S.S. Davis

PLGA nanoparticles prepared by nanoprecipitation: drug loading and release studies of a water soluble drug

The nanoprecipitation technique for preparation of nanoparticles suffers the drawback of poor incorporation of water soluble drugs. The aim of this study was therefore to assess various formulation parameters to enhance the incorporation of a water soluble drug (procaine hydrochloride) into poly(dl-lactide-co-glycolide) (PLGA) nanoparticles prepared by this technique. Approaches investigated for drug incorporation efficiency enhancement included the influence of aqueous phase pH, replacement of procaine hydrochloride with procaine dihydrate and the inclusion of excipients: poly(dl-lactide) (PLA) oligomers, poly(methyl methacrylate-co-methacrylic acid) (PMMA-MA) or fatty acids into the formulation. The nanoparticles produced were submicron size (<210 nm) and of low polydispersity. It was found that an aqueous phase pH of 9.3, replacement of procaine hydrochloride with procaine dihydrate and the incorporation of PMMA-MA, lauric and caprylic acid into the formulation could enhance drug incorporation efficiency without the size, morphology and nanoparticle recovery being adversely influenced. For instance changing the aqueous phase pH from 5.8 to 9.3 increased nanoparticle recovery from 65.1 to 93.4%, drug content from 0.3 to 1.3% w/w and drug entrapment from 11.0 to 58.2%. However, the presence of high ratios of lauric acid and procaine dihydrate in the formulation adversely affected the morphology and size of the nanoparticles. Also, PLA oligomers were not considered a feasible approach since it decreased drug entrapment from 11.0 to 8.4% and nanoparticle recovery from 65.1 to 19.6%. Drug release from nanoparticles appears to consist of two components with an initial rapid release followed by a slower exponential stage. This study has demonstrated that formulation variables can be exploited in order to enhance the incorporation of a water soluble drug into PLGA nanoparticles by the nanoprecipitation technique.

Long circulating microparticulate drug carriers

To exert its activity a drug must reach its pharmacological site(s) of action(s) within the body. One of the current approaches to achieve site specific delivery utilises the use of a carrier. This review focuses on the physicochemical and biological properties of polymeric particulate carriers in the nanometre size range surface modified by poly(ethylene oxide) (PEO). Such systems are able to bypass the normal physiological defence processes occurring after the intravenous injection of particulates and, depending on the particle size and PEO layer properties, remain for a prolonged period of time in the systemic circulation, or have a degree of selectivity for sites of deposition within the body.

Chitosan as a Novel Nasal Delivery System for Peptide Drugs

A nasal solution formulation of the cationic material chitosan was shown to greatly enhance the absorption of insulin across the nasal mucosa of rat and sheep. The absorption promoting effect was concentration dependent with the optimal efficacy obtained for concentrations higher than 0.2% and 0.5% in rats and sheep, respectively. The absorption promoting effect was reversible with time in a “pulse-chase” study. Histological examination of the nasal mucosa of rats exposed to a chitosan solution for 60 minutes showed little change.

Chitosan microspheres prepared by spray drying

Non-crosslinked and crosslinked chitosan microspheres were prepared by a spray drying method. The microspheres so prepared had a good sphericity and a smooth but distorted surface morphology. They were positively charged. The particle size ranged from 2 to 10 micron. The size and seta potential of the particles were influenced by the crosslinking level. With decreasing amount of crosslinking agent (either glutaraldehyde or formaldehyde), both particle size and zeta potential were increased. Preparation conditions also had some influence on the particle size. DSC studies revealed that the H2 antagonist drug cimetidine, as well as famotidine was molecularly dispersed inside the microspheres, in the form of a solid solution. The release of model drugs (cimetidine, famotidine and nizatidine) from these microspheres was fast, and accompanied by a burst effect.

The Preparation and Characterization of Poly(lactide-co-glycolide) Microparticles. II. The Entrapment of a Model Protein Using a (Water-in-Oil)-in-Water Emulsion Solvent Evaporation Technique

Poly(lactide-co-glycolide) (PLG) microparticles with entrapped antigens have recently been investigated as controlled-release vaccines. This paper describes the preparation of PLG microparticles with an entrapped model antigen, ovalbumin (OVA), using a (water-in-oil)-in-water emulsion solvent evaporation technique. In a series of experiments, the effects of process parameters on particle size and OVA entrapment were investigated. It was found that smooth, spherical microparticles 1–2 µm in diameter containing up to 10% (w/w) OVA could be produced using a small volume of external aqueous phase containing a high concentration of emulsion stabilizer and a 1:5 antigen:polymer ratio. PAGE analysis, isoelectric focusing, and Western blotting of OVA released from the microparticles in vitro confirmed that the molecular weight and antigenicity of the protein remained largely unaltered by the entrapment procedure.

Evaluation of the clearance characteristics of bioadhesive systems in humans.

This paper describes the characterisation, radiolabelling and clearance characteristics of three bioadhesive nasal delivery systems; starch microspheres, chitosan microspheres and chitosan solution. The time taken for 50% of these bioadhesive materials and a control to be cleared from the nasal cavity, after nasal administration to human volunteers, was evaluated using gamma scintigraphy. The data show that the control was cleared rapidly, with a half life of 21 min, whereas the bioadhesive delivery systems had much longer half lives. The clearance of the chitosan solution almost doubled to 41 min, whilst the half life of clearance for the starch microspheres more than tripled to 68 min and for the chitosan microspheres the half life of clearance quadrupled to 84 min. From the results reported in this study it is possible to determine that both chitosan systems and the starch microspheres have good bioadhesive characteristics. The results have supported the hypothesis that chitosan delivery systems can reduce the rate of clearance from the nasal cavity, thereby increasing the contact time of the delivery system with the nasal mucosa, providing the potential for increasing the bioavailability of drugs incorporated into these systems.

Surface Modification of Poly(lactide-co-glycolide) Nanospheres by Biodegradable Poly(lactide)-Poly(ethylene glycol) Copolymers

The modification of surface properties of biodegradable poly(lactide-co-glycolide) (PLGA) and model polystyrene nanospheres by poly(lactide)-poly(ethlene glycol) (PLA:PEG) copolymers has been assessed using a range of in vitro characterization methods followed by in vivo studies of the nanospheres biodistribution after intravenous injection into rats. Coating polymers with PLA:PEG ratio of 2:5 and 3:4 (PEG chains of 5000 and 2000 Da, respectively) were studied. The results reveal the formation of a PLA: PEG coating layer on the particle surface resulting in an increase in the surface hydrophilicity and decrease in the surface charge of the nanospheres. The effects of addition of electrolyte and changes in pH on stability of the nanosphere dispersions confirm that uncoated particles are electrostatically stabilized, while in the presence of the copolymers, steric repulsions are responsible for the stability. The PLA:PEG coating also prevented albumin adsorption onto the colloid surface. The evidence that this effect was observed for the PLA:PEG 3:4 coated nanospheres may indicate that a poly(ethylene glycol) chain of 2000 Da can provide an effective repulsive barrier to albumin adsorption. The in vivo results reveal that coating of PLGA nanospheres with PLA:PEG copolymers can alter the biodistribution in comparison to uncoated PLGA nanospheres. Coating of the model polystyrene nanospheres with PLA:PEG copolymers resulted in an initial high circulation level, but after 3 hours the organ deposition data showed values similar to uncoated polystyrene spheres. The difference in the biological behaviour of coated PLGA and polystyrene nanospheres may suggest a different stability of the adsorbed layers on these two systems. A similar biodistribution pattern of PLA:PEG 3:4 to PEG 2:5 coated particles may indicate that poly(ethylene glycol) chains in the range of 2000 to 5000 can produce a comparable effect on in vivo behaviour.

The organ uptake of intravenously administered colloidal particles can be altered using a non-ionic surfactant (Poloxamer 338)

Small polystyrene particles coated with a high M r non‐ionic surfactant (Poloxamer 338) are diverted from the reticuloendothelial system of the liver and spleen to other tissue sites. These results are discussed in terms of the adsorption of the Poloxamer to the particle surface and the implications for drug targeting.

The organ distribution and circulation time of intravenously injected colloidal carriers sterically stabilized with a blockcopolymer - poloxamine 908

Colloidal carriers injected intravenously are normally removed rapidly and efficiently by the liver and this represents a major barrier to drug targeting. By coating model microspheres and emulsions with a block co-polymer (poloxamine) it has been possible to keep the carrier circulating in the vascular compartment with little or no uptake by the reticuloendothelial system.

Drug delivery in poly(lactide-co-glycolide) nanoparticles surface modified with poloxamer 407 and poloxamine 908: in vitro characterisation and in vivo evaluation

Poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles of 150-nm mean size were produced by an interfacial deposition method. The polar model drug Rose Bengal was successfully loaded into the nanoparticles during production and the surface of these particles was subsequently modified with poloxamer 407 and poloxamine 908 in order to create a steric stabilising layer of PEG on the surface. Drug loading was low (<1%) which can be attributed to the polar nature of the drug and the small size of the nanoparticles. Drug release was biphasic with 50% release measured within 30 min in serum. After intravenous injection in rats, the drug loaded nanoparticles substantially avoided capture by the Kupffer cells of the liver as compared to free drug. The half-life of Rose Bengal in the blood stream when administered in the nanoparticles was greatly extended with approximately 30% remaining after 1 h as compared to only 8% of Rose Bengal left 5 min after administration in solution. These surface modified nanoparticles would have potential as carriers for drugs to specific sites within the body or for slow release of drug within the circulation.