Alginates as therapeutic and drug delivery systems

Alginate is widely used as a viscosity enhancer in many different pharmaceutical formulations. The aim of this thesis is to quantitatively describe the functions of this polyelectrolyte in pharmaceutical systems. To do this the techniques used were Viscometry, Light Scattering, Continuous and Oscillatory Shear Rheometry, Numerical Analysis and Diffusion. Molecular characterization of the Alginate was carried out using Viscometry and Light Scattering to determine the molecular weight, the radius of gyration, the second virial coefficient and the Kuhn statistical segment length. The results showed good agreement with similar parameters obtained in previous studies. By blending Alginate with other polyelectrolytes, Xanthan Gum and 'Carbopol', in various proportions and with various methods of low and high shear preparation, a very wide range of dynamic rheological properties was found. Using oscillatory testing, the parameters often varied over several decades of magnitude. It was shown that the determination of the viscous and elastic components is particularly useful in describing the rheological 'profiles' of suspending agent blends and provides a step towards the non-empirical formulation of pharmaceutical disperse systems. Using numerical analysis of equations describing planar diffusion, it was shown that the analysis of drug release profiles alone does not provide unambiguous information about the mechanism of rate control. These principles were applied to the diffusion of Ibuprofen in Calcium Alginate gels. For diffusion in such non-Newtonian systems, emphasis was placed on the use of the elastic as well as the viscous component of viscoelasticity. It was found that the diffusion coefficients were relatively unaffected by increases in polymer concentration up to 5 per cent, yet the elasticities measured by oscillatory shear rheometry were increased. This was interpreted in the light of several theories of diffusion in gels.

The impact of ageing on the barriers to drug delivery

Generally, we like to see ageing as a process that is happening to people older than ourselves. However the process of ageing impacts on a wide range of functions within the human body. Whilst many of the outcomes of ageing can now be delayed or reduced, age-related changes in cellular, molecular and physiological functionality of tissues and organs can also influence how drugs enter, distribute and are eliminated from the body. Therefore, the changing profile of barriers to drug delivery should be considered if we are to develop more age-appropriate medicines. Changes in the drug dissolution and absorption in older patients may require the formulation of oral delivery systems that offer enhanced retention at absorption sites to improve drug delivery. Alternatively, liquid and fast-melt dosage systems may address the need of patients who have difficulties in swallowing medication. Ageing-induced changes in the lung can also result in slower drug absorption, which is further compounded by disease factors, common in an ageing population, that reduce lung capacity. In terms of barriers to drug delivery to the eye, the main consideration is the tear film, which like other barriers to drug delivery, changes with normal ageing and can impact on the bioavailability of drugs delivery using eye drops and suspensions. In contrast, whilst the skin as a barrier changes with age, no significant difference in absorption of drugs from transdermal drug delivery is observed in different age groups. However, due to the age-related pharmacokinetic and pharmacodynamic changes, dose adaptation should still be considered for drug delivery across the skin. Overall it is clear that the increasing age demographic of most populations, presents new (or should that be older) barriers to effective drug delivery. © 2012 Elsevier B.V. All rights reserved.

Characterisation and surface-profiling techniques for composite particles produced by dry powder coating in pharmaceutical drug delivery

The production of composite particles using dry powder coating is a one-step, environmentally friendly, process for the fabrication of particles with targeted properties and favourable functionalities. Diverse functionalities, such flowability enhancement, content uniformity, and dissolution, can be developed from dry particle coating. In this review, we discuss the particle functionalities that can be tailored and the selection of characterisation techniques relevant to understanding their molecular basis. We address key features in the powder blend sampling process and explore the relevant characterisation techniques, focussing on the functionality delivered by dry coating and on surface profiling that explores the dynamics and surface characteristics of the composite blends. Dry particle coating is a solvent- and heat-free process that can be used to develop functionalised particles. However, assessment of the resultant functionality requires careful selection of sensitive analytical techniques that can distinguish particle surface changes within nano and/or micrometre ranges.

Polymeric films for buccal drug delivery

The aim of this research project is to evaluate whether or not pullulan films are suitable to buccal drug delivery of a phosphodiesterase5 (PDE5) inhibitor yonkenafil, which was discovered in our research group and currently is under phase II clinical trial for treatment of erectile dysfunction. Variable formulations of pullulan films were designed and the films were prepared. Mechanical properties of the films, in vitro drug release and polymer dissolution, in vitro drug penetration through porcine esophageal mucosa were investigated. The plasticization effects of solvents, polyols and acids to the films were studied by tensile test, and differential scanning calorimetry, thermogravimetric analysis, fourier transform-infrared, scanning electron microscopy, optical microscopy was applied to analyse the structure and chemical-bonding between pullulan and the additives within the films. Release mathematics models were used in the study of the mechanism of drug releases and polymer dissolutions. Ethanol, menthol, fatty acids, and sodium dodecyl sulphate were employed as penetration enhancers to pretreat the tissue. Various plasticizers and acids were applied into the films and the result showed polyethylene glycol 400 and 600 had the excellent plasticization effect on the drug-free pullulan films, while lactic acid was the best plasticizer for the drug-loaded films. Both PEG400 and lactic acid had a great effect on the drug release from the films in vitro, and all the results indicated that the hydroxyl and carboxyl groups of pullulan and the additives influenced the mechanical properties of the films significantly, and also altered drug release mechanisms. Ethanol shows the greatest enhancing ability on the drug permeation through the porcine esophageal mucosa. A possible mechanism for this is that ethanol interferes with the structure of the lipids in the mucosa, resulting in increased partitioning of the drug into the membrane.

Strategies for local drug delivery targeting the oesophagus

Localised, targeted drug delivery to the oesophagus offers the potential for more effective delivery and reduced drug dosages, coupled with increased patient compliance. This thesis considers bioadhesive liquids, orally retained tablets and films as well as chewable dosage forms as drug delivery systems to target the oesophagus. Miconazole nitrate was used as a model antifungal agent. Chitosan and xanthan gum hydrogels were evaluated as viscous polymer viables with the in vitro retention, drug release and minimum inhibitory concentration values of the formulations measured. Xanthan showed prolonged retention on the oesophageal surface in vitro yet chitosan reduced the MIC value; both polymers offer potential for local targeting to the oesophagus. Cellulose derivatives were investigated within orally retained dosage forms. Both drug and polymer dissolution rates were measured to investigate the drug release mechanism and to develop a formulation with concomitant drug and polymer release to target the oesophagus with solubilised drug within a viscous media. Several in vitro dissolution methods were evaluated to measure drug release from chewable dosage forms with both drug and polymer dissolution quantified to investigate the effects of dissolution apparatus on drug release. The results from this thesis show that a range of drug delivery strategies that can be used to target drug to the oesophagus. The composition of these formulations as well as the methodology used within the development are crucial to best understand the formulation and predict its performance in vivo.

Polymer-peptide conjugate hydrogels:towards controlled drug delivery

Peptide-based materials exhibit remarkable supramolecular self-assembling behavior, owing to their overwhelming propensity to from hierarchical structures from a-helices and ß-sheets. Coupling a peptide sequence to a synthetic polymer chain allows greater control over the final physical properties of the supermolecular material. So-called ‘polymer-peptide conjugates’ can be used to create biocompatible hydrogels which are held together by reversible physical interactions. Potentially, the hydrogels can be loaded with aqueous-based drug molecules, which can be injected into targeted sites in the body if they can exhibit a gel-sol-gel transition under application and removal of a shear force. In this review, we introduce this topic to readers new to the field of polymer-peptide conjugates, discussing common synthetic strategies and their self-assembling behavior. The lack of examples of actual drug delivery applications from polymer-peptide conjugates is highlighted in an attempt to incite progress in this area.

Recent advances in topical ophthalmic drug delivery with lipid-based nanocarriers

Ocular barriers and the poor water solubility of drug candidates present a number of problems for the development of ocular drug delivery systems. Recently, the emergence of lipid-based nanocarriers has provided a viable means of enhancing the bioavailability of ophthalmic formulations. A number of these formulations have been found to be clinically active and several others are currently undergoing clinical trials. In this review, the advantages of lipid-based nanocarriers as non-invasive topical ocular drug delivery systems are presented. Many systems, including emulsions, liposomes, cubosomes, niosomes and other lipid-based nanocarriers, are reviewed.

Amino acids in oral drug delivery:salts, ion-pairs and transcriptomics

Oral drug delivery is considered the most popular route of delivery because of the ease of administration, availability of a wide range of dosage forms and the large surface area for drug absorption via the intestinal membrane. However, besides the unfavourable biopharmaceutical properties of the therapeutic agents, efflux transporters such as Pglycoprotein (P-gp) and multiple resistance proteins (MRP) decrease the overall drug uptake by extruding the drug from the cells. Although, prodrugs have been investigated to improve drug partitioning by masking the polar groups covalently with pre-moieties promoting increased uptake, they present significant challenges including reduced solubility and increased toxicity. The current work investigates the use of amino acids as ion-pairs for three model drugs: indomethacin (weak acid), trimethoprim (weak base) and ciprofloxacin (zwitter ion) in an attempt to improve both solubility and uptake. Solubility was studied by salt formation while creating new routes for uptake across the membranes via amino acids transporter proteins or dipeptidyl transporters was the rationale to enhance absorption. New salts were prepared for the model drugs and the oppositely charged amino acids by freeze drying and they were characterised using FTIR, 1HNMR, DSC, SEM, pH solubility profile, solubility and dissolution. Permeability profiles were assessed using an in vitro cell based method; Caco-2 cells and the genetic changes occurring across the transporter genes and various pathways involved in the cellular activities were studied using DNA microarrays. Solubility data showed a significant increase in drug solubility upon preparing the new salts with the oppositely charged counter ions (ciprofloxacin glutamate salt exhibiting 2.9x103 fold enhancement when compared to the free drug). Moreover, permeability studies showed a 3 fold increase in trimethoprim and indomethacin permeabilities upon ion-pairing with amino acids and more than 10 fold when the zwitter ionic drug was paired with glutamic acid. Microarray data revealed that trimethoprim was absorbed actively via OCTN1 transporters while MRP7 is the main transporter gene that mediates its efflux. The absorption of trimethoprim from trimethoprim glutamic acid ion-paired formulations was affected by the ratio of glutamic acid in the formulation which was inversely proportional to the degree of expression of OCTN1. Interestingly, ciprofloxacin glutamic acid ion-pairs were found to decrease the up-regulation of ciprofloxacin efflux proteins (P-gp and MRP4) and over-express two solute carrier transporters; (PEPT2 and SLCO1A2) suggesting that a high aqueous binding constant (K11aq) enables the ion-paired formulations to be absorbed as one entity. In conclusion, formation of ion-pairs with amino acids can influence in a positive way solubility, transfer and gene expression effects of drugs.

Polymers in drug delivery and molecular recognition

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Biodegradable polymers as drug delivery systems.

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Biodegradable polymers as drug delivery systems

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The design of contact lens based ocular drug delivery systems for single-day use:part (I) structural factors, surrogate ophthalmic dyes and passive diffusion studies

The poor retention and efficacy of instilled drops as a means of delivering drugs to the ophthalmic environment is well-recognised. The potential value of contact lenses as a means of ophthalmic drug delivery, and consequent improvement of pre-corneal retention is one obvious route to the development of a more effective ocular delivery system. Furthermore, the increasing availability and clinical use of daily disposable contact lenses provides the platform for the development of viable single-day use drug delivery devices based on existing materials and lenses. In order to provide a basis for the effective design of such devices, a systematic understanding of the factors affecting the interaction of individual drugs with the lens matrix is required. Because a large number of potential structural variables are involved, it is necessary to achieve some rationalisation of the parameters and physicochemical properties (such as molecular weight, charge, partition coefficients) that influence drug interactions. Ophthalmic dyes and structurally related compounds based on the same core structure were used to investigate these various factors and the way in which they can be used in concert to design effective release systems for structurally different drugs. Initial studies of passive diffusional release form a necessary precursor to the investigation of the features of the ocular environment that over-ride this simple behaviour. Commercially available contact lenses of differing structural classifications were used to study factors affecting the uptake of the surrogate actives and their release under 'passive' conditions. The interaction between active and lens material shows considerable and complex structure dependence, which is not simply related to equilibrium water content. The structure of the polymer matrix itself was found to have the dominant controlling influence on active uptake; hydrophobic interaction with the ophthalmic dye playing a major role. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Functionalised particles using dry powder coating in pharmaceutical drug delivery:promises and challenges

Introduction: Production of functionalised particles using dry powder coating is a one-step, environmentally friendly process that paves the way for the development of particles with targeted properties and diverse functionalities. Areas covered: Applying the first principles in physical science for powders, fine guest particles can be homogeneously dispersed over the surface of larger host particles to develop functionalised particles. Multiple functionalities can be modified including: flowability, dispersibility, fluidisation, homogeneity, content uniformity and dissolution profile. The current publication seeks to understand the fundamental underpinning principles and science governing dry coating process, evaluate key technologies developed to produce functionalised particles along with outlining their advantages, limitations and applications and discusses in detail the resultant functionalities and their applications. Expert opinion: Dry particle coating is a promising solvent-free manufacturing technology to produce particles with targeted functionalities. Progress within this area requires the development of continuous processing devices that can overcome challenges encountered with current technologies such as heat generation and particle attrition. Growth within this field requires extensive research to further understand the impact of process design and material properties on resultant functionalities.