title: Design and in vitro haemolytic evaluation of cryptolepine hydrochloride-loaded gelatine nanoparticles as a novel approach for the treatment of malaria.
abstract: Cryptolepine hydrochloride-loaded gelatine nanoparticles were developed and characterised as a means of exploring formulation techniques to improve the pharmaceutic profile of the compound. Cryptolepine hydrochloride-loaded gelatine-type (A) nanoparticles were developed base on the double desolvation approach. After optimisation of formulation parameters including temperature, stirring rate, incubation time polymer and cross-linker (glutaraldehyde) concentrations, the rest of the study was conducted at two different formulation pH values (2.5 and 11.0) and by two different approaches to drug loading. Three cryoprotectants--sucrose, glucose and mannitol--were investigated for possible use for the preparation of freeze-dried samples. Nanoparticles with desired size mostly less than 350 nm and zeta potential above ±20 were obtained when formulation pH was between 2.5 and 5 and above 9. Entrapment efficiency was higher at pH 11.0 than pH 2.5 and for products formulated when drug was loaded during the second desolvation stage compared to when drug was loaded onto pre-formed nanoparticles. Further investigation of pH effect showed a new isoelectric point of 6.23-6.27 at which the zeta potential of nanoparticles was zero. Sucrose and glucose were effective in low concentrations as cryoprotectants. The best formulation produced an EC(50) value of 227.4 μM as a haemolytic agent compared to 51.61 μM by the free compound which is an indication of reduction in haemolytic side effect. There was sustained released of the compound from all formulation types over a period of 192 h. Stability data indicated that the nanosuspension and freeze-dried samples were stable at 4 and 25°C, respectively, over a 52-week period, but the former was less stable at room temperature. In conclusion, cryptolepine hydrochloride-loaded gelatine nanoparticles exhibited reduced haemolytic effect compared to the pure compound and can be developed further for parenteral delivery.
authors.affiliation: School of Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
authors.forename: Noble
authors.initials: N
authors.lastname: Kuntworbe
authors.forename: Raida
authors.initials: R
authors.lastname: Al-Kassas
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000633:toxicity*; D002626:Chemistry, Pharmaceutical; D003432:Cross-Linking Reagents / Q000737:chemistry; D003451:Cryoprotective Agents / Q000737:chemistry; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004355:Drug Stability; D005612:Freeze Drying; D005780:Gelatin / Q000737:chemistry*; D005947:Glucose / Q000737:chemistry; D005976:Glutaral / Q000737:chemistry; D006461:Hemolysis / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D026121:Indole Alkaloids / Q000737:chemistry / Q000633:toxicity*; D007526:Isoelectric Point; D007700:Kinetics; D008353:Mannitol / Q000737:chemistry; D053758:Nanoparticles; D036103:Nanotechnology; D010316:Particle Size; D011804:Quinolines / Q000737:chemistry / Q000633:toxicity*; D051381:Rats; D012995:Solubility; D013395:Sucrose / Q000737:chemistry; D013678:Technology, Pharmaceutical / Q000379:methods; D013696:Temperature
chemical_list: D000962:Antimalarials; D003432:Cross-Linking Reagents; D003451:Cryoprotective Agents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D026121:Indole Alkaloids; D011804:Quinolines; D008353:Mannitol; C024015:cryptolepine; D013395:Sucrose; D005780:Gelatin; D005947:Glucose; D005976:Glutaral