2 research outputs found
Amorphous Formulation and <i>in Vitro</i> Performance Testing of Instantly Disintegrating Buccal Tablets for the Emergency Delivery of Naloxone
The
aim of this study was to develop a freeze-dried buccal tablet for
the rapid delivery of naloxone in opioid overdose. The tablet composition
was optimized to produce an amorphous matrix, which was confirmed
by the absence of peaks associated with crystallinity observed by
differential scanning calorimetry and powder X-ray diffraction. Tablets
with high gelatin content lacked adequate porosity. Mannitol was added
to the formulation to bridge and intercalate gelatin’s tight
polymer aggregates, however sodium bicarbonate was also required to
prevent crystallization within the tablets. A linear reduction in
mannitol’s recrystallization enthalpy was observed with increasing
sodium bicarbonate concentration (Δ<sub>recry</sub><i>H</i> = −20.3Â[NaHCO<sub>3</sub>] + 220.9; <i>r</i><sup>2</sup> = 0.9, <i>n</i> = 18). The minimum sodium bicarbonate
concentration for full inhibition of mannitol crystallization was
10.9% w/w. Freeze-dried tablets with lower amounts of sodium bicarbonate
possessed a crystalline fraction that PXRD identified as mannitol
hemihydrate from the unique peak at 9.7° 2θ. Mannitol’s
greater affinity for both ions and residual water rather than its
affinity for self-association was the mechanism for the inhibition
of crystallization observed here. The optimized tablet (composition
mannitol 24% w/w (4.26 mg), gelatin 65% w/w (11.7 mg), sodium bicarbonate
11% w/w (1.98 mg), and naloxone 800 μg) formed predominantly
amorphous tablets that disintegrated in less than 10 s. Optimized
tablets were chemically and physically stable over 9 months storage
at 25 °C. As speed of drug liberation is the critical performance
attribute for a solid dosage form designed to deliver drug in an emergency,
a novel imaging based <i>in vitro</i> disintegration assay
for buccal tablets was developed. The assay was optimized with regard
to conditions in the buccal cavity: i.e., temperature 33–37
°C, volume of medium (0.1–0.7 mL), and use of mucin-containing
biorelevant medium. The disintegration assay was sensitive to temperature,
medium volume, and medium composition; naloxone tablet disintegration
was extremely rapid, with full disintegration ranging from 5 to 20
s. In conclusion, rapidly disintegrating tablets have been developed
which are suitable for proof-of-concept clinical trial in humans to
determine the pharmacokinetics of naloxone delivered via the buccal
route