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1.
J Pharm Pharmacol ; 65(8): 1187-94, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23837586

ABSTRACT

OBJECTIVES: Due to the low stability of lipid emulsions, a lipid emulsion of prostaglandin E1 (Lipo-PGE1 ) necessitates daily intravenous drip infusions. To overcome this issue, we developed nanoparticles containing PGE1 (Nano-PGE1 ). Nano-PGE1 showed a good sustained-release profile of PGE1 from the nanoparticles in vitro, which may permit a longer-lasting therapeutic effect to be achieved. We here examined the pharmacological activity of Nano-PGE1 in a rat experimental model of intermittent claudication induced by femoral artery ligation. METHODS: The walking activity of the rat was tested on a rodent treadmill. Tissue levels of PGE1 were determined by enzyme immunoassay, and skeletal muscle angiogenesis (capillary growth) was monitored by immunohistochemical analysis. KEY FINDINGS: PGE1 could be detected in the lesion site one day after the intravenous administration of Nano-PGE1 but not of Lipo-PGE1 . An increased accumulation of Nano-PGE1 in the lesion site compared with control (unlesioned) site was also observed. The ligation procedure reduced the walking activity, which in turn was improved by a single administration of Nano-PGE1 but not of Lipo-PGE1 . The single administration of Nano-PGE1 also stimulated angiogenesis in the skeletal muscle around the ligated artery. CONCLUSIONS: The findings of this study suggest that Nano-PGE1 improves the walking activity of femoral artery-ligated rats through the accumulation and sustained release of PGE1 .


Subject(s)
Alprostadil/therapeutic use , Drug Delivery Systems/methods , Intermittent Claudication/drug therapy , Nanoparticles , Vasodilator Agents/therapeutic use , Walking , Alprostadil/administration & dosage , Alprostadil/pharmacokinetics , Animals , Capillaries/drug effects , Capillaries/metabolism , Capillaries/pathology , Disease Models, Animal , Dose-Response Relationship, Drug , Exercise Test , Femoral Artery/drug effects , Femoral Artery/metabolism , Femoral Artery/pathology , Intermittent Claudication/physiopathology , Lower Extremity/blood supply , Neovascularization, Physiologic/drug effects , Particle Size , Rats , Rats, Wistar , Tissue Distribution , Vasodilator Agents/administration & dosage , Vasodilator Agents/pharmacokinetics
2.
Biomacromolecules ; 11(10): 2700-6, 2010 Oct 11.
Article in English | MEDLINE | ID: mdl-20795699

ABSTRACT

The accelerated blood clearance (ABC) phenomenon is induced upon repeated injections of poly(ethylene glycol) (PEG)-coated colloidal carriers. It is essential to suppress this phenomenon in a clinical setting because the pharmacokinetics must be reproducible. In this study, we evaluated the induction of the ABC phenomenon using nanoparticles coated with various hydrophilic polymers instead of PEG. Nanoparticles encapsulating prostaglandin E1 were prepared by the solvent diffusion method from a blend of poly(lactic acid) (PLA) and block copolymers consisting of various hydrophilic polymers and PLA. Coating of nanoparticles with poly(N-vinyl-2-pyrrolidone) (PVP), poly(4-acryloylmorpholine), or poly(N,N-dimethylacrylamide) led to extended residence of the nanoparticles in blood circulation in rats, although they had a shorter half-life than the PEG-coated nanoparticles. The ABC phenomenon was not induced upon repeated injection of PVP-coated nanoparticles at various time intervals, dosages, or frequencies, whereas it was elicited by PEG-coated nanoparticles. In addition, anti-PVP IgM antibody, which is estimated to be one of the crucial factors for induction of the ABC phenomenon, was not produced after injection of PVP-coated nanoparticles. These results suggest that the use of PVP, instead of PEG, as a coating material for colloidal carriers can evade the ABC phenomenon.


Subject(s)
Drug Carriers/pharmacokinetics , Nanoparticles/chemistry , Polymers/pharmacokinetics , Animals , Blood Circulation Time , Drug Carriers/administration & dosage , Drug Carriers/adverse effects , Enzyme-Linked Immunosorbent Assay , Hydrophobic and Hydrophilic Interactions , Immunoglobulin M/blood , Injections, Intravenous , Male , Metabolic Clearance Rate , Nanoparticles/administration & dosage , Nanoparticles/adverse effects , Polymers/administration & dosage , Polymers/adverse effects , Polyvinyls/administration & dosage , Polyvinyls/adverse effects , Pyrrolidines/administration & dosage , Pyrrolidines/adverse effects , Pyrrolidines/blood , Rats , Rats, Wistar
3.
Pharm Res ; 26(10): 2270-9, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19633820

ABSTRACT

PURPOSE: We recently developed prostaglandin E(1) (PGE(1))-encapsulated nanoparticles, prepared with a poly(lactide) homopolymer (PLA, Mw = 17,500) and monomethoxy poly(ethyleneglycol)-PLA block copolymer (PEG-PLA) (NP-L20). In this study, we tested whether the accelerated blood clearance (ABC) phenomenon is observed with NP-L20 and other PEG-modified PLA-nanoparticles in rats. METHODS: The plasma levels of PGE(1) and anti-PEG IgM antibody were determined by EIA and ELISA, respectively. RESULTS: Second injections of NP-L20 were cleared much more rapidly from the circulation than first injections, showing that the ABC phenomenon was induced. This ABC phenomenon, and the accompanying induction of anti-PEG IgM antibody production, was optimal at a time interval of 7 days between the first and second injections. Compared to NP-L20, NP-L33s that were prepared with PLA (Mw = 28,100) and have a smaller particle size induced production of anti-PEG IgM antibody to a lesser extent. NP-L20 but not NP-L33s gave rise to the ABC phenomenon with a time interval of 14 days. NP-L33s showed a better sustained-release profile of PGE(1) than NP-L20. CONCLUSIONS: This study revealed that the ABC phenomenon is induced by PEG-modified PLA-nanoparticles. We consider that NP-L33s may be useful clinically for the sustained-release and targeted delivery of PGE(1).


Subject(s)
Nanoparticles/administration & dosage , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/pharmacokinetics , Animals , Blood Circulation Time/drug effects , Metabolic Clearance Rate/drug effects , Metabolic Clearance Rate/physiology , Particle Size , Rats , Rats, Wistar , Time Factors
4.
Pharm Res ; 26(7): 1792-800, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19415470

ABSTRACT

PURPOSE: Prostaglandin E(1) (PGE(1)) is an effective treatment for peripheral vascular diseases. The encapsulation of PGE(1) in nanoparticles for its sustained-release would improve its therapeutic effect and quality of life (QOL) of patients. METHODS: In order to encapsulate PGE(1) in nanoparticles prepared with a poly(lactide) homopolymer (PLA) and monomethoxy poly(ethyleneglycol)-PLA block copolymer (PEG-PLA), we synthesized a series of PGE(1) phosphate derivatives and tested their efficacy. RESULTS: Among them, PGE(1) 2-(phosphonooxy)ethyl ester sodium salt (C2) showed the most efficient hydrolysis to yield PGE(1) in human serum. An in vitro platelet aggregation assay showed that C2 inhibited aggregation only after pre-incubation in serum, suggesting that C2 is a prodrug of PGE(1). In vivo, intravenous administration of C2 caused increase in cutaneous blood flow. In the presence of zinc ions, all of the synthesized PGE(1) phosphate derivatives could be encapsulated in PLA-nanoparticles. Use of L-PLA instead of D,L-PLA, and high molecular weight PLA resulted in a slower release of C2 from the nanoparticles. CONCLUSIONS: We consider that C2-encapsulated nanoparticles prepared with L-PLA and PEG-D,L-PLA have good sustained-release profile of PGE(1), which is useful clinically.


Subject(s)
Alprostadil/administration & dosage , Alprostadil/chemical synthesis , Drug Carriers/chemistry , Nanoparticles/chemistry , Phosphates/chemistry , Alprostadil/metabolism , Alprostadil/pharmacology , Animals , Humans , Hydrolysis , Lactic Acid/chemistry , Particle Size , Phosphates/chemical synthesis , Platelet Aggregation/drug effects , Polyesters , Polyethylene Glycols/chemistry , Polymers/chemistry , Prodrugs/metabolism , Rats , Rats, Wistar , Regional Blood Flow/drug effects , Serum/metabolism , Skin/blood supply , Zinc/chemistry
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