Research paperUsage of radiopharmaceuticals in the development of pharmaceutical drug delivery systems: validation of [99mTc]DTPA and [99mTc]ECD
Introduction
During the last 20 years, very important improvements have been achieved in pharmaceutical dosage formulation using radiopharmaceuticals as tracers [1], [2], [3], but only a few systematic studies have been performed to validate the methodology. Radiopharmaceuticals in nuclear medicine were primarily developed for diagnosis purposes and most of them were administered parenterally. In order to optimise the usage of radiopharmaceuticals in the development of pharmaceutical drug delivery systems, the behaviour of the tracers administered by routes other than the normal must be validated in different dissolution media and in the presence of pharmaceutical excipients [4], [5]. Our group has performed stability and in vitro studies of different radiopharmaceuticals with the aim of creating a database of tracers with known physicochemical properties to be used as model drugs in pharmaceutical dosage development [6], [7], [8], [9].
The objective of this study is to examine the way radiotracers model the release of drugs from tablet formulations and to validate the feasibility and limitations of two radiotracers with different physicochemical characteristics through basic in vitro studies. The possibility of developing a database of the physicochemical behaviour of radiotracers would allow selection of the most appropriate drug models when using scintigraphic techniques in the development of pharmaceutical dosage forms [10], [11], [12], [13], [14].
The characterised radiopharmaceuticals were [99mTc]diethylenetriamine-pentaacetic acid ([99mTc]DTPA) and [99mTc]ethyl cysteinate dimer ([99mTc]ECD) [15] which were incorporated into tablets during wet granulation. Tablets with drugs of different lipophilicity, ranitidine and cinarizine, and placebo were prepared as previously reported by our group [16]. Dissolution and disintegration profiles were assessed at different pH values (1, 4 and 7) [17], [18], [19].
Section snippets
Radiopharmaceuticals labelling
[99mTc]DTPA and [99mTc]ECD were obtained by labelling commercial kits with [99mTc]pertechnetate obtained from an Elumatic III generator (Schering CIS)®. Radiochemical purity tests were performed by chromatographic systems using Whatman No. 1/propanone and Whatman No. 1/NaCl 0.9% for [99mTc]DTPA complex. [99mTc]ECD radiochemical purity was studied by chromatography in Whatman No. 1/methanol 85% and HPLC (Shimadzu LC-10 AS) using a Partisphere C18 (Whatman) Column as stationary phase and the
Labelling process
Tracers [99mTc]DTPA and [99mTc]ECD were prepared with radiochemical purity higher than 99% [21].
Stability studies
No physicochemical change of the radiotracer was observed after 120 min incubation of [99mTc]DTPA with the dissolution media at pH 1, 4 and 7 and after the process of wetting and drying the components of the formulation.
The w/o coefficient for [99mTc]DTPA was 0.95 in the saline phase.
[99mTc]ECD during the granulation process showed no changes in radiochemical purity. When it was incubated in the
Discussion
According to the results [99mTc]DTPA is a suitable model for the dissolution of a polar drug such as ranitidine. This is supported by the fact that the dissolution velocity constants of both drug and tracer are of the same order at pH 7 (Table 1). It should be taken into account that according to USP XXV, the dissolution test for ranitidine should be performed at pH 7. Also disintegration studies showed similar profiles (Fig. 1, Fig. 2) as confirmed by scintigraphic studies. [99mTc]DTPA was a
Conclusions
Dissolution studies demonstrate differences in behaviour between similar formulations containing different drugs, presumably due to the physicochemical nature of the drugs themselves and interactions with the tracer. Scintigraphic studies of the disintegration process did not show significant differences between placebos and tablets containing active drugs. As disintegration is a physical process it does not discriminate between chemical differences in tablet formulations. This method does show
Acknowledgements
The authors thank TECHI S.A. for supplying radiopharmaceutical kits and Centro de Medicina Nuclear, Hospital de Clı́nicas for Nuclear Medicine equipment facilities.
References (22)
- et al.
Imaging of oily formulations in the gastrointestinal tract
Adv. Drug Deliv. Rev.
(1997) - et al.
Imaging techniques for assessing drug delivery in man
Pharm. Sci. Technol. Today
(1999) - et al.
Esophageal transit of risedronate cellulose-coated tablet and gelatin capsule formulations
Int. J. Pharm.
(1999) - et al.
Nuclear Medicine in Pharmaceutical Research
(1999) Advances in Pharmaceutical Sciences
(1992)- et al.
The use of small volume ocular sprays to improve the bioavailability of topically applied ophthalmic drugs
Eur. J. Biopharm.
(2003) - et al.
Deposition of aqueous aerosol of [99mTc]DTPA and delivered by novel system (AERx) in healthy subjects
Eur. J. Nucl. Med.
(1999) - et al.
Gamma scintigraphy in the evaluation of pharmaceutical dosage forms (Review article)
Eur. J. Nucl. Med.
(1992) - O. Kosch, Magnetic markers in gastroenterology, Bioelect Biomagnet,...
- et al.
An evaluation of gastro-resistant pulsed release delivery system (Pulsincap) in man
J. Drug Deliv.
(1997)
Nuclear medicine techniques in the evaluation of pharmaceutical formulations
Pharm. World Sci.
Cited by (5)
Gamma scintigraphy in the analysis of ketoprofen behaviour from matrix tablets
2013, International Journal of PharmaceuticsCitation Excerpt :The most serious cases, although rare, are associated to hypersensitivity (allergy) through anaphylactic shock of the patient upon reaction to the unusually chemical agent (Al-Ghananeem et al., 2008). Moreover, comparative with in vitro release assays using both conventional and modified dissolution methods can provide an insight into the performance of drug-delivery systems, and radionuclides incorporated into the dosage form can yield evidence on the in vivo behaviour of these formulations (Terán et al., 2004). Reported studies using X-ray methods give useful information on the gastric emptying of dosage forms, as well as on their passage through the intestine (McDowell et al., 2005), but the gastric emptying of dosage forms is highly variable and generally delayed in the presence of food (Ghimire et al., 2011).
Synthesis, radiolabelling and biodistribution of HYNIC-Tyr<sup>3</sup> octreotide: A somatostatin receptor positive tumour imaging agent
2011, Journal of Radioanalytical and Nuclear ChemistrySynthesis and biological evaluation of <sup>99m</sup>Tc-DHPM complex: A potential new radiopharmaceutical for lung imaging studies
2010, Journal of Radioanalytical and Nuclear Chemistry