CA2176562A1 - Apparatus and method for the preparation of a radiopharmaceutical formulation - Google Patents
Apparatus and method for the preparation of a radiopharmaceutical formulationInfo
- Publication number
- CA2176562A1 CA2176562A1 CA002176562A CA2176562A CA2176562A1 CA 2176562 A1 CA2176562 A1 CA 2176562A1 CA 002176562 A CA002176562 A CA 002176562A CA 2176562 A CA2176562 A CA 2176562A CA 2176562 A1 CA2176562 A1 CA 2176562A1
- Authority
- CA
- Canada
- Prior art keywords
- vial
- vial holder
- radiation
- container
- holder
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- G—PHYSICS
- G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
- G21F—PROTECTION AGAINST X-RADIATION, GAMMA RADIATION, CORPUSCULAR RADIATION OR PARTICLE BOMBARDMENT; TREATING RADIOACTIVELY CONTAMINATED MATERIAL; DECONTAMINATION ARRANGEMENTS THEREFOR
- G21F5/00—Transportable or portable shielded containers
- G21F5/015—Transportable or portable shielded containers for storing radioactive sources, e.g. source carriers for irradiation units; Radioisotope containers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
Abstract
Apparatus and method for producing a radiopharmaceutical formulation utilize a radiation-shielding container (10) for receiving a vial having the non-radioactive components necessary to form a radiopharmaceutical formulation therein. A mixture of such non-radioactive components and a radioactive liquid added thereto is both heated and cooled using a thermoelectric element (94). The container (10) comprises a hollow outer shielding member (12) formed from a radiation shielding material and a vial holder (54) formed from a highly head conductive material received therewithin. The vial holder (54) includes a skirt portion (60) that defines a socket (76). The socket (76) is sized to receive in an intimate heat transmissive relationship a mounting projection (88) that is itself connected in thermally conductive contact with the thermoelectric element (94).
Using the thermoelectric heating and cooling element (94), heat is both applied to and removed from the radioactive liquid and the non-radioactive components within the vial while the vial is held within the vial holder (54) within the radiation shielding container (12), thereby to produce a radiopharmaceutical formulation within the vial.
Using the thermoelectric heating and cooling element (94), heat is both applied to and removed from the radioactive liquid and the non-radioactive components within the vial while the vial is held within the vial holder (54) within the radiation shielding container (12), thereby to produce a radiopharmaceutical formulation within the vial.
Description
WO 95116996 2 1 7 6 ~ 6 2 PCTfUS94fl3913 Apparatus and Method For The p~raliOn Of A l; 'io, ~ Formulation BACKGROUND OF THF INV_NTION
Field of the Invention The present invention relates to apparatus and a method for the rapid prt:,udl dtiOI, of a 15 ,d~iopl~d""ac~:utical formulation.
Des~ iOIl of the Prior Art Technetium Tc99m-Sestamibi is a technetium-labeled ,~.liopl~d""aceutical that is manufactured by 20 DuPont-MerckPl,a""aceuticalCompany Billerica Massachusetts and sold under the trademark Cardiolite~). Technetium Tc99m-Sestamibi finds primary utility as a myocardial imaging agent.
A formulation of the technetium-labeled, ~diopl Idl " .aceutical 25 imaging agent is prepared for use by injecting a volume (on the order of d~-p(uhi~ t~ly one to three milliliters) of a non-pyrogenic sodium pertechnetate Tc99m solution derived from a gel,~,dlur into a vial cor,Ldi"i"g a Iyophilized form of other non-radioactive i"yl~iLn~
[particularly a~,upri~l~ amounts of (2-methoxy isobutyl isonitrile) 30 coppertetraflu~"ubo,dl~ sodiumcitratedihydrate cysteine hy~u~ loride monohydrate mannitol and stannous chloride dihydrate]. The vial is itself placed in a suitable radiation shield typically a cylindrical can-like member with a fitted cap. Label instructions require that after injection the vial cor, , ~9 the mixture 35 of the sodium pert~ul ,ne:ldl~ and the Iyophilized non-radioactive i"g,~ , be removed from the radiation shield and heated in a boiling water bath for at least ten minutes. After heating in the boiling bath the vial is returned to the shield for a cool-down period of a~p,ohi",d~ly fifteen minutes. A Id.l;o, l,er"iGal purity analysis is 40 pe, rur" ,ed to insure that the, ddio~l Idl " ~aceutical formulation so prepared exhibits the desired labeling efficiency prior to use.
_ .. .. .. . _ _ . .. .
WO 95116996 2 L ~ ~ ~ 6 2 PCTIUS94/1391~
These timing r~atli ~s on the pl~JdldliOn of Technetium Tc99m-Sestamibi ,ddiop~,a""aceutical formulation may, in instances such as e",~,y~cy cases, limit its ~v.~ y. In order to reduce the pl~pdldliUn time and, consequently, enhance the ~v.. ' ~ of 10 Technetium Tc99m-Sestamibi imaging formulation, several alternative methods of its pll:,ualdSiOI~ have been proposed.
One method, dis~llcsed in the article by Tallifer, Gagnon, Lambert and Leville, "Labeling procedure and in-vitro stability of Tc-15 99m methoxy isobutyl isonitrile (MIBI): practical col,si~erdtiù"a, apped,i"y at J Nucl Med 1989; 30; 86~ (abs), de""~ that bath times as low as one (1 ) minute may be sufficient to provide a Technetium Tc99m-Sestamibi solution having an ~c~ labeling efficiency and a Iddioul~ dl purity in excess of ninety percent.
20 However, this method still requires a siy, ' ,l amount of time (on the order of ten to twenty-five minutes) be expended to heat to boil the water used for the i,l,, ,,~, aion bath. Thus, the time gain obtained from the reduction in the actual i"""e,aion time is lost because time is still required to heat the water for the i" ""~, ~iui1 bath.
Field of the Invention The present invention relates to apparatus and a method for the rapid prt:,udl dtiOI, of a 15 ,d~iopl~d""ac~:utical formulation.
Des~ iOIl of the Prior Art Technetium Tc99m-Sestamibi is a technetium-labeled ,~.liopl~d""aceutical that is manufactured by 20 DuPont-MerckPl,a""aceuticalCompany Billerica Massachusetts and sold under the trademark Cardiolite~). Technetium Tc99m-Sestamibi finds primary utility as a myocardial imaging agent.
A formulation of the technetium-labeled, ~diopl Idl " .aceutical 25 imaging agent is prepared for use by injecting a volume (on the order of d~-p(uhi~ t~ly one to three milliliters) of a non-pyrogenic sodium pertechnetate Tc99m solution derived from a gel,~,dlur into a vial cor,Ldi"i"g a Iyophilized form of other non-radioactive i"yl~iLn~
[particularly a~,upri~l~ amounts of (2-methoxy isobutyl isonitrile) 30 coppertetraflu~"ubo,dl~ sodiumcitratedihydrate cysteine hy~u~ loride monohydrate mannitol and stannous chloride dihydrate]. The vial is itself placed in a suitable radiation shield typically a cylindrical can-like member with a fitted cap. Label instructions require that after injection the vial cor, , ~9 the mixture 35 of the sodium pert~ul ,ne:ldl~ and the Iyophilized non-radioactive i"g,~ , be removed from the radiation shield and heated in a boiling water bath for at least ten minutes. After heating in the boiling bath the vial is returned to the shield for a cool-down period of a~p,ohi",d~ly fifteen minutes. A Id.l;o, l,er"iGal purity analysis is 40 pe, rur" ,ed to insure that the, ddio~l Idl " ~aceutical formulation so prepared exhibits the desired labeling efficiency prior to use.
_ .. .. .. . _ _ . .. .
WO 95116996 2 L ~ ~ ~ 6 2 PCTIUS94/1391~
These timing r~atli ~s on the pl~JdldliOn of Technetium Tc99m-Sestamibi ,ddiop~,a""aceutical formulation may, in instances such as e",~,y~cy cases, limit its ~v.~ y. In order to reduce the pl~pdldliUn time and, consequently, enhance the ~v.. ' ~ of 10 Technetium Tc99m-Sestamibi imaging formulation, several alternative methods of its pll:,ualdSiOI~ have been proposed.
One method, dis~llcsed in the article by Tallifer, Gagnon, Lambert and Leville, "Labeling procedure and in-vitro stability of Tc-15 99m methoxy isobutyl isonitrile (MIBI): practical col,si~erdtiù"a, apped,i"y at J Nucl Med 1989; 30; 86~ (abs), de""~ that bath times as low as one (1 ) minute may be sufficient to provide a Technetium Tc99m-Sestamibi solution having an ~c~ labeling efficiency and a Iddioul~ dl purity in excess of ninety percent.
20 However, this method still requires a siy, ' ,l amount of time (on the order of ten to twenty-five minutes) be expended to heat to boil the water used for the i,l,, ,,~, aion bath. Thus, the time gain obtained from the reduction in the actual i"""e,aion time is lost because time is still required to heat the water for the i" ""~, ~iui1 bath.
2~
Other proposed methods of pr~pdldSiui~ of Technetium Tc99m-Sestamibi formulation have focused on the use of altemative heat sources. Several dlt~ t~.lC methods discuss the use of a microwave oven as the source of heat. ~1; u. ..~l~ heating methods 30 are rlicc~ssed in an article by Gagnon, Tallifer, Bavaria and Leville, "Fast labeling of technetium-99m s '; ";~i with ~ "u. _~rc oven heating", J Nucl Med Technol 1991; 19; 90-3, and ir~ an article by Hung, Wilson, Brown and Gibbons, "Rapid pl~:pdldLioll and quality control method for le~ m-99m-2 methoxy isobutyl isonitrile
Other proposed methods of pr~pdldSiui~ of Technetium Tc99m-Sestamibi formulation have focused on the use of altemative heat sources. Several dlt~ t~.lC methods discuss the use of a microwave oven as the source of heat. ~1; u. ..~l~ heating methods 30 are rlicc~ssed in an article by Gagnon, Tallifer, Bavaria and Leville, "Fast labeling of technetium-99m s '; ";~i with ~ "u. _~rc oven heating", J Nucl Med Technol 1991; 19; 90-3, and ir~ an article by Hung, Wilson, Brown and Gibbons, "Rapid pl~:pdldLioll and quality control method for le~ m-99m-2 methoxy isobutyl isonitrile
3~ (technetium-99m sestamibi)", J Nucl Med 1991; 32; 2162-8. Another method, rliscl~ssed in a letter by Wilson, Hung and Gibbons, "Simple procedure for ll,;ulu.~ d technetium-99m sestamibi temperature reduction", J Nucl Med Technol 1992; 20;180, focuses on a technique for the rapid cooling of the heated Technetium Tc99m-40 Sestamibi formulation.
WO 95/16996 ~17 6 ~ 6 ~ PCT/lJS94A3913 Although ".ic,~ .~a~e oven-based heating methods appear to overcome some of the o~t~ s pl ~ t~d in the ~ dl dt;~l~ of Technetium Tc99m-Sestamibi formulation such methods appear also to exhibit serious attendant .I~_..Ja- ka such as vial breakage (as outlined in a letter by Hung and Gibbons "Breakage of 1û technetium-99m sestamibi vial with the use of a Ill;~,lu..'~JC oven" I
Nucl Med 1992; 33; 176-8). Other perceived problems with the ",;~ c oven-based heating technique are set forth in an article by Wilson Hung and Gibbons, "An -" " "IC method for rapid p~epd~ ion of 99TCm_Se~Ld"~ 1, Nucl Med Comm~ 1993; 14; 544-15 9. This !atter article proposes an alteMative heating methodinvolving the use of an instant hot water machine as the source of heated water used for the plt:pdldliUI~ of Technetium Tc99m-Sestamibi formulation.
-o-0-o-Other heating sources for raising the temperature of materials used in COI ,l~euLion with life science reactions are known in the art.
For example an apparatus manufactured by MJ Research Inc 25 Wdlt:(lo ~, l Massachusetts and sold as "The MiniCyclerTM
p,uy,d"""able thermal co"~,." r utilizes a heating/cooling element driven by the Ll ,er",oele~ effect to both heat and cool samples for various b,.,l~H ,l1oloy;~ al reactions. The basic operating principle of a II,t:""oelec~ heating/cooling element is the Peltier Cooling Eflect 30 in which heat is absorbed or gel~erdlt:d as a current passes through a junction of two dissimilar materials. Electrons passing across the junction absorb or give up an amount of energy equal to the transport energy and the energy ~ 'r~,~nce between the di~aill, ' -materials conduction bands.
The materials to be heated or cooled in the p,ug,d"""dLle thermal controller apparatus are typically carried in microl~" dcei ,1, iruge tubes also known as "Eppendorf Tubes" or in other suitable reaction tubes. The ,~luyldlllllldble thermal controller 40 includes a sample block in which a plurality of wells are formed.
Each tube carrying a sample therein is inserted into a well and the WO 95/16996 ~ , - ' PCTIUS94/1391~
21765`fi2 `` ` 4 5 app, up, i.h~ heating andlor cooling program initiated. Each of the wells formed in the sample block cGr,~spor,da in configuration to the exterior configuration of the container inserted therein. Use of the p,uy,d"""aL,le thermal controller in conll n with ,ddioauti~lc reactions appears to be c~" , -o-O-o-ln view of the foregoing it is belieYed advantageous to utilize a Il,er",ocl~l,i. (Peltier-effect) heating/cooling elementto precisely 15 control both heating and cooling of Technetium Tc99m-Sestamibi imaging formulation thereby to make p~ d~ n of an effective dosage of the imaging formulation rapidly available for use in eryt:nCy and other situations.
SUMMARY OF THE INVENTION
The present invention is directed to both apparatus and a method for using a thermoelectric heatinglcooling element both to 25 apply heat to and/or remove heat from a vial having the components necessary to form a I ddio~l~dl " ,aceutical formulation co, ,ed therein .
In a first aspect the invention is directed toward a radiation-30 shielding container for receiving a vial having the cGl"lJonentanecessary to form a rd~iopharlllaceutical formulation therein and in which such c~",por,~"b may be both heated and cooled. The container c~" "-, iae5 a hollow outer shielding member formed from a radiation shielding material such as lead or tungsten and a vial 35 holder received within the outer shielding member. The outer shielding member Su~aldl 'Iy c~"".let~ly surrounds the vial holder.
The vial holder is r~,i. dl~d from a material having a high heat conductivity such as aluminum or copper. The vial holder includes a skirt portion that defines a socket. The socket defined by the skirt is 40 sized to receive a mounting pruJ~. liùl) in a heat lldllalll;~SiV~
~ld~ionsl ,i~-. A shielding plug also formed of a radiation shielding _ _ _ _ _ _ . _ _ _ WO 95/16996 PCrmS94/13913 ~ ~ 7~.~li2`
5 material may be disposed within the socket defined by the skirt portion of the viai holder.
In another aspect the invention is directed to an apparatus in which the c~"",ol~ent~ necessaly to form a Id~ioplldllll~r-ell~
10 formulation cu,, ,ed within the vial are both heated and cooled.
The apparatus c~r"p, iaes the container as set forth above a ~I,er",oel~..t~i~ heating and cooling element and a mounting block c~""e- l~d in thermal conductive contact with the Il l~ vt~i..
heating and cooling element. The mounting block has a mounting 15 p",;~iol~ thereon that is sized for receipt in a heat l,di,s" ;~ c rt:ldli~l~s~, within the socket defined by the skirt portion of the vial holder of the container.
In yet another aspect the present invention is directed to a 20 method for preparing rapidly a ,ddi~pl,d""aceutical formulation within a vial. The method cûl "pl ises the steps of inserting into a vial holder a vial having therein the non-radioactive components necessaly to form a ,ddi~ha""aLeutical formulation. In some instances the non-,ddi~dl ti~c c~"" ol,e,lt~ may be in Iyophilized 25 form. The vial holder is disposed within and Sl.lb~ldl " "y surrounded by a radiation-shielding container. The vial holder is rdbli~.dl~d from a material having a high thermal conductivity and includes a skirt pûrtion that defines a socket. A radioactive liquid is added to the non-radioactive co""-ol1e"l~ in the vial pr~r~,dLly after the vial is 30 inserted into the radiation-shielding container. The vial holder is disposed in a heat lldl~slll;s~iv~ lc:ldliul~s~ J with a mounting p, uj~ liun on a mounting block by mounting the skirt portion onto the pruj~ liù,~ such that the p, ., ~ .~ extends into and is in therrnal contact with the skirt portion of the vial holder. The mounting block is 35 itself in thermal conductive contact with a Ill~llllù~ tliU heating and cooling element. Using the II,e""oelecl,ic heating and cooling element heat is both applied to and removed from the mixture of the radioactive liquid and the (Iyophilized) non-radioactive c~",~ol,e"l~
. within the vial while the vial is held within the vial holder within the 40 radiation shielding container thereby to produce a Iddiopltar",aceutical formulation within the vial.
WO 95116996 PCII~S9411391~
21~ ~62 BRIFF DESCRIPTION OF THE DRAWINGS
The invention will be more fully u"de, :.tuod frorn the following 10 detailed des.;,i~,liol1 taken in acc~,ddl,ce with the acco",pd"ying drawings which form a part of this ~ -n and in which:
Figure 1 is an exploded side elevational view entirely in section of a containerfor preparing a Id~ioplldllllaceutical 5 formulation in acc~,.lance with a first aspect of the present invention;
and Figure 2A is a stylized didyldlllllldli~ ~e,ultls~llldliol1 of an apparatus for both heating and cooling the c~r"~,olle"ts necessary to 20 form a radiopha""aceutical formulation using a the""o~ L,ic heating and cooling element the apparatus including the container of Figure 1 which is shown in Figure 2A in a side elevational view entirely in section in its fully ass~",ble~ condition;
Figure 2B is a plan view of the container shown in Figure 2A;
and Figure 2C is an ~, ll ,oy, dpl liC view of the cap of the container of Figures 2A and 2B taken along section lines 2C-2C in Figure 2B.
DET~Il Fn DESCRIPTION OF THE INVENTION
Throughout the following detailed des~ n similar reference numerals refer to similar elements in all Figures of the drawings.
Figure 1 shows an exploded sectional view of a radiation-shielding container generally indicated by the reference character 10 in acco, dd,~ce with a first aspect of the present invention. As will be developed the radiation-shielding container 10 receives a vial V
having co,~ ,ed therein various non-radioactive components WO 95/16996 21 7 6 ~ 6 2 PC'r/US94J13913 5 necessaly to form a ,ddiopl,d""aceutical formulation. In some i"~ld,~ces the non-radioactive c~r"~ol,~:"~i may be in Iyophilized form. A ,ddiopl,d""ac~utical formulation is produced by heating and lI ,ert drLt:r cooling a mixture of the (Iyophilized) non-r ~ J_ c~r"poner,L:, and a, ~ c liquid. The radiation-shielding 10 container 10 supports the vial V while the mixture of the non-i~a .rc C~""~O~ "t~ and the ,d~ioa~ c liquid is being heatedand cooled. The ~r F ~ of heat to and the removal of heat from the mixture is effected utilizing the apparatus did91dllllll " l~y indicated by the reference character 80 of Figure 2. The vial V may 15 carry the c~" ,pone, IL~ necessary to produce any of a variety of rauio~ha,",aceuticalformulations as forexample thetechnetium-labeled I ddiUpl Idl 11 ,aceutical Technetium Tc99m-Sestamibi myocardial imaging agent manufactured by DuPont-Merck Pl,a""aceuticalCompany Billerica Massachusetts andsoldunder 20 the trademark Ca,diuli.~@). The rd~iophdllllaceutical formulation also manufactured by DuPont-Merck Pl ,d""aceutical Company and sold under the trademark Neurolite~ may also be produced using the various aspects of the present invention.
The container 10 includes an outer shielding member 12 perhaps best seen in Figure 2A. The outer shielding member 12 is a hollow tubular member formed from a radiation shielding material such as lead or tungsten. For reasons of structural rigidity and " ,a~ l,, y tungsten is preferred. However in instances where a 3û highly radioactive liquid is being used in the ~l~pdldLioll of the formulation the shielding member 12 for the container 10 may be rdbliCdLt:d from a material such as depleted uranium.
The shielding member 12 has internal threads 14 formed about the inner surface thereof adjacent to a first axial end. The inner surface of the tubular outer shielding member 12 has generally adjacent to its opposite axial end a cutout shelf 16 formed therein Owing to the presence of the shelf 16 a reduced radial thickness dimension is imparted to the shielding member 12 over the major portion of its axial length. The shelf 16 is undercut to define a shoulder 18 thereon. To increase the radiation shielding capability of .
fi~2 WO 95/16996 =. ~ PCTNS94/13913 5 the container 10 an inner shielding member 20 is col~c~"~, i ~ '~y received within the shielding member 12. The inner shielding member 20, which is ~ I,Iy rdL,, i-,dl~d from lead, is closely received within the outer shielding member 12. The inner shielding member 12 seats on the upper surface of the shelf 16, where it is 10 held in place by a snap ring 22. The snap ring 22 is received in a groove 24 formed in the inner surface of the member 12, generally adjacent to the threads 14 provided thereon.
The open first axial end of the outer shielding member 12 is 15 closed by a cap 28. The cap 28 is a generally disc-like member having an annular rim 30 depel, " ,9 from the lower surface thereof.
The exterior surface of the rim 30 is threaded, as at 32, whereby the cap 28 may be secured to the threads 14 on the outer shielding member 12. A opening 34 extends central and axially through the 20 cap 28. Access to the opening 34, and thus to the interior of the shielding member 12, is selectably afforded by a closable plug 36.
The plug 36 slides in a dovetailed channel 38 formed in the cap 28.
The plug 36 has an access port 40 formed therein.
The undersurface of the plug 36 is provided with a groove 42.
The groove 42 accepts a spring loaded detent 44 that is received in a bore 46 provided in the disc portion of the cap 28. The detent 44 limits the sliding motion of the plug 36 within the channel 38, and thus ", ,' ,s the plug 36 on the cap 28. The plug 36 is preferably rdbl icdL~d from tungsten.
When in the closed position (as shown in solid lines in Figure 2B, the opening 40 in the plug 36 is laterally offset from the opening 34 in the cap 28. However, the plug 36 may slide within the channel 38 to a position (shown in the dot-dash lines in Figure 2B) in which the opening 40 in the plug 36 registers with the opening 34 in the cap 28. In this position, a portion of the plug 36 overhangs the cap 28, as illustrated in Figure 2B.
A vial holder 54 is received within and suL,ald" 'Iy surrounded by the outer shielding member 12. The vial holder 54 is . . ~
WO 95/16996 2 ~ 7 ~ ~ 6 2 PCT/US94/13913 5 integrally rdbl i~,dlt:d, as by r"d~,l, , ,9 or stamping, from a material haYing a high heat conductivity, such as alurninum or copper.
Structurally, the vial holder 54 includes a base portion 56 from which a cup-like IrGe~ ,læ 58 upwardly extends. The ,~ce~-t ~ l~ 58 is sized to receive closely the vial V. Preferably, the interior surface of 10 the ,~c~ - le 58 is r;l~cl,u~.ldl~d with nickel to protect against corrosion in the event of vial leakage. A skirt portion 60 depends from the lower surface of the base 56. The upper portion 62 of the inner surface of the skirt 60 is generally cylindrical in shape.
However, the lower extent 64 of the inner surface of the skirt 60 is5 flared outwardly and is fr~alu.,u, li~dl in shape, for a reason to be fully ed herein The vial holder 54 is secured to the outer shielding member 12 in the vicinity of the intemal shoulder 18 by a layer 68 of adhesive material. Any adhesive that is thermally stable to temperatures on the order of ap~ i",r~'y 120C, such as an0 epoxy material, is suitable for use as the adhesive.
To insure that a vial V received within and carried by the ,~ceF~ ,le portion 58 of the vial holder 54 is s~:,ldr," "y totally surrounded by a radiation shielding material, a plug 72 is secured 25 ihto the upper cylindrical portion 62 of the inner surface of the skirt 60. The plug 72 is also formed of tungsten, although another suitable radiation shielding material may alternatively be used. The attachment of the plug 72 to the skirt 60 is effected by a layer 74 of adhesive. The same epoxy material that forms the adhesive layer 68 30 is preferred for the adhesive layer 74.
With the plug 72 in place the inteMal volume bounded by the outer sur~ace of the plug 72 and by the fr~lùcû,~;cal portion 64 of the inner surface of the skirt 60 defines a socket 76 for a purpose to be 35 desu,i~ed. The socket 76 has a ~,~d~l~r" ,ed axial ' "ensiu" 78.
The radiation-shielding container 10 shown in Figure 1 c~"",ri~es an element of an apparatus which serves both to apply heat to and to remove heat from a vial V in which a 40 Id~;opl~d""aceutical formulation is produced. The heating and cooling apparatus, which forms a second aspect of this invention, is WO 95/16996 2 ~ 7 ~ ~ 6 2 PCT/US94/1391~
,~ '"' ~0 5 generally indicated in Figure 2A by the reference character 80. In addition to the container 10 the heating and cooling apparatus 80 also includes a mounting block 84 and a I~,e""o~ L,ic heating and cooling element 94 that is cor,l~ev~-vd in thermally conductive contact with the mounting block 84.
The mounting block 84 is a generally planar member having a base portion 86. A mounting ~,u;__tiv~l~ 88 extends upwardly from base portion 86 for a ~, ~vd~a~vl ", ,ed distance 90. The distance 90 is slightly less than or SU~ldl l - 'Iy equal to the axial ~ "er,siûn 78 of 15 the socket 76 defined by the skirt portion 60 of the vial holder 54.
The socket 76 and the mounting p,uj-vvli~vll 88 are each c~",f,lcn,enld,ily sized and shaped to insure that the socket 76 intimately receives the ~,ujGvvliùl, 88 in an heat I,di,s",;~jive I ~Idliv~l~sl Ii~J. To enhance the intimate nesting of the vial holder 54 20 onto the p,~vj ?vIion 88 the exterior surface of the pruj~viivl, is tapered to conform to the configuration of the lower extent 64 of the skirt portion 60 of the vial holder 54. The flared configuration of the lower extent 64 of the skirt 60 facilitates mounting and dismounting of tne skirt portion 60 to and from the p,uj~vIiv~n 88. The mounting 25 block 84 is preferably rdbricdI~d as by l"acl,, ,9 from a highly heat conductive material such as aluminum.
The Il,~,,,,oelevI,iv heating and cooling element 94 is connected in thermally conductive contact to the mounting block 84 30 as v!idvUldlllllldlivcally ,~ se"It:d by the col~l)evlion line 96. The element 94 is fabricated from a suitable heat conductive material such as aluminum. The th-v,l,,oelevt,ic element 94 applies heat to and removes heat from the mounting block 84 and the vial holder 54 mounted thereon under the control of a Ill;vl ucu" ,~.uter-based 35 controller 98. In practice the controller 98 serves to adjust the potential ulirrel~vnce across the junction of the dissimilar materials forming the element 94. Physically the Il,er,,,v~elev~,iv heating and cooling element 94 and the mounting block 84 may be illI~ldl~d into a single unit in the manner exhibited by c~v"""e" 'Iy available 40 thermoelectric heating and cooling apparatus such as the above-mentioned apparatus manufactured by MJ Research Inc .
WO 95/16996 2 ~ 7 6 5 ~ 2 PCT/US94/13913 5 Wd~ l, Massachusetts and sold as '~he MiniCyclerTM
prc,y,a"""a~l~ thermal c~"l,. .
-Having des~, il,ed the structure of both the container 10 (Figures 1 and 2A 2B 2C) and the heating and cooling apparatus 80 10 (Figure 2A) a method in accc" .Jal~ce with yet another aspect of the present invention whereby a ,ddi~pl.d""aceutical forrnulation is produced within the vial V may now be set forth.
The method includes the step of inserting into a vial holder a 15 Yial V having therein the non-radioactive c~"".oner,t~ necessary to form a ~ ~ ~dl 11 ,aceutical formulation into the vial holder 54. As noted these non-radioactive co",por,~"l:, may in some instances be Iyo~l, rl The vial and the vial holder 54 are themselves disposed within and su~ldl, 'Iy surrounded by the radiation-20 shielding container 10.
Preferably with the vial within the vial holder a radioactiveliquid is next added to the c~r"~oll~"b in the vial V. This step is effected by withdrawing a pr~d~ ", ,ed volume of the radioactive 25 liquid from a radionuclide gel~eral.,r using a shielded syringe. A
suitable radionuclide yenerdlor is disclosed in United States Patent 5 109 160 (Evers) issued April 28 1992 and assigned to the assignee of the present invention. With the plug 36 in the cap 28 slid within the channel 38 to expose the opening 34 in the cap the 30 syringe is inserted into the interior of the shield 12 and radioactive liquid injected through the septum of the vial V. The addition of the radioactive liquid serves to reconstitute the non-radioactive co",poner,l~ in the event they were stored in the vial in Iyophilized form. Although not preferred it should be noted that it lies within the 35 c~"It:r"~,ldlion of the present invention to inject the radioactive liquid injected into the vial V prior to the insertion of the vial V into the vial holder 54.
Next the vial holder 54 is disposed in intimate nested contact 40 with a mounting pruje- Iiol1 88 on the mounting block 84 by mounting the skirt portion 60 of the vial holder 54 onto the pr~ cliol) 88 such WO 95/16996 ~ 1 7 ~ ~ 6 2 PCI~/US94/13911~1 5 that the pr.;e l l 88 extends into and is received in thermaily conductive contact with the skirt portion 60 of the vial holder 54.
Using the tllt:llllo~ heating and cooling element 94 heat is selectively applied to or removed from the mixture of the 10 ,ddi- a..~ c liquid and the non-, 1i e '-IC COlllpul lel 1~ within the vial while the vial is held within the vial holder 54 within the radiation shielding container 10. The rd~;v~l,dllllaceutical forrnulation is thus produced within the vial. Any a~ p,-,pridt~ time-temperature profile whereby the heating and cooling of the mix~ure of the radioactive 15 liquid and the non-radioactive c~ r,~ s within the vial may be used col~si~ with the particular ,d,liv,uha""dceutical formulation being produced.
In acc~, dai~ce with the various aspects of the present 20 invention owing to the c~"l,.~ y and inherent accuracy of a th~""oele.. l,i~ heating and cooling element a Iddiopl,d""aceutical formulation of ~rcerl '~le labeling efficiency and radiochemical purity may be rapidly produced. In addition it should be noted that the use of a radiation shielding container 10 in acc~,~a"- e with the present 25 invention permits the production of the radio- phdl " ,aceutical formulation with the radiation exposure to an operator that is as low as l~asondbly achievable ( ALARA ).
EXAI\1PLE
The use and practice of the various aspects of the present invention may be more fully u, ,der~luod from the following example of the pl t lJd~ of a technetium-labeled, ddiv~,l ,d,,, ,aceutical 35 formulation manufactured by DuPont-Merck ~I,d""aceutical Company Billerica Massachusetts and sold underthe lldde,,,alk Ca,~
A vial cor,l.~;. ,i"g a Iyophilized form of non-radioactive actiYe 40 ingredients [particularly a~p,.,pridl~ amounts of ~2-methoxy isobutyl isonitrile) copper tetraflu~rob~rdl~ sodium citrate dihydrate cysteine , .... _, .. _ . , . ,,, ,, .,, , . ,, _ _ _, ,, , : , WO 95/16996 2 i 7 ~ S ~ ~ PCT/US94/13913 5 hy~ u~ ide monohydrate mannitol and stannous chloride dihydrate] is itself placed in a vial holder 54 within the outer radiation shielding member 12. With a sterile shielded syringe a one to three ml volume of ad~ ';vc free sterile non-pyrogenic sodium p~ lle~dt~ Tc99m [925-555~r~ ~ (15-150mC)] is obtained from a ~0 nuclide g~l~erdt." . The sodium pert~. l " ,~t~t~ Tc99m liquid is aseF 'Iy added to the vial. Without ~ .,9 the needle an equal volume of h.o~ ce is removed from the vial to maintain dtl "o~ eric pressure ll ,e, ~ 'h I. The contents of the vial are swirled for a few seconds.
The vial holder 54 within the outer shield 10 is mounted on the mounting p, ujecti~ 88 of the mounting block 84. The skirt portion 60 of the vial holder 54 receives the p,~ .Li~n 88 such that the projection 88 extends into and is received in thermally conductive 20 contact with the skirt portion 60 of the vial holder 54. Under program control the contents of the vial are heated and cooled using the ll ,~""oele- LI ic element in accordal~ce with the following time temperature profile:
1 ) In one minute the temperature of the block 64 is i".... ,t:ased from ambient temperature (ap,u,uAi" ~t~ly 20C) to 119C;
2) The block is held at 11 9C for four minutes;
3) In two to three minutes the temperature of the block 64 is dec,t:ased from 119C to 10C); and
WO 95/16996 ~17 6 ~ 6 ~ PCT/lJS94A3913 Although ".ic,~ .~a~e oven-based heating methods appear to overcome some of the o~t~ s pl ~ t~d in the ~ dl dt;~l~ of Technetium Tc99m-Sestamibi formulation such methods appear also to exhibit serious attendant .I~_..Ja- ka such as vial breakage (as outlined in a letter by Hung and Gibbons "Breakage of 1û technetium-99m sestamibi vial with the use of a Ill;~,lu..'~JC oven" I
Nucl Med 1992; 33; 176-8). Other perceived problems with the ",;~ c oven-based heating technique are set forth in an article by Wilson Hung and Gibbons, "An -" " "IC method for rapid p~epd~ ion of 99TCm_Se~Ld"~ 1, Nucl Med Comm~ 1993; 14; 544-15 9. This !atter article proposes an alteMative heating methodinvolving the use of an instant hot water machine as the source of heated water used for the plt:pdldliUI~ of Technetium Tc99m-Sestamibi formulation.
-o-0-o-Other heating sources for raising the temperature of materials used in COI ,l~euLion with life science reactions are known in the art.
For example an apparatus manufactured by MJ Research Inc 25 Wdlt:(lo ~, l Massachusetts and sold as "The MiniCyclerTM
p,uy,d"""able thermal co"~,." r utilizes a heating/cooling element driven by the Ll ,er",oele~ effect to both heat and cool samples for various b,.,l~H ,l1oloy;~ al reactions. The basic operating principle of a II,t:""oelec~ heating/cooling element is the Peltier Cooling Eflect 30 in which heat is absorbed or gel~erdlt:d as a current passes through a junction of two dissimilar materials. Electrons passing across the junction absorb or give up an amount of energy equal to the transport energy and the energy ~ 'r~,~nce between the di~aill, ' -materials conduction bands.
The materials to be heated or cooled in the p,ug,d"""dLle thermal controller apparatus are typically carried in microl~" dcei ,1, iruge tubes also known as "Eppendorf Tubes" or in other suitable reaction tubes. The ,~luyldlllllldble thermal controller 40 includes a sample block in which a plurality of wells are formed.
Each tube carrying a sample therein is inserted into a well and the WO 95/16996 ~ , - ' PCTIUS94/1391~
21765`fi2 `` ` 4 5 app, up, i.h~ heating andlor cooling program initiated. Each of the wells formed in the sample block cGr,~spor,da in configuration to the exterior configuration of the container inserted therein. Use of the p,uy,d"""aL,le thermal controller in conll n with ,ddioauti~lc reactions appears to be c~" , -o-O-o-ln view of the foregoing it is belieYed advantageous to utilize a Il,er",ocl~l,i. (Peltier-effect) heating/cooling elementto precisely 15 control both heating and cooling of Technetium Tc99m-Sestamibi imaging formulation thereby to make p~ d~ n of an effective dosage of the imaging formulation rapidly available for use in eryt:nCy and other situations.
SUMMARY OF THE INVENTION
The present invention is directed to both apparatus and a method for using a thermoelectric heatinglcooling element both to 25 apply heat to and/or remove heat from a vial having the components necessary to form a I ddio~l~dl " ,aceutical formulation co, ,ed therein .
In a first aspect the invention is directed toward a radiation-30 shielding container for receiving a vial having the cGl"lJonentanecessary to form a rd~iopharlllaceutical formulation therein and in which such c~",por,~"b may be both heated and cooled. The container c~" "-, iae5 a hollow outer shielding member formed from a radiation shielding material such as lead or tungsten and a vial 35 holder received within the outer shielding member. The outer shielding member Su~aldl 'Iy c~"".let~ly surrounds the vial holder.
The vial holder is r~,i. dl~d from a material having a high heat conductivity such as aluminum or copper. The vial holder includes a skirt portion that defines a socket. The socket defined by the skirt is 40 sized to receive a mounting pruJ~. liùl) in a heat lldllalll;~SiV~
~ld~ionsl ,i~-. A shielding plug also formed of a radiation shielding _ _ _ _ _ _ . _ _ _ WO 95/16996 PCrmS94/13913 ~ ~ 7~.~li2`
5 material may be disposed within the socket defined by the skirt portion of the viai holder.
In another aspect the invention is directed to an apparatus in which the c~"",ol~ent~ necessaly to form a Id~ioplldllll~r-ell~
10 formulation cu,, ,ed within the vial are both heated and cooled.
The apparatus c~r"p, iaes the container as set forth above a ~I,er",oel~..t~i~ heating and cooling element and a mounting block c~""e- l~d in thermal conductive contact with the Il l~ vt~i..
heating and cooling element. The mounting block has a mounting 15 p",;~iol~ thereon that is sized for receipt in a heat l,di,s" ;~ c rt:ldli~l~s~, within the socket defined by the skirt portion of the vial holder of the container.
In yet another aspect the present invention is directed to a 20 method for preparing rapidly a ,ddi~pl,d""aceutical formulation within a vial. The method cûl "pl ises the steps of inserting into a vial holder a vial having therein the non-radioactive components necessaly to form a ,ddi~ha""aLeutical formulation. In some instances the non-,ddi~dl ti~c c~"" ol,e,lt~ may be in Iyophilized 25 form. The vial holder is disposed within and Sl.lb~ldl " "y surrounded by a radiation-shielding container. The vial holder is rdbli~.dl~d from a material having a high thermal conductivity and includes a skirt pûrtion that defines a socket. A radioactive liquid is added to the non-radioactive co""-ol1e"l~ in the vial pr~r~,dLly after the vial is 30 inserted into the radiation-shielding container. The vial holder is disposed in a heat lldl~slll;s~iv~ lc:ldliul~s~ J with a mounting p, uj~ liun on a mounting block by mounting the skirt portion onto the pruj~ liù,~ such that the p, ., ~ .~ extends into and is in therrnal contact with the skirt portion of the vial holder. The mounting block is 35 itself in thermal conductive contact with a Ill~llllù~ tliU heating and cooling element. Using the II,e""oelecl,ic heating and cooling element heat is both applied to and removed from the mixture of the radioactive liquid and the (Iyophilized) non-radioactive c~",~ol,e"l~
. within the vial while the vial is held within the vial holder within the 40 radiation shielding container thereby to produce a Iddiopltar",aceutical formulation within the vial.
WO 95116996 PCII~S9411391~
21~ ~62 BRIFF DESCRIPTION OF THE DRAWINGS
The invention will be more fully u"de, :.tuod frorn the following 10 detailed des.;,i~,liol1 taken in acc~,ddl,ce with the acco",pd"ying drawings which form a part of this ~ -n and in which:
Figure 1 is an exploded side elevational view entirely in section of a containerfor preparing a Id~ioplldllllaceutical 5 formulation in acc~,.lance with a first aspect of the present invention;
and Figure 2A is a stylized didyldlllllldli~ ~e,ultls~llldliol1 of an apparatus for both heating and cooling the c~r"~,olle"ts necessary to 20 form a radiopha""aceutical formulation using a the""o~ L,ic heating and cooling element the apparatus including the container of Figure 1 which is shown in Figure 2A in a side elevational view entirely in section in its fully ass~",ble~ condition;
Figure 2B is a plan view of the container shown in Figure 2A;
and Figure 2C is an ~, ll ,oy, dpl liC view of the cap of the container of Figures 2A and 2B taken along section lines 2C-2C in Figure 2B.
DET~Il Fn DESCRIPTION OF THE INVENTION
Throughout the following detailed des~ n similar reference numerals refer to similar elements in all Figures of the drawings.
Figure 1 shows an exploded sectional view of a radiation-shielding container generally indicated by the reference character 10 in acco, dd,~ce with a first aspect of the present invention. As will be developed the radiation-shielding container 10 receives a vial V
having co,~ ,ed therein various non-radioactive components WO 95/16996 21 7 6 ~ 6 2 PC'r/US94J13913 5 necessaly to form a ,ddiopl,d""aceutical formulation. In some i"~ld,~ces the non-radioactive c~r"~ol,~:"~i may be in Iyophilized form. A ,ddiopl,d""ac~utical formulation is produced by heating and lI ,ert drLt:r cooling a mixture of the (Iyophilized) non-r ~ J_ c~r"poner,L:, and a, ~ c liquid. The radiation-shielding 10 container 10 supports the vial V while the mixture of the non-i~a .rc C~""~O~ "t~ and the ,d~ioa~ c liquid is being heatedand cooled. The ~r F ~ of heat to and the removal of heat from the mixture is effected utilizing the apparatus did91dllllll " l~y indicated by the reference character 80 of Figure 2. The vial V may 15 carry the c~" ,pone, IL~ necessary to produce any of a variety of rauio~ha,",aceuticalformulations as forexample thetechnetium-labeled I ddiUpl Idl 11 ,aceutical Technetium Tc99m-Sestamibi myocardial imaging agent manufactured by DuPont-Merck Pl,a""aceuticalCompany Billerica Massachusetts andsoldunder 20 the trademark Ca,diuli.~@). The rd~iophdllllaceutical formulation also manufactured by DuPont-Merck Pl ,d""aceutical Company and sold under the trademark Neurolite~ may also be produced using the various aspects of the present invention.
The container 10 includes an outer shielding member 12 perhaps best seen in Figure 2A. The outer shielding member 12 is a hollow tubular member formed from a radiation shielding material such as lead or tungsten. For reasons of structural rigidity and " ,a~ l,, y tungsten is preferred. However in instances where a 3û highly radioactive liquid is being used in the ~l~pdldLioll of the formulation the shielding member 12 for the container 10 may be rdbliCdLt:d from a material such as depleted uranium.
The shielding member 12 has internal threads 14 formed about the inner surface thereof adjacent to a first axial end. The inner surface of the tubular outer shielding member 12 has generally adjacent to its opposite axial end a cutout shelf 16 formed therein Owing to the presence of the shelf 16 a reduced radial thickness dimension is imparted to the shielding member 12 over the major portion of its axial length. The shelf 16 is undercut to define a shoulder 18 thereon. To increase the radiation shielding capability of .
fi~2 WO 95/16996 =. ~ PCTNS94/13913 5 the container 10 an inner shielding member 20 is col~c~"~, i ~ '~y received within the shielding member 12. The inner shielding member 20, which is ~ I,Iy rdL,, i-,dl~d from lead, is closely received within the outer shielding member 12. The inner shielding member 12 seats on the upper surface of the shelf 16, where it is 10 held in place by a snap ring 22. The snap ring 22 is received in a groove 24 formed in the inner surface of the member 12, generally adjacent to the threads 14 provided thereon.
The open first axial end of the outer shielding member 12 is 15 closed by a cap 28. The cap 28 is a generally disc-like member having an annular rim 30 depel, " ,9 from the lower surface thereof.
The exterior surface of the rim 30 is threaded, as at 32, whereby the cap 28 may be secured to the threads 14 on the outer shielding member 12. A opening 34 extends central and axially through the 20 cap 28. Access to the opening 34, and thus to the interior of the shielding member 12, is selectably afforded by a closable plug 36.
The plug 36 slides in a dovetailed channel 38 formed in the cap 28.
The plug 36 has an access port 40 formed therein.
The undersurface of the plug 36 is provided with a groove 42.
The groove 42 accepts a spring loaded detent 44 that is received in a bore 46 provided in the disc portion of the cap 28. The detent 44 limits the sliding motion of the plug 36 within the channel 38, and thus ", ,' ,s the plug 36 on the cap 28. The plug 36 is preferably rdbl icdL~d from tungsten.
When in the closed position (as shown in solid lines in Figure 2B, the opening 40 in the plug 36 is laterally offset from the opening 34 in the cap 28. However, the plug 36 may slide within the channel 38 to a position (shown in the dot-dash lines in Figure 2B) in which the opening 40 in the plug 36 registers with the opening 34 in the cap 28. In this position, a portion of the plug 36 overhangs the cap 28, as illustrated in Figure 2B.
A vial holder 54 is received within and suL,ald" 'Iy surrounded by the outer shielding member 12. The vial holder 54 is . . ~
WO 95/16996 2 ~ 7 ~ ~ 6 2 PCT/US94/13913 5 integrally rdbl i~,dlt:d, as by r"d~,l, , ,9 or stamping, from a material haYing a high heat conductivity, such as alurninum or copper.
Structurally, the vial holder 54 includes a base portion 56 from which a cup-like IrGe~ ,læ 58 upwardly extends. The ,~ce~-t ~ l~ 58 is sized to receive closely the vial V. Preferably, the interior surface of 10 the ,~c~ - le 58 is r;l~cl,u~.ldl~d with nickel to protect against corrosion in the event of vial leakage. A skirt portion 60 depends from the lower surface of the base 56. The upper portion 62 of the inner surface of the skirt 60 is generally cylindrical in shape.
However, the lower extent 64 of the inner surface of the skirt 60 is5 flared outwardly and is fr~alu.,u, li~dl in shape, for a reason to be fully ed herein The vial holder 54 is secured to the outer shielding member 12 in the vicinity of the intemal shoulder 18 by a layer 68 of adhesive material. Any adhesive that is thermally stable to temperatures on the order of ap~ i",r~'y 120C, such as an0 epoxy material, is suitable for use as the adhesive.
To insure that a vial V received within and carried by the ,~ceF~ ,le portion 58 of the vial holder 54 is s~:,ldr," "y totally surrounded by a radiation shielding material, a plug 72 is secured 25 ihto the upper cylindrical portion 62 of the inner surface of the skirt 60. The plug 72 is also formed of tungsten, although another suitable radiation shielding material may alternatively be used. The attachment of the plug 72 to the skirt 60 is effected by a layer 74 of adhesive. The same epoxy material that forms the adhesive layer 68 30 is preferred for the adhesive layer 74.
With the plug 72 in place the inteMal volume bounded by the outer sur~ace of the plug 72 and by the fr~lùcû,~;cal portion 64 of the inner surface of the skirt 60 defines a socket 76 for a purpose to be 35 desu,i~ed. The socket 76 has a ~,~d~l~r" ,ed axial ' "ensiu" 78.
The radiation-shielding container 10 shown in Figure 1 c~"",ri~es an element of an apparatus which serves both to apply heat to and to remove heat from a vial V in which a 40 Id~;opl~d""aceutical formulation is produced. The heating and cooling apparatus, which forms a second aspect of this invention, is WO 95/16996 2 ~ 7 ~ ~ 6 2 PCT/US94/1391~
,~ '"' ~0 5 generally indicated in Figure 2A by the reference character 80. In addition to the container 10 the heating and cooling apparatus 80 also includes a mounting block 84 and a I~,e""o~ L,ic heating and cooling element 94 that is cor,l~ev~-vd in thermally conductive contact with the mounting block 84.
The mounting block 84 is a generally planar member having a base portion 86. A mounting ~,u;__tiv~l~ 88 extends upwardly from base portion 86 for a ~, ~vd~a~vl ", ,ed distance 90. The distance 90 is slightly less than or SU~ldl l - 'Iy equal to the axial ~ "er,siûn 78 of 15 the socket 76 defined by the skirt portion 60 of the vial holder 54.
The socket 76 and the mounting p,uj-vvli~vll 88 are each c~",f,lcn,enld,ily sized and shaped to insure that the socket 76 intimately receives the ~,ujGvvliùl, 88 in an heat I,di,s",;~jive I ~Idliv~l~sl Ii~J. To enhance the intimate nesting of the vial holder 54 20 onto the p,~vj ?vIion 88 the exterior surface of the pruj~viivl, is tapered to conform to the configuration of the lower extent 64 of the skirt portion 60 of the vial holder 54. The flared configuration of the lower extent 64 of the skirt 60 facilitates mounting and dismounting of tne skirt portion 60 to and from the p,uj~vIiv~n 88. The mounting 25 block 84 is preferably rdbricdI~d as by l"acl,, ,9 from a highly heat conductive material such as aluminum.
The Il,~,,,,oelevI,iv heating and cooling element 94 is connected in thermally conductive contact to the mounting block 84 30 as v!idvUldlllllldlivcally ,~ se"It:d by the col~l)evlion line 96. The element 94 is fabricated from a suitable heat conductive material such as aluminum. The th-v,l,,oelevt,ic element 94 applies heat to and removes heat from the mounting block 84 and the vial holder 54 mounted thereon under the control of a Ill;vl ucu" ,~.uter-based 35 controller 98. In practice the controller 98 serves to adjust the potential ulirrel~vnce across the junction of the dissimilar materials forming the element 94. Physically the Il,er,,,v~elev~,iv heating and cooling element 94 and the mounting block 84 may be illI~ldl~d into a single unit in the manner exhibited by c~v"""e" 'Iy available 40 thermoelectric heating and cooling apparatus such as the above-mentioned apparatus manufactured by MJ Research Inc .
WO 95/16996 2 ~ 7 6 5 ~ 2 PCT/US94/13913 5 Wd~ l, Massachusetts and sold as '~he MiniCyclerTM
prc,y,a"""a~l~ thermal c~"l,. .
-Having des~, il,ed the structure of both the container 10 (Figures 1 and 2A 2B 2C) and the heating and cooling apparatus 80 10 (Figure 2A) a method in accc" .Jal~ce with yet another aspect of the present invention whereby a ,ddi~pl.d""aceutical forrnulation is produced within the vial V may now be set forth.
The method includes the step of inserting into a vial holder a 15 Yial V having therein the non-radioactive c~"".oner,t~ necessary to form a ~ ~ ~dl 11 ,aceutical formulation into the vial holder 54. As noted these non-radioactive co",por,~"l:, may in some instances be Iyo~l, rl The vial and the vial holder 54 are themselves disposed within and su~ldl, 'Iy surrounded by the radiation-20 shielding container 10.
Preferably with the vial within the vial holder a radioactiveliquid is next added to the c~r"~oll~"b in the vial V. This step is effected by withdrawing a pr~d~ ", ,ed volume of the radioactive 25 liquid from a radionuclide gel~eral.,r using a shielded syringe. A
suitable radionuclide yenerdlor is disclosed in United States Patent 5 109 160 (Evers) issued April 28 1992 and assigned to the assignee of the present invention. With the plug 36 in the cap 28 slid within the channel 38 to expose the opening 34 in the cap the 30 syringe is inserted into the interior of the shield 12 and radioactive liquid injected through the septum of the vial V. The addition of the radioactive liquid serves to reconstitute the non-radioactive co",poner,l~ in the event they were stored in the vial in Iyophilized form. Although not preferred it should be noted that it lies within the 35 c~"It:r"~,ldlion of the present invention to inject the radioactive liquid injected into the vial V prior to the insertion of the vial V into the vial holder 54.
Next the vial holder 54 is disposed in intimate nested contact 40 with a mounting pruje- Iiol1 88 on the mounting block 84 by mounting the skirt portion 60 of the vial holder 54 onto the pr~ cliol) 88 such WO 95/16996 ~ 1 7 ~ ~ 6 2 PCI~/US94/13911~1 5 that the pr.;e l l 88 extends into and is received in thermaily conductive contact with the skirt portion 60 of the vial holder 54.
Using the tllt:llllo~ heating and cooling element 94 heat is selectively applied to or removed from the mixture of the 10 ,ddi- a..~ c liquid and the non-, 1i e '-IC COlllpul lel 1~ within the vial while the vial is held within the vial holder 54 within the radiation shielding container 10. The rd~;v~l,dllllaceutical forrnulation is thus produced within the vial. Any a~ p,-,pridt~ time-temperature profile whereby the heating and cooling of the mix~ure of the radioactive 15 liquid and the non-radioactive c~ r,~ s within the vial may be used col~si~ with the particular ,d,liv,uha""dceutical formulation being produced.
In acc~, dai~ce with the various aspects of the present 20 invention owing to the c~"l,.~ y and inherent accuracy of a th~""oele.. l,i~ heating and cooling element a Iddiopl,d""aceutical formulation of ~rcerl '~le labeling efficiency and radiochemical purity may be rapidly produced. In addition it should be noted that the use of a radiation shielding container 10 in acc~,~a"- e with the present 25 invention permits the production of the radio- phdl " ,aceutical formulation with the radiation exposure to an operator that is as low as l~asondbly achievable ( ALARA ).
EXAI\1PLE
The use and practice of the various aspects of the present invention may be more fully u, ,der~luod from the following example of the pl t lJd~ of a technetium-labeled, ddiv~,l ,d,,, ,aceutical 35 formulation manufactured by DuPont-Merck ~I,d""aceutical Company Billerica Massachusetts and sold underthe lldde,,,alk Ca,~
A vial cor,l.~;. ,i"g a Iyophilized form of non-radioactive actiYe 40 ingredients [particularly a~p,.,pridl~ amounts of ~2-methoxy isobutyl isonitrile) copper tetraflu~rob~rdl~ sodium citrate dihydrate cysteine , .... _, .. _ . , . ,,, ,, .,, , . ,, _ _ _, ,, , : , WO 95/16996 2 i 7 ~ S ~ ~ PCT/US94/13913 5 hy~ u~ ide monohydrate mannitol and stannous chloride dihydrate] is itself placed in a vial holder 54 within the outer radiation shielding member 12. With a sterile shielded syringe a one to three ml volume of ad~ ';vc free sterile non-pyrogenic sodium p~ lle~dt~ Tc99m [925-555~r~ ~ (15-150mC)] is obtained from a ~0 nuclide g~l~erdt." . The sodium pert~. l " ,~t~t~ Tc99m liquid is aseF 'Iy added to the vial. Without ~ .,9 the needle an equal volume of h.o~ ce is removed from the vial to maintain dtl "o~ eric pressure ll ,e, ~ 'h I. The contents of the vial are swirled for a few seconds.
The vial holder 54 within the outer shield 10 is mounted on the mounting p, ujecti~ 88 of the mounting block 84. The skirt portion 60 of the vial holder 54 receives the p,~ .Li~n 88 such that the projection 88 extends into and is received in thermally conductive 20 contact with the skirt portion 60 of the vial holder 54. Under program control the contents of the vial are heated and cooled using the ll ,~""oele- LI ic element in accordal~ce with the following time temperature profile:
1 ) In one minute the temperature of the block 64 is i".... ,t:ased from ambient temperature (ap,u,uAi" ~t~ly 20C) to 119C;
2) The block is held at 11 9C for four minutes;
3) In two to three minutes the temperature of the block 64 is dec,t:ased from 119C to 10C); and
4) The block is held at 1 O~C for one minute.
Using the apparatus and method of the present invention a , d~ivphdl " ,aceutical formulation exhibiting desired purity and desired labeling efficiency is thus prepared. The overall plt:,udl;~ time is on the order of ten minutes in contrast with a pl~Jdldlion time on the order of twenty-five minutes required using the boiling water bath technique of the prior art.
WO 95/16996 PCTIUS94/1391~
21~&~2 1 4 -o-o-o-Those skilled in the art, having the benefit of the ~eacl, ,~s of the present invention as he, _;. ,abo~/e set forth may effect numerous nl~ s thereto. Such ", ' ,~ are to be construed as 10 Iying within the scope of the present invention, as defined by the .,~pel~(led claims.
Using the apparatus and method of the present invention a , d~ivphdl " ,aceutical formulation exhibiting desired purity and desired labeling efficiency is thus prepared. The overall plt:,udl;~ time is on the order of ten minutes in contrast with a pl~Jdldlion time on the order of twenty-five minutes required using the boiling water bath technique of the prior art.
WO 95/16996 PCTIUS94/1391~
21~&~2 1 4 -o-o-o-Those skilled in the art, having the benefit of the ~eacl, ,~s of the present invention as he, _;. ,abo~/e set forth may effect numerous nl~ s thereto. Such ", ' ,~ are to be construed as 10 Iying within the scope of the present invention, as defined by the .,~pel~(led claims.
Claims (5)
1. A radiation-shielding container for receiving a vial having the components necessary to form a radiopharmaceutical formulation contained therein and in which those components may be both heated and cooled the container comprising:
a hollow outer shielding member formed from a radiation shielding material; and a vial holder received within and substantially surrounded by the hollow outer shielding member, the vial holder being fabricated from a material having a high heat conductivity, the vial holder including a skirt portion that defines a socket the socket being sized to receive a mounting projection in a heat transmissive relationship.
a hollow outer shielding member formed from a radiation shielding material; and a vial holder received within and substantially surrounded by the hollow outer shielding member, the vial holder being fabricated from a material having a high heat conductivity, the vial holder including a skirt portion that defines a socket the socket being sized to receive a mounting projection in a heat transmissive relationship.
2. The radiation-shielding container of claim 1 further comprising a plug formed of a radiation shielding material disposed within the skirt portion.
3. An apparatus in which the components necessary to form a radiopharmaceutical formulation contained within a vial are both heated and cooled the apparatus comprising:
a thermoelectric heating and cooling element;
a mounting block having a mounting projection thereon, the block being connected in thermal conductive contact with the thermoelectric heating and cooling element a radiation-shielding container for receiving a vial having the component of a radiopharmaceutical formulation contained therein the container itself comprising:
a hollow outer shielding member formed from a radiation shielding material a vial holder received within and substantially surrounded by the hollow outer shielding member, the vial holder being fabricated from a material having a high heat conductivity the vial holder including a skirt portion that defines a socket, the socket being sized to receive a mounting projection in a heat transmissive relationship.
a thermoelectric heating and cooling element;
a mounting block having a mounting projection thereon, the block being connected in thermal conductive contact with the thermoelectric heating and cooling element a radiation-shielding container for receiving a vial having the component of a radiopharmaceutical formulation contained therein the container itself comprising:
a hollow outer shielding member formed from a radiation shielding material a vial holder received within and substantially surrounded by the hollow outer shielding member, the vial holder being fabricated from a material having a high heat conductivity the vial holder including a skirt portion that defines a socket, the socket being sized to receive a mounting projection in a heat transmissive relationship.
4. The apparatus of claim 3 further comprising a plug formed of a radiation shielding material disposed within the skirt portion.
5. A method for preparing a, radiopharmaceutical formulation within a vial, the method comprising the steps of:
a) inserting into a vial holder a vial having non-radioactive components necessary to form a radiopharmaceutical formulation, the vial holder being itself disposed within and substantially surrounded by a radiation-shielding container, the vial holder being fabricated from a material having a high thermal conductivity and including a skirt portion that defines a socket;
b) adding a radioactive liquid to the non-radioactive components in the vial;
c) disposing the vial holder in a heat transmissive relationship with a mounting projection on a mounting block by mounting the skirt portion of the vial holder onto the projection such that the projection extends into and is in heat transmissive relationship with the skirt portion of the vial holder, the mounting block being itself in thermal conductive contact with a thermoplastic heating and cooling element; and d) using the thermoelectric heating and cooling element, both applying heat to and removing heat from the mixture of the radioactive liquid and the non-radioactive components within the vial while the vial is held within the vial holder within the radiation shielding container, thereby to produce a radiopharmaceutical formulation within the vial.
a) inserting into a vial holder a vial having non-radioactive components necessary to form a radiopharmaceutical formulation, the vial holder being itself disposed within and substantially surrounded by a radiation-shielding container, the vial holder being fabricated from a material having a high thermal conductivity and including a skirt portion that defines a socket;
b) adding a radioactive liquid to the non-radioactive components in the vial;
c) disposing the vial holder in a heat transmissive relationship with a mounting projection on a mounting block by mounting the skirt portion of the vial holder onto the projection such that the projection extends into and is in heat transmissive relationship with the skirt portion of the vial holder, the mounting block being itself in thermal conductive contact with a thermoplastic heating and cooling element; and d) using the thermoelectric heating and cooling element, both applying heat to and removing heat from the mixture of the radioactive liquid and the non-radioactive components within the vial while the vial is held within the vial holder within the radiation shielding container, thereby to produce a radiopharmaceutical formulation within the vial.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/167,685 US5397902A (en) | 1993-12-15 | 1993-12-15 | Apparatus and method for the preparation of a radiopharmaceutical formulation |
| US08/167,685 | 1993-12-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2176562A1 true CA2176562A1 (en) | 1995-06-22 |
Family
ID=22608380
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002176562A Abandoned CA2176562A1 (en) | 1993-12-15 | 1994-12-14 | Apparatus and method for the preparation of a radiopharmaceutical formulation |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | US5397902A (en) |
| EP (1) | EP0734575A1 (en) |
| JP (1) | JPH09508198A (en) |
| KR (1) | KR960706679A (en) |
| CN (1) | CN1137323A (en) |
| AU (1) | AU686312B2 (en) |
| BR (1) | BR9408220A (en) |
| CA (1) | CA2176562A1 (en) |
| CZ (1) | CZ169596A3 (en) |
| FI (1) | FI962417A0 (en) |
| HR (1) | HRP940998A2 (en) |
| HU (1) | HUT75799A (en) |
| IL (1) | IL111806A0 (en) |
| NO (1) | NO962529L (en) |
| NZ (1) | NZ279008A (en) |
| PL (1) | PL314967A1 (en) |
| SK (1) | SK78396A3 (en) |
| TW (1) | TW311886B (en) |
| WO (1) | WO1995016996A1 (en) |
| ZA (1) | ZA949658B (en) |
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| JP3540497B2 (en) * | 1995-04-20 | 2004-07-07 | 日本メジフィジックス株式会社 | Method of manufacturing shielding member for radioactive material |
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| US6781142B2 (en) * | 2001-11-23 | 2004-08-24 | Vulcan Lead, Inc. | Radiation-shielding container |
| ITRM20020071A1 (en) * | 2002-02-11 | 2003-08-11 | Sigma Tau Ind Farmaceuti | CONTAINER FOR RADIOPHARMACEUTICAL BOTTLE, AND KIT FOR ITS INFUSION IN A PATIENT OR FOR ITS TRANSFER ELSEWHERE. |
| US7163031B2 (en) * | 2004-06-15 | 2007-01-16 | Mallinckrodt Inc. | Automated dispensing system and associated method of use |
| KR101415092B1 (en) * | 2004-08-30 | 2014-07-04 | 브라코 다이어그노스틱스 아이엔씨. | Improved containers for pharmaceuticals, particularly for use in radioisotope generators |
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| JP2009502344A (en) * | 2005-07-27 | 2009-01-29 | マリンクロッド・インコーポレイテッド | Radiopharmaceutical dispensing device with counterforce access mechanism, system and method |
| EP1942505A2 (en) * | 2005-07-27 | 2008-07-09 | Mallinckrodt, Inc. | Radiation-shielding assemblies and methods |
| EP2544188A3 (en) * | 2005-07-27 | 2013-08-28 | Mallinckrodt LLC | Radiation-shielding assemblies and methods of using the same |
| WO2007026220A2 (en) * | 2005-08-30 | 2007-03-08 | Ge Healthcare Limited | Method for forming a vial holder device for a vial heater apparatus |
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| US7700926B2 (en) * | 2006-01-12 | 2010-04-20 | Draximage General Partnership | Systems and methods for radioisotope generation |
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| CA2653943C (en) * | 2006-08-24 | 2013-02-19 | Areva Federal Services Llc | Transportation container and assembly |
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| CN112007576B (en) * | 2020-08-26 | 2022-04-22 | 山西医科大学 | Temperature control station |
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-
1993
- 1993-12-15 US US08/167,685 patent/US5397902A/en not_active Expired - Lifetime
-
1994
- 1994-11-29 IL IL11180694A patent/IL111806A0/en unknown
- 1994-12-05 ZA ZA949658A patent/ZA949658B/en unknown
- 1994-12-06 TW TW083111325A patent/TW311886B/zh active
- 1994-12-14 WO PCT/US1994/013913 patent/WO1995016996A1/en not_active Application Discontinuation
- 1994-12-14 CZ CZ961695A patent/CZ169596A3/en unknown
- 1994-12-14 EP EP95907200A patent/EP0734575A1/en not_active Withdrawn
- 1994-12-14 PL PL94314967A patent/PL314967A1/en unknown
- 1994-12-14 CN CN94194499A patent/CN1137323A/en active Pending
- 1994-12-14 CA CA002176562A patent/CA2176562A1/en not_active Abandoned
- 1994-12-14 SK SK783-96A patent/SK78396A3/en unknown
- 1994-12-14 KR KR1019960703155A patent/KR960706679A/en active IP Right Grant
- 1994-12-14 HU HU9601297A patent/HUT75799A/en unknown
- 1994-12-14 JP JP7516802A patent/JPH09508198A/en active Pending
- 1994-12-14 HR HR08/167,685A patent/HRP940998A2/en not_active Application Discontinuation
- 1994-12-14 AU AU15507/95A patent/AU686312B2/en not_active Ceased
- 1994-12-14 NZ NZ279008A patent/NZ279008A/en unknown
- 1994-12-14 BR BR9408220A patent/BR9408220A/en not_active Application Discontinuation
-
1996
- 1996-06-11 FI FI962417A patent/FI962417A0/en unknown
- 1996-06-14 NO NO962529A patent/NO962529L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FI962417A (en) | 1996-06-11 |
| PL314967A1 (en) | 1996-09-30 |
| CN1137323A (en) | 1996-12-04 |
| ZA949658B (en) | 1996-06-05 |
| TW311886B (en) | 1997-08-01 |
| HUT75799A (en) | 1997-05-28 |
| NZ279008A (en) | 1996-11-26 |
| WO1995016996A1 (en) | 1995-06-22 |
| AU686312B2 (en) | 1998-02-05 |
| US5397902A (en) | 1995-03-14 |
| IL111806A0 (en) | 1995-01-24 |
| FI962417A0 (en) | 1996-06-11 |
| NO962529D0 (en) | 1996-06-14 |
| EP0734575A1 (en) | 1996-10-02 |
| BR9408220A (en) | 1997-08-26 |
| JPH09508198A (en) | 1997-08-19 |
| SK78396A3 (en) | 1997-04-09 |
| HU9601297D0 (en) | 1996-07-29 |
| NO962529L (en) | 1996-08-14 |
| KR960706679A (en) | 1996-12-09 |
| HRP940998A2 (en) | 1997-04-30 |
| AU1550795A (en) | 1995-07-03 |
| CZ169596A3 (en) | 1996-09-11 |
| EP0734575A4 (en) | 1996-07-04 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |