Paliperidone (PLP) is an antipsychotic drug indicated for treatment and management of schizophrenia. The current study demonstrates potential of PLP-loaded β-cyclodextrin-based nanosponges (CDNS) for solubility enhancement and prolonged release of PLP. The inclusion complexes of PLP with carbonyldiimidazole (CDI) cross-linked nanosponges were synthesized. The drug-loaded CDNS were characterized for particle size, zeta potential, encapsulation efficiency, stability study, in vitro drug release studies. The interaction of PLP with CDNS was ascertained by FTIR, DSC and PXRD studies. The particle size and zeta potential values were sufficient to obtain stable formulations. Solubility was significantly increased and in vitro drug release studies revealed prolonged release of PLP from the CDNS for 6 h. PXRD study revealed that the crystallinity of PLP was decreased due to complexation with the CDNS. Thus, cyclodextrin-based nanosponges represent a novel approach for solubility enhancement and improved dissolution of selected model drug PLP.
Inclusion complexation with cyclodextrins (CDs) is a promising method for improvement of solubility and bioavailability of poorly soluble drugs since many years. CDs are cyclic oligosaccharides containing D-glucopyranoside monomeric units linked via α-(1, 4)-glycosidic bonds [1, 2]. Among naturally occuring CDs, β-CD is extensively used for poorly soluble drugs. However, β-CD has low solubility in water and less complexation efficiency . Nanosponges (NS) are hyper cross-linked colloidal structures comprised of sub-microscopic units having cavities of nanometer size. Thery are synthesized by cross-linking many cyclodextrins using a suitable cross-linker. The inner cavity of NS resemmbles the pores of a regular sponge having ablity to entrap molecules or drugs, therefore known as cyclodextrin nanosponges (CDNS). They have high potential to entrap variety of molecules [4,5,6,7]. Inclusion complexation with CDNS is an alternative method for overcoming the problems of the solubility and bioavailability of poorly soluble drugs. CDNS have been reported for controlled delivery of many drugs such as anti-cancer drugs, proteins, and anti-inflammatory agents. Wetting and solubility of molecules in water can be greatly improved with CDNS [8,9,10,11].
Schizophrenia is a mental disorder with symptoms such as diminished cognition, depression, reduced thought process, psychotic episodes, poor quality of life, etc. Antipsychotics are the drugs of choice in treatment of schizophrenia. Second generation atypical antipsychotics show a high affinity towards serotonin 5-HT2A receptors in addition to blocking D2 receptors. The relatively high affinity of atypical antipsychotics for 5-HT2A than D2 results in reduced occurrence of adverse effects. Paliperidone (PLP), commonly referred to as 9-hydroxyrisperidone, is second-generation atypical antipsychotic indicated for treatment of schizophrenia in adults. PLP is practically insoluble in water and has poor oral bioavailability of about 28% [12,13,14,15,16,17].
Inclusion complexes of PLP with β-CD and HP-β-CD have been reported using various methods, including kneading, co-evaporation and co-precipitation [18, 19]. The objective of the present work was to develop inclusion complexes of PLP with CDNS for enhancement of solubility and dissolution.
Materials and methods
Paliperidone was obtained as a gift sample from Cadila Pharmaceuticals Ltd, India and β-CD was a kind gift from Gangwal Chemicals Pvt. Ltd., Mumbai, India. Carbonyldiimidazole (CDI) and dimethylformamide (DMF) were procured from Spectrochem, India. All other reagents and chemicals used in the experiments were of analytical grade.
Synthesis of CDNS
The CDNS were synthesized by polymer condensation method using CDI as a cross-linker in 1:4 (NS1) and 1:8 (NS2) molar ratio of β-CD: CDI . For 1:4 ratio of CDNS, briefly 10.0 g of β-CD and 5.71 g of CDI were dissolved in 20 ml DMF and then subjected to heating at 100 °C ± 5 °C in oil bath for 4 h. The product obtained after the reaction was pulverized in a mortar and extracted with ethanol using a Soxhlet apparatus for 24 h. A schematic representation of synthesis of CDNS is shown in Fig. 1.
Preparation of PLP-loaded nanosponges
The nanosponges containing PLP were prepared using sonication method. PLP was weighed accurately and added to CDNS dispersion in water maintaining 1:1 (w/w) ratio of PLP: CDNS. This mixture was sonicated for 30 min at room temperature  followed by centrifugation at 10,000 rpm for 10 min to separate the uncomplexed drug. The supernatant was separated and lyophilized. The lyophilized PLP-loaded NS namely, F1 (1:4 β-CD: CDI) and F2 (1:8 β-CD: CDI) were stored in a desiccator till further studies.
Particle size and zeta potential
The particle size and zeta potential of PLP-loaded nanosponges (F1 and F2) were assessed with a Malvern zetasizer (ZS-90, UK) using the water dispersion method.
Saturation solubility method was employed to estimate the increase in solubility of formulations F1 and F2 in distilled water. Briefly, excess amount of F1 and F2 was added to 10 ml of distilled water in conical flasks. The flasks were stoppered and agitated for 24 h using thermostatic rotary shaker (Orbitek Scigenics Biotech, India) maintained at 25 °C and 100 rpm. After 24 h, the dispersions were allowed to equilibrate, supernatant was separated and filtered using membrane filter. The absorbance of the filtered supernatant was measured at 237 nm on a UV spectrophotometer (Shimadzu, UV 1800). The solubility of PLP was estimated by substituting the absorbance values in standard curve of PLP.
Estimation of PLP loading in nanosponges
Weighed amount of formulations F1 and F2 was dissolved in 10 ml of methanol and sonicated for 30 min at ambient temperature. The drug contents were determined spectrophotometrically at 237 nm.
Pure PLP and PLP-loaded nanosponges formulation F1 samples were scanned on differential scanning calorimeter (Mettler Toledo DSC 822) using Stare SW 10.00 software. The scanning was performed at a heating rate of 10 °C min−1 under nitrogen purge with flow rate of 0.2 kg/m2 using aluminum pans.
The FTIR spectra of PLP and PLP-loaded nanosponge formulation F1 were obtained using FTIR spectrophotometer (Perkin Elmer, USA) using the KBr pellet method in the range of 400–4000 cm−1.
The crystalline characteristic of PLP and PLP-loaded formulation F1 was determined on X-ray diffractometer (PANalytical) at 4°/min scan speed. The samples were analyzed at 2θ angle range of 5° to 60°. The characteristics diffraction patterns of PLP was compared with F1 to determine the change in crystallinity of pure PLP.
In vitro drug release study
The in vitro drug release study was carried out on USP dissolution test apparatus (USP type I) using 500 ml of pH 6.8 phosphate buffer as dissolution medium maintained at 37 ± 0.5 °C at 100 rpm. Pure PLP 8.0 mg and F1 equivalent to 8.0 mg of PLP was used for the study. Aliquots (5 ml) of test samples were withdrawn at fixed time intervals and replenished with same volume of phosphate buffer to keep up sink conditions. The % drug release was estimated spectrophotometrically at 237 nm.
The stability testing of formulation F1 was carried out at 40 °C ± 2/75% RH ± 5 for 3 months. The F1 sample was kept in vials sealed with aluminum stopper and kept in the stability chamber at above condition. The sample was evaluated for physical appearance and solubility.
Particle size and zeta potential
The particle size of pure PLP, F1 and F2 was 3500 nm, 307 nm, and 122 nm, respectively. The zeta potential of F1 and F2 was found to be −14.2 mV and −8.74 mV, respectively.
The solubility of PLP, F1 and F2 formulations was found in the order as PLP < F1 < F2. The solubility of formulations F1 and F2 was 2.95 mg/ml and 3.15 mg/ml, respectively which was 98 and 105 folds higher than the pure PLP.
In vitro drug release study
The in vitro release profile of PLP from formulation F1 and F2 is given in Fig. 2. Formulation F1 and F2 showed controlled drug release over 6 h. About 73.3% and 78.35% drug release was obtained from F1 and F2 formylations, respectively. However, only 55.93% drug release was observed from pure PLP after 3 h. The solubility asd dissolution of F2 was slightly higher than F1, but drastic change in solubility and dissolution was not seen with respect to molar ratios of CDI in F1 and F2. Therefore, formulation F1 was selected for further characterization studies i.e. DSC, FTIR, PXRD and stability studies.
The entrapment efficiency of the formulations F 1 and F 2 were found to be 88.74% and 89.44%, respectively. Results of entrapment efficiency are given in Table 1.
The DSC thermograms of PLP and F1 are shown Fig. 3. The DSC thermogram of PLP showed sharp endotherm at 181.83 °C consistent to its melting point and that of formulation F1 was observed at 178.71 °C.
The FTIR spectrum of PLP showed characteristic peaks at 3294.57 (–OH stretch), 2935.42 ( = C-H stretch), 1733.77 (C = C stretch), 1537.55 (C = N stretch), 1270.72 (C-H bending) and 1131.26 cm−1 (C–F stretch). The IR spectrum of formulation F1 showed significant shift in IR bands of PLP at 3294.57, 2935.42, 1733.77, 1537.55, and 1270.72 and 1131.26 cm−1. The FTIR spectra of PLP and formulation F1 are shown in Fig. 4.
The XRD diffractoagrams of PLP exhibited many peaks of high intensity at diffraction angles 2 Theta (2θ) of 10.21, 14.47, 18.72, 19.17, 21.89, 24.55, 24.97, 27.89, and 31.18 indicating its crystalline nature. The diffractogram of PLP and formulation F1 is shown in Fig. 5.
Formulation F1 was stored in conditions of 40 °C ± 2/75% RH ± 5 for 3 months. There were no significant changes in the physical appearance and solubility of PLP in the accelerated stability testing study. The data of stability testing of F1 is shown as supplementary data (Table 2).
The particle size of the PLP-loaded nanosponges, F1 and F2 was found to be fairly decreased possibly due to the entrapment of PLP in the nanosponge structures (Table 1). The zeta potentials of PLP and the formulations were determined to measure the surface charges. Formulations F1 exhibited relatively higher negative charges on the particles compared to formulation F2, which indicated that the particles tend to aggregate poorly and more stable system . The higher solubility of PLP in F1 and F2 can be attributed to structural characteristics of nanosponges which could have assisted in increasing wetting property of PLP. In addition, the increase in solubility of PLP might be due to higher interaction of aromatic ring with the inner cavity of β-CD and availability of numerous pores of nanosponges for inclusion of drug. When the ratios of cross-linker CDI with respect to β-CD is considered in formulations F1 and F2, the extent of solubility enhancement in F2 is not very large. The controlled release of PLP from formulation F1 and F2 obtained in drug release study can be owed to large degree of cross-linking which allowed inclusion of PLP in nanosponges cavities. The improvements in dissolution can be attributed to improved solubility, reduced crystallinity and entrapment of PLP in nanosponges. The entrapment efficiency for both formulations was sufficiently good. Results of the solubility and in vitro dissolution of F1 and F2 revealed no vast difference in solubility and drug release of F1 and F2. Hence formulation F1 was selected for characterization studies i.e. FTIR, PXRD, DSC, and stability studies.
The DSC thermogram of formulation F1 observed at 178.71 °C and considerable shift and reduction in the intensity of PLP endotherm observed at 181.84 °C might be due to interaction of PLP with CDNS. FTIR study was performed to study the interaction of PLP and nanosponges. The IR spectrum obtained for formulation F1 showed shifting of IR peaks, peaks of reduced intensity and merging/loss of some distinctive peaks of PLP. The significant shift in IR bands of PLP at 3294.57, 2935.42, 1733.77, 1537.55 and 1270.72 and 1131.26 cm−1 suggests interaction of PLP with nanosponges. A comparison of PXRD diffractograms of pure PLP with formulation F1 showed notable changes. The characteristic peaks of PLP at diffraction angles 2 Theta (2θ) of 10.21, 14.47, 18.72, 19.17, 21.89, 24.55, 24.97, 27.89, and 31.18 were completely weakened in formulation F1 indicating formation of a new amorphous solid system. Formulation F1 resulted significant loss of the crystallinity of the PLP. Formulation F1 was stored in conditions of 40 °C ± 2/75% RH ± 5 for 3 months. There were no significant changes in the physical appearance and solubility of PLP in the accelerated stability testing study. The unaffected properties in the accelerated stability testing study confirmed the stability of the complex of PLP and CDI cross-linked β-cyclodextrin nanosponges.
PLP-loaded CDI cross-linked β-CD-based nanosponges were developed for enhancement of solubility and dissolution profile of poorly soluble drug PLP. Significant increase in solubility with controlled in vitro drug release till 6 h was observed for the developed PLP-loaded nanosponges. The remarkably enhanced solubility can be attributed to increased wetting property and decreased crystallinity of the PLP. Thus, β-CD-based nanosponges is a novel and promising carrier for the solubility and dissolution enhancement of PLP.
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We are thankful to Cadila Pharmaceuticals Ltd, India and Gangwal Chemicals Pvt. Ltd., Mumbai, India for gift sample of Paliperidone and β-CD, respectively.
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Sherje, A.P., Surve, A. & Shende, P. CDI cross-linked β-cyclodextrin nanosponges of paliperidone: synthesis and physicochemical characterization. J Mater Sci: Mater Med 30, 74 (2019). https://doi.org/10.1007/s10856-019-6268-0