Category: Formulation and Quality
Purpose: Naltrexone (NTX) is an opioid antagonist used to manage opioid and alcohol dependence. Oral NTX is significantly metabolized in the liver, may cause gastrointestinal upsets and notable hepatotoxicity. Its intramuscular injectable form is considerably expensive, needs a specialist to apply and may cause injection site pain, which may lead to low patient compliance. Transdermal delivery of therapeutics has advantages over traditional delivery routes, however, NTX hydrophilicity limits its effective passive transdermal delivery across the strong barrier structure of the stratum corneum (SC). Microneedle (MN)-assisted transdermal delivery is an attractive alternative that subtly pierces the skin, circumventing the stratum corneum and greatly improving drug delivery to deeper skin layers. Drug microencapsulation into polymers such as chitosan (CTN) is beneficial as it can load large amounts of drug, control drug release and protect drugs from degradation. Spray drying is an efficient microencapsulation technique that converts solution matrices into powders. This study aims to design, characterize and optimize spray-dried CTN-NTX microspheres for MN-assisted transdermal delivery of NTX.
Methods: A quality by design approach was used to assess the influence of formulation and process parameters on CTN-NTX microsphere yield, size, zeta potential, encapsulation efficiency (EE), drug-loading capacity and in vitro release. Size and zeta potential were evaluated using Malvern Zetasizer and EE was determined using a validated HPLC method. ANOVA was used to determine significance levels and general linear modeling to estimate parameters. NTX flux from in vitro skin permeation using intact and MN-treated porcine ear skin was determined from the steady-state portion of cumulative NTX per area vs time plots.
Results: CTN-NTX microsphere yield was 17 - 40 %, size was 1.9 - 9 µm, zeta potential values were > +30. EE varied from 70 - 88 % while drug-loading capacity was 10 to 42.6%. In vitro cumulative NTX release ranged from 62.9 to 94 %. High powder yield was achieved at low feed flow rate while higher feed concentration produced larger particle sizes. Increase in chitosan MW and concentration increased EE, increase in chitosan MW decreased cumulative in vitro NTX release over 24 h while CTN-NTX ratio significantly influenced drug-loading capacity. Chitosan MW did not significantly influence NTX transdermal flux in MN-treated skin. NTX transdermal flux from CTN-NTX microspheres (30 mg/mL) in MN-treated skin was 11.57 ± 2.24 µg/cm2.h while no NTX was detected in the receiver medium of intact skin.
Conclusion: Spray-dried CTN-NTX microspheres had varying yield, size, EE and drug-loading capacity, which can be optimized for MN-assisted transdermal delivery. MN application can significantly improve the transdermal delivery of NTX.