Formulation development and manufacturing of a gastrin/CCK-2 receptor targeting peptide as an intermediate drug product for a clinical imaging study.
Eur J Pharm Sci
; 31(2): 102-11, 2007 Jun.
Article
en En
| MEDLINE
| ID: mdl-17387005
ABSTRACT
A DOTA-gastrin analogue (APH070) which, when labelled with (111)In, has high affinity for the gastrin/CCK-2 receptor (3nM) and low tumour to kidney ratio in animal models, has been formulated and manufactured for a clinical study. Oxidation of the peptide methionine residue greatly reduces receptor affinity, therefore development work focused on producing a stable intermediate drug product (iDP) whilst ensuring that the formulation, container, closure and manufacturing process did not inhibit the extremely sensitive radiolabelling reaction (itself a source of oxidation). Stress testing revealed that APH070 was stable at 2-8 degrees C at pH 6-9. Addition of an antioxidant (monothioglycerol) to the peptide formulation reduced stability when compared to buffer alone. Use of FluroTec (4023/50) stoppers (rather than FluroTec Plus (4110/40)) increased both the stability and radiolabelling efficiency of APH070. Long term stability (6 months) of the final formulation (1mg/ml APH070 in 0.01 M pH 7.2 phosphate buffer) stored at 5 degrees C in type I glass vials with FluroTec (4023/50) stoppers was 98.6+/-0.2% and 98.4+/-0.1% for upright and inverted samples, respectively. Clinical scale radiolabelling of the final formulation routinely achieves the specification of >85% (111)In-APH070 (unoxidised) stable for up to 2h after dilution with 0.9% w/v saline solution. Specific uptake of the radiopharmaceutical in CCK-2R-expressing AR42J tumours in nude mice has been demonstrated.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Oligopéptidos
/
Gastrinas
/
Radioisótopos de Indio
/
Tecnología Farmacéutica
/
Radiofármacos
/
Receptor de Colecistoquinina B
/
Embalaje de Medicamentos
/
Marcaje Isotópico
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Eur J Pharm Sci
Asunto de la revista:
FARMACIA
/
FARMACOLOGIA
/
QUIMICA
Año:
2007
Tipo del documento:
Article
País de afiliación:
Reino Unido