Abstract:
A stopper for use in preventing any volume of gas from escaping from a drug container when used in connection therewith. The stopper has a body having a perimeter for slidable engagement with the interior of a drug receptacle; an outer surface; and an inner surface facing the bottom of the drug receptacle, the inner surface shaped so as to trap any volume of gas located within the drug receptacle when the body is slidably engaged therein. The invention is further directed to a drug container having a hollow body for holding a liquid. The body has an open end and a closed end. The container also has a stopper slidably received in the hollow body, and a feature for entrapping any volume of gas within the container.

Description:
This application claims the benefit of provisional application No. 60/103,586, filed Oct. 9, 1998. 
    
    
     TECHNICAL FIELD 
     The present invention relates to devices and methods for entrapping gas in liquid drug containers, and in particular relates to drug cartridges and stoppers for filling drug delivery devices, and methods relating to such filling. 
     BACKGROUND OF THE INVENTION 
     For reasons of stability and accuracy of delivery it is often desired to store a liquid drug in a container such as a standard drug cartridge. Such cartridges may typically be cylindrical and be sealed at an open end by a penetrable stopper or piston. To release the drug, the stopper is typically punctured by a hollow needle and then moved along the length of the container whereupon it acts as a piston to pump liquid drug from the container through the needle. Such cartridges are typically used in pre-filled syringes of the type manufactured by IMS of So. El Monte, Calif., U.S.A. and by Abbott Laboratories of N. Chicago, Ill., U.S.A. and also in the infusion system, which is the subject of WO 95/13838. 
     If any air or gas is present in the cartridge after it is sealed with the stopper, then air or gas may be transferred from the cartridge with the drug. For systems applied by trained personnel (e.g. nurses and doctors) the air can be eliminated through appropriate orientation. However when such systems are used by patients and untrained caregivers there is a danger that the safety may be affected. There are several safety risks associated with air bubbles getting into an infusion pump, syringe or the like. For example, if there is a volume of air delivered via a drug delivery device, then all of the prescribed volume of drug may not be delivered. 
     Overall accuracy of drug delivery may also be affected when air or other gas is transferred into a drug delivery system. If some of the drug cartridge volume is taken up by air or gas rather than liquid drug, then the prescribed amount of liquid drug is not being delivered to the patient. In cases where the drug being delivered has a narrow therapeutic window, if that window is exceeded due to an air bubble obstruction in the pathway of the drug delivery device, exceeding the window may result in undesirable deleterious side effects. Drugs in this category include aminoglycosides such as Amikacin, Gentamicin, Kanamycin and tobramycin. 
     In addition to the problem of air bubble obstruction, a volume of air or gas in the drug cartridge may result in a decreased volume of drug delivered. Patients that require drugs that have extremely accurate dosing regimes may suffer if the volume of drug delivered is inaccurate due to the excess volume of gas in the cartridge. Pediatric and geriatric patient groups are typically more sensitive to such dose administrations. 
     If the drug is a painkiller, such as morphine, extreme suffering will be caused to the patient due to a cessation of drug delivery. In addition, in the case of intravenous delivery, air bubbles may pass into the user&#39;s blood system and obstruct blood flow, thereby causing serious injury and possibly death. 
     Experience has shown that the manufacturers and fillers of drug cartridges are unable to eliminate air or other gas entirely from their drug cartridges, and for a relatively small volume (5 ml) cartridge, it has not been possible to reduce the amount of air or other gas present to below 25 μl. Typical volumes of gas are in the 100 to 300 μl range. 
     Moreover, most drug cartridges are filled under sterile conditions and via automatic machinery. Thus, any improvement to the standard drug cartridge that would entrap gas therein and prevent from passing through to a drug delivery device must be able to comply with existing filling and assembly machinery presently used in the industry. 
     Thus, there is a need for a drug cartridge assembly that entraps gas therein and prevents it from being transferred with liquid drug to a drug delivery device. 
     There is a further need for a drug cartridge assembly that increases patient safety by preventing any gas from being transferred to a drug delivery device. 
     There is still a further need for a drug cartridge assembly that increases dosage accuracy in liquid drug delivery via a drug delivery device by preventing any gas from being transferred to such drug delivery device. 
     There is yet a further need for a stopper that can be used in connection with a standard drug cartridge that entraps gas between the drug cartridge and stopper and prevents it from being transferred with liquid drug to a drug delivery device. 
     There is a further need for a stopper used in connection with a standard drug cartridge that increases patient safety by preventing any gas transferred from the cartridge to a drug delivery device. 
     There is still a further need for a stopper used in connection with a standard drug cartridge that increases dosage accuracy in liquid drug delivery via a drug delivery device by preventing any gas from being transferred from the drug cartridge to such drug delivery device. 
     There is a further need for a method for entrapping gas within a liquid drug container that prevents such gas from being transferred with liquid drug to a drug delivery device. 
     There is yet a further need for a stopper, used in connection with a standard drug cartridge that prevents gas from being transferred to a drug delivery device, designed for use in presently existing filling and assembly machinery. 
     There is still a further need for a drug cartridge that prevents gas from being transferred to a drug delivery device, designed for use in presently existing filling and assembly machinery. 
     SUMMARY OF THE INVENTION 
     The present invention solves the problems associated with the prior art devices and methods by providing for a stopper for use in preventing any volume of gas from escaping from a drug container when used in connection therewith. The stopper comprises a body having a perimeter for slidable engagement with the interior of a drug receptacle, an outer surface, and an inner surface facing the bottom of the drug receptacle. The inner surface is shaped so as to trap any volume of gas located within the drug receptacle when the body is slidably engaged therein. 
     Such geometries of stopper and/or container create a natural space to trap any gas away from the outlet, as will be described in further detail below. 
     The inner surface of the stopper is preferably convex, and in particular may be conical, or frusto-conical. The body of the stopper is preferably circular in cross-section. 
     The stopper may further include an outlet. The outlet connects the inner surface with the outer surface. The outlet is preferably aligned along the longitudinal axis of the stopper. The outlet may be created by penetrating the stopper. The outlet may comprises a hollow needle extending through the inner and outer surfaces of the stopper. This helps ensure sterility of the liquid drug by preventing any interference with the drug between the filling of the container and the emptying thereof. 
     A second embodiment of the present invention is directed to a liquid drug container. The container includes a hollow body for holding a liquid. The body has an open end and a closed end. The container also includes a stopper slidably received in the hollow body, and means for entrapping a predetermined volume of gas within the container. 
     Preferably, the hollow body is substantially cylindrical in form and the stopper is of substantially circular cross-section to make a sealing sliding fit with the internal bore of the cylindrical hollow body. 
     Suitably, the means for preventing exit of gas and entrapping the gas comprises a convex, conical or frusto-conical liquid-facing surface provided on the stopper. Preferably, the entrapping means is located along the perimeter of the stopper. Alternatively, the means for preventing exit of gas and entrapping the gas comprises a convex, conical or frustoconical surface provided on an internal end surface of the substantially cylindrical hollow body facing the stopper. 
     The container may further include an outlet associated with the stopper through which drug is expelled. Preferably, the outlet is located along the central longitudinal axis of the stopper. For example, the outlet can be a narrow axial bore having a needle or a conduit extending therefrom. Preferably, in such cases, the outlet is created in use by penetrating the stopper. This helps ensure sterility of the liquid drug by preventing any interference with the drug between the filling of the container and the emptying thereof. 
     When the stopper has slidably moved to the closed end of the hollow body, the gas volume in the container is entrapped away from the outlet. The container is designed to prevent any volume of gas from exiting through the outlet and the gas is entrapped within the container regardless of orientation of the body. Preferably, the outlet is sealed when the stopper reaches the limit of its travel. 
     The container may further include means for limiting the travel of the stopper. Such means may be external to the hollow body. The container may also include means for slidably moving the stopper within the hollow body. The container may further include means for limiting the travel of the stopper. Such means may be made up of co-operating surfaces on the hollow body and on the means for slidaby moving the stopper within the hollow body. 
     In further preferred embodiments, the outlet comprises a needle extending partially into the interior of the container through a wall of the container facing the stopper, so as to provide the means for preventing exit of gas and entrapping the gas in the container, the needle limiting the travel of the stopper, thereby forming the entrapment space. The needle may enter the hollow body through either the stopper or a wall of the hollow body. 
     The present invention is also directed to a position independent method of emptying a liquid drug container while retaining any volume of gas within the container. The method includes the steps of providing a hollow body having an open end and a closed end, the body having liquid drug contained therein, closing the open end of the body with a stopper slidably received within the hollow body at the open end to prevent liquid drug from escaping therefrom. The method further includes the steps of creating an outlet through the longitudinal axis of the stopper through which the liquid drug may be expelled, providing a space between the stopper and the closed end of the body for occupation by any volume of gas within the body, moving the stopper from the open end to the closed end of the body, thereby causing the volume of liquid drug to be expelled from the body via the outlet and, when the stopper completes its travel to the closed end of the hollow body, forcing any volume of gas remaining therein to be located in the space thus preventing the volume of gas from escaping from the body via the outlet. 
     The step of moving the stopper may be accomplished by causing the stopper to slide along its longitudinal axis within the hollow body. The outlet may be created by extending a hollow needle through the stopper and into the interior of the container. 
     The use of a volume of gas or an gas trap has been found to eliminate problems associated with the transfer of residual gas trapped in drug containers. It ensures that a small and possibly variable amount of gas, which may become entrapped during the filling process (which in fact is practically impossible to avoid), is never ejected because the container is designed to retain a small amount of liquid drug which would include any entrapped gas when the container is essentially empty. Accordingly, containers according to the invention are designed to ensure that only liquid is expelled by movement of the stopper, and because the dimensions of the stopper and the hollow body can be precisely controlled, it is possible to ensure highly accurate delivery volumes. 
     This design of container allows the container to be used (e.g. in filling a portable infusion pump) by persons having no training. Whereas a certain degree of training and experience is required to prevent gas contained in a syringe from being transferred to the patient&#39;s tissue or bloodstream. The container according to the invention automatically traps and retains the gas away from the outlet. 
     The design of the container and of the stopper are also conducive for use with existing automated filling machinery. The stopper and container of the present invention are of the proper exterior dimensions for use in connection with presently available filling and assembly equipment. Thus, there is no need for any retro-fitting or replacement of such machinery. 
     Other objects, features and advantages of the present invention will become apparent upon reading the following detailed description of the embodiments of the invention when taken in conjunction with the drawings and the appended claims. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIG. 1 is a cross-sectional side view of a first preferred embodiment of the stopper of the present invention; 
     FIG. 2 is a cross-sectional side view of a second preferred embodiment of the liquid drug container of the present invention. 
     FIG. 3 is a detailed cross-sectional side view of a drug loading mechanism for receiving and emptying the container of FIG. 2; 
     FIG. 4 is a detailed cross-sectional side view of the container of FIG. 2 when mounted on the mechanism of FIG. 3, before the container is emptied; 
     FIG. 5 is a cross-sectional side view of the container of FIG. 2 when mounted on the mechanism of FIG. 3, after the container is emptied; 
     FIG. 6 is a cross-sectional side view of a third preferred embodiment of a liquid drug container according to the present invention; 
     FIG. 7 is a cross-sectional side view of the container of FIG. 6, after the container is emptied; 
     FIG. 8 is a cross-sectional side view of a fourth preferred embodiment of a liquid drug container according to the present invention; 
     FIG. 9 is a cross-sectional side view of the container of FIG. 8, after the container is emptied; 
     FIG. 10 is a cross-sectional side view of a fifth preferred embodiment of a liquid drug container according to the present invention; 
     FIG. 11 is a cross-sectional side view of the container of FIG. 10, after the container is emptied; 
     FIG. 12 is a cross-sectional side view of a sixth preferred embodiment of a liquid drug container according to the present invention; 
     FIG. 13 is a cross-sectional side view of the container of FIG. 12, after the container is emptied; 
     FIG. 14 is a cross-sectional side view of a seventh preferred embodiment of a liquid drug container according to the present invention engaged with a drug loading mechanism prior to emptying of the container; and 
     FIG. 15 is a cross-sectional side view of the container of FIG. 14 engaged with a drug loading mechanism following emptying of the container. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Referring now in more detail to the drawings in which like numerals refer to like parts throughout the several views, FIG. 1 shows a stopper  1  having an outer surface  2  and an inner surface  3 . The outer surface  2  is exposed to the atmosphere when inserted in a drug container (not shown). The stopper  1  is circular in cross-section and designed to sliding fit within a drug container. The inner surface  3  is convex in shape and has a partial channel inlet  5  at the tip  6  of the convex inner surface. The channel inlet  5  is located along the central longitudinal axis of the stopper  1 . The stopper is typically made of a rubber or polymer material to provide such a sliding fit. The preferred material of the stopper is butyl. 
     The channel inlet provides for effective transfer of liquid drug from the container as explained in more detail below. The length of most needles used in connection with a stopper of the present invention is limited. Thus, the channel inlet provides clearance for the needle after a relatively short length of travel through the stopper. 
     FIG. 2 shows a second preferred embodiment 10 of present invention. The second embodiment 10 comprised a container  12  having comprises a hollow body  14  and a stopper  1 . The hollow body  14  is in the form of a cylindrical glass tube open at one end  18  and closed at the other end  20 . The stopper  1  is slidably received in the hollow body  14  to define a sealed internal chamber  22  containing a liquid drug  24 . A small air bubble  26  resulting from the filling process is also present. The outer surface  2  of the stopper  1  has an annular recess  28  and the inner surface  3  has a sloping frusto-conical face  30  with the partial channel inlet  5  located at the tip  6  of the face, as shown in part in FIG.  1 . 
     FIG. 3 shows a drug loading mechanism, indicated generally at  40 , for receiving and emptying the container of FIG.  2 . The mechanism  40  is of a type which might be integral with a housing  42  of an infusion system having a reservoir and a pumping means for pumping a liquid drug from the reservoir. The mechanism  40  could also be integral with a syringe of an infusion system. The mechanism  40  is formed in the housing  42  of an infusion system and comprises a cylindrical finger  44  extending axially within a cylindrical bore  46  formed in the housing to create an annular gap  48  along a portion of the length of the mechanism. 
     A needle  50  is mounted on an end  52  of the cylindrical finger  44  and creates an interference fit with the outer surface of one end of a central channel  54 . The central channel  54  is located along the central axis of the cylindrical finger  44  and leads to the reservoir (not shown) of the infusion pump. Referring additionally to FIG. 4, for clarity, the housing  42 , cylindrical finger  44  and central channel  54  can be partially seen in phantom. 
     In use, the container  12  is received into the bore  46  of the mechanism  40  (FIG.  4 ), causing the annular recess  28  of the stopper  1  to abut against the end  52  of the cylindrical finger  44 , and also causing the needle  50  to penetrate into and through the stopper  1 , as shown, so that tip  56  of the needle  50  is in communication with the liquid drug  24  within the hollow body  14 . 
     To empty the container  12 , the hollow body  14  is simply pushed further into the bore  46 . Because the stopper  1  abuts against the end  52  of the cylindrical finger  44 , and the needle  50  has penetrated into and through the stopper, the container  12  is forced to empty by the movement of the stopper towards the closed end  20  of the hollow body  14 , with the liquid drug  24  being pumped through the needle  50  via the central channel  54  to the reservoir. 
     FIG. 5 shows the container  12  when it has been emptied of the liquid drug  24 , i.e. when the stopper  1  has been pushed against the closed end  20  of the hollow body  14 . The frusto-conical face  30  of the stopper  1  creates a space  58  adjacent to the interior of the closed end  20 , entrapping the air bubble  26  along with a small volume of the liquid drug  24 . The invention is particularly adapted for use with containers having a filled volume of not greater than about 20 ml, more preferably not greater than about 10 ml, 5 ml or 1 ml. 
     In FIG. 6 there is illustrated a second preferred embodiment of the liquid drug container according to the invention indicated generally at  60 . The container  60 , like container  12  in FIGS. 2-5, also comprises a hollow body  62  and a stopper  64 . It too is therefore in the form of a liquid drug container from which liquid drug is released by penetrating the stopper  64  and using the stopper  64  as a piston to pump a liquid drug  66  from the interior of the hollow body  62 . For simplicity, the mechanism for emptying the container  60  is not shown, apart from a needle  68  which is penetrating the stopper  64 . Nevertheless, the container  60  is emptied in identical manner to that described in relation to container  12  (FIGS.  2 - 5 ). 
     The container  60  differs from the container  12  (FIGS. 2-5) in that liquid-facing surface  70  of the stopper  64  is substantially flat (apart from a small recess  72  from which the tip  74  of the needle  68  protrudes in use) rather than frusto-conical. Closed end  76  of the hollow body  62  is also flat on its internal end surface  78 . 
     Referring to FIG. 7, it can be seen that when the stopper  64  has reached the end of its travel within the hollow body  62 , thereby effectively emptying the container  60 , a space  80  remains between the internal end surface  78  of the hollow body  62  and the liquid-facing surface  70  of the stopper  64 . A small known volume of fluid (comprising liquid drug  66  and an air bubble  82 ) is thus entrapped in this space  80 . 
     In FIG. 8 there is illustrated a third preferred embodiment of the container according to the present invention indicated generally at  90 . Like the previously described embodiments, the container  90  comprises a hollow body  92  and a stopper  94  slidably mounted therein. However, in the case of the container  90 , the outlet of the container  90  is provided as a hollow needle  96  mounted in closed end  98  of the hollow body  92 , such that the container  90  is in the form of a syringe rather than a drug cartridge. 
     The needle  96  is mounted with an outer end  100  outside the hollow body  92  and an inner end  102  protruding into the hollow body  92 . An internal chamber  104  is defined by the stopper  94  and the interior of the hollow body  92  and this internal chamber  104  is filled with a liquid drug  106  containing an air bubble  108 . 
     The liquid drug  106  is ejected as from a conventional syringe by depressing a plunger (not shown) to slide the stopper  94  within the hollow body  92  and thereby eject the liquid drug  106  via the needle  96 . However, when the internal chamber  104  has been substantially emptied of the liquid drug  106  (as shown in FIG.  9 ), the stopper  94  reaches the limit of its travel by meeting the inner end  102  of the needle  96 . This provides a means for retaining a known volume of fluid in the container  90  because a space  110  remains in which a small volume of the liquid drug  106  and the air bubble  108  are entrapped. Thus, the air bubble  108  is not injected into the patient via the needle  96  as would be the case with a conventional syringe. This makes the container  90  more suitable for use by untrained personnel than conventional syringes which must be carefully freed of any air bubbles before injection occurs. 
     In FIG. 10 there is illustrated a fourth embodiment of the container according to the invention indicated generally at  120 . As with the previously described embodiments, the container  120  comprises a hollow body  122  and a stopper  124  slidably mounted therein. As in the case of the embodiment of FIGS. 8 and 9, the outlet of the container  120  is provided as a hollow needle  126  mounted in closed end  128  of the hollow body  122 , such that the container  120  is in the form of a syringe. Liquid facing surface  130  of the stopper  124  is substantially flat and closed end  128  of the container has a conical surface  132 . The needle  126  is mounted with an outer end  134  outside the hollow body  122  and an inner end  136  which communicates with the hollow body but does not extend beyond conical surface  132 . An internal chamber  138  is defined by the stopper  124  and the interior of the hollow body  122 . The internal chamber  138  is filled with liquid drug  140  containing an air bubble  142 . The liquid drug  140  is ejected from the container  120  in the same manner as for the embodiment of FIGS. 8 and 9. Thus, the stopper  124  reaches the limit of its travel by meeting the inner end  136  of the needle  126 , thereby providing a space  144  in which a small volume of the liquid drug  140  and the air bubble  142  are entrapped (as shown in FIG.  11 ). 
     Referring to FIG. 12, there is illustrated a fifth embodiment of a container according to the invention indicated generally at  160 . The container  160  comprises a hollow body  162  having an open end  164  and a closed end  166  and a stopper  168  slidably mounted therein. The stopper  168  is actuated by a plunger  170  having an annular flange  172  at its end  174  remote from the stopper  168 . As in the case of the embodiments of FIGS. 8 and 9 and FIGS. 10 and 11, the outlet of the container  160  is provided as a hollow needle  176  mounted in closed end  166  of the hollow body  162 , such that the container  160  is in the form of a syringe. Liquid facing surface  178  on the stopper  168  is substantially flat as is closed end  166 . Needle  176  is mounted with an outer end  180  outside of the hollow body  162  and an inner end  182  protruding into said hollow body. An internal chamber  184  is defined by the stopper  168  and the interior of the hollow body  162 . The internal chamber  184  is filled with liquid drug  186  containing an air bubble  188 . The liquid drug  186  is ejected from the container  160  when the plunger  170  is depressed. The stopper  168  reaches the limit of its travel when the flange  172  encounters and abuts wall  190  at the open end  164  of the container  160 . A space  192  is created between the surface  178  and the closed end  166  in which a small volume of liquid drug  186  and the air bubble  188  are entrapped as shown in FIG.  13 . It will be appreciated that the positioning of the flange  172  will determine the volume of the space created. 
     Referring to FIG. 14, there is illustrated a sixth embodiment of a container according to the invention indicated generally at  200  engaging a drug loading mechanism indicated generally at  202  for receiving and emptying the container  200 . The container  200  comprises a hollow body  204  having an open end  206  and a closed end  208  and a stopper  210  slidably mounted therein to define a sealed chamber  212  containing a liquid drug  214  and an air bubble  216 , resulting from the filling process. Liquid facing surface  218  of the stopper  210  is substantially conical and the closed end  208  of the hollow body  204  is substantially flat. As in the case of the embodiment illustrated in FIGS. 2-5, the drug loading mechanism  202  is of a type which might be integral with a housing  220  of an infusion system having a reservoir and a pumping means (not shown) for pumping a liquid drug from the reservoir. The mechanism  202  is formed in the housing  220  of such an infusion system and comprises a cylindrical finger  222  extending axially within a cylindrical bore  224  to create an annular gap  226  along a portion of the length of the mechanism  202 . 
     A needle  228  is mounted on an end  230  of the cylindrical finger  222  and creates an interference fit with the outer surface of one end of a central channel  232 . The central channel  232  is located along the central axis of the cylindrical figure  222  and leads to the reservoir of the infusion pump 
     In use, and as illustrated in FIGS. 14 and 15, the container  200  is received into the cylindrical bore  224  of the mechanism  202 , causing the stopper  210  to abut against the end  230  of the cylindrical finger  222  and also causing the needle  228  to penetrate into and through the stopper  210  as shown, so that tip  234  of the needle  228  is in communication with the liquid drug  214  within the hollow body  204 . 
     To empty the container  200 , the hollow body  204  is pushed further into the bore  224  (relative to the position shown in FIG. 14) and is emptied in the manner described in relation to FIGS. 2-5, except that the stopper  210  reaches the limit of its travel when end  236  of the central bore  224  encounters and abuts wall  338  at the open end  206  of the container  200 . 
     FIG. 14 shows the container  200  when it has been emptied of the liquid drug  214 . A dead space  340  is created between surface  218  of stopper  210  and closed end  208  of the container  204  in which a small volume of the liquid drug  214  and the air bubble  216  are entrapped. It will be appreciated that the length of central bore  224  will determine the volume of the dead space created. 
     It is further appreciated that the present invention may be used to deliver a number of drugs. The term “drug” used herein includes but is not limited to peptides or proteins (and mimetic thereof), antigens, vaccines, hormones, analgesics, anti-migraine agents, anti-coagulant agents, medications directed to the treatment of diseases and conditions of the central nervous system, narcotic antagonists, immunosuppressants, agents used in the treatment of AIDS, chelating agents, anti-anginal agents, chemotherapy agents, sedatives, anti-neoplastics, prostaglandins, antidiuretic agents and DNA or DNA/RNA molecules to support gene therapy. 
     Typical drugs include peptides, proteins or hormones (or any mimetic or analogues of any thereof) such as insulin, calcitonin, calcitonin gene regulating protein, atrial natriuretic protein, colony stimulating factor, betaseron, erythropoietin (EPO), interferons such as α, β or γ interferon, somatropin, somatotropin, somastostatin, insulin-like growth factor (somatomedins), luteinizing hormone releasing hormone (LHRH), tissue plasminogen activator (TPA), growth hormone releasing hormone (GHRH), oxytocin, estradiol, growth hormones, leuprolide acetate, factor VIII, interleukins such as interleukin-2, and analogues or antagonists thereof, such as IL-1ra; analgesics such as fentanyl, sufentanil, butorphanol, buprenorphine, levorphanol, morphine, hydromorphone, hydrocodone, oxymorphone, methadone, lidocaine, bupivacaine, diclofenac, naproxen, paverin, and analogues thereof; anti-migraine agents such as sumatriptan, ergot alkaloids, and analogues thereof; anti-coagulant agents such as heparin, hirudin, and analogues thereof; anti-emetic agents such as scopolamine, ondansetron, domperidone, metoclopramide, and analogues thereof; cardiovascular agents, anti-hypertensive agents and vasodilators such as diltiazem, clonidine, nifedipine, verapamil, isosorbide-5-mononitrate, organic nitrates, agents used in treatment of heart disorders, and analogues thereof; sedatives such as benzodiazepines, phenothiazines, and analogues thereof; chelating agents such as deferoxamine, and analogues thereof; antidiuretic agents such as desmopressin, vasopressin, and analogues thereof; anti-anginal agents such as nitroglycerine, and analogues thereof; anti-neoplastics such as fluorouracil, bleomycin, and analogues thereof; prostaglandins and analogues thereof; and chemotherapy agents such as vincristine, and analogues thereof, treatments for attention deficit disorder, methylphenidate, fluvoxamine, bisoprolol, tacrolimus, sacrolimus and cyclosporin. 
     It will be appreciated that the embodiments discussed above are preferred embodiments, falling within the scope of the appended claims, and that various alternative embodiments are contemplated. For example, it is envisioned that an insert may be made in accordance with the invention and inserted into a drug container prior to or during filling thereby enabling the use of existing equipment yet providing means to entrap the gas.