WO2024073743A1

WO2024073743A1 - Drug handling device

Info

Publication number: WO2024073743A1
Application number: PCT/US2023/075635
Authority: WO
Inventors: Avi Eliahu; Patrick James GRANDT; Michelle Rose HATCH; Mariano MUMPOWER; Benjamin R. Lane; Chester B. LARROW; Thomas D. JAMES; Michael KIELY; Iii Martin M. Coyne; Christopher J. FRANZESE; Amy C. RINALDI; Katherne Ford BRIGHAM
Original assignee: Genentech, Inc.
Priority date: 2022-09-30
Filing date: 2023-09-29
Publication date: 2024-04-04

Abstract

A drug handling device includes a drug-vial receiver and a liquid-vial receiver, each including a spike on a distal surface to pierce a seal on a vial inserted into the respective receiver. The drug-vial receiver further includes one or more drug access ports located on a proximal surface of the drug-vial receiver. The proximal surface of the drug-vial receiver is detachably connected to a proximal surface of the liquid-vial receiver to facilitate combination of a liquid and a drug product into a drug while connected and reveal the drug access ports once detached. While the receivers are connected, the connected components form an air channel and a liquid channel for air to flow from the drug vial into the liquid vial while the liquid flows from the liquid vial into the drug vial. After detachment, an air vent facilitates withdrawal of the reconstituted drug from the drug vial.

Description

DRUG HANDLING DEVICE

CROSS-REFERENCE TO RELATED APPLICATION

[1] The current application claims priority under 35 U.S.C. §119(e) to U.S. Provisional application serial number 63/412, 140, filed on September 30, 2022, and entitled “DRUG HANDLING DEVICE,” which is incorporated by reference herein in its entirety.

TECHNICAL FIELD

[2] This disclosure generally relates to medical devices for handling and administration of drugs.

BACKGROUND

[3] Lyophilized drug products distributed in sealed vials are typically reconstituted by the addition of a liquid into the vial. Oftentimes, the liquid is distributed in a sealed vial together with the lyophilized drug product. Conventionally, after disinfection of the surfaces of both vials’ seals (e.g., rubber stoppers), the liquid was withdrawn from the liquid vial (e.g., using a syringe with a needle inserted through the seal) and then injected into the drug vial, after which the reconstituted drug could be withdrawn from the drug vial using a syringe. These conventional drug preparation and administration steps are prone to error, wastage, leakage, dislodgement of vial closure, and introduction of particulates. Further, multiple piercing of the seal on the vial may cause fragmentation, and/or coring of the seal. Certain devices have been introduced to assist with the drug preparation process. However, such devices may have problems with flow hesitation due to the entrapment of air bubbles within the channel in which the liquid is intended to flow, fluid dynamic constraints, fluid path resistance, or other variables, while others rely on manual withdrawal and transfer of fluid which can result in ergonomic challenges or enable measurement errors. While such devices may be sufficient to prepare small volume (e.g., 1-20 ml) drug products administered as a bolus dose via syringe injection, none address the challenges associated with large volume (e.g., 50-100 ml) and/or multi-modal administration routines. [4] After reconstitution from a lyophilized form, certain drugs may need to be administered to the same patient through multiple modalities (e.g., bolus dose, followed by infusion dose over time). For example, administering Activase® (alteplase) for acute ischemic stroke requires delivery of 10% of the total dose as an initial bolus dose over 1 minute, followed by infusion of the remainder of the dose over 60 minutes. However, transferring the reconstituted drug from the drug vial to an intravenous (IV) fluid bag or attaching an IV set to convert the drug vial for IV use may introduce challenges. Such additional steps required to manually manipulate the lyophilized drug or the solvent during the reconstitution process, or to manually transfer the reconstituted drug during the administration process also increase the risk of introduction of bacteria, skin oils, and other undesirable elements, which may lead to infection, in addition to the issues noted above.

[5] Such steps may be complicated by the pressure to administer the drug as quickly as possible. In the example of acute ischemic stroke, alteplase must be administered as soon as possible but within three hours after onset of symptoms.

SUMMARY

[6] Embodiments of a drug handling device may facilitate preparation of a drug from a drug product contained in a drug vial and a liquid in a liquid vial, as well as administration of the drug through one or more delivery modalities. The drug handling device may be well suited for administration of drugs such as Activase® (alteplase), which require rapid administration of the drug after onset of symptoms, including delivery of an initial bolus dose of a small percentage of a total dose, followed by an infusion dose over a period of time. The drug handling device may also facilitate discarding a particular volume of the drug after reconstitution in order to reduce the total dose to the correct amount as calculated for a specific patient.

[7] Certain embodiments of a drug handling device may comprise a drug-vial receiver detachably connected to a liquid-vial receiver. The proximal surface of the drug- vial receiver may be detachably connected to a proximal surface of the liquid-vial receiver in order to facilitate preparation of the drug while connected and to facilitate administration of the drug once detached. The drug-vial receiver may include a drug-vial spike extending from a distal surface of the drug-vial receiver and one or more drug access ports located on a proximal surface of the drug-vial receiver. The drug-vial spike may be configured to pierce a seal on a mouth of a drug vial containing a drug product. The liquid-vial receiver may include a liquid-vial spike extending from a distal surface of the liquid-vial receiver. The liquid-vial spike may be configured to pierce a seal on a mouth of a liquid vial containing a liquid for combination with the drug product to form a drug. While the proximal surface of the drug-vial receiver is connected to the proximal surface of the liquid-vial receiver, the drug-vial spike of the drug-vial receiver and the liquid-vial spike of the liquid-vial receiver may form a liquid channel (for the liquid to flow from the liquid vial into the drug vial and thereby combine with the drug product) and an air channel (for air to flow from the drug vial into the liquid vial as the liquid flows from the liquid vial into the drug vial).

[8] The one or more drug access ports located on the proximal surface of the drug-vial receiver may be accessible after the drug-vial receiver may be detached from the liquid-vial receiver. The one or more drug access ports may include a syringe access port configured for use of a syringe to facilitate withdrawal of a dose of the drug after preparation. The syringe access port may be a Luer port configured for a needle-free Luer lock syringe. The syringe access port may provide access to the drug through the liquid channel. The one or more drug access ports may include an infusion access port configured for connection to an IV administration set for intravenous infusion of the drug. The infusion access port may be located between the liquid channel and an edge of the proximal surface of the drug-vial receiver.

[9] The liquid-vial spike extending from a distal surface of the liquid-vial receiver and the drug-vial spike extending from a distal surface of the drug-vial receiver may each be dual-lumen spikes including a first lumen configured to form the air channel and a second lumen configured to form the liquid channel. The liquid channel may run vertically along a straight path through a longitudinal axis of the drug handling device. A path of the air channel may run adjacent to the liquid channel along the drug-vial spike, diverge from the liquid channel between a base of the drug-vial spike and a base of the liquid-vial spike, then run adjacent to the liquid channel along the liquid-vial spike.

[10] The drug-vial receiver may include a valved port to prevent leakage of the drug through the air channel during withdrawal of the drug after the drug-vial receiver may be detached from the liquid-vial receiver. The liquid channel may be proportionally configured with respect to the air channel to create greater pressure in the liquid channel than the air channel. A size of the air channel may be proportionally configured with respect to a size of the liquid channel to create greater flow resistance in the air channel than the liquid channel. The first lumen of the liquid-vial spike may have a greater length than the second lumen of the liquid-vial spike. The first lumen of the liquid-vial spike may have a narrower diameter than the second lumen of the liquid-vial spike. The first lumen of the liquid-vial spike extends farther from the distal surface than the second lumen of the liquid- vial spike.

[11] The liquid-vial receiver may include a flow control mechanism configured to resolve flow hesitation, which may include flow stall, flow slowdown, or temporal, substantial or complete flow stop, upon actuation by briefly, temporarily or permanently pressing the liquid vial further onto the liquid-vial spike extending from the distal surface of the liquid-vial receiver and thereby increasing pressure through the air channel. The liquid-vial receiver may include a flow control mechanism configured to resolve flow hesitation upon actuation by displacing air through the air channel, thereby clearing any fluid occlusion of the air channel and transferring positive pressure into the liquid vial. The flow control mechanism may be actuated upon insertion of the liquid vial into the liquid- vial receiver.

[12] The drug-vial receiver may include an air vent for facilitating ingress of air into the drug vial during withdrawal of the drug in order to normalize gas pressure within the drug vial. The air vent may include a valved port. The drug-vial receiver further may include an air filter that filters air entering through the air vent. The drug-vial receiver further may include a check valve to prevent the drug from flowing into the air channel and contacting the air filter.

[13] The drug handling device may be oriented vertically, wherein the drug-vial receiver may be configured to be positioned on top of a mouth of the drug vial when the drug vial may be placed right side up on a surface, and wherein the liquid-vial receiver may be configured to be positioned underneath a mouth of the liquid vial. The drug-vial receiver further may include a drug-vial housing extending from the distal surface of the drug-vial receiver. The drug-vial housing may be configured to hold the drug vial in an axially centered position. The drug-vial housing may include support structures configured to provide lateral stability. The liquid-vial receiver further may include a liquid-vial housing extending from the distal surface of the liquid-vial receiver. The liquid-vial housing may be configured to hold the liquid vial in an axially centered position.

[141 The drug handling device may include drug vial retention structures to retain the drug vial in place once inserted into the drug handling device. The drug vial retention structures may be located on the drug-vial receiver. The drug vial retention structures may be located on the drug-vial housing. The drug handling device may include liquid vial retention structures to retain the liquid vial in place once inserted into the drug handling device. The liquid vial retention structures may be located on the liquid-vial receiver. The liquid vial retention structures may be located on the liquid-vial housing.

[15] The drug-vial receiver may be detached from the liquid-vial receiver by a twisting motion, further comprising a retention affordance designed to help prevent the twisting motion until the drug may be ready for withdrawal. The retention affordance may include one or more removable parts that must be removed prior to detachment of the drug- vial receiver from the liquid-vial receiver. The drug handling device may include a hanging affordance to position the drug handling device with the one or more access ports oriented downward. The drug handling device may include an anti-roll structure at a distal end of the liquid-vial receiver designed to prevent rolling.

[16] The liquid-vial housing may be configured for a liquid vial with a capacity of at least 50 ml. The liquid-vial housing may be configured for a liquid vial with a capacity of no more than 500 ml. The drug product may be a solid, a powder, or a combination thereof. The drug product may be a lyophilized drug product, a spray-dried drug product, or a combination thereof. The liquid may be aqueous. The liquid may act as a solvent to reconstitute the drug product. The liquid may act as a diluent to dilute the drug product.

[17] The drug product may be alteplase, a biosimilar of alteplase, another tissue plasminogen activator, or a biosimilar thereof. Instructions for use of the drug product may indicate administration through a plurality of modalities. The instructions for use may indicate administration of a bolus dose of the drug, followed by an infusion dose.

[18] Embodiments of a kit may comprise a drug handling device as described herein, a drug vial containing a drug product, and a sealed liquid vial containing a liquid for combination with the drug product. The drug handling device further may include a plug that prevents insertion of the liquid vial into the drug handling device, wherein the plug can only be dislodged by insertion of the drug vial into the drug handling device. The drug vial may be included in the kit separately from the drug handling device, and wherein a mouth of the drug vial may be sealed. The drug vial may be pre-inserted into the drug handling device.

[19] Steps of a method for preparing a drug product for administration may include inserting a liquid vial into a drug handling device as described herein to combine a liquid in the liquid vial with a drug product in a drug vial inserted into the drug handling device to form a drug. Once flow from the liquid vial has ceased, the steps may include detaching the drug-vial receiver of the drug handling device from the liquid-vial receiver of the drug handling device, followed by steps for withdrawing a dose of the drug from the drug vial.

[20] The steps may include inserting the drug vial into the drug handling device prior to inserting the liquid vial. The steps may include removing a plug from the drug handling device prior to inserting the liquid vial. Inserting the liquid vial into the drug handling device may actuate a flow control mechanism of the drug handling device. The steps may include removing a retention affordance that prevents the drug-vial receiver from being detached from the liquid-vial receiver prior to detaching the drug-vial receiver from the liquid-vial receiver. Pressing down on a bottom surface of the liquid vial may actuate the flow control mechanism of the drug handling device. Withdrawing a dose of the drug from the drug vial may include steps for attaching a needle-free Luer lock syringe to the Luer port of the drug handling device and withdrawing a bolus dose of the drug. Withdrawing a dose of the drug from the drug vial may include steps for attaching an IV administration set to the infusion access port of the drug handling device and using the hanging affordance to hang the drug handling device with the infusion access port oriented downward. The steps may include removing a cap from the infusion access port prior to attaching the IV administration set.

[21] Steps of a method for preparing a drug for administration can include inserting a drug vial into a drug-vial receiver of a drug handling device as described herein, wherein the drug vial includes a drug product, and inserting a liquid vial into a liquid-vial receiver of the drug handling device, wherein the liquid vial includes a liquid, to combine the liquid with the drug product and produce a prepared drug.

[22] The steps can include separating the liquid-vial receiver from the drug handling device. The drug handling device can include a retention affordance, wherein the retention affordance can be removed prior to separating the liquid-vial receiver. The steps can include withdrawing a bolus of the prepared drug. The bolus can be withdrawn from a drug access port of the drug handling device. The bolus can be administered to a subject. The steps can include connecting the drug vial to an IV administration set. The drug vial can be connected to the IV administration set via a drug access port of the drug handling device. The drug product can include a powder, a solid, a lyophilized drug product, a spray- dried drug product, or a combination thereof. The drug for administration can be configured to be administered with or without processing the drug product. Processing the drug product can include reconstitution and/or dilution of the drug product. The steps can include swabbing a seal of the drug vial with alcohol. The steps can include swabbing a seal of the liquid vial with alcohol. One or more retention structures in the drug-vial receiver can retain the drug vial inside the drug-vial receiver after insertion. One or more retention structures in the liquid-vial receiver retain the liquid vial inside the liquid-vial receiver after insertion. The liquid-vial receiver can include a plug, and the plug can be ejected when the drug vial is inserted into the drug-vial receiver. The steps can include actuating a flow control mechanism. The flow control mechanism can be actuated by pressing the liquid vial further onto a liquid-vial spike.

[23] Steps of a method for preparing a drug for administration without seal failure can include inserting a drug vial into a drug-vial receiver of a drug handling device as described herein, wherein the drug vial includes a drug product, and inserting a liquid vial into a liquid-vial receiver of the drug handling device, wherein the liquid vial includes a liquid, to combine the liquid with the drug product to produce the prepared drug.

[24] Seal failure can include leakage, collapse, and/or fragmentation of a drug vial seal. The steps can include separating the liquid-vial receiver from the drug handling device. The drug handling device can include a retention affordance, wherein the retention affordance can be removed prior to separating the liquid-vial receiver. The steps can include withdrawing a bolus of the prepared drug. The bolus can be withdrawn from a drug access port of the drug handling device. The bolus can be administered to a subject. The steps can include connecting the drug vial to an IV administration set. The drug vial can be connected to the IV administration set via a drug access port of the drug handling device. The drug product can include a powder, a solid, a lyophilized drug product, a spray-dried drug product, or a combination thereof. The drug for administration can be configured to be administered with or without processing the drug product. Processing the drug product can include reconstitution and/or dilution of the drug product. The steps can include swabbing a seal of the drug vial with alcohol. The steps can include swabbing a seal of the liquid vial with alcohol. One or more retention structures in the drug-vial receiver can retain the drug vial inside the drug-vial receiver after insertion. One or more retention structures in the liquid-vial receiver retain the liquid vial inside the liquid-vial receiver after insertion. The liquid-vial receiver can include a plug, and the plug can be ejected when the drug vial is inserted into the drug-vial receiver. The steps can include actuating a flow control mechanism. The flow control mechanism can be actuated by pressing the liquid vial further onto a liquid-vial spike.

[25] Steps of a method for administering a drug to a subject can include inserting a drug vial into a drug-vial receiver of a drug handling device as described herein, wherein the drug vial includes a drug product, inserting a liquid vial into a liquid-vial receiver of the drug handling device, wherein the liquid vial includes a liquid, to combine the liquid with the drug product to produce a prepared drug, and administering the prepared drug to the subject.

[26] The steps can include separating the liquid-vial receiver from the drug handling device. The drug handling device can include a retention affordance, wherein the retention affordance can be removed prior to separating the liquid-vial receiver. The steps can include withdrawing a bolus of the prepared drug. The bolus can be withdrawn from a drug access port of the drug handling device. The bolus can be administered to a subject. The steps can include determining a dosage amount. When the dosage amount is less than an amount of prepared drug in the drug vial, an excess amount of the prepared drug can be withdrawn from the drug vial. The excess amount can be withdrawn from a drug access port of the drug handling device prior to administering the prepared drug to the subj ect. The steps can include connecting the drug vial to an IV administration set. The drug vial can be connected to the IV administration set via a drug access port of the drug handling device. The prepared drug can be administered to the subject by intravenous administration through the IV administration set. The steps can include withdrawing a portion of the prepared drug and administering the portion of the prepared drug to the subject by intravenous administration through an IV administration set. The steps can include swabbing a seal of the drug vial with alcohol. The steps can include swabbing a seal of the liquid vial with alcohol. One or more retention structures in the drug-vial receiver can retain the drug vial inside the drug-vial receiver after insertion. One or more retention structures in the liquid- vial receiver retain the liquid vial inside the liquid-vial receiver after insertion. The liquid- vial receiver can include a plug, and the plug can be ejected when the drug vial is inserted into the drug-vial receiver. The steps can include actuating a flow control mechanism. The flow control mechanism can be actuated by pressing the liquid vial further onto a liquid- vial spike.

[27] Steps of a method for administering alteplase to a subject can include inserting a drug vial into a drug-vial receiver of a drug handling device as described herein, wherein the drug vial includes alteplase; inserting a liquid vial into a liquid-vial receiver of the drug handling device, wherein the liquid vial includes a liquid, to combine the liquid with the alteplase to produce prepared alteplase, and administering the prepared alteplase to the subject.

[28] The steps can include determining a dosage amount. The dosage amount can be determined based on weight of the subject. The dosage amount can be about 0.9 milligrams alteplase per kilogram body weight (mg/kg). The dosage amount can be about 1.25 milligrams alteplase per kilogram body weight (mg/kg). The dosage amount can be about 100 mg alteplase. The dosage amount can be an amount that does not exceed 90 mg alteplase. Determining a dosage amount can include determining a bolus amount. The bolus amount can be 6-10 mg, about 15 mg, or 0.075 mg/kg. The steps can include withdrawing a bolus of the prepared alteplase and administering the bolus to the subject. The bolus can be administered to the subject by intravenous administration. The bolus amount can be withdrawn from a drug access port of the drug handling device. When the dosage amount is less than an amount of prepared alteplase in the drug vial, an excess amount of the prepared alteplase can be withdrawn from the drug vial prior to administering the prepared alteplase to the subject. The excess amount can be withdrawn from a drug access port of the drug handling device. The excess amount can be discarded. The steps can include connecting the drug vial to an IV administration set. The drug vial can be connected to the IV administration set via a drug access port of the drug handling device. The prepared alteplase can be administered to the subject by intravenous administration. The steps can include swabbing a seal of the drug vial with alcohol. The steps can include swabbing a seal of the liquid vial with alcohol. One or more retention structures in the drug-vial receiver can retain the drug vial inside the drug-vial receiver after insertion. One or more retention structures in the liquid-vial receiver retain the liquid vial inside the liquid-vial receiver after insertion. The liquid-vial receiver can include a plug, and the plug can be ejected when the drug vial is inserted into the drug-vial receiver. The steps can include actuating a flow control mechanism. The flow control mechanism can be actuated by pressing the liquid vial further onto a liquid-vial spike.

[29] Steps of a method for treating acute ischemic stroke in a subject can include inserting a drug vial into a drug-vial receiver of a drug handling device as described herein, wherein the drug vial includes alteplase, inserting a liquid vial into a liquid-vial receiver of the drug handling device, wherein the liquid vial includes a liquid, to combine the liquid with the alteplase to produce prepared alteplase, and administering the prepared alteplase to the subject.

[30] The steps can include determining a dosage amount. The dosage amount can be about 0.9 milligrams alteplase per kilogram body weight (mg/kg). The steps can include determining a bolus amount. The bolus amount can be about 10% of the dosage amount. The dosage amount can be 0.9 milligrams alteplase per kilogram body weight, where the dosage amount can be an amount that does not exceed 90 mg alteplase, wherein 10% of the dosage amount can be administered as an initial intravenous bolus over 1 minute and the remainder of the dosage amount can be intravenously infused over 60 minutes. The steps can include withdrawing a bolus of the prepared alteplase and administering the bolus to the subject. The bolus can be administered to the subject by intravenous administration. The bolus can be administered over one minute. When the dosage amount is less than an amount of prepared alteplase in the drug vial, an excess amount of the prepared alteplase can be withdrawn from the drug vial prior to administering the prepared alteplase to the subject. The steps can include administering the dosage amount to the subject. The prepared alteplase can be administered intravenously. The prepared alteplase can be administered over about 60 minutes. The steps can include swabbing a seal of the drug vial with alcohol. The steps can include swabbing a seal of the liquid vial with alcohol. One or more retention structures in the drug-vial receiver can retain the drug vial inside the drug-vial receiver after insertion. One or more retention structures in the liquid-vial receiver retain the liquid vial inside the liquid-vial receiver after insertion. The liquid-vial receiver can include a plug, and the plug can be ejected when the drug vial is inserted into the drug-vial receiver. The steps can include actuating a flow control mechanism. The flow control mechanism can be actuated by pressing the liquid vial further onto a liquid-vial spike.

[31] Steps of a method for treating acute myocardial infarction in a subject can include inserting a drug vial into a drug-vial receiver of a drug handling device as described herein, wherein the drug vial includes alteplase, inserting a liquid vial into a liquid-vial receiver of the drug handling device, wherein the liquid vial includes a liquid, to combine the liquid with the alteplase to produce prepared alteplase, and administering the prepared alteplase to the subject.

[32] The steps can include determining a dosage amount. The dosage amount can be based on a subject’s weight, not exceeding 100 mg. The dosage amount can be about 100 mg or less. The dosage amount can be about 1.25 mg alteplase per kg of the subject’s body weight. The steps can include determining a bolus amount. The bolus amount can be about 15 mg. The bolus amount can be about 6 mg to about 10 mg. The bolus amount can be about 0.075 mg alteplase per kg of the subject’s body weight. The steps can include withdrawing a bolus of the prepared alteplase and administering the bolus to the subject. The bolus can be administered to the subject by intravenous administration. When the dosage amount is less than an amount of prepared alteplase in the drug vial, an excess amount of the prepared alteplase can be withdrawn from the drug vial prior to administering the prepared alteplase to the subject. The prepared alteplase can be administered intravenously. The prepared alteplase can be administered as follows: if the subject’s weight is more than 67 kg, 15 mg of the prepared alteplase can be administered by intravenous bolus, 50 mg of the prepared alteplase can be administered for about first 30 minutes by intravenous infusion, and 35 mg of the prepared alteplase can be administered for about next 60 minutes by intravenous infusion; and if the subject’s weight is equal to or less than 67 kg, 15 mg of the prepared alteplase can be administered by intravenous bolus, 0.75 mg alteplase per kg of the subject’s body weight (mg/kg) of the prepared alteplase can be administered for about first 30 minutes by intravenous infusion, and 0.50 mg/kg of the prepared alteplase can be administered for about next 60 minutes by intravenous infusion. The prepared alteplase can be administered as follows: if the subject’s weight is 65 kg or more, 6-10 mg of the prepared alteplase can be administered by intravenous bolus, 50-54 mg of the prepared alteplase can be administered for about first one hour by intravenous infusion, 20 mg of the prepared alteplase can be administered for about second one hour by intravenous infusion, and 20 mg of the prepared alteplase can be administered for about third one hour by intravenous infusion; and if the subject’s weight is less than 65 kg, 0.075 mg alteplase per kg of the subject’s body weight (mg/kg) of the prepared alteplase can be administered by intravenous bolus, 0.675 mg/kg of the prepared alteplase can be administered by intravenous infusion for about first one hour, 0.25 mg of the prepared alteplase can be administered for about second one hour by intravenous infusion, and 0.25 mg of the prepared alteplase can be administered for about third one hour by intravenous infusion. The prepared alteplase can be administered over about 90 minutes or about 3 hours. The steps can include swabbing a seal of the drug vial with alcohol. The steps can include swabbing a seal of the liquid vial with alcohol. One or more retention structures in the drug-vial receiver can retain the drug vial inside the drug-vial receiver after insertion. One or more retention structures in the liquid-vial receiver retain the liquid vial inside the liquid-vial receiver after insertion. The liquid-vial receiver can include a plug, and the plug can be ejected when the drug vial is inserted into the drug- vial receiver. The steps can include actuating a flow control mechanism. The flow control mechanism can be actuated by pressing the liquid vial further onto a liquid-vial spike.

[33] Steps of a method of treating acute massive pulmonary embolism in a subject can include inserting a drug vial into a drug-vial receiver of a drug handling device as described herein, wherein the drug vial includes alteplase, inserting a liquid vial into a liquid-vial receiver of the drug handling device, wherein the liquid vial includes a liquid, to combine the liquid with the alteplase to produce prepared alteplase, and administering the prepared alteplase to the subject. [34] The steps can include determining a dosage amount. The dosage amount can be about 100 mg. When the dosage amount is less than an amount of prepared alteplase in the drug vial, an excess amount of the prepared alteplase can be withdrawn from the drug vial prior to administering the prepared alteplase to the subject. The steps can include administering the dosage amount to the subject. The prepared alteplase can be administered intravenously. The prepared alteplase can be administered over about 2 hours. 100 mg of the prepared alteplase can be administered by intravenous infusion over 2 hours. The steps can include swabbing a seal of the drug vial with alcohol. The steps can include swabbing a seal of the liquid vial with alcohol. One or more retention structures in the drug-vial receiver can retain the drug vial inside the drug-vial receiver after insertion. One or more retention structures in the liquid-vial receiver retain the liquid vial inside the liquid-vial receiver after insertion. The liquid-vial receiver can include a plug, and the plug can be ejected when the drug vial is inserted into the drug-vial receiver. The steps can include actuating a flow control mechanism. The flow control mechanism can be actuated by pressing the liquid vial further onto a liquid-vial spike.

[35] The embodiments disclosed above are only examples, and the scope of this disclosure is not limited to them. Particular embodiments may include all, some, or none of the components, elements, features, functions, operations, or steps of the embodiments disclosed above. The dependencies or references back in the attached claims are chosen for formal reasons only. However any subject matter resulting from a deliberate reference back to any previous claims (in particular multiple dependencies) can be claimed as well, so that any combination of claims and the features thereof are disclosed and can be claimed regardless of the dependencies chosen in the attached claims. The subject-matter which can be claimed comprises not only the combinations of features as set out in the attached claims but also any other combination of features in the claims, wherein each feature mentioned in the claims can be combined with any other feature or combination of other features in the claims. Furthermore, any of the embodiments and features described or depicted herein can be claimed in a separate claim and/or in any combination with any embodiment or feature described or depicted herein or with any of the features of the attached claims.

[36] The details of one or more variations of the subject matter described herein are set forth in the accompanying drawings and the description below. Other features and advantages of the subject matter described herein will be apparent from the description and drawings, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[37] The accompanying drawings, which are incorporated in and constitute a part of this specification, show certain aspects of the subject matter disclosed herein and, together with the description, help explain some of the principles associated with the disclosed implementations. In the drawings,

[38] FIG. 1 illustrates an example drug handling device during preparation of the drug.

[39] FIGS. 2A and 2B illustrate exploded views of an example drug handling device as oriented during drug preparation.

[40] FIG. 2C illustrates an example liquid-vial receiver with a liquid vial.

[41] FIG. 3A illustrates a perspective view of an example drug vial spike plate with a top plate translucent.

[42] FIG. 3B illustrates a perspective view of the example drug vial spike plate of FIG. 3A with the top plate hidden from view.

[43] FIG. 3C illustrates a perspective view of the example drug vial spike plate of FIG. 3 A with the top plate and an air filter hidden from view.

[44] FIG. 3D illustrates a perspective view of the example drug vial spike plate of FIG. 3 A with a lower portion of a body hidden from view.

[45] FIG. 3E illustrates a cross-sectional view of the example drug vial spike plate of FIG. 3 A.

[46] FIG. 3F illustrates another cross-sectional view of the example drug vial spike plate of FIG. 3 A.

[47] FIG. 4 illustrates an example drug-vial receiver.

[48] FIG. 5A illustrates an example plane (A-A) at which the cross-section of the drug handling device 110 shown in FIG. 5B was taken.

[49] FIGS. 5B-5C illustrate views of a liquid channel and an air channel in an example drug handling device during preparation of a drug. [50] FIGS. 6A-6C illustrate views of a liquid channel and an air channel in an example drug delivery device during withdrawal of a drug.

[51] FIGS. 7A-7L illustrate usage of an example drug handling device for reconstitution and administration of a lyophilized drug product.

[52] FIGS. 8A-8C illustrate a method of preparing a drug using an example drug handling device.

[53] When practical, similar reference numbers denote similar structures, features, or elements.

DESCRIPTION OF EXAMPLE EMBODIMENTS

[54] When handling certain types of drugs, such as Activase® (alteplase), certain special challenges may present themselves. First, the drug is not typically distributed in ready-to-use form and may need to be reconstituted at the time of use from a lyophilized drug product distributed in a drug vial and a solvent distributed in a liquid vial. Second, the drug is typically administered in a dual-modality approach for certain indications (e.g., acute ischemic stroke), involving an initial bolus dose to be delivered using a syringe, followed by a larger dose to be delivered by infusion. Third, there is a need for rapid preparation and administration of the drug after onset of symptoms and within a critical window of time (e.g., three hours for acute ischemic stroke). Finally, the larger volumes involved (e.g., 50 ml, 100 ml) make manual reconstitution (preparation with a syringe and needle) impractical or ergonomically challenging, requiring a device to aid in this process. Use of available devices can be problematic due to dislodgment (unseating) of vial seals, leakage of diluent or reconstituted drug product, or unreliable flow initiation (hesitation) due to the low- pressure differential created by gravity-driven devices. On some occasions, one or more drugs that are needed for administration are in the form of solid or liquid. Therefore, multiple different combinations such as a solid drug and a liquid drug or two different liquid drugs need to be prepared quickly for administration. Further, on some other occasions, a drug that is in the solid or liquid form needs to be diluted or reconstituted quickly without loss of any volume using a diluent before administration. In some cases, drug products to be reconstituted or diluted may be in the form of solid such as powder or lyophilized drug such that it needs to be mixed with one or more liquids, e.g., one or more of a solvent, a diluent, or a liquid drug, to form a prepared drug ready for administration. In some cases, the drug product may be a liquid drug product that needs to be mixed with one or more liquids, e g., one or more of a solvent, a diluent, or a liquid drug, to form a prepared drug ready for administration.

[551 Embodiments described herein provide an example drug handling device suitable to assist with preparation and dual-modality administration of a drug that may need to be quickly and precisely reconstituted from a drug product contained in a drug vial and a liquid contained in a liquid vial. Specifically, FIG. 1 illustrates an example drug-preparation assembly 100 including a drug handling device 110 with a drug vial 102 and a liquid vial 104 already inserted during preparation of a drug. The drug handling device 110 may have a shape designed to hold a drug vial 102 containing the drug product right-side up in a lower portion of the drug handling device 110 (i.e., drug-vial receiver 120) and a liquid vial 104 up-side down in an upper portion of the drug handling device 110 (i.e., liquid-vial receiver 140) in order to facilitate liquid flow from the liquid vial 104 into the drug vial 102. The drug handling device 110 does not comprise the drug vial 102 or the liquid vial 104. Drug preparation assembly 100 is a system comprising the drug handling device 110, a drug vial 102 inserted into drug-vial receiver 120, and a liquid vial 104 inserted into liquid-vial receiver 140. Drug-vial receiver 120 and liquid-vial receiver 140 may be connected at their proximal surfaces (i.e., proximal to the plane of connection), through which liquid and air pass during preparation of the drug after insertion of the drug vial 102 into the distal end of the drug-vial receiver 120, followed by insertion of the liquid vial 104 into the distal end of the liquid-vial receiver 140. The drug handling device 110 may be generally cylindrical and be configured to hold both vials in position and aligned along a longitudinal axis of the drug handling device 110. If there is any difference in the diameter or shape of the two vials, the drug handling device 110 may include internal ribs or other support structures to assist in holding one or both of the vials in place or in aligning the vials during insertion. As discussed further below, ensuring that the vials are in position and aligned along a longitudinal axis of the drug handling device 110 may be accomplished by one or more subcomponents of the drug handling device 110. The drug handling device 110 may include one or more support structures 112 at a distal end of the drug- vial receiver 120 designed to provide lateral stability while waiting for completion of the flow of liquid from the liquid vial 104 into the drug vial 102. The drug handling device 110 may also include anti-roll structures 114 at a distal end of the liquid-vial receiver 140 designed to prevent rolling (e.g., of the liquid-vial receiver 140 after detachment if placed horizontally on a surface). The drug handling device 110 may be configured for a liquid vial 104 with a capacity of at least 50 ml, and may be configured for a liquid vial 104 with a capacity of no more than 500 ml. For example, the capacity of the liquid vial 104 may be any one of 50 ml, 100 ml, 150 ml, 200 ml, 250 ml, 300 ml, 350 ml, 400 ml, 450 ml or 500 ml.

[56] FIGS. 2A and 2B illustrate exploded views of an example drug preparation assembly 100 as oriented during drug preparation from alternate perspective angles. As shown on the bottom right side of the figures, a seal 202 on a mouth of a drug vial 102 containing a drug product is oriented right-side up so that the drug vial 102 can be inserted into the drug-vial receiver 120 (shown on the right side of FIGS. 2A and 2B).

[57] Drug-vial receiver 120 may be manufactured as a single unit, or it may comprise an assembly of two or more subcomponents, as shown in the example drug handling device 110 shown in FIGS. 2A and 2B, which illustrate a two-component structure: a drug-vial spike plate 210 attached to a drug-vial housing 220. Once drug vial 102 is inserted into drug-vial receiver 120, a drug-vial spike 212 extending from a distal surface of the drug-vial receiver 120 pierces the seal 202 on the mouth of the drug vial 102. The seal 202 of the drug vial 102 may be swabbed with alcohol prior to insertion into the drug-vial receiver 120. As illustrated in FIGS. 2A and 2B, the drug-vial receiver 120 includes one or more drug access ports 214 (e.g., syringe drug access port 214a and infusion drug access port 214b) on a proximal surface of the drug-vial receiver 120. The infusion drug access port 214b can be located between a liquid channel and an edge of the proximal surface of the drug-vial receiver 120. As explained in more detail below, the drug-vial receiver 120 may include one or more retention structures that retain the drug vial 102 inside the drug-vial receiver 120 after insertion. The drug handling device 110 may be designed for insertion of the drug vial 102 prior to insertion of the liquid vial 104, in order to ensure that a receptacle is in place to receive the flow of liquid as soon as the liquid vial 104 is inserted into the liquid-vial receiver 140 (as illustrated on the left side of FIGS. 2A and 2B). Alternatively, the drug handling device 110 may be designed for insertion of the liquid vial 104 prior to insertion of the drug vial 102. Alternatively, the drug handling device 110 may be designed for insertion of the liquid vial 104 and insertion of the drug vial 102 simultaneously. As shown on the upper left side of the figures, a seal 204 on a mouth 205 of a liquid vial 104 containing a liquid is oriented up-side down so that the liquid vial 104 can be inserted into the liquid-vial receiver 140. The seal 204 of the liquid vial 104 may be swabbed with alcohol prior to insertion into the liquid-vial receiver 140. As explained in more detail below the liquid-vial receiver 140 may include one or more retention structures that retain the liquid vial 104 inside the liquid-vial receiver 140 after insertion.

[58] Liquid-vial receiver 140 may be manufactured as a single unit, or it may comprise an assembly of two or more subcomponents, as shown in the examples in FIGS. 2A and 2B, which illustrate a two-component structure: a liquid-vial spike plate 230 attached to a liquid-vial housing 240. Once liquid vial 104 is inserted into liquid-vial- receiver 140, a liquid-vial spike 232 extending from a distal surface of the liquid-vial receiver 140 pierces the seal 204 on the mouth 205 of the liquid vial 104. The liquid vial spike 232 may have a first lumen and a second lumen. The first lumen of the liquid vial spike 232 may have a greater length, and/or a narrower diameter, and/or extend farther from the distal surface of the liquid-vial receiver 140 than the second lumen of the liquid vial spike 232. The drug-vial housing and the liquid-vial housing may be precisely configured to ensure that the vials are in position and aligned along a longitudinal axis of the drug handling device 110. Each of the vial housings may be manufactured to closely fit the corresponding vial (e.g., wherein the diameter of the vial housing is just large enough to permit insertion of the vial, or wherein the vial housing includes internal support structures) and hold it in alignment while preventing lateral movement.

[59] The proximal surface of the drug- vial receiver 120 may be detachably connected to a proximal surface of the liquid-vial receiver 140 in order to facilitate preparation of the drug while connected and to facilitate access to the drug for administration once detached. Detachment of the drug-vial receiver 120 from the liquid-vial receiver 140 may be accomplished by a twisting motion (e.g., to disengage retention tabs or clips 282 or unscrew the two halves along a threaded region).

[60] While the proximal surface of the drug-vial receiver 120 is connected to the proximal surface of the liquid-vial receiver 140, the drug-vial spike 212 of the drug-vial receiver 120 and the liquid-vial spike 232 of the liquid-vial receiver 140 may form a liquid channel for the liquid to flow from the liquid vial 104 into the drug vial 102 and thereby combine with the drug product and an air channel for air to flow from the drug vial 102 into the liquid vial 104 as the liquid flows from the liquid vial 104 into the drug vial 102. This liquid channel may be formed in part by a connection between the liquid-vial spike plate 230 and the drug- vial spike plate 210 by way of a male Luer connecter 216 (partially hidden behind a clip on the liquid-vial spike plate 230) located on the proximal surface of the liquid- vial spike plate 230, which extends through syringe drug access port 214a (which may be a female Luer port). This air channel may be formed in part by a connection between the drug- vial spike plate 210 and the liquid-vial spike plate 230 by way of a tubular extension 217 (as shown in FIG. 2B) that passes through an air channel port 218 on the proximal surface of the drug-vial receiver 120 (as shown in FIG. 2A). The air channel port 218 may be recessed with respect to the proximal surface of the drug-vial receiver (in order to distinguish the syringe drug access port 214a and deter the user from accessing the air channel port 218 erroneously).

[61] Any drug product that is in the form of liquid, solid or powder, e.g., a lyophilized drug product that may need a reconstitution before administration to a subject can be handled with the drug preparation assembly or drug handling device disclosed herein. In some embodiments, the drug product may be a lyophilized or spray-dried solid, such as powder or cake, or may be a liquid. The liquid in the liquid vial 104 may act as a solvent to dissolve the drug product. In some embodiments, the drug product may be a liquid or gel. The liquid in the liquid vial 104 may act as a diluent to dilute the drug product to an appropriate strength for administration. The liquid may be an aqueous solution, or it may have an alternate level of viscosity appropriate for use with the drug handling device disclosed herein. The liquid in the liquid vial 104 may be a liquid drug. In some embodiments, the liquid in the liquid vial 104 is substantially (i.e., more than 50% of the total volume of the liquid) or entirely water. In some embodiments, one or more drug products in drug vial 102 are in the form of liquid such that a reconstitution or dilution before administration to a subject can be done by mixing the one or more liquid drug products in the drug vial 102 with the liquid in liquid vial 104, which may be one or more of another liquid drug product, a solvent, or a diluent. In some embodiments, both vials 102 and 104 contain different liquid drug products. In some other embodiments, drug vial 102 contains a liquid drug product and liquid vial 104 contains a solvent or diluent that does not have an active drug product but can dilute the liquid drug product in drug vial 102 during or after reconstitution in preparation for administration of the drug. In some embodiments, there can be two or more vials 102, 104 used to prepare a drug for administration wherein one or more vials 102, 104 may contain one or more drug products, either in a solid or liquid form, and other one or more vials 102, 104 may contain one or more diluents or solvents for reconstitution. In some embodiments, there are multiple liquid vials 104 that can be used with the drug handling device 110 sequentially or in no specific order, such that the drug product in drug vial 102 is mixed with multiple liquids (e.g., one or more solvents, diluents, and/or liquid drug products) from multiple liquid vials 104 during the preparation of a drug for administration. In some embodiments, the drug product in drug vial 102 is configured to be administered as a drug with or without processing the drug product, wherein processing the drug product includes reconstitution and/or dilution of the drug product.

[62] FIG. 2C illustrates an enlarged view of the example liquid-vial spike plate 230 shown in FIGS. 2A and 2B coupled with a liquid vial 104 (shown in dashed lines to avoid obscuring the structure of the liquid-vial spike 232). The liquid-vial spike plate 230 is configured to be positioned underneath a mouth or opening 205 of the liquid vial 104. As illustrated, the liquid-vial spike 232 is positioned along the liquid vial spike plate 230 such that the liquid-vial spike 232 is aligned with a longitudinal axis of the drug handling device 110 to facilitate alignment with a longitudinal axis of the liquid vial 104 and thereby pierce the seal 204 along the mouth 205 of the liquid vial 104 upon insertion of the liquid vial 104 into the liquid-vial receiver 140. The liquid-vial receiver 140 may include one or more retention structures 312, as shown in FIG. 2C, that can assist with securing (including releasably securing) the liquid vial 104 to the liquid-vial spike plate. For example, the retention structures 312 can include one or more clips, tabs, or gaskets. The liquid vial retention structures 312 may be located on the liquid-vial receiver 140 and/or the liquid-vial housing 240.

[63] In some embodiments, the liquid-vial receiver 140 can include a flow control mechanism 310 that can assist with resolving flow hesitation (e g., between the drug vial 102 and the liquid vial 104), which may include flow stall, flow slowdown, or temporal, substantial or complete flow stop. For example, the flow control mechanism can assist with transferring positive pressure into the liquid vial 104, thereby reducing pressure in the drug vial 102 and reducing flow hesitation. For example, flow hesitation can include a resistance (e.g., stall, slowdown, or temporal, substantial or complete stop) to the flow of fluid (e.g., liquid, air) due to formation of a vacuum in the drug preparation assembly 100, such as within the liquid vial 104 (e.g., as a result of fluid being dispensed from the liquid vial 104). Such vacuum can resist or prevent fluid flow and inhibit the effectiveness of fluid transfer and flow within the drug preparation assembly 100. As such, the flow control mechanism 310 can improve the efficiency and effectiveness of the drug preparation assembly 100.

[64] For example, in some embodiments, as shown in FIG. 5C, the flow control mechanism 310 can include a bellows cover 288, an umbrella valve 276, an outer bellows gasket 278, and an inner bellows gasket 280. The bellows cover 288, outer bellows gasket 278, and inner bellows gasket 280 can define a bellows space 281 that can contain air. In some embodiments, actuation of the flow control mechanism 310 can include deformation or linear displacement of the bellows cover 288 to thereby transfer air within the bellows space 281 into the liquid vial 104, reducing flow hesitation, which may include flow stall, flow slowdown, or temporal, substantial or complete flow stop.

[65] For example, briefly, temporarily, or permanently pressing the liquid vial 104 further onto the liquid-vial spike 232 extending from the distal surface 228 of the liquid- vial spike plate 230 and the distal surface of the liquid-vial receiver 140 can allow the liquid vial 104 to apply a force on the distal surface 228 of the liquid vial-spike plate 230, thereby activating the flow control mechanism 310 (e.g., linearly displacing or deforming the bellows cover 288). Linear displacement or elastic deformation of the bellows cover 288 can force air within the bellows space 281 through the air channel 273 and into the liquid vial 104, increasing the pressure within the liquid vial 104 and decreasing the pressure within the drug vial 102. As such, the flow control mechanism 310 may operate like a pump by pressurizing the liquid vial 104 and thereby increasing pressure (and fluid flow) through the first drug fluid passageway 285 and drug-vial spike 212. The flow control mechanism 310 may also operate like a bellows by displacing air through the air channel 273 of liquid- vial spike 232, thereby clearing any fluid occlusion along the air channel 273. In some embodiments, the bellows cover 288 may be made of a resilient material (e.g., rubber material, flexible and/or expandable material) that can deform as a result of an applied force, as well as reform after the applied force is removed. As the bellows cover 288 returns to its original, non-displaced or non-deformed position, the bellows space 281 increases in size, lowering the pressure within the bellows space 281 and creating a pressure differential between the bellows space 281 and the first air channel 258 of the air channel port 218. This pressure differential allows the umbrella valve 276 to open as air moves into the bellows space 281 until the pressure between the bellows space 281 and the first air channel 258 is equalized.

[66] FIG. 4 illustrates an example drug-delivery assembly 400 including a drug- vial receiver 120 (after detachment from the liquid-vial receiver 140) and a drug vial 102 containing the reconstituted drug 286. As illustrated, the drug access ports 214 (e.g., syringe drug access port 214a and infusion drug access port 214b) are revealed and accessible after detachment of the liquid-vial receiver 140 from the drug-vial receiver 120. The drug access ports 214 conveniently allow withdrawal of the drug 286 (e.g., from the drug vial 102) after preparation of the drug 286 without having to pierce the seal 202 of the drug vial 102 more than once, thereby reducing dislodgement and/or fragmentation of the seal 202, as well as reducing the likelihood of leaks, contamination, and/or waste of the drug 286 contained in the drug vial 102.

[67] The drug access ports 214 may include a syringe drug access port 214a configured for use with a syringe, such as to facilitate withdrawal of a dose of the drug 286 into the syringe after preparation of the drug 286. The syringe drug access port 214a can thus be configured to provide a fluidic seal (e.g., prevent fluid from passing through the syringe drug access port 214a) unless engaged with and/or coupled to a syringe. As shown in FIGS. 3E, 4, 5B, and 5C, the syringe drug access port 214a can be in fluid communication with a first drug fluid passageway 285 that extends between the syringe drug access port 214 and a first distal fluid port 271 of the drug-vial spike 212. As shown in FIGS. 3E, 4, 5B, and 5C, the drug-vial spike 212 can include the first distal fluid port 271 and a second distal fluid port 270. For example, the first distal fluid port 271 can allow one or more fluids to be delivered from the liquid vial 104 to the drug vial 102, such as to form the drug 286, as well as allow the drug 286 formed in the drug vial 102 to be drawn out of the drug vial 102, such as into a syringe. As will be described in greater detail below, the second distal fluid port 270 can be in fluid communication with one or more airflow pathways such that the second distal fluid port 270 can allow airflow to pass into and out of the drug vial 102.

[68] In the example drug-delivery assembly 400 shown in FIG. 4, the syringe drug access port 214a is illustrated as a raised Luer lock port configured for a needle-free Luer lock syringe. Alternatively, the syringe drug access port 214a may be configured for access using a blunt cannula or a needle. In some embodiments, the drug access ports 214 may include an infusion drug access port 214b that is configured to couple (including releasably couple) to an IV administration set, such as for intravenous administration of the drug 286 from the drug vial 102. An IV administration set typically includes a spike (vented or non-vented), a drip chamber, tubing, a roller clamp, a Y-connector for injections, a connector such as a luer lock connector, and a needle. The infusion drug access port 214b (illustrated with a cap 215b) can be in fluid communication with a second drug fluid passageway 284 that extends between the infusion drug access port 214b and the first distal fluid port 271 of the drug spike 212. As such, the first drug fluid passageway 285 and the second drug fluid passageway 284 can merge either before or along the drug spike 212, such as upstream from the first distal fluid port 271. In some embodiments, the infusion drug access port 214b may be located to the side of the liquid channel, which can include one or more of the first drug fluid passageway 285 and the second drug fluid passageway 284, and closer to an outer circumferential edge of the drug-vial receiver 120, which can allow clearance for a syringe to connect to the syringe drug access port 214a.

[69] FIG. 3A illustrates a top perspective view of an embodiment of the drug- vial spike plate 210 with a top plate 241 shown translucent and offset from a body 231 of the drug-vial spike plate 210. The top plate 241 can be offset from a top surface 233 of the body 231 by a gap distance 243 and forming an air access slit 242. The air access slit 242 can allow airflow to flow from outside of the drug-vial spike plate 210 into one or more airflow pathways extending along and through the drug-vial spike plate 210, as will be described in greater detail below. For example, airflow can flow through the air access slit 242 and through an air filter 244 that extends along at least a part of the top surface 233, as shown in FIG. 3A. As also shown in FIG. 3B, the air filter 244 can be coupled to the top surface 233, such as by a seal or air filter seam 246 that extends in a continuous path surrounding a recess channel 250 along the top surface 233. For example, the air filter seam 246 can form a fluidic seal and require airflow flowing from the air access slit 242 into the recess channel 250 to pass through the air filter 244.

[70] As shown in FIGS. 3C and 3F, the recess channel 250 can include a check valve 252 that can allow airflow to pass from the direction of the recess channel 250 into a central air channel 260 and can prevent fluid passage in the opposite direction. In some embodiments, the check valve 252 can require directional flow. The check valve 252 can be any of a variety of valves (e g., duckbill, umbrella, etc.). The check valve 252 can prevent the drug 286 from contacting the air filter 244, which could reduce its operational efficiency or even rupture the air filter 244 if pressure builds up in the drug vial 102 due to manual injection of air or liquid. In addition, the air access slit 242 can include a valved port in order to further prevent the drug 286 from leaking out through the air channel during withdrawal of the drug 286 after the drug-vial receiver 120 is detached from the liquid-vial receiver 140.

[71] As shown in FIG. 3E, the top surface 233 of the body 231 of the drug- vial spike plate 210 can include an air channel port 218 that is in fluid communication with a first air channel 258 that extends between the central air channel 260 and the air channel port 218. The check valve 252 can be in fluid communication with the central air channel 260 via a second air channel 254. The central air channel 260 can be fluidically sealed, such as by a gasket 256, to limit airflow only along the defined airflow pathways in communication with the central air channel 260, such as the first air channel 258 and the second air channel 254. The central air channel 260 can also be in fluid communication with an air connection pathway 263 that extends between the central air channel 260 and a drug- vial spike air pathway 268. The drug-vial spike air pathway 268 can extend at least partly along the drug-vial spike 212 and be in communication with the second distal fluid port 270, as shown in FIG. 3E. As shown in FIGS. 3D and 3E, an O-ring 266 can provide a fluidic seal along the air connection pathway 263, such as at a junction between two mating parts of the body 231.

[72] For example, the drug-vial spike plate 210 can include a first airflow pathway 275 that extends between air outside of the drug preparation assembly 100 (or any part thereof) and the drug vial 102, such as to equalize, normalize, and/or change a gas pressure within the drug vial 102 during withdrawal of the reconstituted drug 286. For example, the first airflow pathway 275 can be defined to include an airflow pathway that passes through the air access slit 242, the air filter 244, the check valve 252, and extends along the second air channel 254 and into the central air channel 260, as shown in FIGS. 3B and 3F. From the central air channel 260, the first airflow pathway 275 can continue along the air connection pathway 263 and out the drug-vial spike 212 through the second distal fluid port 270, as shown in FIG. 6A. For example, this first airflow pathway 275 can allow filtered air to be introduced into the drug vial 102, such as to equalize the pressure at least within the drug vial 102 (as well as equalize and/or reduce pressure along other fluid pathways in fluid communication with the drug vial 102, such as the first or second drug fluid passageways 285 and 284, respectively). As discussed, such changes in pressure along the fluid passageways can improve the efficiency and effectiveness of fluid flow along such fluid passageways thereby improving usability and reducing drug waste in the drug-delivery assembly 400.

[73] FIG. 5A illustrates an example plane (A-A) at which the cross-section of the drug preparation assembly shown in FIG. 5B was taken. FIG. 5B illustrates the liquid channel and the air channel in an example drug preparation assembly, together with the path of the flow of liquid 274 (illustrated using a solid arrow leading from the liquid vial 104 to the drug vial 102) and the path of the flow of air 272 (illustrated using a dashed arrow leading from the drug vial 102 to the liquid vial 104) during combination of the drug product with the liquid. FIG. 5C depicts an enlarged view of FIG. 5B.

[74] As shown in FIGS. 5B and 5C, the drug-vial spike plate 210 can include a second airflow pathway 272 that extends at least partway between the liquid vial 104 and the drug vial 102, such as to equalize and/or change a pressure within the drug vial 102 and/or liquid vial 104. For example, the second airflow pathway 272 can be defined to include the air channel port 218, the first air channel 258, the central air channel 260, the air connection pathway 263, the drug-vial spike air pathway 268, and the second distal fluid port 270, as shown in FIGS. 5B and 5C. In some embodiments, the air channel port 218 can form a closed configuration that is fluidically sealed to prevent fluid leakage therethrough. The air channel port 218 can also from an open configuration that allows airflow to flow therethrough, thus allowing the second airflow pathway 272 to extend between the drug vial 102 and the liquid vial 104, such as when the drug vial 102 and liquid vial 104 are coupled to the drug-vial receiver 120 and liquid-vial receiver 140, respectively. In some embodiments, the liquid-vial spike plate 230 can include a tubular extension 217 that can extend into and/or engage the air channel port 218 to allow the air channel port 218 to form the open configuration when the liquid-vial spike plate 230 is coupled to the drug- vial spike plate 210, as shown in FIGS. 5B and 5C. As such, decoupling of the liquid-vial spike plate 230 from the drug-vial spike plate 210 can allow the air channel port 218 to reform back to the closed configuration, thereby preventing fluid leak from the drug vial 102.

[75] As shown in FIGS. 5B and 5C, the liquid-vial spike 232 extends from a distal surface 228 of the liquid-vial spike plate 230 and a distal surface of the liquid-vial receiver 140. The liquid-vial spike 232 may be a dual-lumen spike including a first lumen configured to form the air channel and a second lumen configured to form the liquid channel. The first lumen (for the air channel) may be proportionally configured with respect to the second lumen (for the liquid channel) to create greater pressure in the liquid channel than in the air channel in order to facilitate the flow of liquid from the liquid vial 104 into the drug vial 102 through the liquid channel and the flow of air from the drug vial 102 into the liquid vial 104 through the air channel while avoiding or mitigating flow hesitation due to the intrusion of air bubbles into the liquid channel or liquid into the air channel. A higher- pressure differential in the liquid channel may be accomplished by configuring physical dimensions of the second lumen to be positioned lower in the vial relative to the first lumen thereby creating a larger fluid column pressure at the position of the second lumen. Flow of liquid through the intended liquid channel may be encouraged by configuring physical dimensions of the fluid channel by increasing the cross-sectional area of the liquid channel relative to the dimensions of the air channel to decrease the flow resistance of liquid through the liquid channel relative to the air channel. The drug-vial spike 212 extends from a bottom surface of body 231 of the drug-vial spike plate 210 and a distal surface of the drug-vial receiver 120. The drug-vial spike 212 may also be a dual-lumen spike including a first lumen configured to form the air channel and a second lumen configured to form the liquid channel. During preparation of the drug, in order to facilitate normalization of gas pressure between the vials, a path 272 of the air channel permits the flow of air from within the drug vial 102 to the liquid vial 104 (see FIGS. 5B and 5C). As shown in FIGS. 5B and 5C, liquid flows vertically through the liquid channel on a straight path 274 when flowing from the liquid vial 104 to the drug vial 102 (e.g., during preparation of the drug). As shown in FIG. 5C, the drug-vial spike plate 210 or the drug-vial receiver 120 can include one or more clips 282 to secure, retain, and or hold the drug vial 102 within the drug-vial receiver 120 once it is inserted into the drug-vial receiver 120.

[76] FIG. 6A is an enlarged cross-section view illustrating the liquid channel and drug access ports 214 in an example drug delivery device 400, including the path of the flow of liquid 269 (illustrated using a solid arrow leading out of the drug vial 102) and the path of the flow of air 275 (illustrated using a dashed arrow leading into the drug vial 102) during withdrawal of the drug through one of the drug access ports 214. As shown in FIG. 6B, when using the syringe drug access port 214a, the drug flows from the drug vial 102 through the liquid channel during withdrawal of a bolus dose of the drug. When using the infusion drug access port 214b (see FIG. 6C), the drug flows from the drug vial 102 through a branch of the liquid channel within the drug-vial receiver 120. During withdrawal of the reconstituted drug 286 (from the drug access ports 214), the air channel may permit the flow of outside air from the air access slit 242 into the drug vial 102 (see FIG. 6A).

[77] During preparation of the drug, the air channel may run adjacent to the liquid channel through the first lumens in the drug-vial spike 212 and the liquid-vial spike 232, while diverging from this straight path to a network of internal channels connecting alternate branches of the air channel between a base of the drug- vial spike 212 and a base of the liquid-vial spike 232. The air channel port 218 in the top surface 233 of the drug-vial spike plate 210 in the path of the air channel between the drug-vial receiver 120 and the liquid-vial receiver 140 may include a valve designed to prevent leakage of the drug from the drug vial 102 after detachment of the liquid-vial receiver 140. Prior to detachment of the liquid-vial receiver 140, this valve may be held open by a tubular extension 217 of the liquid-vial receiver 140 that is inserted into the valve; after detachment of the liquid-vial receiver 140, the tubular extension 217 is thereby removed, returning the valve to its normally closed state.

[78] In particular embodiments, the drug handling device 110, the drug vial 102 containing the drug product, and the liquid vial 104 may be provided in a kit. The drug vial 102 and the liquid vial 104 may be included in the kit, separately from the drug handling device 110, each with a seal and/or a cap over its mouth. In some embodiments, the drug vial 102 may be pre-inserted into the drug handling device 110. In some embodiments, the drug vial 102 and the liquid vial 104 may be pre-installed or built into the drug handling device 110. The kit may include instructions for use of the drug product indicating administration through a plurality of modalities, such as administration of an intravenous bolus dose of the drug, followed by an intravenous infusion dose. In some embodiments, the drug product in the drug vial 102 is a solid form of drug product, e.g., powder or lyophilized drug product. In some embodiments, the drug product in the drug vial 102 is a liquid form of drug product such that a liquid drug in drug vial 102 may be diluted with a liquid from the liquid vial 104 using the drug handling device 110. In some embodiments, both the drug vial 102 and the liquid vial 104 contain a drug product, where the drug vial 102 can contain a solid drug product, a lyophilized drug product, or a liquid drug product, and the liquid vial 104 can contain a liquid drug product. For example, a liquid drug product in drug vial 102 can be mixed with a liquid drug product from liquid vial 104 to prepare a drug for administration. In some embodiments, there are multiple liquid vials 104 that can be used with the drug handling device 110 sequentially or in no specific order, such that the drug product in drug vial 102 is mixed with multiple liquids from multiple liquid vials 104 during the preparation of a drug for administration. In some embodiments, the drug vial 102 can contain multiple drug products.

[79] In particular embodiments, the drug product may be a thrombolytic agent, such as a tissue plasminogen activator. In some embodiments, the drug product may be alteplase (e.g., Activase®), a biosimilar of alteplase (e.g., REVELISE or ALTEPLASE STRAGEN), another tissue plasminogen activator (e.g., desmoteplase, reteplase, or tenecteplase, such as TNKase®), or a biosimilar thereof (e.g., biosimilars of TNKase® include ELAXIM, TENECTEPLASE TPP, R-TPR-012, TENECTEPLASE ZYDUS).

[80] FIGS. 7A-7L illustrate usage of an example drug handling device 110 for reconstitution and administration of a lyophilized drug. Prior to use, the drug handling device 110 may include a plug 710 (see FIGS. 7C-7D) that prevents insertion of the liquid vial 104 into the drug handling device 110, until the drug vial 102 has first been inserted into the drug handling device 110, thereby ensuring that the drug vial 102 is in place to receive the liquid flow prior to piercing the seal on the liquid vial 104. The plug 710 may be included in the liquid-vial receiver 140, and the plug 710 may be ejected from the liquid- vial receiver 140 when the drug vial 102 is inserted into the drug-vial receiver 120.

[81] As shown in FIG. 7A, there may be a protective cover 720 over an opening on the bottom of the drug handling device 110 where the drug vial 102 is to be inserted that must be removed prior to use. As the drug vial 102 is inserted into the bottom opening of the drug handling device 110, it may be necessary to press the drug vial 102 in firmly enough to engage drug vial retention structures such as one or more clips 282 to hold or retain the drug vial 102 inside of the drug handling device 110 (see FIG. 7B). The drug vial retention structures, such as one or more clips 282, may be located on the drug-vial receiver 120 and/or the drug-vial housing 220. Once the drug vial 102 is completely inserted onto the drug-vial receiver 120, the plug 710 blocking insertion of any vials into the opening on the top of the drug handling device 110 may be released (e.g., FIG. 7C), thereby enabling insertion of the liquid vial 104 into the top opening (see FIG. 7D). The liquid-vial receiver 140 may include retention structures that retain the liquid vial 104 inside the liquid-vial receiver 140 after insertion of liquid vial 104.

[82] As the liquid flows from the liquid vial 104 into the drug vial 102 to combine with the drug product within drug-preparation assembly 100 (FIG. 7E), bubbles may appear in the liquid vial 104, which is an indication that air is correctly flowing from the drug vial 102 into the liquid vial 104. The flow control mechanism 310 may be actuated by pressing the liquid vial 104 further onto the liquid vial spike 232 if air is not correctly flowing from the drug vial 102 into the liquid vial 104. Once the liquid flow has ceased and the liquid vial 104 is substantially empty, the liquid-vial receiver 140 may be detached from the drug-vial receiver 120, thereby converting the drug-preparation assembly 100 into a drug-delivery assembly 400. Detachment may require removal of a retention affordance 730 (e.g., peeling off an adhesive label around a middle portion of the device) designed to help prevent the twisting motion until the drug is ready for administration (see FIG. 7F), followed by twisting off the liquid-vial receiver 140 from the drug-vial receiver 120 (see FIG. 7G). The retention affordance 730 may comprise one or more removable parts (e.g., one or more adhesive portions) that must be removed (e.g., peeled off or torn at a perforated location) prior to detachment of the drug-vial receiver from the liquid-vial receiver. [83] At this point, the drug vial 102 seated within the drug-vial receiver 120 may be inspected (FIG. 7H) to ensure that the drug product has been completely combined with the liquid and no particulates or areas of discoloration remain. As shown in FIG. 71, once the drug has been determined to be ready for administration, a bolus dose may be withdrawn through the syringe access port using a syringe 740. After administration of the bolus dose, an IV administration set 750 may be attached to the infusion access port of the drug-delivery assembly 400, as shown in FIG. 7H, to facilitate intravenous infusion of the drug (FIG. 7J). The IV administration set 750 can include a spike (vented or non-vented), a drip chamber, tubing, a roller clamp, a Y-connector for injections, a connector such as a luer lock connector, and a needle. As shown in FIG. 7K, the drug-delivery assembly 400 may incorporate a hanging affordance (e.g., a hanger, loop, hook, or grommet) to position the drug-delivery assembly 400 with the one or more drug access ports 214 oriented downward.

[84] Finally, if flow hesitation is observed (e.g., flow does not commence automatically after initial insertion of the liquid vial 104 into the liquid-vial receiver 140), the pump mechanism may be actuated by pressing down the liquid vial 104 (see FIG. 7L) in order to clear the air channel (in case of intruding liquid) and/or pressurize the liquid vial to overcome flow resistance in the liquid channel (in case of air bubble occlusion).

[85] FIGS. 8A-8C illustrate a method of preparing a drug using the drug preparation assembly 100. As shown in FIG. 8A, a first step can include removing caps from both the drug vial 102 and liquid vial 104, wiping each stopper or seal of the drug vial 102 and liquid vial 104 with separate alcohol swabs, and removing a protective cover from the opening of drug-vial receiver 120. A next step can include fully inserting the drug vial 102 into the drug-vial receiver 120 and confirming the drug vial 102 snaps into place and is fully spiked, which will unlock or eject a cap or plug covering the opening of the liquid-vial receiver 140. A next step can include fully inserting the liquid vial 104 into the liquid-vial receiver 140 and checking for bubbles to confirm that liquid is flowing from the liquid vial 104 to the drug vial 102.

[86] As shown in FIG. 8B, a next step can include waiting for all liquid to transfer from the liquid vial 104 to the drug vial 102 and troubleshooting if liquid does not transfer. As shown in FIG. 8C, troubleshooting can include pressing the liquid vial 104 down to activate flow control mechanism 310 and clear the line with a burst of air. As further shown in FIG. 8B, a next step can include removing a retention affordance such as a label or sticker once all liquid has transferred from the liquid vial 104 to the drug vial 102. A next step can include twisting liquid-vial receiver 140 counter-clockwise to separate the liquid- vial receiver 140 from the drug-vial receiver 120. A next step can include swirling the drug vial 102 gently to dissolve the drug product, inspecting the prepared drug 286 to confirm that it is free of discoloration or particulates, and letting the drug vial 102 stand undisturbed for several minutes to dissipate foam and/or undissolved particles if present.

[87] As shown in FIG. 8C, a next step can include preparing a dose by pushing and twisting a syringe directly onto the needle free syringe drug access port 214a, withdrawing the excess or discard quantity and bolus dose as needed, and leaving the infusion dose in the vial. A next step can include removing cap 215b from infusion drug access port 214b and fully inserting an IV spike into the infusion drug access port 214b. A next step can include lifting a hanging affordance such as a plastic hanger and administering the bolus dose and IV infusion doses as needed for treatment.

[88] The drug handling device 110 and the drug preparation assembly 100 may be used in the treatment of acute ischemic stroke in a subject. For example, the drug vial 102 may contain lyophilized alteplase. For a subject suffering from acute ischemic stroke, a dosage of reconstituted alteplase can be given as soon as possible but within 3 hours after onset of symptoms. The alteplase dose can be calculated using the subject’s weight. For example, for a victim of acute ischemic stroke, the dosage amount can be 0.9 mg alteplase per kilogram body weight (mg/kg) not to exceed 90 mg total dose. For a 60 kg subject, this results in a total dose of 54 mg alteplase. For acute ischemic stroke victims, 10% of the alteplase dose can be administered as an initial intravenous bolus over 1 minute, and 90% of the alteplase dose can be administered via an IV infusion over 60 minutes. For a 60 kg patient, 5.4 mg alteplase can be administered as a bolus, and 48.6 mg alteplase can be administered via an IV drip. The drug preparation assembly 100 can prepare 100 mL of prepared alteplase solution at a concentration of 1 mg alteplase per 1 mL solution. The amount of prepared alteplase solution in the drug vial 102 in excess of the total required dose can be withdrawn from the drug vial 102 prior to administration of the total required dose. For a 60 kg patient, 46 mL of 1 mg/mL alteplase solution can be withdrawn via the a first syringe connected to the syringe drug access port 214a and discarded as excess. A second syringe can then be connected to the syringe drug access port 214a and 5.4 mL of the 1 mg/mL alteplase solution can be withdrawn and administered to the patient as a bolus, leaving 48.6 mL of 1 mg/mL alteplase solution remaining in the drug vial 102. An IV spike of an IV administration set can then be connected to the infusion drug access port 214b to administer the remaining 48.6 mL of 1 mg/mL alteplase solution to the patient via an IV drip. Alternatively, the remaining 48.6 mL of 1 mg/mL alteplase solution in the drug vial can be withdrawn from the drug vial using a third syringe connected to the syringe drug access port 214a and placed into an IV bag for IV administration to the patient.

[89] The drug handling device 110 and the drug preparation assembly 100 may be used in the treatment of acute myocardial infarction in a subject to reduce mortality and incidence of heart failure. For example, the drug vial 102 may contain lyophilized alteplase. For a subject suffering from acute myocardial infarction, a dosage of reconstituted alteplase can be given as soon as possible after the onset of symptoms. The alteplase dose can be calculated using the subject’s weight, not to exceed 100 mg alteplase as a total dose. The alteplase dose can be administered in an accelerated regimen or in a 3 hour regimen.

[90] For the accelerated alteplase dose regimen and a victim of acute myocardial infarction weighing more than 67 kg, the dosage amount can be a total of 100 mg alteplase. For the accelerated regimen for a victim of acute myocardial infarction weighing more than 67 kg, 15 mg of the 100 mg alteplase dose can be administered as an initial intravenous bolus, then 50 mg of the 100 mg alteplase dose can be administered via an IV infusion over the first 30 minutes, and finally 35 mg of the 100 mg alteplase dose can be administered via an IV infusion over the following 60 minutes. For the accelerated alteplase regimen and a victim of acute myocardial infarction weighing 67 kg or less, 15 mg of alteplase can be administered as an initial intravenous bolus, then a dose of 0.75 mg alteplase per kg body weight (mg/kg) can be administered via an IV infusion over the first 30 minutes, and finally a dose of 0.50 mg/kg alteplase can be administered via an IV infusion over the following 60 minutes.

[91] For example, a 60 kg patient being treated for acute myocardial infarction with the accelerated alteplase regimen can receive an initial intravenous bolus of 15 mg alteplase, then 45 mg alteplase can be administered via an IV infusion over the first 30 minutes, and finally 30 mg alteplase can be administered via an IV infusion over the following 60 minutes. The drug preparation assembly 100 can prepare 100 mL of prepared alteplase solution at a concentration of 1 mg alteplase per 1 mL solution. The amount of prepared alteplase solution in the drug vial 102 in excess of the total required dose can be withdrawn from the drug vial 102 prior to administration of the total required dose. For the 60 kg patient, 10 mL of the 1 mg/mL alteplase solution can be withdrawn via a first syringe connected to the syringe drug access port 214a and discarded as excess. A second syringe can then be connected to the syringe drug access port 214a and 15 mL of the 1 mg/mL alteplase solution can be withdrawn and administered to the patient as a bolus, leaving 75 mL of the 1 mg/mL alteplase solution remaining in the drug vial 102. An IV spike of an IV administration set can then be connected to the infusion drug access port 214b to administer 45 mL of the 1 mg/mL alteplase solution for the first 30 minutes via IV infusion and then the remaining 30 mL of the 1 mg/mL alteplase solution in the drug vial 102 for the following 60 minutes to the patient via IV infusion. The infusion rate of the IV administration set can be adjusted in order to administer the first and second IV infusion doses at the appropriate rates. Alternatively, one or both of the IV infusion doses can be withdrawn from the drug vial 102 using one or more syringes connected to the syringe drug access port 214a and placed into one or more IV bags for IV infusion administration to the patient.

[92] In other embodiments, for the 3 hour alteplase dose regimen and a victim of acute myocardial infarction weighing 65 kg or more, 6-10 mg of alteplase can be administered as an initial intravenous bolus, then 50-54 mg of alteplase can be administered via an IV infusion over the first hour, then 20 mg of alteplase can be administered via an IV infusion over the second hour, and finally 20 mg of alteplase can be administered via an IV infusion over the third hour, resulting in a total dose of 100 mg of alteplase. For the 3 hour alteplase dose regimen and a victim of acute myocardial infarction weighing less than 65 kg, a dose of 0.075 mg alteplase per kg body weight (mg/kg) can be administered as an initial intravenous bolus, then a dose of 0.675 mg/kg alteplase can be administered via an IV infusion over the first hour, then a dose of 0.25 mg/kg alteplase can be administered via an IV infusion over the second hour, and finally a dose of 0.25 mg/kg alteplase can be administered via an IV infusion over the third hour, resulting in a total dose of 1.25 mg/kg alteplase. [93] For example, a 60 kg patient being treated for acute myocardial infarction with the 3 hour alteplase regimen can receive an initial intravenous bolus of 4.5 mg alteplase, then 40.5 mg alteplase can be administered via an IV infusion over the first hour, then 15 mg alteplase can be administered via an IV infusion over the second hour, and finally 15 mg alteplase can be administered via an IV infusion over the third hour. The drug preparation assembly 100 can prepare 100 mb of prepared alteplase solution at a concentration of 1 mg alteplase per 1 mL solution. The amount of prepared alteplase solution in the drug vial 102 in excess of the total required dose can be withdrawn from the drug vial 102 prior to administration of the total required dose. For the 60 kg patient, 25 mL of the 1 mg/mL prepared alteplase solution can be withdrawn via a first syringe connected to the syringe drug access port 214a and discarded as excess. A second syringe can then be connected to the syringe drug access port 214a and 4.5 mL of the 1 mg/mL alteplase solution can be withdrawn and administered to the patient as a bolus, leaving 70.5 mL of the 1 mg/mL alteplase solution remaining in the drug vial 102. An IV spike of an IV administration set can then be connected to the infusion drug access port 214b to administer 40.5 mL of the 1 mg/mL alteplase solution for the first hour via IV infusion, 15 mg of the 1 mg/mL alteplase solution for the second hour via IV infusion, and finally the remaining 15 mg of the 1 mg/mL alteplase solution in the drug vial 102 for the third hour via IV infusion. The infusion rate of the IV administration set can be adjusted in order to administer the first, second, and third IV infusion doses at the appropriate rates. Alternatively, one, two, or all of the IV infusion doses can be withdrawn from the drug vial 102 using one or more syringes connected to the syringe drug access port 214a and placed into one or more IV bags for IV infusion administration to the patient.

[94] The drug handling device 110 and the drug preparation assembly 100 may be used in the treatment of pulmonary embolism, e.g., acute massive pulmonary embolism in a subject for lysis. Acute massive pulmonary embolism can include acute pulmonary emboli obstructing blood flow to a lob or multiple lung segments and/or acute pulmonary emboli accompanied by unstable hemodynamics, e.g., failure to maintain blood pressure without supportive measures. For example, the drug vial 102 may contain lyophilized alteplase. For a subject suffering from acute massive pulmonary embolism, a dosage of reconstituted alteplase can be given. The alteplase dose can be 100 mg of alteplase and can be administered via IV infusion over 2 hours.

[95] For example, a 60 kg patient being treated for acute massive pulmonary embolism can receive 100 mg alteplase administered via IV infusion over 2 hours. The drug preparation assembly 100 can prepare 100 mL of prepared alteplase solution at a concentration of 1 mg alteplase per 1 mL solution. For the 60 kg patient, an IV spike of an IV administration set can be connected to the infusion drug access port 214b to administer 100 mL of the 1 mg/mL alteplase solution via IV infusion over 2 hours. Alternatively, 100 mL of the 1 mg/mL alteplase solution can be withdrawn from the drug vial 102 using a syringe connected to the syringe drug access port 214a and placed into an IV bag for IV infusion administration of 100 mL of 1 mg/mL alteplase solution over 2 hours to the patient.

[96] The drug handling device 110 and the drug preparation assembly 100 may be used in the treatment of obstructed or occluded catheters, or other treatments involving reconstitution or dilution of a drug product.

[97] Herein, “or” is inclusive and not exclusive, unless expressly indicated otherwise or indicated otherwise by context. Therefore, herein, “A or B” means “A, B, or both,” unless expressly indicated otherwise or indicated otherwise by context. Moreover, “and” is both joint and several, unless expressly indicated otherwise or indicated otherwise by context. Therefore, herein, “A and B” means “A and B, jointly or severally,” unless expressly indicated otherwise or indicated otherwise by context.

[98] The scope of this disclosure encompasses all changes, substitutions, variations, alterations, and modifications to the example embodiments described or illustrated herein that a person having ordinary skill in the art would comprehend. The scope of this disclosure is not limited to the example embodiments described or illustrated herein. Moreover, although this disclosure describes and illustrates respective embodiments herein as including particular components, elements, feature, functions, operations, or steps, any of these embodiments may include any combination or permutation of any of the components, elements, features, functions, operations, or steps described or illustrated anywhere herein that a person having ordinary skill in the art would comprehend. Furthermore, reference in the appended claims to an apparatus or system or a component of an apparatus or system being adapted to, arranged to, capable of, configured to, enabled to, operable to, or operative to perform a particular function encompasses that apparatus, system, component, whether or not it or that particular function is activated, turned on, or unlocked, as long as that apparatus, system, or component is so adapted, arranged, capable, configured, enabled, operable, or operative. Additionally, although this disclosure describes or illustrates particular embodiments as providing particular advantages, particular embodiments may provide none, some, or all of these advantages.

Claims

1. A drug handling device, comprising a drug-vial receiver with a drug-vial spike extending from a distal surface of the drug-vial receiver and one or more drug access ports located on a proximal surface of the drug-vial receiver, wherein the drug-vial spike is configured to pierce a seal on a mouth of a drug vial containing a drug product; and a liquid-vial receiver with a liquid-vial spike extending from a distal surface of the liquid- vial receiver, wherein the liquid-vial spike is configured to pierce a seal on a mouth of a liquid vial containing a liquid for combination with the drug product to form a drug; wherein the proximal surface of the drug- vial receiver is detachably connected to a proximal surface of the liquid-vial receiver; and wherein, while the proximal surface of the drug-vial receiver is connected to the proximal surface of the liquid-vial receiver, the drug-vial spike of the drug-vial receiver and the liquid-vial spike of the liquid-vial receiver form a liquid channel for the liquid to flow from the liquid vial into the drug vial and thereby combine with the drug product and an air channel for air to flow from the drug vial into the liquid vial as the liquid flows from the liquid vial into the drug vial.

2. The drug handling device of claim 1, wherein the one or more drug access ports located on the proximal surface of the drug-vial receiver are accessible after the drug-vial receiver is detached from the liquid-vial receiver.

3. The drug handling device of any one of claims 1 to 2, wherein the one or more drug access ports comprise a syringe access port configured for use of a syringe to facilitate withdrawal of a dose of the drug after preparation.

4. The drug handling device of claim 3, wherein the syringe access port is a Luer port configured for a needle-free Luer lock syringe.

5. The drug handling device of claims 3 or 4, wherein the syringe access port provides access to the drug through the liquid channel.

6. The drug handling device of any one of claims 1 to 5, wherein the one or more drug access ports comprise an infusion access port configured for connection to an IV administration set for intravenous infusion of the drug.

7. The drug handling device of claim 1, wherein the proximal surface of the drug-vial receiver is detachably connected to a proximal surface of the liquid-vial receiver in order to facilitate preparation of the drug while connected and to facilitate administration of the drug once detached.

8. The drug handling device of any one of claims 1 to 7, wherein the liquid-vial spike extending from a distal surface of the liquid-vial receiver and the drug-vial spike extending from a distal surface of the drug-vial receiver are each dual-lumen spikes including a first lumen configured to form the air channel and a second lumen configured to form the liquid channel.

9. The drug handling device of any one of claims 1 to 8, wherein the liquid channel runs vertically along a straight path through a longitudinal axis of the drug handling device.

10. The drug handling device of any one of claims 1 to 9, wherein a path of the air channel runs adjacent to the liquid channel along the drug-vial spike, diverges from the liquid channel between a base of the drug-vial spike and a base of the liquid-vial spike, then runs adjacent to the liquid channel along the liquid-vial spike.

11. The drug handling device of any one of claims 1 to 10, wherein the drug-vial receiver comprises a valved port to prevent leakage of the drug through the air channel during withdrawal of the drug after the drug-vial receiver is detached from the liquid-vial receiver.

12. The drug handling device of any one of claims 1 to 11, wherein the liquid channel is proportionally configured with respect to the air channel to create greater pressure in the liquid channel than the air channel.

13. The drug handling device of claim 12, wherein a size of the air channel is proportionally configured with respect to a size of the liquid channel to create greater flow resistance in the air channel than the liquid channel.

14. The drug handling device of any one of claims 1 to 13, wherein the liquid-vial receiver comprises a flow control mechanism configured to resolve flow hesitation upon actuation by pressing the liquid vial further onto the liquid-vial spike extending from the distal surface of the liquid-vial receiver and thereby increasing pressure through the air channel.

15. The drug handling device of any one of claims 1 to 14, wherein the liquid-vial receiver comprises a flow control mechanism configured to resolve flow hesitation upon actuation by displacing air through the air channel, thereby clearing any fluid occlusion of the air channel and transferring positive pressure into the liquid vial.

16. The drug handling device of claims 14 or 15, wherein the flow control mechanism is actuated upon insertion of the liquid vial into the liquid-vial receiver.

17. The drug handling device of any one of claims 1 to 16, wherein the drug-vial receiver comprises an air vent for facilitating ingress of air into the drug vial during withdrawal of the drug in order to normalize gas pressure within the drug vial.

18. The drug handling device of claim 17, wherein the air vent comprises a valved port.

19. The drug handling device of claims 17 or 18, wherein the drug- vial receiver further comprises an air fdter that filters air entering through the air vent.

20. The drug handling device of claim 19, wherein the drug-vial receiver further comprises a check valve to prevent the drug from flowing into the air channel and contacting the air filter.

21. The drug handling device of any one of claims 1 to 20, wherein the drug handling device is oriented vertically, wherein the drug-vial receiver is configured to be positioned on top of a mouth of the drug vial when the drug vial is placed right side up on a surface, and wherein the liquid-vial receiver is configured to be positioned underneath a mouth of the liquid vial.

22. The drug handling device of any one of claims 1 to 21, wherein the drug-vial receiver further comprises a drug-vial housing extending from the distal surface of the drug-vial receiver.

23. The drug handling device of claim 22, wherein the drug-vial housing is configured to hold the drug vial in an axially centered position.

24. The drug handling device of claims 22 or 23, wherein the drug-vial housing comprises a support structure configured to provide lateral stability.

25. The drug handling device of any one of claims 1 to 24, wherein the liquid-vial receiver further comprises a liquid-vial housing extending from the distal surface of the liquid-vial receiver.

26. The drug handling device of claim 25, wherein the liquid-vial housing is configured to hold the liquid vial in an axially centered position.

27. The drug handling device of any one of claims 1 to 26, further comprising drug vial retention structures to retain the drug vial in place once inserted into the drug handling device.

28. The drug handling device of any one of claims 1 to 27, further comprising liquid vial retention structures to retain the liquid vial in place once inserted into the drug handling device.

29. The drug handling device of any one of claims 1 to 28, wherein the drug-vial receiver is detached from the liquid-vial receiver by a twisting motion, further comprising a retention affordance designed to help prevent the twisting motion until the drug is ready for withdrawal.

30. The drug handling device of claim 29, wherein the retention affordance comprises one or more removable parts that must be removed prior to detachment of the drug-vial receiver from the liquid-vial receiver.

31. The drug handling device of any one of claims 25 to 30, wherein the liquid-vial housing is configured for a liquid vial with a capacity of at least 50 ml.

32. The drug handling device of claim 31, wherein the liquid-vial housing is configured for a liquid vial with a capacity of no more than 500 ml.

33. The drug handling device of any one of claims 1 to 32, wherein the drug product is a solid.

34. The drug handling device of any one of claims 1 to 33, wherein the drug product is a powder.

35. The drug handling device of any one of claims 1 to 34, wherein the drug product is a lyophilized drug product.

36. The drug handling device of any one of claims 1 to 34, wherein the drug product is a spray-dried drug product.

37. The drug handling device of any one of claims 1 to 32, wherein the drug product is a liquid drug product.

38. The drug handling device of any one of claims 1 to 37, wherein the liquid is aqueous.

39. The drug handling device of any one of claims 1 to 38, wherein the liquid is water.

40. The drug handling device of any one of claims 1 to 39, wherein the liquid acts as a solvent to reconstitute the drug product.

41. The drug handling device of any one of claims 1 to 39, wherein the liquid acts as a diluent to dilute the drug product.

42. The drug handling device of any one of claims 1 to 41, wherein the drug product is alteplase, a biosimilar of alteplase, another tissue plasminogen activator, or a biosimilar thereof.

43. The drug handling device of any one of claims 1 to 42, wherein instructions for use of the drug product indicate administration through a plurality of modalities.

44. The drug handling device of claim 43, wherein the instructions for use indicate administration of a bolus dose of the drug, followed by an infusion dose.

45. A kit, comprising: the drug handling device of any one of claims 1 to 44; a drug vial containing a drug product; and a liquid vial containing a liquid for combination with the drug product.

46. The kit of claim 45, wherein the drug handling device further comprises a plug that prevents insertion of the liquid vial into the drug handling device, wherein the plug can only be dislodged by insertion of the drug vial into the drug handling device.

47. The kit of claims 45 or 46, wherein the drug vial is included in the kit separately from the drug handling device, and wherein a mouth of the drug vial is sealed.

48. The kit of claim 45, wherein the drug vial is pre-inserted into the drug handling device.

49. A method of preparing a drug product for administration, the method comprising: inserting a liquid vial into a drug handling device according to any one of claims 1 to 44 to combine a liquid in the liquid vial with a drug product in a drug vial inserted into the drug handling device to form a drug; detaching the drug-vial receiver of the drug handling device from the liquid-vial receiver of the drug handling device; and withdrawing a dose of the drug from the drug vial.

50. The method of claim 49, further comprising: prior to inserting the liquid vial, inserting the drug vial into the drug handling device.

51. The method of claims 49 or 50, further comprising: prior to inserting the liquid vial, removing a plug from the drug handling device.

52. The method of any one of claims 49 to 51, wherein inserting the liquid vial into the drug handling device actuates a flow control mechanism of the drug handling device.

53. The method of any one of claims 49 to 52, further comprising: prior to detaching the drug-vial receiver from the liquid-vial receiver, removing a retention affordance preventing the drug-vial receiver from being detached from the liquid-vial receiver.

54. The method of any one of claims 49 to 53, further comprising: pressing down on a bottom surface of the liquid vial to actuate the flow control mechanism of the drug handling device.

55. The method of any one of claims 49 to 54, wherein withdrawing a dose of the drug from the drug vial comprises: attaching a needle-free Luer lock syringe to the Luer port of the drug handling device; and withdrawing a bolus dose of the drug.

56. The method of any one of claims 49 to 55, wherein withdrawing a dose of the drug from the drug vial comprises: attaching an IV administration set to the infusion access port of the drug handling device; and using the hanging affordance to hang the drug handling device with the infusion access port oriented downward.

57. The method of claim 56, further comprising: prior to attaching the IV administration set, removing a cap from the infusion access port.

58. A method of preparing a drug for administration, comprising: a. inserting a drug vial into a drug-vial receiver of a drug handling device of any one of claims 1 to 44, wherein the drug vial comprises a drug product; and b. inserting a liquid vial into a liquid-vial receiver of the drug handling device, wherein the liquid vial comprises a liquid, to combine the liquid with the drug product to produce a prepared drug.

59. A method of preparing a drug for administration without seal failure, comprising: inserting a drug vial into a drug-vial receiver of a drug handling device of any one of claims 1 to 44, wherein the drug vial comprises a drug product; and inserting a liquid vial into a liquid-vial receiver of the drug handling device, wherein the liquid vial comprises a liquid, to combine the liquid with the drug product to produce a prepared drug.

60. The method of claim 59, wherein seal failure comprises leakage, collapse, and/or fragmentation of a drug vial seal.

61. The method of any one of claims 1-60, further comprising: separating the liquid-vial receiver from the drug handling device.

62. The method of claim 61, the drug handling device comprising a retention affordance, wherein the retention affordance is removed prior to separating the liquid-vial receiver.

63. The method of any one of claims 58-62, further comprising withdrawing a bolus of the prepared drug.

64. The method of claim 63, wherein the bolus is withdrawn from a drug access port of the drug handling device.

65. The method of claim 63 or 64, wherein the bolus is administered to a subject.

66. The method of any one of claims 58-65, further comprising connecting the drug vial to an IV administration set.

67. The method of claim 66, wherein the drug vial is connected to the IV administration set via a drug access port of the drug handling device.

68. The method of any one of claims 58-67, wherein the drug product comprises a powder, a solid, a lyophilized drug product, a spray-dried drug product, or a combination thereof.

69. A method of administering a drug to a subject, the method comprising: a. inserting a drug vial into a drug-vial receiver of a drug handling device of any one of claims 1 to 44, wherein the drug vial comprises a drug product; b. inserting a liquid vial into a liquid-vial receiver of the drug handling device, wherein the liquid vial comprises a liquid, to combine the liquid with the drug product to produce a prepared drug; and c. administering the prepared drug to the subject.

70. The method of claim 69, further comprising: separating the liquid-vial receiver from the drug handling device.

71. The method of claim 70, the drug handling device comprising a retention affordance, wherein the retention affordance is removed prior to separating the liquid-vial receiver.

72. The method of any one of claims 69-71, further comprising withdrawing a bolus of the prepared drug.

73. The method of claim 72, wherein the bolus is withdrawn from a drug access port of the drug handling device.

74. The method of claim 72 or 73, wherein the bolus is administered to a subject.

75. The method of any one of claims 69-74, further comprising determining a dosage amount.

76. The method of claim 75, wherein when the dosage amount is less than an amount of prepared drug in the drug vial, an excess amount of the prepared drug is withdrawn from the drug vial.

77. The method of claim 76, wherein the excess amount is withdrawn from a drug access port of the drug handling device prior to step c).

78. The method of any one of claims 69-77, further comprising connecting the drug vial to an IV administration set.

79. The method of claim 78, wherein the drug vial is connected to the IV administration set via a drug access port of the drug handling device.

80. The method of claim 78 or 79, wherein the prepared drug is administered to the subject by intravenous administration through the IV administration set.

81. The method of any one of claims 69-77, further comprising withdrawing a portion of the prepared drug and administering the portion of the prepared drug to the subject by intravenous administration through an IV administration set.

82. A method of administering alteplase to a subject, the method comprising: a. inserting a drug vial into a drug-vial receiver of a drug handling device of any one of claims 1 to 44, wherein the drug vial comprises alteplase; b. inserting a liquid vial into a liquid-vial receiver of the drug handling device, wherein the liquid vial comprises a liquid, to combine the liquid with the alteplase to produce prepared alteplase; and c. administering the prepared alteplase to the subject.

83. The method of claim 82, further comprising determining a dosage amount.

84. The method of claim 83, wherein the dosage amount is determined based on weight of the subject.

85. The method of claim 83 or 84, wherein the dosage amount is about 0.9 milligrams alteplase per kilogram body weight (mg/kg).

86. The method of claim 83 or 84, wherein the dosage amount is about 1.25 milligrams alteplase per kilogram body weight (mg/kg).

87. The method of any one of claims 83-86, wherein the dosage amount is about 100 mg alteplase.

88. The method of any one of claims 83-86, wherein the dosage amount does not exceed 90 mg alteplase.

89. The method of any one of claims 83-88, wherein determining a dosage amount comprises determining a bolus amount.

90. The method of claim 89, wherein the bolus amount is about 10% of the dosage amount.

91. The method of claim 89, wherein the bolus amount is 6-10 mg, about 15 mg, or 0.075 mg/kg.

92. The method of any one of claims 89-91, further comprising withdrawing a bolus of the prepared alteplase and administering the bolus to the subject.

93. The method of claim 92, wherein the bolus is administered to the subject by intravenous administration.

94. The method of claim 92 or 93, wherein the bolus is withdrawn from a drug access port of the drug handling device.

95. The method of any one of claims 83-94, wherein when the dosage amount is less than an amount of prepared alteplase in the drug vial, an excess amount of the prepared alteplase is withdrawn from the drug vial prior to step c).

96. The method of claim 95, wherein the excess amount is withdrawn from a drug access port of the drug handling device.

97. The method of claim 95 or 96, wherein the excess amount is discarded.

98. The method of any one of claims 82-97, further comprising connecting the drug vial to an IV administration set.

99. The method of claim 98, wherein the drug vial is connected to the IV administration set via a drug access port of the drug handling device.

100. The method of any one of claims 82-99, wherein the prepared alteplase is administered to the subject by intravenous administration.

101. A method of treating acute ischemic stroke in a subject, the method comprising: a. inserting a drug vial into a drug-vial receiver of a drug handling device of any one of claims 1 to 44, wherein the drug vial comprises alteplase; b. inserting a liquid vial into a liquid-vial receiver of the drug handling device, wherein the liquid vial comprises a liquid, to combine the liquid with the alteplase to produce prepared alteplase; and c. administering the prepared alteplase to the subject.

102. The method of claim 101, further comprising determining a dosage amount.

103. The method of claim 102, wherein the dosage amount is about 0.9 milligrams alteplase per kilogram body weight (mg/kg).

104. The method of claim 102 or 103, further comprising determining a bolus amount.

105. The method of claim 104, wherein the bolus amount is about 10% of the dosage amount.

106. The method of claim 102, wherein the dosage amount is 0.9 milligrams alteplase per kilogram body weight, where the dosage amount does not exceed 90 mg alteplase, wherein 10% of the dosage amount is administered as an initial intravenous bolus over 1 minute and the remainder of the dosage amount is intravenously infused over 60 minutes.

107. The method of claim 104 or 105, further comprising withdrawing a bolus of the prepared alteplase and administering the bolus to the subject.

108. The method of claim 107, wherein the bolus is administered to the subject by intravenous administration.

109. The method of claim 108, wherein the bolus is administered over one minute.

110. The method of any one of claims 101-109, wherein when the dosage amount is less than an amount of prepared alteplase in the drug vial, an excess amount of the prepared alteplase is withdrawn from the drug vial prior to step c).

111. The method of any one of claims 102-110, comprising administering the dosage amount to the subject.

112. The method of any one of claims 101-111, wherein the prepared alteplase is administered intravenously.

113. The method of claim 112, wherein the prepared alteplase is administered over about 60 minutes.

114. A method of treating acute myocardial infarction in a subject, the method comprising: a. inserting a drug vial into a drug-vial receiver of a drug handling device of any one of claims 1 to 44, wherein the drug vial comprises alteplase; b. inserting a liquid vial into a liquid-vial receiver of the drug handling device, wherein the liquid vial comprises a liquid, to combine the liquid with the alteplase to produce prepared alteplase; and c. administering the prepared alteplase to the subject.

115. The method of claim 114, further comprising determining a dosage amount.

116. The method of claim 115, wherein the dosage amount is based on a subject’s weight, not exceeding 100 mg.

117. The method of any one of claims 114-116, wherein the dosage amount is about 100 mg or less.

118. The method of any one of claims 114-116, wherein the dosage amount is about 1.25 mg alteplase per kg of the subject’s body weight.

119. The method of any one of claims 114-118 further comprising determining a bolus amount.

120. The method of claim 119, wherein the bolus amount is about 15 mg alteplase.

121. The method of claim 119, wherein the bolus amount is about 6 mg alteplase to about 10 mg alteplase.

122. The method of claim 119, wherein the bolus amount is about 0.075 mg alteplase per kg of the subj ect’ s body weight.

123. The method of any one of claims 119-122, further comprising withdrawing a bolus of the prepared alteplase and administering the bolus to the subject.

124. The method of claim 123, wherein the bolus is administered to the subject by intravenous administration.

125. The method of any one of claims 115-124, wherein when the dosage amount is less than an amount of prepared alteplase in the drug vial, an excess amount of the prepared alteplase is withdrawn from the drug vial prior to step c).

126. The method of any one of claims 115-125, comprising administering the dosage amount to the subject.

127. The method of any one of claims 114-126, wherein the prepared alteplase is administered intravenously.

128. The method of claim 126, wherein the prepared alteplase is administered as follows: if the subject’s weight is more than 67 kg, 15 mg of the prepared alteplase is administered by intravenous bolus, 50 mg of the prepared alteplase is administered for about first 30 minutes by intravenous infusion, and 35 mg of the prepared alteplase is administered for about next 60 minutes by intravenous infusion; and if the subject’s weight is equal to or less than 67 kg, 15 mg of the prepared alteplase is administered by intravenous bolus, 0.75 mg alteplase per kg of the subject’s body weight (mg/kg) of the prepared alteplase is administered for about first 30 minutes by intravenous infusion, and 0.50 mg/kg of the prepared alteplase is administered for about next 60 minutes by intravenous infusion.

129. The method of claim 126, wherein the prepared alteplase is administered as follows: if the subject’s weight is 65 kg or more, 6-10 mg of the prepared alteplase is administered by intravenous bolus, 50-54 mg of the prepared alteplase is administered for about first one hour by intravenous infusion, 20 mg of the prepared alteplase is administered for about second one hour by intravenous infusion, and 20 mg of the prepared alteplase is administered for about third one hour by intravenous infusion; and if the subject’s weight is less than 65 kg, 0.075 mg alteplase per kg of the subject’s body weight (mg/kg) of the prepared alteplase is administered by intravenous bolus, 0.675 mg/kg of the prepared alteplase is administered by intravenous infusion for about first one hour, 0.25 mg of the prepared alteplase is administered for about second one hour by intravenous infusion, and 0.25 mg of the prepared alteplase is administered for about third one hour by intravenous infusion.

130. The method of claim 127, wherein the prepared alteplase is administered over about 90 minutes or about 3 hours.

131. A method of treating pulmonary embolism in a subject, the method comprising: a. inserting a drug vial into a drug-vial receiver of a drug handling device of any one of claims 1 to 44, wherein the drug vial comprises alteplase; b. inserting a liquid vial into a liquid-vial receiver of the drug handling device, wherein the liquid vial comprises a liquid, to combine the liquid with the alteplase to produce prepared alteplase; and c. administering the prepared alteplase to the subject.

132. The method of claim 131, further comprising determining a dosage amount.

133. The method of claim 132, wherein the dosage amount is about 100 mg.

134. The method of claim 131 or 132, wherein when the dosage amount is less than an amount of prepared alteplase in the drug vial, an excess amount of the prepared alteplase is withdrawn from the drug vial prior to step c).

135. The method of any one of claims 132-134, comprising administering the dosage amount to the subject.

136. The method of any one of claims 131-135, wherein the prepared alteplase is administered intravenously.

137. The method of claim 136, wherein the prepared alteplase is administered over about 2 hours.

138. The method of claim 136, wherein 100 mg of the prepared alteplase is administered by intravenous infusion over 2 hours.