U.S. patent application number 11/518442 was filed with the patent office on 2009-07-02 for device for ¹23;i-adam and automatic manufacturing device thereof.
Invention is credited to Chia-Chieh Chen, Tseng-Chung Huang, Hung-Chun Kao, Ai-Ren Lo.
Application Number | 20090169439 11/518442 |
Document ID | / |
Family ID | 40798694 |
Filed Date | 2009-07-02 |
United States Patent
Application |
20090169439 |
Kind Code |
A1 |
Lo; Ai-Ren ; et al. |
July 2, 2009 |
DEVICE FOR ¹23;I-ADAM AND AUTOMATIC MANUFACTURING DEVICE
THEREOF
Abstract
A manufacturing method for .sup.123I-ADAM and an automatic
manufacturing device thereof are disclosed. The manufacturing
process for .sup.123I-ADAM consists of four steps-add [.sup.123I]
ammonium iodide solution, make oxidation reaction occur, terminate
the reaction and neutralize the solution, filter and collect the
filtrate. The automatic manufacturing device includes a plurality
of units for taking each of the four steps that is disposed inside
a chassis and is operated by automatic control. Users only need to
put reactants into storage bottles respectively, turn on the power,
and initiate the operation system, Then the preparation process of
drugs for clinical diagnosis is finished within twenty minutes.
Inventors: |
Lo; Ai-Ren; (Taipei City,
TW) ; Chen; Chia-Chieh; (Jhongli City, TW) ;
Huang; Tseng-Chung; (Jhongli City, TW) ; Kao;
Hung-Chun; (Shulin City, TW) |
Correspondence
Address: |
ROSENBERG, KLEIN & LEE
3458 ELLICOTT CENTER DRIVE-SUITE 101
ELLICOTT CITY
MD
21043
US
|
Family ID: |
40798694 |
Appl. No.: |
11/518442 |
Filed: |
September 11, 2006 |
Current U.S.
Class: |
422/130 |
Current CPC
Class: |
C07C 319/20 20130101;
B01J 2219/00286 20130101; B01J 2219/00756 20130101; B01J 2219/0072
20130101; B01J 2219/00759 20130101; B01J 2219/0059 20130101; B01J
2219/00409 20130101; C07B 59/001 20130101; B01J 19/004 20130101;
C07C 319/20 20130101; C07C 323/37 20130101 |
Class at
Publication: |
422/130 |
International
Class: |
B01J 19/00 20060101
B01J019/00 |
Claims
1-7. (canceled)
8. An automatic manufacturing device of .sup.123I-ADAM (Iodine-123
labeled
2-([2dimethylamino]methyl)phenyl]thio)-5-.sup.123I-iodophenylamin-
e), comprising: a central processing unit controlling the operation
of said automatic manufacturing device; a plurality of reactant
storage bottles, each of said plurality of reactant storage bottles
containing a reactant selected from a group consisting of
[.sup.123I] ammonium iodide solution, oxidizing agent, deoxidizing
agent, neutralization agent, and water; a reaction bottle
containing a SnADAM
([2-((2-amino-4-tri-n-butyltinphenyl)thio)benzyl] dimethylamine)
precursor and connected with the reactant storage bottles by a
plurality of pipelines, each of said plurality of pipelines being
disposed with a respective solenoid valve, said central processing
unit being coupled to each said respective solenoid valve to
control an order and duration of supply of the reactants from said
plurality of reactant storage bottles to said reaction bottle to
produce a .sup.123I-ADAM containing pre-product in said reaction
bottle; a column connected to the output of said reaction bottle by
a transport pipe to receive said .sup.123I-ADAM containing
pre-product from said reaction bottle under control of said control
processing unit; an eluant storage bottle coupled to said column by
an elution pipe, said eluant being added to said .sup.123I-ADAM
containing pre-product in said column in the controlled fashion to
form a first product containing .sup.123I-ADAM; a first product
storage bottle connected with the column to store said first
product transported from said column through by a first collection
pipe; a filtering device connected with the first product storage
bottle by a filtering pipe to filter said first product and to
generate a purified .sup.123I-ADAM product; and a second product
storage bottle connected with the filtering device by a second
collection pipe to receive said purified .sup.123I-ADAM product
from said filtering device.
9. The device as claimed in claim 8, wherein the column further
comprises a liquid level monitoring device coupled to the column
for monitoring said pre-product of in the column and liquid level
of pipes while eluting.
10. (canceled)
11. The device as claimed in claim 8, wherein said oxidizing agent
is hydrogen peroxide, said deoxidizing agent is sodium sulfite, and
said neutralization agent is disodium hydrogen phosphate.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to a manufacturing method and
an automatic manufacturing device thereof, especially to a
manufacturing method for .sup.123I-ADAM and an automatic
manufacturing device thereof applied to brain SPECT(single photon
emission computed tomography) imaging in nuclear medicine.
[0002] Nuclear medicine is a branch of medicine pertaining to
diagnostic, therapeutic and investigative use of radioactive
chemical elements. Radiopharmaceuticals are made from radioactive
nuclides (radioisotopes) that label various chemical elements.
These chemicals enter specific organs in human bodies and involve
in physiological mechanisms or biochemical reactions. By
scintillation camera, distribution and metabolism of radioisotopes
are learned so as to diagnose diseases. When diseases occur,
changes happen firstly in Physiology and Biochemistry and anatomy
the last. Thus, nuclear medical technology detects diseases in
early stage, and about three to six months earlier than other
tests. Earlier therapy leads to higher cure rates. Besides
diagnostic use, radioisotopes are also applied to cancer therapy. A
specific compound is labeled with therapeutic radioisotope and is
sent to the position required for treatment. By high energy
releasing from radioisotopes in short distance, the cancer cells
are killed while normal cells are not affected. Thus side effects
are reduced to minimum.
[0003] How are radiopharmaceuticals used? Nowadays
radiopharmaceuticals are applied to various fields in
medicine--ranging from Pediatrics, Psychiatry to Cardiology. The
use of radiopharmaceuticals ranges broadly, covering almost all of
important organs or systems. Besides specific, highly precise,
highly accurate diagnostic radiopharmaceuticals, new therapeutic
nuclear medicines have been developed rapidly. According to a
report from US Biotech in 2003, the use of therapeutic nuclear
medicines increases dramatically. Refer to a notice published by
department of health, Executive Yuan, the top ten leading causes of
death includes heart disease, Malignant neoplasms, liver diseases
and Cerebrovascular disease. Thus the domestic research and
development institutes are dedicated to early detection and
intervention of various diseases. Preventive medicine is one of the
most important fields to be developed in 21 century.
[0004] Nuclear medicine imaging visualizes a regional biochemical
and physiological function in living humans by administration of
radioactive agents. And a scintillation camera is used to detect
distribution and metabolism of the radioactive agents inside human
bodies for diagnosis of diseases. The radioactive agents in
clinical use are divided into two categories--the first is single
photon radionuclide that emits gamma ray with different energy
levels while decaying and is imaging by Single Photon Emission
Computed Tomography, (SPECT). The other is positron radionuclide
that decays by emitting a positron. This positron quickly stops and
annihilates with a nearby electron. In this annihilation
interaction, two coincident 511 keV gamma rays are produced. Then
Positron Emission Tomography (PET) is used to image.
[0005] Moreover, .sup.123I-ADAM is disclosed by a professor of
University of Pennsylvania, Hank F. Kung in 2000. The way he
synthesizes the ADAM is used thiosalicylic acid and
2,5-dibromonitrobenzene as reactants and the final product is
obtained after eight steps. The whole synthesis process takes quite
a long time.
[0006] The present invention improves the manufacturing processes.
There is no need to use High Performance Liquid Chromatographic
Column for separating and purifying products. Thus preparation
steps and time are saved. Moreover, not only the preparation time
is reduced, the yield rate is also increased.
SUMMARY OF THE INVENTION
[0007] Therefore it is a primary object of the present invention to
provide a manufacturing method for .sup.123I-ADAM (Iodine-123
labeled
2-([2-([dimethylamino]methyl)phenyl]thio)-5-.sup.123I-iodophenylamine
) and an automatic manufacturing device thereof so that the
radiochemical purity of products is over 90% and the average
labeled yield rate achieves 60%(decay corrected).
[0008] It is another object of the present invention to provide a
manufacturing method for .sup.123I-ADAM and an automatic
manufacturing device thereof that makes synthesis productivity of
the products over 50%.
[0009] In order to achieve objects, the present invention uses a
precursor--[2-((2-amino-4-tri-n-butyltinphenyl) thio) benzyl]
dimethylamine (SnADAM) to synthesize .sup.123I-ADAM. Firstly,
.sup.123I ammonium iodide solution is filled into a reaction bottle
and is mixed with the precursor-SnADAM. Then oxidation agent is
added into the mixture. Next the solution in the reaction bottle
flows through a C-8 column for adsorption and the filtrate is
discharged into a waste container. Elute the C-8 column with
ethanol, the eluant is filled into an empty tube and then wash the
column again in reverse direction. Then the eluant is filled into a
receiving bottle, mixed with normal saline and vitamin C. At last,
the solution is filtered by a filtration membrane to collect the
final product.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] The structure and the technical means adopted by the present
invention to achieve the above and other objects can be best
understood by referring to the following detailed description of
the preferred embodiments and the accompanying drawings,
wherein
[0011] FIG. 1 is a flow chart of an embodiment of a manufacturing
method according to the present invention;
[0012] FIG. 2 is a block diagram of an embodiment of an automatic
manufacturing device according to the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0013] Refer to the step S10 in FIG. 1, solution of a precursor
-[2-((2-amino-4-tri-n-butyltinphenyl) thio)benzyl]dimethylamine
(SnADAM) is mixed with ammonium iodide solution for being oxidized.
Then take the step S20, add a deoxidizing agent into the solution
to terminate the reaction. Next run the step S30, make the
neutralization reaction occur. Refer to step S40, fill the solution
into a column and then inject water for injection for washing the
column. Then run the step S50, after eluting the column with
ethanol, fill the eluant into a first receiving bottle and mix the
eluant with normal saline and Vitamin C. At last, take the step
S60, start the filtering process and the filtrate is
.sup.123I-ADAM.
[0014] Take an embodiment as an example. A precursor is mixed with
a small amount of [.sup.123I] ammonium iodide solution and hydrogen
peroxide is added for initiating the oxidation reaction. After five
minutes, sodium sulfite is added to terminate the reaction and then
disodium hydrogen phosphate is added for neutralization. Next, the
solution with pre-product is filled into a column for filtration.
The filtrate is filled into a waste container and then wash the
column with water for injection. Then elute the column with ethanol
and the ethanol needs to be to-and-fro in the column for at least
three times. Then the eluant is filled into a first receiving
bottle, mixed with normal saline and vitamin C(j). Finally, the
mixture is filtered by a sterile film with pore size such as 0.22
.mu.m and then is filled into a second receiving bottle so as to
obtain the final product required-.sup.123I-ADAM.
[0015] Refer to FIG. 2, an automatic manufacturing device includes
a plurality of reactant storage bottles 10, a reaction bottle 20, a
column 30, a first product storage bottle 40, a filtering device
50, a second product storage bottle 60.
[0016] The reaction bottle 20 connects with the reactant storage
bottles 10 by a plurality of pipelines 12 and the pipelines 12 are
disposed with a plurality of solenoid valves 14. Through a
transport pipe 32, the column 30 connects with the reaction bottle
20 and it also joins with an eluant storage bottle 36 by an elution
pipe 34. The first product storage bottle 40 is connected with the
column 30 by a first collection pipe 42 while the filtering device
50 connects with the first product storage bottle 40 by a filtering
pipe 52. The second product storage bottle 60 is connected with the
filtering device 50 by a second collection pipe 62.
[0017] By a central processing unit 70 that controls the solenoid
valves 14, the order and duration of reactants from the reactant
storage bottles 10 to the reaction bottle 20 are controlled.
Transportation of the pre-product from the reaction bottle 20 to
the column 30 through the transport pipe 32 as well as the eluant
from the eluant storage bottle 36 to the column 30 is controlled by
the central processing unit 70. After elution, the eluant is sent
to the first product storage bottle 40 through the first collection
pipe 42 for storage. Then a first product in the first product
storage bottle 40 is transported to the filtering device 50 by the
filtering pipe 52 for being filtered. Then the solution is further
transported into the second product storage bottle 60 through the
second collection pipe 62 for storage of the second product inside
the second product storage bottle 60. The way that the central
processing unit 70 controls transportation of each pipe is a prior
art. For example, through the design of valves in combination with
a motor, transportation of liquid is controlled by a central
processing unit or an electronic controller that controls each of
the solenoid valves, receives measured pressure signal and connects
with a personal computer so as to process the received signals and
controls the whole manufacturing processes of the synthetic system
according to the preset conditions. Thus an automatic or
semi-automatic operation is achieved. The column 30 is further
disposed with a liquid level monitoring device 38 for monitoring
pre-product of the column 30 and learning liquid level of pipelines
while eluting.
[0018] Take an embodiment as an example. The device according to
the present invention should be arranged inside the lead room. The
reactant storage bottles 10 respectively contain hydrogen peroxide,
sodium sulfite, disodium hydrogen phosphate, pure water and
[.sup.123I] ammonium iodide solution. The reaction bottle is a
bottom-pointed bottle with volume of 5 ml. The precursor weighted
100 .mu.g needs to be set into the reaction bottle in advance and
is dissolved in 50 .mu.l ethanol. The [.sup.123I] ammonium iodide
solution is produced with nuclear reactions induced by high-energy
proton beam generated by Cyclotron. In the beginning, carrier gas
is filled into the reaction bottle and is mixed with the precursor.
Then the hydrogen peroxide solution in the reactant storage bottle
is conducted into the reaction bottle by the carrier gas and is
aerated stirred for several seconds. In this embodiment, the
carrier gas is nitrogen gas. Then leave the reaction bottle
statically at the room temperature for five minutes. Next the
sodium sulfite in the reactant storage bottle is filled into the
reaction bottle by means of the carrier gas and is also aerated
stirred for several seconds by to terminate the reaction. The
disodium hydrogen phosphate in the reactant storage bottle is also
transported into the reaction bottle by the carrier gas and is
stirred for several seconds for neutralization. And the pre-product
is generated. During the process, gas generated and exhausted from
the reaction bottle is filtered by active charcoal so as to prevent
gas with .sup.123I from leaking into surroundings and causing
pollution.
[0019] After that, the pre-product in the reaction bottle is
conducted into the column for adsorption by the carrier gas.
Depending on users needs, the carrier gas can be disposed with flow
and pressure adjustment device. The filtrate is filled into the
waste container. Subsequently, by carrier gas, part of the water
for injection in the reactant storage bottle is drawn through the
control valve, filled into the reaction bottle and stirred for
seconds. Then the residual pre-product in the reaction bottle is
conducted into the column and the filtrate is filled into the waste
container. Next, by carrier gas, the rest water for injection in
the reactant storage bottle passes through the control valve,
filled into the column for washing out the un-reacted precursor or
drugs. Only pre-product is adsorbed by the column.
[0020] In the next step, ethanol inside the reactant storage bottle
passing through the control valve is filled into the column by
means of the carrier gas for eluting the adsorbed pre-product. In
order to enhance elution effects, ethanol inside the column is not
flowing into the receiving bottle. Instead, the ethanol is filled
into an empty tube by means of carrier gas in combination with the
control valve. An infrared liquid level sensor between the column
and the empty tube is used to monitor whether the ethanol runs out.
Once the ethanol flows out of the column completely, the direction
of the carrier gas is changed to the reverse direction so as to
make the ethanol flows from the empty tube into the column. When
the ethanol flows out of the empty tube completely, the direction
of the carrier gas is changed once again so that the ethanol flows
from the column into the empty tube. After repeating the above
steps for about five times, the ethanol inside the column is filled
into the receiving bottle by carrier gas. At last, the ore-product
is transported from the first product storage bottle by the carrier
gas, passing through the control valve, and filtered by a
filtration membrane with pore size of 0.22 .mu.m for purification.
Thus the product of .sup.123I-ADAM is obtained and received inside
a sterile second product storage bottle.
[0021] It takes only twenty minutes from finishing preparation of
reactants to obtaining the final product by an automatic
manufacturing device according to the present invention. This
matches requirements of the automatic synthesis system for
manufacturing short half-life nuclear medicine. At room
temperature, it takes five minutes for the precursor to react with
hydrogen peroxide while filling the solution into the column for
adsorption needs about 1 minute. Then it takes five minutes to wash
the column. Another five minutes is to elute the column up and down
with ethanol and the eluant is filled into the first product
storage bottle. The filtering and collecting process needs about
three minutes. After repeating tests for several times, it shows
that each step of the manufacturing process are carried out
precisely according to commands from a control program. Variations
in liquid level, pressure and radiation intensity inside pipelines
are monitored during the whole manufacturing process. Moreover, the
reaction finishes within twenty minutes.
[0022] Additional advantages and modifications will readily occur
to those skilled in the art. Therefore, the invention in its
broader aspects is not limited to the specific details, and
representative devices shown and described herein. Accordingly,
various modifications may be made without departing from the spirit
or scope of the general inventive concept as defined by the
appended claims and their equivalents.
* * * * *