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European Biopharmaceutical Review

A Topical Subject


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
  1. Broughton G et al, A Brief History of Wound Care, Plastic and Reconstructive Surgery 117(7S): pp6S-11S, 2006
  2. Naude L, The Practice and Science of Wound Healing: History and Physiology of Wound Healing, Professional Nursing Today 14(3): pp17-21, 2010
  3. Leaper DJ and Harding KG (eds), Wounds Biology and Management, 1998
  4. Khan MN, Antiseptics, Iodine, Povidone Iodine and Traumatic Wound Cleansing, J Tissue Viability 16(4): pp6-10, 2006
  5. Towler J, Cleansing Traumatic Wounds with Swabs, Water or Saline, Journal of Wound Care 10(6): pp231-233, 2001
  6. Pudner R, Wound Cleansing, Journal of Community Nursing 11(7): pp30-36, 1997
  7. Dua HS et al, The Amniotic Membrane in Ophthalmology, Survey of Ophthalmology 49(1): pp51-77, 2004
  8. Shimmura S et al, Anti-Inflammatory Effects of Amniotic Membrane Transplantation in Ocular Surface Disorders, Cornea 20(4): pp408-413, 2001
  9. Negrel AD and Thylefors B, The Global Impact of Eye Injuries, Ophthalmic Epidemiol 5(3): pp143-169, 1998
  10. 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
  11. 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
  12. 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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Paul Titley is Managing Director for Formulation Development at Aesica. Paul founded R5 Pharmaceuticals in 2006, which was aquired by Aesica in June 2010 to operate as Aesica Formulation Development. Prior to establishing R5 Pharmaceuticals, Paul qualified as a chemist during his 25 years’ service with Wellcome where he left in 1996 as Head of Worldwide Technical Support. He also worked in business development and senior management for Quintiles and Encap Drug Delivery, before becoming an independent consultant in 2005, working with clients in India and the Czech Republic. Paul is a member of the Royal Society of Chemistry.
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