contributions of radiopharmaceuticals to dosage formulation
TRANSCRIPT
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Contributions ofradiopharmaceuticals to dosage
formulation development
Dra.Mariella Terán
Radiochemistry Department
Montevideo [email protected]
Development of new drug formulations requires theperformance of extensive studies
• in the laboratory• in vivo (animals and volunteers)
In vitro studies can be very expensive but costs areeven higher when in vivo stages are reached.
INTRODUCTION
A methodology that can generate relevant informationmeans important savings in economic, human and timeterms.
Gamma scintigraphy provides rapid, complementaryinformation that often cannot be obtained by othermethodologies.
It has been successfully used during:
• development stages of feasibility studies
• determining specific parameters of the final product.
The information obtained by scintigraphy gives supportduring investigation and development, and alsocomplements the development of registration dossiersand marketing publicity.
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The incorporation of a radiopharmaceutical into a drugformulation allows determination of:
• the biodistribution kinetics• the release sites
It is very important to choose the proper radionuclide,often 99mTc (technetium), as this has optimalcharacteristics of :
• half-life (6 hours)• energy (141 KeV)•Availability from generator
• Images can be obtained with high efficiency and lowdoses.
• Many studies to validate the methodology mentionedabove have already been undertaken , but, in generalwithin these studies, radiopharmaceuticals are onlyrarely used as drug surrogates.
Drug delivery studies in gastrointestinal tract
Selective delivery of aradiopharmaceutical in aparticular place like colonmaximises thetherapeutic concentration.The exposure of the rest ofthe body is minimised andsecondary effects are alsodiminishedEx : Ulcerative colitis can betreated with high localsteroids doses.
Courtesy of A.Perkins and M. Frier
Nuclear Medicine in PharamaceuticalResearch
The administration of drugsdirectly in the lungs , providesof a high therapeutic index,allowing to use low doses in thesite of action.The main factor is the particlesize, <5µ oropharyngeal andairways and 0.5<5µ in lungs.Studies with radiotracers canestablish the viability of theformulation and if the way it isadministered is properly done.
Drug delivery studies in respiratory tract
Courtesy of A.Perkins and M. Frier
Nuclear Medicine in PharamaceuticalResearch
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Topic way is the most usedmethod for drugadministratrion in the eyes. Intheory when the drug isintroduced in the inner cantusit should act immediatelly andavoid first pass metabolism. Infact there is a rapid precorneal depuration, ineficientabsorption of the cornea andlosses via lacrimal secretion.
Drug delivery studies in the eyes
Courtesy of A.Perkins and M. Frier
Nuclear Medicine in PharamaceuticalResearch
In order to optimize the usage of radiopharmaceuticalsin the development of pharmaceutical drug-deliverysystems, the behaviour of these tracers followingadministration by other routes must be validated.
Radiopharmaceuticalswere primarilydeveloped fordiagnostic purposesin nuclear medicine,most of them beingintended forintravenousadministration.
Provided that the tablet formulation can beradiolabelled with a suitable gamma emitter withoutaltering its characteristics, imaging with a gammacamera can be used to monitor
• in vivo transit and dispersion of the tablet
• give some indication of deposition
• absorption of the drug.
The objective of our work was to :
• Examine the way radiotracers model the release ofdrugs from tablet formulations
• Validate the feasibility and limitations of fourradiotracers with different physicochemical characteristicsthrough basic in vitro and in vivo studies.
• Evaluate the possibility of developing a database of thephysicochemical behaviour of radiotracers that wouldallow selection of the most appropriate drug models usingscintigraphic techniques.
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The characterised radiopharmaceuticals were:
• 99mTc-DTPA• 99mTc-ECD• 99mTc-MDP• 99mTc-MIBI
Tablets with drugs of different lipophilicity , ranitidineand cinarizine, and placebo were prepared.
• Radiopharmaceuticals were incorporated intotablets during wet granulation.
• Four different formulations were studied
Dissolution and disintegration profiles were assessedat different pH values (1,4 and 7).
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Scintigraphic images of dissintegration process
In vitro disolution studies
99mTc-DTPA - Ranitidine
-20,00
-10,00
0,00
10,00
20,00
30,00
40,00
50,00
60,00
70,00
80,00
0 5 10 15 20 25 30 35 40 45
time (min)
% d
iss
pH1
pH4
pH7
99m Tc- ECD -Ranitidine
-5
0
5
10
15
20
0 5 10 15 20 25 30
time (min)
% d
iss
pH1
pH4
pH7
a)
In vitro disolution studies
In vitro disintegration studies
99mTc-ECD Placebo
0,00
20,00
40,00
60,00
80,00
100,00
120,00
140,00
0 5 10 15 20 25 30
time (min)
% d
isin
t pH1
pH4
pH7
c)
In vitro disintegration velocity constants
0
0,02
0,04
0,06
0,08
0,1
0,12
99mTc-DTPA-
ranit
99mTc-DTPA-
cinar
Placebo-
DTPA
99mTc-ECD-
ranit
99mTc-ECD-
cinar
Placebo-ECD
Ko
pH1
pH4
pH7
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Ranitidine - 99mTc- DTPA tablet Static images at 1, 2 and 3 hours post administration
In vivo disintegration studies
Scintigraphic study of a [99mTc]-MDP placebo tablet.
Two hours post administration
Scintigraphicimages of adinamic study at0, 15, 30 and 45min postadministration ofF2 and F4 to thesame volunteer
Voluntario 1 Voluntario 4
Voluntario 2 Voluntario 5
Voluntario 3 Voluntario 6
Static images 2 hspost adminstration ofF4 to 6 volunteers.
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In vivo gastric transit constants Pearson correlation coefficients for
dissolution-disintegration processes in vitro
pH 99m
Tc MIBI 99m
Tc ECD 99m
Tc
MDP
99mTc DTPA
1 0.75 0.99 0.68 0.99
4 0.77 0.78 0.90 0.99
7 0.50 0.94 0.68 0.99
Pearson correlation coefficients fordisintegration processes in vivo
pH 99m
Tc MIBI 99m
Tc ECD 99m
Tc MDP 99m
Tc DTPA
1 0.29 0.44 0.29 0.8
4 0.21 0.29 0.08 0.12
Pearson correlation coefficientsfor in vitro dissoluction-in vivo disintegration
processes
pH 99m
Tc MIBI 99m
Tc ECD 99m
Tc MDP 99m
Tc DTPA
1 0.13 0.08 0.68 0.07
4 0.51 0.69 0.59 0.12
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CONCLUSIONS
Even though 99mTc-ECD, 99mTc-MIBI and 99mTc-DTPAshowed high in vitro correlation between dissolutionand disintegration, statistical tests revealed that noneof them was an adequate predictor of in vivoperformance for this particular tablet formulation, forany region of the gastrointestinal tract.
CONCLUSIONS
The method is an interesting tool especially at earlystages of pharmaceutical formulation developmentwhen different formulations are being chosen, but maynot have adequate sensitivity to discriminate betweenformulation variables.
Careful choice of drug model, together with substantialin vitro validation is essential in order to reduce in vivostudies and make significant savings of human andfinancial resources.
Acknowledgments
• TECHI S.A. for supplying radiopharmaceutical kits
• Centro de Medicina Nuclear, Hospital de Clínicasfor Nuclear Medicine equipment facilities
•PEDECIBA – Química
•CSIC - UR