Track: Formulation and Delivery - Chemical - Drug Delivery - Other Routes of Administration - Transdermal and Topical
Category: Poster Abstract
In Vitro Evaluation of Poloxamer 407 as a Potential Vehicle for Delivery of Diclofenac to Chronic Wound Sites
Purpose: While most wounds heal in a timely manner through a process called the “wound cycle,” nearly 6.5 million Americans annually suffer from chronic wounds that become suspended within the wound cycle without healing for a prolonged period. Chronic wounds often have prolonged inflammation which results in hypersensitivity of the wound site for the patient, particularly when the site is handled. As a result, clinical care of chronic wounds is a painful process, particularly during dressing changes. Chronic wound pain can be treated systemically using opioids or non-steroidal anti-inflammatory drugs (NSAIDs), but both treatment strategies are associated with well-characterized side effects. A topical treatment providing an extended effect to minimize the need for dressing changes and reapplication would be preferable. However, topical gels and creams that would be capable of providing a prolonged dose of an analgesic compound are difficult to administer to a chronic wound site and often require the use of an applicator, which is painful for the patient.
Thermosensitive polymers (known as poloxamers) which exist as liquids at low temperatures and form gels at higher temperatures could potentially be used as a vehicle to deliver analgesia to a chronic wound site. Thermosensitive polymers could be administered as liquids with minimal wound site contact to form a gel within the warm wound for a prolonged residence time and extend the delivery of an analgesic compound directly into the wound site. The purpose of this research is to evaluate poloxamer 407 as a potential vehicle to deliver diclofenac, an analgesic compound, topically to a chronic wound. Methods: Aqueous gels of 17% or 20% w/w poloxamer 407 containing 1% w/v diclofenac sodium, a model topical analgesic compound, were prepared via dissolution of solid polymer in water under constant stirring at 4°C followed by dissolution of appropriate drug mass under cold stirring. Gelation temperatures of the poloxamer solutions with and without diclofenac sodium were determined using an ARES-G2 rotational rheometer via measurement of change in the sample’s storage modulus over time during heating from 14 to 38°C. To determine the effect of poloxamer gelation on drug delivery, diffusion studies were conducted in which doses of diclofenac sodium were administered to membranes held at approximate skin temperature for 24 hours, and the amount of drug that passed through the membrane was measured. The first study compared rate of diclofenac sodium delivery from poloxamer through snakeskin dialysis membrane to rate of drug delivery from water through snakeskin dialysis membrane. Next, to determine the effect of poloxamer gelation on drug delivery through skin, diffusion studies were conducted comparing rate of diclofenac sodium delivery from poloxamer through excised porcine ear skin to rate of drug delivery from water through excised porcine ear skin. Finally, to measure the rate of drug delivery through a membrane that is more representative of a chronic wound site than intact skin, diffusion studies were conducted using a membrane of porcine ear skin impaired via tape-stripping. Transepidermal water loss (TEWL) measurements were used to quantify the barrier disruption of the skin caused by tape stripping. Results: 17% poloxamer containing 1% diclofenac sodium gelled at 29.0±1.3°C, while 20% poloxamer containing 1% diclofenac sodium gelled at 23.0±0.0°C. Over a 24-hour diffusion study, 66.7±3.9% of the initial diclofenac sodium dose administered in water permeated the snakeskin dialysis membrane, as compared to 41.0±7.2% or 40.8±4.3% when administered in 17% or 20% w/w poloxamer, respectively. Over 24 hours, 0.15±0.06% of the initial dose administered to intact porcine ear skin in 17% poloxamer and 0.19±0.06% of the initial dose in 20% poloxamer reached the receiver solution, as opposed to 2.87±1.88% of the dose administered in water. The effect of tape-stripping in impairing the stratum corneum was indicated by a TEWL increase (in g/m2h) by a factor of 6.5±0.8 on average. When applied to impaired porcine ear skin over 24 hours, 4.1±0.7% of the initial dose administered in 17% poloxamer and 3.6±1.0% of the dose administered in 20% poloxamer was collected in the receiver solution compared to 53.3±5.9% of the dose administered in water. Conclusion: Based on the results of these experiments, use of poloxamer as a thermosensitive polymer to prolong delivery of an analgesic compound presents a promising formulation approach for the treatment of chronic wound pain. The results of our experiments indicate that a solution of poloxamer containing a 1% w/v concentration of a model analgesic compound can be administered as a liquid at room temperature, gel within the warmth of a wound site, and prolong the delivery of the analgesic compound through impaired skin compared to a solution of the same compound in water without poloxamer. Future studies will focus on evaluating the performance of the poloxamer formulation for analgesic delivery in an in vivo model wound site.