Preparation and Evaluation of Paliperidone Thermal Muco-Adhesive in Situ Gel as a Nasal to Brain Delivery System
Abstract
Background: Paliperidone PAL is a second-generation (atypical) antipsychotic medication widely used in the treatment of schizophrenia disorders. It is practically insoluble in water (class II) and has a first-pass metabolism, with oral bioavailability of about 28%.
Objective: To optimize and evaluate PAL in a nanothermal residence gel as an intranasal in situ gel formula near or at the site of the nasal-brain delivery system.
Methods: The previously prepared nanosuspension formula of PAL was introduced into the creation of in-situ gel formulas using Poloxamer 407 (18–20%w/v), hydroxypropyl methylcellulose HPMC K4 (0.5–1%w/v), and hyaluronic acid (0.5–1%w/v). The selected prepared formula was subjected to different in vitro evaluation studies.
Results: The previously prepared nanosuspension formula of PAL, which enhanced its dissolution rate using Soluplus® as a stabilizer, was incorporated into mucoadhesive thermal sensitive gel formulas, using poloxamer 407 as a thermal gelling agent and different concentrations of mucoadhesive polymers. The formula NIG, which contains 20% w/w poloxamer 407 and 1%w/w HPMC K4, exhibited favorable and accepted characteristics, including the ideal gelation temperature of 33°C and drug content of 99.96%, gel strength of 55.0 seconds, spreadability of 5.2cm, and 98.0% in vitro cumulative drug release extended for 6 hours in simulated nasal fluid (SNF) at pH 6.5 maintained at 34°C.
Conclusions: The current mucoadhesive in situ gel PAL formula is a promising nasal-to-brain formula that can be used for the management of psychotic disorders drug therapy in the future.
Introduction
Intranasal administration is a recognized method for delivering active pharmaceutical ingredients, achieving either local or systemic effects. Its significance is increasing due to the unique anatomical connection it has with the brain [1]. The olfactory and trigeminal nerves, situated in the olfactory and respiratory regions, respectively, facilitate the absorption of drugs from the nose to the brain, targeting the central nervous system (CNS) [2].
Consequently, direct access to the brain enables drugs to skip the first-pass effect and circumvent the blood-brain barrier; this will lead to enhanced bioavailability, greater accumulation in the central nervous system, and a more rapid onset of action. These properties are crucial for managing acute seizure episodes [3]. Nanosuspensions (NS) present an important opportunity for nose-to-brain drug delivery by enhancing the absorption and bioavailability of various poorly soluble drugs through intranasal administration. Nanosuspensions
are defined as dispersions of drug nanoparticles in appropriate polymers and/or surfactants, with particle sizes typically less than 1 μm, predominantly ranging from 200 to 500 nm [4]. Due to their small particle size and extensive surface area, nanostructures have advantages in augmenting the solubility and dissolution rate of poorly soluble pharmaceuticals [5]. Nevertheless, liquid suspensions experience brief retention durations in the nasal cavity owing to swift mucociliary clearance. This issue can be addressed through the application of intelligent stimuli-responsive systems[6]. The in situ gelling formulation is one of the most often employed procedures among these systems. Following intranasal administration, induced by physiological parameters (temperature, ion concentration, and water content), the solution converts into a gel, facilitating a more precise dosage delivery [7]. These in situ gels have a number of benefits, including a simple manufacturing procedure and great permeability of therapeutic agents, and they have been found to increase the nasal retention period, which in turn improves the drug delivery efficiency [8].
Paliperidone (PAL) is an antipsychotic drug used in schizophrenia. It belongs to the class of benzisoxazole derivatives and is the primary active metabolite of risperidone. Paliperidone acts primarily through antagonizing dopamine D2 and serotonin 5-HT2A receptors in the brain, leading to its therapeutic effects in managing psychotic symptoms [9]. PAL (Figure 1) has an MWt of 426 g/mole, is practically insoluble in water (30 mg/L), is class II, and has a log p of 2.39.
The pharmacokinetic properties of paliperidone include its relatively long half-life of t½ 23 hours, with oral bioavailability of 28% [10]. Nanosuspensions incorporated within an in situ gel represent a compelling approach for the nose-to-brain administration of poorly soluble pharmaceuticals, leveraging the benefits of both nanosuspensions and in situ gels. The formulation of PAL as a nasal nanosuspension utilizing nanotechnology addresses the primary barrier to drug delivery, mucociliary clearance. This is achieved by incorporating a temperature-sensitive polymer, such as poloxamer 407, to enhance the poor oral bioavailability of PAL in tablet form and to facilitate in-situ gelling properties [11]. This study aims to optimize and evaluate PAL in a nanothermal residence gel as an intranasal in situ gel formula near or at the site of the nasal-brain delivery system.
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Materials
PAL powder was purchased from Heowns Biochem Technologies, LLC, in Tianjin, China. Hangzhou Hyper Chemicals Limited of Zhejiang, China, provided Soluplus®, HPMC KM4, and hyaluronic acid. Poloxamer 407 was obtained as a generous gift from BASF. Benzalkonium chloride was obtained as a generous gift from Al-Hayat, Iraq. HIMEDIA (Mumbai, India) provided the dialysis membrane 70. All remaining chemicals and solvents were of analytical reagent grade quality.
Ismail, M. Y., & Al-Gawahri, F. J. (2025). Preparation and Evaluation of Paliperidone Thermal Muco-Adhesive in Situ Gel as a Nasal to Brain Delivery System. Al-Rafidain Journal of Medical Sciences ( ISSN 2789-3219 ), 8(2), 82–87. https://doi.org/10.54133/ajms.v8i2.1830
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