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L Illum

Publications and source records attributed to L Illum.

At least 37 records · Page 2Linked to original sources
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↗
PubMed2000

A mucosal vaccine against diphtheria: formulation of cross reacting material (CRM(197)) of diphtheria toxin with chitosan enhances local and systemic antibody and Th2 responses following nasal delivery.

The development of new generation vaccines against diphtheria is dependent on the identification of antigens and routes of immunization that are capable of stimulating immune responses similar to, or greater than, those obtained with the parenterally-delivered toxoid vaccine, while reducing the adverse effects that have been associated with the traditional vaccine. In this study, we examined the cellular and humoral immune responses in mice generated after both parenteral and mucosal immunizations with cross-reacting material (CRM(197)) of diphtheria toxin. We found that both native and mildly formaldehyde-treated CRM(197) and conventional diphtheria toxoid (DT) induced mixed Th1/Th2 responses and similar levels of anti-DT serum IgG following parenteral immunization. In contrast, CRM(197) preparations were poorly immunogenic when administered intranasally in solution. However, formulation of the antigens with chitosan significantly enhanced their immunogenicity, inducing high levels of antigen-specific IgG, secretory IgA, toxin-neutralizing antibodies and T cell responses, predominately of Th2 subtype. Furthermore, intranasal immunization with CRM(197) and chitosan induced protective antibodies against the toxin in a guinea pig passive challenge model. We also found that priming parenterally with DT in alum and boosting intranasally with CRM(197) was a very effective method of immunization in mice, capable of inducing high levels of anti-DT IgG and neutralizing antibodies in the serum and secretory IgA in the respiratory tract. Our findings suggest that boosting intranasally with CRM(197) antigen may be very effective in adolescents or adults who have previously been parenterally immunized with a conventional diphtheria toxoid vaccine.

Administration, Intranasal↗
PubMed2000

Defining the drug incorporation properties of PLA-PEG nanoparticles.

The drug incorporation and physicochemical properties of PLA-PEG micellar like nanoparticles were examined in this study using a model water soluble drug, procaine hydrochloride. Procaine hydrochloride was incorporated into nanoparticles made from a series of PLA-PEG copolymers with a fixed PEG block (5 kDa) and a varying PLA segment (3-110 kDa). The diameter of the PLA-nanoparticles increased from 27.7 to 174.6 nm, with an increase in the PLA molecular weight. However, drug incorporation efficiency remained similar throughout the series. Incorporation of drug into the smaller PLA-PEG nanoparticles made from 3:5, 15:5 and 30:5 copolymers did not influence the particle size, while an increase was observed for the larger systems comprising 75:5 and 110:5 copolymers. An increase in drug content for PLA-PEG 30:5 nanoparticles was achieved by increasing the theoretical loading (quantity of initially present drug). The size of these nanoparticles remained unchanged with the increasing drug content, supporting the proposed micellar type structure of the PLA-PEG 30:5 nanoparticles. The morphology of these systems remained unchanged both at low and high theoretical drug loadings. Formulation variables, such as an increase in the aqueous phase pH, replacement with the base form of the drug and inclusion of lauric acid in the formulation did not improve the incorporation efficiency of drug into PLA-PEG 30:5 nanoparticles. While poly(aspartic acid) as a complexation agent did not improve the drug incorporation efficiency of procaine hydrochloride, it did so for another water soluble drug diminazene aceturate. This may be attributed to a stronger interaction of diminazene aceturate with poly(aspartic acid) relative to procaine hydrochloride, as confirmed by thermodynamic analysis of isothermal titration calorimetric data. The drug incorporation and physicochemical characterisation data obtained in this study may be relevant in optimising the drug incorporation and delivery properties of these potential drug targeting carriers.

Anesthetics, Local↗
PubMed2000

Carbohydrate biopolymers enhance antibody responses to mucosally delivered vaccine antigens.

We have evaluated the ability of two carbohydrate biopolymers, chitosan and gellan, to enhance antibody responses to subunit influenza virus vaccines delivered to the respiratory tracts of mice. Groups of mice were vaccinated three times intranasally (i.n.) with 10 microg of purified influenza B/Panama virus surface antigens (PSAs), which consist of hemagglutinin (HA) and neuraminidase (NA), either alone or admixed with chitosan or gellan solutions. Separate groups were vaccinated subcutaneously (s.c.) with PSAs adsorbed to Alhydrogel or chitosan or gellan alone i.n. Serum antibody responses were determined by enzyme-linked immunosorbent assay (ELISA) for influenza virus-specific immunoglobulin G (IgG) and by HA inhibition (HAI) and NA inhibition (NAI) assays. The local respiratory immune response was measured by assaying for influenza virus-specific IgA antibody in nasal secretions and by enumerating nasal and pulmonary lymphocytes secreting IgA, IgG, and IgM anti-influenza virus-specific antibodies by enzyme-linked immunospotting (ELISPOT). When administered alone i.n., B/Panama PSA was poorly immunogenic. Parenteral immunization with B/Panama PSA with Alhydrogel elicited high titers of anti-B/Panama antibodies in serum but a very poor respiratory anti-B/Panama IgA response. In contrast, i.n. immunization with PSA plus chitosan stimulated very strong local and systemic anti-B/Panama responses. Gellan also enhanced the local and serum antibody responses to i.n. PSA but not to the same extent as chitosan. The ability of chitosan to augment the immunogenicity of influenza vaccines given i.n. was confirmed using PSA prepared from an influenza A virus (A/Texas H1N1).

Animals↗
PubMed2000

Schizophrenia and drug delivery systems.

Schizophrenia is a severe non-curable illness of the brain with serious consequences if not properly treated and kept under control. Antipsychotic drugs have revolutionised the therapy and management of schizophrenia. However, patient compliance rates are notoriously poor due to the nature of the disease and troublesome side-effects, and are major causes of symptom recurrence. Although some new antipsychotic agents have been marketed to offer broader efficacy with much reduced side-effect profiles, the drug delivery systems for antipsychotics are still in the stage of conventional dosage forms, such as tablets, capsules and solutions, and need to be dosed at the frequency of 2-4 times daily. Doubtless. novel drug delivery systems, such as sustained and controlled release systems, will be useful for antipsychotics. They should reduce the frequency of dosing. enhance drug bioavailability and improve patient compliance. In this article, the specificity and characterisation of schizophrenia and pathophysiology. drug therapy. and the development and future prospects of neuroleptic drug delivery systems are reviewed.

Antipsychotic Agents↗
PubMed1999

Preparation and in vitro characterization of HSA-mPEG nanoparticles.

Surface modified human serum albumin (HSA) nanoparticles with a size of approximately 150 nm in diameter were prepared from a PEG-HSA conjugate, methoxy-polyethylene glycol modified human serum albumin (HSA-mPEG) using a coacervation method and crosslinked with glutaraldehyde. The zeta-potential of the surface modified nanoparticles was significantly lower than that of unmodified HSA nanoparticles. The existence of a hydrated steric barrier surrounding the nanoparticles was confirmed by electrolyte and pH induced flocculation tests. The surface modified nanoparticles showed a reduced plasma protein adsorption on the particle surface compared with unmodified particles.

Animals↗
PubMed1999

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.

Biocompatible Materials↗
PubMed1999

Detection and determination of surface levels of poloxamer and PVA surfactant on biodegradable nanospheres using SSIMS and XPS.

The surface chemical characterisation of sub-200 nm poly(DL-lactide co-glycolide) nanospheres has been carried out using the complementary analytical techniques of static secondary ion mass spectrometry (SSIMS) and X-ray photoelectron spectroscopy (XPS). The nanospheres, which are of interest for site-specific drug delivery, were prepared using an emulsification-solvent evaporation technique with poly(vinyl alcohol), Poloxamer 407 and Poloxamine 908 respectively as stabilisers. The presence of surfactant molecules on the surface of cleaned biodegradable colloids was confirmed and identified on a qualitative molecular level (SSIMS) and from a quantitative elemental and functional group analysis (XPS) perspective. SSIMS and XPS data were also used in combination with electron microscopy to monitor the effectiveness of cleaning procedures in removing poorly bound surfactant molecules from the surface of nanospheres. The findings are discussed with respect to the development of nanoparticle delivery systems, particularly the composition of the surface for extending blood circulation times and achieving site-specific deposition.

Adsorption↗
PubMed1999

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.

Buffers↗
PubMed1999

Intranasal insulin delivery and therapy.

Intranasal insulin delivery has been widely investigated as an alternative to subcutaneous injection for the treatment of diabetes. The pharmacokinetic profile of intranasal insulin is similar to that obtained by intravenous injection and, in contrast to subcutaneous insulin delivery, bears close resemblance to the 'pulsatile' pattern of endogenous insulin secretion during meal-times. The literature suggests that intranasal insulin therapy has considerable potential for controlling post-prandial hyperglycaemia in the treatment of both IDDM and NIDDM. However, effective insulin absorption via the nasal route is unlikely without employing the help of absorption enhancers or promoters which are able to modulate nasal epithelial permeability to insulin and/or prolong the residence time of the drug formulation in the nasal cavity. This article discusses the structure and function of the nasal cavity, the barriers which prevent nasal insulin absorption and through the use of absorption enhancers or promoters methods by which these barriers may be overcome.

Journal Article↗
PubMed1999

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.

Adhesiveness↗
PubMed1999

Potential of polymeric lamellar substrate particles (PLSP) as adjuvants for vaccines.

In recent years microspheres or microparticles produced from biodegradable polymers such as poly(D,L-lactide) (PLA) and poly(D, L-lactide-co-glycolide) (PLGA) containing encapsulated vaccine antigens have been investigated for administration via parenteral, oral, and intranasal routes. These microparticles allow the controlled release of vaccines with an aim to reduce the number of doses for primary immunisation or to develop single dose vaccines. The polymer materials have been widely regarded as being of minimal toxicity. Evaluation of candidate systems in animal studies have shown antibody levels and cell responses similar to or greater than those observed with adjuvants such as alum. 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. An alternative approach would be to adsorb antigens to the surface of biodegradable polymer particles. Polymeric lamellar substrate particles (PLSP), produced by a simple precipitation of PLA, are suitable for this purpose. The adsorption of antigens onto these particles is a simple procedure. It avoids pH changes due to bulk polymer degradation and the use of solvents and therefore will be less damaging to the vaccine. Moreover, such systems will be much easier to scale up for a clinical study and eventual manufacture. The aim of this article is to discuss the preparation and physical characteristics of PLSP, antigen adsorption, in vivo efficacy of PLSP antigen systems and to consider the potential of PLSP as controlled release adjuvants for protein, peptide or viral vaccines.

Adjuvants, Immunologic↗
PubMed1999

Complex formation between the anionic polymer (PAA) and a cationic drug (procaine HCI): characterization by microcalorimetric studies.

PURPOSE: Due to the importance of drug-polymer interactions in, inter alia, drug loading/release, supramolecular assemblies and DNA delivery for gene therapy, the aim of this study was therefore to establish the mechanism of interaction between a model polymer (Polyacrylic acid, PAA) and a model drug (procaine HCl). METHODS: This was performed by studying the effect of salt (KCl) concentration on their heat released values using Isothermal Titration Microcalorimetry (ITM). The integrated released heat data were computer fitted to a one class binding model and the thermodynamic parameters (Kobs, deltaH, and N) were determined. RESULTS: As the KCl concentration was increased, Kobs decreased thus establishing the salt dependence of the interaction. The linear variation of deltaGobs with deltaSobs indicated that their interaction was entropically driven. The stoichiometry of the interaction was calculated to be one procaine molecule per monomer of PAA. Dissection of the total observed free energy at each KCI concentration indicated that the contribution of the non-electrostatic attractions to the interaction of PAA with procaine HCl was greater than those of the electrostatic attractions. CONCLUSIONS: We have shown that the interaction between PAA and procaine HCl is dependent upon the presence of counterions (monovalent ions) and is mainly entropically driven. The calculated stoichiometry indicated that one procaine HCl molecule neutralised one carboxylic acid group on PAA. Although electrostatic interactions were necessary for initiating complex formation, the non-electrostatic forces were dominant in stabilising the PAA-procaine HCl complex.

Acrylic Resins↗
PubMed1998

A poly(D,L-lactide-co-glycolide) microsphere depot system for delivery of haloperidol.

Haloperidol-loaded biodegradable poly(d,l-lactide-co-glycolide) (PLG) microspheres, with theoretical mean particle sizes of about 0. 8, 2 and 8 micrometer, have been successfully prepared by using an emulsification-solvent evaporation method. The effect of various processing parameters such as the content of polymer in dichloromethane, the content of polyvinyl alcohol in the aqueous phase, and the stirring speed of emulsification on the particle size and size distribution of microspheres has been investigated and three optimal procedures suggested. The influence of particle size on drug content and incorporation efficiency of haloperidol-loaded PLG microspheres also has been evaluated. In vitro a linear release of haloperidol from PLG microspheres over an extended period of time without a significant burst effect has been achieved; the time of 50% drug release (T50%) being around 55 days. The effect of drug content and particle size on the cumulative release of haloperidol from PLG microspheres was also studied together with the reproducibility of drug content and release profile from batch-to-batch with different particle sizes.

Antipsychotic Agents↗
PubMed1998

The effect of lymphatic oedema on the uptake of colloids to the lymph nodes.

The majority of pathological conditions of the lymphatic system can result in some degree of lymphoedema, which in turn causes a reduced rate of lymph flow. In some cases, such as when nodes are invaded by tumour metastases, blockage of the lymphatic vessels may occur. In order to investigate the effect of such pathology on nanosphere uptake in regional lymph nodes, the fate of model polystyrene nanospheres, surface modified with block co-polymers of the poloxamine series, was determined following subcutaneous administration in a rat model with lymphoedema (induced by the administration of lambda-carrageenan). A drastic reduction of injection site drainage and lymph node uptake of nanospheres was observed in the inflammation model compared to control animals. The observations suggest that biodegradable nanospheres based on these will be suitable for the detection of oedema in the lymphatic system.

Animals↗