Dissertation
Evaluation of thermosensitive Poloxamer 407 hydrogels intended to deliver topical analgesic compounds to chronic wound sites
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2022
DOI: 10.25820/etd.006530
Abstract
Most wounds heal almost completely within a few weeks of wounding through a well-regulated process called the “wound cycle,” yet millions of Americans annually suffer from chronic wounds which fail to heal for weeks or months at a time. A topical approach to pain management could improve the comfort and safety of long-term clinical care for patients suffering from chronic wounds. Because of the limited skin barrier present at a chronic wound site, topically administered drug compounds are likely to have a low residence time at the application site. Therefore, formulations intended for this purpose should aim to locally prolong delivery of the analgesic compound. However, due to the hypersensitivity of the wound site, existing topical products that require prolonged direct contact from the caregiver to be administered are contraindicated; this includes some semisolid dosage forms that offer prolonged residence at the wound site, such as gels or creams. Poloxamer 407 is a polymer that, when heated in aqueous solution to approximately physiological temperatures, transitions from a liquid to a hydrogel. This would provide many advantages for painless and rapid delivery to a wound site, without requiring direct or prolonged caregiver contact with the wound. The goal of the present research was to characterize the gelation and drug delivery properties of poloxamer 407 in order to evaluate its potential for the delivery of depot doses of analgesic compounds to chronic wound sites. Aqueous solutions of 15%, 17%, and 20% w/w poloxamer 407 were evaluated rheologically for their gelation temperatures (Tsol-gel) via change in storage modulus as a function of temperature. The Tsol-gel of 17% and 20% w/w poloxamer solutions containing between 0.4% and 1.7% w/v diclofenac sodium, a model analgesic compound, were measured using the same method. Tsol-gel of aqueous poloxamer systems varied inversely with the concentration of poloxamer 407 in solution and increased with addition of diclofenac sodium at higher concentrations > 0.9% w/v.
To evaluate the ability of poloxamer 407 vehicles to establish a diclofenac depot at an application site, 0.9% diclofenac sodium was prepared in both 17% and 20% poloxamer 407 and administered in vitro to snakeskin dialysis membrane, excised porcine skin, and barrier impaired excised porcine skin. Diclofenac delivery from poloxamer formulations was compared to a solution of diclofenac sodium in water and a commercial diclofenac sodium gel product. Diclofenac release from both 17% and 20% poloxamer systems was faster than release from the commercial gel product. Additionally, diclofenac permeation through both intact and impaired porcine skin occurred at similar rates from 17% and 20% poloxamer 407 systems. Very little drug permeated both intact and impaired skin from either system, indicating successful formation of a diclofenac depot at the site of administration.
To further explore the effects of formulation additives on poloxamer 407 gelation and drug delivery, the above experiments were repeated using three additional diclofenac salts: potassium, diethylamine, and epolamine. Magnitude of gelation temperature increase with the addition of diclofenac salt forms varied in the order: sodium > potassium > diethylamine > epolamine. This indicates that the increase in gelation temperature is driven by a salt effect and changed solubility of the polypropylene oxide block of poloxamer 407. Regardless of salt form, poloxamer formulations were successfully used to administer depot sources of diclofenac in an in vitro setting. Additionally, despite differences in the gelation character of systems containing different diclofenac salt forms, there were minimal differences observed in the effects of the poloxamer gel system to prolong drug delivery through impaired skin.
Details
- Title: Subtitle
- Evaluation of thermosensitive Poloxamer 407 hydrogels intended to deliver topical analgesic compounds to chronic wound sites
- Creators
- Jackson Russo
- Contributors
- Nicole K Brogden (Advisor)Reza Nejadnik (Committee Member)Aliasger K Salem (Committee Member)Lewis Stevens (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Pharmacy
- Date degree season
- Spring 2022
- DOI
- 10.25820/etd.006530
- Publisher
- University of Iowa
- Number of pages
- xviii, 128 pages
- Copyright
- Copyright 2022 Jackson Russo
- Language
- English
- Description illustrations
- illustrations (some color)
- Description bibliographic
- Includes bibliographical references (pages 113-128).
- Public Abstract (ETD)
While typical wounds heal almost completely within a few weeks, millions of Americans annually suffer from chronic wounds that fail to heal for months at a time. Clinical care of chronic wounds is a difficult and painful process, particularly when caregivers make prolonged contact with the wound site to perform routine wound care procedures. Existing pain-relieving treatments can be used to relieve chronic wound pain, but each of these treatment strategies is associated with serious side effects. Delivering a pain-relieving drug to the site of the wound itself would be preferred. However, wound sites have characteristics that complicate delivery of locally acting products. The research in this work uses poloxamer 407 formulations that can be administered as a liquid but then change into a gel when heated and can remain within a wound site as a source of a pain-relieving drug until the next dressing change.
In this work, the gelling properties of poloxamer liquids were evaluated to select an ideal product for use within a wound site. Next, the drug delivery characteristics of selected poloxamer formulations were evaluated for diclofenac sodium, a pain-relieving compound. Finally, to better understand the effect of the drug compound on the gelling properties of the liquid, the gelation and drug delivery properties with other forms of diclofenac were evaluated.
Poloxamer gelation temperature decreased with increasing poloxamer concentration, meaning that a lower temperature was needed for a gel to form with higher poloxamer amounts. Poloxamer gelation temperature increased when diclofenac sodium was added, and prolonged diclofenac sodium delivery was achieved through skin with similar characteristics as a chronic wound site. Poloxamer gelation temperature increased to different levels when different forms of diclofenac were used. Drug delivery properties of poloxamer formulations were not affected by minor changes in the drug being delivered.
- Academic Unit
- Pharmacy; Craniofacial Anomalies Research Center
- Record Identifier
- 9984271453302771
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