should be recognized that other coating configurations are possible.  
     [0023] To describe the dip-spin coating process of the present invention, the following figures and description are provided. FIG. 2 is a perspective view of a prior art stent  130  compatible with the coating process of the present invention. Those skilled in the art will recognize that numerous stents, grafts, and implantable prosthetic devices are compatible with the disclosed coating method and that the described stent  130  example is merely one illustration of the process. The stent  130  is an example of a wire-tubular hybrid stent disclosed by U.S. Pat. No. 5,935,162 issued to Dang.  
     [0024] The stent  130  includes a generally tubular body defining a passageway extending along a longitudinal axis  131 . The stent  130  is formed from a plurality of cylindrical segments  132  arranged successively along the longitudinal axis  131 . Each of cylindrical segments  132  has a length along the longitudinal axis  131  and includes a plurality of W-shaped elements  135 . The W-shaped elements  135  open in alternating directions along the longitudinal axis  131  about the perimeter or circumference of the cylindrical segments  132 . The W-shaped elements  135  are connected to each other by a tie member  136  that is attached to center sections of each of the W-shaped elements  135 .  
     [0025] The stent  130  is shown in an expanded state in which the cylindrical segments  132  have been expanded radially outward from the longitudinal axis  131 . The stent  130  may be compressed into a smaller diameter for delivery within a vessel lumen at which point the stent  130  may be expanded to provide support to the vessel. The stent  130  may be of the self-expanding variety and manufactured from nickel titanium alloys and other alloys that exhibit superlastic behavior (i.e., capable of significant distortion without plastic deformation). Alternatively, the stent  130  may be designed to be expanded by a balloon or some other device, and may be manufactured from an inert, biocompatible material with high corrosion resistance. The biocompatible material should ideally be plastically deformed at low-moderate stress levels. Suitable materials include, but are not limited to, tantalum, MP35N, stainless steel, titanium ASTM F63-83 Grade 1, niobium or high carat gold K 19-22.  
     [0026]FIG. 3 is a magnified view of two W-shaped elements  135  of the stent  130  in FIG. 1. The surface of the W-shaped elements is shown with a polymeric coating  140  having coating anomalies  141 . The anomalies  141  may take on numerous configurations, but common examples include pooling  142 , dry spots  143 , and bridging  144 . The anomalies  141  are typically produced during an imperfect coating process. Ideally, a coating process should produce an even coating  140  free of pooling  142 , dry spots  143 , and bridging  144 . Such coating anomalies  141  may lead to inaccurate, non-uniform drug dose delivery and therapeutic variability. In addition, anomalies such as bridging  144  may break off causing complications or may prevent the stent  130  from expanding or functioning properly. For example, bridging  144  materials may enter the bloodstream thereby releasing therapeutic agents in undesired locations. Accordingly, it is desirable to minimize coating anomalies  141 .  
     [0027] Turning now to FIG. 4, a stent coating process made in accordance with the present invention is shown generally as numeral  150 . The coating process  150  provides one or more coatings on a portion of a stent device  160 . A stent device  160 , referred herein as “stent”, may be any number of implantable prosthetic devices capable of carrying a coating. The stent  160  may include a body  161  and at least one coating  162  rotationally applied to a portion of the body  161 , while the body  161  is at least partially immersed in a coating liquid  165 . The stent  160  may be manufactured from a skeletal framework or mesh of material forming a tube-like structure and may be capable of self-expanding or being expanded by another device such as a balloon. The stent  160  material may include any number of metallic and polymeric biocompatible materials recognized in the art for such devices.  
     [0028] To apply the coating  162 , the stent  160  may be slidably mounted on a cylindrically shaped mandrel  170  that is fixably attached to a rod  171 . The stent  160 , mandrel  170 , and rod  171 , may be moved during the coating process  150  by an actuator  180 . The actuator  180  may provide vertical  175  (e.g., immersion and withdrawal) and rotational  176  movements. The actuator  180  may include a logic chip  181  programmed with a control sequence to control timing, speed, directionality, and variations of the vertical  175  and rotational  176  movement characteristics. The actuator  180  may further include a keypad  182  and display  183  for modifying and viewing portions of the control sequence, respectively. The control sequence and corresponding movement characteristics may be actuated by one or more motors  185  controlled by the logic chip  181 . The motors  185  may be of any variety of electric motors, hydraulic units, and the like, recognized in the art for providing rotational and liner movements.  
     [0029] The stent  160  may be dipped in the coating liquid  165  carried within a compatible container  190  (i.e., inert with respect to the coating liquid  165 ). In one embodiment, the coating liquid  165  may be a polymeric solution. The polymeric solution may include one or more polymers, solvents, and therapeutic agents. The polymer may be dissolved in an appropriate solvent to provide a matrix for incorporating the therapeutic agent within the coating. Suitable polymers include, but are not limited to, urethane, polycaprolactone (PCL), polymethylmethacrylate (PMMA), polybutylmethacrylate (PBMA), and the like. Suitable solvents include, but are not limited to, acetone, ethyl acetate, tetrahydrofuran (THF), chloroform, N-methylpyrrolidone (NMP), and the like. Suitable therapeutic agents include, but are not limited to, antiangiogenesis agents, antiendothelin agents, antimitogenic factors, antioxidants, antiplatelet agents, antiproliferative agents, antisense oligonucleotides, antithrombogenic agents, calcium channel blockers, clot dissolving enzymes, growth factors, growth factor inhibitors, nitrates, nitric oxide releasing agents, vasodilators, virus-mediated gene transfer agents, agents having a desirable therapeutic application, and the like. Specific example of therapeutic agents include abciximab, angiopeptin, colchicine, eptifibatide, heparin, hirudin, lovastatin, methotrexate, streptokinase, taxol, ticlopidine, tissue plasminogen activator, trapidil, urokinase, and growth factors VEGF, TGF-beta, IGF, PDGF, and FGF. In a further embodiment, the drug coating composition may be fashioned using the drug 42-Epi-(tetrazolyl)-rapamycin, set forth in U.S. Pat. No. 6,329,386 assigned to Abbott Laboratories, Abbott Park, Ill. and dispersed within a coating fashioned from phosphorylcholine coating of Biocompatibles International pIc, set forth in U.S. Pat. No. 5,648,442.  
     [0030] The stent coating process  150  may begin by preparing the coating liquid  165 , such as a polymeric solution. In one embodiment, preparation of the polymeric solution may include dissolving polymer in solvent. The choice of solvent controls the ability to place the polymer into solution and, thus, should be considered. The use of solvent blends may also be considered. A blend of solvents may be preferred to ensure uniform coating  162  with a smooth surface. Solvent volatility may also be considered. Too rapid solvent evaporation may result in surface imperfections; too slow solvent evaporation may result in handling defects as well as high solvent retention. As such, the polymer-solvent solution should ideally provide a uniform coating  162 , smooth surface without major imperfections, and little to no solvent retention. In one embodiment, the polymer-solvent solution may have a solids range from about 1 to 10 percent and a viscosity of about 5 to 30 centipoise.  
     [0031] One or more therapeutic agents may be added to the polymeric solution. Ideally, the polymer-solvent solution should be capable of dispersing the agent evenly throughout the solution. Furthermore, the polymer-solvent solution should not chemically alter the therapeutic character of the agent. Examples of suitable polymer/solvent therapeutic agent combinations include: polylactic acid/trichloroethane/colchicines; polyurethane/THF/taxol; (poly(D,L-lactide)/PCL)/dimethylformamide/hirudin; (poly(D,L-lactide)/polygycolide)/ethylacetate/ticlopidine; and polyethylene oxide/ethanol/heparin. These combinations are merely exemplary, and it should be recognized that other combinations are possible.  
     [0032] After the polymer and therapeutic agent have been dissolved in the solvent, the polymeric solution may be aged and cleared. In one embodiment, the solution may be mixed for 12 or more hours while being stirred to ensure complete dissolution and homogeneity. The solution may also be filtered with an appropriate filter to remove any impurities land haziness. Those skilled in the art will recognize that the preparation of the coating liquid  165  may vary greatly and may be contingent upon the materials used. After the coating liquid  165  has been prepared, it may be transferred to the container  190 .  
     [0033] The stent  160  mounted on the mandrel  170  may begin rotation as effected by the actuator motor  185 . The stent  160  may be rotated initially at a rate of about 100 to 3,500 rotations per minute (rpm). More preferably, the stent  160  may-be rotated at about 500 to 700 rpm. The stent  160  may then be immersed in the coating liquid  165  at a rate of about 0.1 to 60.0 millimeters per second (mm/sec). More preferably, the stent  160  may be immersed at a rate of about 0.5 to 15.0 millimeters per second. The immersion may continue until the stent body  161  portion requiring coating has been immersed. The stent  160  may be immersed for a total time of about 5 seconds to 10 minutes. More preferably, the stent  160  may be immersed for about 5 to 20 seconds. The immersion time may control a stent wetting characteristic; the characteristic relating to how completely the stent is covered with the coating liquid  165 . Ideally, the stent  160  should be evenly “wetted” free from any dry spots. A lower viscosity coating liquid  165  generally require shorter immersion time. The temperature of the coating liquid  165  affects its viscosity and, therefore, may also be a factor in determining immersion time.  
     [0034] Once the stent  160  has been immersed, the stent  160  may begin withdrawal wherein it is rotated at about 100 to 25,000 rpm. More preferably, the stent  160  may be rotated during withdrawal at a rate of about 500 to 3,000 rpm. The rate of rotation during withdrawal may influence the uniformity of the coating  162 . For example, too slow rotation during withdrawal may lead to coating pooling; too fast rotation may excessively remove coating material. The stent  160  may be withdrawn at a rate of about 0.1 to 25.0 mm/sec. More preferably, the stent  160  may be withdrawn initially at 0.1 mm/sec and then at 0.7 mm/sec providing a uniform coating  162 . The withdrawal rate may control a coating thickness. Generally, faster withdrawal rates produce greater coating thickness. The coating  162  may be in the range of about 1 to 150 microns thick. More preferably, the coating  162  may be about 5 to 30 microns thick. The rotating stent  160  may experience a significant centrifugal force  177 . The coating liquid  165  may be forced substantially from an inner to an outer surface portion of the stent  160 . As a result, the bulk of the coating  162  and integral therapeutic agent may be positioned proximate to where the stent  160  contacts the vessel wall. This topography may provide efficient coating liquid  165  utilization and an effective drug delivery method.  
     [0035] Another factor affecting the coating process  150  pertains to the manner in which the coated stent  160  is dried. Ideally, the coated stent  160  should be dried to allow for a desirable rate of solvent evaporation. For example, too rapid drying causes moisture to be entrained in the coating  162  causing surface blemishes; too slow drying increases solvent retention. The drying conditions may vary greatly and are generally dependant upon the nature of the coating liquid  165  and, to a great extent, the solvent used. After the coating  162  has dried, the stent coating process  150  may be repeated to provide additional coating(s) positioned on top of, or on other locations of the stent  160 .  
     [0036] The described stent coating process  150  may provide a coating  162  that is controllable, uniform, efficient, and free from bridging and pooling anomalies. The process  150  may be optimized by customizing the timing, speed, directionality, and variations of the vertical  61  and rotational  62  movement characteristics. These characteristics may be adjusted based on the nature of the stent  160  and coating liquid  165  used. The concurrent spinning and dipping of the stent  160  may speed the rate at which the coating  162  is applied. In addition, the process  150  may provide efficient utilization of coating liquid  165 . Accordingly, the process  150  may reduce the time and cost of conventional coating strategies.  
     [0037] FIGS.  5 A- 5 D show stent surfaces for stents prepared by spraying and by the stent coating process of the present invention. The figures illustrate the improvement in surface smoothness possible with the method of the present invention. A smooth stent coating is less thrombogenic than a rough stent coating. During manufacture, a smooth stent coating provides better control and precision in determining the amount of drug or therapeutic agent in the stent coating, regulating the amount of drug absorbed for coatings that are drug loaded by absorption, and regulating coating thickness for multiple layered coatings. During implantation, a smooth stent coating provides increased contact area, retaining the stent on the balloon more firmly and tracking (seating) the stent at the implant location more precisely. During use, a smooth stent coating provides more control of drug elution. In addition, a smooth stent coating avoids coating damage because the smooth stent coating lacks the peaks and rough spots that may be broken off when the stent is implanted through the customary tortuous path.  
     [0038] The data for the stent surfaces were collected using an atomic force microscope (AFM) with nanometer resolution. The stent coatings of FIGS. 5A &amp; 5B are baseline coatings for comparison prepared by the conventional method of spraying the coating on the stent. The stent coatings of FIGS. 5C &amp; 5D were prepared by dipping and rotating the stent according to the present invention. The stent coatings for FIGS.  5 A- 5 D were applied to a production stent made of 316L stainless steel covered with a 0.1 to 0.2 micron thick epoxy primer. The stent coatings for FIGS.  5 A- 5 D were formed from a coating liquid comprising in part polybutylmethacrylate (PBMA) dissolved in chloroform.  
     [0039] The coating liquid forming the stent coatings of FIGS. 5A &amp; 5B was sprayed on the epoxy primed base stent. The coating liquid was applied manually using a pneumatic atomizer at a distance of 2 to 10 centimeters and a flow rate of 1 to 5 cubic centimeters per minute.  
     [0040] The coating liquid forming the stent coatings of FIGS. 5C &amp; 5D was applied to the epoxy primed base stent with the dipping and rotating method of the present invention. The base stent was rotated at 700 revolutions per minute and immersed in the coating liquid at 10 millimeters per second (mm/sec). The stent was immersed for 10 seconds, and then withdrawn from the coating liquid at 40 mm/sec. The stent was rotated at 700 revolutions per minute for 5 seconds after the stent was fully withdrawn from the coating liquid. After drying, the coating thickness was about 1.5 microns.  
     [0041] The average surface roughness and maximum peak heights for the stent coatings applied by the dipping and rotating method were much less than the stent coating applied by the spray method. The spray baseline cases of FIGS. 5A &amp; 5B had respective average surface roughness (Ra) of 142 nanometers and 77 nanometers, with respective peak heights of 842 nanometers and 1.15 micrometers. The dipping and rotating cases of FIGS. 5C &amp; 5D had respective average surface roughness (Ra) of 2.35 nanometers and 16.3 nanometers, with respective peak heights of 2-6.5 nanometers and 400 nanometers.  
     [0042] The test results presented in FIGS.  5 A- 5 D are illustrative only and are not intended to limit the scope of the present invention. Similar results would be expected for different base stent materials; coating liquids containing different polymers, co-polymers, and solvents; and for different method parameters, such as rotation rate and immersion time.  
     [0043] While the embodiments of the invention disclosed herein are presently considered to be preferred, various changes and modifications can be made without departing from the spirit and scope of the invention. For example, the stent configuration is not limited to any particular stent design. In addition, the coating liquid composition and coating process movement characteristics may be varied considerably while providing a desirable coating. Upon reading the specification and reviewing the drawings hereof, it will become immediately obvious to those skilled in the art that myriad other embodiments of the present invention are possible, and that such embodiments are contemplated and fall within the scope of the presently claimed invention. The scope of the invention is indicated in the appended claims, and all changes that come within the meaning and range of equivalents are intended to be embraced therein.