Dissertation
Thermosensitive poloxamer 407 hydrogels to improve microneedle assisted transdermal delivery of naltrexone
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Summer 2023
DOI: 10.25820/etd.007129
Abstract
Alcohol and opioid dependency affect millions of Americas every year. Even though treatments are available for lifelong management of alcohol and opioid dependency, a lowpercentage of Americans suffering from these disorders receive medication-assisted treatment. Naltrexone, a µ-opioid receptor antagonist, is one of these treatment options. Naltrexone can be delivered as an oral tablet, which suffers from extensive first-pass metabolism and requires daily medication, or as a depot injection that provides extended delivery for a month but requires clinical visits, can be painful, and is costly. These limitations create compliance issues for treating alcohol and opioid dependency. Since lifelong treatment is required, these naltrexone delivery systems could use improvements that would make treatment more affordable and easier for patients to use. Transdermal delivery of naltrexone would allow for patient self administration and would provide more consistent plasma drug concentrations, which could help patients adhere to a treatment plan by reducing cravings. Due to the physicochemical properties of naltrexone, it does not pass freely through skin at fast enough rates to achieve therapeutic concentrations. Microneedles, small projections that painlessly create micropores in the skin, allow naltrexone to be delivered transdermally, but the natural healing process of the skin closes these micropores within ~48 hours. Closure of the micropores then blunts further drug delivery. Poloxamer 407 is a thermosensitive polymer that transitions from a liquid to a gel at temperatures close to human physiological temperature of 37 °C. Formulations with poloxamer 407 could extend the delivery time of a naltrexone transdermal patch by generating a gel depot in the micropores before they close at the skin surface. This drug depot in the skin could extend drug delivery time beyond micropore closure, thus increasing the time between necessary patch changes. This could both improve the ease of therapy for patients and contribute to increased compliance. The objective of the present research project was to characterize the gelation properties of poloxamer 407 formulations with naltrexone and evaluate the naltrexone delivery profile when applied to microneedle-treated skin in vitro.
Naltrexone solubility in poloxamer 407 formulations and gelation properties resulting from changes in poloxamer 407 or naltrexone concentration were measured. Gelation temperature was measured to ensure that the selected formulations could produce gels between room and skin temperature, as it is important that gelation occurs after application to skin in vivo to achieve controlled drug release. Three methods for measuring gelation temperature (stir bar, temperature sweep, and Winter-Chambon methods) were applied to 17-20% poloxamer formulations in water. The methods produced similar measurements and showed that gelation temperature increases with the addition of 7.0% naltrexone and decreases with increased poloxamer concentration, but all formulations gelled before reaching skin temperature (32 °C).
The release of naltrexone from 17-20% poloxamer 407 formulations was measured to further understand how naltrexone interacts with and releases from poloxamer formulations. Non-Fickian first-order release was observed, and naltrexone release was progressively slower as poloxamer concentration increased. Naltrexone permeation through excised porcine skin was evaluated in vitro. The effect of microneedle geometry was assessed comparing 600 or 750 µm length microneedles and applying them once or twice to produce 50 or 100 micropores, respectively, within the same area. Microneedle length affected NTX-HCl permeation while doubling the number of micropores did not result in any change in permeation from 20% P407 gels. Naltrexone-loaded poloxamer formulations provided sustained permeation compared to aqueous solutions after formulation was removed from the skin at 48 hours (formulation removal was done to mimic micropore closure that would occur in vivo).
Next, the impact of chemical permeation enhancers on poloxamer formulation propertieswas analyzed with the goal of improving patch size for patient convenience. Due to the small area of available drug transport that the micropores provide, chemical permeation enhancers could interact with the skin around the micropores and provide a secondary delivery path to increase overall delivery rate. This would reduce the required patch size to meet clinical goals. The pKa and LogD of naltrexone were measured to understand how naltrexone interacts with poloxamer and micropores in the skin. Naltrexone solubility in poloxamer 407 formulations with various excipients was evaluated to select formulation drug concentrations for further study. Decreasing poloxamer concentration, buffering at lower pH, and addition of select permeation enhancers increased naltrexone solubility. The gelation temperature of buffered 15-17% poloxamer formulations with and without select permeation enhancers were measured to ensure that the chosen formulations could produce gels below skin temperature. The gelation temperature of these formulations decreased when the permeation enhancers dimethyl sulfoxide and benzyl alcohol were added, but the 16% poloxamer formulations (containing 7.5% naltrexone) all gelled below skin temperature. Naltrexone permeation through microneedle-treated porcine skin from poloxamer formulations with chemical permeation enhancers was evaluated in vitro. Permeation through intact skin was slow and highly variable despite the presence of poloxamer or chemical permeation enhancers. Poloxamer provided sustained and less variable naltrexone permeation through intact skin compared to aqueous solution. In accordance with previous data, formulation viscosity negatively correlated with flux for poloxamer formulations and formulations previously used for in-human microneedle studies with naltrexone. Naltrexone permeation through microneedle-treated skin from poloxamer formulations with dimethyl sulfoxide and benzyl alcohol was similar to previously reported (non-poloxamer) formulations that delivered naltrexone to therapeutic concentrations in humans. However, the presently developed formulation would require half of the necessary patch area and half the concentration of naltrexone compared to previous studies.
Last, migration of poloxamer formulations into micropores generated using solid microneedles was visualized. This study was performed to confirm that poloxamer can enter themicropores despite the almost instantaneous gelation when applied to skin and the high formulation viscosity (especially once gelled). Poloxamer was fluorescently labeled with 5-DTAF at ambient conditions, the products were isolated using dialysis, and then the products were reconstituted to the correct concentration after lyophilization. Reaction efficiency was measured using spectrophotometric assays, demonstrating that 22% of the poloxamer tails were labeled. The product isolation efficiency was qualitatively assessed using HPLC, confirming that dialysis removed all unreacted 5-DTAF. The reconstituted labeled poloxamer was applied to microneedle-treated skin before tissue sectioning using a cryotome. The skin sections were imaged on a confocal microscope, and it was visually confirmed that labeled poloxamer enters micropores within 30 min.
Details
- Title: Subtitle
- Thermosensitive poloxamer 407 hydrogels to improve microneedle assisted transdermal delivery of naltrexone
- Creators
- Kevin V. Tobin
- Contributors
- Nicole K Brogden (Advisor)Jennifer Fiegel (Committee Member)Reza Nejadnik (Committee Member)Lewis Stevens (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Pharmacy (Pharmaceutics)
- Date degree season
- Summer 2023
- DOI
- 10.25820/etd.007129
- Publisher
- University of Iowa
- Number of pages
- xxiv, 174 pages
- Copyright
- Copyright 2023 Kevin V Tobin
- Language
- English
- Date submitted
- 06/28/2023
- Description illustrations
- illustrations, tables, graphs
- Description bibliographic
- Includes bibliographical references (pages 157-174).
- Public Abstract (ETD)
- Untreated alcohol and opioid misuse disorders lead to hundreds of thousands of deaths every year in the United States. Naltrexone is a common treatment for managing these disorders, but oral and injectable delivery methods both have challenges. Delivering naltrexone through the skin could make treatment more affordable and easier for patients to use. However, because the skin acts as a barrier to keep foreign materials out of the body, naltrexone cannot absorb through the skin well. To overcome this challenge, we used microneedles to successfully deliver naltrexone through the skin. Microneedles are small projections that painlessly create small pores in the skin that allow drugs like naltrexone to freely pass into the body. After microneedles are applied to the skin, a naltrexone gel can be applied to the skin and covered by a patch, and naltrexone can enter the body quickly enough to achieve therapeutic effect. One challenge of using microneedles is that the skin naturally heals by closing these pores within 48-72 hours. After the pores close, any naltrexone remaining in the gel stops entering the body. If the timeframe of naltrexone delivery through the skin can be extended, this would make treatment more convenient for patients because they would not need to replace a gel as frequently. Naltrexone has been successfully delivered to humans using microneedles, but four patch sites were required for therapeutic benefit; this is unreasonable for patient convenience. Poloxamers are gels with unique behaviors; they are liquid at room temperature and turn into a gel at or near body temperature. These properties are appealing because a poloxamer liquid with naltrexone can enter the pores created using microneedles and then form a gel inside the pores when warmed to skin temperature. This creates a drug depot in the skin that can continue to deliver naltrexone after the pores close over the top. This work aimed to develop poloxamer gels that can simultaneously sustain naltrexone delivery through microneedle-treated skin while also reducing the required number of patches to be more patient-acceptable. Reducing the required number of patches can be achieved using permeation enhancer agents which interact with the skin to promote permeation. In this document we describe the behavior of naltrexone in poloxamer formulations, which were assessed to develop an ideal formulation that would successfully sustain naltrexone permeation through microneedle-treated skin. First, changes in poloxamer gelation properties, naltrexone solubility, and naltrexone release from these formulations were assessed. The ability of the formulations to sustain naltrexone delivery through microneedle-treated skin was evaluated. Next, the impact of permeation enhancer agents on naltrexone solubility, gelation properties, and viscosity of poloxamer formulations was determined. Delivery of naltrexone from poloxamer formulations with permeation enhancers through microneedle-treated skin was evaluated. Last, the migration of poloxamer formulation into pores was visually confirmed by labeling the poloxamer with a fluorescent molecule. Naltrexone solubility increased with a decrease in poloxamer concentration and when certain permeation enhancer agents were included. The gelation temperature decreased as poloxamer concentration increased and when permeation enhancer agents were included. Increasing poloxamer concentration produced slower naltrexone release from the gels. The delivery of naltrexone through skin was affected by the length of microneedles and poloxamer did sustain the delivery. Adding permeation enhancer agents resulted in approximately the same amount of naltrexone delivered through pores made by microneedles as previously has been used in humans, while requiring half of the naltrexone loaded into the formulations. Poloxamer entered micropores in skin that were generated using microneedles within 30 minutes.
- Academic Unit
- Pharmacy
- Record Identifier
- 9984454541402771
Metrics
15 File views/ downloads
63 Record Views