2 research outputs found
Fabrication and Characterization of Clozapine Nanoemulsion Sol–Gel for Intranasal Administration
Clozapine is the most effective antipsychotic
for treatment-resistant
schizophrenia. However, it causes many adverse drug reactions (ADRs),
which lead to poor treatment outcomes. Nose-to-brain (N2B) drug delivery
offers a promising approach to reduce peripheral ADRs by minimizing
systemic drug exposure. The aim of the present study was to develop
and characterize clozapine-loaded nanoemulsion sol–gel (CLZ-NESG)
for intranasal administration using high energy sonication method.
A range of oils, surfactants, and cosurfactants were screened with
the highest clozapine solubility selected for the development of nanoemulsion.
Pseudoternary phase diagrams were constructed using a low-energy (spontaneous)
method to identify the microemulsion regions (i.e., where mixtures
were transparent). The final formulation, CLZ-NESG (pH 5.5 ±
0.2), comprising 1% w/w clozapine,
1% w/w oleic acid, 10% w/w polysorbate 80/propylene glycol (3:1), and 20% w/w poloxamer 407 (P407) solution, had
an average globule size of ≤30 nm with PDI 0.2 and zeta potential
of −39.7 ± 1.5 mV. The in vitro cumulative
drug release of clozapine from the nanoemulsion gel at 34 °C
(temperature of nasal cavity) after 72 h was 38.9 ± 4.6% compared
to 84.2 ± 3.9% with the control solution. The permeation study
using sheep nasal mucosa as diffusion barriers confirmed a sustained
release of clozapine with 56.2 ± 2.3% cumulative drug permeated
after 8 h. Additionally, the histopathological examination found no
severe nasal ciliotoxicity on the mucosal tissues. The thermodynamic
stability studies showed that the gel strength and viscosity of CLZ-NESG
decreased after temperature cycling but was still seen to be in “gel”
form at nasal temperature. However, the accelerated storage stability
study showed a decrease in drug concentration after 3 months, which
can be expected at elevated stress conditions. The formulation developed
in this study showed desirable physicochemical properties for intranasal
administration, highlighting the potential value of a nanoemulsion
gel for improving drug bioavailability of clozapine for N2B delivery
Cyclic Penta- and Hexaleucine Peptides without <i>N</i>‑Methylation Are Orally Absorbed
Development of peptide-based drugs
has been severely limited by
lack of oral bioavailability with less than a handful of peptides
being truly orally bioavailable, mainly cyclic peptides with <i>N</i>-methyl amino acids and few hydrogen bond donors. Here
we report that cyclic penta- and hexa-leucine peptides, with no <i>N</i>-methylation and five or six amide NH protons, exhibit
some degree of oral bioavailability (4–17%) approaching that
of the heavily <i>N</i>-methylated drug cyclosporine (22%)
under the same conditions. These simple cyclic peptides demonstrate
that oral bioavailability is achievable for peptides that fall outside
of rule-of-five guidelines without the need for <i>N</i>-methylation or modified amino acids