Papers by Michael Hinchcliffe
The findings of this project have added to the pool of information reported in the literature reg... more The findings of this project have added to the pool of information reported in the literature regarding the application of the nasal route for the delivery of insulin and other peptide drugs. The preliminary studies reported in this project were apparently the first studies performed to investigate the potential use of chitosan in nasal delivery systems. Nasal delivery systems were investigated in rat and sheep models. The efficacy of chitosan as a nasal absorption enhancer for insulin was compared to that of several other compounds which had been reported in the literature to enhance nasasl drug absorption. Erythrocyte haemolysis studies were also performed to evaluate the membrane damaging effects of the various compounds tested. The grade of chitosan predominantly used was a medium viscosity glutamate salt (MVCSN) which was 82% deacetylated and had a molecular weight of about 162,000. Other grades of chitosan of similar degree of deacetylation were also investigated for comparison with MVCSN (low viscosity grades of chitosan glutamate (LVCSN) and lactate (CSN lactate), medium viscosity chitosan hydrochloride (CSN HC1) and high viscosity chitosan base (HVCSN)). The efficacy of chitosan in enhancing the nasal absorption of both insulin and salmon calcitonin, used an an alternative peptide, was demonstrated in rat and sheep models. Nasal insulin delivery systems were extensively investigated in rat and sheep models. In the rat model, insulin / LVCSN formulations at pH-4 were more effective than formulations at pH-7 in enhancing intranasal insulin absorption which was assessed indirectly from the degree of hypoglycaemia following dose administration. The reduced absorption in the latter formulation which was in the form of a suspension was attributed to complex formation between insulin and LVCSN. In the rat model, the absorption enhancing efficacy of MVCSN was second only to that of LPC. This was encouraging in view of the severe membrane damaging effects that LPC solutions have been shown to cause. In contrast, chitosan solutions have been shown to be relatively non-toxic to biomembranes. In the sheep model, a formulation incorporating MVCSN was much more effective than a formulation containing LPC in promoting nasal insulin absorption. These differences were attributed to the animal models used to investigate nasal absorption. The degree of nasal absorption enhancement was improved by increasing the solution concentration of MVCSN until and optimal concentration was attained (approximately 0.5% and 0.35% in rat and sheep models, respectively). Further evaluation of nasal insulin / chitosan formulations in sheep, suggested that the formulation concentration of chitosan was important for its absorption enhancing efficacy and at optimal chitosan concentration nasal insulin absorption was limited by the dose concentration of insulin. In both rat and sheep models, the nasal administration of hypotonic or isotonic formulations of insulin with chitosan did not influence the degree of nasal absorption enhancement attained. However, in rats, a hypertonic formulation was shown to further I wish to thank Allison for her encouragement, support and assistance during the last twelve months. Finally, I would like to express great appreciation to Marjorie Wood for support throughout my education. Special thanks too to Kenneth Wood. Contents Section Ti le P Chapter 1 1.6.2 Overcoming the barriers to peptide or protein drug delivery 44 1.6.2.1 Bile salts 45 1.6.2.2 Surfactants 49 1.6.2.3 Chelating agents 52 2.4.2.4 Blood sampling 103 2.5 Measurement of glucose, insulin or calcium 103 concentrations 2.5.1 Measurement of blood or plasma glucose concentrations 104 2.5.2 Measurement of insulin concentrations 104 2.5.3 Measurement of calcium concentrations 105 2.6 Calculation of results following glucose, insulin or 105 calcium analysis 2.6.1 Calculation of results following glucose analysis 105 2.6.2 Calculation of results following insulin analysis 106 2.6.3 Calculation of results following calcium analysis 107 4.2.3 Results and Discussion 126 4.3 Effect of different concentrations of chitosan on the 131 intranasal absorption of insulin in rats 4.3.1 Aims and objectives 131 4.3.2 Study outline 4.3.2.1 Materials 131 4.3.2.2 Preparation of insulin formulations 131 4.3.2.3 Absorption study in the rat model 131 4.3.3 Results and Discussion 131 4.4 Investigation of the transient effect of chitosan on the 136 intranasal absorption of insulin in the rat 4.4.1 Aims and objectives 136 4.4.2 Study outline 4.4.2.1 Materials 136 4.4.2.2 Preparation of insulin and chitosan formulations 136 4.4.2.3 Absorption study in the rat model 137 4.4.3 Results and Discussion 137 6.3 Results and Discussion 156 6.4 Conclusions 159 Chapter 7 Evaluation and further optimisation of nasal insulin formulations containing chitosan in sheep 7.1 Introduction 165 7.2 Effect of chitosan concentration on intranasal insulin 166 absorption in sheep 7.2.1 Aims and objectives 166 7.
Pharmaceutics, 2019
Nasal delivery of large peptides such as parathyroid 1-34 (PTH 1-34) can benefit from a permeatio... more Nasal delivery of large peptides such as parathyroid 1-34 (PTH 1-34) can benefit from a permeation enhancer to promote absorption across the nasal mucosa into the bloodstream. Previously, we have published an encouraging bioavailability (78%), relative to subcutaneous injection in a small animal preclinical model, for a liquid nasal spray formulation containing the permeation enhancer polyethylene glycol (15)-hydroxystearate (Solutol® HS15). We report here the plasma pharmacokinetics of PTH 1-34 in healthy human volunteers receiving the liquid nasal spray formulation containing Solutol® HS15. For comparison, data for a commercially manufactured teriparatide formulation delivered via subcutaneous injection pen are also presented. Tc-99m-DTPA gamma scintigraphy monitored the deposition of the nasal spray in the nasal cavity and clearance via the inferior meatus and nasopharynx. The 50% clearance time was 17.8 min (minimum 10.9, maximum 74.3 min). For PTH 1-34, mean plasma Cmax of 5 pg...
International Journal of Pharmaceutics, 2001
This paper describes the clearance characteristics of two bioadhesive nasal delivery systems in t... more 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.
Journal of Controlled Release, 2002
A novel nasal formulation, in the form of a nicotine-Amberlite resin complex powder has been deve... more 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.
Degenerative Neurological and Neuromuscular Disease, 2017
Amyotrophic lateral sclerosis (ALS) is the commonest form of motor neuron disease and is a fatal,... more Amyotrophic lateral sclerosis (ALS) is the commonest form of motor neuron disease and is a fatal, degenerative, multisystem disorder affecting upper and/or lower motor neurons in the motor cortex, brain stem, and spinal cord. ALS is characterized by progressive atrophy of associated bulbar, limb, thoracic, and abdominal muscles and supporting cells manifesting in a range of muscular symptoms such as weakness and wasting and eventual paralysis; the majority of patients will die from respiratory failure within 2-5 years of onset. Riluzole, a synthetic benzothiazole drug with glutamine antagonist activity, is indicated for the treatment of patients with ALS and is the only drug that has been shown to slow the course of the disease and extend survival in ALS patients. The original analyses, and subsequent meta-analyses, of data obtained from randomized controlled trials (RCTs) suggest that riluzole typically extends survival by 2-3 months and increases the chance of an additional year of survival by ~9%. However, published real-world evidence (RWE) from 10 clinical ALS databases indicates that riluzole therapy may afford much greater extension of survival, and improvements in median survival times of more than 19 months have been reported in the overall ALS patient population. This article will review the available data from RCTs and RWE on riluzole therapy.
Pharmaceutical Research
Investigate the effect of blood sampling site and physicochemical characteristics of drugs on the... more Investigate the effect of blood sampling site and physicochemical characteristics of drugs on the pharmacokinetic (PK) parameters obtained after intravenous and nasal administration in sheep and compare results with computer simulations. Three drugs, insulin, morphine, and nicotine, were administered nasally and by intravenous (IV) injection to sheep, and serial blood samples collected concurrently from the carotid artery (insulin, morphine) or cephalic vein (nicotine) and jugular vein. Plasma drug concentrations were measured, and pharmacokinetic and statistical analyses performed, to evaluate sampling site differences. After nasal insulin, bioavailabilities calculated from the two blood sampling site data were comparable. In contrast, apparent bioavailabilities following nasal morphine or nicotine were significantly higher when sampling was from the jugular vein. These results were supported by computer simulations. These observations are attributed to the greater effects of nonin...
Mucosal Delivery of Biopharmaceuticals, 2014
Nasal vaccination offers a number of attractions, including the potential for generating mucosal ... more Nasal vaccination offers a number of attractions, including the potential for generating mucosal and systemic antibody responses and the avoidance of syringes and needles for dosing. However, many antigens are not capable by themselves of eliciting an adequate immune response when administered intranasally and coadministration with an adjuvant will be required. ChiSys®, a chitosan-based delivery platform, has shown potential in preclinical and clinical investigations as an adjuvant for a variety of intranasally administered vaccine antigens. Chitosan is a cationic biopolymer, typically derived from crustaceans and fungi, and is available in high purity grades suitable for pharmaceutical applications. The polymer is mucoadhesive, able to modulate epithelial tight junctions, and has immunostimulant properties. The safety of ChiSys® has been demonstrated in numerous preclinical and clinical studies. ChiSys® has been used as a nasal vaccine delivery platform (in some instances combined with other adjuvants) for a number of different antigens, including diphtheria, seasonal influenza, avian influenza, anthrax, and Norwalk virus; both enhanced antibody responses and efficacy have been demonstrated.
Human Vaccines & Immunotherapeutics, 2013
PLoS ONE, 2014
We investigated the protective efficacy of two intranasal chitosan (CSN and TM-CSN) adjuvanted H5... more We investigated the protective efficacy of two intranasal chitosan (CSN and TM-CSN) adjuvanted H5N1 Influenza vaccines against highly pathogenic avian Influenza (HPAI) intratracheal and intranasal challenge in a ferret model. Six groups of 6 ferrets were intranasally vaccinated twice, 21 days apart, with either placebo, antigen alone, CSN adjuvanted antigen, or TM-CSN adjuvanted antigen. Homologous and intra-subtypic antibody cross-reacting responses were assessed. Ferrets were inoculated intratracheally (all treatments) or intranasally (CSN adjuvanted and placebo treatments only) with clade 1 HPAI A/ Vietnam/1194/2004 (H5N1) virus 28 days after the second vaccination and subsequently monitored for morbidity and mortality outcomes. Clinical signs were assessed and nasal as well as throat swabs were taken daily for virology. Samples of lung tissue, nasal turbinates, brain, and olfactory bulb were analysed for the presence of virus and examined for histolopathological findings. In contrast to animals vaccinated with antigen alone, the CSN and TM-CSN adjuvanted vaccines induced high levels of antibodies, protected ferrets from death, reduced viral replication and abrogated disease after intratracheal challenge, and in the case of CSN after intranasal challenge. In particular, the TM-CSN adjuvanted vaccine was highly effective at eliciting protective immunity from intratracheal challenge; serologically, protective titres were demonstrable after one vaccination. The 2-dose schedule with TM-CSN vaccine also induced cross-reactive antibodies to clade 2.1 and 2.2 H5N1 viruses. Furthermore ferrets immunised with TM-CSN had no detectable virus in the respiratory tract or brain, whereas there were signs of virus in the throat and lungs, albeit at significantly reduced levels, in CSN vaccinated animals. This study demonstrated for the first time that CSN and in particular TM-CSN adjuvanted intranasal vaccines have the potential to protect against significant mortality and morbidity arising from infection with HPAI H5N1 virus.
Pharmaceutical Research - PHARMACEUT RES, 2002
Purpose. To investigate whether the widely accepted advantages associated with the use of chitosa... more Purpose. To investigate whether the widely accepted advantages associated with the use of chitosan as a nasal drug delivery system, might be further improved by application of chitosan formulated as nanoparticles.
Journal of Pharmacy and Pharmacology, 2005
The effects of a chitosan-based delivery system on the pharmacokinetics of intranasally administe... more The effects of a chitosan-based delivery system on the pharmacokinetics of intranasally administered salmon calcitonin (sCT) were investigated in a sheep model. In particular, the feasibility of producing a formulation with a comparable or improved bioavailability and/or less variability than the currently marketed nasal product (Miacalcin nasal spray, Novartis Pharmaceuticals) was assessed. A comparator (control) formulation comprising sCT solution was also tested. Sheep (n = 6) were dosed intranasally according to a randomized crossover design. The intranasal sCT dose was 1100 IU (equivalent to approximately 17 IU kg−1). After completion of the nasal dosing legs, five of the sheep received 300 IU sCT (equivalent to approximately 5 IU kg−1) by subcutaneous injection to estimate relative bioavailability. After intranasal or subcutaneous dosing, serial blood samples were taken and plasma separated by centrifugation before measuring sCT concentrations by ELISA. Pharmacokinetic (non-co...
Journal of Pharmacy and Pharmacology, 2001
The gastrointestinal transit of liquid, pellet and tablet formulations was measured under fasted ... more 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.
Journal of Pharmacology and Experimental Therapeutics, 2002
Morphine administered nasally to humans as a simple solution is only absorbed to a limited degree... more 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
Journal of Pharmaceutical Sciences, 1998
This study was designed to investigate the existence of an ileal brake mechanism in the pig model... more This study was designed to investigate the existence of an ileal brake mechanism in the pig model. The test substances used (oleic acid, deoxycholic acid, taurocholic acid) had all been previously shown to affect the ileal brake mechanism in other species including man. The substances were infused directly into the terminal ileum of surgically modified pigs, 45 min after the pigs had ingested a meal containing a drug marker. The marker used was sulfasalazine, which is cleaved to form a metabolite, sulfapyridine, when it reaches the colon. The subsequent HPLC analysis of collected blood samples allowed the appearance of sulfapyridine in the plasma and hence the arrival of sulfasalazine in the colon to be determined. Any differences in transit between control and test could be evaluated from a profile of plasma concentrations and corresponding values of AUC. The findings from this study show that the various substances did not affect transit of a test meal in the pig and suggest that it is not possible to use this pig model to make predictions about the human ileal brake.
Journal of Controlled Release, 1996
The distribution and the retention time of a novel bioadhesive intravaginal delivery system based... more The distribution and the retention time of a novel bioadhesive intravaginal delivery system based on HYAFF microspheres were studied in a sheep model. In a preliminary experiment, the vagina of the ewe was outlined by gamma scintigraphy following vaginal administration of a radiolabelled gel and this data was used as a reference for subsequent evaluation of the distribution of bioadhesive vaginal formulations. Technetium-labelled HYAFF microspheres were administered intravaginally, either as a dry powder or suspended in a vaginal pessary, and the intensity and distribution of radioactivity in the genital tract was determined for a period of 12 h. With both HYAFF formulations, the radiolabelled microspheres were dispersed along the length of the vagina and were retained at this site for the duration of the study. Twelve hours after administration, between 60 and 80% of the radioactivity remained within the vagina with retention of the microspheres being slightly higher for the dry powder formulation than for the vaginal pessary. Importantly, there was no indication of movement of the microspheres from the vagina to the upper levels of the genital tract. These studies further demonstrated the potential of HYAFF microspheres as a long-acting intravaginal delivery system and illustrated the utility of the sheep model and the gamma-scintigraphy methodology for a direct assessment of the distribution, spreading and retention time of bioadhesive formulations.
Influenza and Other Respiratory Viruses, 2012
Background Highly pathogenic avian influenza A ⁄ H5N1 virus remains a potential pandemic threat, ... more Background Highly pathogenic avian influenza A ⁄ H5N1 virus remains a potential pandemic threat, and it is essential to continue vaccine development against this subtype. A local mucosal immune response in the upper respiratory tract may stop influenza transmission. It is therefore important to develop effective intranasal pandemic influenza vaccines that induce mucosal immunity at the site of viral entry. Objectives We evaluated the humoral and cellular immune responses of two promising mucosal adjuvants (Chitosan and c-di-GMP) for intranasal influenza H5N1 vaccine in a murine model. Furthermore, we evaluated the concept of co-adjuvanting an experimental adjuvant (c-di-GMP) with chitosan. Methods BALB ⁄ c mice were intranasally immunised with two doses of subunit NIBRG-14 (H5N1) vaccine (7AE5, 1AE5 or 0AE3 lg haemagglutinin (HA) adjuvanted with chitosan (CSN), c-di-GMP or both adjuvants. Results All adjuvant formulations improved the serum and local antibody responses, with the highest responses observed in the 7AE5 lg HA CSN and c-di-GMP-adjuvanted groups. The c-di-GMP provided dose sparing with protective single radial haemolysis (SRH), and haemagglutination inhibition (HI) antibody responses found in the 0AE3 lg HA group. CSN elicited a Th2 response, whereas c-di-GMP induced higher frequencies of virus-specific CD4 + T cells producing one or more Th1 cytokines (IFN-c + , IL-2 + , TNF-a +). A combination of the two adjuvants demonstrated effectiveness at 7AE5 lg HA and triggered a more balanced Th cytokine profile. Conclusion These data show that combining adjuvants can modulate the Th response and in combination with ongoing studies of adjuvanted intranasal vaccines will dictate the way forward for optimal mucosal influenza vaccines.
European Journal of Pharmaceutical Sciences, 1994
... of specially designed delivery systems such as the bioadhesive powders and chitosan (Nagai et... more ... of specially designed delivery systems such as the bioadhesive powders and chitosan (Nagai et al., 1984; Illum et al., 1987; Farraj et al ... 6b). This was 160' 140 120 ~8 :~s 8o. 60 I. Jabbal Gill et al./European Journal of Pharmaceutical Sciences 1 (1994) 237-248 40 20 -50 i - i . iii ...
European Journal of Pharmaceutical Sciences, 2005
The effectiveness of chitosan in promoting the intranasal bioavailability of recombinant human gr... more The effectiveness of chitosan in promoting the intranasal bioavailability of recombinant human growth hormone (hGH) has been evaluated. hGH was formulated with chitosan to produce a powder blend (Formulation A) and granules (Formulation B) for intranasal administration. The in vivo pharmacokinetic performance of the formulations was evaluated in a group of six sheep in a randomised crossover study. A subcutaneous injection of hGH solution was administered as a control. The intranasal and subcutaneous doses of hGH were 0.3 and 0.03 mg/kg, respectively. The intranasal formulations appeared to be well tolerated. Mean bioavailabilities of hGH from Formulations A and B were 14 and 15%, respectively relative to subcutaneous injection. It is concluded that chitosan-based intranasal powder formulations may provide a practical means for non-injectable delivery of hGH and, potentially, other therapeutic protein molecules.
Infection and Immunity, 2000
ABSTRACTWe have evaluated the ability of two carbohydrate biopolymers, chitosan and gellan, to en... more ABSTRACTWe 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 μg 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 vir...
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Papers by Michael Hinchcliffe