INTRODUÇÃO: O nervo facial (NF) desempenha um papel importante em diversas funções fisiológicas do organismo e controla a musculatura da mímica facial, responsável por transmitir sentimentos e emoções. O tratamento padrão-ouro para reconstrução do NF após trauma com secção é a anastomose término-terminal com cola de fibrina, que na maioria dos casos ainda produz resultados subótimos. Por isso, objetivou-se testar o efeito de uma nova técnica de reconstrução usando um protocolo de fusão axonal por polietilenoglicol (PEG), denominada sutura química, utilizando parâmetros eletrofisiológicos e histomorfométricos. MÉTODOS: Ratos Wistar foram divididos em 4 grupos. Após transecção do ramo mandibular do NF, o grupo controle foi submetido a anastomose dos cotos neurais com microssuturas. O grupo 2 foi tratado com microssuturas mais a sutura química. A sutura química consistiu de lavagem dos cotos neurais com solução de Krebs hipotônica contendo azul de metileno antes das microssuturas. Depois da sutura, seguiu-se a lavagem com solução de PEG e, por último, aplicação de solução de Krebs contendo cálcio. O grupo 3 recebeu microssuturas mais a solução com azul de metileno. E o grupo 4 foi tratado com microssuturas mais a solução de PEG. Os potenciais de ação musculares compostos (PAMCs) foram avaliados no pré-operatório e após 3 e 6 semanas das intervenções. A análise histomorfométrica foi realizada após 6 semanas. RESULTADOS: Os animais submetidos à sutura química apresentaram maior amplitude e menor duração dos PAMCs 3 e 6 semanas após a cirurgia em comparação com todos os demais grupos; na análise histológica, apresentaram maior contagem axonal e maior diâmetro axonal. CONCLUSÕES: A sutura química produziu recuperação mais intensa do NF após secção e sutura quando comparada à sutura isoladamente, pela avaliação eletrofisiológica e histomorfométrica, e pode ser útil em situações clinicas nas quais haja secção seguida de reparo neural imediato / BACKROUND: The gold standard treatment for traumatic transection of the FN continues to be end-to-end anastomosis using fibrin glue, which often yields unsatisfying results. OBJECTIVE: To test the outcome of a novel method of polyethylene glycol (PEG)-fusion on FN transection using electrophysiological and histophormometric parameters. METHODS: Wistar rats were divided into 4 groups. After FN transection, the control group was submitted to end-to-end anastomosis with microsutures. Group 2 was submitted to microsutures plus the PEG-fusion protocol. This protocol consisted in bathing nerve stumps with a calcium-free Krebs solution containing methylene blue (MB) before suturing. After suturing, the repaired nerve received a PEG solution followed by a calcium-containing Krebs solution. Group 3 received microsutures plus the MB solution and group 4 received microsutures plus the PEG solution. Compound muscle action potentials (CMAPs) were recorded before the intervention and 3 and 6 weeks afterwards. Histomorphometric analysis was done at 6 weeks time. RESULTS: The PEG-fusion protocol yielded larger CMAP amplitude, smaller CMAP duration at 3 and 6 weeks and a larger axon count and axon diameter. Between the other groups, no significant difference was seen. CONCLUSION: PEG-fusion produces better FN recovery after transection, when considering electrophysiological and histomorphometric analysis and may be of use in clinical scenarios of FN cut-severance followed by immediate repair

A epilepsia é normalmente a associação de pré-disposição genética e doença ou uma lesão cerebral. Aproximadamente 1 entre 50 a 100 pessoas apresentam essa pré-disposição à convulsões. Um dos fármacos mais prescritos e utilizados para o tratamento de convulsões é o ácido valpróico (AV), tornando-se a medicação de primeira escolha no tratamento da epilepsia infantil por apresentar um amplo espectro de ação, embora apresente efeitos colaterais bastante conhecidos como pancreatite e a hepatotoxicidade, que pode ser fatal. Sistemas nanoparticulados como nanocápsulas, obtidas a partir da utilização de polímeros biodegradáveis como o polietilenoglicol (PEG) e macromoléculas naturais como a quitosana (QS), que proporcionam hidrofilia e bioadesividade, têm sido estudadas com o objetivo de aumentar a penetração cerebral e reduzir a dosagem do fármaco. Nesse contexto, o presente trabalho teve como objetivo desenvolver e caracterizar físico-quimicamente nanocápsulas de poli(ε-caprolactona) contendo AV e revestidas com QS (NCQ) e/ou com PEG 6000 (NCP e NCQP), investigar a farmacocinética plasmática, a penetração do AV através da barreira hematoencefálica (BHE) por microdiálise e a hepatotoxicidade em ratos Wistar. Nanocápsulas revestidas com QS (NCQ) foram obtidas pelo método de nanoprecipitação do polímero pré-formado seguido do revestimento com adição de 5 mL de solução de QS a 1%. Para a preparação de NCP, foi utilizada metodologia similar adicionando 0,7% de PEG 6000 na fase aquosa. Para a preparação de NCQP, as nanocápsulas preparadas com a adição de 0,35% de PEG 6000 e revestidas posteriormente com solução de QS a 1% (2,5 mL). As formulações foram caracterizadas físico-quimicamente avaliando-se o tamanho das partículas, potencial zeta, pH e taxa de incorporação. As nanocápsulas foram visualizadas por MET e a estabilidade foi investigada por retroespalhamento de luz (Turbiscan Lab®). As formulações (AV 5 mg/mL) apresentaram um pequeno tamanho de partícula (144,2 ± 2,0 nm, 153,2 ± 1,8 nm, e 231,3 ± 15,6 nm, para NCQ, NCP e NCQP, respectivamente), com baixo índice de polidispersão, alta taxa de incorporação (95 a 98 %), pH ácido, potencial zeta positivo para NCQ (+8,7 ± 0,4 mV) e negativo para NCP (- 6,6 ± 0,8 mV) e NCQP (- 2,8 ± 1,3 mV). As fotomicrografias mostraram partículas de forma esférica e as formulações demonstraram boa estabilidade durante 24h de análise a 40°C. As concentrações plasmáticas foram investigadas em ratos Wistar (15 mg/kg via i.v. de AV) para todas as formulações e valproato sódico (grupo controle). A análise farmacocinética compartimental apresentou uma distribuição muito rápida para o AV em NCQ e a ASC0-∞ aproximadamente duas vezes menor em comparação à NCP, NCQP e o fármaco livre (3874 ± 1775; 8280 ± 2136; 7849 ± 1021 e 7978 ± 3622 μg/mL/min, respectivamente). O clearance do AV aumentou significativamente para NCQ (0,284 ± 0,156 L/h/kg) (α = 0,05%). A penetração do AV através da BHE foi realizada em ratos Wistar acordados por microdiálise (MD) cerebral, no córtex frontal utilizando sondas CMA/12 (3 mm). Os experimentos de MD mostraram um aumento de 5 vezes no fator de penetração cerebral após a administração de NCQ em comparação com o fármaco em solução (0,110 and 0,021, respectivamente), demonstrando a viabilidade da utilização de QS como polímero de revestimento objetivando a BHE. A NCP demonstrou um aumento de 1,7 vezes no fator de penetração cerebral e NCQP não demonstrou qualquer diferença na penetração. A investigação da hepatotoxicidade do AV foi realizada após cinco dias de tratamento (dose de 30 mg/kg q12h de AV) em solução ou em nanocápsulas (NCQ ou NCP) com grupo controle de solução salina. Os níveis séricos de asparto aminotransferase (AST), alanina aminotransferase (ALT), gama-glutamiltransferase (GGT), fosfatase alcalina (FAL), creatinina (CRE) e uréia foram determinados. Os resultados mostram a manutenção dos níveis normais de enzimas hepáticas como a ALT e FAL para NCQ (54,2 ± 11,2 UI/mL and 149 ± 26 UI/mL) demonstrando um efeito hepatoprotetor não observado para os outros grupos. Análises histológicas do fígado dos animais não apresentaram a formação de esteatose microvesicular para NCQ em comparação com a formação de esteatoses em todos os outros grupos, incluindo o grupo controle. Ao final, os resultados indicaram que NCQ possa ser uma formulação em potencial, necessitando ser investigada pelo aumento da penetração cerebral de AV e efeito hepatoprotetor observados. / Epilepsy is usually a combination of genetic pre-disposition and a disease or a brain damage. About 1 in 50 to 100 people has this genetic predisposition to seizures. One of the world’s most prescribed drugs to treat epileptic seizures is valproic acid (VA), which is the first choice drug to treat epilepsy in childhood due to its broad spectrum of action, although its well known side effects such as pancreatitis, hepatotoxicity can be fatal. Nanoparticulated systems such as nanocapsules, obtained from biodegradable polymers like polyethylene glycol and natural macromolecules like chitosan, who gives the system hidrophilicity and bioadhesivity, have been used to increase brain penetration and reduce drug doses. In this context, the present work aimed to develop and physicochemically characterize poly(ε-caprolactone) nanocapsules loaded with VA and coated with chitosan (NCQ) and/or polyethylene glycol (PEG) 6000 (NCP and NCQP), and to investigate their plasma pharmacokinetics, VA blood-brain barrier penetration (BBB) by microdialysis and hepatotoxicity in Wistar rats. Nanocapsules coated with chitosan were obtained by nanoprecipitation of preformed polymer followed by coating with 1% chitosan solution added prior to final adjustments at a volume of 5 mL. For NCP preparation, similar methodology was used adding 0.7% PEG 6000 in the aqueous phase. For NCQP preparation, the nanocapsules prepared with PEG 6000 (0.35% w/v) was further coated with chitosan 1% in solution adding 2.5 mL prior to the final adjustments. The formulations were physicochemical characterized by particle size, zeta potential, pH, incorporation efficiency. The particles were visualized by MET and the stability investigated by backscattering (Turbiscan Lab®). The formulations (VA 5 mg/mL) presented small particle sizes (144.2 ± 2.0 nm, 153.2 ± 1.8 nm, and 231.3 ± 15.6 nm, for NCQ, NCP and NCQP, respectively), with low polidispersion index, high incorporation efficiency (95 to 98 %) and acid pH. The zeta potential was positive for NCQ (+8.7 ± 0.4 mV) and negative for NCP (- 6.6 ± 0.8 mV) and NCQP (- 2.8 ± 1.3 mV). The photomicrography of all formulations showed spherically shaped particles. The formulations showed good stability during 24 hours investigation at 40 ºC. Plasma concentrations were investigated in Wisar rats after 15 mg/kg i.v. dosing of all formulations and sodium valproate solution (control group). The pharmacokinetic compartmental analysis showed a very rapid distribution of VA when incorporated in NCQ in comparison to the other formulations and the AUC0-∞ about two times lower in comparison to NCP, NCQP and the drug alone (3874 ± 1775; 8280 ±2136; 7849 ± 1021 and 7978 ± 3622 μg/mL/min, respectively). VA clearance was significantly increased after NCQ dosing (0.284 ± 0.156 L/h/kg) (α = 0.05 %). Drug penetration through BBB was performed in awaken Wistar rats by brain microdialysis at the frontal cortex using CMA/12 probes (3 mm). The microdialysis experiments showed a five times increase in VA brain penetration factor after NCQ administration in comparison to drug alone (0.110 and 0.021, respectively), demonstrating the viability of chitosan as coating polymer to aim the BBB. NCP showed only a 1.7 times increase in brain penetration factor and NCQP did not showed any difference in comparison to drug alone. The investigation of drug hepatotoxicity was conducted after 5 days i.v. dosing of VA 30 mg/kg q12h as solution or nanocapsules (NCQ or NCP). A saline control group was also investigated. Serum levels of asparte aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, alkaline phosfatase, creatinin and urea were determined. The results showed the maintenance of normal levels of hepatic enzymes such as alanine aminotransferase and alkaline phosfatase for NCQ (54.2 ± 11.2 IU/mL and 149 ± 26 IU/mL) showing a hepatoprotective effect not observed in the other groups investigated. Histological analysis of animals livers showed no microvesicular steatosis formation when NCQ was administered in comparison with the formation of steatosis in all other groups including control. Overall the results indicate that NCQ is a potential formulation to be investigated for the treatment of epilepsy due to its increase in VA brain penetration and hepatoprotective effect observed.

Este trabalho visou investigar as interações entre enzimas e polímeros em solução e a adsorção das mesmas sobre superfícies sólidas e para isto foi dividido em duas partes distintas. Na primeira parte a influência do poli(etileno glicol) (PEG), polímero considerado inerte e utilizado em muitos processosbiotecnológicos, na atividade enzimática e na conformação estrutural de enzimas foi estudada através de medidas de espectrofotometria- UV, calorimetria e espalhamento de raio-X de baixo ângulo (SAXS). Foram escolhidas neste estudo as enzimas glicose-6-fosfato desidrogenase (G-6-PDH) e hexoquinase (HK), que são enzimas largamente aplicadas em análises clínicas na determinação de glicose no sangue, e também a enzima álcool desidrogenase (AD), utilizada para determinação de concentração de álcool. Foram obtidos resultados quantitativos, numa faixa de baixa concentração de enzima, que indicam uma forte influência de PEG na atividade das enzimas estudadas. Medidas de calorimetria revelaram que PEG interage não só com a enzima em estudo mas também com a coenzima NADP+. Numa faixa de concentração maior, os resultados de SAXS mostraram que PEG exerce também um efeito significativo no processo de agregação das enzimas. Acima de tudo, foi evidenciado neste estudo que PEG não pode ser tratado como um polímero inerte, pois ele interfere na atividade e conformação de enzimas. As enzimas são macromoléculas complexas e PEG interage de forma diferenciada com cada enzima, merecendo atenção especial caso a caso. Na segunda parte do trabalho, o estudo da adsorção de hexoquinase (HK) e creatina fosfoquinase (CPK) sobre lâminas de silício foi realizado através de medidas de ângulo de contato, elipsometria in situ e microscopia de força atômica (AFM) em água. A CPK é uma enzima bastante utilizada em kits de determinação de creatina no sangue e no diagnóstico de desordens musculares. Este trabalho revelou que o mecanismo de adsorção de CPK sobre silício depende fortemente do pH. Em pH 4, 7 ou 9 CPK adsorveu mantendo a mesma conformação que tinha em solução. Medidas de espectrofotometria UV-Vis revelaram uma mudança no pH ótimo para atividade enzimática de CPK de 6,8 para 9 após adsorção. A HK imobilizada em esferas de vidro mostrou atividade maior do que HK imobilizada nas placas. A reutilização das esferas e placas recobertas com HK foi testada e observou-se que as atividades das enzimas adsorvidas no substrato esférico foram mantidas. Entretanto, nas placas revestidas a atividade foi perdida. As enzimas imobilizadas sobre esferas puderam ser reutilizadas pelo menos 3 vezes, mantendo a atividade por um período de até 3 semanas. / This work aimed to investigate the interactions between enzymes and polymers in solution and also the adsorption behavior of these enzymes on solid surfaces. For that reason it was divided into two parts. In the first part, the influence of poly(ethylene glycol) (PEG), a polymer considered inert and utilized in several biotechnological processes, on the enzymatic activity and structure of the enzyme was studied by means of UV spectrophotometry, calorimetric titration, circular dichroism (CD) and small angle X-ray scattering (SAXS). Glucose-6-phosphate dehydrogenase (G-6-PDH) and hexokinase (HK) were chosen because of their large application in clinical analysis for determination of glucose in the blood strain. Alcohol dehydrogenase (AD), which is widely used to determine alcohol concentration in various samples, was also used. Quantitative results, in a low enzyme concentration range, indicated a strong influence of PEG on the enzymes activity. The calorimetric measurements revealed no favorable interactions between enzyme and polymer, but indicated favorable interactions between PEG and co-enzyme NADP+. In a higher concentration range, SAXS results showed that PEG also exerts a significant effect on the enzyme aggregation process. This work showed that PEG shall no longer be treated as an inert polymer since it interferes in the enzyme activity and structure. The enzymes are complex macromolecules and PEG interacts differently with each one, deserving special attention in each case. In the second part of the work, the adsorption behavior of creatine phosphokinase (CPK) and hexokinase (HK) onto silicon wafers was studied by means of contact angle measurements, in situ ellipsometry and atomic force microscopy (AFM) in water. CPK was chosen due to its large application on the diagnosis of several muscle disorders. This work revealed that the adsorption mechanism of CPK on silicon surfaces is strongly dependent on pH. At pH 4, 6.8 or 9, CPK adsorbed keeping the same conformation as in solution. pectrophotometric measurements revealed a shift on the optimum pH from 6,8 to 9 upon CPK adsorption. HK adsorbed onto glass beads showed higher activity than HK immobilized on silicon wafers. HK covered glass beads could also be reused three times and for a period of at least three weeks. In the contrary, HK covered silicon wafers could not be reused. For practical purposes, HK covered glass beads showed to be a better “biosensor” than HK covered silicon wafers.

Plusieurs substrats issus de la chimie organique, inorganique et organométallique ont été synthétisés et fonctionnalisés avec différents groupes chimiques, notamment des polyethylene glycol qui leur permet d’améliorer leur solubilité dans l’eau et de les rendre biocompatible pour une éventuelle application dans le milieu biomédical. Ces substrats sont des dendrimères synthétisés sur plusieurs générations, des polymères obtenus soit par polymérisation d’un dendron soit par dendronisation d’un polymère, ou encore des nanoparticules d’or qui peuvent être stabilisées par des ligands thiolates ou bien par des dendrimères de manière intra- ou inter-dendritique. Ces nano-objets ont été designés dans l’objectif d’encapsuler, de stabiliser ou d’améliorer différentes molécules biologiques telles que des vitamines (vitamine C, B3 et B6), des neurotransmetteurs (acétylcholine et dopamine) ou des agents anti-cancéreux (daunorubicine). / Several substrates resulting from the organic, inorganic and organometallic chemistry were synthesized and functionalized with various chemical groups, including polyethylene glycol which enables them to improve their water solubility and to make them biocompatible for a possible application in the biomedical field. These substrates are dendrimers synthesized for several generations, polymers obtained either by polymerization of a dendron or by dendronization of a polymer, or gold nanoparticules which can be stabilized by thiolate ligands or by dendrimers in an intra- or inter-dendritic way. These nano-objects were designed with the aim of encapsulating, stabilizing or improving various biological molecules such as vitamins (vitamin C, B3 and B6), neurotransmitters (acetylcholine and dopamine) or anti-cancerous agents (daunorubicine).

No description available.

Diabetes has, in the past three decades, surged immensely. Because of this, new insulin analogues are constantly in the making.  In clinical studies, the presence of antidrug antibodies can prove a challenge when measuring insulin. In order to overcome the interference from antidrug antibody complexes on the total insulin measurement in human serum, several pre-treatment methods on insulin and polyclonal antibodies spiked samples were tried using ELISA analysis. Several different methods were tried, acid dissociation using a glycine buffer with and without ethanol in different concentrations, high ionic strength dissociation using MgCl2, Polyethylene glycol (PEG) and filtration. The best results were found when using the acid dissociation technique. Using glycine promising results were achieved, especially when 20 % ethanol was added to the acid mixture. Pre-treatment using PEG, MgCl2 and filtration was unsuccessful with the methods used. The main goal was reached through the use of glycine with the addition of 20% ethanol for acid dissociation. The proposed method still leaves significant room for optimisation and needs further verification on real patient samples. However, it is a good step in the direction of a global methodology using ELISA to overcome antidrug antibody interference for total insulin measurement in human serum.

Indiana University-Purdue University Indianapolis (IUPUI) / Large protein molecules are abundant in biological cells but are very difficult to study in physiological conditions due to molecular disorder. For large proteins, most structural information is obtained in crystalline states which can be achieved in certain conditions at very low temperature. X-ray and neutron crystallography methods can then be used for determination of crystalline structures at atomic level. However, in solution at room or physiological temperatures such highly resolved descriptions cannot be obtained except in very few cases. Scattering methods that can be used to study this type of structures at room temperature include small-angle x-ray and neutron scattering. These methods are used here to study two distinct proteins that are both classified as glycoproteins, which are a large class of proteins with diverse biological functions. In this study, two specific plasma glycoproteins were used: Fibrinogen (340 kDa) and Alpha 1-Antitrypsin or A1AT (52 kDa). These proteins have been chosen based on the fact that they have a propensity to form very large molecular aggregates due to their tendency to polymerize. One goal of this project is to show that for such complex structures, a combination of scattering methods that include SAXS, SANS, and DLS can address important structural and interaction questions despite the fact that atomic resolution cannot be obtained as in crystallography. A1AT protein has been shown to have protective roles of lung cells against emphysema, while fibrinogen is a major factor in the blood clotting process. A systematic approach to study these proteins interactions with lipid membranes and other proteins, using contrast-matching small-angle neutron scattering (SANS), small angle x-ray scattering (SAXS) and dynamic light scattering (DLS), is presented here. A series of structural reference points for each protein in solution were determined by performing measurements under osmotic stress controlled by the addition of polyethylene glycol-1,500 MW (PEG 1500) in the samples. Osmotic pressure changes the free energy of the molecular mixture and has consequences on the structure and the interaction of molecular aggregates. In particular, the measured radius of gyration (Rg) for A1AT shows a sharp structural transition when the concentration of PEG 1500 is between 33 wt% and 36 wt%. Similarly, a significant structural change was observed for fibrinogen when the concentration of PEG 1500 was above 40 wt%. This analysis is applied to a study of A1AT interacting with lipid membranes and to a study of fibrinogen polymerization in the presence of the enzyme thrombin, which catalyzes the formation of blood clots. The experimental approach presented here and the applications to specific questions show that an appropriate combination of scattering methods can produce useful information on the behavior and the interactions of large protein systems in physiological conditions despite the lower resolution compared to crystallography.

We report on a novel and simple approach to surface ligand design of CdSe-based nanocrystals (NCs) with biocompatible, heterobifunctional polyethylene glycol (PEG) molecules. This method provides high transfer yields of the NCs into aqueous media with preservation of the narrow and symmetric emission bands of the initial organic-capped NCs regardless of their interior crystal structure and surface chemistry. The PEG-functionalized NCs show small sizes, high photoluminescence quantum yields of up to 75%, as well as impressive optical and colloidal stability. This universal approach is applied to different fluorescent nanomaterials (CdSe/CdS, CdSe/CdSCdxZn1–xS, and CdSe/CdS/ZnS), extending the great potential of organic-capped NCs for biological applications.

Sublingual administration of drugs offers advantages including avoidance of first pass metabolism and quick absorption into the systemic circulation. In spite of being one of the oldest routes of drug delivery, there is dearth of literature on characterization of the barrier properties of the sublingual mucosa. Therefore, the aim of this research was to gain an insight into the barrier properties of the porcine sublingual mucosa. The studies conducted in this dissertation research focused on an important aspect of sublingual permeation, the dependence of permeability on different physicochemical properties of the permeant such as the degree of ionization, distribution coefficient and molecular weight/size on drug transport across sublingual mucosa. Further the data from the sublingual permeation of model compounds was used in development of a predictive model which provided us with some understanding regarding the important descriptors required for sublingual drug delivery. A series of β-blockers were employed as the model drugs to study the dependence of permeability on lipophilicity across the sublingual mucosa. Eighth different β-blockers with log D (distribution coefficient) values ranging from -1.30 to 1.37 were used in this study. The most hydrophilic drug atenolol showed the lowest permeability (0.19 ± 0.04 x 10 -6 ) cm/sec and the most lipophilic drug propranolol showed the highest permeability (38.25 ± 4.30 x 10 -6 ) cm/sec. The log-log plot of permeability coefficient and the distribution coefficient showed a linear relationship. It was concluded that the increase in lipophilicity results in improved partitioning across the lipid bilayers of sublingual mucosa which results in increased permeation for the drugs. As the sublingual mucosa contains a significant amount of the polar lipids bonded with water molecules, therefore, it was hypothesized that the hydrophilic or ionized permeants will have significant permeation across the sublingual mucosa. The objective of this research was to study the effect of ionization on permeation across sublingual mucosa using a model drug nimesulide. Based on the relationship between the permeability coefficient and distribution coefficient of nimesulide at different pH, the lipoidal route was suggested as the dominant transport route for nimesulide across the sublingual mucosa. The contribution of individual ionic species of nimesulide to the total drug flux was quantitatively delineated. It was observed that the ionized species of nimesulide contributes significantly to the total flux across the sublingual mucosa. The contribution of the ionized species to total flux was almost (90%) at a pH where the drug was almost completely ionized. Polyethylene glycols (PEGs) were used as the model permeants to study the dependence of permeability on molecular weight. An inverse relationship between molecular weight and permeability coefficients was observed. This relationship was used to estimate the molecular weight cut off for the sublingual mucosa. The molecular weight cut off was estimated to be around 1675 daltons. Further, the Renkin function was used to estimate the theoretical pore size of the sublingual mucosa and the pore size of the sublingual mucosa was estimated to be around 30–53 Å based on two separate calculations using the radius of gyration and Stokes-Einstein radius for PEG molecules, respectively. No specific model is present in literature to predict the in vitro sublingual drug permeability. In this dissertation a specific model was developed and validated by performing permeation studies of 14 small molecules across the porcine sublingual mucosa. It was shown that the lipophilicity (logD 6.8 ) and the number of hydrogen bond donors (HBD) were the most significant descriptors affecting sublingual permeability. Research conducted in this dissertation provided an in-depth understanding about the barrier properties of the porcine sublingual mucosa and role of different physicochemical properties on sublingual transport. Such an understanding will hopefully expand the suitable lead candidates for sublingual delivery.

No description available.