Haloperidol nasal solution: formulation and physicochemical stability study
5 October 2022A. Ressault, A. Dory, L. Perello, L. Gheddar, P. Kintz, G. Ubeaud Séquier, B. Gourieux
CHU de Strasbourg, France
Agitation can be treated with neuroleptics such as haloperidol. Haloperidol is administered orally or by intramuscular injection according to the French regulation agency1. For elderly patients, parenteral administration may be contraindicated or refused, especially by patients with dementia: therefore nasal administration would be a good alternative. The objective of this study is the formulation, and evaluation of the physicochemical stability of a haloperidol nasal solution.
Materials and methods
The nasal solution was formulated with haloperidol lactate (HALDOL, JANSSEN CILAG SA) 4.9 mg/mL, sodium acetate buffer (SIGMA®), mannitol (COOPER®) and LM pectin, low methylated pectin (GUINAMA®). The pH was controlled by a pH-meter with potentiometry. Osmolality was monitored by an osmometer using freezing point depression (Advanced® 2020) with automated calibration. Dose homogeneity was verified using samples taken from the surface and bottom of the solution and, after shaking, from its center. The physicochemical stability study included: the organoleptic characteristics, the pH and the haloperidol concentration measured by HPLC-UV at 254 nm (Shimadzu®). The assays were carried out on D0, D7, D14, D21, D28, D42 and D56 at room temperature.
To obtain 10 mL of a haloperidol nasal solution with a pH between 4.3 and 4.9, an osmolality between 270 and 330 mOsm/L and gel formation with Ca2+, 180 µL of a buffer of sodium acetate (pH 5.75 and molarity 400 mmol/L), 100 mg of mannitol and 100 mg of LM pectin were added to 10 mL of haloperidol. The coefficient of variation between the different samples is less than 10%. After 56 days, the pH is stable between 4.3 and 4.9 throughout the stability study. The variation in pH is less than 10% (maximum variation of 2.7% between D42 and D56), as is the variation in the concentration of haloperidol (maximum variation of 1.54% between D0 and D56).
The nasal solution meets the requirements of the European Pharmacopoeia2 regarding pH, osmolality and dose homogeneity. The physicochemical stability of the proposed haloperidol nasal solution 4.9 mg/mL is at least two months at room temperature. An additional physicochemical stability study is in progress for the nasal solution. In order to validate the formulation, a microbiological study must still be carried out, as well as an in vitro study of diffusion, for instance with Franz Cells. Once in vitro tests are complete, the next stage would be in vivo tests in rats to evaluate the diffusion of haloperidol in the central nervous system and its local toxicity on the nasal membrane.
1. HALDOL 5 mg/ml sol inj [Internet]. VIDAL. [cité 29 juin 2022]. Disponible sur: https://www.vidal.fr/medicaments/haldol-5-mg-ml-sol-inj-7923.html
2. Guide technique pour l’élaboration des monographies, édition 8, 2022 – EDQM – Pharmacopées Européennes.