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European Biopharmaceutical Review
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With considerable progress being made in the areas of biologics and
specific cell-based therapeutics, and technical developments in both the
production and properties of the materials involved, the topical wound
care industry is set for a quantum leap forward
Wounds come in a variety of shapes and sizes and can be either chronic
or acute. Their diversity means that each wound must be approached
according to its own unique characteristics and how best to heal the
patient. Correspondingly, there are many different types of wound care
(1- 3). It’s always hard to know when a wound becomes a non-wound, but
the essence of this discussion is any topical application that involves
treating a break in the skin of some description. All wounds contain
bacteria. Hence, a key issue in wound care has been the preparation and
application of antiseptic solutions (4-6). Demand for more sophisticated
wound treatments has increased as a result of a number of factors,
including increased military activity and an ageing population needing
to address burns, sores and pressure ulcers. As people age, the
structure of the skin breaks down; it becomes easier to damage and more
susceptible to injury. The sequential phases of wound healing and the
cells involved are summarised in Figure 1 and Table 1.
Wound Care Options
Numerous advanced treatment methods for chronic, non-healing wounds are
available, which can be segmented into three main categories:
pharmaceutical agents, wound dressings and medical devices. This is
further complemented by a wide variety of wound dressings that can be
used for various types of wound, including amorphous hydrogels,
hydrocolloid dressings, alginate and composite dressings, transparent
films and silver dressings. There’s no point only pouring a sterile
solution onto a wound – the product has to stay there, so it’s essential
to make the formulation bioadhesive. At the same time, it can’t simply
function as a ‘lump of glue’. The active substance must be able to reach
and treat the fungus, for example, or whatever is causing the problem,
during a given period of time. Another important consideration is the
patient − treatments can’t be packaged within a complicated applicator
that an 80-year old person with arthritis cannot open, or bend down to
apply to their knee. Administration is a key consideration.
Formulation and Preservation
With any serious wound, the first critical aspect is to stop the
bleeding, for which a number of products are currently available,
including physical applications such as patches and emollient pads.
These help to both staunch the blood flow and help to reduce post-wound
scarring. Scar prevention/reduction is key to both the military and the
cosmetic surgery sector, including mole removal and post-operative skin
cancer treatments. A lot of the drugs in this area are freeze-dried
proteins and peptides – organic molecules – which have stability and
preservation issues. Selecting the correct preservative is paramount for
the majority of wound-care formulations. The wrong choice of
preservative will detract from the efficacy of the drug or possibly make
it unstable. Without a preservative, there is no medicine at all,
because it has no shelf-life.
Ensuring the active ingredient and the preservative are compatible is a
key formulation issue. Many features of an emollient, for example, will
have an impact on texture, the most basic one being the emulsion type
(see Figure 2). The initial feel derives from the continuous phase, so
oil-in-water emulsions feel less greasy than water-in-oil emulsions. An
oil emollient would only be considered in the context of oil-in-water
emulsions: the oil’s viscosity, feel, skin penetration, formula
composition and volatility all affect the final texture. Commonly, a
blend of oils is used. For example, liquid paraffin has poor skin
penetration and gives an oily feel; white soft paraffin is a good
emollient, but gives a greasy feel; isopropyl myristate offers good skin
penetration and a light feel; and silicone oils/dimethicone add
lubricity to rubout, with higher viscosity silicones giving prolonged
rubout. Medium-chain triglycerides (caprylic/capric triglyceride) are
good solubilisers/carriers and waxes add 'body' to an emulsion
(emulsifying wax, beeswax). Generally, the lower the oil phase content,
the lighter the cream. A very light cream may have an oil phase of only
five per cent, whereas a heavy cream could have a 30 per cent oil phase.
The emulsifier has textural properties of its own and can also affect
how the emulsion breaks, releasing the oil, and the type and amount of
thickener affects texture. Clays have little effect on thickness on
application, for example, xanthan gum gives a slimy feel, carbomers give
a quick break and hydroxyethylcellulose is a good general thickener
with many applications. In addition, the smaller the droplet size, the
smoother and lighter the feel. Water-phase ingredients and humectants
such as glycerin give a heavier feel.
Beyond physicochemical considerations, there are also more human factors
to take into account. How does the treatment feel; for example, is it
smooth and not gritty? It has to have the right skinfeel and it must
spread well, all of which is important for patient compliance, as self
medication is very common with topical wound care products. An
acceptable smell is also critical, but must not negatively affect the
active ingredient.
Advanced Technologies
Pushing the science of wound care forward, one emerging technology
currently being examined is the use of tissue material recovered via
elective caesarean from human postpartum amniotic sacs as a biological
wound bandage. The placenta, usually discarded after birth and in
abundant supply, is harvested and the amniotic membrane is isolated and
processed using a strict protocol that ensures the standardised
treatment of the amnion from birth of the foetus to storage in a freezer
within six hours. The key benefits of this unique process are a product
that is more uniform and potentially ‘purer’ than earlier methods could
achieve. The processed membrane is dried according to a standardised
procedure to stabilise its biochemical and biomechanical properties and
to preserve the functional beneficial wound healing properties. Dried
membranes can then be prepared in any shape and size for application as a
bespoke wound dressing; the stability of the product at room
temperature, and its sustained shelf-life and long-term storage, all
have further positive implications for commercialisation and wide
product adoption, particularly for export supply and overseas field use
by the military.
Amniotic membrane is an established wound care treatment modality
throughout the body. It is particularly useful for wounds of the eye.
Many of the useful effects of amniotic membrane are derived from its
gross physical properties. It is accepted that the application of an
amnion patch to the injured ocular surface has the effect of improving
patient comfort and relieving pain (7). The mechanical separation of
inflamed tissues may also prevent scarring. Amnion can function as a
scaffold in areas of stromal tissue loss and as a substrate for
epithelial cell growth. It may also provide a barrier to white blood
cells, physically trapping them on the stromal side and causing cell
death through as yet unclear mechanisms (8).
The reported biological properties of amnion include anti-inflammatory,
antifibrotic, antimicrobial, antineovascular and proepithelialising –
all potentially desirable ingredients of any treatment for acute wounds.
Even more compelling are the claims that amnion restores and preserves
limbal stem cell function and obviates the need for subsequent limbal
stem cell transplantation. The presumed mediators of these effects may
become degraded by cryopreservation techniques and are mostly present in
minimal quantities in therapeutic amnion, but this enhanced dry product
preserves these properties as proven during extensive in vitro evaluations.
Topical Foams
Topical foams are commonly used as a wound healing dosage form (9- 12).
However, foams can be tricky to formulate because of stability issues,
controlling the release of the active ingredient and getting the
preservatives right to manage shelf-life and prevent mould growth if
impure air enters the container (although this can be overcome by using
airless bottles). Formulated topical foams for multiple applications are
now available, such as for incorporation into transdermal patches to
encourage blood clotting. Haemostatix have developed a new class of
active clotting agent to control bleeding and are working to scale up to
GMP supplies. They have pioneered a new approach to haemostasis, one
that is based on a peptide that binds to fibrinogen, inducing the rapid
and targeted formation of clots. This innovative technology platform is
being used to develop a pipeline of topical and systemic products to
prevent or control different forms of bleeding. PeproStat, for example,
is a new class of topical haemostat that is applied directly to a wound
during surgery or trauma to control bleeding. It polymerises fibrinogen
into a fibrinlike clot, without the need for the enzyme thrombin. In a
comparative trial, PeproStat was significantly faster and more effective
than four current therapies and, as a result, is now being developed in
a range of topical dosage forms to meet varying surgical or trauma
needs. The key advantage of the product is its stability, which enables
the development of ready-to-use formulations.
The Future of Wound Care
Looking forward, the future of wound care – much like many markets – may
lie in biologics, gene therapy and specific cell-based therapies for
molecular and genomic deficiencies. Future innovations, particularly
drug-device combinations, will create expansion opportunities for some
technologies and obsolescence risk for others (such as dressings and
vacuum-assisted closures). The newest active products promise crosstalk
in the wound environment to dynamically control which growth factors and
wound-regulatory elements are activated, and at what time, and
diagnostic tools for biomarkers of chronicity will be developed that
will tell you what exactly is wrong and which therapy to choose.
Wound care is a big and growing business, particularly in the advanced
and active segments in which innovations are occurring at an
accelerating pace. And, as with all medico-pharma sectors, competition
is on the rise and will be increasingly price-based in the traditional
segment; with advanced products, differentiation will be the key to
success. The selection of the applicator and/or primary container is an
essential part of any topical development project, and manufacturers in
the active product segment will need to be especially mindful of the
importance of crossdisciplinary device-pharma-biotech collaborations.
The ability to provide traditional, advanced and active wound care
products, and take a wound care concept from formulation through
scale-up and development to GMP production for clinical trials and
beyond, is where the future of wound care lies.
References
- Broughton G et al, A Brief History of Wound Care, Plastic and Reconstructive Surgery 117(7S): pp6S-11S, 2006
- Naude L, The Practice and Science of Wound Healing: History and
Physiology of Wound Healing, Professional Nursing Today 14(3): pp17-21,
2010
- Leaper DJ and Harding KG (eds), Wounds Biology and Management, 1998
- Khan MN, Antiseptics, Iodine, Povidone Iodine and Traumatic Wound Cleansing, J Tissue Viability 16(4): pp6-10, 2006
- Towler J, Cleansing Traumatic Wounds with Swabs, Water or Saline, Journal of Wound Care 10(6): pp231-233, 2001
- Pudner R, Wound Cleansing, Journal of Community Nursing 11(7): pp30-36, 1997
- Dua HS et al, The Amniotic Membrane in Ophthalmology, Survey of Ophthalmology 49(1): pp51-77, 2004
- Shimmura S et al, Anti-Inflammatory Effects of Amniotic Membrane
Transplantation in Ocular Surface Disorders, Cornea 20(4): pp408-413,
2001
- Negrel AD and Thylefors B, The Global Impact of Eye Injuries, Ophthalmic Epidemiol 5(3): pp143-169, 1998
- Davies P and Rippon M, Comparison of Foam and Hydrocolloid
Dressings in the Management of Wounds: A Review of the Published
Literature, visit www.worldwidewounds. com/2010/july/daviesrippon/
daviesrippon.html
- Thomas S, Laboratory Findings on the Exudate-Handling Capabilities
of Cavity Foam and Foam-Film Dressings, J Wound Care 19(5): pp192,
194-199, 2010
- Thomas S et al, An In Vitro Comparison of the Physical
Characteristics of Various Hydrocolloids, Hydrogels, Foams and
Alginate/CMC Fibrous Dressings Commissioned by Coloplast, visit
www.dressings.org/ technicalpublications/pdf/coloplastdressings-
testing-2003-2004.pdf.
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