A novel extended-release diphenidol pharmaceutical composition has been developed to address the limitations of current immediate-release formulations, offering improved patient compliance through reduced dosing frequency while maintaining therapeutic efficacy.
Addressing Current Treatment Limitations
Diphenidol (α,α-diphenyl-1-piperidinebutanol) serves as an established antiemetic and anti-vertigo agent, with its antiemetic effects mediated through action at chemoreceptor trigger zones in the area postrema and anti-vertigo effects attributed to vestibular apparatus modulation. Currently available immediate-release solutions and tablets require administration every 6 hours due to diphenidol's 4-hour half-life and peak plasma concentrations occurring between 1.5 and 3 hours after oral administration.
This frequent dosing regimen presents significant challenges for patient adherence, potentially leading to missed doses or inadvertent overdosing, ultimately compromising therapeutic outcomes.
Novel Formulation Composition
The newly developed extended-release composition comprises diphenidol hydrochloride (15-50%) combined with carefully selected excipients designed to control drug release over extended periods. The formulation includes binding agents (0.1-20%), diluent agents (5-90%), release-modifying agents (5-50%), lubricating agents (0.25-10%), and gliding agents (0.1-10%).
In the preferred embodiment, the composition contains 16-40% diphenidol hydrochloride, 0.5-5% povidone, 0.1-3% sodium alginate, 20-90% microcrystalline cellulose, 20-90% silicified microcrystalline cellulose, 5-50% hypromellose, 0.25-5% magnesium stearate, and 0.1-1% silicon dioxide.
Sustained Release Profile
Dissolution testing demonstrated that the extended-release tablets maintain 90% or greater active ingredient concentration between 7.5 to 10 hours, confirming sustained drug release throughout the intended dosing interval. The formulation achieves controlled release through a matrix system that modulates drug dissolution and diffusion rates.
Following initial administration, the extended-release formulation produces average diphenidol plasma concentrations of 40-46 ng/mL after 1 hour, 53-66 ng/mL after 2 hours, 64-83 ng/mL after 3 hours, 72-94 ng/mL after 4 hours, 87-114 ng/mL after 6 hours, 75-93 ng/mL after 8 hours, and 61-74 ng/mL after 12 hours.
Clinical Bioavailability Study Results
A comprehensive bioavailability study compared the new extended-release formulation (Product B) with commercially available immediate-release tablets (Product A) in 16 healthy male volunteers with an average age of 27.8 years and weight of 70 kg. The study employed a monocentric, prospective, longitudinal, single-blind, repeated-dose, crossover design with a 13-day washout period.
Group A received 25mg immediate-release diphenidol tablets every 6 hours for three days, while Group B received 100mg extended-release tablets every 12 hours for the same duration. Blood samples were collected at predetermined intervals over 72 hours to assess pharmacokinetic parameters.
After initial administration, Product A achieved a maximum concentration (Cmax) of 79.54 ± 9.37 ng/mL at 1.46 ± 0.12 hours, while Product B reached 108.83 ± 13.87 ng/mL at 5.96 ± 0.58 hours. The area under the curve (AUC0-t) was 279.61 ± 42.48 and 868.64 ± 114.63 h*ng/mL for Products A and B, respectively.
At steady state, achieved after three days of repeated dosing, Product A demonstrated a Cmax of 126.84 ± 19.69 ng/mL at 1.46 ± 0.11 hours, compared to Product B's 202.95 ± 29.46 ng/mL at 4.46 ± 0.45 hours. The steady-state AUC0-t values were 555.42 ± 90.90 and 1933.93 ± 316.26 h*ng/mL for Products A and B, respectively.
Notably, the fluctuation percentage was significantly lower for the extended-release formulation (48.45 ± 4.79%) compared to the immediate-release product (76.68 ± 7.46%), indicating more stable plasma concentrations throughout the dosing interval.
Safety and Tolerability Profile
Both formulations demonstrated acceptable safety profiles with no clinically significant changes in vital signs including blood pressure, heart rate, respiratory rate, and body temperature. Two adverse events occurred in one volunteer receiving the extended-release formulation, but these were deemed unrelated to the study medication and consistent with typical bioequivalence study observations.
The calculated clearance half-life was 4.5 hours for the immediate-release product and 18 hours for the extended-release formulation, confirming the sustained-release characteristics of the new formulation.
Clinical Implications
The extended-release diphenidol formulation successfully reduces dosing frequency from six times daily (every 4 hours) to twice daily (every 12 hours), representing a significant improvement in dosing convenience. This reduction in administration frequency is expected to enhance patient compliance while maintaining therapeutic plasma concentrations within the established therapeutic range of 120-300 mg per 24 hours.
The formulation's ability to maintain consistent drug levels with reduced fluctuation compared to immediate-release products may also contribute to improved therapeutic outcomes and reduced side effects associated with peak-trough variations in plasma concentrations.
Manufacturing and Quality Considerations
The extended-release tablets are manufactured using conventional pharmaceutical techniques including mixing and sieving, wet granulation, drying, dry granulation, final mixing, lubrication, and tabletting. Quality control testing ensures tablets meet specifications for content uniformity, dissolution profile, and friability (not greater than 1%).
The formulation's robust manufacturing process and well-characterized release profile support its potential for commercial development and regulatory approval as an improved therapeutic option for patients requiring diphenidol therapy.
