Niosomes containing N-(2-hydroxypropyl)methacrylamide copolymer-doxorubicin (PK1): effect of method of preparation and choice of surfactant on niosome characteristics and a preliminary study of body distribution

Uchegbu, I.F. and Duncan, R. (1997) Niosomes containing N-(2-hydroxypropyl)methacrylamide copolymer-doxorubicin (PK1): effect of method of preparation and choice of surfactant on niosome characteristics and a preliminary study of body distribution. International Journal of Pharmaceutics, 155 (1). pp. 7-17. 10.1016/S0378-5173(97)00141-5.

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DOI: 10.1016/S0378-5173(97)00141-5

Abstract

PK1 is an N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin conjugate currently in early clinical development. Niosome encapsulation is a means to increase PK1 blood residence time, potentially promote tumour uptake and produce a slow, sustained release of active drug. Factors effecting encapsulation efficiency and size of PK1-niosome formulations were studied. Five surfactants were used to prepare PK1-niosomes; hexadecyl poly-5-oxyethylene ether (C16EO5); octadecyl poly-5-oxyethylene ether (C18EO5); hexadecyl diglycerol ether (C16G2); sorbitan monopalmitate (Span 40) and sorbitan monostearate (Span 60). All were mixed in equimolar ratio with cholesterol and varying amounts of Solulan C24 (a cholesteryl poly-24-oxyethylene ether) (9-39 mol%). Dicetylphosphate (DCP) was also added (2 mol%). Passive association of PK1 with preformed C16G2 and Span 60 vesicles was low (3-4%) while subsequent dehydration (freeze drying) followed by rehydration of the formulation increased the entrapment to 61% in the C16G2 formulation. Transmission electron microscopy revealed that these niosomes had an electron dense core, evidence of intravesicular concentration of PK1. Increasing Solulan C24 content resulted in decreased PK1 entrapment after freeze drying, and the vesicle size was also decreased. Solulan C24 (39 mol%) caused pronounced vesicle aggregation on freeze drying, whereas at lower levels (9 mol%), PK1 appeared to act as a cryoptrotectant and the mean size of C16G2 niosomes was 235 nm. A PK1:surfactant/lipid ratio of 0.3 (11.2 mg ml-1 doxorubicin) was achieved with Span 60 niosomes. This formulation, and the C16G2 niosomes, did not induce red blood cell lysis at the proposed dose for in vivo use. Preliminary in vivo biodistribution studies showed PK1-C16G2 niosomes to be mainly taken up by the liver and spleen. After 24 h, 25 and 3% of dose administered was present as free doxorubicin in these organs respectively. |

Item Type:Article
Uncontrolled Keywords:HPMA copolymer-doxorubicin; Niosomes; PK1
Departments, units and centres:Department of Pharmaceutics > Department of Pharmaceutics
ID Code:3103
Journal or Publication Title:International Journal of Pharmaceutics
Deposited By:Library Staff
Deposited On:26 Apr 2012 11:47
Last Modified:26 Apr 2012 11:47

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