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Development of an antiviral injectable depot formulation to target human
papilloma virus.
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Contrary to popular belief the development of dermatological products can be
more complicated than that for transdermal products.
Although only 1-15% of a dose is bioavailable from a transdermal product, local tissue
concentrations can be much higher.
Topical formulations (creams, ointments gels etc) exhibit variable drug activity, nonsteady state kinetics and a short duration of action.
Following application of a topical formulation to the skin, a sequence of four events is
triggered;
1. Drug partitioning from the formulation onto the skin surface, the results in a
decrease in drug activity within the formulation and a net diffusive movement of
drug occurs towards the skins surface.
2. Diffusion of additional drug toward the skin surface, which facilitates particulate
drug near the skin surface to dissolve in the surrounding media
3. The concentration of drug on the skins surface is then determined by the relative
rate of dissolution into the vehicle, diffusion through the vehicle and uptake by
the skin.
4. The activity of the drug at the formulation-skin interface determines the rate of
partitioning of the drug into the skin
Intradermal injectable formulation for local delivery of agents.
Intradermal injections bypass the stratum corneum and deliver drugs directly to the
dermis and epidermis.
Within the UK there are currently three formulations marketed for intra-dermal injection:
Name
Adcortyl™
BOTOX®
Manufacturer
E R Squibb
Allergan Ltd
Active agent
triamcinolone acetonide
Tuberculin Purified Chiron
human
strains
Protein Derivative
Vaccines
Mycobacterium
Evans
tuberculosis
These formulations are all short acting with specific indications.
Indication
neurodermatitis
axillary
hyperhidrosis
of Vaccination
This proposal is to develop a sustained release dermal injection for the delivery of
antiviral agents in the treatment of skin warts.
Formulation strategies for long-term therapy and duration of action include:
Non-aqueous solutions
The drug may be formulated in an oily vehicle to improve its loading due to enhanced
solubility and to protect the drug from aqueous degradation, the oil vehicle also delays
drug release into the surrounding aqueous media and prolongs the duration of action.
Commercial examples include preparations for contraception and depot procaine
penicillin G.
Disadvantages of oily vehicles include the limited injection volume and the local irritancy
that may be experienced at the site of injection.
Sesame oil has been the oil of choice due to its content of natural antioxidants.
There are no marketed oil based injections for intradermal delivery.
Suspensions
A suspension provides the drug at the site of action in a solid form whereby the erosion
and relative solubility of the drug at the site will determine the duration of action.
The presence of solid materials often results in pain associated with this type of delivery
system.
Emulsions
Within the dermis the surrounding fluid is aqueous in nature thus an oily formulation will
control the release of drug and thus the drug release may be prolonged. When injected
intramuscularly or subcutaneously emulsions migrate and accumulate at the lymph
nodes before becoming available systemically.
Liposomes
Liposomes are spherical vehicles, the walls of which consist of one or several bilayers of
ampiphilic molecules.
In contrast to traditional topical formulations, liposomally
entrapped drugs have reported increased permeation through the superficial layers of
the skin with concomitant decrease in systemic levels. Liposomal formulations are
versatile drug carrier systems because their physicochemical properties can be relatively
easily altered and both water and lipid soluble drugs can be incorporated at relatively
high concentrations. The size of liposomes can also be manipulated for optimal efficacy.
In depot form liposomes are capable of sustained release of a variety of drugs over
several days. Following im or sc injection the largest sized liposomes provide the
longest residence times thus making them ideal candidates for this type of delivery.
Encapsulation of the active drug
Polymer microspheres are similar to liposomes in their model of action. Small spherical
particles are formed from polymers that encapsulate the drug moiety and control the rate
of release.
This study aims to investigate the relative properties of these formulation types on the
formulation of a depot injection for the treatment of warts.
The objectives of this research project are as follows:
 To prepare a formulation of each type containing the antiviral agents and monitor
the drug release from this over time
 To measure the stability of the formulation
 To manipulate the formulation to provide the desired in vitro release profile
 To measure the dermal disposition of the drug as released from these
formulations using in vitro techniques.
This project will be supported by Dr Hannah Batchelor who has experience in the design
of formulations for drug delivery Dr Yvonne Perrie who has worked extensively in the
field of liposomal and particulate drug delivery.