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Biomedical subjects

L Illum

Publications and source records attributed to L Illum.

At least 55 records · Page 3Linked to original sources
PubMed1998

Stimulation of mucosal and systemic antibody responses against Bordetella pertussis filamentous haemagglutinin and recombinant pertussis toxin after nasal administration with chitosan in mice.

Mice were intranasally immunised with a mixture of Bordetella pertussis filamentous haemagglutinin (FHA) and recombinant pertussis toxin, PT-9K/129G (rPT) in combination with chitosan. For both antigens, this formulation induced systemic responses as measured by serum IgG and also mucosal responses as measured by secretory IgA in lung lavage and nasal washes. Immunosorbant assays were used to measure these responses. Both the systemic and mucosal responses were considerably higher than those produced when a mixture of rPT and FHA was administered nasally without chitosan. In comparison, intraperitoneally administered rPT/FHA adsorbed to Alhydrogel elicited only a systemic response, and nasal chitosan solution produced neither systemic nor mucosal response. This study clearly demonstrated that chitosan potentiated the serum and mucosal immune responses to nasally administered FHA and rPT in mice. Hence, this nasal chitosan delivery system has potential as a new non-injectable vaccine for the prophylaxis of whooping cough.

Adhesins, Bacterial↗
PubMed1998

Intranasal absorption of granulocyte-colony stimulating factor (G-CSF) from powder formulations, in sheep.

Granulocyte-colony stimulating factor (G-CSF) was administered to sheep in three different nasal formulations and as a subcutaneous injection. The nasal formulations were: a solution containing L-alpha-lysophosphatidylglycerol (LPG), a powder formulation comprising small starch microspheres (SSMS) and a powder formulation comprising SSMS and LPG. Absorption of G-CSF was assessed directly by quantitation in plasma and indirectly by measurement of the pharmacodynamic response in terms of leucocyte and neutrophil counts. After the nasal delivery of the G-CSF powder formulation containing SSMS and LPG the absorption of G-CSF was significantly higher (P<0.01) than that from the simple nasal solution or the powder without the enhancer, but the resulting pharmacological response was not significantly different. The bioavailability of G-CSF from the powder formulation containing SSMS and LPG relative to the subcutaneous injection was 8.4% (+/-3.4). We also found that at the respective G-CSF doses investigated, the pharmacodynamic response of this nasal formulation, was similar to that obtained after the subcutaneous administration. The study indicates that the powder formulation containing enhancers could offer an alternative delivery route for G-CSF in the form of intranasal administration.

Administration, Intranasal↗
PubMed1998

In vitro displacement by rat serum of adsorbed radiolabeled poloxamer and poloxamine copolymers from model and biodegradable nanospheres.

Poloxamer 407 and poloxamine 908 have been used by many research groups to modify the surface of both model latex and biodegradable nanospheres, thereby producing nanospheres that have shown reduced protein adsorption in vitro and extended circulation times in vivo. A potential limitation of such systems is the desorption of the copolymer coating layer. We describe a two-stage process to radiolabel poloxamer 407 and poloxamine 908 that has facilitated an investigation into this potential desorption, in vitro. The first stage of the labeling procedure involved the substitution of the terminal hydroxyl groups in each poly(ethylene oxide) (PEO) chain of poloxamer 407 and poloxamine 908 with an amino group. The aminated copolymers were then radiolabeled with 125Iodine Bolton-Hunter reagent. The efficiency of labeling was calculated to be approximately 20% for the tetramine poloxamine 908 and approximately 33% for the diamine poloxamer 407. Remaining free amino groups were then either acetylated, using acetic anhydride, or left in the free amino form. Covalent linkage of the radiolabel to the copolymer was confirmed by nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy. The stability of the link between radiolabel and copolymer to hydrolysis was also confirmed; <4% loss of radiolabel occurred from poloxamine 908 after incubation in phosphate-buffered saline (PBS) at 37 degrees C for 8 days. The radiolabeled copolymers (with the free amino groups acetylated) were then used in experiments that have given the first direct evidence that adsorbed copolymers can be displaced by serum proteins in significant amounts from the surface of model and biodegradable nanospheres. The displacement was highly dependent on copolymer-nanosphere compatibility, with up to 78% of 125I tetramine poloxamine 908 being displaced from poly(lactide-co-glycolide) (PLGA) nanospheres in 24 h, compared with 20% displacement of 125I tetramine poloxamine 908 in 24 h from polystyrene nanospheres. These results have direct implication for the future design of drug delivery systems based on coated nanospheres.

Animals↗
PubMed1998

Chitosan and its use as a pharmaceutical excipient.

Chitosan has been investigated as an excipient in the pharmaceutical industry, to be used in direct tablet compression, as a tablet disintegrant, for the production of controlled release solid dosage forms or for the improvement of drug dissolution. Chitosan has, compared to traditional excipients, been shown to have superior characteristics and especially flexibility in its use. Furthermore, chitosan has been used for production of controlled release implant systems for delivery of hormones over extended periods of time. Lately, the transmucosal absorption promoting characteristics of chitosan has been exploited especially for nasal and oral delivery of polar drugs to include peptides and proteins and for vaccine delivery. These properties, together with the very safe toxicity profile, makes chitosan an exciting and promising excipient for the pharmaceutical industry for present and future applications.

Absorption↗
PubMed1998

Modification of the copolymers poloxamer 407 and poloxamine 908 can affect the physical and biological properties of surface modified nanospheres.

PURPOSE: To investigate the effects of the modification of the copolymers poloxamer 407 and poloxamine 908 on the physical and biological properties surface modified polystyrene nanospheres. METHODS: A method to modify poloxamer 407 and poloxamine 908, introducing a terminal amine group to each PEO chain has been developed. The aminated copolymers can be subsequently radiolabelled with Iodinated (I125) Bolton-Hunter reagent. The aminated copolymers were used to surface modify polystyrene nanospheres. The physical and biological properties of the coated nanospheres were studied using particle size, zeta potential, in vitro non-parenchymal cell uptake and in vivo biodistribution experiments. RESULTS: The presence of protonated amine groups in the modified copolymers significantly affected the physical and biological properties of the resulting nanospheres, although the effects were copolyme specific. The protonated surface amine groups in both copolymers reduced the negative zeta potential of the nanospheres. Acetylation of the copolymer's free amine groups resulted in the production of nanospheres with comparable physical properties to control unmodified copolymer coated nanospheres. In vivo, the protonated amine groups in the copolymers increased the removal of the nanospheres by the liver and spleen, although these effects were more pronounced with the modified poloxamer 407 coated nanospheres. Acetylation of the amine groups improved the blood circulation time of the nanospheres providing modified poloxamine 908 coated nanospheres with comparable biological properties to control poloxamine 908 coated nanospheres. Similarly, modified poloxamer 407 coated nanospheres had only slightly reduced circulation times in comparison to control nanospheres. CONCLUSIONS: The experiments have demonstrated the importance of copolymer structure on the biological properties of surface modified nanospheres. Modified copolymers, which possess comparable properties to their unmodified forms, could be used in nanosphere systems where antibody fragments can be attached to the copolymers, thereby producing nanospheres which target to specific body sites.

Animals↗
PubMed1997

Lymph node localisation of biodegradable nanospheres surface modified with poloxamer and poloxamine block co-polymers.

Studies were performed to develop a sub-100 nm biodegradable colloidal system for the efficient delivery of drugs and diagnostic agents to the lymphatic system. Nanospheres of poly(lactide-co-glycolide) were prepared by interfacial polymer deposition. The nanospheres were coated with block co-polymers in order to modify their surface characteristics. Radiolabelling of the nanospheres for in vivo tracing was achieved by the incorporation of the lipophilic complex 111In-oxine during nanosphere preparation. In vitro stability of the radiolabelled nanospheres was determined in rat serum at 37 degrees C. The lymphatic distribution of the nanospheres was determined after subcutaneous administration to the rat. Lymphatic uptake of all coated systems was enhanced compared to the uncoated nanospheres, and a maximal uptake of 17% of the administered dose in the regional lymph nodes was achieved. These observations suggest that the nanospheres are suitable for diagnostic and therapeutic applications in clinical and experimental medicine.

Animals↗
PubMed1997

Preparation of surface-modified albumin nanospheres.

Surface-modified human serum albumin (HSA) nanospheres with a size of around 100 nm in diameter were prepared from poly(amidoamine)-poly(ethylene glycol) copolymer grafted human serum albumin (HSA-PAA-PEG) and poly(thioetheramido acid)-poly(ethylene glycol) copolymer grafted human serum albumin (HSA-PTAAC-PEG). The nanospheres were produced using a pH-coacervation method and cross-linked with glutaraldehyde. The cross-linking efficiency was affected by the type of albumin conjugate used. The zeta potential of the surface-modified nanospheres was significantly lower than that of unmodified particles. The existence of a hydrated steric barrier surrounding the nanospheres was confirmed by electrolyte- and pH-induced flocculation tests. The surface-modified nanospheres showed a reduced plasma protein adsorption on the particle surface compared with unmodified particles.

Adsorption↗
PubMed1997

Biodegradable polymeric microparticles for drug delivery and vaccine formulation: the surface attachment of hydrophilic species using the concept of poly(ethylene glycol) anchoring segments.

Poly(ethylene glycol)-dextran (PEG-DEX) conjugates have been used as a combined stabilizer and surface modifier to produce resorbable poly(DL-lactide-co-glycolide) (PLG) microparticles by an emulsification/solvent evaporation technique. The use of PEG or dextran polymers alone was incapable of producing microparticles. Particle size measurements revealed smaller mean particle sizes (480 nm) and improved polydispersity when using a 1.2% PEG substituted conjugate relative to a 9% substituted material (680 nm). PLG microparticles modified by post-adsorbed PEG-DEX conjugates flocculated in 0.01 M salt solutions, whereas PLG microparticles prepared using PEG-DEX as a surfactant were stable in at least 0.5 M NaCl solutions. Surface modification of PLG microparticles was confirmed by zeta potential measurements and surface analysis using X-ray photoelectron spectroscopy. The presence of surface exposed dextran was confirmed by an immunological detection method using a dextran-specific antiserum in an enzyme-linked immunosorbent assay. The findings support a model in which the PEG component of the PEG-DEX conjugate provides an anchor to the microparticle surface while the dextran component extends from the particle surface to contribute a steric stabilization function. This approach offers opportunities for attaching hydrophilic species such as targeting moieties to biodegradable microparticles to improve the interaction of drug carriers and vaccines with specific tissue sites.

Biocompatible Materials↗
PubMed1997

Long circulating biodegradable poly(phosphazene) nanoparticles surface modified with poly(phosphazene)-poly(ethylene oxide) copolymer.

The biodistribution of biodegradable poly(organo phosphazene) nanoparticles surface modified by adsorption of a novel poly(organo phosphazene)-poly(ethylene oxide) copolymer with a 5000 M(W) PEO chain (PF-PEO[5000]), following intravenous administration in rats and rabbits, is described. The data are compared to the biodistribution of poly(organo phosphazene) and poly(lactide-co-glycolide) nanoparticles coated with a tetrafunctional copolymer of poly(ethylene oxide)-poly(propylene oxide) ethylenediamine, commercially available as Poloxamine 908. This copolymer has a PEO chain of the same size as the poly(organo phosphazene)-PEO derivative used. The results in the rat model reveal that poly(organo phosphazene) nanoparticles with a Poloxamine 908 coating were mainly captured by the liver, although a retardation in clearance from the systemic circulation was seen. In contrast, the poly(organo phosphazene) nanoparticles coated with PF-PEO(5000) showed a prolonged blood circulating profile, with only a small amount of the nanoparticles sequestered by the liver. This indicates the importance of the nature of both the anchoring group and the particle surface on the biological performances of the system. Study of the biodistribution of the PF-PEO(5000)-coated poly(organo phosphazene) nanoparticles in the rabbit model also indicated a prolonged systemic circulation lifetime and reduced liver uptake, whereby a significant amount of the administered nanoparticles was targeted to the bone marrow.

Animals↗
PubMed1997

Chitosan as a nasal delivery system: the effect of chitosan solutions on in vitro and in vivo mucociliary transport rates in human turbinates and volunteers.

In these studies, we examined the effect on mucociliary transport rates (MTR) of various 0.25% (w/v) chitosan solutions applied to human nasal tissue both ex vivo and in vivo. In the first study a range of chitosans with different molecular weights were applied to freshly amputated human nasal turbinates, and their effect on MTR was recorded. The transient inhibitory effect on turbinate MTR that was found for most of the chitosan preparations showed a marked dependence on the volume of chitosan solution applied and the molecular weight of the chitosan tested. The higher the molecular weight of the chitosan and the more chitosan applied, the longer the original MTR was depressed. A small scale human trial, investigating the effect of chitosan glutamate, on saccharin clearance times, was also undertaken. The study showed that a once daily application of a 0.25% solution of the chitosan for 7 days had no effect on either saccharin clearance times or nasal histology as examined by light microscopy.

Adult↗
PubMed1997

Preparation of biodegradable, surface engineered PLGA nanospheres with enhanced lymphatic drainage and lymph node uptake.

PURPOSE: Nanospheres can be utilised for the targeting of drugs and diagnostic agents to the regional lymph nodes. The surface modification of model polystyrene, (PS), and poly(lactide-co-glycolide),(PLGA), nanospheres by poly(lactide)-poly(ethylene glycol), (PLA:PEG), copolymers has been assessed by in vitro characterisation and in vivo biodistribution studies following subcutaneous administration of the nanospheres to the rat. METHODS: Three PLA:PEG copolymers were investigated, with PEG chain lengths of 750, 2000 and 5000 Da. The PLA:PEG copolymers were either coated onto the surface of PS and PLGA nanospheres or used as a co-precipitate in the formation of PLGA-PLA:PEG nanospheres. Coating of the nanospheres was confirmed by an increase in their particle size and a corresponding decrease in the surface potential. The kinetics of injection site drainage and lymph node retention was determined over a 24 hour time course for naked, coated and co-precipitated nanosphere systems. RESULTS: Dependent on the surface characteristics, the distribution of the nanospheres can be significantly modified and the lymph node localisation dramatically enhanced by coating their surfaces with PLA:PEG copolymers or by producing co-precipitate nanospheres of PLGA and PLA:PEG. CONCLUSIONS: A fully biodegradable nanosphere system has been developed with excellent lymph node targeting characteristics.

Animals↗
PubMed1997

Activation of the mononuclear phagocyte system by poloxamine 908: its implications for targeted drug delivery.

PURPOSE: To investigate the effect of poloxamine 908 on the MPS activity and the importance of its mode of presentation to the immune system. METHODS: Solutions of endotoxin free poloxamine 908 were injected daily intravenously to rats, and the effect on the degree of sequestration by the liver of I125 labelled, poloxamine 908-coated 60 nm polystyrene particles was investigated by studying effect of dosing regimen(s) and assessment of opsonic activity. RESULTS: After 3 or 4 days repeated dosing with poloxamine 908 (0.7 mg) in solution, the poloxamine 908-coated polystyrene particles (60 nm) were rapidly cleared from the circulation. The increase sequestration of the particles by the liver lasted for more than 7 days after last dosing with the poloxamine 908 solution. In subsequent studies, it was found that a single dose of poloxamine 908 (0.7 mg) in solution was sufficient to activate the MPS 4 days after the injection. The increased uptake was found not be mediated by a serum component, nor was it due to proliferation of the Kupffer cells in the liver. CONCLUSIONS: The results provide evidence that a solution of endotoxin-free poloxamine 908 activates the MPS so that 4 days after injection otherwise long-term circulating poloxamine 908-coated particles are sequestered by the liver. This finding has implications for use of such coated systems in therapeutic situations.

Animals↗
PubMed1997

Human serum albumin as a probe for surface conditioning--a study of the ageing effect.

I125 radiolabelled HSA (HSA-I125) was utilised as a probe to quantify protein adsorption onto polystyrene (PS) and Poloxamine 908 coated PS (PS-908) particles. Upon ageing of the HSA-I125 a dramatic increase in the amount of protein adsorbed onto the two particle systems was observed. This phenomenon was not due to lability of the protein-radionuclide bond and no modifications in the secondary structure of the native and radiolabelled protein could be identified which could explain this unusual ageing effect. Using the amount of protein adsorbed to the uncoated particles as a control for each time point, it was possible to reproducibily determine the amount of HSA adsorbed to the coated particles.

Adsorption↗
PubMed1997

Human serum albumin as a probe for protein adsorption to nanoparticles: relevance to biodistribution.

A range of poloxamers and poloxamines were adsorbed to biodegradable poly(lactide-co-glycolide) (PLGA) and non-biodegradable polystyrene (PS) particulate systems in order to alter their surface characteristics and produce potential drug targeting systems. Human serum albumin (HSA) was chosen as a model protein to investigate protein adsorption to the above systems and was quantified by two techniques. I125 radiolabelled HSA proved to be a useful probe for determining protein adsorption but was limited by a modification that occurred on storage. Also, HSA eluted from the particle surface was quantified by densitometry following it's development on an SDS-PAGE gel. Both techniques produced similar results. For cleaned coated PS particles it was found that the PEO chain length and the molecular structure of the block copolymer were important in preventing protein adsorption. The presence of excess block copolymer in the uncleaned preparations resulted in further suppression of HSA adsorption, which was thought to be due to their detergent properties. Due to the different results obtained with similarly coated PLGA particles, it was concluded that the block copolymers adsorb onto the surface of the PLGA particles in a different conformation to those adsorbed onto PS particles. Correlating in vivo biodistribution in terms of the prevention of protein (opsonin) adsorption was of only limited success and it was concluded that adsorption data for a single model protein can only be used with caution to predict the in vivo behaviour of colloidal targeting systems.

Adsorption↗
PubMed1996

Nasal administration of morphine-6-glucuronide in sheep--a pharmacokinetic study.

The pharmacokinetics of morphine-6-glucuronide (M6G) after both intravenous dosing and nasal administration were studied in sheep. The nasal formulation consisted of M6G in combination with an absorption promoting delivery system in the form of chitosan. The mean half-life of M6G after intravenous administration was 51.0 +/- 8.2 min and that after intranasal dosing was 45.0 +/- 5.5 min. M6G clearance and volume of distribution were 5.4 +/- 1.5 mL min-1 kg-1 and 0.4 +/- 0.1 L kg-1 respectively. The plasma profile after nasal administration demonstrated rapid absorption of M6G. The bioavailability of M6G in the chitosan formulation was found to be 31.4%. These results suggest that M6G administered in combination with the chitosan delivery system may be considered as a suitable non-parenteral means of administering this analgesic.

Absorption↗
PubMed1996

Development and validation of a pig model for colon-specific drug delivery.

The purpose of this investigation was to develop a pig model for colonic drug delivery and to validate the model by determining whether the physiology of the pig colon had been significantly altered after the surgical implantation of a gut cannula into the terminal ileum of the pig. A fistula was created in the terminal ileum of the pig, and a cannula fitted for the purpose of directly administering drug formulations to a point just anterior to the ileocaeco-colonic valve of the gastrointestinal tract. The cephalic vein of the pig was also cannulated to enable continued blood sampling. Sulphasalazine was used as the model drug for the validation study. In the intact colon, sulphasalazine is metabolized by the gut microflora to sulphapyridine which is then absorbed. Sulphasalazine was administered orally to non-fistulated and fistulated pigs and then ileally, via the gut cannula, to fistulated pigs. Absorption of sulphapyridine was monitored by HPLC analysis of plasma samples. There was no significant difference in the absorption obtained for the three groups. Thus it is demonstrated that the colon physiology had not been altered. The colonic pig model is ideal for studying factors affecting the colonic absorption of drugs and as a means for developing drug delivery systems with improved absorption properties.

Animals↗
PubMed1995

Immune responses and protection against Bordetella pertussis infection after intranasal immunization of mice with filamentous haemagglutinin in solution or incorporated in biodegradable microparticles.

The intranasal (i.n.) immunization of mice with Bordetella pertussis filamentous haemagglutinin (FHA) either as a solution or incorporated in biodegradable microparticles induced very similar immune responses. Both resulted in strong systemic IgG responses to FHA and good levels of anti-FHA IgG and IgA in the lungs of immunized mice. In comparison, the intraperitoneal (i.p.) immunization of mice with FHA, as a solution, engendered anti-FHA antibody responses which were stronger for serum IgG, similar for lung IgG and lower for lung IgA. The anti-FHA antibody levels, as measured by immunosorbent assay, were shown to correlate with their functional activity in the blocking of B. pertussis adhesion to HeLa tissue-culture cells. All three forms of immunization appeared to stimulate T-cell responses as assessed by in vitro antigen-specific spleen cell proliferation and IL-2 secretion indicative of a Th1 type response, however, cells from i.p. immunized mice only secreted low levels of IL-5. All three methods of FHA immunization provided mice with significant protection against subsequent aerosol challenge with virulent B. pertussis. Mice which had been immunized intra-nasally eliminated the bacteria from their lungs slightly more rapidly than i.p. immunized mice, demonstrating the efficacy of intranasal administration of FHA in solution and in the more practical biodegradable microparticle form.

Administration, Intranasal↗