Developing mucoadhesive and mucuspenetrating nanoparticles for drug delivery: silica and chitosan models

Mucosal drug delivery is often limited by the presence of several barriers including mucus, the harsh pH and enzymatic activity on the mucosal surfaces. Nanoparticles have shown some potential to overcome these barriers. The aim of this thesis was to investigative how functionalisation of nanoparticles with non-ionic hydrophilic polymers (polyethylene glycol (PEG), polyhydroxyethyl acrylate (PHEA), poly-2-ethyl-2-oxazoline (POZ) and polyvinyl pyrrolidone (PVP)) affects their physicochemical and mucoadhesive properties, diffusion in mucin solution as well as ability to penetrate into mucosal tissues. Silica and chitosan nanoparticles were chosen. Thiolated silica nanoparticles were functionalised with PEG and POZ and therefore three types of silica nanoparticles were obtained; thiolated, PEGylated and POZylated. After the synthesis, the effect of the pH on the size of the silica nanoparticles was studied. No significant change in the size of PEGylated silica nanoparticles over the pH range of 1.5–9 was observed. A significant increase in the size of thiolated and POZylated silica nanoparticles at pH  ≤ 2 was observed. Fluorescently labelled thiolated, PEGylated and POZylated silica nanoparticles were incubated with freshly excised rat intestinal mucosae. Then, the mucosae with the nanoparticles were washed with phosphate buffer solution for several cycles and their fluorescent images were taken. It was found that PEGylated and POZylated silica nanoparticles were less mucoadhesive compared to the thiolated counterpart. This was evident by the lower fluorescence signal of the PEGylated and POZylated silica nanoparticles compared to the thiolated counterpart. Four chitosan derivatives (PEG-, PHEA-, POZ- and PVP-chitosan) were synthesised, which showed complete solubility over a broad pH range (3-9). Unmodified and modified chitosan nanoparticles were prepared using ionic gelation with sodium tripolyphosphate. Modified chitosan nanoparticles diffused faster in bovine submaxillary mucin solution measured by nanoparticle tracking analysis. The penetration of chitosan nanoparticles was evaluated using fluorescence microscopy and demonstrated that modified chitosan nanoparticles penetrated deeper into sheep nasal mucosa compared to unmodified chitosan nanoparticles. The possibilities of incorporating psychoactive drugs (haloperidol and phenobarbital) into unmodified and PVP-chitosan nanoparticles were investigated. Haloperidol-unmodified chitosan nanoparticles showed a relatively low loading capacity. However, phenobarbitalunmodified and PVP-chitosan nanoparticles showed a high loading capacity and provided a sustained drug release. These findings illustrate how the functionalisation of nanoparticles affect their physicochemical properties, which in turn determine their mucoadhesive properties and ability to penetrate mucus. They provide an important contribution to the field of mucosal drug delivery

Chitosan and its derivatives for application in mucoadhesive drug delivery systems

Mucoadhesive drug delivery systems are desirable as they can increase the residence time of drugs at the site of absorption/action, provide sustained drug release and minimize the degradation of drugs in various body sites. Chitosan is a cationic polysaccharide that exhibits mucoadhesive properties and it has been widely used in the design of mucoadhesive dosage forms. However, its limited mucoadhesive strength and limited water-solubility at neutral and basic pHs are considered as two major drawbacks of its use. Chemical modification of chitosan has been exploited to tackle these two issues. In this review, we highlight the up-to-date studies involving the synthetic approaches and description of mucoadhesive properties of chitosan and chitosan derivatives. These derivatives include trimethyl chitosan, carboxymethyl chitosan, thiolated chitosan, chitosan-enzyme inhibitors, chitosan-ethylenediaminetetraacetic acid (chitosan-EDTA), half-acetylated chitosan, acrylated chitosan, glycol chitosan, chitosan-catechol, methyl pyrrolidinone-chitosan, cyclodextrin-chitosan and oleoyl-quaternised chitosan. We have particularly focused on the effect of chemical derivatization on the mucoadhesive properties of chitosan. Additionally, other important properties including water-solubility, stability, controlled release, permeation enhancing effect, and in vivo performance are also described

Silica nanoparticles in transmucosal drug delivery

Transmucosal drug delivery includes the administration of drugs via various mucous membranes, such as gastrointestinal, nasal, ocular, and vaginal mucosa. The use of nanoparticles in transmucosal drug delivery has several advantages, including the protection of drugs against the harsh environment of the mucosal lumens and surfaces, increased drug residence time, and enhanced drug absorption. Due to their relatively simple synthetic methods for preparation, safety profile, and possibilities of surface functionalisation, silica nanoparticles are highly promising for transmucosal drug delivery. This review provides a description of silica nanoparticles and outlines the preparation methods for various core and surface-functionalised silica nanoparticles. The relationship between the functionalities of silica nanoparticles and their interactions with various mucous membranes are critically analysed. Applications of silica nanoparticles in transmucosal drug delivery are also discussed

Synthesis of thiolated, PEGylated and POZylated silica nanoparticles and evaluation of their retention on rat intestinal mucosa in vitro

In this study, we synthesised thiolated silica nanoparticles using 3-mercaptopropyltrimethoxysilane and functionalised them with either 5 kDa methoxy polyethylene glycol maleimide (PEG) or 5 kDa alkyne-terminated poly(2-ethyl-2-oxazoline) (POZ). The main objectives of this study are to investigate the effects of pH on the size and ξ-potential of these nanoparticles and evaluate their mucoadhesive properties ex vivo using rat intestinal mucosa. The sizes of thiolated, PEGylated and POZylated silica nanoparticles were 53 ± 1, 68 ± 1 and 59 ± 1 nm, respectively. The size of both thiolated and POZylated nanoparticles significantly increased at pH ≤ 2, whereas no size change was observed at pH 2.5–9 for both these two types of nanoparticles. On the other hand, the size of PEGylated nanoparticles did not change over the studied pH range (1.5–9). Moreover, thiolated nanoparticles were more mucoadhesive in the rat small intestine than both PEGylated and POZylated nanoparticles. After 12 cycles of washing (with a total of 20 mL of phosphate buffer solution pH 6.8), a significantly greater amount of thiolated nanoparticles remained on the intestinal mucosa than FITC-dextran (non-mucoadhesive polymer, p  0.1 for both). Thus, this study indicates that thiolated nanoparticles are mucoadhesive, whereas PEGylated and POZylated nanoparticles are non-mucoadhesive in the ex vivo rat intestinal mucosa model. Each of these nanoparticles has potential applications in mucosal drug delivery

Preparation of mucoadhesive methacrylated chitosan nanoparticles for delivery of ciprofloxacin

Mucoadhesive polymers and their nanoparticles have attracted a lot of attention in pharmaceutical applications, especially transmucosal drug delivery (TDD). Mucoadhesive polysaccharide-based nanoparticles, particularly chitosan, and its derivatives, are widely used for TDD owing to their outstanding features such as biocompatibility, mucoadhesive, and absorption-enhancing properties. Herein, this study aimed to design potential mucoadhesive nanoparticles for the delivery of ciprofloxacin based on methacrylated chitosan (MeCHI) using the ionic gelation method in the presence of sodium tripolyphosphate (TPP) and compared them with the unmodified chitosan nanoparticles. In this study, different experimental conditions including the polymer to TPP mass ratios, NaCl, and TPP concentration were changed to achieve unmodified and MeCHI nanoparticles with the smallest particle size and lowest polydispersity index. At 4:1 polymer /TPP mass ratio, both chitosan and MeCHI nanoparticles had the smallest size (133 ± 5 nm and 206 ± 9 nm, respectively). MeCHI nanoparticles were generally larger and slightly more polydisperse than the unmodified chitosan nanoparticles. Ciprofloxacin-loaded MeCHI nanoparticles had the highest encapsulation efficiency (69 ± 13 %) at 4:1 MeCHI /TPP mass ratio and 0.5 mg/mL TPP, but similar encapsulation efficiency to that of their chitosan counterpart at 1 mg/mL TPP. They also provided a more sustained and slower drug release compared to their chitosan counterpart. Additionally, the mucoadhesion (retention) study on sheep abomasum mucosa showed that ciprofloxacin-loaded MeCHI nanoparticles with optimized TPP concentration had better retention than the unmodified chitosan counterpart. The percentage of the remained ciprofloxacin-loaded MeCHI and chitosan nanoparticles on the mucosal surface was 96 % and 88 %, respectively. Therefore, MeCHI nanoparticles have an excellent potential for applications in drug delivery

Formation of supramolecular gels from host-guest interactions between PEGylated chitosan and α-cyclodextrin

Chitosan-based hydrogels were prepared via the formation of polypseudorotaxanes (PPR), by selectively threading α-cyclodextrin (α-CD) macrocycles onto polymeric chains, which, through the formation of microcrystalline domains, acted as junction points for the network. Specifically, host-guest inclusion complexes were formed between α-CD and PEGylated chitosan (PEG-Ch), resulting in the formation of supramolecular gels. PEG-grafted chitosan was obtained with a reaction yield of 79.8%, a high degree of grafting (50.9% GW) and water solubility (~16 mg/mL), as assessed by turbidimetry. A range of compositions for mixtures of PEG-Ch solutions (0.2-0.8 %w/w) and α-CD solutions (2−12 %w/w, or 0.04-0.2 %mol) were studied. Regardless of PEG content, gels were not formed at low α-CD concentrations (< 4%). Dynamic rheology measurements revealed stiff gels (G’ above 15k) and a narrow linear viscoelastic region, reflecting their brittleness. The highest elastic modulus was obtained for a hydrogel composition of 0.4% PEG-Ch and 6% α-CD. Steady-state measurements with cycling between low and high shear rate values confirmed the thixotropic nature of the gels, demonstrating their capacity to fully recover their mechanical properties after being exposed to high stress, making them good candidates to use as in-situ gel-forming materials for drug delivery to topical or parenteral sites

Mucus-penetrating nanoparticles based on chitosan grafted with various non-ionic polymers: synthesis, structural characterisation and diffusion studies

Transmucosal administration offers numerous advantages for drug delivery as it usually helps to avoid first pass metabolism, provides rapid onset of action, and is a non-invasive route. Mucosal surfaces are covered by a viscoelastic mucus gel layer which acts as a protective barrier preventing the entrance of harmful substances into the human tissues. This function of mucus also inhibits the diffusion of drugs and nano-formulations and can result in a significant reduction of their efficacy. The design of mucus-penetrating nanoparticles can overcome the barrier function of mucus which may lead to better therapeutic outcomes. In this study, chitosan was chemically modified by grafting short chains of poly(ethylene glycol), poly(2-hydroxyethyl acrylate), poly(2-ethyl-2-oxazoline), or poly(N-vinyl pyrrolidone) and the resulting chitosan derivatives were used to prepare nanoparticles using an ionic gelation method with sodium tripolyphosphate. These nanoparticles were characterised using dynamic light scattering, transmission electron microscopy, small-angle neutron scattering and nanoparticle tracking analysis. Small-angle neutron scattering data revealed the presence of a large amount of water inside these nanoparticles and lack of a heterogeneous internal structure. The nanogel model with low crosslinking density is suggested as the most feasible model to describe the structure of these nanoparticles. The studies of the behaviour of these nanoparticles in bovine submaxillary mucin solutions and their penetration into sheep nasal mucosa indicated greater diffusivity of modified chitosan nanoparticles compared to unmodified chitosan nanoparticles with the best results achieved for the chitosan grafted with poly(N-vinyl pyrrolidone)

Formation of supramolecular gels from host-guest interactions between PEGylated chitosan and alpha-Cyclodextrin

Chitosan-based hydrogels are prepared via the formation of polypseudorotaxanes (PPR), by selectively threading alpha-cyclodextrin (alpha-CD) macrocycles onto polymeric chains, which, through the formation of microcrystalline domains, act as junction points for the network. Specifically, host-guest inclusion complexes are formed between alpha-CD and PEGylated chitosan (PEG-Ch), resulting in the formation of supramolecular gels. PEG-grafted chitosan is obtained with a reaction yield of 79.8%, a high degree of grafting (50.9% GW) and water solubility (approximate to 16 mg mL(-1)), as assessed by turbidimetry. A range of compositions for mixtures of PEG-Ch solutions (0.2-0.8% w/w) and alpha-CD solutions (2-12% w/w, or 0.04-0.2% mol) are studied. Regardless of PEG content, gels are not formed at low alpha-CD concentrations (<4%). Dynamic rheology measurements reveal stiff gels (G' above 15k) and a narrow linear viscoelastic region, reflecting their brittleness. The highest elastic modulus is obtained for a hydrogel composition of 0.4% PEG-Ch and 6% alpha-CD. Steady-state measurements, cycling between low and high shear rates, confirm the thixotropic nature of the gels, demonstrating their capacity to fully recover their mechanical properties after being exposed to high stress, making them good candidates to use as in-situ gel-forming materials for drug delivery to topical or parenteral sites