Radiopharmaceutical capsule dispensing system

BACKGROUND OF THE INVENTION

1. Field of the Invention

In the field of nuclear medicine, radiopharmaceuticals are commonly prescribed for both diagnostic and therapeutic purposes. Most radiopharmaceuticals are dispensed into unit dose syringes under sterile conditions. Some radiopharmaceuticals, such as I-131 radioiodine are also dispensed in capsules so that they can be easily taken by the patient. The present invention is an apparatus and method to safely and accurately dispense radiopharmaceuticals from an open vial into capsules.

2. Description of Related Art

Radiopharmaceuticals are commonly packaged in glass vials sealed with a rubber septum and metal band. In order to reduce radiation exposure during transportation and dispensing, these glass vials are typically placed in a lead container which is referred in the industry as a pig. Radiopharmacies located across the country often keep several pigs on hand each containing a different radiopharmaceutical. When a prescription is received at a radiopharmacy, an aliquot of the radiopharmaceutical will be dispensed from the sealed glass vial in the pig to a unit dose syringe or one or more capsules for administration to a patient.

In the past, some radiopharmaceuticals have been dispensed from a sealed vial into capsules by hand using a syringe. A radiopharmacist grasps the lead pig housing a glass vial containing a radiopharmaceutical in one hand and grasps a syringe with a needle in the other hand. The radiopharmacist punctures the rubber septum with the needle and withdraws an aliquot of the radiopharmaceutical into the syringe. The proximity of the hands to the radiopharmaceutical, especially in high concentrations, results in a rapid extremity exposure to the radiopharmacist. After transfer to the syringe, the activity level of the radiopharmaceutical in the syringe is measured using a dose calibrator. Corrections may be made for radioactive decay. An aliquot of the radiopharmaceutical is transferred from the syringe to one or more capsule bottoms filled with an excipient. A capsule top is placed on each capsule bottom and the completed capsules are placed in a transportation pig(s) for delivery to a hospital. At the hospital, the capsules containing the radiopharmaceutical are orally administered to the patient for therapeutic or diagnostic purposes.

This manual prior art dispensing process is time consuming and subjects the radiopharmacist to high extremity exposure rates from the radiopharmaceutical. There is a need for a better method and apparatus to dispense radiopharmaceuticals to reduce extremity exposure to occupational workers.

Some stock solutions of radiopharmaceuticals have low concentrations because of safety concerns, which often requires use of multiple capsules to dispense the prescribed dose. If higher concentrations of stock solution were used, the number of capsules required for a single prescription may be reduced and in many cases limited to a single capsule. Reducing the number and size of capsules also reduces the amount of excipient consumed by the patient. There is therefore a need for a method and apparatus that will allow radiopharmacies to use stock solutions of radiopharmaceuticals that have higher concentrations than those commonly used in the past to reduce the number of capsules necessary to fill the prescription.

Because some radiopharmaceuticals are highly volatile, such as I-131 radioiodine, radiopharmacists have been reluctant to dispense such materials from an open vial because of harmful vapors that may escape and the possibility that the liquid radioiodine could be spilled. There is a need for an apparatus and method that can capture and filter vapors arising from an open vial of a volatile radiopharmaceutical and provide safety and accuracy during the dispensing process.

SUMMARY OF THE INVENTION

The present invention is a method and apparatus for accurate dispensing of radiopharmaceuticals, including but not limited to highly volatile compounds such as I-131 radioiodine, from an open vial into capsules which reduces extremity exposure to occupational workers and facilitates use of stock solutions with high concentrations. This capsule dispensing system is contained within a traditional lead lined glove box with two glove ports and a leaded glass window to view the inside of the glove box. This dispensing system includes several off-the-shelf components and others that have been especially adapted for this invention.

A rectangular lead cave is positioned inside the glove box to further reduce exposure to occupational workers. Inside the cave is the bottom half of the pig containing a vial with the radiopharmaceutical. A removable capsule tray is also positioned in the cave. In order to dispense the radiopharmaceutical, an electronic dispensing system is mounted on a handlebar assembly and is positioned inside the glove box. The electronic dispensing system comprises four primary components, including a dispensing grip, a dispensing component (sometimes referred to as a pipette) an electronic keypad and two foot pedals.

In nuclear medicine, the inverse square law is a recognized principal of safety that applies to the present invention. As distance from the radiation source doubles, the exposure rate is reduced by four. Therefore, the handlebar assembly is an important part of the invention to increase the distance between the operator's hands and the radiopharmaceutical in order to reduce extremity exposure rates. The handlebar assembly also provides a stable platform for the electronic dispensing system. A dose calibrator is needed to measure the activity level of the radiopharmaceutical. Dose calibrators are typically cylindrical with a hollow dose calibrator chamber well in the center. The operator of the present invention has easy access to the dose calibrator chamber well from inside the glove box.

In the best mode, the capsule tray, the bottom of the pig with the vial of radiopharmaceutical and the dose calibrator are generally aligned on an axis in the glove box directly in front of the operator. The lead cave contains the removable capsule tray and the pig with the vial of radiopharmaceutical. The lead cave is lined with a stainless steel pan to contain any spills of the radiopharmaceutical. Opposite the cave and the operator is the dose calibrator. Again, in the best mode, the travel distance from the center of the dose calibrator chamber well to the edge of the capsule tray is approximately 12 inches. Other linear configurations of the invention will also produce the advantages discussed above, for example, instead of placing the dose calibrator farthest away from the operator, it could be placed nearest the operator and the location of the capsule tray and the bottom of the pig with the vial of radiopharmaceutical could be rearranged. Also other shielding techniques can be used instead of a lead cave, such as a wall of lead bricks.

Some radiopharmaceuticals such as I-131 radioiodine, are particularly volatile and care must be taken to contain any escaping radioactive vapors so that they do not contaminate the environment, the glove box filter system or harm occupational workers. One way to capture the vapors from a volatile radiopharmaceutical is to use a primary filter system, separate from the glove box filter system. The primary filter system includes a filter cup, a vacuum pump, conduits connecting the cup to the pump and one or more replaceable filters to capture the vapors. The filtration cup is placed over the vial in the pig and the vacuum pump is turned on. Suction from the vacuum pump places the inside of the filter cup and the area immediately surrounding the vial under negative pressure. A plurality of ventilation holes are formed in the filtration cup allowing air from inside the glove box to flow through the cartridge filters to capture any vapors that might escape from an open vial containing a volatile radiopharmaceutical. In conjunction with the primary filter, a filtration syringe may be used to evacuate the headspace before the vial is opened and exposed to the primary filter.

The method for dispensing a radiopharmaceutical from an open vial into a capsule involves the following procedures. A radiopharmaceutical is packaged in a vial and is sealed with a conventional rubber septum and metal band. The vial containing the radiopharmaceutical is placed in the bottom of a pig and the lid is screwed on the bottom. The pig with the vial of radiopharmaceutical is moved into the vestibule of the lead-lined glove box. The operator puts his/her hands in the glove ports and moves the pig from the vestibule to the inside (sometimes called the containment area) of the glove box. The pig containing the vial of radiopharmaceutical is placed in a lead-lined cave inside the glove box and the containers lid is unscrewed and placed aside. A conventional decrimping tool is used to remove the metal band from the vial. A filter syringe with a needle penetrates the rubber septum and is inserted into the headspace in the vial. The headspace is evacuated into the filter syringe. Any vapors in the headspace are captured in the filter syringe which is discarded after a single use.

The primary filter system is used to capture vapors after the vial has been opened. The filter cup is placed over the pig and the vial and the vacuum pump is turned on. The top of the filter cup is removed allowing access to the vial which is still sealed with the rubber septum. A hemostat is used to remove the rubber septum which is set aside. The primary filter system keeps negative pressure on the inside of the filter cup and the area surrounding the open vial to capture any vapors that may escape.

The operator then transfers a known small volume (typically 15 microliters) of the radiopharmaceutical from the open vial into the dispensing component (pipette) of an electronic dispensing system mounted on a handlebar assembly. The handlebar assembly is then repositioned over the dose calibrator and the dispensing component is lowered into the dose calibrator chamber. The operator measures the activity of the known volume of radiopharmaceutical in the dispensing component of the electronic dispensing system. The operator then raises and repositions then handlebar assembly and the electronic dispensing system over the glass vial and returns the known volume of the radiopharmaceutical to the vial. The foregoing is a dosage concentration calibration procedure.

When a prescription for a radiopharmaceutical is received, the operator transfers a calculated volume of the radiopharmaceutical in accordance with this prescription from the vial into the dispensing component of the electronic dispensing system. (The calculation accounts for a radioactive decay correction.) Again, the dispensing component is lowered into the dose calibrator chamber well to confirm the activity of the calculated volume of the radiopharmaceutical. After confirmation of the activity, the handlebar assembly is raised and repositioned over the capsule tray and the calculated volume of the radiopharmaceutical is dispensed from the dispensing component into the capsule bottom containing a suitable excipient. The capsule top is placed on the capsule bottom and the completed capsule is placed in a transportation pig. The top is screwed on the transportation pig and it is moved into the vestibule. The operator removes his/her hands from the glove ports and removes the transportation pig from the vestibule. The transportation pig with the completed capsule is then transported to a hospital for oral administration to a patient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a section view of a lead pig holding a sealed glass vial containing a radiopharmaceutical.

FIG. 2 is an exploded section view of the lead pig of FIG. 1. In FIG. 2 the glass vial is open.

FIG. 3 is a perspective view of the glove box used to dispense radiopharmaceuticals into capsules. The arrows indicate the flow of air into and out of the glove box.

FIG. 4 is a schematic view of the glove box and glove box filtration system of the present invention. The schematic includes a perspective view of a waste bin and a product room for bulk storage of radiopharmaceuticals. The arrows indicate the flow of air through the filtration system and duct work.

FIG. 5 is a plan view of the inside of the glove box of FIG. 1 and the radiopharmaceutical dispensing system.

FIG. 6 is a section view of the inside of the glove box and dispensing system along the line 6-6 of FIG. 5.

FIG. 7 is a plan view of the inside of the glove box and dispensing system of FIG. 5 with the operator's hands inserted through the glove ports. The handlebar assembly is shown in various positions.

FIG. 8 is a section view of the inside of the glove box of FIG. 7 along the axis D-D. The dispensing system showing the handlebar assembly is shown in various positions.

FIG. 9 is a perspective view of the capsule tray holding a capsule bottom and the L-tool holding the capsule top prior to completion of the capsule.

FIG. 10 is an enlarged section view of the bottom of a stationary pig with an open glass vial covered by the filter cup. The dispensing component (pipette) is inserted through the opening in the filtration cup and into the glass vial to withdraw and aliquot of the radiopharmaceutical. The flow arrows indicate the flow of air through the primary filtration system. Vapors from the radiopharmaceutical are also indicated by the flow arrows.

FIG. 11 is a section view of a filtration syringe.

FIG. 12 is an enlarged elevation view of capsules.

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1 is a section view of a lead pig generally identified by the numeral 20. The pig 20 is also sometimes referred to as a safe. Inside the pig 20 is a vial 22 which is typically manufactured from glass. The vial 22 has a hollow section 24 which holds a radiopharmaceutical 26. Between the septum 28 and the radiopharmaceutical 26 is an open area 30 typically referred to as headspace. The air in the headspace 30 may contain radioactive vapors from the radiopharmaceutical 26.

FIG. 2 is an exploded section view of the pig 20 of FIG. 1. The pig 20 has a lid 32 which screws on the threads 34 of the bottom section 36. Also shown in exploded view are the components of the vial 22 including the metal band 38 which surrounds and captures the septum 28 on the rim 40 of vial 22. The metal band 38 and the septum 28 are conventional components well known to those skilled in the art. The vial 22 in FIG. 2 is open.

FIG. 3 is a perspective view of the glove box 42 which contains the radiopharmaceutical capsule dispensing system 68 (better seen in FIG. 5). The glove box 42 sits on a table 14. The glove box 42 has an inside 44 and an outside 46 where an operator stands. A window 48 positioned in a wall 47 of the glove box 42 allows the operator, not shown, to view the inside 44 of the glove box 42. The window 48 is typically formed from leaded glass.

The glove box 42 has an air inlet 50 which contains a HEPA inlet filter 52. An outlet duct 54 is positioned on the vestibule 58. Ambient air flows through the inlet 50 as indicated by the flow arrow, through the inlet filter 52, through the inside 44 of the glove box 42 through the vestibule 56 and exits through the outlet duct 54 as indicated by the flow arrows. The air and vapors, if any, that exit the outlet duct 54 are captured in a glove box filter assembly generally identified by the numeral 55, better seen in FIG. 4.

The vestibule 56 has an access door 58 that allows the operator access to the inside of the vestibule 56. The operator, not shown, places the pig 20 with the radiopharmaceutical 26 in the vestibule 56 before it is transferred to the inside 44 of the glove box 42.

The glove box 42 also has an equipment door 60 that allows the operator, not shown, access to the inside 44 of the glove box to insert and remove equipment from the inside 44 as necessary. The glove box 42 also has a left glove port 62 and a right glove port 64 to receive the hands and a portion of the arms of the operator, not shown. As well known to those skilled in the industry, the glove ports, 62 and 64, are equipped with elastomeric gloves to isolate the hands and arms of the operator while they perform tasks on the inside 44 of the glove box 42. The gloves can be straight or accordion. The glove box 42 has an inner lining 45 of lead, better seen in FIG. 6 to shield the operator from radiation. However, the elastomeric gloves typically do not contain any lead shielding material.

Mounted on the outside of the glove box 42 is a control pad/key pad 66 which is one of the components in the electronic dispensing system generally identified by the numeral 68. A conductor 70 connects the control pad 66 with the dispensing grip 71 which is also one of the components of the electronic dispensing system 68.

A dose calibrator 72 fits through a hole 74 in the floor 75 of the glove box 42. The table 14 also has a hole 15 sized and aligned with the hole 74 to accommodate the dose calibrator 72. A shelf 76 is secured by rods 78 and 80 which are mounted in the table 14. The dose calibrator 72 sits on the shelf 76 and is thus supported by the rods 78 and 80. The dose calibrator 72 has a dose calibrator chamber well 82 which is accessible from the inside 44 of the glove box 42.

There are a number of equivalent ways to position the dose calibrator 72 so that the dose calibrator chamber well 82 is accessible from the inside 44 of the glove box 42. One equivalent way is to modify the design of the glove box 42 so that it has a trough that would support the base of the dose calibrator 72 and still allow access to the dose calibrator chamber well 82 from inside 44 the glove box 42.

On the outside 46 of the glove box 42 is an up pedal 84 and a down pedal 86 which are components of the electronic dispensing system 68. The pedals 84 and 86 are connected to the keypad by a conductor 87. The operation of the pedals 84 and 86 will be discussed below. On the top of the glove box 42 is the dose calibrator display assembly 88 which has an LCD/LED 89 which displays the radioactivity of materials placed inside the dose calibrator chamber well 82. Conductors, not shown connect the dose calibrator display assembly 88 with the dose calibrator 72. The table 14 is supported by a plurality of legs, 90, 92, 94 and 96.

FIG. 4 is a diagrammatic view of the ventilation system for a typical radiopharmacy. In this radiopharmacy is at least one glove box 42, a first waste bin 100 and a second waste bin 102. In addition, there is a product room 104 where bulk radiopharmaceutical materials are stored as well as generators for such radiopharmaceutical material. An exhaust fan 106 applies negative pressure (suction) to the ductwork shown in FIG. 4. Ambient air is drawn into the inlet 50 of the glove box 42 and exits the outlet duct 54 as shown by the flow arrows. This exhaust air and any radioactive vapors pass through the glove box filtration system 55, the duct work 108 and 110 into the exhaust duct 112 which is vented to atmosphere.

The glove box filter system generally identified by the numeral 55 includes a prefilter 114, a HEPA filter 116, a first carbon bed filter 118, and a second carbon bed filter 120. Other filter configurations as within the scope of this invention provided they provide adequate protection to occupational workers and the environment. As known to those skilled in the art, the carbon bed filter 118 has a small replaceable cartridge 119 that is removed on a weekly basis and tested for radioactivity. The activity is entered in a log which is kept to maintain safety of workers and the environment. A new cartridge 119 is placed in the filter 118 every week to determine incremental weekly contamination, if any.

The exhaust fan 106 maintains negative pressure on waste bin 100 and 102 so that air is exhausted from the waste bins through the duct 122. Duct 122 feeds into the glove box filter system 55 and out the duct work 108, 110 and 112 to atmosphere.

Negative pressure is held on the product room 104 as a result of the exhaust fan 106. Air that is removed from the product room 104 moves through the duct 124, the duct 110 and the duct 112 to atmosphere.

Referring to FIGS. 5 and 6, the operator gains access to the inside 44 of the glove box 42 through arm ports 62 and 64. The operator observes the inside 44 of the glove box 42 through the window 48. Other means to view the inside 44 of the glove box 42 include a video camera 12 mounted on the inside 44 which connects to a monitor 11 located on the outside 46 which can be viewed by the operator. A rectangular lead cave 150 is positioned on the inside 44 of the glove box 42. The cave 150 is formed from a plurality of lead bricks, not shown. A stainless steel pan 152 surrounds the lead cave 150. A removable capsule tray 154 having feet 156 and 158 is positioned in the shielded area 160 defined by the walls 161, 17, 165 and 167 of the rectangular cave 150.

The bottom section 36 of the pig 20 is positioned inside the shielded area 160 of the cave 150. The lid 32 has been removed from the pig 20. A filter cup 162 is positioned over the bottom section 36 of the open pig 20. The filter cup 162 is designed to contain volatile vapors escaping from the radiopharmaceutical 26 in the vial 22. The cup 162 defines an opening 159 which is sized and arranged to receive a removable top 164 when the capsule dispensing system 68 is not in use.

The filter cup 162 is connected to a conduit 168 which is in fluid communication with a first charcoal cartridge filter 170 and a second charcoal cartridge filter 172. Another conduit 173 connects the charcoal cartridge filters with a vacuum pump 174. The vacuum pump 174 has a first gauge 176 which displays the amount of suction that is being pulled through cartridge filters 170, 172 and conduits 168 and 173. Ultimately, this suction is applied to the inside 166 of the cup 162 to remove volatile radioactive vapors, if any, that may escape from the radiopharmaceutical 26 in the open vial 22. A typical suction will be approximately 18 inches of mercury with two charcoal cartridge filters. An exhaust conduit, not shown, leads from the vacuum pump 174 into the vestibule 56. A second gauge 178 is positioned on the vacuum pump 174 to display the pressure on the compressed air exiting from the vacuum pump 174. The filter cup 162, the top 164, the vacuum pump 174, the charcoal cartridge filters 170 and 172 and the conduits 168 and 173 are collectively referred to for claim interpretation purposes as the primary filter system 13.

A handlebar assembly 202 is secured to the dispensing grip 71 of the electronic dispensing system 68. The handlebar assembly 202 includes a left handle 204 and a right handle 206 which are respectively gripped by the left and right hands of the operator through left hand port 62 and right hand port 64. When the electronic dispensing system 68 is not in use, the handlebar assembly 202 rests on a stand 208. The stand 208 is mounted on a wall 17 of the cave 150. As will be recognized by those skilled in the art, the stand 208 could assume many different forms which are equivalent to the stand 208 shown in these figures. For example, a pair of J-hooks could be mounted to the rear wall 209 of the inside 44 of the glove box 42 or the inside top 211 to hold the electronic dispensing system 68 when it is not in use. Any stand, hook or other resting device positioned on the inside 44 of the glove box 42 is equivalent to the stand 208.

The electronic dispensing system 68 includes the dispensing grip 71, the dispensing component 200 (also referred to as a pipette adapter or dispensing tip) the key pad 66, the up and down pedals 84 and 86 and associated conductors 70 and 87. Applicants have determined that the electronic dispensing system model EDOS522 produced by Eppendorf AG of Hamburg, Germany is suitable for this purpose. The Eppendorf electronic dispensing system has sufficient accuracy for the present use and is proven to be a reliable off-the-shelf component. However, other electronic dispensing systems from other manufacturers that are sufficiently accurate may also function in the present dispensing system 43. An Instruction Manual, incorporated herein by reference, for the Eppendorf EDOS522 electronic dispensing system is included in the Information Disclosure Statement filed concurrently herewith.

The dose calibrator 72 sits on the shelf 76 and protrudes through a hole 74 in the floor 75. Applicants have found that the model CRC-12, model CRC-127R and the model 15R dose calibrators from Capintec, Inc. of Ramsey, N.J. are suitable for this application although other brands and models may also be used in this invention, provided they can accurately measure the activity of the radiopharmaceutical being dispensed. One dose calibrator used by applicants is about 16 inches high and the dose calibrator chamber well 82 is about ten inches deep. The dose calibrator chamber well 82 needs to be accessible from the inside 44 of the glove box 42. The Eppendorf Dispensing System 200 comes with a dispensing component in two different sizes.

Referring now to FIGS. 7 and 8, the operator's left hand 220 and a portion of the left arm are inserted into the left glove port 62. The operator's right hand 222 and a portion of the right arm are inserted through the right glove port 64. The operator's left hand 220 grips the left handle 204 of the handlebar assembly 202. The operator's right hand 222 grips the right handle 206 of the handlebar assembly 202. The operator can move the handlebar assembly 202 and the electronic dispensing system generally identified by the numeral 68 to several different positions identified by the letters A, B and C.

In position A, the dispensing tip 200 is inserted through the opening 159 in the cup 162 and into the open vial 22 containing the radiopharmaceutical 26. The operational sequence of the electronic dispensing system 68 will be described in greater detail below; however, the operator manipulates the up pedal 84 to transfer an aliquot 85 or an a calculated volume 87 of the radiopharmaceutical 26 into the dispensing component 200 while the handlebar assembly 202 is held in position A.

In position B, the dispensing component 200 of the electronic dispensing system 68 is positioned inside the dose calibrator chamber well 82 allowing the dose calibrator 72 to measure the activity of the aliquot 85 or the calculated volume 87 of the radiopharmaceutical in the dispensing component 200. The amount of activity of the radiopharmaceutical is displayed to the operator through the LCD/LED 89 resting on the top of the glove box 42.

In position C, the dispensing component 200 is positioned directly over the capsule bottom 224 in the capsule tray 154. The operator presses the down pedal 86 dispensing the aliquot 85 or the calculated volume 87 of the radiopharmaceutical into the capsule bottom 224. The operator then places the handlebar assembly 202 back on the rest 208 as shown in FIGS. 5 and 6. In the best mode, the operator's hands and a portion of the arms are placed in the glove ports 62 and 64 to move the handlebar assembly 202. It would be equivalent to use remote operated mechanical arms to further distance the operator from the radiopharmaceutical. The remote operated mechanical arms allow the operator to keep his/her arms completely outside the glove box.

As shown in FIG. 7, the dispensing grip 71 as the dispensing component 200 of the electronic dispensing system 68 and the handlebar assembly 202 are moved along the line D-D which forms an axis directly in front of the operator. This movement along the axis D-D is for the convenience of the operator, not shown. The axis D-D aligns the dose calibrator chamber well 82, the opening 159 in the filter cup 162 and the capsule tray 154. However, other movements on a different axis on the inside 44 of the glove box 42 are also within the scope of this invention, provided that prescriptions can be accurately dispensed. Also, the level of the top 169 of the dose calibrator 72, the opening 159 in the filter cup 162 and the top of the capsule tray 154 are generally located in a common plane, although the capsule tray is slightly lower than the other components. Again the location of these components and their relative height one to the other is for the convenience of the operator. Other arrangements and levels are within the scope of this invention, provided that prescriptions can be accurately dispensed.

The bottom capsule 224 is filled with a suitable excipient and may include a buffer, an antioxidant and a sealer. When the radiopharmaceutical contacts the excipient, an exothermic reaction occurs and care must be taken not to melt the capsule causing a spill of the radiopharmaceutical. One of the purposes of the stainless steel liner 152 is to contain any spills that might occur and to facilitate clean up. After the aliquot 85 or the calculated volume 87 of radiopharmaceutical has been dispensed into capsule bottom 224, it is then time to close the capsule.

Applicants have found that granular anhydrous dibasic sodium phosphate is a suitable excipient 225. Bulk sodium phosphate is passed through a number 30 sieve (0.6 mm) and a number 50 sieve (0.6 mm). The granular sodium phosphate that passes through the number 30 sieve and is retained on the number 50 sieve has been found by Applicants to be useful in the present invention to reduce the likelihood that the capsule bottom will melt during dispensing of the radiopharmaceutical; however, other excipients with different sizes may also be suitable, provided the capsule does not melt during the dispensing process. The capsule bottom 224 is filled four-fifths full with excipient 225.

FIG. 9 is an enlarged perspective view of the Plexiglas capsule tray 154 and the capsule bottom 224. The excipient 225 is placed in the capsule bottom 224 and receives the aliquot 85 or the calculated volume 87 of radiopharmaceutical. The capsule top 226 is held by an L-tool 228 and the capsule top 226 is then placed on the capsule bottom 224 as shown by the arrow in FIG. 9 to form a completed capsule.

The L-tool 228 has a flexible piece of tubing 230 positioned on the end which is sized and arranged to easily fit over the capsule top 226. After the capsule top 226 has been placed on the capsule bottom 224, the completed capsule can be removed from the capsule tray 154 by the L-tool 228 and placed in an empty transportation pig, not shown, located on the inside 44 of the glove box 42.

For purposes of claim interpretation, two tools could be used in this process in lieu of the single L-tool 228. For example, a straw or piece of tubing could be used to put the capsule top 226 on the capsule bottom 224. A second tool, such as a pair of tweezers could then be used to transfer the completed capsule to the transportation pig.

The transportation pig is similar to the lead pig 20 of FIG. 1 and FIG. 2 except the inside has been reconfigured to receive the completed capsule. After the completed capsule has been placed inside the transportation pig, the lid is screwed on for safety purposes. The operator then moves the transportation pig, not shown, from the inside 44 of the glove box to the vestibule 56 and closes the interior door, not shown. The operator then removes his/her hands from the glove port 62 and 64 and opens the door 58 to remove the transportation pig and completed capsule from the vestibule. The transportation pig and the completed capsule with an individual dose of a radiopharmaceutical are then shipped to a hospital for dispensing to a patient for diagnostic and/or therapeutic purposes.

There are a plurality of shallow depressions 232, 234 and 236 in the capsule tray 154; however, only one prescription is filled at a time. A piece of double-faced adhesive tape 238 can be positioned on one side of the capsule tray 154 and the capsule top 226 can be positioned open side down on the adhesive tape 238. In the alternative, the capsule top 226 can be positioned open side down in these depressions. In the alternative, the capsule top 226 can simply be manually inserted into the L-tool 228 prior to dispensing the radiopharmaceutical.

Other depressions 240, 242 and 244 can be formed in the capsule tray 154 using various sizes to accommodate various size capsules discussed below. The removable capsule tray can be formed in a variety of different sizes and shapes as a matter of manufacturing convenience.

FIG. 10 is an enlarged section view of the bottom section 36 of the pig 20 containing an open vial 22 with a radiopharmaceutical 26. The filter cup 162 is positioned over the threads 34 so that the bottom 246 of the cup 162 rests against the inside 248 of the bottom section 36 of pig 20.

The filter cup 162 has a plurality of vent ports 250 to allow air from the inside 44 of the glove box 42 to enter the inside 166 of the cup 162 as indicated by the flow arrows. Air from the inside 44 of the glove box 42 also enters through the opening 159 of the cup 162 and is exhausted through the conduit 168 as indicated by the flow arrows. For purposes of claim interpretation a primary filter system 13 includes the cup 162, the removable top 164, the conduit 168, the charcoal filter cartridges 170 and 172, the conduit 173 and the vacuum 174. Together these components capture radioactive vapors as indicated by the arrows 254 that may be escaping from the open vial 22 that contains radiopharmaceutical 26.

The exact size and dimensions of the filter cup 162 may vary, but the primary filter system 13 should capture approximately 300-3,000 microcuries in the filter cartridges 170 and 172 per week in an active radiopharmacy. The filter cartridges 170 and 172 should be replaced weekly. This avoids premature contamination of the glove box filter system 55. The applicants have found that a filter cup 162 with a height of approximately 2.5 inches and an outside diameter of approximately 2.5 inches is suitable for this purpose. Approximately eight vent holes 250 having a diameter of approximately ⅛ inch are also suitable. The conduit 168 has a nominal diameter of ⅜ inch and the vacuum pump pulls a suction of approximately 18 inches of mercury with two charcoal filters. Other specific dimensions may prove successful, but applicant has found this configuration to be suitable.

FIG. 11 is a section view of a filter syringe generally identified by the numeral 260. A 10 mL syringe is suitable for this purpose. The syringe 260 is approximately four inches long. The syringe 260 has a conventional lure lock 262 to receive a needle 264. The syringe has a conventional plunger assembly 266 that moves to and fro in the barrel 268. The filter syringe 260 comes precharged with a wad of cotton 270, granulated charcoal 272, and another wad of cotton 274. The purpose of the filter syringe 260 is to evacuate the headspace 30 from the vial 22 prior to removal of the metal band 38 and the septum 28. After the headspace 30 has been evacuated by the filter syringe 260, it is disposed. The filter syringe 260 is a single use apparatus that is only used once per vial.

FIG. 12 is an enlarged diagrammatic view of capsules 276 size 5 through 000. On the right-hand side is an enlarged scale in inches and on the left-hand side is an enlarged scale in centimeters. FIG. 12 is an enlargement of the actual size of the capsules. In the preferred embodiment, applicants have determined that the capsule 278 (size 3) is best suited for the present invention. However, depending on prescription requirements and other factors, other size capsules may be used. As previously described, the capsule tray 154 may contain depressions 240, 242 and 244 of varying sizes so that different capsules can be accommodated.

Operational Sequence

Various radiopharmaceuticals may be dispensed with the present capsule dispensing system 68; however, it is particularly useful with volatile radiopharmaceuticals at a high concentration, i.e. in excess of 1,000 millicuries per milliliter such as I-131 radioiodine. For purposes of the following example, I-131 will be used, although the invention is not limited to this single radiopharmaceutical. I-131 stock solution is produced by MDS Nordion of Ottawa, Ontario, Canada and is packaged in 1 mL glass vials by the Mallinckrodt Maryland Heights facility in St. Louis, Mo. The vials are sealed in a conventional fashion with a rubber septum 28 and metal band 38 around the rim 40. A single vial 22 could be placed in a lead pig 20 for shipment to one of the 39 Mallinckrodt radiopharmacies, independent radiopharmacies or hospitals that use the present invention. The glass vial 22 contains approx. 0.15 to 0.8 mL of I-131 radioiodine and approx. 0.2 to 0.85 mL of vent headspace 30. Concentrations of I-131 used in prior art hand held dispensing systems currently are limited to approx. 25 millicuries per milliliter, but using the present invention, higher concentrations in the range of 1,200-1,300 millicuries per milliliter could be used. I-131 is a highly volatile radiopharmaceutical.

Upon receipt at the radiopharmacy, the lead pig 20 with the glass vial 22 of I-131, is placed in a glove box 42. (The pig 20 is placed in the vestibule 56 and is then transferred into the inside 44 of the glove box 42 where the present invention is located.) The electronic dispensing system 68 is operated by a keypad 66 that is mounted on the outside of the glove box and two foot pedals 84 and 86. The dose calibrator 72 has an LCD/LED 89 that is also mounted on the outside of the glove box 84 and 86. For the convenience of the operator, a calculator 63 is mounted on the outside of the glove box 42 to facilitate dose calculations.

The Eppendorf dispensing component 200 has two different sizes of pipettes adapters, i.e., 0.5-10 microliters and 10-100 microliters. The operator selects the size that is appropriate for each individual prescription. Because the dispensing component 200 is purged after each dispensing cycle, it can be reused.

The glove box 42 is under negative pressure and air from the glove box 42 passes through a filter system 55. The system 55 includes a prefilter 114 and a HEPA 116 filter in series (the prefilter costs approx. $4.00 and the HEPA filter costs approx. $70-140). The second and third filters 118 and 120 hold reusable carbon filter cells that cost approx. $1,000 each new. In total, the filters cost approx. $2,000 new. Recharging each carbon filter cell costs about $140 to $230. Replacement takes about 30 minutes and is typically done at intervals greater than one year.

Decrimping

The bottom section 36 of the lead pig 20 with the glass vial 22 of I-131 is placed in a lead cave in the glove box 42 and the top 32 is unscrewed. The needle 264 on a filter syringe 260 is inserted through the rubber septum 28 into the vent headspace 30 which is evacuated with the filter syringe 260. The headspace 30 of the vial 22 is now under negative pressure. The filter syringe 260 is single use and is then placed in the “hot waste,” not shown, container in the glove box. The filter syringe is packed with cotton, charcoal and cotton. The purpose of this filtration step is to remove any volatile radioiodine vapors from the headspace 30 of the vial to prevent premature contamination of the glove box filters system 55 or the primary filter system 13. The needle presents a risk of stick to the operator and caution must be exercised.

A decrimp tool is used to remove the metal band from the glass vial. The decrimp tool is approximately 12 inches long; however tools of other lengths may also be suitable. The metal band 38 is likewise placed in the “hot waste” container in the glove box.

A filter cup 162 is placed over the bottom section 36 of the pig 20 and the glass vial 22 which is still sealed with a rubber septum 28. The filter cup 162 has a central opening 163 that allows access to the vial. This central opening 159 is closed with a removable top 164. Negative pressure is drawn on the inside 161 of the filter cup 162 by a vacuum pump 174. The top 164 is removed. The vial's rubber septum 28 is removed with a hemostat, not shown. The rubber septum 28 is placed to the side of the vial during the dispensing procedure. Afterward, the septum is returned to the vial 22 with the hemostat. Applicants recommend use of a hemostat that is approximately 4 inches long; however, hemostats of other lengths may also be suitable. The stream of air and vapors that is collected by the filter cup 162 passes through two disposable in-line charcoal filter cartridges 170 and 172 that cost about $0.10 each. These charcoal filters should be replaced weekly. Again the purpose of the primary filter system 13 is to remove any volatile radioiodine vapors 254 from the inside 44 of the glove box 42 and thus prevent premature contamination of the glove box filters system 55.

Calibration

The Eppendorf electronic dispensing system 68 has a series of three indicator lights. The green light indicates that it is ready to draw an aliquot 85 of fluid. The amber light indicates that it is ready to dispense an aliquot 85 of fluid. The red light is an error message. At the start of the week, an known volume of I-131 is withdrawn from the vial 22 of stock solution and placed in the dose calibrator 72 to determine its radioactive concentration which is displayed to the operator on the LCD/LED 89 located on the outside of the glove box 42. A correction factor may be applied to the LCD/LED displayed radioactivity for minor variations in the liquid volume (i.e., the volume configuration in a dispensing component 200 versus the capsule).

The method for dispensing radiopharmaceuticals in capsules is as follows:

The operator grasps the handles 204 and 206 of handlebar assembly 202 and takes the assembly 202 off the rest 208. The electronic dispensing system 68 which is attached to the handlebar assembly 204 is moved over the vial 22 and the dispensing component 200 is lowered into the stock solution of I-131 in the glass vial 22. The indictor light is green and the operator depresses the up pedal 84. An aliquot 85 of I-131 is drawn into the pipette and the indicator light turns amber. The handlebar assembly 202 is moved up and back in a straight line to the dose calibrator 72. The handlebar assembly 204 is lowered and the pipette dispensing component 200 is placed in the dose calibrator chamber well 82. The activity is displayed on the LCD/LED 89 and is manually noted by the operator. Thereafter the operator can decay correct the dose for radioactivity. This aliquot 85 is then returned to the vial 22 of stock solution of I-131. The operator presses the down pedal 86 once to expel the I-131 back into the vial 22 of stock solution and then presses the down pedal 86 a second time to purge the dispensing component 200. The indicator light turns green when the down pedal 86 is depressed the second time.

I-131 has an 8-day half-life. In 4 weeks there is not much radioactivity left (approx. 94% has decayed). In 90 days it is considered that all the radioactivity has decayed. The operator can decay correct for the rest of the week after the activity has been checked at the start of the week. I-131 is kept at the radiopharmacy for approx. 14 days beyond its calibration date and then it is no longer useful for dispensing purposes.

Dispensing

The radiopharmacy receives an order from a hospital for an individual unit dose of I-131. Doses typically range from 12-30 mCi. Although the dose could range from as little as 1 mCi to 200 mCi. The purpose of the present invention is to enable the radiopharmacy to prepare an individual unit dose for one patient at a specific time. An active radiopharmacy may prepare from 10-15 doses per day and a slow radiopharmacy may prepare 1 dose per day or less.

The excipient is granulated dibasic sodium phosphate. The present invention preferably uses relatively small capsules (size 3). However, other capsule sizes can be used, if necessary. Other sizes can range from a size 4 (smaller than 3) to larger capsule sizes (size 2 and 1).

The operator calculates the volume of I-131 that is necessary to provide the activity called for in the prescription and decay corrects based on the calibration data determined at the beginning of the week.

The operator grasps the handlebar assembly 202 that is sitting on the rest 208 and moves the dispensing component 200 over the open vial 22. The dispensing component 200 is lowered into the vial 22 of stock solution. The indicator light is green. He/she enters the desired volume on the keypad 66 and depresses the up pedal 84. The calculated volume 87 is drawn into the dispensing component 200. The indicator light turns amber.

The operator moves the handlebar assembly 202 upward, and removes the dispensing component 200 from the vial 22. The handlebar assembly 202 is then moved toward the dose calibrator 72. The dispensing component 200 is lowered into the dose calibrator chamber well 82 and the operator confirms the activity on the LCD/LED 89 to insure that it complies with the prescription. A correction factor may be applied to the LCD/LED 89 displayed radioactivity for minor variations in the liquid volume geometry.

If the level of activity is correct, the operator moves the handlebar assembly 202 upward and removes the dispensing component 200 from the dose calibrator chamber well 82. The handlebar assembly 202 is then moved over the capsule tray 154 and dispensing component 200 is lowered to a position immediately over the capsule bottom 224. The operator presses the down pedal 86 to expel the I-131 onto the excipient 225 and then presses the pedal down 86 a second time to purge the dispensing component 200. The light then changes to green.

The operator then places the handlebar assembly 202 back on the rest 208. The total length of linear travel from the dose calibrator 72 to the capsule tray 154 is approximately 12 inches.

The L-tool 228 has the capsule top 226 positioned in the terminal section 230. The capsule top 226 is slipped over the capsule bottom 224 in the tray 154. The completed capsule is then removed from the tray 154 by the L-tool 228 and placed into a shipment pig. The shipment pig is transferred to the vestibule 56 from the inside 44 of the glove box 42. The pig is removed from the vestibule 56 with the capsule in place, packaged, and is delivered to the hospital for oral administration to the patient. This system allows same day delivery of I-131 doses.

The filter cup 162 has a removable top 164 that is kept in place, except when access is needed to the vial 22. The primary filter system 13 captures volatile radioiodine vapors 254 and keeps them out of the glove box filter system 55.

Prior art manual dispensing systems produce extremity exposure because the operator's hands are approx. 2-3 inches from the source of radiation. When the operator's hands are on the handlebar assembly 202 of the present invention, they are about 9-10 inches away from the unshielded source. When the operator's hands are on the L-tool 228, they are about 9 inches from the vial 22. During the decrimping step, the hands are about 5 inches from the vial. During the septum removal process the hands are about 5 inches from the vial 22. For short periods of time, during decrimping and septum removal, the operator's hands are directly above the vial 22.

Prior art manual dispensing of radiopharmaceuticals into capsules takes more time than the present, semi-automated process. The present invention provides speed and accuracy of dispensing the correct volume and thereby reducing the time for preparing a completed capsule and reducing extremity exposures to the operator.

The Nuclear Regulatory Commission (NRC) has established an annual limit of 50 uCi for a radioiodine uptake for occupational workers. The NRC has also established an annual limit of radiation exposure to the extremities of an occupational worker of 50,000 mrem. The present invention should reduce radiation exposure to the extremities of an occupational worker that regularly works with radioiodine by approx. 80% or more compared with the prior art hand dispensing system.

Radiopharmaceutical capsule dispensing system

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