Description:
Introduction
There are many applications for gel-based topical therapies. There is
frequently a desire to apply poorly soluble agents or to apply agents that are
not ordinarily soluble at the neutral values of pH required for topical
administration. We have applied this to an active ingredient with demonstrated
activity in improving wound healing. Phenytoin sodium has well-established use
as an anticonvulsant, administered orally or intravenously. A relatively common side effect is
gingival hyperplasia, leading to its proposed use to accelerate wound-healing.
Numerous published animal and clinical studies support a positive role for
topically administered phenytoin in wound healing including diabetic ulcers,
venous ulcers, pressure sores, burns and traumatic wounds. Progress in
developing pharmacological treatments to aid in the topical management of wounds
has been disappointing and this area remains a huge unmet therapeutic need. The
wound care market is estimated to have a value exceeding $10bn annually.
While some have attempted to develop cytokine-containing products for
application to wounds, results have been disappointing and the active substances
are expensive and unstable. The mode of action of phenytoin is likely to be via increased
expression of cytokines at a local level.
Technology
Investigational studies with phenytoin have often employed the active
substance as a powder or as a solution. Often phenytoin was obtained by opening
capsules or ampoules. The development of usable formulations is complicated by
the poor solubility of phenytoin and the high pH of solutions (around 12), not
desirable for application to damaged tissue. Little published work refers to
phenytoin in a suitable formulation for convenient and reproducible topical
administration. Published prior art in support of the efficacy of phenytoin also
provides a potential obstacle to ownership of Intellectual property. The School
of Pharmacy at RCSI has developed a product in which phenytoin sodium is
incorporated in a matrix that maintains a stable reservoir of phenytoin sodium
at a pH in the range 7-8. This reservoir releases phenytoin to the wound in a
prolonged fashion. Data in experimental wound models supports the efficacy of
the product in wound healing in both diabetic and non-diabetic wounds.
Importantly, there is no significant systemic absorption of phenytoin.
The product is easy to manufacture and scale-up. A 100 kg test batch
of a 5% gel has been manufactured and filled with good stability at one
year.
Figure 2:
Stability of a manufactured batch.
Applications
Therapies
for wound healing address a huge unmet need. In particular the development of
pharmacological agents has been slow. There are many opportunities to use or
further develop this product for a variety of indications including diabetic
ulcers, venous ulcers, pressure sores, burns and traumatic wounds and to
incorporate the product into dressings, sprays or adhesive plasters. The
increasing prevalence of type 2
diabetes and associated ulcerative conditions makes this one area of significant
value. The technology is also
applicable to other active substances such as antiinfectives or analgesics.
Advantages
- Convenient pharmacological therapy for wounds
- Applicable to a variety of wounds
- Good published background
- Good intellectual Property position
- Convenient and inexpensive to manufacture
- Applicable to other active substances
References
- Shaw
J, Hughes CM, Lagan KM, Bell PM. The clinical effect of topical phenytoin on
wound healing: a systematic review.Br J Dermatol. 2007 Nov;
157(5):997-1004.
- Arinzon
Z, Zeilig G, Berner YN, Adunsky A. Antiepileptic drug use and the occurrence
of pressure ulcers among bedridden institutionalized elderly patients: a
retrospective chart review. Am J Geriatr Pharmacother. 2005 Sep;
3(3):180-5.
Contacts:
Dr. Gearóid Tuohy, RCSI Technology Transfer, 123 St Stephen’s Green, Dublin 2,
Ireland.
Email: gearoidtuohy@rcsi.ie Tel: +353 1
4022362
Phenytoin Formulations and uses thereof in Wound
Healing
PCT Date: 03/08/2004