WO2013066355A1

WO2013066355A1 - Safely preparing and administering drug substances

Info

Publication number: WO2013066355A1
Application number: PCT/US2011/059452
Authority: WO
Inventors: Bahman Shimiaei
Original assignee: Spectrum Pharmaceuticals, Inc
Priority date: 2011-11-04
Filing date: 2011-11-04
Publication date: 2013-05-10
Also published as: AU2011323060A1

Abstract

Described herein are apparatus, systems and methods of using the systems to safely prepare and administer a drug to an animal in need of treatment. The systems and methods prevent exposure by a non-patient administrator to the drugs.

Description

SAFELY PREPARING AND ADMINISTERING DRUG SUBSTANCES

FIELD

[0001 ] The present invention relates to systems and methods of use to safely prepare and administer a drug substance to an animal in need of treatment.

BACKGROUND

[0002] Syringes with needles are a commonly used tool for administering drugs. However, drug administration using a syringe and a needle is associated with many risks including needle prick injury to the administrator, exposure of the administrator to the drug, contamination of the environment with the drug and contamination of the drug with environmental microbes bringing about potential risk of patient infection.

[0003] High powered drugs have been developed that can be cytotoxic, for example, but can provide therapeutic benefit to patients. At the same time, these drugs can be harmful to the administrator if inhaled, touched, ingested or otherwise contacted. The harm is particularly elevated when administration of such drugs occurs in a less controlled environment such as a doctor's office or emergency room with a needle.

[0004] It is not uncommon for cytotoxic and/or highly potent drugs to be distributed in vials in a lyophilized form that must be reconstituted prior to delivery. This reconstitution can often require an elaborate multi-step process. In such cases, needles are often used to transfer fluids to and from the vial containing the drug. Needle sticks, as discussed above, are a dangerous proposition as is spillage, contamination, skin contact, ocular contact and the like.

[0005] In light of the potential risks associated with drug administration using a syringe and a needle, in particular with cytotoxic or highly potent drugs, methods and devices for safe preparation and administration of such substances need to be developed, because such drugs can be highly beneficial for patient therapy. The present description provides systems and methods of preparation and administration of cytotoxic and/or highly potent drugs safely, without the risks discussed above.

SUMMARY

[0006] Described herein generally are systems for the safe preparation of drug formulations comprising a stopcock having at least three ports; at least one vial adapter; a delivery device interface; and instructions for use, e.g. assembling the set of parts and preparing the drug formulation. The systems and methods prevent exposure of a non- patient administrator to drug substances by providing a closed system during reconstitution of the drug substances/drug/formulations(s). In yet another embodiment, the drug formulation preparation system further includes a vial including a diluent and a vial containing at least one cytotoxic drug. Even further still, in another embodiment, the drug formulation preparation system further includes a syringe.

[0007] In some embodiments, the drugs and drug formulations are cytotoxic and/or highly potent. In one embodiment, the drug is cytotoxic. In yet another embodiment the cytotoxic agent is apaziquone for use in the treatment of bladder cancer.

[0008] In one embodiment, the stopcock has three ports. In some embodiments, the delivery device interface includes an I.V. tube adapter. In others, the delivery device interface includes a catheter tube adapter. In one embodiment, the drug formulation preparation system does not include an exposed needle.

[0009] In still other embodiments, the drug formulation preparation system includes one vented vial adapter and one non-vented vial adapter. The stopcock can include a one use, locking valve.

[0010] In another embodiment, the open ports on the three-way stopcock may include protective covers to guard against accidental contamination during reconstitution and administration.

[0011] Also described herein are methods of preparing drug formulations for administration comprising the steps: connecting a syringe to a vial adapter; inserting the vial adapter into a vial including a diluent; drawing the desired amount of diluent into the syringe; disconnecting the syringe from the vial adapter; attaching the syringe containing the desired amount of diluent at a free port of a closed system device comprising a stopcock with at least two free ports, and associated with a delivery device interface; attaching a second vial adapter to a second free port of the closed system device; inserting a second vial containing at least one cytotoxic drug into the second vial adapter; moving the diluent from the syringe into the second vial through the closed system device thereby forming a drug formulation; transferring the drug formulation from the second vial to the syringe; closing the stopcock of the closed system device to the second vial; and attaching the delivery device interface to a delivery device, wherein the method prevents exposure to the at least one drug. [0012] In one embodiment, the vial adapter is a vented vial adapter. Also, the stopcock can have one free port. Further, the delivery device interface can include an I.V. tube adapter or catheter tube adapter.

[0013] In further embodiments, in the closing step, the stopcock includes a one use, locking valve that locks after it is closed. The delivery device can also be an I.V. line or a catheter tube connected directly to urinary bladder or other body cavities.

[0014] Further described herein is a drug formulation preparation system for preparation and administration of an apaziquone drug formulation comprising: a three- way stopcock; a vented vial adapter; a second vial adapter; a vial including a diluent; a vial containing a lyophilized apaziquone; a delivery device interface having a catheter tube connector; and instructions for use. In another embodiment, the drug formulation preparation system further comprises a syringe.

[0015] Even further still, described herein is a method of preparing an apaziquone pharmaceutical formulation for treatment of a bladder cancer comprising the steps: connecting a syringe to a vented vial adapter; inserting the vented vial adapter into a vial including a diluent; drawing the desired amount of diluent into the syringe; disconnect the syringe from the vial adapter; attaching the syringe containing the desired amount of diluent to an open port on a three-way stopcock associated with a delivery device interface; attaching a second vial adapter to a second free port of the three-way stopcock; inserting the second vial adapter into a second vial containing a lyophilized apaziquone into the second vial adapter; moving the diluent from the syringe into the second vial through the three-way stopcock thereby forming an apaziquone formulation; transferring the apaziquone formulation from the second vial to the syringe; closing the three-way stopcock to the second vial; attaching the delivery device interface to catheter line; releasing the slide-clamp, if closed, and delivering the apaziquone formulation through the catheter line to the bladder, wherein the method prevents administrator exposure to apaziquone.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1A illustrates a drug formulation preparation system according to the present description. Figure 1 B illustrates a second drug formulation preparation system according to the present description. Figure 1 C illustrates a third drug formulation preparation system according to the present description [0017] Figure 2 illustrates an exemplary embodiment of a fused system according to an embodiment of the present description.

[0018] Figure 3 illustrates an exemplary embodiment of an additional fused system according to an embodiment of the present description.

[0019] Figures 4A-E illustrate exemplary steps of preparing a drug formulation according to an embodiment of the present description. Figure 4A illustrates filling of a syringe with diluent. Figure 4B illustrates assembly of parts on a three-way stopcock. Figure 4C illustrates reconstitution of lyophilized drug. Figure 4D illustrates the transfer of drug formulation to syringe. Figure 4E illustrates delivery of the formulation through the delivery device interface and ultimately trough the delivery device.

[0020] Figures 5A-E illustrate alternate exemplary steps of preparing a drug formulation according to an embodiment of the present description. Figure 5A illustrates filling of a syringe with diluent. Figure 5B illustrates assembly of parts on a three-way stopcock. Figure 5C illustrates reconstitution of lyophilized drug. Figure 5D illustrates the transfer of drug formulation to syringe. Figure 5E illustrates delivery of the formulation through the delivery device interface and ultimately trough the delivery device.

[0021 ] Figure 6A illustrates a three-way stopcock leak test showing vapor emission from an open port to demonstrate that the vapor would be visible if there were a leak. Figure 6B illustrates a three-way stopcock leak test showing no vapor emission once connected proving there are no leaks. Figure 6C illustrates a PhaSeal leak test indicating no vapor emission during reconstruction.

DETAILED DESCRIPTION

[0022] Described herein are apparatus, systems, and methods of use thereof to safely prepare and administer a drug substance to an animal in need of treatment. The systems and methods prevent exposure of a non-patient administrator to the drugs by providing a closed system during reconstitution and subsequent administration of the drug substances/drug/formulations(s). The herein described apparatus, systems and methods also prevent potential contamination of the drug substance. "Closed system" as used herein means that the system does not leak to the outside environment and the outside environment does not leak into the inside during use. [0023] The term "drug" as used herein describes a pharmaceutically beneficial, therapeutically effective substance to be administered to a patient in need thereof. Drugs can include hormones, vaccines, anti-caner drugs, anti-inflammatory drugs, toxins, and the like. The drugs can be non-hazardous, hazardous, potent (e.g. hormones), delicate (e.g. vaccines), dangerous and/or cytotoxic (e.g. cancer therapies). In addition to the above, the drugs can potentially inflict burns, rashes, hair loss, blindness, nausea, or the like if associated with a human at a location other than the treatment site.

[0024] "Cytotoxic drug" as used herein described any drug that can have an adverse effect on an administrator without descrimination. Some example cytotoxic drugs may include apaziquone, mitomycin, carboplatin, cisplatin, oxaliplatin, Cytoxan, valrubicin and doxomycin.

[0025] In one embodiment, the cytotoxic drugs described herein are useful for treating one or more types of cancer. For example, the cytotoxic drugs can be delivered locally at the point of cancer using a catheter line surgically placed at the cancer. One exemplary cancer to be treated is bladder cancer using apaziquone.

[0026] Further the apparatus, systems, and methods described herein do not require or involve the use of an exposed needle(s). Exposed needles are dangerous and can cause injury to an administrator. Further, the use of exposed needles would prevent the present systems from being closed to the outside environment, and therefore, are not used with the presently described systems. Again, eliminating the need for exposed needles renders the present apparatus, systems and methods safe and closed to the outside environment.

[0027] The systems generally include at least one vial adapter, a stopcock having at least three ports, a delivery device interface, instructions for use, and a means of packaging. The systems optionally include at least one vial containing a drug substance which may be cytotoxic and/or highly potent, a vial containing a diluent (e.g. if the drug requires reconstitution) and a syringe.

[0028] The number of vials included in a system is highly dependent on the substance to be administered. For example, a single vial is needed if the substance is ready for administration. However, generally, cytotoxic drugs come in powdered, freeze-dried, or lyophilized form that must be reconstituted prior to administration. In such an embodiment, at least one vial is used to house the powdered drug and at least one additional vial is used to house a reconstitution diluent. In other embodiments, multiple diluents, solvents, or additional drugs may be used. For example, two cytotoxic drugs can be housed in two separate vials each requiring a separate diluent vial. Many additional combinations can be envisioned by a skilled artisan and are considered within the scope of the present invention.

[0029] The diluent can be selected from water, ethanol, saline, physiological buffer, or a combination of polar and non-polar solvent (co-solvent).

[0030] The delivery device interface is a connection capable of transferring a substance from the present systems directly to a patient or to a delivery device associated with the patient. Methods of delivering the substance to a patient include subcutaneous delivery, localized administration, targeted administration, systemic venupuncture, into an intravenous line, through a catheter, rectally, instillation into the bladder, and the like.

[0031] An exemplary drug formulation preparation system is illustrated in Figure 1A. Drug formulation preparation system 100 includes a first vial 102 that contains diluent 104. Second vial 106 includes lyophilized drug 108 for delivery to a patient. In one embodiment, drug 108 is cytotoxic. Each vial includes a cap 110, 110' that covers a piercable cover (not illustrated). The drug formulation preparation system also includes first vial adapter 112 and second vial adapter 114. Each vial adapter includes piercing member 116, 116' used to pierce the piercable covers of first vial 102 and second vial 106.

[0032] The drug formulation preparation system further includes stopcock 118 having first port 120, second port 122 and third port 124 connected to delivery device interface 126. Delivery device interface 126 can be fused to third port 124 or can be removable. In a preferred embodiment, the connection is fused to prevent potential leakage. Stopcock 118 further includes selection valve 130 to dial in particular flows there through. Delivery device interface 126 further includes optional retention clip 128 to stop flow of substances through tube 132. Delivery device interface 126 has delivery end 134 that can be interchangeable or selectable depending on the delivery method.

[0033] The drug formulation preparation system further includes syringe 136 that is connectable to stopcock 118. Syringe 136 can be a standard syringe made of plastic or can be manufactured of custom materials depending on the substance to be delivered. For example, if the substance is light sensitive, the syringe can be made of an amber colored material to prevent light degradation.

[0034] Further still, the drug formulation preparation system includes instructions for use 138. The instructions include relevant drug information, warnings, instructions for use, storage instructions and the like. The instructions can be in any language applicable to the target consumer.

[0035] Finally, the contents of the drug formulation preparation system are fitted into container 140. Container 140 can be constructed of any material that adequately protects the contents. For example, container 140 can be constructed of dense cardboard with a foam insert with custom slots for each of the components to fit snugly and protected.

[0036] The systems themselves are packaged so that they can be stored at appropriate conditions for survival and adequate shelf life of the diluent and the at least one cytotoxic substance. For example, if the contents require refrigeration, the materials are made to withstand storage in a cold or damp environment.

[0037] In another embodiment, illustrated in Figure 1 B the drug formulation preparation system includes first vial adapter 112 and second vial adapter 114. The drug formulation preparation system further includes stopcock 118 having first port 120, second port 122 and third port 124 connected to delivery device interface 126. Stopcock 118 further includes selection valve 130 to dial in particular flows there through. Delivery device interface 126 further includes optional retention clip 128 to stop flow of substances through tube 132. Delivery device interface 126 has delivery end 134 that can be interchangeable or selectable depending on the delivery method. The drug formulation preparation system further includes syringe 136 that is connectable to stopcock 118. The drug formulation preparation system also includes instructions for use 138 and container 140.

[0038] In another embodiment, illustrated in Figure 1 C the drug formulation preparation system includes first vial adapter 112 and second vial adapter 114. The drug formulation preparation system further includes stopcock 118 having first port 120, second port 122 and third port 124 connected to delivery device interface 126. Stopcock 118 further includes selection valve 130 to dial in particular flows there through. Delivery device interface 126 further includes optional retention clip 128 to stop flow of substances through tube 132. Delivery device interface 126 has delivery end 134 that can be interchangeable or selectable depending on the delivery method. The drug formulation preparation system also includes instructions for use 138 and container 140.

[0039] In one embodiment, not illustrated, a drug formulation preparation system can include a filter to be inserted between a vial adapter and the three-way stopcock. This would allow for filtration of a drug and/or a diluent prior to administration. Such a filter can prevent contamination of the drug with environmental microbes bringing about potential risk of patient infection or loss of potency of the drug itself. In other embodiments, the filter can be located, for example, between the three-way stopcock and the delivery device interface. In still other embodiments, multiple filters can be used, in some cases between each connection in the system.

[0040] The systems are generally used to prepare drug formulations for administration to a patient. In some embodiments, the drug formulation is cytotoxic. Methods for preparing cytotoxic formulations generally involve mixing or reconstitution of a cytotoxic agent and subsequent delivery of the cytotoxic formulation without leakage or contamination to the administrator. In other embodiments, the drug formulation is radioactive or caustic. In still other embodiments, the cytotoxic formulation is otherwise hazardous or irritating to the skin. In still other embodiments, the drug is potent and sometimes highly potent.

[0041] Figures 2 and 3 illustrate fused system 200, 300. In Figure 2, fused system 200 includes three-way stopcock 202 associated with delivery device interface 204. In this embodiment, three-way stopcock 202 and delivery device interface 204 are permanently fused together at junction 206. Fusing the two parts reduces the likelihood of contamination or leaking at junction 206. However, in some embodiments, this junction is not fused for reasons such as ease of packaging or interchangeable delivery device configurations. Even if not fused, the junction is manufactured to prevent any potential leakage when assembled.

[0042] In the exemplary embodiment illustrated in Figure 2, three-way stopcock 202 includes first port 208 and second port 210. First port 208 is a female luer connector and second port 210 is a male luer adapter. In other embodiments, different combinations of luer locking ports can be used. For example both can be male, both can be female, or the oppose male/female configuration can be used. The type of adapter fittings used in the present description can vary. For example, pressure fittings and other locking connection types known in the art can be used.

[0043] Three-way stopcock 202 also includes selection valve 212 used to isolate different channels in the system. For example, first port 208 can be open to second port 210 but not to third port 214 in one configuration and first port 208 can be closed to second port 210 and third port 214 in another configuration. In this embodiment, selection valve 212 is a twist type valve, but other types of valves are known in the art and can be used herein. For example, one time use valves can be used. With these valves, for example, initially, first port 208 can be open to second port 210 but not to third port 214. Then, selection valve 212 can be twisted to a locked final second position wherein first port 208 can be closed to second port 210 and third port 214, preventing accidental valve turns.

[0044] Like Figure 2, in Figure 3, fused system 300 includes three-way stopcock 302 associated with delivery device interface 304. In this embodiment, three-way stopcock 302 and delivery device interface 304 are permanently fused together at junction 306. Fusing the two parts reduces the likelihood of contamination or leaking at this junction. However, in some embodiments, this junction is not fused for reasons such as ease of packaging or interchangeable delivery device configurations. In the exemplary embodiment illustrated in Figure 3, three-way stopcock 302 includes first port 308, second port 310, selection valve 312 and third port 314.

[0045] A difference between fused system 200 and fused system 300 is that fused system 300 includes I.V. or catheter tube adapter 316 whereas fused system 200 includes a universal adapter 216 which can be, for example, a male or female luer adapter. These adapters are fused to the delivery device interface and can be tailored to a particular delivery device system.

[0046] In one embodiment, the first step in preparing a drug formulation according to the present description using the systems described is to connect syringe 402 to vial adapter 404 as illustrated in Figure 4A. In one embodiment, vial adapter 404 is a vented vial adapter. Then, once connected, vial adapter 404 is used to connect syringe 402 to vial 406 containing diluent 408. Plunger 410 is drawn back and diluent 408 is transferred into syringe 402. At this point, vial adapter 404 and vial 406 still connected to each other can be disconnected from syringe 402 and discarded. [0047] Then, as illustrated in Figure 4B, syringe 402 is connected to first port 412 of three-way stopcock 414. Second vial adapter 416 is attached to second port 418 of three-way stopcock 414. Then, second vial 420 including lyophilized drug 422, for example, apaziquone, is attached to second vial adapter 416.

[0048] As illustrated in Figure 4C, once syringe 402 and second vial adapter 416 are secure, plunger 410 is advanced inward transferring diluent 408 from syringe 402, through three-way stopcock 414, and into second vial 420. As diluent 408 enters second vial 420, lyophilized drug 422 starts to reconstitute. Once filled, second vial 420 is used to reconstitute lyophilized drug 422 and form drug formulation 424.

[0049] As illustrated in Figure 4D, after drug formulation 424 has been formed in second vial 420, plunger 410 can be drawn back thereby pulling drug formulation 424 out of second vial 420, through three-way stopcock 414 and back into syringe 402. At this point, or at some point before, the system is hooked to a delivery device, for example, an I.V. line.

[0050] Then, as illustrated in Figure 4E, while leaving second vial 420 attached to three-way stopcock 414 to preserve the closed nature of the present system, valve 426 controlling three-way stopcock 414 is turned, for example, 180 degrees opening first port 412 to third port 428 and closing off second port 418. Plunger 410 can then be depressed pushing drug formulation 424 out of syringe 402, through three-way stopcock 414, through delivery device interface 430 and into a delivery device (not illustrated).

[0051] In an alternate embodiment, as illustrated in figure 5A, diluent 408 is loaded into syringe 402 as described above. Then, as illustrated in Figure 5B, syringe 402 is connected to third port 428 of three-way stopcock 414. Second vial adapter 416 is attached to second port 418 of three-way stopcock 414. Then, second vial 420 including lyophilized drug 422, for example, apaziquone, is attached to second vial adapter 416.

[0052] As illustrated in Figure 5C, once syringe 402 and second vial adapter 416 are secure, plunger 410 is advanced inward transferring diluent 408 from syringe 402, through three-way stopcock 414, and into second vial 420. As diluent 408 enters second vial 420, lyophilized drug 422 starts to reconstitute. Once filled, second vial 420 is used to reconstitute lyophilized drug 422 and form drug formulation 424. [0053] As illustrated in Figure 5D, after drug formulation 424 has been formed in second vial 420, plunger 410 can be drawn back thereby pulling drug formulation 424 out of second vial 420, through three-way stopcock 414 and back into syringe 402. At this point, or at some point before, the system is hooked to a delivery device, for example, an I.V. line.

[0054] Then, as illustrated in Figure 5E, while leaving second vial 420 attached to three-way stopcock 414 to preserve the closed nature of the present system, valve 426 controlling three-way stopcock 414 is turned, for example, 180 degrees opening third port 428 to first port 412 to and closing off second port 418. Plunger 410 can then be depressed pushing drug formulation 424 out of syringe 402, through three-way stopcock 414, through delivery device interface 430 and into a delivery device (not illustrated).

[0055] In another example embodiment, the drug formulation preparation system as illustrated in Figures 1 , 2 or 3 can be configured as needed by a skilled artisan but within the closed system parameters described herein having no potential leakage onto the administrator of the cytotoxic drug formulation. For example, instead of two vial adapters, the system can include only one vial adapter that connects to both vials (e.g. is reusable for the cytotoxic drug after the diluent). Further, the diluent can be transferred to the syringe through the three-way stopcock. In such an embodiment, the valve cannot be a one use valve.

[0056] The above exemplary methods prevent exposure of the administrator to the at least one cytotoxic pharmaceutical drug. Such prevention can eliminate injury to an administrator. Injuries can include burns, rashes, nausea, numbness, blindness, paralysis, bleeding, irritation, cancer, other disease, or a combination thereof. The systems described herein simply provide a safer and more desirable work environment when administering otherwise dangerous cytotoxic drugs to treat otherwise horrible illnesses.

Example 1

[0057] Two different "closed systems" were evaluated for reconstitution of an apaziquone drug product. These two systems were compared based on ease of use.

[0058] The two systems for assessment were PhaSeal: Manufactured by Carmel Pharma in Ohio and a three-way stopcock system as described herein. (Stopcock Manufactured by Halkey-Roberts). The stopcock was used in combination with two spiked vial adaptors manufactured by Medimop in Israel and distributed by West Pharmaceuticals Inc. The PhaSeal system is a commercially available system for the reconstitution of cytotoxic and potent products.

[0059] Ease-of-use evaluation using the two systems was conducted by two physicians familiar with instillation of cytotoxic products in the bladder. The following table outlines the steps that were involved for reconstitution and administration for the PhaSeal and three-way stopcock system.

Table 1 : Operation steps for use of PhaSeal and three-way stopcock closed-system

[0060] Each step of the reconstitution process was scored. The lower the score, the more user-friendly was the system. The tables below summarize the scoring of the two systems under evaluation.

Table 2: PhaSeal System

Table 3: Three-way Stopcock System

[0061] Based on these scores, the three-way stopcock was the easier of the two systems to use.

Example 2

[0062] Retention of Drug Product (Void Volume) was tested as follows. The two systems described above were used to reconstitute vials of apaziquone placebo (three replications per device). The instructions described in Table 1 were used to perform the reconstitution steps.

[0063] The amount of each effluent collected from each device was weighed. The amount of effluent was recorded in Table 4 below (filled with 40 mL). The net weight of the reconstituted product was subtracted from the net weight of the effluent (instilled product) to calculate the retention volume in each system.

[0064] A syringe with a hypodermic needle was used to reconstitute one vial of drug product as in conventional practice. The conventional "syringe and needle" system is the method of reconstituting the active drug product using a 12 gauge needle to withdraw the diluent from the diluent vial and injecting it into the drug product vial. The reconstituted drug product was then withdrawn from the drug product vial and mixed with the remainder of the diluent in the syringe. The needle was then removed and the syringe was connected to the catheter adapter via the luer connector. This system was used as a control for this section of the experiment.

Table 4: Retention of Drug Product

[0065] Per table 4, the retention volume in both the PhaSeal system and the th way stopcock system were low and comparable.

Example 3

Drug Product Containment During Reconstitution and Instillation

[0066] A type of test commonly performed to determine whether a device will be deemed as a "closed system" is a titanium tetrachloride vapor test during reconstitution and a mock instillation to test for gaseous leaks at the connector points.

[0067] The vapor test is a far more sensitive determination of leaks than commonly used fluorescent dye tests. The titanium tetrachloride vapor test was used to determine whether a system was deemed as a "closed system". Principles of the test method: titanium tetrachloride is a liquid that when exposed to the air will react with the moisture in the air and form visible hydrochloric acid fumes.

[0068] A 5% solution of titanium tetrachloride (TiCI₄) was prepared by diluting the concentrate in dichloromethane. The 5% solution was used to simulate the diluent. If there was a leak in any of the connection points of the system during the reconstitution, the TiCI₄ molecules escape and react with the moisture in the air and emit a visible vapor of hydrochloric acid (see Figure 6A).

[0069] The reconstitution steps were performed for the three-way stopcock system as described in Example 1 . This test was also performed by the manufacturer, Cannel Pharma, for the PhaSeal system.

[0070] An empty stoppered and sealed 10 ml_ vial was used as a mock drug product container. The reconstitution and instillation steps of apaziquone were simulated using the two systems. The connection points of each system were observed and photographed for leaks. The leaks appeared as a white hydrochloric acid gas. Figures 6B and 6C illustrate that there was no leakage from either system either at the connection to the drug product vial or the connection to the syringe during the reconstitution steps.

[0071] Upon comparison of the two alternative "closed systems" the three-way stopcock ranked higher than the PhaSeal system for the "ease of use" study. Retention volumes in the two systems were somewhat different. Both systems passed the leak test without leaks at any connection points in the systems. As such, the three-way stopcock closed system was easier to use than current systems while providing acceptable retention volume and no leaking during reconstitution.

[0072] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0073] The terms "a," "an," "the" and similar referents used in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0074] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0075] Certain embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above- described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contraindicated by context.

[0076] In closing, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the present invention may be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to that precisely as shown and described.

Claims

I claim:

1 . A drug formulation preparation system comprising: a stopcock having at least three ports; at least one vial adapter; a delivery device interface; and instructions for use.

2. The drug formulation preparation system according to claim 1 , further comprising a drug formulation.

3. The drug formulation preparation system according to claim 1 , further including a vial including a diluent and a second vial containing at least one drug.

4. The drug formulation preparation system according to claim 2 or 3, further including a syringe.

5. The drug formulation preparation system according to claim 1 , wherein the stopcock has three ports.

6. The drug formulation preparation system according to claim 2 or 3, wherein the drug or drug formulation is cytotoxic.

7. The drug formulation preparation system according to claim 1 , wherein the delivery device interface includes an I.V. tube adapter.

8. The drug formulation preparation system according to claim 1 , wherein the delivery device interface includes a catheter tube adapter.

9. The drug formulation preparation system according to claim 1 , wherein the drug formulation preparation system does not include an exposed needle.

10. The drug formulation preparation system according to claim 1 , wherein further comprising one vented vial adapter and one non-vented vial adapter.

1 1 . The drug formulation preparation system according to claim 1 , wherein the stopcock includes a one use, locking valve.

12. A method of preparing a drug formulation for administration to a patient comprising the steps: connecting a syringe to a vial adapter; inserting the vial adapter into a vial including a diluent; drawing the desired amount of diluent into the syringe creating a diluent syringe; disconnecting the diluent syringe from the vial adapter; attaching the diluent syringe to a closed system device comprising a stopcock including at least two free ports and a delivery device interface, at one of the at least two free ports; attaching a second vial adapter to a second free port of the closed system device; inserting a second vial containing at least one drug into the second vial adapter; moving the diluent from the syringe into the second vial through the closed system device thereby forming a drug formulation; transferring the drug formulation from the second vial to the syringe; closing the stopcock of the closed system device to the second vial; and attaching the delivery device interface to a delivery device, wherein the method prevents exposure to said at least one drug.

13 The method according claim 12 wherein the drug is cytotoxic

14 The method according to claim 13 wherein the cytotoxic drug is apaziquone

15 The method according to claim 12 wherein the drug is highly potent.

16. The method according to claim 12, wherein the vial adapter is a vented vial adapter.

17. The method according to claim 12, wherein the stopcock has two free ports.

18. The method according to claim 12, wherein the delivery device interface includes an I.V. tube adapter.

19. The method according to claim 12, wherein the delivery device interface includes a catheter tube adapter.

20. The method according to claim 12, wherein the closing step, the stopcock includes a one use, locking valve that locks after it is closed.

21 . The method according to claim 12, wherein the delivery device is an I.V. line.

22. The method according to claim 12, wherein the delivery device is a catheter tube connected directly to a baldder.

23. A drug formulation preparation system for administration of an apaziquone drug formulation for treatment of bladder cancer comprising: a three-way stopcock; a vented vial adapter; a second vial adapter; a vial including a diluent; a vial containing a lyophilized apaziquone; a delivery device interface having a catheter tube connector; and instructions for use.

24. The drug formulation preparation system according to claim 23, further comprising a syringe.

25. A method of preparing and administering an apaziquone formulation for treatment of a bladder cancer comprising the steps: connecting a syringe to a vented vial adapter; inserting the vented vial adapter into a vial including a diluent; drawing the desired amount of diluent into the syringe; disconnect the syringe from the vial adapter; attaching the syringe containing the desired amount of diluent to an open port on a three-way stopcock associated with a delivery device interface; attaching a second vial adapter to a second free port of the three-way stopcock; inserting a second vial containing a lyophilized apaziquone into the second vial adapter; moving the diluent from the syringe into the second vial through the three-way stopcock thereby forming an apaziquone formulation; transferring the apaziquone formulation from the second vial to the syringe; closing the three-way stopcock to the second vial; attaching the delivery device interface to catheter line; and delivering the apaziquone formulation through the catheter line to the bladder cancer, wherein the method prevents expose to the apaziquone.