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Amgad

Amgad Rezk

Year of Award: 2014 Award State: Victoria Health And Medicine > General
Health And Medicine > Diseases, Disorders And Syndromes
To analyse needle-free pulmonary delivery of peptide for the treatment of Osteoporosis patients - Singapore
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The most common form of bone disease, osteoporosis is  estimated  to  affect  75 million people across USA, Europe and Japan (Johnell & Kanis, 2006). A variety of factors lead to reduced bone mass density and hence higher risk of fracture in osteoporosis, such as poor nutrition (vitamin D deficiency and low calcium intake), increased prevalence of chronic alcohol abuse, smoking and asthma (prolonged use of corticosteroids is known to influence bone metabolism), as well   as  more widespread sedentary lifestyles and physical inactivity (generally associated with increasing population wealth).

It is projected that more than 50% of all osteoporotic hip fractures will occur in Asia by 2050 (Gullberg et al., 1997), where it is usually underdiagnosed and undertreated, even amongst patients who have  already undergone fracture. A little known fact is that osteoporosis induces a heavy toll, both personally and economically. The disability  rates  due to  osteoporosis  can  exceed that due to cancer and other chronic  non-communicable  diseases  such  as rheumatoid arthritis, asthma and high-blood-pressure related heart disease (Johnell & Kanis, 2006). Appropriate therapeutic management is therefore critically important to quality of life.

Whilst a wide range of drug treatment is available, poor compliance due to the necessity of long-term treatment leaves patients at risk  of  fractures, creates substantial burden to individuals and families and often restricts individuals’ activities for a lifetime, in addition to imposing higher cost burdens on national healthcare systems (McCombs et al., 2004; Rabenda et  al.,  2008).  

Patient compliance is expected to be even lower for teriparatide, which is administered as daily injections as the half-life of peptides in blood plasma is typically short, necessitating frequent administration to maintain therapeutic levels (DeFelippis, 2003). Moreover, most peptide formulations including teriparatide require constitution prior to delivery via the parenteral (injection) route. Not only is the necessity of a preparatory step a burden to patient convenience, parenteral delivery limits the potential of marketing the product since patients are often unwilling to endure the repeated painful and traumatic  experience  associated  with  chronic  administration. For this reason, there have been extensive efforts to find alternative delivery systems for PTH, although none has yet reached the market.

A comprehensive review summarises these approaches, which include oral, transdermal, nasal  and pulmonary delivery systems, out of which the pulmonary route is deemed most promising (Morley, 2006). This is due to the large absorptive surface area, relatively permeable membranes and rich blood perfusion of the lungs, allowing inhaled peptides up to 30 kDa to be rapidly absorbed into the bloodstream without the need for penetration enhancers (Corkery, 2000).

However, current devices such as dry powder inhalers, metered dose inhalers and traditional nebulisers used for the delivery of asthma drugs are not suitable for the delivery of peptides to the deep lung alveoli where peptide absorption occurs. There is clearly a need for breakthrough in device design. Our vision is thus for a low cost, portable device which can both minimize the inconvenience of dose preparation using microfluidic technology as well as circumvent the invasive nature of delivery by administering teriparatide through the pulmonary route within a single integrated miniature chip-scale device for improved patient comfort and compliance.

Peptides with therapeutic potential have received significant attention in the past decade given their importance in the regulation of a wide number of physiological processes. Though a number of peptides have already been marketed or are currently under clinical trials (Degim & Celebi, 2007), the efficacious delivery of these molecules remains a barrier to their widespread use as a therapeutic.

Oral delivery, for example, is plagued by poor solubility, in vivo stability and bio-absorption as well as problems due to enzymatic degradation within the gastrointestinal tract (Soares et al., 2007). Whilst other administration routes have been studied, there is a definite need to develop effective, low-cost, safe and reproducible non-invasive and non- injectable means for peptide delivery (Smith, 1997), especially since these could lead to minimization of adverse side effects, faster onset and hence improved drug efficacy, targeted site-specificity and reduce dosage (Malavolta & Cabral, 2011).

In fact, the huge challenge of developing non-parenteral (i.e. non-injection) routes of administration is often cited to be a significant impediment to the success of peptide therapeutics (Breimer, 1999; DeFelippis, 2003).

 

Thespecificaimofthisprojectisthereforetoinvestigatethefeasibilityofdelivering peptidesinaerosolizedformthroughthepulmonaryrouteusinganovelmicrofluidic drugnebulizationplatformthatexploitssurfaceacousticwaves(SAWs).SAWsare nanometeamplitudelectroelastic wavethapropagate alonthsurfacoa piezoelectricsubstrate(inthiscase,thesinglecrystallithiumniobate(LiNbO3))and haverecentlybeendemonstratedtobeapowerfulmicroscaleactuationmechanism  todriveawiderangeofmicrofluidicprocesses(Friend&Yeo,2011). 

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