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theses

ETD doctoral

Oxicams are a class of non-steroidal anti-inflammatory drugs (NSAID) structurally related to the enolic acid class of 4-hydroxy-1,2-benzothiazine carboxamides. Most oxicams are unselective inhibitors of the cyclooxygenase (COX) enzymes. They are used clinically to treat inflammation, relieve both acute and chronic pain associated with arthritis. However, adverse effects, such as gastro-intestinal toxicity/bleeding, headaches, rash, increased risk of cardiovascular events, etc., are frequently reported when Oxicams are administrated at high doses and on long-term treatment.

Topical drug delivery across the stratum corneum can provide local (dermal), or systemic (transdermal) effects, which can greatly reduce side-effects. However, the barrier function of the skin impairs the penetration and absorption of drugs. In the past three decades, nanotechnology and nanocarriers, such as microemulsion, solid lipid nanoparticles, polymeric nanoparticles, dendrimers, liposome, etc., have been extensively assessed to improve drug transport into the skin. The unique physicochemical properties of nanoparticles allow them to overcome the biological barriers and hence, improve the bioavailability of their payload.

Among these innovative drug delivery systems, liposomes have drawn a great attention during the last few decades as a drug delivery system due to the biodegradable and biocompatible composition of liposomes and their distinctive capacity to accommodate both water-soluble and lipid-soluble agents. They showed a number of advantages over other nanocarrier systems, such as enhanced delivery of drug, protection of active drug from environmental factors, improved performance features of the product, preventing early degradation of the encapsulated drug, cost-effective formulations of expensive drugs and efficient treatment with reduced systemic toxicity. However, the conventional liposomes have been shown to be incapable of deeply penetrating the skin due to their rigid structure and size. In 1990s, transfersome, the first generation of deformable liposomes, has been introduced to greatly enhance the skin permeability of the encapsulated drugs.

The goal of this research was to explore and optimize the dermal and transdermal delivery of meloxicam (MX), a model oxicam drug, using deformable liposome delivery system. MX loaded deformable liposomal formulations have been developed and characterized for particle size, drug entrapment efficiency, zeta potential, morphology, stability and skin permeability.

In order to appropriately characterize the deformable liposomes, an HPLC method was developed for the determination of drug entrapment efficiency, drug loading and drug content in permeation study samples. The method had been subsequently validated and proven to be specific, linear, sensitive, accurate, reproducible and stable at room temperature for the simultaneous quantitation of MX, quercetin (QCT) and dihydroquercetin (DHQ).

To conduct predictive bioavailability of topical formulations, ex vivo skin permeation tests using Franz Diffusion Cells have been performed to assess the skin kinetics of topical formulations. In this study, human cadaver skin model was used to generate a concentration profile following topical application of liposomal suspension or hydrogel formulations by conducting skin deposition study on both epidermal and dermal layers, flux determination on permeated samples, and visualization using Confocal Laser Microscopy (CLSM).

The composition and preparation process of conventional liposomes and transfersomes were investigated. It was found that the type, grade and the content of phospholipids played a key role in the characteristics of liposomes, such as vesicle size, PDI, zeta potential and entrapment efficiency. Based on the obtained data, vesicles were prepared using 0.8% USPC which showed the highest loading of MX, and particle size less than 200 nm with uniform size distribution (PDI less than 0.3). This finding helped guide the optimal liposomal formulations using 0.8% USPC in further experiments.

The prepared vesicles along with two different types of microemulsions were evaluated as potential dermal delivery carriers for MX. When comparing the water-in-oil (w/o) and oil-in-water (o/w) microemulsion performance with the use of an ex vivo model involving human cadaver skin, the highest flux and permeation values were obtained for transfersomes, indicating these drug carriers as the most promising in terms of topical drug delivery.

Thus, the transfersome composition served as the base formulation. In order to impart stability and enhanced permeability to transfersomes, flavonoids were selected leading to the discovery of flavosomes, as novel deformable liposomes for the topical delivery of anti-inflammatory compounds. These carriers were prepared by incorporating flavonoids, specifically quercetin (QCT) and dihydroquercetin (DHQ), into transfersomes. Characterization of the flavosomes was conducted in terms of their vesicle size, zeta potential, entrapment efficiency and deformability index. These vesicles exhibited homogeneous particle size of less than 150 nm with a higher degree of deformability as compared to transfersome. Ex-vivo skin permeation and confocal laser scanning microscopy studies demonstrated that the flavosome formulations improved the skin permeation of MX compared to that for transfersomes.

Notably, significant skin distribution of the two flavonoids, QCT and DHQ was observed in ex-vivo skin permeation studies. Since flavonoids are natural anti-inflammatory compounds, flavosomes might be used as potential nanocarriers for co-delivery of other anti-inflammatory compounds such as MX.

To increase the encapsulated content of MX and improve the stability of deformable liposomal formulations (transfersomes and flavosomes), the formulation and preparation processes were further optimized. These deformable liposomal vesicles exhibited homogeneous particle size of less than 120 nm with a significantly higher entrapment rate and deformability as compared to conventional liposomes. The liposomal gel formulation was prepared by incorporating these liposomal vesicles into 20% (w/w) poloxamer P407 hydrogel. The gel formulations were evaluated for content uniformity, rheology, particle size, morphology, stability and skin permeability.

The deformable liposomal gel formulations showed improved permeability compared to a conventional liposomal gel and a liposome-free gel. The enhancement effect was also visible by confocal laser microcopy. These deformable liposomal hydrogel formulations have the potential of being a promising alternative to conventional oral delivery of non-steroidal anti-inflammatory drugs (NSAIDs) with enhanced local and systemic onset of action and reduced gastrointestinal side effects. Notably, flavosome loaded gel formulations displayed the highest permeability through the deeper layers of the skin and shortened lag time, indicating a potential faster on-site pain relief and anti-inflammatory effect.

ETD_11327

doi:10.7282/t3-5mjf-zf42

Ph.D.

Includes bibliographical references

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