Abstract:
A medical fluid flowline connector comprised of axially aligned relatively rotatable male and female Luer parts and an axially compressible elastomeric seal therebetween. An elastomeric stopper may be provided in the female Luer, the stopper having a swabbable end urged outwardly of the female Luer. The stopper is guided on an axially extending elongated flow conducting insert which has an end which contacts a deformable slit in the swabbable end of the stopper to ensure deformation and opening of the slot as a male Luer at the end of a fluid flowline is pushed against the stopper. The stopper skirt is deformed and displaced into annular space between the female Luer and the insert, the stopper having bellows like walls which engage the female Luer and insert. A retrograde flow preventer may be positioned in the fluid flow path comprising a resilient member having a perforation which remains closed when its exterior surface is exposed to retrograde flow of medication or blood and which may open when its interior surface is exposed to sufficient negative flow pressures as when drawing blood.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
   This application is a continuation in part of U.S. application Ser. No. 10/376,886 filed Feb. 28, 2003 now U.S. Pat. No. 7,118,560 by Jean M. Bonaldo for a NEEDLELESS LUER ACTIVATED MEDICAL CONNECTOR and assigned to the assignee of the present invention. 

   BACKGROUND OF THE INVENTION AND PRIOR ART 
   The present invention relates to connectors for use in medical flow lines for blood transfer, intravenous medication and nutritional supply, and the like. In accord with usual medical terminology, the connector may be referred to as having distal and proximal ends respectively designating the ends of the connector which are ordinarily positioned nearest and farthest from the patient. 
   U.S. Pat. No. 5,273,533 issued Dec. 28, 1993 and U.S. Pat. No. 5,306,243 issued Apr. 26, 1994 to Bonaldo each disclose a medical connector having an elastomeric element in the form of a septum or fluid barrier disposed in a two part plastic housing. The septum is pierced by a pointed cannula in the connector when making the connection to the fluid flowline. Disconnection of the flow line allows the elastomer to re-seal the connector. Repeated usage of such connectors may cause the connector to leak or become contaminated with particulate material such as particles which may detach from the septum. Repeated disconnection of the flowlines from the connector and decontamination of the connector and flowlines, as by swabbing with alcohol, is at least a daily occurrence. Thus, these connectors may be actuated or cycled many times and must remain leak free and reliably avoid introduction of contaminants such as cotton fibers from swabs used to clean the connectors into the flowline. 
   Medical connectors which use resilient flow barriers which are repeatedly pierced during use of the connector become more subject to fluid leakage with increased actuation cycles, particularly if connected in an infusion pump line which may subject the connector to pressures as high as 27 psi. U.S. Pat. No. 5,947,954 issued Sep. 7, 1999 to Bonaldo, the teachings of which are incorporated herein by reference, discloses a needleless connector which is addressed to the above concerns which includes attached relatively rotatable male and female Luer connector parts with an eccentrically positioned flow passageway at the inner end of the female Luer connector. A removable plastic plug, permanently attached to the connector by a strap, and which fulfills the function of a cleansing swab for the female Luer connector is also provided as an optional feature. 
   Although the removable plug when properly used closes the female Luer when the female Luer is not connected to a flowline, it has been found in practice that additional manipulation of the plug is required for proper use and that the plug can inadvertently become dislodged leaving the female Luer open to atmosphere and possible contamination. Accordingly, a more reliable and easy to use swabbable stopper for the female Luer part of the connector has been developed which always remains in proper position yet which also permits easy connection/disconnection of the male Luer end of a flowline to/from the connector valve is disclosed and claimed in a more recent U.S. Pat. No. 6,364,869 issued Apr. 2, 2002 to Bonaldo, the full teachings of which are also incorporated herein by reference. This stopper has an exterior end which essentially completely closes the otherwise open end of the female Luer when the connector is not in use to prevent introduction of fibers or other contaminants into the flow path in the connector. However, since fluid flow takes place along the outside of a stopper guide post mounted in the connector, it has been found that fluid may remain in the annular space between the post and inside wall of the swabbable stopper. 
   There remains a need to provide a further improved medical connector which includes a female Luer end having a swabbable elastomeric stopper which still further reduces the likelihood of contaminant entry to the fluid flow path. Also, there remains a need for a connector which has readily observable indicators thereon to enable the user to determine if the relatively rotatable parts of the connector are positioned to place the connector in the open or closed position. 
   Medical connectors are provided in fluid flowlines which ordinarily deliver blood, plasma or medication to a patient by gravity flow or with the assistance of an infusion pump. Often, when the medication in the container is exhausted, a pressure condition can be created by the patient&#39;s vascular pressure which results in retrograde flow of medication back from the patient to the flowline. Also, since it is frequently necessary to interrupt the flow of fluid to the patient as when changing the supplies of blood, plasma or medication or when it is necessary to draw blood from the patient, positive fluid pressure in the flowline which is ordinarily present is absent and undesired retrograde flow of blood from the patient into the flowline may take place. Retrograde flow is ordinarily prevented by inserting a separate one-way valve such as a duckbill valve, sometimes referred to as a heparin lock, in the flow line. Duckbill valves remain open under positive line pressure during delivery of flow to the patient but automatically close to prevent retrograde flow of medication and blood when delivery pressure is absent. The one-way valves used in the prior art, although effective for preventing retrograde flow, must be separately installed in the flowline and prevent the drawing of blood unless the one-way valve is removed from the flowline. Further improvements in medical connectors such as the connectors referred to in the above Bonaldo patents are desired to provide connectors having a self contained means of preventing retrograde flow of medication and blood and which permit the drawing of blood when desired. 
   SUMMARY OF THE INVENTION 
   Disclosed herein is a medical connector having a longitudinal axis and interconnected axially aligned relatively rotatable male and female Luer parts aligned to provide a housing whereby relative rotation of said parts opens and closes a fluid flow path through the connector, the parts being configured for connection to external male and female Luer flowlines. The device includes a fluidic channel insert, also referred to herein as a flow conducting insert, which is non-rotatably supported in the female Luer part. The insert has an internal fluid passageway extending from a first axially aligned end to a second end, said second end being offset from the connector axis. A compressible seal is positioned in the male Luer part and abuts the second end of the insert, the seal having a flow passageway extending between a first axially offset end at the second end of the insert to an axially aligned second end, such that said ends of said flow passageways in abutting ends of the insert and seal may be aligned to open a fluid flow path through the connector. An elastomeric stopper is mounted over the insert, the stopper having a swabbable end providing a deformable normally closed opening which may be opened when the swabbable end of the stopper is pushed over the end of the insert by an external male Luer received in said female Luer part. The stopper has an annular axially collapsible skirt engaged with the female Luer part and insert. 
   Also disclosed is a medical connector having interconnected axially aligned relatively rotatable parts forming a housing, the parts being configured for connection to external male and female Luer flowlines, a compressible seal in the housing having a flow passageway extending from an axially aligned end to an axially offset end whereby relative rotation of said parts opens and closes a fluid flow path through said connector; and a retrograde flow preventer positioned in the fluid flow path. The retrograde flow preventer is comprised of or includes a resilient member having a perforation which remains closed at patient vascular pressures to which an exterior surface of the preventer is exposed when flow, such as medication or blood, is not being delivered to the patient and which opens when an interior surface is exposed to flow pressures when administering medication or blood to a patent as by gravity or infusion pump pressures. 
   A swabbable stopper having a unique configuration is also disclosed and claimed. 

   
     BRIEF DESCRIPTION OF THE DRAWINGS 
     In the accompanying drawings: 
       FIG. 1  comprises an exploded perspective view of the presently preferred embodiment of a medical connector according to the present invention including a contamination cap for a male Luer part; 
       FIGS. 2A and 2   b  comprises a longitudinal cross-section views showing the medical connector of  FIG. 1  with a swabbable stopper at the end of the female Luer part and with the connector in the closed position; 
       FIG. 3A  is a view like  FIG. 2A  with the stopper end displaced from the  FIG. 2A  position by an external male Luer in a flowline and showing the connector in the open position; 
       FIG. 3B  is a portion of  FIG. 3A  to a substantially enlarged scale; 
       FIG. 4  is a cross-sectional elevation of a female Luer housing part; 
       FIG. 5  is a left end view of the female Luer housing part; 
       FIG. 6  is a right end view of the female Luer housing part; 
       FIG. 7  is a cross-sectional elevation of a male Luer housing part; 
       FIG. 8  is a left end view of the male Luer housing part; 
       FIG. 9  is a right end view of the male Luer housing part; 
       FIG. 10  is a cross-sectional elevation view of the swabbable stopper; 
       FIG. 11  is a left end view of the stopper; 
       FIG. 12  is a right end view of the stopper; 
       FIG. 13  is a cross-sectional elevation view of the flow conducting insert; 
       FIG. 14  is a left end view of the insert; 
       FIG. 15  is a right end view of the insert; 
       FIG. 16  is a perspective view of a seal; 
       FIG. 17  is a left end view of the seal; and 
       FIG. 18  is a right end view of the seal. 
       FIG. 19  is a perspective view like  FIG. 16  of a modified seal having a first form of retrograde flow preventer integrally formed therewith. 
       FIG. 20  is an end view of the modified seal of  FIG. 19 . 
       FIGS. 21A and 21B  are longitudinal cross section views of the modified seal taken at lines A-A and B-B of  FIG. 20 , respectively. 
       FIG. 22  is a view like  FIG. 2A  showing a connector having the modified seal of  FIG. 19  therein. 
       FIG. 23  is a perspective view of a second form of retrograde flow preventer. 
       FIG. 24  is an end view of the retrograde flow preventer of  FIG. 23 . 
       FIG. 25  is a side view of the retrograde flow preventer of  FIG. 23 . 
       FIG. 26  is a view like  FIG. 2A  showing a connector having the second form of retrograde flow preventer therein. 
   

   DESCRIPTION OF THE PREFERRED EMBODIMENTS 
   The medical connector  10  in which the present invention is used comprises essentially a five part connector comprising a housing formed by a male Luer configured part  20  connected to a female Luer configured part  30  with a cylindrical resilient seal  40  the outer edges of which are compressed between a valve seat  22  formed at the end wall in the male Luer part  20  and an end wall  32  of the female Luer part  30 . The male Luer part  20  and female Luer part  30  are aligned on a common longitudinal axis and are rotatable with respect to each other through an angle of preferably about 180° around the longitudinal axis to activate and deactivate the connector by opening and closing flow passageway through the connector. The female Luer part  30  includes a collar  31  having a face which abuts an end face of the male Luer part  20 , preferably along a transverse or radial plane. The collar  31  functions to block ingress of fluid which may be spilled during disconnection of an external male Luer  100  axially between the facing portions of the male and female Luer parts  20 ,  30  since any spilled fluid ordinarily contacts the left end or side (as viewed in the drawings) of the female Luer  30 . The Exteriorly exposed surfaces adjacent the abutting faces are provided with visible or tactile indicia such as arrows  33 ,  43  which may be aligned by relative rotation of the female and male Luer parts  20 ,  30  to indicate the activated and deactivated, i.e., the full open and closed positions of the connector. 
   A longitudinally extending rib  37  inside the male Luer part  30  slides along a cam surface on the exterior of the right end of the female Luer part  30  and snaps into one of two axially extending cam grooves  27  on the exterior surface of the right end of the female Luer part when the Open and Closed indicia  33 ,  43  are aligned at the full open and full closed positions of the connector. The grooves  27  and finger  37  are preferably configured as shown in  FIGS. 6 and 8  with curved portions bounded by flat generally radially extending sides at the ends of the curved portions to assure proper full open and full closed relative positioning of the parts  20 ,  30 . A concave gripping surface  21  on the male Luer part  20  may include elongated indentations or other roughening to facilitate fingertip gripping of the connector. 
   As seen in  FIGS. 1-3  and  7 - 9 , the male Luer part  20  includes an internal flow passageway  24  in a frusto-conical Luer tapered male extension  26  and an internally threaded skirt  28  for connection to an external female slip or lock Luer in a flowline. The female Luer part  30  has an internal frusto-conical Luer taper at its left end as seen in the drawings and is also configured as a lock Luer externally threaded at  34 ; however, either or both of the Luer parts  20 ,  30  can be configured instead as a slip or as a threaded lock Luer part. As shown, it will be apparent that the female Luer  30  is configured so that it may receive either an external male lock Luer or an external male slip Luer to make the fluid connection. Similarly, internal threads  29  are provided inside the skirt  28  of the male Luer part  20  so that it can be readily connected to either an external female lock Luer or an external female slip Luer. 
   The fluid flow passageway  24  in the male Luer part  20  extends longitudinally from the male extension part  26  to the valve seat  22 . The female Luer part  30  shown in  FIGS. 1-3  and  4 - 6 , has an axially extending internal cavity  36  which may have an end portion  38  of non-circular configuration, for a purpose to be described. 
   The seal  40  (see  FIGS. 16-18 ) has a generally cylindrical shape with a fluid flow passageway  44  extending from an axially aligned end  46  in fluid communication with passage  24  to an off-center positioned end  48 . The seal  40  is made of a firm but compressible elastomer, preferably silicone, the peripheral edge of which is preferably partially compressed between the valve seat  22  and the end wall  32  of the female Luer housing during assembly of the valve. The seal  40  has at least one and preferably three axially extending grooves  43  on its annular surface which mate with axially extending ribs  23  ( FIG. 8 ) in the male Luer part  20  to non-rotatably position the seal  40  in the male Luer part  20 . A longitudinally extending locating groove  45  is also provided on the annular surface of the seal  40  so that the seal  40  may be inserted into the male Luer part  20  along the finger  37 . 
   A male end Luer contamination cap  50  which may be made of polyethylene plastic, may be provided for enclosing the extension  26  of the medical connector during shipment or when not in use. 
   As seen in  FIGS. 10-12 , a swabbable elastomeric stopper  60  having a normally closed end  62  and a depending corrugated skirt  64  is slidably mounted in the female Luer part  30  to normally close the open end thereof. A transversely extending slit  66  is provided through the normally closed end  62  of the elastomeric stopper  60  so that the slit can be opened when a male Luer end  102  of an external lock Luer  100  ( FIG. 3A ) engages the end  62  to push it over the end of a flow conducting insert  90  (to be described) when a flowline connection is made to the connector. It will be understood that the slit  66  may be a single transversely extending slit or two or more slits in form of a cross or any other functionally equivalent configuration such that the normally closed end  62  of the stopper  60  may be displaced as desired by the male Luer end  102  when a flowline connection is made. The stopper  60  also has an annular collar  68  which slidably engages the interior annular wall of the cavity  36  in the female Luer part  30  and a cylindrical end  69  which engages and seals off between the inside of the female Luer and the exterior of the insert  90  which also functions as a stopper guide. 
     FIGS. 13-15  show the fluidic channel insert or fluid conducting insert  90 , which may be made of polycarbonate, polypropylene, polyethylene or the like. The insert  90  may be integrally formed as shown or of multi-piece construction with a rigid or axially collapsible lumen having a central flow passageway  92 . Axial collapsibility of the insert  90  is preferably provided by making the insert  90  of polypropylene or polyethylene with flexible corrugations  98  near the heel  96  of the insert  90 . The corrugations  98  are not considered essential but, if provided, permit slight axial collapsibility of the insert  90  if contacted during activation by the end of an external male Luer  100 . This avoids force transmission by the insert  90  and undesired deformation of the seal  40 . Preferably the insert  90  is rounded at its left end as seen in the drawings for opening the slit  66  without damage. The flow passageway  92  axially extends from the left end of the insert  90  to an offset opening  94  in an end which provides a seat for the swabbable stopper  60 , the seat being hereinafter referred to as a heel  96  due to its non-circular configuration shown in the drawings, at the other end of insert  90 . The heel  96  is non-rotatably positioned in non-circular end portion  38  of the internal cavity  36  in the female Luer part  30  and is preferably restrained from axial sliding relative to the female Luer part  30  by an interference or press fit. Other complementary non-circular configurations of the heel  96  and end portion  38  can of course be chosen instead of the heel configuration depicted and those skilled in the art will appreciate that non-circular configurations, while preferred, are not essential. 
   Fluid flow is conducted through the connector from an external fluid flowline through the normally closed slit or slits  66  in the end wall  62  of the stopper which are displaced to the open position by engagement of the end wall  62  with an external male Luer  100 , the end  102  of which pushes the end  62  of the stopper  60  to the right as best shown in the enlarged scale  FIG. 3B  so that the end of the insert  90  opens the slit or slits  66  allowing fluid flow axially through the flow passageway  92  in the insert  90  to the offset opening  94 , then through the passageway  44  in the elastomeric valve element  40  to the passageway  24  in the male Luer extension  26 . 
   The resiliency and configuration of the skirt  64  of the swabbable stopper  60  are selected such that, during insertion of the external male Luer  100  into the female Luer part  30 , the end  102  of an external male Luer  100  first engages the end wall  62  of the stopper which in turn is pushed over the rounded end of the insert  90  with the end wall  62  folding and compressing between the end  102  of the external male Luer and the insert  90  to prevent fluid entry into the annular space between the stopper  60  and the insert  90  as seen in  FIG. 3A . Note that the end of the external male Luer  100  also engages the end  62  of the stopper  60  to prevent fluid leakage to annular space between the stopper  90  and interior wall of the female Luer part  30 . The bellows portion of the skirt  64  between the collar  68  and the open end  69  of the skirt is compressed in the annular space between the inside wall of the female Luer part  30  and the outside wall of the insert  90  by engagement of at least some of the pleats of the bellows with the confining walls. It will be noted from viewing  FIGS. 2A and 2B  that the right end of the stopper  60  is also engaged with both the inside wall of the female Luer and the outside of the insert even when no flowline connection is made and when the end wall  62  of the stopper is flush with the end of the female Luer  30 . 
   It will also be noted that the stopper collar  68  preferably axially engages an internally projecting stop shoulder  35  inside the female Luer part  30  with some axial compression of the stopper skirt  64  to provide a slight pre-load, and that the open end  64  of the skirt continuously engages and is resiliently seated against the heel  96  on the insert  90  to retain the swabbable stopper in position. Also, the stopper  60  can be retained in position in the female Luer in any other suitable fashion, for example by adhesive bonding to the heel  96  of the insert  90  in which instance the skirt collar  68  and abutting shoulder  35  in the female Luer are unnecessary. 
   Axial pressure which may be exerted on the insert  90  during connection by the external male Luer  100  may slightly move the insert to the right as seen in  FIG. 3  if the insert  90  is slidably fitted into the female Luer. This may serve to further compress the seal  40  whose outer edge preferably has already been slightly compressed by the end wall  32  of the female Luer part  30  during assembly into the male Luer part  20 . This compression of the seal may be avoided by use of the corrugations  98  on the insert  90  as described above. The Luer parts  20 ,  30  are preferably connected together by a snap fit provided by a mating annular groove and collar depicted at  29 . The stopper skirt  64  may have what is described as a bellows or accordion like configuration as shown or it may be of sine wave or any other functionally equivalent configuration suitable for its intended purpose. 
   In the deactivated or closed position of the connector seen in  FIGS. 2A and 2B , the bellows configuration of the skirt  64  of the stopper  60  urges the stopper end  62  outwardly of the female Luer part  30  so that the outer surface of the normally closed end  62  of the stopper  60  is substantially aligned or flush with the outer end of the female Luer part  30 . This position is assured by provision of the skirt collar  68  and its engagement with the stop shoulder  35  in the female Luer part  30  at the positions shown. This permits easy swabbing of the stopper whenever the flowline is disconnected from the connector and prior to the making of a new connection thereto. 
   Needleless medical connectors constructed as above described eliminate exposure to diseases such as hepatitis and HIV caused by needle sticks and are suitable in various medical flow lines low pressure gravity drips as well as highly pressurized fluid flow lines due to the relatively straight fluid flow path through the connector which substantially eliminate sharp bends and other internal flow restrictions in the fluid flow passageways  92 ,  94 ,  44 ,  24 . The connector can therefore be safely used for gravity blood transfusions without concern that pressurization induced by an infusion pump may degrade delicate blood cells. 
   All dead annular space between the female Luer part  30  and the swabbable stopper  60  and between the swabbable stopper and the lumen of the insert  90  is sealed from fluid entry by engagement of the walls of the stopper  60  and the adjacent parts. This feature results in minimization of potential infections resulting from solid and bacterial contaminants from fluid which may collect or stagnate in dead space as well as reduction in the amount of fluid, such as expensive medication, required to prime the connector prior to activation since only the internal passageways  92 ,  94  in the connector need be filled with priming fluid. 
   Negative pressure (suck back) upon disconnection of the external male Luer  100  is prevented simply by ensuring that the male and female Luer parts have been rotated to the Closed position prior to disconnection. 
   The connector may be made of clear plastic materials to enable visualization of the flow path and the parts may be readily injection molded and assembled without the use of ultrasonic welding or adhesives, swaging or additional fasteners of any kind. 
     FIGS. 19-21  depict a modified seal  40 , preferably of silicone, having a first form of retrograde flow preventer  110  integrally formed with the seal  40 . The retrograde flow preventer  110  is preferably formed as a thin protruding envelope  112  of the same resilient material of which the seal  40  is molded, preferably silicone. The envelope  112  has a fluid flow passageway therein which terminates in a normally closed transverse flow conducting slit  114  which automatically opens when the interior surface of the retrograde flow preventer  110  is exposed to normal pressures present when medication or blood is delivered by gravity or an infusion pump to the patient (the left to right direction in  FIG. 19 ). The opposed broad sides of the envelope  112  of the retrograde flow preventer  110  are designed to automatically come together due to inherent resilience of the material from which they are molded to close the slit  114  whenever fluid delivery pressures are no longer present to prevent retrograde flow of medication or blood (right to left direction in  FIG. 19 ) at patient vascular pressures. 
   Preferably, the envelope  112  is also designed to open by collapsing rearwardly into the fluid flow passageway  44  of the seal  40  when sufficiently high negative pressures are applied to the interior surface of the retrograde flow preventer  110 , as when using an aspirating syringe to draw blood from the patient. Other configurations of retrograde flow preventers  110  such as cylindrical, rectangular, conical or pyramid shape can also be integrally formed with the seal  40  and provided with any suitable configuration of flow conducting slit or slits or other perforations operable for the intended purposes. 
   By way of example and without limitation, the seal  40  may be formed of resilient elastomer such as clear silicone with the side walls of the envelope  112  having a wall thickness in the range of 0.10″-0.15″ and a length L ( FIG. 21B ) in the range of 0.030″-0.040″. The end wall through which the slit  114  is made may have a wall thickness of about 0.010″. 
   To receive the modified seal  40  and integral retrograde flow preventer  110  which protrudes from the modified seal  40 , a recess  116 , preferably cylindrical, is formed in the male Luer part  20 . Note that a clearance space  118  between the external sides of retrograde flow preventer  110  and the side wall of the recess  116  is provided. The clearance space  118  is intended to fill with retrograde flow of medication or retrograde flow of blood when medication is not being delivered to the patient so that the pressure of this fluid will be exerted on the external side of the envelope  112  to assist in keeping the slit  114  closed under these conditions 
   A second form of retrograde flow preventer  120  is depicted in  FIGS. 23-26 . In this embodiment, the retrograde flow preventer  120  comprises a separate part preferably formed, at least in part, of resilient elastomer such as silicone or similar material. As with the first form of retrograde flow preventer, the preventer  120  may have the configuration of an envelope  122  having a transverse slit  124  or it may be of any other suitable configuration such as conical or pyramid configuration. The preventer  120  may have a rim  126  at its base which may be closely received in a seating groove  128  in the recess  116 . The retrograde flow preventer  120  functions in essentially the same manner as the first form of retrograde flow preventer  110 . 
   Negative pressure (suck back) upon disconnection of the external male Luer  100  is automatically prevented by use of either the first or the second form of retrograde flow preventers  110 ,  120  described above even if the male and female Luer parts have inadvertently not been rotated to the Closed position prior to disconnection. 
   A further optional feature of the invention comprises the provision of a cam surface on the end of the female Luer part  30  such that rotation of the Luer parts  23 ,  30  to the Closed position urges the seal  40  more tightly against its seat in the male Luer part  20 . One suitable form of achieving this result comprises a dimple  130  integrally formed on the end of the insert  90  in the position shown in  FIGS. 13-15 . This feature is beneficial in squeezing the seal  40  into the clearance space  118  ro minimize the amount of fluid which would otherwise remain therein. 
   Prior to the use of needleless medical connectors, a typical clinical protocol would require the clinician to add a heparin lock to the IV system for “locking in” heparin at the end of a medication delivery so that a flowline would not clot off. this heparin protocol is still widely used today. The needleless Luer activated medical connectors disclosed herein with retrograde flow prevention are particularly beneficial since the prevention of retrograde flow eliminates the need for a heparin lock and permits a saline flush to be used after administration of medication rather than the typical heparin flush which many patients cannot tolerate. 
   While the foregoing constitutes a complete description of the invention, it will be appreciated by persons skilled in the art that changes and modifications of an obvious nature can be made from the illustrated embodiment and that such changes and modifications are considered within the scope of protection which is to be evaluated solely with respect to the attached claims.