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Biomedical subjects

L Illum

Publications and source records attributed to L Illum.

At least 19 recordsLinked to original sources
PubMed2003

Nasal delivery of chitosan-DNA plasmid expressing epitopes of respiratory syncytial virus (RSV) induces protective CTL responses in BALB/c mice.

Respiratory syncytial virus (RSV), an important pathogen of the lower respiratory tract, is responsible for severe illness both in new born and young children and in elderly people. Due to complications associated with the use of the early developed vaccines, there is still a need for an effective vaccine against RSV. Most pathogens enter the body via mucosal surfaces and therefore vaccine delivery via routes such as the nasal, may well prove to be superior in inducing protective immune responses against respiratory viruses, since both local and systemic immunity can be induced by nasal immunisation. Previously we have shown that intradermal immunisation of a plasmid DNA encoding the CTL epitope from the M2 protein of RSV induced protective CTL responses. In the present study, the mucosal delivery of plasmid DNA formulated with chitosan has been investigated. Chitosan is a polysachharide consisting of copolymers of N-acetylglucosamine and glucosamine that is derived from chitin, a material found in the shells of crustacea. Intranasal immunisation with plasmid DNA formulated with chitosan induced peptide- and virus-specific CTL responses in BALB/c mice that were comparable to those induced via intradermal immunisation. Following RSV challenge of chitosan/DNA immunised mice, a significant reduction (P<0.001) in the virus load was observed in the lungs of immunised mice compared to that in the control group. These results indicate the potential of immunisation with chitosan-formulated epitope-based vaccines via the intranasal route.

Animals↗
PubMed2002

Development of a novel nasal nicotine formulation comprising an optimal pulsatile and sustained plasma nicotine profile for smoking cessation.

A novel nasal formulation, in the form of a nicotine-Amberlite resin complex powder has been developed that provided an optimal combined pulsatile and sustained plasma nicotine profile for smoking cessation. The adsorption isotherms of nicotine hydrogen tartrate salt on two types of Amberlite resins (IRP69 and IR120) were evaluated and the subsequent in vitro release properties of nicotine from the nicotine-Amberlite complex powders were tested using a Franz diffusion cell. Amberlite IRP69 and Amberlite IR120 are similar cationic exchange materials with the same ion-exchange capacity but due to a smaller particle size range (10-150 microm) Amberlite IRP69 had a better flow property and a better adsorptive capacity than Amberlite IR120. The material is used as an excipient in marketed pharmaceutical formulations. The highly water soluble salt, nicotine hydrogen tartrate, displayed good adsorption onto both types of Amberlite resin. The maximum adsorption of nicotine onto Amberlite IRP69 was 1.071 mg drug per mg resin. The cumulative release of drug from nicotine hydrogen tartrate-Amberlite complex powders showed that the higher the drug loading, the faster was the rate of release of the drug. Based on these results, various nicotine hydrogen tartrate-Amberlite IRP69 powder formulations containing different ratios of free to bound drug (50% to 100% bound) and a control solution were prepared and evaluated in a sheep model by nasal administration. The nicotine plasma profiles demonstrated that an initial rapid peak plasma level of nicotine followed by a sustained elevated level could be achieved by adjusting the ratio of free to bound nicotine in the Amberlite powder formulation. The curves obtained from some of the formulations were comparable to those predicted from a computer-generated pharmacokinetic model.

Administration, Intranasal↗
PubMed2002

Nasal delivery of insulin using novel chitosan based formulations: a comparative study in two animal models between simple chitosan formulations and chitosan nanoparticles.

PURPOSE: To investigate whether the widely accepted advantages as sociated with the use of chitosan as a nasal drug delivery system might be further improved by application of chitosan formulated a nanoparticles. METHODS: Insulin-chitosan nanoparticles were prepared by the ionotropic gelation of chitosan glutamate and tripolyphosphate pentasodium and by simple complexation of insulin and chitosan. The nasal absorption of insulin after administration in chitosan nanoparticle formulations and in chitosan solution and powder formulations wa evaluated in anaesthetised rats and/or in conscious sheep. RESULTS: Insulin-chitosan nanoparticle formulations produced a pharmacological response in the two animal models, although in both cases the response in terms of lowering the blood glucose levels was less (to 52.9 or 59.7% of basal level in the rat, 72.6% in the sheep than that of the nasal insulin chitosan solution formulation (40.1% in the rat, 53.0% in the sheep). The insulin-chitosan solution formulation was found to be significantly more effective than the complex and nanoparticle formulations. The hypoglycaemic response of the rat to the administration of post-loaded insulin-chitosan nanopar ticles and insulin-loaded chitosan nanoparticles was comparable. As shown in the sheep model, the most effective chitosan formulation for nasal insulin absorption was a chitosan powder delivery system with a bioavailability of 17.0% as compared to 1.3% and 3.6% for the chitosan nanoparticles and chitosan solution formulations, respectively. CONCLUSION: It was shown conclusively that chitosan nanoparticles did not improve the absorption enhancing effect of chitosan in solution or powder form and that chitosan powder was the most effective for mulation for nasal delivery of insulin in the sheep model.

Administration, Intranasal↗
PubMed2002

Intranasal delivery of morphine.

Morphine administered nasally to humans as a simple solution is only absorbed to a limited degree, with a bioavailability of the order of 10% compared with intravenous administration. This article describes the development of novel nasal morphine formulations based on chitosan, which, in the sheep model, provide a highly increased absorption with a 5- to 6-fold increase in bioavailability over simple morphine solutions. The chitosan-morphine nasal formulations have been tested in healthy volunteers in comparison with a slow i.v. infusion (over 30 min) of morphine. The results show that the nasal formulation was rapidly absorbed with a T(max) of 15 min or less and a bioavailability of nearly 60%. The shape of the plasma profile for nasal delivery of the chitosan-morphine formulation was similar to the one obtained for the slow i.v. administration of morphine. Furthermore, the metabolite profile obtained after the nasal administration of the chitosan-morphine nasal formulation was essentially identical to the one obtained for morphine administered by the intravenous route. The levels of both morphine-6-glucuronide and morphine-3-glucuronide were only about 25% of that found after oral administration of morphine. It is concluded that a properly designed nasal morphine formulation (such as one with chitosan) can result in a non-injectable opioid product capable of offering patients rapid and efficient pain relief.

Absorption↗
PubMed2001

The effect of surface coverage and conformation of poly(ethylene oxide) (PEO) chains of poloxamer 407 on the biological fate of model colloidal drug carriers.

Poloxamer 407 was adsorbed onto the surface of model colloidal drug carriers, polystyrene nanoparticles of 40, 70 and 137 nm in diameter, and the effect of the degree of surface coverage and the conformation of the poly(ethylene oxide) (PEO) chains on biological fate was studied. The relationship between the physicochemical and the biological properties of the nanoparticle systems was also investigated. The adsorbed layer of poloxamer 407 was characterised in terms of percentage surface coverage, thickness of the adsorbed layer and average surface area per PEO chain. Computer modelling of the adsorbed layer was performed (applying the self-consistent field technique), to obtain the structural information of the PEO chains in the layer. The in vitro interaction of the nanoparticles with different degrees of poloxamer 407 surface coverage with serum components and the in vivo biodistribution in the rat model were assessed. The results demonstrated that an increase in the surface coverage with poloxamer 407 resulted in an increased volume fraction of the PEO in the adsorbed layer, further extension of the PEO chains from the surface and closer packing of the chains at the surface. With regard to the interaction with the serum components, an increased surface coverage resulted in a reduction of the amount of serum proteins adsorbed, and, importantly, affected the type of proteins adsorbed. High molecular weight proteins were not adsorbed onto the nanoparticles with a surface coverage above approx. 25%. Following the intravenous administration to rats, even the nanoparticles with the lowest degree of surface coverage (approx. 5%) showed improved circulation profiles relative to the uncoated nanoparticles. The effect was more pronounced for the 40 nm nanoparticles. A further increase in the surface coverage to approx. 25% resulted in a significant increase in circulation time, as compared to uncoated and 5% coated systems, for all sizes of nanoparticles. Importantly, it was found that a long in vivo blood circulation time could be achieved for nanoparticles with a relatively low degree of surface coverage with PEO chains.

Adsorption↗
PubMed2001

Chitosan as a novel nasal delivery system for vaccines.

A variety of different types of nasal vaccine systems has been described to include cholera toxin, microspheres, nanoparticles, liposomes, attenuated virus and cells and outer membrane proteins (proteosomes). The present review describes our work on the use of the cationic polysaccharide, chitosan as a delivery system for nasally administered vaccines. Several animal studies have been carried out on influenza, pertussis and diphtheria vaccines with good results. After nasal administration of the chitosan-antigen nasal vaccines it was generally found that the nasal formulation induced significant serum IgG responses similar to and secretory IgA levels superior to what was induced by a parenteral administration of the vaccine. Animals vaccinated via the nasal route with the various chitosan-antigen vaccines were also found to be protected against the appropriate challenge. So far the nasal chitosan vaccine delivery system has been tested for vaccination against influenza in human subjects. The results of the study showed that the nasal chitosan influenza vaccine was both effective and protective according to the CPMP requirements. The mechanism of action of the chitosan nasal vaccine delivery system is also discussed.

Administration, Intranasal↗
PubMed2001

Polymeric lamellar substrate particles for intranasal vaccination.

In recent years, several strategies have been under investigation to achieve safe and effective immunisation, in terms of new antigens, adjuvants and routes of vaccination. The latter include mucosal sites such as oral, rectal, vaginal and nasal. Biodegradable microparticles produced from polymers such as poly(D,L-lactide) (PLA) and poly(D,L-lactide-co-glycolide) (PLGA) containing encapsulated vaccine antigens have been extensively studied for immunisation. These microparticles allow controlled release of vaccines with the aim to develop as single dose vaccines. However there are concerns regarding the integrity and immunogenicity of the antigen during the encapsulation process when the antigen is exposed to organic solvents, high shear stresses and the exposure of antigen to low pH which is caused by polymer degradation. Polymeric lamellar substrate particles (PLSP) produced by simple precipitation of PLA, form a novel polymeric system for the adsorption of antigens. This procedure avoids pH changes, exposure to organic solvents and hence allows the integrity of the antigen to be retained. The aim of this article is to discuss the factors affecting the characteristics of PLSP and adsorption of antigens onto PLSP and consider their potential as adjuvants for the nasal delivery of protein, peptide or viral vaccines.

Administration, Intranasal↗
PubMed2001

Drug-polyionic block copolymer interactions for micelle formation: physicochemical characterisation.

While covalent attachment of small drug molecules to AB copolymers for the formation of polymeric micelles for drug delivery has been investigated, few studies have focused on non-covalent interactions. The aim of this study was therefore to explore the potential of non-covalent interactions between an AB copolymer, Poly(aspartic acid)-poly(ethylene glycol) (Pasp-PEG), with anionic pendant groups and diminazene aceturate, a small molecular weight cationic drug. Micelles were prepared by mixing solutions of Pasp-PEG and diminazene in 25 mM Tris-HCl buffer. At all Pasp-PEG concentrations studied, the micelles appeared to be water soluble with a unimodal size distribution and ranged in size from approximately 22 to 60 nm. The polyionic micelles also displayed similar and small absolute zeta potential values at various drug:monomer molar ratios which confirmed stabilisation by the PEG corona. The scattering intensity was maximal and remained unchanged, while particle size increased slightly at pH range from 3.4 to 7.2. At this pH range both the polymer and drug would be ionised and ionic interactions possible to drive micellar formation. An increase in size and scattering intensity with addition of NaCl to the micelles was attributed to dehydration of the PEG corona which may have led to aggregation of the micelles. The absence of micellar dissociation upon addition of salt was attributed to the dominance of hydrogen bonding between Pasp and diminazene aceturate, as assessed by isothermal titration microcalorimetry. Morphological evaluation of these constructs showed them to be discrete and fairly uniform in size and shape. This study was therefore successful in confirming the potential of non-covalent interactions using an AB copolymer to form polyionic micelles for drug delivery.

Drug Delivery Systems↗
PubMed2001

Bioadhesive starch microspheres and absorption enhancing agents act synergistically to enhance the nasal absorption of polypeptides.

This paper investigates the effect of starch microspheres on the absorption enhancing efficiency of various enhancer systems in formulations with insulin after application in the nasal cavity of sheep. The enhancers studied were lysophosphatidylcholine, glycodeoxycholate and sodium taurodihydroxyfusidate, a bile salt derivative. The enhancers were selected on the basis of their perceived or proven mechanism of action and worked predominantly by interacting with the lipid membrane. The bioadhesive starch microspheres were shown to increase synergistically the effect of the absorption enhancers on the transport of the insulin across the nasal membrane. Dependent on the potency of the enhancer system the increment in absorption enhancement was shown to be from 1.4 times to 5 times that obtained for the absorption enhancer in solution.

Absorption↗
PubMed2001

Clearance characteristics of chitosan based formulations in the sheep nasal cavity.

This paper describes the clearance characteristics of two bioadhesive nasal delivery systems in the form of chitosan microspheres and chitosan solution, from the nasal cavity of conscious sheep. The pattern of deposition and clearance of the nasal dosage forms were evaluated using a radioactive tracer and the non-invasive technique of gamma scintigraphy. The clearance of chitosan microsphere and solution formulations was compared with that of a control solution. The data show that the control was cleared rapidly from the sheep nasal cavity with a half-time of clearance (time taken for 50% clearance; t(50%)) of about 15 min. The bioadhesive chitosan delivery systems were cleared at a slower rate, with half-times of clearance of 43 min and 115 min, for solution and microsphere formulations respectively. From the results reported in this study it can be concluded that the chitosan delivery systems investigated had significantly reduced rates of clearance from the sheep nasal cavity, as compared to the control. Consequently, chitosan delivery systems have the ability to increase the residence time of drug formulations in the nasal cavity thereby providing the potential for improved systemic medication. The nasal clearance rates recorded in the sheep model mimic very closely the clearance rates found in a previous study using human subjects. It can also be concluded that the sheep can be considered a suitable model for in vivo nasal clearance studies of novel bioadhesive drug delivery systems.

Adhesives↗
PubMed2001

Preparation and characterisation of rose Bengal-loaded surface-modified albumin nanoparticles.

Surface-modified albumin nanoparticles were prepared from two poly(ethylene glycol)-human serum albumin conjugates: poly(thioetheramido acid)-poly(ethylene glycol) copolymer-grafted HSA (HSA-PTAAC-PEG) and methoxy poly(ethylene glycol)-grafted HSA (HSA-mPEG). Rose bengal (RB) was used as a model drug for encapsulation into the nanoparticles either during the particle production or by adsorption post particle preparation. The drug incorporation and release was affected by the different production methods and the different polymer compositions. When RB was loaded in HSA and HSA/HSA-PTAAC-PEG nanoparticles, up to 5% (w/w) drug content was achieved. The drug loading in HSA-mPEG nanoparticles was much lower and the results from the microcalorimetry study indicated that the low loading efficiency was due to less drug-protein binding sites available in the HSA-mPEG molecule as compared to the HSA molecule. The release of RB from the albumin nanoparticles was very slow in PBS and dramatically accelerated in the presence of trypsin. Compared with unmodified nanoparticles, the slower release of RB from the surface-modified HSA nanoparticles in the presence of the enzyme suggested that the existence of a steric hydrophilic barrier on the surface of the nanoparticles made digestion of the nanoparticles more difficult.

Administration, Oral↗
PubMed2001

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.

Animals↗
PubMed2001

Development of systems for targeting the regional lymph nodes for diagnostic imaging: in vivo behaviour of colloidal PEG-coated magnetite nanospheres in the rat following interstitial administration.

PURPOSE: Nanoparticles can be utilised for targeting drugs to the regional lymph nodes or as diagnostic agents. The surface modification of magnetite nanospheres with poly(ethylene glycol) (PEG) has been assessed by in vitro characterisation and in vivo studies following subcutaneous administration to the rat. METHODS: Magnetite nanospheres were prepared with a grafted PEG layer using various PEG lengths from 350 to 1,000 Da. Thermogravimetric analysis was utilised to measure the adsorbed amount of PEG. Colloid stability was confirmed by measurement of the particle size and electrophoretic mobility. The kinetics of injection site drainage and lymph node retention were determined 2 hours after subcutaneous administration, for nanospheres coated with PEG lengths of 350, 550. 750, and 1,000 Da. For the 750 PEG coated nanospheres, the kinetics of distribution was determined over a 48-hour time course. RESULTS: The distribution of the nanospheres was modified and the lymph node localisation enhanced by altering the surface coverage of PEG on the magnetic surface. CONCLUSIONS: PEG-coated magnetite nanospheres with different surface characteristics can be utilised to target a diagnostic agent to regional lymph nodes.

Animals↗
PubMed2001

The effect of the nasal cycle on mucociliary clearance.

The nasal cycle is a well-recognised physiological phenomenon where each side of the nose alternates through phases of congestion and decongestion. Although many physiological properties of the nose alternate with the nasal cycle whether this has any effect on the nasal mucociliary clearance is less clear. As the nose is a potential site for the administration of pharmaceuticals, it is essential that any factors that could affect clearance (and hence absorption) are identified. This study set out to investigate if mucociliary clearance rates differed between the clear and obstructed airway at a morning peak of the nasal cycle in five healthy volunteers with normal nasal anatomy using a dual-radioisotope labelling procedure that allows both sides of the nose to be assessed simultaneously. The clearance of the radiopharmaceutical formulations from the nasal cavity was monitored using gamma scintigraphy and decay-adjusted 50%-clearance times were calculated for each nostril. The ratios of clearance times from the patent nostril when compared to the obstructed nostril were statistically significant (two-tailed t-test; P = 0.039), the mean ratio being 2.5 : 1 (SEM +/- 0.5). It can be concluded that the nasal cycle has a marked effect on the mucociliary clearance patterns of the nose. This may have both theoretical and practical implications for the nasal delivery of drugs.

Adolescent↗
PubMed2001

Gastrointestinal transit of dosage forms in the pig.

The gastrointestinal transit of liquid, pellet and tablet formulations was measured under fasted conditions in the domestic pig (n = 4) using the technique of gamma scintigraphy. The mean times for 50% gastric emptying for liquid and pellet systems were 1.4 and 2.2 h, respectively; tablets emptied between 1.5 and 6.0 h. Total transit times were in the order of 50 h. These data conform well to published values for the transit of liquid and solid food materials in the pig. The times are much shorter than those previously published for the transit of solid dosage forms in the pig. We conclude that the domestic pig would be a good model to study the gastrointestinal transit of pharmaceutical formulations and the absorption of drug compounds.

Animals↗
PubMed2001

Transport of nanoparticles across the rat nasal mucosa.

The transport of 125I-radiolabelled latex nanoparticles across the nasal mucosa of rats was studied using a range of particle sizes and surface coatings. Translocation of the particles into the blood stream was examined by means of monitoring the radiolabel associated with the particles. Particles were detected in the blood after 5 minutes. The number of particles in the blood peaked at 60 minutes, and then remained constant for a further 2 hours. The smallest particles (20 nm) showed greater uptake than the largest particles investigated (1000 nm). The total maximum uptake seen for the smallest particles was in the order of 3.25% of administered dose. 100 nm particles coated with chitosan showed an increase in both the extent and rate of uptake, with the concentration in the blood peaking at 15 minutes rather than at 60 minutes. It is suggested that transport of the particles across the nasal membrane is due mainly to a transcellular transport mechanisms by the nasal associated lymphoid tissue (NALT), especially the M-cell like cells. However, some paracellular transport cannot totally be ruled out for the smallest particles, especially if coated with chitosan.

Analysis of Variance↗
PubMed2001

Polylactide-poly(ethylene glycol) micellar-like particles as potential drug carriers: production, colloidal properties and biological performance.

The micellar-like particle systems produced from poly-D,L-lactide-poly(ethylene glycol) (PLA-PEG) copolymers have been assessed using a range of physicochemical characterisation methods, followed by in vivo studies of their biodistribution after intravenous administration to the rat. The size of the PEG chain was kept constant at 5 or 2 kDa, while the PLA size increased within a series from 2 to 25 kDa. The results obtained reveal, that in an aqueous medium the copolymers assembled into micellar-like structures, with the PLA segments forming the core and the PEG segments the surrounding corona. The size of the PLA segments dominated the process of assembly of the molecules and the characteristics of the resultant micellar-like particles. The PLA-PEG micellar particles were found to be less dynamic than those obtained from conventional surfactants. Particles formed from the lower molecular weight PLA polymers allowed a level of chain mobility while the cores of the micellar particles formed from higher molecular weight PLA appeared to be solid-like in nature. The size of the micellar particles was dependent on the copolymer molecular weight and the z-average diameter increased from 25 to 76 nm as the molecular weight of the PLA moiety increased. This provides an ability to control the particle size by adjusting the molecular weight of the PLA moiety. Following intravenous administration to the rat model, micellar-like particles smaller than approximately 70 nm accumulated in the liver, despite the fact that the PEG corona provided an effective steric stabilization effect. Micellar-like particles with a diameter of more than approximately 70 nm exhibited prolonged systemic circulation and reduced liver uptake, although the steric stabilisation of these particles was shown to be less effective. These findings agree with recent observations from other research groups; that indicate a possibility that very small particulates can pass through the sinusoidal fenestrations in the liver and gain access to the parenchymal cells of the liver.

Animals↗