Over the past couple of years there has been rapid progress in the development and design of safe and effective delivery systems for the administration of protein and peptide drugs. The effective delivery of these type of drugs are not always as simple as one may think, due to various inherent characteristics of these compounds. Due to the hydrophilic nature and molecular size of peptide and protein drugs, such as recombinant human growth hormone, they are poorly absorbed across mucosal epithelia, both transcellularly and paracellularly. This problem can be overcome by the inclusion of absorption enhancers in peptide and protein drug formulations but this is not necessarily the best method to follow. This investigation focussed specifically on the evaluation of the ability of the PheroidTM carrier system to transport recombinant human growth hormone across mucosal epithelia especially when administered via the nasal cavity. The PheroidTM delivery system is a patented system consisting of a unique submicron emulsion type formulation. The PheroidTM delivery system, based on PheroidTM technology, will for ease of reading be called Pheroid(s) only throughout the rest of this dissertation. The Pheroid carrier system is a unique microcolloidal drug delivery system. A Pheroid is a stable structure within a novel therapeutic system which can be manipulated in terms of morphology, structure, size and function. Pheroids consist mainly of plant and essential fatty acids and can entrap, transport and deliver pharmacologically active compounds and other useful substances to the desired site of action. The specific objectives of this study can be summarised as follows: a literature study on Pheroid technology; a literature study on chitosan and N-trimethyl chitosan chloride; a literature study on recombinant human growth hormone (somatropin); a literature study on nasal drug administration; formulation of a suitable Pheroid carrier; entrapment of somatropin in the Pheroid carrier, and in vivo evaluation of nasal absorption of somatropin in Sprague-Dawley rats. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2007.

<p>The nasal administration of drugs offers advantages over administration by intravenous injection. Drugs can be rapidly absorbed through the nasal mucosa, resulting in a rapid onset of action, and also avoiding degradation in the gastrointestinal tract and first-pass metabolism in the liver. The olfactory receptor cells, which are in direct contact with both the environment and the central nervous system (CNS), are potential routes for drugs into the CNS. The olfactory pathway thus circumvents the blood brain barrier (BBB) which prevents many systemically administered drugs from entering the brain.</p><p>The studies used compounds active in the CNS and the experiments were performed in rodents. The nasal bioavailability of (S)-UH-301, NXX-066 and [³H]-dopamine was investigated in a rat model; uptake into the cerebrospinal fluid (CSF) was compared after nasal and intravenous administration. The concentrations of S-UH-301 and NXX-066 in plasma and CSF were measured with high performance liquid chromatography. The possible transfer of dopamine and neurotensin along the olfactory pathway after nasal administration to mice was studied using brain tissue sampling and autoradiography. The radioactivity content in blood, CSF and dissected brain tissue samples after administration of [³H]-dopamine and [³H]-neurotensin was assessed using liquid scintillation, and thin layer chromatography (TLC) was used to investigate the metabolic fate of [³H]-dopamine.</p><p>The results of this thesis suggest that nasal administration of CNS-active compounds with low oral bioavailability is an interesting and workable alternative to intravenous injection. The small lipophilic compounds (S)-UH-301 and NXX-066 were rapidly and completely absorbed after nasal administration, although hard evidence of direct transfer from the nose remains elusive. Radioactivity measurements in the olfactory bulb following nasal administration of</p><p>[³H]-dopamine and [³H]-neurotensin indicate that transfer occurred. The TLC results showed the presence of unchanged dopamine in the olfactory bulb but it is less clear from initial results with neurotensin, which radioactive products of this molecule reached the olfactory bulb, and further studies are required.</p>

The nasal administration of drugs offers advantages over administration by intravenous injection. Drugs can be rapidly absorbed through the nasal mucosa, resulting in a rapid onset of action, and also avoiding degradation in the gastrointestinal tract and first-pass metabolism in the liver. The olfactory receptor cells, which are in direct contact with both the environment and the central nervous system (CNS), are potential routes for drugs into the CNS. The olfactory pathway thus circumvents the blood brain barrier (BBB) which prevents many systemically administered drugs from entering the brain. The studies used compounds active in the CNS and the experiments were performed in rodents. The nasal bioavailability of (S)-UH-301, NXX-066 and [3H]-dopamine was investigated in a rat model; uptake into the cerebrospinal fluid (CSF) was compared after nasal and intravenous administration. The concentrations of S-UH-301 and NXX-066 in plasma and CSF were measured with high performance liquid chromatography. The possible transfer of dopamine and neurotensin along the olfactory pathway after nasal administration to mice was studied using brain tissue sampling and autoradiography. The radioactivity content in blood, CSF and dissected brain tissue samples after administration of [3H]-dopamine and [3H]-neurotensin was assessed using liquid scintillation, and thin layer chromatography (TLC) was used to investigate the metabolic fate of [3H]-dopamine. The results of this thesis suggest that nasal administration of CNS-active compounds with low oral bioavailability is an interesting and workable alternative to intravenous injection. The small lipophilic compounds (S)-UH-301 and NXX-066 were rapidly and completely absorbed after nasal administration, although hard evidence of direct transfer from the nose remains elusive. Radioactivity measurements in the olfactory bulb following nasal administration of [3H]-dopamine and [3H]-neurotensin indicate that transfer occurred. The TLC results showed the presence of unchanged dopamine in the olfactory bulb but it is less clear from initial results with neurotensin, which radioactive products of this molecule reached the olfactory bulb, and further studies are required.

Over the past couple of years there has been rapid progress in the development and design of safe and effective delivery systems for the administration of protein and peptide drugs. The effective delivery of these type of drugs are not always as simple as one may think, due to various inherent characteristics of these compounds. Due to the hydrophilic nature and molecular size of peptide and protein drugs, such as recombinant human growth hormone, they are poorly absorbed across mucosal epithelia, both transcellularly and paracellularly. This problem can be overcome by the inclusion of absorption enhancers in peptide and protein drug formulations but this is not necessarily the best method to follow. This investigation focussed specifically on the evaluation of the ability of the PheroidTM carrier system to transport recombinant human growth hormone across mucosal epithelia especially when administered via the nasal cavity. The PheroidTM delivery system is a patented system consisting of a unique submicron emulsion type formulation. The PheroidTM delivery system, based on PheroidTM technology, will for ease of reading be called Pheroid(s) only throughout the rest of this dissertation. The Pheroid carrier system is a unique microcolloidal drug delivery system. A Pheroid is a stable structure within a novel therapeutic system which can be manipulated in terms of morphology, structure, size and function. Pheroids consist mainly of plant and essential fatty acids and can entrap, transport and deliver pharmacologically active compounds and other useful substances to the desired site of action. The specific objectives of this study can be summarised as follows: a literature study on Pheroid technology; a literature study on chitosan and N-trimethyl chitosan chloride; a literature study on recombinant human growth hormone (somatropin); a literature study on nasal drug administration; formulation of a suitable Pheroid carrier; entrapment of somatropin in the Pheroid carrier, and in vivo evaluation of nasal absorption of somatropin in Sprague-Dawley rats. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2007.

Orientador: Marlus Chorilli / Resumo: O diabetes mellitus (DM) é uma síndrome metabólica caracterizada por deficiência na produção/secreção pancreática de insulina e/ou resistência à ação do hormônio nos tecidos alvo, resultando em hiperglicemia. Diversas pesquisas têm desencadeado o desenvolvimento de novos sistemas de administração de insulina que possibilitem a utilização de vias alternativas à parenteral, com destaque à administração de insulina por via nasal. Esta via tem-se mostrado promissora, pois pode promover uma rápida absorção do fármaco e aumentar a sua biodisponibilidade. Entretanto, existem mecanismos de depuração mucociliar que limitam a administração de fármacos, além da baixa permeabilidade do epitélio nasal, o qual dificulta a absorção de fármacos com alto massa molar. Uma estratégia para vencer tais barreiras é a utilização de sistemas nanoestruturados (lipossomas), pois são amplamente utilizados para o aperfeiçoamento da potencialização da ação terapêutica de fármacos. Além disso estes lipossomas foram funcionalizados com peptídeos de transdução de membrana (CPPs), tais como os peptídeos TAT e Penetratin (PNT), que atuam como promotores da penetração e absorção do fármaco, com posterior dispersão em hidrogel de hidroxietilcelulose. O objetivo deste trabalho foi desenvolver e caracterizar lipossomas contendo solução de insulina, funcionalizados com CPPs (TAT e PNT) e dispersos em hidrogel, avaliar o potencial pela via nasal, in vivo, para a melhora dos níveis séricos e efeito hipoglicemiante d... (Resumo completo, clicar acesso eletrônico abaixo) / Doutor

Nasal administration of analgesics for achieving rapid pain relief is currently a topic of great interest. The blood-brain barrier (BBB) restricts access to the central nervous system (CNS) for several central-acting drugs, such as morphine and dihydroergotamine, which results in a substantial effect delay. Evidence for the olfactory transfer of drugs from the nasal cavity to the CNS after nasal administration, bypassing the BBB, is available for both animals and humans. The aims of this thesis were to study the olfactory transfer of morphine to the CNS after nasal administration, and to compare the nasal transport of analgesic drugs across nasal respiratory and olfactory mucosa. In vivo studies in rodents demonstrated that morphine is transferred via olfactory pathways to the olfactory bulbs and the longitudinal fissure of the brain after nasal administration. Further, olfactory transfer of morphine significantly contributed to the early high morphine brain hemisphere concentrations seen after nasal administration to rats. Olfactory transfer was tracked by collecting and analysing brain tissue and blood samples after right-sided nasal administration and comparing the results to the situation after i.v. administration. The olfactory transfer was also visualised by brain autoradiography. In vitro studies indicated that the olfactory mucosa should not be a major barrier to the olfactory transfer of dihydroergotamine or morphine, since transport of these drugs was no more restricted across the olfactory mucosa than across the nasal respiratory mucosa. The in vitro studies were performed using the horizontal Ussing chamber method. This method was further developed to enable comparison of drug transport across nasal respiratory and olfactory mucosa which cannot be achieved in vivo. In conclusion, these analgesic drugs showed potential for olfactory transfer, and access to the CNS by this route should be further investigated in humans, especially for the drugs with central effects that are currently under development for nasal administration.