Caffeine Encapsulated in Small Unilamellar Liposomes: Characerization and In Vitro Release Profile

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Poly(epsilon-caprolactone) nanocapsules carrying the herbicide atrazine: effect of chitosan-coating agent on physico-chemical stability and herbicide release profile

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Mathematical modelling of controlled drug release from polymer micro-spheres : incorporating the effects of swelling, diffusion and dissolution via moving boundary problems

Controlled drug delivery is a key topic in modern pharmacotherapy, where controlled drug delivery devices are required to prolong the period of release, maintain a constant release rate, or release the drug with a predetermined release profile. In the pharmaceutical industry, the development process of a controlled drug delivery device may be facilitated enormously by the mathematical modelling of drug release mechanisms, directly decreasing the number of necessary experiments. Such mathematical modelling is difficult because several mechanisms are involved during the drug release process. The main drug release mechanisms of a controlled release device are based on the device’s physiochemical properties, and include diffusion, swelling and erosion. In this thesis, four controlled drug delivery models are investigated. These four models selectively involve the solvent penetration into the polymeric device, the swelling of the polymer, the polymer erosion and the drug diffusion out of the device but all share two common key features. The first is that the solvent penetration into the polymer causes the transition of the polymer from a glassy state into a rubbery state. The interface between the two states of the polymer is modelled as a moving boundary and the speed of this interface is governed by a kinetic law. The second feature is that drug diffusion only happens in the rubbery region of the polymer, with a nonlinear diffusion coefficient which is dependent on the concentration of solvent. These models are analysed by using both formal asymptotics and numerical computation, where front-fixing methods and the method of lines with finite difference approximations are used to solve these models numerically. This numerical scheme is conservative, accurate and easily implemented to the moving boundary problems and is thoroughly explained in Section 3.2. From the small time asymptotic analysis in Sections 5.3.1, 6.3.1 and 7.2.1, these models exhibit the non-Fickian behaviour referred to as Case II diffusion, and an initial constant rate of drug release which is appealing to the pharmaceutical industry because this indicates zeroorder release. The numerical results of the models qualitatively confirms the experimental behaviour identified in the literature. The knowledge obtained from investigating these models can help to develop more complex multi-layered drug delivery devices in order to achieve sophisticated drug release profiles. A multi-layer matrix tablet, which consists of a number of polymer layers designed to provide sustainable and constant drug release or bimodal drug release, is also discussed in this research. The moving boundary problem describing the solvent penetration into the polymer also arises in melting and freezing problems which have been modelled as the classical onephase Stefan problem. The classical one-phase Stefan problem has unrealistic singularities existed in the problem at the complete melting time. Hence we investigate the effect of including the kinetic undercooling to the melting problem and this problem is called the one-phase Stefan problem with kinetic undercooling. Interestingly we discover the unrealistic singularities existed in the classical one-phase Stefan problem at the complete melting time are regularised and also find out the small time behaviour of the one-phase Stefan problem with kinetic undercooling is different to the classical one-phase Stefan problem from the small time asymptotic analysis in Section 3.3. In the case of melting very small particles, it is known that surface tension effects are important. The effect of including the surface tension to the melting problem for nanoparticles (no kinetic undercooling) has been investigated in the past, however the one-phase Stefan problem with surface tension exhibits finite-time blow-up. Therefore we investigate the effect of including both the surface tension and kinetic undercooling to the melting problem for nanoparticles and find out the the solution continues to exist until complete melting. The investigation of including kinetic undercooling and surface tension to the melting problems reveals more insight into the regularisations of unphysical singularities in the classical one-phase Stefan problem. This investigation gives a better understanding of melting a particle, and contributes to the current body of knowledge related to melting and freezing due to heat conduction.

Effect of chemical conjugation of L-leucine to chitosan on the dispersibility and drug release of a dry powder inhaler nanoparticle formulation

Purpose: This study investigated the effect of chemical conjugation of the amino acid L-leucine to the polysaccharide chitosan on the dispersibility and drug release pattern of a polymeric nanoparticle (NP)-based controlled release dry powder inhaler (DPI) formulation. Methods: A chemical conjugate of L-leucine with chitosan was synthesized and characterized by Infrared (IR) Spectroscopy, Nuclear Magnetic Resonance (NMR) Spectroscopy, Elemental Analysis and X-ray Photoelectron Spectroscopy (XPS). Nanoparticles of both chitosan and its conjugate were prepared by a water-in-oil emulsification – glutaraldehyde cross-linking method using the antihypertensive agent, diltiazem (Dz) hydrochloride as the model drug. The surface morphology and particle size distribution of the nanoparticles were determined by Scanning Electron Microscopy (SEM) and Dynamic Light Scattering (DLS). The dispersibility of the nanoparticle formulation was analysed by a Twin Stage Impinger (TSI) with a Rotahaler as the DPI device. Deposition of the particles in the different stages was determined by gravimetry and the amount of drug released was analysed by UV spectrophotometry. The release profile of the drug was studied in phosphate buffered saline at 37 ⁰C and analyzed by UV spectrophotometry. Results: The TSI study revealed that the fine particle fractions (FPF), as determined gravimetrically, for empty and drug-loaded conjugate nanoparticles were significantly higher than for the corresponding chitosan nanoparticles (24±1.2% and 21±0.7% vs 19±1.2% and 15±1.5% respectively; n=3, p<0.05). The FPF of drug-loaded chitosan and conjugate nanoparticles, in terms of the amount of drug determined spectrophotometrically, had similar values (21±0.7% vs 16±1.6%). After an initial burst, both chitosan and conjugate nanoparticles showed controlled release that lasted about 8 to 10 days, but conjugate nanoparticles showed twice as much total drug release compared to chitosan nanoparticles (~50% vs ~25%). Conjugate nanoparticles also showed significantly higher dug loading and entrapment efficiency than chitosan nanoparticles (conjugate: 20±1% & 46±1%, chitosan: 16±1% & 38±1%, n=3, p<0.05). Conclusion: Although L-leucine conjugation to chitosan increased dispersibility of formulated nanoparticles, the FPF values are still far from optimum. The particles showed a high level of initial burst release (chitosan, 16% and conjugate, 31%) that also will need further optimization.

Preparation and in vitro evaluation of a polymer based controlled release dry powder inhaler formulation for pulmonary delivery

This thesis described the synthesis of an L-leucine conjugate of the biodegradable polymer, chitosan and its potential application for the development of controlled release nanoparticulate dry powder inhaler (DPI) formulations. The study demonstrated that the physicochemical properties of conjugated chitosan nanoparticles had favourable effects on the dispersibility and controlled release profile of a model drug. The toxicity profile of the nanoparticulate formulation revealed promising outcome for its use in pulmonary delivery. The chitosan conjugate produced in this project would be useful for the application of polymer nanoparticulate systems for efficient lung delivery of drugs.

Adsorption and release of biocides with mesoporous silica nanoparticles

In this proof-of-concept study, an agricultural biocide (imidacloprid) was effectively loaded into the mesoporous silica nanoparticles (MSNs) with different pore sizes, morphologies and mesoporous structures for termite control. This resulted in nanoparticles with a large surface area, tunable pore diameter and small particle size, which are ideal carriers for adsorption and controlled release of imidacloprid. The effect of pore size, surface area and mesoporous structure on uptake and release of imidacloprid was systematically studied. It was found that the adsorption amount and release profile of imidacloprid were dependent on the type of mesoporous structure and surface area of particles. Specifically, MCM-48 type mesoporous silica nanoparticles with a three dimensional (3D) open network structure and high surface area displayed the highest adsorption capacity compared to other types of silica nanoparticles. Release of imidacloprid from these nanoparticles was found to be controlled over 48 hours. Finally, in vivo laboratory testing on termite control proved the efficacy of these nanoparticles as delivery carriers for biopesticides. We believe that the present study will contribute to the design of more effective controlled and targeted delivery for other biomolecules.

Evaluation of microwave assisted grafted sago starch as controlled release polymeric carrier

In the present investigation an attempt has been made to develop a new co-polymeric material for controlled release tablet formulations. The acrylamide grafting was successfully performed on the backbone of sago starch. The modified starch was tested for acute toxicity and drug-excipient compatibility study. The grafted material was used in making of controlled release tablets of lamivudine. The formulations were evaluated for physical characteristics such as hardness, friability, %drug content and weight variations. The in vitro release study showed that the optimized formulation exhibited highest correlation (R) value in case of Higuchi model and the release mechanism of the optimized formulation predominantly exhibited combination of diffusion and erosion process. There was a significant difference in the pharmacokinetic parameters (T-max, C-max, AUC, V-d, T-1/2 and MDT) of the optimized formulation as compared to the marketed conventional tablet Lamivir (R) was observed. The pharmacokinetics parameters were showed controlled pattern and better bioavailability. The optimized formulation exhibited good stability and release profile at the accelerated stability conditions. (c) 2013 Elsevier B.V. All rights reserved.

Development and release mechanism of diltiazem HCl prolonged release matrix tablets

A coated matrix tablet formulation has been used to develop controlled release diltiazem HCl (DIL) tablets. The developed drug delivery system provided prolonged drug release rates over a defined period of time. DIL tablets prepared using dry mixing and direct compression and the core consisted of hydrophilic and hydrophobic polymers such as hydroxypropylmethylcellulose (HPMC), Eudragits RLPO/RSPO, microcrystalline cellulose, and lactose. Tablets were coated with Eudragit NE 30D, and the influence of varying the inert hydrophobic polymers and the amount of the coating polymer were investigated. The release profile of the developed formulation was described by the Higuchi model. Stability trials up to 6 months displayed excellent reproducibility.

Chitosan derivatives alter release profiles of model compounds from calcium phosphate implants

The aim of the current study was to evaluate the impact of chitosan derivatives, namely N-octyl-chitosan and N-octyl-O-sulfate chitosan, incorporated in calcium phosphate implants to the release profiles of model drugs. The rate and extent of calcein (on M.W. 650 Da) ED, and FITC-dextran (M.W. 40 kDa) on in vitro release were monitored by fluorescence spectroscopy. Results show that calcein release is affected by the type of chitosan derivative used. A higher percentage of model drug was released when the hydrophilic polymer N-octyl-sulfated chitosan was present in the tablets compared with the tablets containing the hydrophobic polymer N-octyl-chitosan. The release profiles of calcein or FD from tablets containing N-octyl-O-sulfate revealed a complete release for FD after 120 h compared with calcein where 20% of the drug was released over the same time period. These results suggest that the difference in the release profiles observed from the implants is dependent on the molecular weight of the model drugs. These data indicate the potential of chitosan derivatives in controlling the release profile of active compounds from calcium phosphate implants. (C) 2009 Elsevier Ltd. All rights reserved.

In vitro release of bovine serum albumin from alginate/HPMC hydrogel beads

In recent years, the use of swelling polymeric matrices for the encapsulation and controlled release of protein drugs has received significant attention. The purpose of the present study was to investigate the release of albumin, a model protein from alginate/hydroxypropyl-methylcellulose (HPMC) gel beads. A hydrogel system comprised of two natural, hydrophilic polymers; sodium alginate and HPMC was studied as a carrier of bovine serum albumin (BSA) which was used as a model protein. The morphology, bead size and the swelling ratio were studied in different physical states; fully swollen, dried and reswollen using scanning electron microscopy and image analysis. Finally the effect of different alginate/HPMC ratios on the BSA release profile in physiological saline solution was investigated. Swelling experiments revealed that the bead diameter increases with the viscosity of the alginate solution while the addition of HPMC resulted in a significant increase of the swelling ratio. The BSA release patterns showed that the addition of HPMC increased the protein-release rate while the release mechanism fitted the Peppas model. Alginate/HPMC beads prepared using the ionic gelation exhibited high BSA loading efficiency for all formulations. The presence of HPMC increased the swelling ability of the alginate beads while the particle size remained unaffected. Incorporation of HPMC in the alginate gels also resulted in improved BSA release in physiological saline solution. All formulations presented a non-Fickian release mechanism described by the Peppas model. In addition, the implementation of non-parametric tests showed significant differences in the release patterns between the alginate/HPMC and the pure alginate beads, respectively.

Chitosan nanoparticle as protein delivery carrier - Systematic examination of fabrication conditions for efficient loading and release

Chitosan nanoparticles fabricated via different preparation protocols have been in recent years widely studied as carriers for therapeutic proteins and genes with varying degree of effectiveness and drawbacks. This work seeks to further explore the polyionic coacervation fabrication process, and associated processing conditions under which protein encapsulation and subsequent release can be systematically and predictably manipulated so as to obtain desired effectiveness. BSA was used as a model protein which was encapsulated by either incorporation or incubation method, using the polyanion tripolyphosphate (TPP) as the coacervation crosslink agent to form chitosan-BSA-TPP nanoparticles. The BSA-loaded chitosan-TPP nanoparticles were characterized for particle size, morphology, zeta potential, BSA encapsulation efficiency, and subsequent release kinetics, which were found predominantly dependent on the factors of chitosan molecular weight, chitosan concentration, BSA loading concentration, and chitosan/TPP mass ratio. The BSA loaded nanoparticles prepared under varying conditions were in the size range of 200-580 nm, and exhibit a high positive zeta potential. Detailed sequential time frame TEM imaging of morphological change of the BSA loaded particles showed a swelling and particle degradation process. Initial burst released due to surface protein desorption and diffusion from sublayers did not relate directly to change of particle size and shape, which was eminently apparent only after 6 h. It is also notable that later stage particle degradation and disintegration did not yield a substantial follow-on release, as the remaining protein molecules, with adaptable 3-D conformation, could be tightly bound and entangled with the cationic chitosan chains. In general, this study demonstrated that the polyionic coacervation process for fabricating protein loaded chitosan nanoparticles offers simple preparation conditions and a clear processing window for manipulation of physiochemical properties of the nanoparticles (e.g., size and surface charge), which can be conditioned to exert control over protein encapsulation efficiency and subsequent release profile. The weakness of the chitosan nanoparticle system lies typically with difficulties in controlling initial burst effect in releasing large quantities of protein molecules. (C) 2007 Elsevier B.V. All rights reserved.

Pharmacological Activity of Ibuprofen Release from Measoporous Silica

Novel drug delivery systems (DDS) to improve the pharmacokinetic profile of hydrophobic drugs following oral administration are an area of keen interest in drug research. An ideal DDS should not adversely affect drug activity, be capable of delivering a therapeutic dose of drug, and allow homogenous drug loading and drug release. Mesoporous silica has been proposed for this application, with ibuprofen employed as the model drug. It was hypothesised that mesoporous silica MCM-41 is capable of delivering a pharmacologically therapeutic dose of ibuprofen. Ibuprofen-loaded MCM-41 can be prepared reproducibly at a drug to carrier ratio of 30% (wt/wt). The release profile was seen to be 90% within 2 h. Initial assessment of COX-1 inhibitory activity suggests the absence of adverse effects attributable to drug-carrier interaction. The results of this study provide further evidence in support of the proposed use of mesoporous silica in drug delivery.