Hydrophilic and lipophilic radiopharmaceuticals as tracers in pharmaceutical development: In vitro – In vivo studies

BACKGROUND: Scintigraphic studies have been performed to assess the release, both in vitro and in vivo, of radiotracers from tablet formulations. Four different tracers with differing physicochemical characteristics have been evaluated to assess their suitability as models for drug delivery. METHODS: In-vitro disintegration and dissolution studies have been performed at pH 1, 4 and 7. In-vivo studies have been performed by scintigraphic imaging in healthy volunteers. Two hydrophilic tracers, ((99m)Tc-DTPA) and ((99m)Tc-MDP), and two lipophilic tracers, ((99m)Tc-ECD) and ((99m)Tc-MIBI), were used as drug models. RESULTS: Dissolution and disintegration profiles, differed depending on the drug model chosen. In vitro dissolution velocity constants indicated a probable retention of the radiotracer in the formulation. In vivo disintegration velocity constants showed important variability for each radiopharmaceutical. Pearson statistical test showed no correlation between in vitro drug release, and in vivo behaviour, for (99m)Tc-DTPA, (99m)Tc-ECD and (99m)Tc-MIBI. High correlation coefficients were found for (99m)Tc-MDP not only for in vitro dissolution and disintegration studies but also for in vivo scintigraphic studies. CONCLUSION: Scintigraphic studies have made a significant contribution to the development of drug delivery systems. It is essential, however, to choose the appropriate radiotracers as models of drug behaviour. This study has demonstrated significant differences in release patterns, depending on the model chosen. It is likely that each formulation would require the development of a specific model, rather than being able to use a generic drug model on the basis of its physicochemical characteristics

CONTINUING EDUCATION IN RADIOPHARMACY IN LATIN AMERICA

Introduction/Justification: Radiopharmacy is an area with increasing development and technological complexity. According to WHO´s official documents (WHO Annex 2,3) the production of radiopharmaceuticals requires the supervision of qualified personnel with postgraduate training and appropriate experience in their function. Although most countries in Latin America have adopted these documents in their legislation the real situation is highly heterogeneous and specific qualification in Radiopharmacy is not clearly specified in the national regulations. Furthermore, the adequate educational offer is very restricted and heterogeneous in all Latin American countries. Objectives: With the objective to prepare the future generations of Radiopharmacists according to international and national regulations we have developed a series of options for postgraduate and continuing education in the field. Materials and Methods: N/A. Results: The Diploma of Specialization in Radiopharmacy offers a postgraduate program for specialization in Radiopharmacy. This diploma integrates comprehensive theoretical knowledge with the necessary practical experience to prepare professionals for specialized roles in this field. Admission to the program requires candidates to hold a university degree, with a minimum duration of four years, in Pharmacy, Chemistry, or Biochemistry, obtained from institutions in Uruguay or other countries. Applications from candidates with alternative qualifications are reviewed by a dedicated admission committee, and additional courses may be prescribed to supplement their foundational knowledge. The curriculum comprises both theoretical and practical components, totaling approximately 300 hours of instruction. The courses can be partially performed virtually, thus facilitating the participation of foreign students. However, practical laboratory sessions and supervised practice are required to be completed in Uruguay, typically spanning a duration of 3-4 months. Additionally, partial validation of prior studies may be considered, allowing eligible students to receive credit for relevant coursework completed elsewhere. Besides the postgraduate program we also offer the possibility of taking continuous education courses both with basic (physics of radiation, chemistry of radiopharmaceuticals, etc) and applied topics (legislation, clinical applications, et). We also offer customized courses for institutions or private radiopharmaceutical firms. Up to the moment we have more than 10 graduates, 40% coming from Colombia, Costa Rica or Bolivia and 7 students, 6 of which are from different countries in Latinamerica. Our continuing education courses have been taken by around 100 professionals from Chile, Costa Rica, México, Bolivia, Ecuador, Perú, Costa Rica, Panamá, República Dominicana, etc. Conclusão: Radiopharmacy is a flourishing specialty of increasing complexity that requires solid theoretical knowledge and specialized practical skills. The Radiochemistry Area in the public University of Uruguay is fostering the development and generational replacement in our continent with the objective to improve the quality of the Radiopharmaceuticals received by our population. Acknowledgments: Centro Uruguayo de Imagenología molecular, CUDIM and Centro de Medicina Nuclear e Imagenología Molecular del Hospital de Clínicas

Scintigraphy in pharmaceutical development stage / in vitro / in vivo studies of Ranitidine tablets

El presente trabajo tiene como objetivo evaluar la utilidad de los estudios centellográficos in vitro e in vivo en el desarrollo de una formulación farmacéutica. Se eligió como trazador del proceso el radiofármaco 99mTc-ácido dietilentriaminopentaacético, que se incorporó a 4 formulaciones (F1 a F4) de comprimidos de ranitidina. Se llevaron a cabo estudios de estabilidad del radiofármaco en polvos, granulados y comprimidos. Las formulaciones en las cuales se verificó su estabilidad durante 24 h (F2 y F4) fueron utilizadas para ensayos in vitro de disolución y desintegración y estudios en 6 voluntarios sanos. La desintegración in vitro e in vivo fue monitoreada por centellografía gamma. El radiofármaco presentó diferentes cinéticas de disolución a partir de F2 y F4, siendo las respectivas constantes del mismo orden que para la ranitidina en cada formulación en estudio. La centellografía posibilitó establecer una correlación entre las constantes de desintegración in vitro e in vivo. Esto permitiría predecir el comportamiento en el tracto gastro-intestinal de cada formulación a partir de la desintegración in vitro. Los estudios centellográficos brindan información relevante con economía de tiempo en etapas de desarrolloScintigraphic studies in vitro and in vivo were carried out to evaluate their utility in the development of pharmaceutical forms. A radiopharmaceutical (99mTc-dietilentríaminepentacetic acid) was incorporated as the tracer in four tablet formulations (F1 to F4) of ranitidine. Stability of the radiopharmaceutical with the excipients, granulates and tablets was assesed. Those formulations where the tracer verified stability during 24 hours (F2 and F4) were tested through dissolution and desintegration studies. Scintigraphic images were acquired in gamma camera after administration of ranitidine tablets to 6 healthy volunteers. The radiopharmaceutical showed different dissolution profiles from F2 and F4, The dissolution constants for ranitidine and the radiopharmaceutical had similar values in each formulation. A correlation between in vitro/in vivo disintegration was established. This would enable to predict gastro-intestinal transit from in vitro disintegration data. Scintigraphic studies give relevant information in short time during development stages of a pharmaceutical dosage.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Scintigraphy in pharmaceutical development stage / in vitro / in vivo studies of Ranitidine tablets

El presente trabajo tiene como objetivo evaluar la utilidad de los estudios centellográficos in vitro e in vivo en el desarrollo de una formulación farmacéutica. Se eligió como trazador del proceso el radiofármaco 99mTc-ácido dietilentriaminopentaacético, que se incorporó a 4 formulaciones (F1 a F4) de comprimidos de ranitidina. Se llevaron a cabo estudios de estabilidad del radiofármaco en polvos, granulados y comprimidos. Las formulaciones en las cuales se verificó su estabilidad durante 24 h (F2 y F4) fueron utilizadas para ensayos in vitro de disolución y desintegración y estudios en 6 voluntarios sanos. La desintegración in vitro e in vivo fue monitoreada por centellografía gamma. El radiofármaco presentó diferentes cinéticas de disolución a partir de F2 y F4, siendo las respectivas constantes del mismo orden que para la ranitidina en cada formulación en estudio. La centellografía posibilitó establecer una correlación entre las constantes de desintegración in vitro e in vivo. Esto permitiría predecir el comportamiento en el tracto gastro-intestinal de cada formulación a partir de la desintegración in vitro. Los estudios centellográficos brindan información relevante con economía de tiempo en etapas de desarrolloScintigraphic studies in vitro and in vivo were carried out to evaluate their utility in the development of pharmaceutical forms. A radiopharmaceutical (99mTc-dietilentríaminepentacetic acid) was incorporated as the tracer in four tablet formulations (F1 to F4) of ranitidine. Stability of the radiopharmaceutical with the excipients, granulates and tablets was assesed. Those formulations where the tracer verified stability during 24 hours (F2 and F4) were tested through dissolution and desintegration studies. Scintigraphic images were acquired in gamma camera after administration of ranitidine tablets to 6 healthy volunteers. The radiopharmaceutical showed different dissolution profiles from F2 and F4, The dissolution constants for ranitidine and the radiopharmaceutical had similar values in each formulation. A correlation between in vitro/in vivo disintegration was established. This would enable to predict gastro-intestinal transit from in vitro disintegration data. Scintigraphic studies give relevant information in short time during development stages of a pharmaceutical dosage.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Development and Evaluation of ^99mTc Tricarbonyl Complexes Derived from Flutamide with Affinity for Androgen Receptor

With the objective to develop a potential 99mTc radiopharmaceutical for imaging the androgen receptor (AR) in prostate cancer, four ligands bearing the same pharmacophore derived from the AR antagonist flutamide were prepared, labeled with 99mTc, and their structures corroborated via comparison with the corresponding stable rhenium analogs. All complexes were obtained with high radiochemical purity. Three of the complexes were highly stable, and, due to their favorable physicochemical properties, were further evaluated using AR-positive and AR-negative cells in culture. All complexes exhibited considerable uptake in AR-positive cells, which could be blocked by an excess of flutamide. The efflux from the cells was moderate. They also showed significantly lower uptakes in AR-negative cells, indicating interactions with the AR receptor. However, the binding affinities were considerably reduced by the coordination to 99mTc, and the complex that exhibited the best biological behavior did not show sufficient specificity towards AR-positive cells

Multi-centre evaluation of accuracy and reproducibility of planar and SPECT image quantification: An IAEA phantom study

International audienceAccurate quantitation of activity provides the basis for internal dosimetry of targeted radionuclide therapies. This study investigated quantitative imaging capabilities at sites with a variety of experience and equipment and assessed levels of errors in activity quantitation in Single-Photon Emission Computed Tomography (SPECT) and planar imaging. Participants from 9 countries took part in a comparison in which planar, SPECT and SPECT with X ray computed tomography (SPECT-CT) imaging were used to quantify activities of four epoxy-filled cylinders containing 133Ba, which was chosen as a surrogate for 131I. The sources, with nominal volumes of 2, 4, 6 and 23mL, were calibrated for 133Ba activity by the National Institute of Standards and Technology, but the activity was initially unknown to the participants. Imaging was performed in a cylindrical phantom filled with water. Two trials were carried out in which the participants first estimated the activities using their local standard protocols, and then repeated the measurements using a standardized acquisition and analysis protocol. Finally, processing of the imaging data from the second trial was repeated by a single centre using a fixed protocol. In the first trial, the activities were underestimated by about 15% with planar imaging. SPECT with Chang's first order attenuation correction (Chang-AC) and SPECT-CT overestimated the activity by about 10%. The second trial showed moderate improvements in accuracy and variability. Planar imaging was subject to methodological errors, e.g., in the use of a transmission scan for attenuation correction. The use of Chang-AC was subject to variability from the definition of phantom contours. The project demonstrated the need for training and standardized protocols to achieve good levels of quantitative accuracy and precision in a multicentre setting. Absolute quantification of simple objects with no background was possible with the strictest protocol to about 6% with planar imaging and SPECT (with Chang-AC) and within 2% for SPECT-CT