WO2011130738A1

WO2011130738A1 - Methods of using an asymmetric mixing device for preparation of c1-esterase inhibitor medicament

Info

Publication number: WO2011130738A1
Application number: PCT/US2011/032890
Authority: WO
Inventors: Jack Bradley; Frank L. Nazzario; Elizabeth P. Eberhardt
Original assignee: Viropharma Incorporated
Priority date: 2010-04-16
Filing date: 2011-04-18
Publication date: 2011-10-20

Abstract

A method is provided for mixing medicaments from two containers. More specifically, a method is provided for mixing C1-esterase inhibitor drug product stored as a lyophilized powder in a bottle or container. The C1-esterase inhibitor is reconstituted using an asymmetric mixing device having a first portion configured to receive a diluent container and a second portion configured to receive a C1-esterase inhibitor container. The first portion is configured to impede erroneously inserting the C1-esterase inhibitor container into the first portion.

Description

Methods of Using an Asymmetric Mixing Device for Preparation of C1 -Esterase Inhibitor Medicament

Jack Bradley

Frank L. Nazzario

Elizabeth P. Eberhardt

Priority

[001 ] This application claims priority to U.S. Provisional Patent Application No.

61 / 325,005 filed on April 16, 2010. The entire disclosure of the foregoing application is hereby incorporated herein by reference.

Field of the invention

[002] The present invention relates to the field of preparing C1 -esterase inhibitor containing product for administration to patients for the treatment of hereditary angioedema. More specifically, the present invention relates to a method for improving the preparation of C1 -esterase inhibitor in order to reduce waste of the product and/or delaying administration of the medicine, which can be problematic in an emergency situation or prophylactic self-administration situation.

Background

[003] C1 -esterase inhibitor is a medicament used to treat patients with hereditary angioedema (HAE). The treatment of HAE with a C1 -esterase inhibitor containing product may be done by treatment of acute attacks when they occur or by preventative treatments. The later is accomplished by prophylactic administration of suitable amounts of a C1 -esterase inhibitor product in order to reduce or prevent acute attacks and symptoms. HAE is a disease

characterized by painful, unpredictable, recurrent attacks of inflammation affecting the hands, feet, face, abdomen, urogenital tract, and the larynx. The inflammation can be disfiguring, debilitating, or in the case of laryngeal attacks, life-threatening. HAE is estimated to occur in at least 6,000 people in the US and is caused by deficient or dysfunctional levels of C1 -esterase inhibitor, a naturally occurring molecule that is known to modulate the inflammatory cascade. If left untreated, HAE can result in a mortality rate as high as 40% primarily due to upper airway obstruction. ] Symptoms of an HAE attack generally present as swelling of one or more organ systems, most commonly affecting the skin, gastrointestinal tract, or respiratory tract. Patients who experience gastrointestinal attacks typically have significant abdominal pain and vomiting usually resulting from intestinal obstruction caused by swelling in the gut. Gastrointestinal patients may also experience attacks of acute abdominal pain that can mimic other acute surgical conditions, leading to unnecessary abdominal surgeries. More severe symptoms of HAE include laryngeal and upper airway edema that may lead to respiratory tract compromise and potential death from asphyxiation. In acute laryngeal attacks, death may result in as quickly as 20 minutes. [005] HAE attacks account for approximately 15,000 to 30,000 emergency department (ED) visits per year. And, because symptoms of HAE can mimic a surgical emergency, about one-third of patients with undiagnosed HAE have been reported to have undergone unnecessary surgery during abdominal attacks, because the symptoms very closely resemble appendicitis and other medical conditions that frequently require surgery.

[006] C1 -esterase inhibitor drug product is generally stored as a lyophilized

powder in a bottle or container under vacuum prior to use. To prepare the medicament for use, the C1 -esterase inhibitor is reconstituted using sterile water as a diluent. To facilitate the mixing of the lyophilized C1 - esterase inhibitor and the diluent, a fluid transfer and mixing device may be used, such as the one disclosed in Zinger et al. U.S. Patent No. 6,558,365.

[007] Although the use of a mixing device such as the one disclosed by Zinger, may make the task of reconstituting lyophilized medicaments more convenient, several issues associated with C1 -esterase inhibitor and its administration remain. For example, the Zinger device includes two cup-shaped elements for receiving the medicament and the diluent. The diluent is first placed into the cup for the diluent container and the C1 -esterase inhibitor container is then inserted into the cup for the medicament. If the two containers are placed into the proper cups in the proper order, the diluent will flow into the powder, so that the C1 -esterase inhibitor containing product can be reconstituted and administered. However, if the containers are reversed and inserted into the wrong mixing cups or inserted in the wrong order, the medicament will not be properly reconstituted, and the C1 -esterase inhibitor will be wasted. In an emergency situation, the need for immediate action increases the chance of improperly connecting the C1 -esterase inhibitor and diluent containers, thereby leading to a delay in administering the medication. Additionally, in both emergency and non-emergency situations, erroneously reconstituting C1 - esterase inhibitor makes the medicament unuseable, which is quite costly. For example, if the vacuum is prematurely lost in the C1 -esterase inhibitor container by connecting it incorrectly or in the wrong order to the mixing device, then the medicament typically is considered usable for patient administration.

[008] In light of the foregoing, there exists a need for a method for reconstituting C1 -esterase inhibitor in a manner that reduces or substantially eliminates the possibility of human error.

Summary of the Invention

[009] A method for preparing C1 -esterase inhibitor containing drug product is provided that uses an asymmetric device to transfer fluid, reconstitute and mix product components prior to administration to a patient. The method comprises the steps of providing a container of lyophilized C1 -esterase inhibitor, wherein the container has a cap covering a pierceable seal, and the cap has a first diameter. The method further comprises the step of providing a diluent in a second container having a second cap covering a second pierceable seal, wherein the second cap has a second diameter that is smaller than the first diameter of the C1 -esterase inhibitor container. An asymmetric mixing device is provided having a diluent adapter connected with and in fluid communication with a medicament adapter. The medicament adapter is selected to have an internal diameter configured to receive the cap of the C1 - esterase inhibitor container. The diluent adapter is selected to have an internal diameter large enough to receive the cap of the diluent container, but small enough to significantly impede insertion of the C1 -esterase inhibitor cap into the diluent adapter. The method further comprises the step of inserting the cap of the diluent container into the medicament adapter so that a cannula in the adapter pierces the second seal. After the diluent container is inserted into the diluent adapter and the second seal is pierced, the C1 -esterase inhibitor container is inserted into the medicament adapter so that a cannula in the medicament adapter pierces the first seal. The combined assembly of the medicament adaptor, diluent adapter, C1 -esterase inhibitor container and diluent container are oriented so that the diluent is vertically positioned over the C1 -esterase inhibitor container when the first seal is pierced thereby releasing the vacuum to allow the diluent to flow into the C1 -esterase inhibitor container. After the diluent is transferred to the C1 -esterase inhibitor container to reconstitute the C1 -esterase inhibitor, the diluent adapter is disconnected from the medicament adapter, while maintaining the medicament adapter connected with the C1 -esterase inhibitor container. A medical device, such as a syringe is then connected to the medicament adapter and the reconstituted C1 -esterase inhibitor is withdrawn into the medical device for infusion to the patient.

[010] According to another aspect of the invention, the method includes the step of placing the connected medicament and diluent adapters into a container having a sealed opening, wherein the method includes removing the seal and inserting the diluent container into the diluent adapter while the diluent adapter is in the container.

[01 1 ] Another aspect of the invention is a method of improving the safety of

administering a C1 -esterase inhibitor containing product by using an asymmetric mixing device to reconstitute drug product prior to administration to a patient.

[012] A further aspect of the invention is a method of preventing the premature loss of vacuum within a C1 -esterase inhibitor product container by using an asymmetric mixing device during the process of reconstituting the drug product prior to administration to patient.

[013] A further aspect of the invention is a method of avoiding wasting a C1 - esterase inhibitor containing product by using an asymmetric mixing device during the process of reconstituting the drug product prior to administration to patient. [014] An aspect of the invention is a method of improving doctor and/or patient compliance in connection with the use of a C1 -esterase inhibitor containing product by using an asymmetric mixing device during the process of reconstituting the drug product prior to administration to patient.

[015] An aspect of the invention is a method of improving speed and/or ease of reconstituting a C1 -esterase inhibitor containing product by using an asymmetric mixing device during the process of reconstituting the drug product prior to administration to patient.

[016] An aspect of the invention is a method of preventing or reducing delay in administering a C1 -esterase inhibitor containing product by using an asymmetric mixing device during the process of reconstituting the drug product prior to administration to patient.

[017] An aspect of the invention is a method of improving the safety and efficacy of a C1 -esterase inhibitor containing product by including instructional information in product labeling or other product promotional materials as to how to use an asymmetric mixing device during the process of reconstituting the drug product prior to administration to patient.

[018] An aspect of the invention is a method of improving the treatment of HAE disease (both acute treatment of attacks and prophylactic treatments) with a C1 -esterase inhibitor containing product by using an asymmetric mixing device to reconstitute drug product prior to administration to a patient.

[019] Another aspect of the invention is a mixing apparatus for mixing

medicaments from two containers. In particular, the mixing apparatus may include a first portion having a socket configured to receive a first container of a first size and a piercing element in the socket to pierce a seal of the first container. The mixing apparatus further includes a second portion detachably connected with the first portion. The second portion includes a socket sized to receive a second container having a second size that is smaller than the first size. The second portion also includes a piercing element for piercing a seal of the second container. The socket of the second portion is further configured to impede insertion of the first container into the socket of the second portion.

[020] In one aspect, the second socket may be configured to impede insertion of a container of the first size into the second socket. For instance, the second socket may include a stop configured to engage a container of the first size while not engaging a container of the second size.

[021 ] The mixing apparatus may be used to mix a variety of medicaments in

containers. For instance, the apparatus may be used to mix a container of medicament with a container of diluent. More specifically, the apparatus may be used to mix a container of lyophilized medicament in a container having a first diameter with a diluent in a container having a second diameter smaller than the first diameter. A first portion of the apparatus is then inserted onto the diluent container while the diluent container is oriented with a pierceable seal disposed vertically above the bottom of the diluent container. A first piecing element of the apparatus pierces the seal of the diluent container when the first portion is inserted onto the diluent container. The medicament container is then oriented so that a pierceable seal of the medicament container is disposed vertically above the bottom of the medicament container. A second portion of the apparatus is then inserted onto the medicament container so that a second piercing element pierces the seal of the medicament container. The diluent flows from the diluent container into the medicament container through the two piercing elements. After the diluent and the medicament are mixed, the mixture may be administered by detaching the first portion from the second portion. An injection device, such as a syringe may then be releasably connected to the second portion to discharge the mixture from the medicament container into the injection device.

Description of the Drawings

[022] The foregoing summary and the following detailed description of the

preferred embodiments of the present invention will be best understood when read in conjunction with the appended drawings, in which:

[023] Fig. 1 is a an exploded perspective view of a mixing device for preparing C1 -esterase inhibitor medicament shown with a container of diluent and a container of lyophilized C1 -esterase inhibitor; [024] Fig. 2 is a side view of the mixing device of Fig. 1 , shown with the diluent container and C1 -esterase inhibitor container connected with the mixing device;

[025] Fig. 3 is a cross-sectional view of two adapters of the mixing device shown in Fig. 1 ;

[026] Fig. 4 is a perspective view of the mixing device shown in Fig. 1 ;

[027] Fig. 5 is a perspective view of the mixing device shown in Fig. 1 , illustrated with the C1 -esterase inhibitor container improperly partially inserted into the device.

[028] Fig. 6 is a perspective view of the mixing device of Fig. 3 illustrated in combination with a package adapted to hold the device and a container of diluent; and

[029] Fig. 7 is a perspective view of the mixing device of Fig. 7 after removal from the package.

Detailed Description of the Invention

[030] Referring now to the figures in general, and to Fig.1 specifically, a mixing device for preparing C1 -esterase inhibitor is generally designated 30. The mixing device 30 is configured to facilitate reconstitution of lyophilized C1 - esterase inhibitor stored in a medicament container 20 by adding a diluent from a diluent container 10. The mixing device 30 contains two releasably connectable adapters: a diluent adapter 40 configured to receive the diluent container 10 and a medicament adapter 60 configured to receive the medicament container 20. The mixing device 30 includes cannulae for piercing seals on the containers 10, 20 to facilitate the sterile transfer of the diluent to the medicament container.

[031 ] As shown in Fig. 1 , the medicament container 20 is a generally closed

container, such as a glass vial or bottle 22. The vial has a reduced diameter neck 24 and a forward open end having a circumferential bead that projects radially outwardly. A pierceable seal 28, such as a septum, covers the open end of the vial, forming a fluid tight seal. A cap 26 extends over the cap and is fixedly attached to the vial. For instance, the cap may be crimped onto the vial so that the cap is bent under the rim of the open end to prevent the cap from being removed from the vial. The cap includes a central opening providing access to the septum 18 for piercing the septum to provide for fluid transfer into or out of the vial.

[032] Similarly, diluent container 10 is a generally closed container, such as a glass vial or bottle 22. The diluent container 10 also has a reduced diameter neck 24 and a forward open end having a circumferential bead that projects radially outwardly similar to the medicament container. As with the medicament container, the diluent container includes a pierceable seal, such as a septum 18, sealing the open end of the vial, and a cap 16 that extends over the septum to retain the septum in place on the vial.

[033] Although the diluent container 10 and the medicament container 20 include similar features, the two containers are configured to differentiate the one container from the other. Specifically, in the present instance, the medicament container has an enlarged diameter opening relative to the diluent container, so that the diameter of the cap 26 is larger than the diameter of the cap 16 covering the end of the diluent container. More specifically, the outside diameter of the cap 26 for the medicament container is preferably at least 5% larger than the outside diameter of the cap 16 for the diluent container. The dimensions of the caps for the containers may vary depending on various factors, however, in the present instance, the outside diameter of the cap 26 for the medicament container is approximately 17 mm and the outside diameter of the cap is approximately 20 mm.

[034] Referring now to Fig. 3, the details of the mixing device 30 will be described in greater detail. The mixing device 30 includes two cup shaped adapters configured to releasably connect with one another. The first adapter 40 is configured to cooperate with the diluent container 10. The second adapter is configured to cooperate with the medicament container 20.

[035] The diluent adapter 40 is a generally cup-shaped element having a socket 42 for receiving the head of the diluent container 10, specifically, the cap 16 and neck 14 of the diluent container. The socket 42 has a base wall 43, forming the bottom of the socket. The side walls of the socket are formed by a plurality of fingers 44, 45 that project longitudinally away from the base wall 43. The fingers are resiliently radially deformable.

[036] The fingers include latching fingers 44 configured to engage and retain the diluent container in the diluent adapter. Specifically, the latching fingers have latching elements 48 that project radially inwardly to latch against the underside of the cap 16 of the diluent container 10. In the present instance, the free ends of the latching fingers 44 are flat, forming a ledge as shown in Fig. 3, and as discussed further below.

[037] All of the fingers of the diluent adapter 40 may be in the form of the latching fingers, as described above. However, in the present instance, the socket includes a plurality of guide fingers 45 interspaced among the latching fingers. Specifically, in the present instance, the socket includes six fingers

circumferentially spaced apart from one another forming the annular socket for receiving the diluent cap 16. Three of the fingers are latching fingers, and three of the fingers are guide fingers 45. However, the number and type of fingers can be varied.

[038] The guide fingers 45 are elongated fingers, extending longitudinally away from the base further than the latching fingers. The guide fingers 45 have a first portion that is generally coextensive with the latching fingers, and a second portion in the form of flared tip 46 that projects longitudinally beyond the end of the latching fingers. Although the guide fingers may include latching elements similar to the latching fingers, in the present instance, the guide fingers do not. Instead, the first portion of the guide fingers are substantially straight, without any portion that projects radially inwardly. The flared tip 46 of the guide fingers flare radially outwardly. The tips 46 flare out a sufficient distance to form an internal diameter that is slightly larger than the internal diameter within the socket 42 between the latching fingers and the first portion of the guide fingers. In the present instance, the distance that the tips flare outwardly is less than approximately 2 mm.

[039] Projecting inwardly into the socket 42 from the base wall 43 is a piercing cannula 50. The piercing cannula has a tip configured to puncture the septum 18 of the diluent container 10. The longitudinal length of the cannula 50 is shorter than the longitudinal length of the guide fingers, as shown in Fig. 3. In Fig. 3 the cannula is illustrated as having a longitudinal length that is longer than the latching fingers. However, preferably, the cannula 50 has a length that is shorter than the length of the latching fingers 44.

[040] The cannula 50 is intergrally formed with the diluent adapter 40, and

includes a hollow bore for allowing fluid passage of the diluent through the cannula once the cannula pierces the septum 18 of the diluent container. [041 ] The diluent adapter 40 further includes a connector 52 for releasably connecting the diluent adapter with the medicament adapter 60. Specifically, the connector 52 is formed on the base wall 43, on the side opposing the cannula 50. The connector includes an element for releasably connecting the diluent adapter 40 with the medicament container in a manner to provide fluid communication between the diluent container 10 and the medicament container 20. For instance, the connector may be a Luer type fitting.

Specifically, in the present instance, the connector is a female Luer lock fitting having a stem 54 projecting from the base wall 43, and an internally threaded collar circumscribing the stem. The stem 54 is in fluid communication with the cannula 50 through a hole in the base wall.

[042] The second cup of the mixing device 30 is the medicament adapter 60, which is configured to engage and retain the vial of C1 -esterase inhibitor 20. The medicament adapter 60 is a generally cup-shaped element having a socket 62 for receiving the head of the medicament container 20, specifically, the cap 26 and neck 24 of the medicament container. The socket 62 has a base wall 63, forming the bottom of the socket. The side walls of the socket are formed by a plurality of fingers 64 that project longitudinally away from the base wall 63. The fingers 64 are resiliently radially deformable, and include latching elements 68 configured to engage and retain the medicament container 20 in the medicament adapter 60. Specifically, the latching elements 68 project radially inwardly to latch against the underside of the cap 26 of the medicament container 20. Beyond the latching elements 68, the free ends of the fingers flare radially outwardly to form an enlarged opening having a diameter larger than the diameter of the cap 26 for the medicament container.

[043] Projecting inwardly into the socket 62 from the base wall 63 is a piercing cannula 70. The piercing cannula has a tip configured to puncture the septum 28 of the medicament container 20. The longitudinal length of the cannula 50 is shorter than the longitudinal length of the fingers 64, as shown in Fig. 3. The cannula 70 is integrally formed with the medicament adapter 60, and includes a hollow bore for allowing fluid passage through the cannula.

[044] The medicament adapter 60 further includes a connector 72 for releasably connecting the medicament adapter 60 with the diluent adapter 40, as shown in Fig. 4. Specifically, referring to Fig. 3, the connector 72 is formed on the base wall 63, on the side opposing the cannula 70. The connector includes an element for releasably connecting the medicament adapter 60 with the diluent adapter 40 container in a manner to provide fluid communication between the diluent container 10 and the medicament container 20. For instance, the connector may be a Luer type fitting. Specifically, in the present instance, the connector is a male Luer lock fitting having a stem 72 projecting from the base wall 63, and an externally threaded portion internally collar circumscribing the stem. The internal diameter of the stem 72 is configured to mate with the external diameter of the stem 52 to form a fluid-tight seal. The stem 72 is in fluid communication with the cannula 70 through a hole in the base wall. 5] As can be seen in Fig. 3, the diluent adapter 40 has a socket 42 having an internal diameter that is smaller than the internal diameter of the socket 62 of the medicament adapter 60. In this way, the mixing device is asymmetric. The asymmetry facilitates connection of the diluent to the diluent adapter, but impedes connection of the medicament container 20 to the diluent adapter. Specifically, the internal diameter of the socket 42 is substantially similar to the outer diameter of the cap 16 of the diluent container 10. Additionally, the distance between ends of opposing fingers 44, 45 is substantially similar to or slightly larger than the external diameter of the diluent cap 16. In this way, the diluent container 10 can be readily inserted into the diluent adapter. As the cap 16 of the diluent container is inserted into the adapter 40, the guide arms 45 may flex radially outwardly to allow insertion of the container. As the cap 16 continues to enter the socket 42, the cap engages the latching elements of the latching fingers 44. The latching elements project inwardly to form a reduced diameter area that is smaller than the external diameter of the cap 16.

Accordingly, as the cap is inserted into the socket, the latching elements engage the outer surface of the cap, causing the latching fingers to deform radially outwardly to provide clearance for the cap to enter the socket. The longitudinal length of the latching fingers between the base wall 43 and the latching elements is longer than the longitudinal length of the cap. In this way, when the cap is fully inserted into the adapter so that the end of the cap abuts or is adjacent to the base wall 43, the latching elements resiliently rebound radially inwardly so that the latching elements overlie the reduced diameter of the neck and latch onto the rearward edge of the cap to impede removal of the diluent container from the adapter 40. 6] In addition to being configured to readily receive the diluent container, the diluent adapter 40 is configured to impede insertion of the medicament container 20 into the diluent adapter. Specifically, referring to Figs. 3 and 5, the internal diameter of the socket 42 is smaller than the outer diameter of the cap 26 of the medicament container, and in the present instance is

substantially smaller. The outer diameter of the free ends of the latching fingers 44 has a diameter of "d", which is less than the outer diameter of the cap 26 of the medicament. Therefore, as shown in Fig. 5, although the flared tips 46 of the guide fingers 45 may deform radially outwardly to accommodate the larger medicament container, as the medicament container is displaced toward the socket, the forward surface of the cap 26 will abut the flat end surfaces of the latching fingers. In this way, the ends of the latching fingers engage the cap 26 to act as stops impeding the insertion of the medicament container into diluent adapter. Further, the guide fingers operate to center the cap within the center of the socket opening, thereby reducing the possibility of inserting the container into the socket at an angle, which could allow the forward end of the cap to deflect the latching fingers radially outwardly, rather than acting as stops as described above. Further, since the latching fingers extend from the base further than the cannula, the cannula will not pierce the septum of a container until the container is inserted into the socket beyond the latching elements, which act as stops against the larger medicament container. In this way, the structure of the diluent adapter impedes insertion of the medicament container into the diluent adapter, and impedes and/or prevents inadvertent puncture of the medicament septum if the operator erroneously attempts to insert the medicament container into the diluent adapter.

[047] Referring now to Fig. 6, a holder 80 is provided for the mixing device.

Specifically, the holder 80 is in the form of a sterile package in which the mixing device 30 is stored prior to use. The holder 80 comprises a cylindrical or frustoconical enclosed package, having an open upper end 82. A removable seal (not shown) encloses the open upper end to preserve the sterility of the package. The seal may be attached so that it can be pealed off of the upper end of the package to expose the mixing device.

[048] The mixing device 30 is positioned in the holder 80 so that the diluent adapter 40 faces upwardly, and the medicament adapter faces downwardly toward the bottom of the package 86. Additionally, the interior of the package may be configured to engage the mixing device to impede displacement of the mixing device within the package. For instance, the holder tapers inwardly toward the base 86, and the interior of the base may include an annular ridge adapted to cooperate with the lip around the free ends of the latching fingers 64 of the medicament adapter.

[049] The method of using the mixing device 30 to prepare C1 -esterase inhibitor will now be described in greater detail. A vial of lyophilized C1 -esterase inhibitor is provided in a container having a cap with a first diameter. A bottle of diluent is provided in a container having a cap with a second diameter, wherein the diluent bottle is selected so that the cap of the diluent bottle is smaller than the diameter of the cap for the medicament container. In an exemplary mode, the vial of C1 -esterase inhibitor comprises 500 units of lyophilized product (under vacuum in the container), and the diluent container comprises 5 mL of sterile water. The two containers are prepared for use by wiping the cap of the vial of C1 -esterase inhibitor with an alcohol wipe or other disinfecting item and wiping the cap of the diluent container with a similar alcohol wipe or other disinfecting item. 0] The mixing device 30 is provided in a package that also operates as a holder. The mixing device is positioned within the package so that the diluent adapter is connected to the C1 -esterase inhibitor vial and the diluent adapter faces upwardly toward the opening in the package. The cover sealing the opening of the package is removed to allow access to the mixing device, however, the mixing device is maintained within the package with the diluent adapter accessible through the package opening. The diluent container is then inserted into the socket 42 of the diluent adapter while maintaining the adapter within the package 80. Specifically, the diluent container is inserted into the opening between the flared tips of the guide fingers 45. More specifically, while the diluent container is upright with the seal upward, the mixing device is attached to the diluent container by placing the package 80 and the enclosed mixing device 30 onto the diluent container 10 so that the diluent adapter 40 engages the top of the diluent container (Note: in Fig. 6 the drawing illustrates the diluent container 10 inverted and inserted into the mixing device 30 rather than the diluent container being upright with the mixing container being placed over the diluent container as described above). The guide fingers tend to center the cap of the diluent container within the socket as the diluent adapter 40 is mounted onto the diluent container. As the socket is placed over the cap, the cap engages the reduced diameter formed by the latching elements of the latching fingers 44, causing the latching fingers to displace radially outwardly. Continued advancement of the diluent adapter onto the diluent container pierces the cannula through the septum 18 so that the diluent can flow through the cannula. The diluent adapter is inserted onto the diluent container until the latching fingers deform radially inwardly to latch onto the rearward end of the cap to retain the diluent container in the adapter. 1 ] Referring to Figs. 6-7, after the diluent adapter 40 in the holder 80 is mounted onto the diluent container 10, the mixing device is removed from the holder. More specifically, the holder 80 is displaced upwardly to uncover the mixing device 30 and expose the medicament adapter 60.. The medicament container (or for example a C1 -esterase inhibitor vial) is then oriented in an upright position with the cap 26 facing upwardly, such as by placing the C1 - esterase inhibitor vial on a horizontal surface, such as a counter. The mixing device is inverted so that the diluent container is vertically positioned above the medicament adapter. The medicament adapter 60 of the mixing device is aligned with the upward facing medicament container, and the mixing device is positioned over the medicament vial so that the cap of the medicament vial is inserted into the socket of the medicament adapter. As the mixing device 30 is mounted onto the medicament container 20, the cap of the container 20 engages inwardly projecting latching elements of the latching fingers. The medicament container is inserted into the adapter until the piercing cannula pierces the septum of the medicament container thereby breaking the vacuum to allow diluent to flow into the piercing cannula and into the medicament container. The latching fingers resiliently rebound to engage against the rearward edge of the cap to impede disconnection of the medicament container from the adapter.

[052] In the present instance, the interior of the C1 -esterase inhibitor container (that is the medicament container) is under vacuum. In this way, since the diluent is positioned vertically above the C1 -esterase inhibitor container and since the C1 -esterase inhibitor container is under vacuum, the diluent flows from the diluent container into the medicament container so that the C1 - esterase inhibitor can be reconstituted. The diluent is transferred to the medicament container 20 through the cannula 50, stem 54, cannula 70 and the stem of the second connector 72. After the diluent is transferred to the C1 - esterase inhibitor container, the C1 -esterase inhibitor is reconstituted by agitating the assembly to dissolve the C1 -esterase inhibitor while the containers remain connected to the mixing device.

[053] Fig. 2 illustrates the completed assembly once the diluent container 10 and medicament container 20 have been connected with the mixing device 40. It should be understood that the horizontal orientation of the view in Fig. 2 is for illustration of the assembly. As discussed above, during actual use, the assembly would be in a vertical orientation with the diluent container disposed vertically above the medicament container.

[054] After the C1 -esterase inhibitor is reconstituted, the diluent adapter 40 is disconnected from the medicament container. Specifically, the diluent and attached diluent container as detached by disconnecting the first connector from the second connector. For instance, in the present instance, the first and second connectors are Luer lock fittings. Accordingly, the diluent and attached diluent adapter is disconnected from the medicament adapter by rotating the diluent adapter relative to the medicament to unscrew the female Luer fitting of the diluent container from the male Luer fitting of the medicament container.

[055] The reconstituted C1 -esterase inhibitor is ready for administration. In the present instance, the method provides for administration of the C1 -esterase inhibitor via infusion. Specifically, the C1 -esterase inhibitor is drawn into a syringe by attaching a mating Luer fitting on the end of the syringe with the connector 72 on the medicament adapter 60. The plunger of the syringe is then withdrawn to draw the C1 -esterase inhibitor out of the medicament container so that the medicine can be administered to the patient.

[056] Configured as described above, it can be seen that an apparatus is

provided for mixing C1 -esterase inhibitor contained within a medicament container with a diluent contained within a diluent container, wherein the medicament container comprises a cap having a first diameter and the diluent container comprises a cap having a second container that is smaller than the first diameter. The apparatus for mixing C1 -esterase inhibitor comprises a first adapter configured to engage the container of C1 -esterase inhibitor, wherein the first adapter comprises: (a) a first socket having a first internal diameter; (b) a first connector external of the first socket; and (c) a first piercing cannula within the first socket. The apparatus further comprises a second adapter configured to engage the container of diluent and configured to substantially impede insertion of the container of C1 -esterase inhibitor into the second adapter, wherein the second adapter comprises: (a) a second socket having a second diameter smaller than the first diameter, (b) a second piercing cannula within the second socket; and (c) a second connector external of the second socket of the second adapter, and releasably connectable with the first connector to form a fluid tight seal between the first cannula and the second cannula. 7] Additionally, the apparatus for mixing C1 -esterase inhibitor may be configured so that the first socket comprises a plurality of resiliently radially deformable fingers operable to latch onto the cap of the C1 -esterase inhibitor container to retain the C1 -esterase inhibitor container within the first socket. The apparatus may also be configured so that the second socket comprises a stop configured to impede insertion of the C1 -esterase inhibitor container into the second adapter without substantially impeding insertion of the diluent container into the second adapter.

[058] The apparatus may further be configured so that the second socket

comprises a plurality of resiliently radially deformable longitudinally elongated latching fingers and a plurality of resiliently radially deformable guide fingers spaced apart from the latching fingers, and wherein the guide fingers extend longitudinally longer that the latching fingers. Further still, the second socket may be configured so that inserting the diluent container into the socket of the second adapter causes the diluent container to engage the guide fingers prior to engaging the latching fingers.

[059] The apparatus may also comprise a holder for holding the mixing device, wherein the holder is configured to enclose one of the first and second adapters while providing an opening to acess the other of the first and second adapters. The mixing device may be positioned in the holder so that the first adapter is enclosed and the second adapter is accessible through the opening.

[060] Examples of commercially available C1 -esterase inhibitor containing

product that may be used with the instant invention are listed below:

Name of C1 -esterase Source inhibitor product

CINRYZE™ ViroPharma Incorporated

(Exton, Pennsylvania, USA)

BERINERT™ CSL Behring, Inc.

(Marburg, Germany)

CETOR® Sanguin

(The Netherlands)

[061 ] It will be recognized by those skilled in the art that changes or modifications may be made to the above-described embodiments without departing from the broad inventive concepts of the invention. It should therefore be understood that this invention is not limited to the particular embodiments described herein, but is intended to include all changes and modifications that are within the scope and spirit of the invention as set forth in the claims.

Claims

CLAIMS A method for preparing C1 -esterase inhibitor, comprising the steps of: providing lyophilized C1 -esterase inhibitor in a container having a sealed end having a first diameter;

selecting a container of diluent so that the diluent container has a sealed end having a second diameter smaller than the first diameter;

providing an asymmetric mixing device comprising the steps of:

providing a first adapter configured to engage the container of C1 - esterase inhibitor, wherein the first adapter comprises a socket having a first internal diameter;

selecting a second adapter having a socket having a second

diameter smaller than the first diameter, wherein the socket of the second adapter is configured to engage the container of diluent and configured to substantially impede insertion of the container of C1 -esterase inhibitor into the socket of the second adapter; and

releasably connecting the first adapter with the second adapter; inserting the sealed end of the diluent container into the second adapter so that a piercing cannula in the second adapter pierces the sealed end of the diluent container;

inserting the sealed end of the C1 -esterase inhibitor container into the first adapter so that a piercing cannula in the first adapter pieces the sealed end of the C1 -esterase inhibitor container; positioning the diluent container so that the diluent container is disposed vertically above the medicament container while the diluent container and C1 -esterase inhibitor container are inserted within the mixing device to facilitate fluid transfer from the diluent container to the C1 - esterase inhibitor container;

mixing the diluent and the C1 -esterase inhibitor in the medicament

container to reconstitute the C1 -esterase inhibitor;

disconnecting the first adapter from the second adapter while the

medicament container remains inserted in the first adapter;

connecting a medical device to the first adapter;

using the medical device to withdraw the reconstituted C1 -esterase inhibitor from the medicament container through the first adapter.

2. The method of claim 1 comprising the step of releasably latching the C1 -esterase inhibitor container in the first adapter.

3. The method of claim 1 comprising the step of providing a stop

configured to impede insertion of the C1 -esterase inhibitor container into the second adapter without substantially impeding insertion of the diluent container into the second adapter.

4. The method of claim 1 wherein the socket of the second adapter comprises a plurality of resiliently radially deformable longitudinally elongated latching fingers and a plurality of resiliently radially deformable guide fingers spaced apart from the latching fingers, and wherein the guide fingers extend longitudinally longer that the latching fingers.

5. The method of claim 4 comprising the step of inserting the diluent container into the socket of the second adapter so that the diluent container engages the guide fingers prior to engaging the latching fingers.

6. The method of claim 1 comprising the steps of:

providing a holder for holding the mixing device, wherein the holder is configured to enclose one of the first and second adapters while providing an opening to acess the other of the first and second adapters, and

positioning the mixing device in the holder so that the first adapter is

enclosed and the second adapter is accessible through the opening.

7. The method of claim 6 wherein the step of inserting the diluent

container into the second adapter comprises inserting the diluent container into the second adapter to attach the diluent container with the mixing device while the mixing device is in the holder.

8. The method of claim 7 comprising the step of removing the mixing device and attached diluent container from the holder.

9. A method for improving the safety of administering a C1 -esterase inhibitor containing product, comprising the steps of:

providing lyophilized C1 -esterase inhibitor in a container having a sealed end having a first diameter;

providing an asymmetric mixing device comprising the steps of:

selecting a second adapter having a socket having a second

releasably connecting the first adapter with the second adapter; directing a user to reconsititute the C1 -esterase inhibitor with the diluent using the mixing device, by directing the user to perform the steps of: inserting the sealed end of the diluent container into the second

adapter so that a piercing cannula in the second adapter pierces the sealed end of the diluent container; inserting the sealed end of the C1 -esterase inhibitor container into the first adapter so that a piercing cannula in the first adapter pieces the sealed end of the C1 -esterase inhibitor container; positioning the diluent container so that the diluent container is

disposed vertically above the medicament container while the diluent container and C1 -esterase inhibitor container are inserted within the mixing device to facilitate fluid transfer from the diluent container to the C1 -esterase inhibitor container; mixing the diluent and the C1 -esterase inhibitor in the medicament container to reconstitute the C1 -esterase inhibitor;

disconnecting the first adapter from the second adapter while the medicament container remains inserted in the first adapter; connecting a medical device to the first adapter;

10. The method of claim 9 wherein the step of directing the user

comprises the step of directing the user to releasably latch the C1 - esterase inhibitor container in the first adapter.

1 1 . The method of claim 9 comprising the step of providing a stop

12. The method of claim 9 wherein the socket of the second adapter comprises a plurality of resiliently radially deformable longitudinally elongated latching fingers and a plurality of resiliently radially deformable guide fingers spaced apart from the latching fingers, and wherein the guide fingers extend longitudinally longer that the latching fingers.

13. The method of claim 9 comprising the steps of:

positioning the mixing device in the holder so that the first adapter is

enclosed and the second adapter is accessible through the opening.

14. The method of claim 13 wherein the step of directing the user to insert the diluent container into the second adapter comprises directing the user to insert the diluent container into the second adapter to attach the diluent container with the mixing device while the mixing device is in the holder.

15. The method of claim 14 comprising the step of directing the user to remove the mixing device and attached diluent container from the holder.