Radiolabeling of intact tablets by neutron activation for in vivo scintigraphic studies
2
Radiolabeling of Intact Tablets by Neutron Activation for In Vivo Scintigraphic Studies To the Editor: External scintigraphy has been used extensively in these laboratories to monitor the biodistribution and biopharmaceut- ical parameters of various radiolabeled dosage forms including tablets,’ capsules,2 suppositories: enema^,^ aerosol^,^ and oth- ers. The dosage forms are usually radiolabeled by incorporating a radionuclide such as technetium-99m or indium-111 during preparation. This is often a simple procedure for preparing radiolabeled solutions or suspensions, but complications may occur in the preparation of some radiolabeled capsules or tab- lets, particularly if they are enterically coated. Some of the problems which may occur are: (a) production time may be too long to be amenable to labeling with short-lived radionuclides; (b) special equipment may be required which may not be easily decontaminated or may itself cause a contamination problem in the facility during production; (c) the labeling procedure may not be applicable to multiparticulate dosage forms or inert drug delivery devices, or may compromise the integrity of the dosage form; (d) on-site preparation of radiolabeled dosage forms is limited to the handling of relatively small volumes of materials, and the products may not accurately represent the same dosage forms produced under industrial scale conditions. This com- munication describes a neutron activation procedure in which intact tablets containing small amounts of BaSO., were irradi- ated in a nuclear reactor to produce 13’Ba-labeled tablets. This procedure has the potential to overcome the problems listed above for conventional labeling experiments. Tablets (300 mg) manufactured using a direct compression method and composed of lactose (272 mg), starch (15 mg), magnesium stearate (3 mg), and barium sulfate (10 mg) were prepared and irradiated intact in a flux trap type 10 MW steady-state reactor (University of Missouri Research Reactor, Columbia, MO). The tablets were irradiated for a period of 15 min in a neutron flux of 4.4 x lOI3 neutrons/cm2/s. The theoretical yield for the production of barium-139 from barium- 138 (71.6% natural abundance) can be calculated from the following equation: where A is the activity of barium-139 produced at time .td after the end of neutron bombardment, N is the number of barium- 138 nuclei present initially, 0 is the neutron capture cross- section for barium-138, C$ is the neutron flux, X is the decay constant for barium-139, and ti is the time of irradiation. Thus, 5 h after the end of irradiation, we expect to have 3.13 X lo6 dps (84.5 pCi) of barium-139 in each tablet. The actual meas- ured amount of barium-139 in a dose calibrator was 91 pCi per tablet (the dose calibrator is accurate to +lo% for barium-139). This permitted ample time to ship the irradiated tablets on a singie-engine plane a distance of 460 miles (740 km) to our imaging facilities. Increasing the amount of BaS04 in the tablets will increase the ultimate amount of radioactivity formed per tablet, but may also alter the dosage form. Prolon- 590 /Journal of Pharmaceutical Sciences Vol. 74, No. 5, May 1985 gation of the time of irradiation will also increase the produc- tion of barium-139, but may possibly result in the formation of radiochemical impurities. Under the conditions we employed, the only radiochemical impurity of significance detected by assay in a high resolution Ge(Li) semiconductor detector inter- faced with a multichannel analyzer was sodium-24, which had gamma photon energies of 1.37 and 2.75 MeV. In a tablet containing 930 pCi of barium-139 (0.167 MeV) immediately after irradiation, the amount of sodium-24 contaminant formed was 0.11 pCi. The distribution of radioactivity throughout these tablets was found to be uniform. The radiolabeled tablets were administered to dogs that had been positioned before a gamma scintillation camera, and the disintegration rate and gastric retention time were determined. Figure 1 shows the intact tablet in the stomach of the dog 3 min after administration and Figure 1-Posterior scintigraphic images of a 13gBa-labeled tablet 3 min and 25 min after oral administration to a dog. the disintegrated tablet after 25 min. The disintegration of the dosage form in the GI tract was easily observable as with other external scintigraphic studies of radiolabeled dosage forms.’ Thus, the tablets containing barium-139, which has a gamma photon energy of 0.167 MeV and a half-life of 83 min, also proved to be amenable to external scintigraphic studies. The initial dosimetry estimates (Oak Ridge Associated Universities Radiopharmaceutical Dose Information Center) indicated that the I3’Ba-labeled dosage forms can be used for human studies with radiation dose levels comparable to “‘In-labeled dosage forms (whole body dose = 0.0016 rad/50 pCi). The advantages of incorporating a nonradioactive label into intact dosage forms or complex devices which feature controlled release patterns would permit the most optimized formulation skills to be employed in the preparation of such delivery sys- tems. Thus, neutron activation methods permit noninvasive 0022-3549/85/0500-0590$0 1.00/0 0 1985, American Pharmaceutical Association
Transcript of Radiolabeling of intact tablets by neutron activation for in vivo scintigraphic studies
Radiolabeling of Intact Tablets by Neutron Activation for In Vivo Scintigraphic Studies
To the Editor: External scintigraphy has been used extensively in these
laboratories to monitor the biodistribution and biopharmaceut- ical parameters of various radiolabeled dosage forms including tablets,’ capsules,2 suppositories: enema^,^ aerosol^,^ and oth- ers. The dosage forms are usually radiolabeled by incorporating a radionuclide such as technetium-99m or indium-111 during preparation. This is often a simple procedure for preparing radiolabeled solutions or suspensions, but complications may occur in the preparation of some radiolabeled capsules or tab- lets, particularly if they are enterically coated. Some of the problems which may occur are: (a) production time may be too long to be amenable to labeling with short-lived radionuclides; (b) special equipment may be required which may not be easily decontaminated or may itself cause a contamination problem in the facility during production; (c) the labeling procedure may not be applicable to multiparticulate dosage forms or inert drug delivery devices, or may compromise the integrity of the dosage form; ( d ) on-site preparation of radiolabeled dosage forms is limited to the handling of relatively small volumes of materials, and the products may not accurately represent the same dosage forms produced under industrial scale conditions. This com- munication describes a neutron activation procedure in which intact tablets containing small amounts of BaSO., were irradi- ated in a nuclear reactor to produce 13’Ba-labeled tablets. This procedure has the potential to overcome the problems listed above for conventional labeling experiments.
Tablets (300 mg) manufactured using a direct compression method and composed of lactose (272 mg), starch (15 mg), magnesium stearate (3 mg), and barium sulfate (10 mg) were prepared and irradiated intact in a flux trap type 10 MW steady-state reactor (University of Missouri Research Reactor, Columbia, MO). The tablets were irradiated for a period of 15 min in a neutron flux of 4.4 x l O I 3 neutrons/cm2/s. The theoretical yield for the production of barium-139 from barium- 138 (71.6% natural abundance) can be calculated from the following equation:
where A is the activity of barium-139 produced a t time .td after the end of neutron bombardment, N is the number of barium- 138 nuclei present initially, 0 is the neutron capture cross- section for barium-138, C$ is the neutron flux, X is the decay constant for barium-139, and ti is the time of irradiation. Thus, 5 h after the end of irradiation, we expect to have 3.13 X lo6 dps (84.5 pCi) of barium-139 in each tablet. The actual meas- ured amount of barium-139 in a dose calibrator was 91 pCi per tablet (the dose calibrator is accurate to +lo% for barium-139). This permitted ample time to ship the irradiated tablets on a singie-engine plane a distance of 460 miles (740 km) to our imaging facilities. Increasing the amount of BaS04 in the tablets will increase the ultimate amount of radioactivity formed per tablet, but may also alter the dosage form. Prolon-
590 /Journal of Pharmaceutical Sciences Vol. 74, No. 5, May 1985
gation of the time of irradiation will also increase the produc- tion of barium-139, but may possibly result in the formation of radiochemical impurities. Under the conditions we employed, the only radiochemical impurity of significance detected by assay in a high resolution Ge(Li) semiconductor detector inter- faced with a multichannel analyzer was sodium-24, which had gamma photon energies of 1.37 and 2.75 MeV. In a tablet containing 930 pCi of barium-139 (0.167 MeV) immediately after irradiation, the amount of sodium-24 contaminant formed was 0.11 pCi. The distribution of radioactivity throughout these tablets was found to be uniform. The radiolabeled tablets were administered to dogs that had been positioned before a gamma scintillation camera, and the disintegration rate and gastric retention time were determined. Figure 1 shows the intact tablet in the stomach of the dog 3 min after administration and
Figure 1-Posterior scintigraphic images of a 13gBa-labeled tablet 3 min and 25 min after oral administration to a dog.
the disintegrated tablet after 25 min. The disintegration of the dosage form in the GI tract was easily observable as with other external scintigraphic studies of radiolabeled dosage forms.’ Thus, the tablets containing barium-139, which has a gamma photon energy of 0.167 MeV and a half-life of 83 min, also proved to be amenable to external scintigraphic studies. The initial dosimetry estimates (Oak Ridge Associated Universities Radiopharmaceutical Dose Information Center) indicated that the I3’Ba-labeled dosage forms can be used for human studies with radiation dose levels comparable to “‘In-labeled dosage forms (whole body dose = 0.0016 rad/50 pCi).
The advantages of incorporating a nonradioactive label into intact dosage forms or complex devices which feature controlled release patterns would permit the most optimized formulation skills to be employed in the preparation of such delivery sys- tems. Thus, neutron activation methods permit noninvasive
0022-3549/85/0500-0590$0 1.00/0 0 1985, American Pharmaceutical Association
formulation and retention of basic integrity since the marker can be incorporated as a normal excipient in the dosage form or device. The production of iron-59 by neutron activation for the study of iron absorption after oral administration has recently been reported by Christensen and co-workers.6 How- ever, the extremely low production yield and unfavorable half- life and gamma photon energies preclude the use of this isotope for human studies. We are currently investigating the use of I3’Ba-labeled tablets in human subjects. In addition, we are exploring the possibility of using tablets containing gold-197, erbium-170, and samarium-152 for the production of gold-198, erbium-171, and samarium- 153 by neutron activation, respec- tively. These radionuclides omit gamma rays of suitable energy for external detection with half-lives ranging from 7.5 h to 2.7 d. Thus, a considerable number of isotopes with varying half- lives can be chosen for neutron activation studies depending on the desired application.
References and Notes Digenis, G. A. in “Radionuclide Imaging in Drug Research”; Wil- son, C. G.; Hardy, J . G.; Davis, S. S.; Frier, M., Eds.; Croon Helm: London, 1982; pp 103-143. Casey, D. L.; Beihn, R. M.; Digenis, G. A.; Shambhu, M. B. J. Pharm. Sci. 1976, 65, 141Z!. Jay, M.; Beihn, R. M.; Snyder, G. A.; McClanahan, J. S.; Digenis, G. A.; Caldwell, L.; Mlodoztmiec, A. Int. J. Phurm. 1983, 14,343.
4. Jay, M.; Digenis, G. A.; Foster, T. S.; Antonow, D. R. unpublished
5. Smith, M. F.; Bryant, S.; Welch, S.; Digenis, G. A. J. Phurm. Sci.
6. Christensen, J. M.; Ghannam, M.; Ayers, J. W. J. Pharm. Sci.
results.
1984, 73,1091.
1984, 73, 1529.
Acknowledgments The authors are grateful to Mr. James Carni for sample irradiations,
Ms. Susan Yonts for assistance with external imaging, Dr. James E. Chaney for air delivery of the radioactive doses, and INTEK, Merck, Sharp & Dohme Research Laboratories for financial support.
ALAN PAW* MICHAEL JAY” GEORGE A. DIGENIS** ROBERT M. BEIHN*
Divisions of ‘Medicinal Chemistry
Colleges of Pharmacy and Medicine University of Kentucky Lexington, KY 40536
and *Nuclear Medicine
Received October 26, 1984 Accepted for publication February 5, 1985.
Journal of Pharmaceutical Sciences I 5 9 1 Vol. 74, No. 5, May 1985
![Strategies of regioselective radiolabeling of Nanofitin binder for … · 2015-06-23 · STRATEGIES OF REGIOSELECTIVE RADIOLABELING OF NANOFITIN BINDER FOR IMAGING Goux M.[1,2,*],](https://static.fdocuments.us/doc/165x107/5f9b4c8acec93f523e0a009b/strategies-of-regioselective-radiolabeling-of-nanofitin-binder-for-2015-06-23.jpg)
