Design, Development, Evaluation, and In Vivo Performance of Buccal Films Embedded with Paliperidone-Loaded Nanostructured Lipid Carriers
Abstract
The therapeutic effectiveness of paliperidone in the treatment of schizophrenia has been limited by its poor oral bioavailability; hence, an alternative route could be appropriate. This study investigates the feasibility of developing a buccal film impregnated with paliperidone-loaded nanostructured lipid carriers (NLCs) and assesses the potential to enhance its bioavailability. Box–Behnken-based design optimization of NLCs was performed by examining the particles’ physical characteristics. The polymeric film was used to load optimized NLCs, which were then assessed for their pharmaceutical properties, permeability, and pharmacokinetics. The optimization outcomes indicated that selected formulation variables had a considerable (p < 0.05) impact on responses such as particle size, entrapment efficiency, and % drug release. Desired characteristics such as a negative charge, higher entrapment efficiency, and nanoparticles with ideal size distribution were shown by optimized NLC dispersions. The developed film demonstrated excellent physico-mechanical properties, appropriate texture, good drug excipient compatibility (chemically stable formulation), and amorphous drug nature. A sustained Weibull model drug release (p < 0.0005) and superior flux (~5-fold higher, p < 0.005) were seen in NLC-loaded film compared to plain-drug-loaded film. The pharmacokinetics profile in rabbits supports the goal of buccal therapy as evidenced by significantly higher AUC0–12 (p < 0.0001) and greater relative bioavailability (236%) than the control. These results support the conclusion that paliperidone-loaded NLC buccal film has the potential to be an alternate therapy for its effective administration in the treatment of schizophrenia.
Introduction
Schizophrenia is a severe and debilitating mental illness that often manifests a range of symptoms and generally affects the quality of life of the working-age population. The exact cause of schizophrenia is still unknown, but it is believed to be a combination of genetic, environmental, and neurobiological factors. Cognitive, positive, and negative symptoms among individuals with schizophrenia can have an impact on many elements of their daily life [1]. This disabling health condition is typically treated with medication and psychotherapy. Several drugs are available for early and maintenance therapy with the aim of controlling symptoms, despite the fact that there is no known cure for schizophrenia [2]. Antipsychotic medications can help to alleviate the positive symptoms of schizophrenia, such as hallucinations and delusions. Atypical new-generation antipsychotics are the preferred medications for the initial management of schizophrenia, due to their higher tolerability profile and greater range of clinical action [2,3]. In addition, these second-generation antipsychotics are capable of producing lesser extrapyramidal symptoms at therapeutic levels and have a better patient-reported life quality [4].
Paliperidone, a long-acting second-generation antipsychotic, has been shown to reduce acute schizophrenia symptoms and provide clinical benefits in both acute and maintenance therapy in adults [5]. Typically, paliperidone (9-OH-risperidone) is a pharmacologically active metabolite of risperidone with a distinct pharmacokinetics profile from the parent compound. The proposed therapeutic activity in the treatment of schizophrenia is due to its high affinity and antagonistic activity towards dopamine (D2) and serotonin (5-HT2A) type 2 receptors [6]. The drug is commercially available as extended-release oral tablets and an intramuscular suspension with similar safety profiles and is well tolerated [5]. However, the oral bioavailability of paliperidone is very low (~28%), owing to its extremely poor aqueous solubility [7,8]. Hence, employing formulation techniques to enhance solubility and/or finding an alternative route of administration to improve bioavailability is necessary for its effective therapeutic use [9]. Numerous approaches have been explored through extensive research to enhance the effectiveness of paliperidone. Formulation techniques such as cocrystallization [10], lipid nanoconstructs [8], and ion-exchange resin complexes [11] were attempted. Similarly, transdermal and nose-to-brain routes were also assessed [4,9,12,13].
The buccal mucosal membrane is an attractive site for delivering drugs owing to its unique characteristics such as high blood flow, high permeability, low enzymatic activity, and less sensitivity. The buccal route has various advantages over other routes of administration which include avoiding acid hydrolysis, bypassing the first-pass metabolism, enhancing bioavailability, providing rapid onset of action, being noninvasive, being effective for local or systemic action, and being easy to administer or remove in the case of adverse effects [14]. Mucoadhesive drug delivery systems are capable of adhering to the highly vascularized mucus membrane, providing faster drug absorption through the jugular vein, and transporting the drug to the heart directly [15]. Considering the significance of buccal therapy, the US FDA has approved several therapeutic actives (buprenorphine, fentanyl, naloxone, lidocaine, etc.) that have been commercially successful [16]. Among buccal formulations, biocompatible mucoadhesive films are a popular dosage form owing to their versatility, adaptability, ease of scaleup, light weight, physical flexibility, customized size, and high patient compliance [17]. In addition, the buccal films are capable of providing rapid onset and extended duration of action, which are ideal for the management of schizophrenia episodes. The characteristics of paliperidone, including its molecular weight (426.48 Da), lipophilicity (log p =1.8), melting point (179.8 °C) and dose (3–12 mg/day), support its prospects for buccal therapy. However, this drug belongs to BCS class II (practically insoluble in water) and hence requires solubility enhancement to improve bioavailability.
Nano-drug carriers have the potential to address numerous biopharmaceutical obstacles that are associated with the delivery of drugs through the buccal route. The potential of nanoparticles incorporated in buccal film for drug delivery has recently attracted attention [15,18,19]. In this regard, nanostructured lipid carriers (NLCs) have been extensively studied as versatile and efficient vesicles that can enhance the solubility, dissolution rate, bioavailability, and therapeutic efficacy of inadequately soluble drugs across various drug delivery systems [20]. Several studies have reported the ability of NLCs to increase the solubility and diffusion coefficient of drugs across the mucosal epithelial layers and the stability of drugs against degradation in the buccal environment [21,22,23,24]. Compared to solid lipid nanoparticles, the utilization of both solid and liquid lipids in NLCs enables higher drug loading, minimal drug loss during storage, and sustained drug release [25,26].
Meanwhile, the fabrication of a buccal film with desirable properties requires polymers with film-forming and mucoadhesive properties. In general, the films prepared using two different polymers exhibit improved mucoadhesive and physical properties due to the combination of their constituent polymers. From this perspective, hydroxypropyl methylcellulose (HPMC) possesses good film-forming properties, high water-absorbing capacity, rapid swelling, and mucoadhesive properties, making it a popular choice for formulating buccal films [17]. Similarly, polycarbophil (PC), a high-molecular-weight acrylic acid polymer, has good bioadhesive properties and can increase buccal retention by entangling within the mucus layer [27]. Given that both HPMC and PC possess favorable biological and mucoadhesive properties, these combinations were explored in bioadhesive drug delivery systems [27,28]. Therefore, this study aimed to develop and optimize paliperidone-loaded NLCs embedded in a buccal mucoadhesive film and preliminarily evaluate their potential as an alternative therapy for schizophrenia. Solid (glycerol monostearate) and liquid (oleic acid) lipids were selected according to the preliminary solubility study results, and the NLCs were formulated using the heat homogenization process. The Box–Behnken experimental design was utilized to develop paliperidone-loaded NLCs by evaluating the influence of formulation components (lipid content, surfactant concentration, and ultrasonication time) on particle properties. The optimized NLCs with suitable characteristics were successfully impregnated in a film containing HPMC and PC and evaluated for film characteristics, drug release, permeation, and absorption in rabbits.
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Materials
A complimentary sample of paliperidone (MW, 426.49 Da) was acquired from Emcure Pharmaceuticals, Gandhinagar, India. Tween 80 and glyceryl monostearate were purchased from CDH Pvt. Ltd., Mumbai, India. Labrafil® M 2125 CS, Labrafil® M 1944 CS, and Labrafac® CC of USPNF/EP quality were purchased commercially (Gattefosse, Saint-Priest, France). Hydroxypropyl methylcellulose (HPMC) K4M and polycarbophil (PC) were obtained from Chemidyes, Ahmedabad, India. Oleic acid was procured from Sigma Aldrich, Munich, Germany. Methanol and acetonitrile used in high-performance liquid chromatography (HPLC) analysis were obtained from Fisher Scientific (Loughborough, UK).
AlMulhim, F.M.; Nair, A.B.; Aldhubiab, B.; Shah, H.; Shah, J.; Mewada, V.; Sreeharsha, N.; Jacob, S. Design, Development, Evaluation, and In Vivo Performance of Buccal Films Embedded with Paliperidone-Loaded Nanostructured Lipid Carriers. Pharmaceutics 2023, 15, 2530. https://doi.org/10.3390/pharmaceutics15112530
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