Formulation, particle size and rheological characterization of a pediatric suspension of prazosin for the treatment of post-traumatic night terrors

M. Cristofoli, P. Espi, C. Moreau, C. Paillet, C. Marchand, M. Pichon-Pramyl, C. Merienne, F. Pirot
Groupement Hospitalier Edouard Herriot - Hospices Civils de Lyon, France

Post-traumatic stress disorder (PTSD) is a psychiatric affection characterized by stimulation of α1-adrenergic receptors that cause sleep disturbances and night terrors. Recent studies report an improvement of PTSD in pediatrics by initial oral administration of 1 mg prazosin (i.e., α1-adrenergic antagonist) at bedtime (1).

The discontinuation of immediate-release oral form of prazosin led to a feasibility study of a pediatric magistral preparation of prazosin (PM2P, 1 mg/mL) for oral and enteral administration.

Materials and Methods
The formulation for PM2P, adapted from a USP-NF monograph (2), involves an oral speciality of prazosin hydrochloride (pKa = 7.24, aqueous solubility at 25°C 1 mg/mL) with osmotic controlled release (5 mg) milled and suspended simultaneously (using a dispersion system, homogenization, agitation and grinding) in a mixture of complex excipients (purified water, sucrose, glycerin, sorbitol, microcrystalline cellulose, carboxymethyl cellulose, xanthic gum, calcium sulfate, citric acid and sodium phosphate, pH = 4.2). A granulometric and stability analysis of the obtained suspension was performed by optical microscopy and light scattering measurements (3). A rheological study and flow tests of PM2P were conducted in an enteral tube for pediatric use (NG CH08 and CH06).

Results and Discussion
Optical analysis of PM2P showed the presence of particles of size < 100 µm in accordance with the specifics of the dispersion system used. The light scattering measurement of the suspension showed, over the whole height of the sedimentation column, identical transmission and backscattering profiles, confirming the absence of deflocculation of the suspension after 24 h (theoretical sedimentation rate: 5 mm/24h). The rheological analysis of PM2P showed a rheofluidic behavior (4) limiting the sedimentation rate at rest and facilitating oral intake after shaking of the package and flow into the NG. The choice of a pharmaceutical speciality reduced (i) the controls inherent to the reception of a raw material for pharmaceutical use and (ii) the cost of the raw material by half.

In the absence of a commercial specialty available for the pediatric treatment of night terrors, a magistral formulation was developed taking into account the physicochemical properties of the AP and the biopharmaceutical aspects of the route of administration.

1 Prazosin in Children and Adolescents With Posttraumatic Stress Disorder Who Have Nightmares” Adefolake Akinsanya, MD, Raman Marwaha, MD, and Rajesh R. Tampi, MD, MS, DFAPA
2 USP 42 – NF37, Prazosin hydrochloride compounded oral suspension.
3 Turbiscan MA 2000: multiple light scattering measurement for concentrated emulsion and suspension instability analysis, Talanta, 50(2): 445-456.
4 Development of a safe and versatile suspension vehicle for pediatric use: Formulation development. International Journal of Pharmaceutics 569 (2019) 118552.

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