Hairui Li

Novel engineered systems for oral, mucosal and transdermal drug delivery

Abstract Technological advances in drug discovery have resulted in increasing number of molecules including proteins and peptides as drug candidates. However, how to deliver drugs with satisfactory therapeutic effect, minimal side effects and increased patient compliance is a question posted before researchers, especially for those drugs with poor solubility, large molecular weight or instability. Microfabrication technology, polymer science and bioconjugate chemistry combine to address these problems and generate a number of novel engineered drug delivery systems. Injection routes usually have poor patient compliance due to their invasive nature and potential safety concerns over needle reuse. The alternative non-invasive routes, such as oral, mucosal (pulmonary, nasal, ocular, buccal, rectal, vaginal), and transdermal drug delivery have thus attracted many attentions. Here, we review the applications of the novel engineered systems for oral, mucosal and transdermal drug delivery.

NANO/MICROSCALE TECHNOLOGIES FOR DRUG DELIVERY

Nano- and microscale technologies have made a marked impact on the development of drug delivery systems. The loading efficiency and particle size of nano/micro particles can be better controlled with these new technologies than conventional methods. Moreover, drug delivery systems are moving from simple particles to smart particles and devices with programmable functions. These technologies are also contributing to in vitro and in vivo drug testing, which are important to evaluate drug delivery systems. For in vitro tests, lab-on-a-chip models are potentially useful as alternatives to animal models. For in vivo test, nano/micro-biosensors are developed for testing chemicals and biologics with high sensitivity and selectivity. Here, we review the recent development of nanoscale and microscale technologies in drug delivery including drug delivery systems, in vitro and in vivo tests.

A drug-laden elastomer for surgical treatment of anal fistula

Anal fistula is a common surgical problem with high incidence and causes suffering to patients. The management of high and complex anal fistula is challenging. The purpose of this work is to develop drug-laden elastomer not only to act as seton in the surgical management of anal fistula but also provide painkilling effect during the treatment. Elastic silicone bands were fabricated with different concentrations of lidocaine, with different in vitro drug release profiles. Muscle cutting experiment showed that the drug-laden elastic silicone bands were as effective as the surgical rubber bands in cutting function. Preliminary clinical trial indicated that the drug-laden silicone bands can be used as setons with analgesic effect in the treatment of anal fistula. The findings showed that the drug-laden elastic silicone bands are potentially useful as seton for surgical treatment of anal fistula.

Selected Biomarkers Revealed Potential Skin Toxicity Caused by Certain Copper Compounds

Copper is an essential mineral and plays important roles in skin growth and activity. Copper delivery through skin can provide beneficial effects but its potential to induce skin irritation reactions is often overlooked. Data on dermal toxicity caused by copper compounds is scant. Some recognized in vitro skin toxicity methods are unsuitable for all metal compounds. Here, we employ a keratinocyte-based model and evaluated the skin irritation potential of copper compounds at cellular, genomic and proteomic levels. We determined cell viability and cytotoxicity by using tetrazolium reduction assay and Lactate Dehydrogenase (LDH) assay, performed real-time PCR and protein quantification to assess the expression of biomarkers after treating cells with copper peptide (GHK-Cu), copper chloride (CuCl2) and copper acetate (Cu(OAc)2). These copper compounds exhibited different irritancy potentials at the same treatment concentrations. GHK-Cu was not cytotoxic and did not induce any significant change in the expression levels of various skin irritation-related biomarkers. IL-1α and IL-8, HSPA1A and FOSL1 were significantly upregulated following 24-h treatment with CuCl2 and Cu(OAc)2 at 58 and 580 μM without concomitant inhibition in cell viability. GHK-Cu has a low potential of inducing skin irritation and therefore provides a safer alternative for the delivery of copper through skin.

Fabrication of non-dissolving analgesic suppositories using 3D printed moulds.

Conventional suppositories sometimes fail in exerting their therapeutic activity as the base materials melt inside body cavities. Also they are not suitable to provide long term treatment. Biomedical grade silicone elastomers may be used to fabricate non-dissolvable suppositories to overcome these disadvantages. We kneaded 4 analgesics into the 2 kinds of silicone polymers at 1%, 5% and 10% drug loading, respectively, to test their mechanical properties and drug release profiles. The optimized drug-polymer combinations were used to fabricate suppositories, and three dimensional printing (3DP) was used to create the suppository moulds. Subsequently, the drug release profiles and biocompatibility of the suppositories were studied. It was found that, the mechanical properties of the drug laden silicone elastomers and the rate of drug release from the elastomers can be tuned by varying drug-polymer combinations. The silicone elastomers containing 1% (w/w) and 5% (w/w) diclofenac sodium were the optimal formulations with prolonged drug release and biocompatibility at cellular level. These properties, together with complex geometries offered by 3DP technique, potentially made the non-dissolving suppositories promising therapeutic agents for personalized medicine.

Regulation of cosmetics

Cosmetic providers, be it a manufacturer or a distributor, have legal responsibility to ensure the safety and quality of the merchandise. Compliance to the regulation is highly recommended because it ensures product safety and minimizes unintended adverse effects, benefitting both the manufacturers and the consumers. In this chapter, the cosmetic legislation and regulation in major markets will be reviewed to facilitate a greater understanding of the different requirements in the respective markets and the subsequent adoption of the recommendations provided by the respective legislatures.

History of cosmeceutics

The rapid increase in usage and varieties of cosmeceutics has brought about a wide impact and change in the life of consumers. Cosmeceutics, being in between the spectrum of an active pharmaceutical product and cosmetics, are very complex and need to have new regulations and guidelines to ensure safe usage of these products. Ways of testing of these products also need to be redefined so that consumers can be better informed to make decisions on usage of cosmeceutics. This chapter will give a brief introduction of the history of cosmeceutics and the impact they have on the economy, regulation and testing methods.

Skin permeation of cosmetics

In this chapter we provide a brief overview of skin’s anatomy and various mechanisms that have been postulated for percutaneous absorption. The concept of flux, a parameter used to quantify absorption, will be described in detail with mathematical formulae to calculate flux and determine the permeability of a particular compound. We will also discuss in vitro permeation experiments using diffusion cells and their relevance in pre-formulation studies, using excised animal and human skin. An overview of the correlation between animal and human skin’s permeability will be provided to enable the formulator to predict human absorption. Finally, we will discuss briefly the calculation of limits of cosmeceutical excipients, to prevent adverse effects and to lead the readers into the next two chapters which specifically deal with systemic and topical adverse effects of cosmetic ingredients.

Systemic effect of cosmeceutics – cancer

Currently, no database is available to monitor the number of skin products in a pharmacy or functions of the ingredients used and there is no central platform whereby information on the safety and carcinogenicity of the ingredients is available. There is no guide on the ability of the compounds to permeate the skin and there are no guidelines issued on the recommended limits that should be used on probable carcinogens in the cosmeceutics. This chapter will summarize the procedures done to establish the limits to be proposed.

Local effect of cosmeceutics – allergic contact dermatitis

Cosmeceutical firms are accountable for ensuring the safety of their products. However, the safety of products and ingredients are often overestimated. Ingredients that can cause allergic contact dermatitis are found in a wide range of products. To address this issue, scientists and dermatologists have initiated various approaches to identify allergens in the cosmeceutics.