Thermosensitive poloxamer 407 hydrogels to improve microneedle assisted transdermal delivery of naltrexone
Creators: name: Tobin, Kevin V.
Publisher: name: University of Iowa
Year: 2024
Subjects: Microneedles
Poloxamer
Thermosensitive gels
Transdermal drug delivery
public abstract
Rheology

description: 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.
description: 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).
description: 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).
description: 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.
description: 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.