A Formulation-Based Approach to Infection Prevention
Professor Barbara Conway,
Head of Pharmacy, University of Huddersfield
Introduction
Professors of Pharmaceutics mix and make the actual medicines into dosage forms – tablets,
caplets, liquids, creams, ointments. They produce the “recipes” for the drugs.
Our job: to make sure that we can get the right amount of drug to the right place in the body at
the right dose at the right time so it can do its job.
What is the most effective way to do that?
Targeted drug delivery
Delivering medication to a patient in a manner that increases the concentration of the
medication in some parts of the body and even some cells relative to others.
Largely founded on nanomedicine, which plans to employ nanoparticle-mediated drug delivery
in order to combat the downfalls of conventional drug delivery
We can make nano-sized drug delivery carriers so the drug is trapped within particles that are
100-200 nanometers in dimension.
For wound care, we need lipid-based nanocarriers.
Application: Topical antiseptics
Initially looking at skin antisepsis:
pre-surgery to prevent SSI
to reduce wound bioburden
Increased effectiveness of the skin antiseptics should ultimately decrease the use of antibiotics.
Topical antiseptics are preferable to antibiotics because less likely to induce resistance, owing to
their unspecific mode of action and the high concentrations in which they can be used.
Topical antiseptics can prevent biofilm build-up as well as antimicrobial action.
Challenge: unknown depth of penetration and unknown effective concentration
Transdermal delivery routes: 3 pathways
Stratum corneum is the outermost layer of skin; it’s the major barrier. 3 ways drugs can get
though it:
1.
The paracellular path: tortuous route through the membrane
2.
The transcellular path
3.
The transappendageal path: follicular route
Transappendageal pathway is ideal, as hair follicles penetrate deep into the skin. But follicles
encompass only 1% of total skin area, and also varies per individual depending on follicle density
and size. Other factors that affect transport ability of transappendageal pathway are other fill
materials, such as sebum and desquamated cells, in addition to cultural habits and weather
conditions (sweat, deodorant, etc.)
Microorganisms reside both on the skin surface as well as in hair follicles and lower skin depths.
Endogenous infections arise from endoflora from skin, mucous membranes and hollow viscera,
seeding from another infection. Follicles also present a unique microbial niche for
microorganisms within the skin.
When the barrier is breached, commensal microoganisms may therefore persist at the site.
Therefore, effective and rapid permeation of the antimicrobial into the deeper layers of the skin
may prevent infection.
Our goal: Try and increase how much drugs penetrate into the skin and influence where
they go.
Penetration enhancers
Terpenes are the major ingredient in essential oils. They bind in large quantities to SC and act as
skin penetration enhancers by
increasing drug partitioning into the skin (solvent effect)
enhancing drug diffusion
reversibly disrupting lipid bilayers
Furthermore, these volatile compounds may alter the thermodynamic activity of the drug due to
evaporation of terpenes like alcohol
Skin permeation studies are done by putting the formulation to be tested on top of a skin
sample (varying depths) and then measuring below what penetrated at what depth.
Case study: does eucalyptus oil help penetration? Tested with above methodology.
Conclusion: it did. Even after 2 minutes, drugs were found in a deeper layer of the skin.
It seemingly did not work as well as crude oil for penetration effectiveness, however.
Olive oil, however, did not work as well as eucalyptus oil in permeation studies.
Nanotechnology and targeting
Goal: to target drugs to the hair follicles and have them accumulate and remain there. Sustained
release and preferential targeting.
Unique size dependent properties of lipid nanoparticles offer possibilities for delivery of drug for
both controlled release and site specific drug delivery.
Control of particle size and surface properties determines how delivery system interacts with
target.
Example: Triclosan targeting via nanoparticle
Triclosan is difficult to work with. It doesn’t dissolve in water, BUT it does form well into a lipid
nanoparticle. We can get more triclosan into the skin by forming it into nanoparticles.
Process: melting of lipids and dissolving drug into the lipid > hot aqueous surfactant solution >
high shear homogenization > hot pre-emulsion > ultrasonication > hot nanoemulsion > solid lipid
nanoparticles.
When emulsion particle size is decreased to the nano level, it becomes clear (no longer diffuses
light) and you can get a nice, even particle size distribution.
Much higher percentage of triclosan retained in skin when delivered by nanoparticles.
Example: Chlorhexidine targeting via nanoparticle
Also increases skin penetration.
We’ve tried incorporating chlorhexidine into Altrazeal gels in saline – what happens?
Chlorhexidine solution is crosslinked with gel and not released
Chlorhexidine in nanoemulsions can be incorporated and released
Where we are now with this work
1.
Successful formulation of potentially synergistic combination of ingredients into
nano-sized delivery systems (solid and liquid)
2.
Preferential increase in delivery of antimicrobial to hair follicles
3.
Incorporation of nanoemulsions into porous flexible gel structure, sustaining
release of CHG
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