WO2009007350A1

WO2009007350A1 - Device and method for the preparation and the use of radiopharmaceuticals

Info

Publication number: WO2009007350A1
Application number: PCT/EP2008/058807
Authority: WO
Inventors: Bernard Van Gansbeke; Serge Goldman
Original assignee: Universite Libre De Bruxelles
Priority date: 2007-07-06
Filing date: 2008-07-07
Publication date: 2009-01-15

Abstract

The present invention is related to a device for injecting a radioactive pharmaceutical composition from a microbiologically and mechanically closed vial (4) and which comprises : - this vial (4) encompassing neutral atmosphere with an inflatable balloon (l)in contact with this vial (4) and neutralizing positive and negative pressure from this vial (4) and - radiation shielding means (3,5) covering this vial (4), except a connection site available to an injector (10).

Description

Device and method for the preparation and the use of radiopharmaceuticals

Field of the invention

[0001] The present invention is in the medical field, more particularly, related to a medical device and to the use of this device for the preparation of radiopharmaceuticals.

Background of the invention

[0002] Radiopharmaceuticals or radioactive pharmaceutical compositions consist or comprise radioactive drugs or active elements used in nuclear medicine for diagnosis or therapy. They are produced by pharmaceutical companies under several different forms: ready-to-use radiopharmaceuticals or composition , as multiple dose vials or other forms; - non radioactive kits for labeling with radiopharmaceuticals ; generators producing radiopharmaceuticals; radioactive precursors for cell labeling.

As they are radioactive, these radiopharmaceuticals or composition have to be handled as hazardous drugs.

[0003] Radiopharmaceuticals or compositions used as intravenous medicaments are currently prepared as other intravenous medicaments, i.e. with a syringe and a needle to prepare the solution into a vial and to extract individual doses (or individual volumes) from this vial. Ready-to-use radiopharmaceuticals or composition are prepared in a one-step manipulation: extraction of the needed (individual) volume (or dose) of a solution comprising them from the vial.

[0004] Kits for labeling are prepared from non radioactive vials and generator-produced radioactivity ("eluate") in a three-step manipulation: extraction of the required (individual) volume (or dose) of an eluate from a first vial, transfer to the labeling vial, (incubation, heating if necessary) and extraction from this second vial of the needed (individual) volume (or dose) . [0005] Radiopharmaceuticals are recognized as hazardous drugs for the professionals handling these drugs and for the environment since they are radioactive products with high volumic activity. All precautions must be taken to reduce the irradiation of an operator as well as patients and population. Irradiation results from several mechanisms :

- direct exposition to radiopharmaceuticals or radioactive compositions :

- by handling these radiopharmaceuticals or compositions without appropriate shielding : irradiation by the product contained in the vial, the syringe, ...

- by spreading these radiopharmaceuticals or compositions in the working place during handling : irradiation by the product spread all around the worker or the patient

- contamination of the operator or patient : - external contamination (skin) : irradiation by a product present on the skin

- internal contamination (swallowing, breathing) : irradiation by a product distributed in the body

- environmental contamination affecting the population.

[0006] Protection of an operator is needed to prevent irradiation during handling of these radiopharmaceuticals or composition; this is currently achieved by the use of shielded screens placed between the product and the worker.

[0007] In addition, exposition is limited in time to the period necessary to prepare and administer these radiopharmaceuticals or compositions.

[0008] Actions that reduce exposition are: increasing the distance between the operator and the product, reducing the working time, - using of vial and syringe shielding devices and using of shielding screens placed between the product and the worker.

[0009] Contamination on the other hand is continuous and will only decrease through physical decay or biological elimination of the contaminant. Actions that reduce contamination are:

- using of gloves and protective garment and

- working inside a negative pressure environment (hoods, laminar flow hoods, isolators) or a closed environment (isolators)

[0010] These radiopharmaceuticals and compositions require precautions during preparation and administration to the patient since they are mostly sterile injectable drugs. All these drugs are sterile at the production, but they all need further manipulations to produce the individual doses for the patients. All precautions must be taken to maintain the original sterility until administration to the patient. [0011] These radiopharmaceuticals or compositions also require precautions during preparation and administration to the patient since they are in most cases poorly stable products. Indeed, independently from physical radioactive decay, most of these radiopharmaceuticals and compositions present a limited chemical stability. The most used radiopharmaceuticals and compositions (in number of administered doses) are the ^99mTc radiopharmaceuticals or compositions comprising them. However, other beta and gamma-emitting compounds are used, such as ⁴⁷Calcium, ¹¹Ca-TbOn, ⁵¹Chromium, ⁵⁷Cobalt, ⁵⁸Cobalt, ¹⁸Fluorine, ⁶⁷Gallium, ^U1lndium, ¹²³Iodine, ¹³¹Iodine, ⁵⁹Iron, ¹³Nitrogen, ¹⁵Oxygen, ³²Phosphorus, ⁷⁵Selenium, ²²Sodium, ²⁴Sodium,... [0012] The ^99mTc radiopharmaceuticals are extemporaneously prepared by adding generator-produced radioactivity (^99mTc-pertechnetate) to non radioactive kits formulated to produce a radioactive complex as a result of two consecutive chemical reactions:

reduction of pertechnetate Sn^{2+ ■}* Sn⁴⁺ + 2 e^~

Tcθ4^~ + 3 e^~ + 8 H⁺ -> Tc⁴⁺ + 4 H₂O

complexation of the resulting product by a ligand : Tc⁴⁺ + ligand Φ=> Tc-complex

[0013] Both reactions can be reverted, leading to a chemical degradation of these radiopharmaceuticals or compositions. Kits are formulated to produce them with a minimal purity of 95% which will be maintained during the validity period cited in the package insert (4-6 hours) if the recommended handling conditions are respected. The main source of degradation is reversion of the reduction step by oxidants (re-oxidation) . Kits are formulated to avoid re- oxidation and are produced under neutral atmosphere (nitrogen) . All precautions must be taken to maintain initial labeling conditions.

[0014] Today, there are still no existing device able to combine an effective protection of the operator (irradiation but also contamination) and of the product (sterility) for the preparation (and use) of these radiopharmaceuticals and compositions. Furthermore, there are no existing devices combining these protections with the specific protection of the chemical stability of radioactive compounds, such as ^99mTc compounds. [0015] An underestimated problem is that the system is open (leakage through the needle and entrance of contaminants into the solution are possible) . Out of these contaminants, micro-organisms and oxygen are the most dangerous for the quality of the product. In addition the efficacy of this technique is dependent on the operator' s dexterity.

[0016] Even if some preparation labs are equipped with vertical laminar flow hoods or isolators to prevent entrance of micro-organisms into the injectable drugs and dispersion of liquids or aerosols that should be generated by the use of an open system, they do not prevent them and result in a less flexible procedure.

[0017] A way to prevent leakage of solution or aerosols is the use of a technique of preparation where no differential pressures are generated: when adding liquid to a vial, a same volume of air is taken from the vial to prevent positive pressure. Before extracting a liquid from a vial, a same volume of air is taken into the syringe and transferred to the vial to prevent negative pressure. [0018] Besides radiopharmaceuticals, other drugs are also considered as hazardous, like cytotoxics. However, they are not subjected to the same kind of chemical degradation. Cytotoxic drugs are prepared in vertical laminar flow hoods or in isolators, in order to reduce risks of environmental contamination and to maintain sterility. Several different medical devices were designed for handling these drugs in order to prevent these two problems and to reduce the contamination inside hoods and isolators. The existing devices are of two types:

open systems, with or without needle closed systems o physically closed, notably the Pha Seal™ (Carmel Pharma) and Genie-Spiros™ (ICU medical) systems o functionally closed, like Tevadaptor™ (Teva

Pharmaceuticals Europe) .

[0019] US patents 6,409,708 and 6,602,239 describe other closed systems for the administration of toxic fluids wherein the device is connected to an infusion bag.

[0020] It however exists specific requirements for a safe preparation of radiopharmaceuticals and compositions, as well as for devices allowing safe and more flexible handling (i.e. without a hood and/or external shielded screens) .

[0021] It has been established that protection of the operator against irradiation is one of the main goal when preparing radiopharmaceuticals, and the ALARA principle (As Low As Reasonably Achievable) is the rule is this field. As a matter of fact, existing devices reduce irradiation by shielding but do not prevent contamination through aerosols or projections. On the other hand, protection of the product is also important but is often forgotten in this context of operator' s protection and is today only dependent on human factors. Use of laminar flow hoods or isolators only protects microbiological quality of radiopharmaceuticals, but not their chemical quality. [0022] For instance, patent application WO 2008/037939 describes a whole system of shielding both the vial and the syringe allowing dilution and injection of radiopharmaceuticals without irradiating the operator or the patient. However, the use of this complex apparatus is far from flexible. In addition, this is not a microbiologically closed device upon removing the syringe and not mechanically closed, since oxygen (from the atmosphere) is inserted to the vial when the pharmaceutical composition is taken, resulting into the degradation of the pharmaceutical compound.

Aims of the invention

[0023] The present invention relates to improved methods and means for an easy preparation and an easy use of these radiopharmaceuticals and radioactive compositions that do not present the drawbacks of the state of the art. [0024] A preferred aim of the invention is to provide a method and device of easy and efficient manipulation that can be used for improving the preparation and injection of these radiopharmaceuticals and radioactive compositions and simultaneously for obtaining a reduction or a suppression of consumers irradiation, microbiological contamination and/or chemical degradation of these radiopharmaceuticals and radioactive compositions.

Summary of the invention

[0025] The present invention relates to a device for preparing and/or injecting a radioactive pharmaceutical composition from a microbiologically and mechanically closed vial and which comprises:

- this vial encompassing neutral atmosphere and preferably comprising a radioactive pharmaceutical composition with an inflatable balloon in contact with the inside atmosphere of this vial (or being present within this vial) and able to neutralize positive and/or negative pressure in this vial and

- beta and/or gamma radiation shielding means covering at least this vial (which means an anti beta and/or gamma radiation shielding means for protecting the operator/consumer) and comprising a first opening (preferably present in this cap) for a connection site of this vial available to an injection mean. [0026] Advantageously, the radiation shielding means of the invention further comprises a second opening for the inflatable balloon in contact with (connected to) this vial and possibly which expands outside (the limits of: the walls of) these radiation shielding means. [0027] Preferably, the radiation shielding means comprise a hollow body (cylinder) and a cap (of this body) both comprising complementary shoulders and the second opening is present in the complementary shoulders to ensure the closure of the body with this cap. [0028] Preferably, this second opening is present at the junction of the complementary shoulders. [0029] Advantageously, the radiation shielding means comprise a first and a second opening which are respectively adapted to (which comprise complementary means to) this connection site of the vial and to means connecting this inflatable balloon to this vial. [0030] Preferably, the radioactive pharmaceutical composition present in the device of the present invention is present as an aqueous solution. [0031] Alternatively, the radioactive pharmaceutical composition present in the device of the present invention is an anhydrous powder.

[0032] Preferably, the radioactive pharmaceutical composition of the invention is gamma-emitting composition.

[0033] Advantageously, in the vial, the atmosphere remains neutral, preferably since no air, no oxygen or another gaz is introduced during subsequent steps of extraction of a desired volume of this composition from this vial.

[0034] The present invention is also related to a system made of

- beta and/or gamma radiation shielding means for covering at least a vial (which means anti beta and/or gamma radiation shielding means) having preferably the form of a hollow body (cylinder) with a cap able to cover this vial

(and possibly its expansion chamber) and comprising a first opening for a connection site of this vial available to an injection mean. [0035] In the system of the invention, the radiation shielding means may further comprise a second opening for an inflatable balloon.

[0036] The system of the invention may also further comprise this vial encompassing neutral atmosphere. [0037] Another aspect of the invention is related to a method providing a radioactive pharmaceutical composition, preferably in the form of an aqueous solution for injection; this method comprising the steps of: selecting a microbiologically and mechanically closed vial comprising a radioactive pharmaceutical composition (able to emit beta and/or gamma radiation) ,

- connecting this vial to an inflatable balloon and/or to another system neutralizing positive and negative pressure from this vial, putting this vial into beta and/or gamma radiation shielding means (preferably having the form a hollow body (cylinder) with a cap) able to cover this vial and possibly its inflatable balloon, wherein these shielding means further comprising a first opening (preferably present in the cap) for a connection site of this vial available for injection, - adapting an injector to this vial connection site and extracting a desired volume of the radioactive pharmaceutical composition from the vial into a syringe (through this injection mean) .

[0038] Alternatively, the method according to the invention allows to provide a radioactive pharmaceutical composition, in the form of a powder, for injection and this method comprises the steps of:

-selecting a mechanically and microbiologically closed vial having an inflatable balloon and/or another system neutralizing positive and negative pressure from this vial comprising a radioactive pharmaceutical powder, -putting this vial into beta and/or gamma radiation shielding means (preferably having the form of a cylinder with a cap) able to cover this vial (and possibly its inflatable balloon) and wherein this shielding means further comprising a first opening (preferably present in the cap) for a connection site of this vial available for injection,

-adapting an injector to this vial connection site, -injecting to this vial a desired amount of a liquid and mixing this amount of liquid to the radioactive pharmaceutical powder to form a homogenous composition, and -extracting a desired volume of the radioactive pharmaceutical composition from this vial into a syringe (through this injector). [0039] In the method according to the invention, the radiation shielding means advantageously further comprises a second opening for this inflatable balloon, which expands outside the radiation shielding means . [0040] According to the invention, the radiopharmaceutical composition comprise elements that are gamma-emitting elements or isotopes.

[0041] Preferably, the flexible wall of the inflatable balloon comprises at least one layer made of any flexible material impermeable to aqueous solutions and/or to air.

[0042] The flexible wall of the inflatable balloon according to the invention may comprise at least two layers, a layer being a polyolefin and the other layer being one, or a mixture of several polymer (s) selected from the list comprising polyamide, polyester and/or ethylene vinyl alcohol polymers, possibly metal-enriched (preferably lead) rubber or epoxy polymer.

Detailed description:

[0043] Inflatable balloons (1, 11) also referred in the art to as infusion bags or expansion chambers allow equal pressure upon injection or extraction of a liquid in a (hermetically) closed vial (4, 14). They usually contain flexible walls (2, 12), preferably double layer walls avoiding leakage. A pressure equalization is obtained, via an expansion of this inflatable balloon (1, 11) . The inflatable balloon may be presented fully inside the vial 14 (as in Fig. 2), or attached to the vial 4 and present at least partly outside this vial 4 (as in Fig. 1) .

[0044] These vials (4, 14) are mechanically closed vials defined by the NIOSH (National Institute for Occupational Safety and Health as devices that mechanically prohibits the transfer of environmental contaminants into the system and the escape of hazardous drug or vapor concentrations outside the system.

[0045] Furthermore, these vials (4,14) inherently and fully prohibit the transfer of environmental micro- organisms into the system are defined as being microbiologically closed.

[0046] The present invention is in the field of Radiopharmacology which includes the study and the preparation of radiopharmaceuticals or radioactive compositions which comprises radioactive pharmaceuticals.

[0047] These Radiopharmaceuticals and compositions are used in the field of nuclear medicine as tracers in the diagnosis and treatment of many diseases, including cancer. [0048] The device of the invention comprises two parts: a (hermetically) mechanically and microbiologically closed vial (4, 14) that may comprise these radioactive pharmaceuticals or a radioactive composition, this vial (4, 14) being connected to an inflatable balloon (1, 11) and - radiation shielding means (3, 13) adapted to the use of this vial (4, 14), but protecting the operator/consumer from radiation (s) issued from these radioactive pharmaceuticals . [0049] This vial (4, 14) according to the invention is glass-derived and robust enough to prevent accidental breaking.

[0050] The vial (4, 14) present a size adapted to contain from about 1 to about 100 ml, more preferably from about 5 ml to about 50 ml, and even more preferably from about 7 ml to about 15 ml of a radioactive solution.

[0051] Alternatively, the vial (4, 14) may contain these radiopharmaceuticals in the form of a powder, subsequently put into solution by the addition of about 5 ml to about 50 ml, and even more preferably from about 7 ml to about 15 ml of a sterile aqueous solution (containing preferably physiological salt(s) and/or sugar (s) adequate concentrations) .

[0052] Adequate pressure within the inflated balloon is ranging from about 100 kPa to about 250 kPa, more preferably from about 100 kPa to about 180 kPa, even more preferably from about 100 to 150 kPa.

[0053] By about, it is meant a value plus or minus 10 percent (%) . [0054] This inflatable balloon comprises an internal space and is surrounded at least partially by flexible wall (s) (2,12), at least one outlet channel is arranged through one of its walls for a communication between interior of this inflatable balloon (1, 11) and the vial (4, 14) containing the radiopharmaceutical composition. This inflatable balloon (1, 11) is tightly attached (connected) to this vial (4, 14) by means well known to the person skilled in the art. Therefore, these attachment and communication means between the inflatable balloon 1 and the vial 4 require a second opening 7 in the radiation shielding means (cylinder 3 and its caps) .

[0055] The flexible walls (2, 12) of the inflatable balloon (1, 11) are made of any flexible material that prevents any leakage. This flexible material may be in plastic, suitable polymer or synthetic (or naturally occurring) elastomeric material.

[0056] Advantageously, the polymer of the inflatable balloon is impermeable to water and aqueous solutions. Examples of such polymers are polyolefin, preferably polyethylene or polypropylene.

[0057] Advantageously, the polymer of the inflatable balloon according to the invention is impermeable to air and/or oxygen, such as polyamide, polyester or ethylene vinyl alcohol polymers. [0058] In addition, the inflatable balloon and elements on which it is fastened should be made of polymer that resists to radiation-induced degradation. In this regard, polypropylene is a less preferred polymer than polyethylene. However, depending on the isotope used, the skilled person in the art may select polyethylene as preferred polymer.

[0059] A preferred composition of the flexible walls (2, 12) composing the inflatable balloon according to the invention is a multilayer system, wherein the first layer, closer to the vial, is in polyethylene and a second layer, facing air (or oxygen) , is in an oxygen-impermeable polymer (or mixture thereof) preferably selected from the group consisting of polyamide, polyester and ethylene vinyl alcohol polymers .

[0060] The vial (4, 14) is enclosed by a (radiation) shielding metallic means made of a shielding metallic cylinder (3, 13) , preferably a lead cylinder having metallic walls, a top opening for the introduction of the vial (4, 14) and a metallic bottom surface. This shielding metallic means further comprise a metallic cap complementary (adaptable) to the top opening of the cylinder, preferably a lead cap (5, 15) presenting a

(possibly sealable) first opening (6, 16) to a connection site within the vial (4, 14) to allow the access to the radiopharmaceuticals (radioactive compositions) present in the vial (4, 14) .

[0061] Advantageously the radiation shielding means (hollow body such as a cylinder (3, 13) and its cap (5, 15) ) prevent emission of at least 80%, preferably at least , 90%, more preferably 95%, still more preferably almost 100% of the radioactivity emission issued from the radiopharmaceuticals (radioactive compositions) present in the vial (4, 14) outside the radiation shielding means towards the operator/consumer.

[0062] The radiation shielding means (the cylinder

(3, 13) and its cap (5, 15)) are preferably made in lead or in an alloy comprising lead and having a thickness comprised between about 0.1 cm and about 1.5 cm, preferably between about 0.3 cm and about 1 cm , more preferably about

0.5 cm (thick) .

[0063] Alternatively, these radiation shielding means of the invention are made of another gamma-ray attenuating material having a thickness adapted to the amount of radioactivity contained into the vial and to the half-value layer (HVL) of the material (defined as "the thickness of any given material where 50% of the incident energy has been attenuated") , preferably a thickness comprised between about 0.3 and about 0.8 cm. [0064] Advantageously, the radiation shielding means are made in metal-enriched (preferably lead) rubber or epoxy polymer. [0065] A metal-enriched rubber or epoxy polymer allows increased protection to the vial in case of accident and are obtained in a more economical production. [0066] The inflatable balloon 1 can partly expands outside the walls of radiation shielding means (3 and 5) and therefore these combined means provide a (second) opening 7 adapted to said inflatable balloon 1, especially to the attachment and communication means present between the balloon 1 and the vial 4. This second opening 7 is advantageously present in a shoulder 8 of the (lateral) wall of the cylinder 3 and present in a complementary shoulder 9 of the (lateral) wall of the corresponding cap 5. (See Fig. 1)

[0067] When these two means (cylinder 3 and its cap 5) are put together by manual or robotic manipulation, these two complementary shoulders (8 and 9) adapted to each others provide an adequate opening 7 for the introduction of the attachment and communication means present between the vial 4 and its balloon 1. This means that contrary to the first opening 6, this second opening 7 is not sealable. [0068] These radiation shielding means present an adequate geometry to fully encompass this inflatable balloon when inflated preferably an opening (7) profile which is a chanfrein or is cut into the hollow body (3) to allow the handling of the inflatable balloon (1) (see Fig.

D •

[0069] The cap (5, 15) and the cylinder (3, 13) present are reversibly and strongly fixed together, preferably through an adaptation upon complementary shoulders (8 and 9) and/or fastened through an adapted system (locking elements not represented) .

[0070] After its use, these fastened cylinder (3, 13) and cap (5, 15) are separated and the vial (4, 14) with its balloon (1) is discarded and/or treated as radioactive waste, while the cylinder (3, 13) and cap (5, 15) are reused, reducing the costs for achieving efficient protection .

[0071] The invention is illustrated by the following non-limiting examples. The person skilled in the art may easily add or adapt the characteristics of the device of the invention to other closed systems using or not inflatable balloons for the handling of dangerous compounds . [0072] The invention is not limited to ⁹⁹Tc compounds, as a lot of other Radiopharmaceuticals (elements (isotopes) such as ⁴⁷Calcium, ¹¹Carbon, ⁵¹Chromium, ⁵⁷Cobalt, ⁵⁸Cobalt, ¹⁸Fluorine, ⁶⁷Gallium, ¹¹¹InCUUm, ¹²³Iodine, ¹³¹Iodine, "iron, ¹³Nitrogen, ¹⁵Oxygen, ³²Phosphorus, ⁷⁵Selenium, ²²Sodium, ²⁴Sodium, ...) are routinely used, and their application may benefit from the present invention. [0073] ²H (Deuterium) , ¹⁸Oxygen, ¹⁵Nitrogen and all stable isotopes are outside the scope of the invention, as being non-radioactive.

[0074] ³H (Tritium) and ¹⁴Carbon emit radiations of too low energy to benefit from the present invention. [0075] Every isotope emitting radiations that cannot pass from about 0.5 mm to about 2 mm glass, preferably about 1 mm glass and/or every stable isotope are outside the scope of the present invention.

[0076] The radiopharmaceuticals according to the invention are gamma-emitting (or beta- and gamma-emitting) elements (isotopes) preferably selected from the group consisting of ⁴⁷Calcium, ⁵¹Chromium, ⁵⁷Cobalt, ⁵⁸Cobalt, "Gallium, ¹¹¹InCUUm, ¹²³Iodine, ¹³¹Iodine, ⁵⁹Iron, ⁷⁵Selenium, ^99mTc or a mixture thereof .

[0077] The device according to the invention allows advantageously an efficient protection to the operator/consumer, as well as microbiological and chemical stability of the treated radiopharmaceuticals and radioactive composition.

Example 1. Use of the shielded device in combination with the PHASEAL™ system (Fig. 1)

[0078] The known Pha Seal™ device is based on the use of an expansion chamber to handle positive and negative pressures generated during preparation of solutions. Briefly, the Protector™ device (comprising 1 and 2, a connection and inflatable balloon) is attached on a vial and an Injector™ (1.8; connection and transfer) is attached on a syringe. This Injector™ is connected to this Protector™ (by a dry connection) . The combination of a 10 ml vial) + Protector™ is placed in a lead cylinder 3 having a diameter of about 40 mm, a height of about 75 mm and an about 3 mm thickness. This Injector™, when connected, the encapsulated needle is unlocked and enters into a vial. When a liquid is added to this vial, air contained in this vial is transferred in the inflatable balloon 1. When the solution is extracted, the air moves from the inflatable balloon 1 to the vial to equilibrate the pressure.

[0079] Method for the preparation qf_ radiopharmaceuticals with shielded Pha Seal™

A. Ready-to-use radiopharmaceuticals

- Attaching a Protector™ on a vial 4 (figlA) - placing this vial 4 into a lead shielding cylinder 3 and closing this shielding cylinder 3 by the addition of the lead cap 5 but leaving the connection site present in the cap 5 available (fig IB, 1C and ID) attaching an Injector™ on a syringe (fig IE) - connecting the Injector™ and the Protector^Tand and unlocking the needle (of the Syringue) (fig IF and IG) and extracting a desired volume of radiopharmaceuticals (fig IH) .

B. ^99mTc radiopharmaceuticals B.I. Extraction of eluate the extraction of the needed volume of eluate is possible in two ways : o with Pha Seal™ (if working in ISO class five device as a biological safety cabinet or compounding aseptic containment isolator) ^■ placing a ^mTc eluate vial 4 into a lead shielding cylinder 3 (fig IB) ,

^■ attaching a Protector™ 10 on this ^99mTc eluate vial (fig IA) , ■ closing this shielding cylinder 3 by the addition of a lead cap 5 but leaving the connection site present in the cap 5 available (fig 1C and ID),

^■ taking a volume of sterile air (preferably nitrogen) into a syringe (corresponding to the needed volume of eluate) ,

^■ attaching an Injector™ on the syringe (fig IE),

^■ connectilng the Injector™ and the Protector™ (fig IF and IG)

^■ injecting air (the expansion chamber will inflate)

^■ extracting a needed volume of eluate (fig IH) and

^■ disconnecting the elements (fig IF)

This procedure is extendable to other systems (if not working in ISO class Five device as a biological safety cabinet or compounding aseptic containment isolator)

^■ placing a ^99mTc eluate vial 4 into a lead shielding cylinder 3 ■ attaching a vented system (such as Codan Chemoprotect™ Spike, Braun Chemo Mini-Spike Plus™, Baxter Chemo-Aide™ , ...) on this ^99mTc eluate vial 4,

^■ closing this shielding cylinder 3 by the addition of a lead cap 5 but leaving the connection site present in the cap 5 available and

^■ extracting a needed volume of eluate B . 2 . Label ing attaching a Protector™ on a labeling vial 4 (fig IA) , placing this vial 4 into a lead shielding cylinder 3 and closing this shielding cylinder 3 by the addition of the lead cap 5 but leaving the connection site present in the cap 5 available (fig IB, 1C and ID) , attaching an Injector™ on a syringe containing the eluate (fig IE) , connecting the Injector™ and the Protector™ and unlocking the needle (fig IF and IG) , injecting the eluate through the Pha Seal™ connection and disconnecting the elements (fig IF)

B.3. Dose extraction attaching the Injector™ on the syringe (fig IE), connecting the Injector™ and the Protector™, unlocking the needle (fig IF and IG) , extracting a desired volume of radiopharmaceuticals from the vial (fig IH) and disconnecting the elements (fig IF)

[0080] Advantages of the new combined method for the preparation of radiopharmaceuticals .

The usual technique for preparation of radiopharmaceuticals is the use of a needle and a syringe. This "open" system may cause radioactive solution spreading and accidental auto-puncture of the operator. Pha Seal™ acts as a needle-free device (the needle is encapsulated) , which is recommended by the National Institute for Occupational Safety and Health (NIOSH) for the safe preparation of hazardous drugs. The "open" system allows the contamination by spreading of solution but also of aerosols generated by pressure variations (contamination of the work place end of the environment). Pha Seal™ is a mechanically closed system that, will prevent, the escape of fluids (fluids are transferred to the expansion chamber) and contaminating gaz.

An "open" system allows the entrance of micro-organisms into the vial (loss of sterility) . In opposite advantageously, Pha Seal™ is a mechanically closed system that will prevent contamination by microorganisms during preparation.

The usual technique requires pressure equalizing through extraction of nitrogen when injecting an eluate and injection of air when extracting the radiopharmaceuticals. Repeated extraction of doses from the vial will replace the protective nitrogen atmosphere by air (oxygen) . The stability of the radiopharmaceuticals will be compromised since oxygen can cause re-oxidation of the radiopharmaceuticals. Since Pha Seal™ is working as a closed system, it is able to maintain the initial nitrogen atmosphere into the radiopharmaceutical vial and the expansion chamber. The usual technique requires maintaining the vial with the hands during injection of the eluate. The vial with the Protector™ on it top can easily be included in shielding means firmly maintaining the vial, with a reduced opening for the injection site. The expansion chamber will not be included in the shielding cylinder but there is no radioactivity in this part of the device. The shielding means (and not the vial itself) will be maintained with the hands, reducing the operator irradiation during preparation. In the same manner, repeated extraction of doses from the vial can be performed without separating the shielding means, which reduces the irradiation of the operator during use of the multi-dose vial. - The usual technique generates a syringe closed by the needle as final presentation. This is an open system from which liquid could escape. The Injector™ attached on the syringe prevents leakage of the syringe's content .

Efficacy of the new combined method for the preparation of radiopharmaceuticals

[0081] Several preparations of ^99mTc-Technescan DMSA™ (dimercaptosuccinic acid) were made with both the conventional system (needle-syringe) and the Pha Seal™ device. The inventors demonstrated that: use of Pha Seal was compatible with the preparation technique and easy to handle; radioactive contamination was detected when using the conventional system: gloves, vials and working area were contaminated with variable but significant amounts. Advantageously, when Pha Seal™ was used, the contamination decreased below the detection level, evidencing the interest of closed systems; - the stability of ^99mTc-Technescan DMSA™ was maintained for at least 6 hours, even if the manufacturer limits the use at 4 hours, evidencing increased stability gained by the closed system under protective atmosphere; residual volumes lost into the devices were similar in both systems. Example 2. Use of the shielded device in combination with the GENIE-SPIROS™ system (Fig. 2)

[0082] The Genie™ device is a closed, needle free vial access device that equalizes vial pressure through an inflatable balloon 11 during the extraction of solutions.

It is a needle-free closed system. Briefly, Genie™ is attached on the vial 14 and Spiros™ is attached on the syringe. When liquid is added to the vial 14, the air contained in the vial 14 is transferred to the syringe. When the solution is extracted, the balloon 11 inflates into the vial 14 with air taken outside the vial.

[0083] Ready-to-use radiopharmaceuticals attaching a Genie™ on a vial 14 (fig 2A) , - placing this vial 14 into lead shielding cylinder 13, close the shielding cylinder 13 by addition of the lead cap 15 but leaving the connection site present in the cap 15 available (fig 2B, 2C and 2D) attaching a Spiros™ on a syringe (fig 2G) , - connecting the Spiros™ and the Genie™ (fig 2E and 2F) and extracting a desired volume of the radiopharmaceuticals needed (fig 2H)

A. 99mTc radiopharmaceuticals B.I. Extraction of an eluate,

Placing the ^99mTc eluate vial 14 into the lead shielding cylinder 13 (fig 2B) ,

- Attaching a Genie™ on the ^99mTc eluate vial 14 (fig 2A) ,

Closing the shielding cylinder 13 by addition of the lead cap 15 but leaving the connection site present in the cap 15 available (fig 2C, and 2D) , Attaching a Spiros™ on a syringe (fig 2G) , Connecting the Spiros™ and the Genie™ (fig 2E and 2F),

Extracting the volume of the needed eluate: the balloon inflates inside the vial 14 (fig 2H) and Disconnecting the elements (fig 2E) .

B.2. Labeling

Attaching a Genie™ on a labeling vial 14 (fig 2A) , - Placing this vial 14 into a lead shielding cylinder

13, closing the shielding cylinder 13 by addition of the lead cap 15 but leaving the connection site present in the cap 15 available (fig 2B, 2C and 2D), - Connecting the Spiros™ and the Genie™ (fig 2E and

2F),

Injecting the eluate through the Spiros-Genie™ connection,

Taking the same volume of gas into a syringe and - Disconnecting the elements (fig 2E) .

B.3. Dose extraction

Attaching a Spiros™ 20 on a syringe (2G) , Connecting the Spiros™ and the Genie™ (2F) enclosed in a protective shield cylinder 13,

Extracting a desired volume of radiopharmaceuticals : the balloon inflates inside the vial 14 (2H) and Disconnecting the elements (2E) .

Genie-Spiros™ is a needle-free device, which is recommended by NIOSH for the safe preparation of hazardous drugs. [0084] Advantages of the new combined method for the preparation of radiopharmaceuticals .

The "open" system allows the contamination by spreading of solution but also of aerosols generated by pressure variations (contamination of r^o ΛOK o__acc ana of the enviroⁿment ) . Advantageously, Genie-Spiros™ is a mechanically closed system 1 ha⁺ '.ill o^ypven, t "^Ω PSC<JP°

The "open" system allows the entrance of micro-organisms into the vial (loss of sterility) . Genie-Spiros™ is a mechanically closed system th-at: WT , J prevent f e .ncrresc o*^■ v , z co~ o fg^ir sπs cLr^ng prepar-atⁿ o" .

The usual techniques require pressure equalizing through extraction of nitrogen when injecting the eluate and injection of air when extracting the radiopharmaceutical. Repeated extraction of doses from the vial will replace the protective nitrogen atmosphere by air (oxygen) . The stability of the radiopharmaceutical will be compromised since oxygen can cause re-oxidation of the radiopharmaceutical. Genie- Spiros™ working as a closed system will prevent the entrance of air (oxygen) into the radiopharmaceutical vial . The usual techniques require maintaining the vial with the hands during injection of the eluate. The vial with the Genie on it top can easily be included in a shielding cylinder firmly maintaining the vial, with a reduced opening for the injection site. The shielding means (and not the vial itself) will be maintained with the hands, reducing the operator irradiation during preparation

In the same manner, repeated extraction of doses from the vial can be performed without separating the shielding means , which reduces the irradiation of the operator during use of the multi-dose vial. The usual techniques generate a syringe closed by a needle as final presentation. This is an open system from which liquid could escape. Spiros™ attached on the syringe prevents leakage of the syringe's content.

Bibliography www . cdc . qov/niosh/docs /2004-165 : hazardous drugs - www .mcgil I . ca/ehs/radi ati on /manual /3/ : radiation dose limit wvjw. nuclearonline . org/PI /MaIlinckrodt%20DTPA.pdf :

Technescan DTPA package insert - Directions for use - www.niiclearonline.ora/PI/Nycomed%20DM5A.pdf : DMSA package insert - Preparation www . carmelpharrna . com www.icumed.com

Claims

1. A device for preparing and/or injecting a radioactive composition from a microbiologically and mechanically closed vial (4, 14) and which comprises :

- the vial (4, 14) encompassing neutral atmosphere and able to comprise a radioactive pharmaceutical composition, with an inflatable balloon (1, 11) in contact with the inside atmosphere of said vial (4, 14) or being present within said vial (4, 14) and able to neutralize positive and/or negative pressure in said vial (4, 14), and

- beta and/or gamma radiation shielding means (3, 13, 5, 15) covering at least said vial (4, 14), and comprising a first opening (6, 16) for a connection site of the vial (4, 14) available to an injection means (10, 20) .

2. The device of claim 1 wherein the radiation shielding means (3, 5) further comprise a second opening (7) for the inflatable balloon (1), which expands outside said radiation shielding means (3, 5) .

3. The device of claim 2, wherein the radiation shielding means comprise a hollow body (3) able to receive the vial (4, 14) and a cap (5), both comprising complementary shoulders (8 and 9) to ensure the closure of said hollow body (3) with said cap (5) .

4. The device of claim 3, wherein the second opening (7) is present at the junction of the complementary shoulders (8 and 9) of the body (3) and of the cap (5) .

5. The device of any of the preceding claims, wherein the first opening (6, 16) presents a closed profile, while the second opening (7) presents an open profile in the hollow body (3) and an open profile in the cap (5) so as when the hollow body (3) and the cap (5) are in contact, the said opening (7) presents a closed profile.

6. The device of claims 5, wherein the closed profile of the opening (7) is a chanfrein or is cut into the hollow body 3 in order to allow the handling of the inflatable balloon (1, 11).

7. The device of any of the preceding claims 1 to 6, wherein the radioactive pharmaceutical composition is an aqueous solution.

8. The device of any of the preceding claims 1 to 7, wherein the radioactive pharmaceutical composition is an anhydrous powder.

9. The device according to any of the preceding claims, wherein the dimensions and the form of the first opening (6) and the second opening (7) are chosen so that at least 80% and preferably 90% of the emission of radioactivity is prevented to go outside of the radiation shielding means.

10. A system made of beta and/or gamma radiation shielding means (3, 13, 5, 15) for covering a microbiological and mechanical closed vial (4, 14) wherein said vial encompassing neutral atmosphere and is able to comprise a radioactive pharmaceutical composition with an inflatable balloon (1, 11) in contact with the inside atmosphere of said vial (4, 14) or being with said vial (4, 14) and able to neutralized positive and/or negative pressure in said vial (4, 14), said shielding means comprising at least of first opening (6, 16) for a connection site of the vial (4, 14) available to an injection mean (10, 20) .

11. The system of claim 10, wherein the radiation shielding means (3, 5) further comprise a second opening (7) for the inflatable balloon (1), which expands outside said radiation shielding means (3, 5) .

12. The system according to claim 11, further comprising a hollow body (3) able to receive the vial (4, 14) and a cap (5), both comprising complementary shoulders (8 and 9) to ensure the closure of said hollow body (3) with said cap (5) .

13. The system according to claim 12, wherein the second opening (7) is present at the junction of the complementary shoulders (8 and 9) of the body (3) and of the cap (5) .

14. The system according to claim 13, wherein the first opening (6, 16) presents a closed profile, while the second opening (7) presents an open profile in the hollow body (3) and an open profile in the cap (5) so as when the hollow body (3) and the cap (5) are in contact said opening (7) presents a closed profile.

15. The system according to claim 14, wherein the closed profile of the opening (7) is a chanfrein or is cut into the hollow body 3 in order to allow the handling of the inflatable balloon (1, 11).

16. The system according to any of the claims

10 to 15, wherein the dimensions and the form of the first opening (6) and the second opening (7) are chosen so that at least 80% and preferably 90% of the emission of radioactivity is prevented to go outside of the radiation shielding means.

17. A method to provide a radioactive pharmaceutical composition for injection and comprising the steps of: selecting a microbiologically and mechanically closed vial (4, 14) connected to an inflatable balloon

(1, 11) neutralizing positive and negative pressure from said vial and comprising said radioactive pharmaceutical solution, - putting the said vial (4, 14) into beta and/or gamma radiation shielding means (3, 13, 5, 15) comprising a first opening (6) for a connection site of the vial (4, 14),

-adapting an injector (10, 20) to the vial connection site, and

-extracting a desired volume of the radioactive pharmaceutical composition from the said vial (4, 14) to a syringe so that the neutral atmosphere within the vial (4, 14) is maintained by action of the inflatable balloon (1, 11) .

18. A method to provide a radioactive pharmaceutical composition for injection and comprising the steps of: -selecting a microbiologically and mechanically closed vial (4, 14) connected to an inflatable balloon (1, 11) neutralizing positive and negative pressure from the vial (4, 14) and comprising a radioactive pharmaceutical powder,

-putting the said vial into beta and/or gamma radiation shielding means (3, 13, 5, 15) comprising a first opening (6) for a connection site of the vial (4, 14),

-adapting an injector (10, 20) to the vial connection site,

-injecting to the said vial (4, 14) a desired amount of a liquid and mixing this amount of liquid to the radioactive pharmaceutical powder to form a homogenous composition so that the neutral atmosphere within the vial (4, 14) is maintained by action of the inflatable balloon (1, 11), and

-extracting a desired volume of the radioactive pharmaceutical composition from the said vial (4, 14) into a syringe so that the neutral atmosphere within the vial (4, 14) is maintained by action of the inflatable balloon (1, 11).

19. The method of claims 17 and 18, wherein the radiation shielding means (3, 5) further comprises a second opening (7) for the inflatable balloon (1), which expands outside said radiation shielding means (3, 5) .

20. The method of claim 19 wherein the first opening (6) and the second opening (7) of the radiation shielding means are respectively adapted to a connection site of the vial (4, 14) and to means connecting the inflatable balloon (1) to the vial (4) .