Ondansetron/Cyclodextrin inclusion complex nanofibrous webs for potential orally fast-disintegrating antiemetic drug delivery.

Ondansetron (ODS) is an effective antiemetic drug which suffers from limited solubility and bioavailability during oral administration due to first-pass metabolism. However, these limitations can be mitigated through inclusion complexation with cyclodextrins (CDs). In this study, we have reported the electrospinning of polymer-free, free-standing ODS/CD nanofibrous webs (NW), a promising approach for developing a fast-disintegrating delivery system of an antiemetic drug molecule. Highly water soluble hydroxypropyl-beta-cyclodextrins (HPßCD) were used as both complexation agent and electrospinning matrix. The computational study revealed that the 1/2 (drug/CD) stoichiometry was more favorable compared to 1/1. The ODS/HPßCD NW was obtained with higher loading efficiency (∼96 %) compared to the control sample of ODS/polyvinyl alcohol (PVA) NW (∼80 %). The amorphous distribution of ODS raised by complexation and the highly water-soluble nature of HPßCD resulted into faster and better release profile and quite faster disintegration property (∼2 s) in artificial saliva than polymeric ODS/PVA NW. Here, ODS/HPßCD NW was generated in the absence of a toxic solvent or chemical to enable the drug loading in an amorphous state. From all reasons above, ODS/HPßCD NW might be a promising alternative to the polymeric based systems for the purpose of fast-disintegrating oral drug delivery.

GPCR large-amplitude dynamics by 19F-NMR of aprepitant bound to the neurokinin 1 receptor.

Comparisons of G protein-coupled receptor (GPCR) complexes with agonists and antagonists based on X-ray crystallography and cryo-electron microscopy structure determinations show differences in the width of the orthosteric ligand binding groove over the range from 0.3 to 2.9 Å. Here, we show that there are transient structure fluctuations with amplitudes up to at least 6 Å. The experiments were performed with the neurokinin 1 receptor (NK1R), a GPCR of class A that is involved in inflammation, pain, and cancer. We used 19F-NMR observation of aprepitant, which is an approved drug that targets NK1R for the treatment of chemotherapy-induced nausea and vomiting. Aprepitant includes a bis-trifluoromethyl-phenyl ring attached with a single bond to the core of the molecule; 19F-NMR revealed 180° flipping motions of this ring about this bond. In the picture emerging from the 19F-NMR data, the GPCR transmembrane helices undergo large-scale floating motions in the lipid bilayer. The functional implication is of extensive promiscuity of initial ligand binding, primarily determined by size and shape of the ligand, with subsequent selection by unique interactions between atom groups of the ligand and the GPCR within the binding groove. This second step ensures the wide range of different efficacies documented for GPCR-targeting drugs. The NK1R data also provide a rationale for the observation that diffracting GPCR crystals are obtained for complexes with only very few of the ligands from libraries of approved drugs and lead compounds that bind to the receptors.

Simultaneous quantification of sumatriptan succinate and prochlorperazine maleate in orodispersible films using two validated UV-spectroscopic methods.

The study aimed at simultaneous quantification of sumatriptan succinate (SUM) and prochlorperazine maleate (PCP) in an orodispersible film using two validated spectroscopic methods viz. simultaneous equation (Method I) and the Q-absorption ratio (Method II). The Method I involved measurement of absorbances at λmax of both drugs while in Method II, absorbances were measured at isosbestic wavelength and λmax of one of the two components. Method validation were accomplished as per the ICH guidelines. A 1:1 mixture of the drugs and an orodispersible film (ODF) containing these drugs were assayed by both methods. The absorbance data of SUM and PCP in both methods were linear at respective wavelengths with correlation coefficient values >0.995. Both methods were precise as % RSD in repeatability, interday and intraday precision was less than 2. The estimation of SUM and PCP from the film dosage form by method I was104.74% and 98.34% and by method II was 103.45% and 98.85%, respectively, with a standard deviation <2. The study concluded that both the methods were simple, reliable and robust and can be applied successfully for the simultaneous quantification of SUM and PCP in mixture and orodispersible film dosage form.

In Vitro Inhibition of Renal OCT2 and MATE1 Secretion by Antiemetic Drugs.

The organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) mediate the renal secretion of drugs. Recent studies suggest that ondansetron, a 5-HT3 antagonist drug used to prevent nausea and vomiting, can inhibit OCT2- and MATE1-mediated transport. The purpose of this study was to test the ability of five 5-HT3 antagonist drugs to inhibit the OCT2 and MATE1 transporters. The transport of the OCT2/MATE1 probe substrate ASP+ was assessed using two models: (1) HEK293 kidney cells overexpressing human OCT2 or MATE1, and (2) MDCK cells transfected with human OCT2 and MATE1. In HEK293 cells, the inhibition of ASP+ uptake by OCT2 listed in order of potency was palonosetron (IC50: 2.6 µM) > ondansetron > granisetron > tropisetron > dolasetron (IC50: 85.4 µM) and the inhibition of ASP+ uptake by MATE1 in order of potency was ondansetron (IC50: 0.1 µM) > palonosetron = tropisetron > granisetron > dolasetron (IC50: 27.4 µM). Ondansetron (0.5-20 µM) inhibited the basolateral-to-apical transcellular transport of ASP+ up to 64%. Higher concentrations (10 and 20 µM) of palonosetron, tropisetron, and dolasetron similarly reduced the transcellular transport of ASP+. In double-transfected OCT2-MATE1 MDCK cells, ondansetron at concentrations of 0.5 and 2.5 µM caused significant intracellular accumulation of ASP+. Taken together, these data suggest that 5-HT3 antagonist drugs may inhibit the renal secretion of cationic drugs by interfering with OCT2 and/or MATE1 function.

Stability of Aprepitant Injectable Emulsion in Alternate Infusion Bags, in Refrigerated Storage, and Admixed with Dexamethasone and Palonosetron.

PURPOSE: The stability of aprepitant injectable emulsion is evaluated in various admixture bags and solutions, under different storage conditions, and when combined with other antiemetics. METHODS: A volume of 18 mL aprepitant injectable emulsion was added to infusion bags (either non-di-(2-ethylhexyl) phthalate [DEHP], polyvinyl chloride [PVC]-containing bags or non-DEHP, non-PVC bags) containing 100, 130, or 250 mL of 0.9% normal saline solution (NSS) or 5% dextrose in water (D5W). Bags were stored at controlled room temperature (20-25°C) for up to 12 hours or refrigerated (2-8°C) for up to 72 hours. Compatibility/stability was also assessed in admixtures combined with either dexamethasone or palonosetron. At specified time points, bags were tested for appearance, pH, assay for aprepitant (ie, percent label claim of aprepitant) and aprepitant-related substances, Z-average particle size, globule size distribution, particulate matter, and DEHP content (PVC bags). In separate analyses to assess microbial burden, bags containing aprepitant were inoculated with seven different organisms and assessed for microbial growth. RESULTS: There was no detectable impact on the physicochemical properties or potential to promote microbial growth of aprepitant when diluted with various amounts of either NSS or D5W and when admixed with either dexamethasone or palonosetron at room temperature for at least 6 hours or during refrigeration for up to 72 hours in either PVC- or non-PVC-containing bags. CONCLUSION: Aprepitant-containing admixtures are stable under these conditions, a finding that may improve patient and provider convenience and reduce medication wastage.

[6]-Gingerol Ameliorates Cisplatin-Induced Pica by Regulating the TPH/MAO-A/SERT/5-HT/5-HT3 Receptor System in Rats.

PURPOSE: [6]-gingerol is a bioactive compound extracted from ginger, a traditional anti-emetic herb in Chinese medicine. Previous studies have demonstrated that [6]-gingerol can ameliorate chemotherapy-induced pica in rats, although the underlying mechanism has not been elucidated. This study is designed to investigate [6]-gingerol's antiemetic mechanism focusing on the 5-hydroxytryptamine (serotonin, 5-HT) system by evaluating the synthesis, metabolism and reuptake of 5-HT, as well as the mechanism of 5-hydroxytryptamine type 3 receptor (5-HT3 receptor), in a cisplatin-induced pica model of rats. METHODS: Rats were randomly divided into control group (vehicle + saline, Con), [6]-gingerol control group (50 mg/kg [6]-gingerol + saline, G-con), ondansetron control group (2.6 mg/kg ondansetron + saline, O-con), cisplatin model group (vehicle + cisplatin, Model), ondansetron-treated group (2.6 mg/kg ondansetron + cisplatin, O-treated), high dosage of [6]-gingerol-treated group (100 mg/kg [6]-gingerol + cisplatin, GH-treated), and low dosage of [6]-gingerol-treated group (50 mg/kg [6]-gingerol + cisplatin, GL-treated). The rats were administered with [6]-gingerol, ondansetron, and vehicle (3% Tween-80) by gavage twice (7:00 AM and 7:00 PM). One hour after the first treatment (8:00 AM), rats in groups Model, O-treated, GH-treated and GL-treated were injected intraperitoneally (i.p.) with 6 mg/kg cisplatin, and the other groups were injected i.p. with saline of equal volume. The consumption of kaolin of the rats were measured. All the rats were anesthetized by i.p. injection of pentobarbital sodium at 24 h post-cisplatin. After blood samples were taken, medulla oblongata and ileum were removed. The levels of 5-HT and its metabolite 5-HIAA in ileum, medulla oblongata and serum were determined using high-performance liquid chromatography with electrochemical detection (HPLC-ECD). The mRNA expression levels of 5-HT3 receptor, tryptophan hydroxylase (TPH), monoamine oxidase A (MAO-A) and serotonin reuptake transporter (SERT) were detected by real-time PCR. The protein expression levels and distribution of 5-HT3 receptor, TPH and MAO-A in the medulla oblongata and ileum were measured by Western blotting and immunohistochemistry, respectively. RESULTS: [6]-gingerol treatment significantly reduced the kaolin ingestion and the increase in 5-HT concentration in rats induced by cisplatin. TPH, MAO-A, SERT, and 5-HT3 receptor are important in 5-HT metabolism, and cisplatin-induced alterations in the associated protein/mRNA levels were restored when treated with [6]-gingerol. CONCLUSION: This suggests that the antiemetic effect of [6]-gingerol against cisplatin-induced emesis may be due to 5-HT attenuation via modulating the TPH/MAO-A/SERT/5-HT/5-HT3 receptor system.

The Binding of Palonosetron and Other Antiemetic Drugs to the Serotonin 5-HT3 Receptor.

Inaccurately perceived as niche drugs, antiemetics are key elements of cancer treatment alleviating the most dreaded side effect of chemotherapy. Serotonin 5-HT3 receptor antagonists are the most commonly prescribed class of drugs to control chemotherapy-induced nausea and vomiting. These antagonists have been clinically successful drugs since the 1980s, yet our understanding of how they operate at the molecular level has been hampered by the difficulty of obtaining structures of drug-receptor complexes. Here, we report the cryoelectron microscopy structure of the palonosetron-bound 5-HT3 receptor. We investigate the binding of palonosetron, granisetron, dolasetron, ondansetron, and cilansetron using molecular dynamics, covering the whole set of antagonists used in clinical practice. The structural and computational results yield detailed atomic insight into the binding modes of the drugs. In light of our data, we establish a comprehensive framework underlying the inhibition mechanism by the -setron drug family.

Development of Nasal Mucoadhesive Microspheres of Granisetron: A Potential Drug.

BACKGROUND: Granisetron is a serotonin 5-HT3 receptor antagonist used as an antiemetic to treat nausea and vomiting following chemotherapy and radiotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center in the medulla oblongata. OBJECTIVES: In this research mucoadhesive microspheres were developed in order to carry out the absorption of drug through nasal mucosa with the aim to improve therapeutic efficacy, avoid hepatic first pass metabolism and increase residence time. MATERIAL AND METHODS: Mucoadhesive microspheres of Granisetron using chitosan as polymer were prepared by emulsification cross-linking method to increase the residence time on the mucosa. The surface of prepared microspheres was characterized by SEM (Scanning electron microscopy) and evaluated for particle size, encapsulation efficiency, production yield, swelling ability, in-vitro mucoadhesion, in-vitro drug release and stability study. RESULT: Among all the formulations F6 with drug/polymer ratio of 1:3 displayed the best result. On drug release kinetic model study, all the formulations follow Zero order. Stability studies revealed that the microspheres kept at 25±2°C and 60±5% RH showed the maximum stability. CONCLUSION: After all the evaluation parameters and result obtained it can be said that these results confirmed the suitability of Granisetron mucoadhesive chitosan microspheres for nasal delivery system.

Compatible stability of methylprednisolone sodium succinate and tropisetron in 0.9% sodium chloride injection.

Background: A combination of methylprednisolone sodium succinate and tropisetron hydrochloride is commonly used to treat the nausea and vomiting associated with antineoplastic therapy. The objective of this study was to investigate the stability of tropisetron hydrochloride and methylprednisolone sodium succinate in 0.9% sodium chloride injection for up to 48 hours. Methods: Commercial solutions of methylprednisolone sodium succinate and tropisetron hydrochloride were obtained and further diluted with 0.9% sodium chloride injection to final concentrations of either 0.4 or 0.8 mg/mL (methylprednisolone sodium succinate) and 0.05 mg/mL (tropisetron). The admixtures were assessed for periods of up to 48 hours after storage at 4°C with protection from light and at 25°C without protection from light. Physical compatibility was determined visually, and the chemical compatibility was measured with high-performance liquid chromatography (HPLC) and by measurement of pH values. Results: HPLC analysis demonstrated that methylprednisolone sodium succinate and tropisetron hydrochloride in the various solutions were maintained at 97% of the initial concentrations or higher during the testing period. There were no changes observed by physical precipitation or pH in any of the prepared solutions. Conclusions: Tropisetron hydrochloride injection and methylprednisolone sodium succinate injection in 0.9% sodium chloride injection are stable for up to 48 hours at 4°C and 25°C.

Long-term stability of an infusion containing paracetamol, alizapride, ketorolac and tramadol in glass bottles at 5±3°C.

Background and objective: Infusion containing paracetamol, alizapride, ketorolac and tramadol is used after a general anaesthesia in order to limit pain, fever and nausea. Currently, these infusions are prepared according to demand in the anaesthesia unit, but the preparation in advance could improve quality of preparation and time management. The aim of this study was to investigate the long-term stability of this infusion in glass bottles at 5°C ± 3 °C. Method: Five bottles of infusion were stored at 5°C ± 3 °C for 60 days. A visual and microscope inspection were performed periodically to observe any particle appearance or colour change. pH and absorbance at three wavelengths were measured. The concentrations were measured by ultra-high performance liquid chromatography - diode array detection. Results: Multiple verifications were performed during the first 35 days and no crystal, impurity or colour change were observed. At the next time point (42nd day), crystals were visible to the naked eye. pH and absorbance at 350 nm and 550 nm were stable. A slight increase in the absorbance at 410 nm was observed during the study, suggesting that a degradation product could be formed and absorb at this wavelength. The infusion was considered chemically stable while the lower one-sided prediction limit at 95% remains superior to 90% of the initial concentration. Concentration measurements demonstrated that ketorolac and alizapride remained stable in the infusion for 35 days. The stability of tramadol was 28 days. However, degradation of paracetamol was much faster given that concentration has fallen below 90% of the initial concentration after 7 days. Conclusion: Infusion of paracetamol, alizapride, ketorolac and tramadol remains stable for 7 days in glass bottles at 5°C ± 3 °C and could be prepared in advance with these storage conditions.

Stability and Compatibility of Ramosetron with Midazolam in 0.9% Sodium Chloride Injection for Postoperative Nausea and Vomiting Administration.

BACKGROUND: Combination antiemetic therapy has become a common practice for the prevention of postoperative nausea and vomiting (PONV). The aim of the present study was to evaluate the stability and compatibility of ramosetron hydrochloride and midazolam in 0.9% sodium chloride injection when stored at 4°C and 25°C for up to 14 days. METHODS: Admixtures were assessed initially and for 14 days after preparation in polyolefin bags and glass bottles using 0.9% sodium chloride injection as the diluent and stored at 4°C or 25°C. The initial concentrations were 0.3 mg/100 mL ramosetron hydrochloride and 0.5 mg/100 mL midazolam hydrochloride. For all samples, the compatibility parameters (including precipitation, cloudiness, discoloration and pH values) were evaluated. Chemical stability was also determined using high-performance liquid chromatography (HPLC) analysis. RESULTS: After a 14-day period of storage at 4°C or 25°C, the percent of the initial concentration of ramosetron hydrochloride and midazolam hydrochloride in the various solutions were maintained at a minimum of 97%. All of the mixtures remained clear and colourless throughout the observation period, and no colour change or precipitation was observed. CONCLUSION: The results indicate that admixtures of 0.3 mg/100 mL ramosetron hydrochloride and 0.5 mg/100 mL midazolam hydrochloride in normal saline were stable for 14 days at 4°C or 25°C when packaged in polyolefin bags or glass bottles and protected from light.

Mucoadhesive thermoreversible formulation of metoclopramide for rectal administration: a promising strategy for potential management of chemotherapy-induced nausea and vomiting.

The study aimed to investigate the feasibility of incorporation of metoclopramide hydrochloride (MCP HCl) in mucoadhesive thermoreversible liquid suppository (MCP HCl-LS) to bypass the first-pass metabolism and maximize its efficacy to be a promising substitute for parenteral therapy. MCP HCl-LS was formulated using Pluronic (PF127/PF68) and hydroxypropylmethylcellulose (HPMC) and in vitro evaluated through their gelation temperature, gel strength (GS), mucoadhesive force, and in vitro release studies. Also, the MCP HCl-LS was evaluated for its rheological behavior and examined for rectal mucosal integrity after administration. The results revealed that the MCP HCl-LS; composed of PF127/PF68/HPMC (20/7/0.5% w/w) was in the liquid state at room temperature, experienced gelation at 30.23 °C, with suitable GS of 28.66 s and rectal retention force of 43.03 × 102 dyne/cm2. The pharmacokinetic data showed that the MCP HCl-LS exhibited a significant increase (p < 0.05) in AUC0-480 (219.688 vs 172.333 ng.h.mL-1 of the marketed) and 1.3-fold increase in relative bioavailability compared to Primperan® suppository, indicating that LS formula bypassed the first-pass metabolism. Moreover, MCP HCl-LS did not cause any morphological harm to the rectal tissues suggested that the developed formulation was safe and could be a potentially useful alternative drug carrier for rectal delivery of MCP HCl in patients experiencing chemotherapy-induced nausea and vomiting.

Sustained release formulation of Ondansetron HCl using osmotic drug delivery approach.

Ondansetron HCl (OSH) is a 5-HT3 receptor antagonist indicated for the prevention of nausea and vomiting associated with radiotherapy (adults: 8 mg, t.i.d) and/or chemotherapy (adults: 8 mg, b.i.d to t.i.d) and prevention of postoperative nausea and/or vomiting (adults: 8 mg, b.i.d). In elderly subjects, bioavailability may be somewhat higher (65%) and lower clearance, presumably due to reduced hepatic first-pass metabolism. OSH is extensively distributed in the body; about 70-75% of the drug in plasma is protein-bound and terminal elimination half-life is about 3 h after oral administration. The study was aimed to develop Push-pull Osmotic Pump (PPOP) bi-layered tablets for Ondansetron HCl ER tablets. The granulation was carried out using non-aqeous solvents followed by compression, seal coating, semi permeable coating, laser drilling (0.6 mm), and drug film coating with loading dose. The drug release was controlled by swelleable osmotic polymers of pull layer and push layer and orifice on the surface of tablet. The formulations were optimized for its core composition, extended release coating (Semipermeable membrane) polymer as to plasticizer ratio and orifice diameter. Optimized formulations were evaluated for micromeritic properties and in vitro drug release. The analytical methods were developed and validated to estimate in vitro drug potency, drug release, and in vivo pharmacokinetic parameters. Stability studies were done as per the ICH guidelines. The results of in vivo study concludes that the once OSH ER dose consistently maintains plasma concentration of drug within the therapeutic window over a period of 24 h.

Unraveling the Mechanisms Behind the Complete Suppression of Cocaine Electrochemical Signals by Chlorpromazine, Promethazine, Procaine, and Dextromethorphan.

The present work investigates the challenges accompanied by the electrochemical cocaine detection in physiological conditions (pH 7) in the presence of chlorpromazine, promethazine, procaine, and dextromethorphan, frequently used cutting agents in cocaine street samples. The problem translates into the absence of the cocaine oxidation signal (signal suppression) when in a mixture with one of these compounds, leading to false negative results. Although a solution to this problem was provided through earlier experiments of our group, the mechanisms behind the suppression are now fundamentally investigated via electrochemical and liquid chromatography quadrupole-time-of-flight mass spectrometry (LC-QTOF-MS) strategies. The latter was used to confirm the passivation of the electrodes due to their interaction with promethazine and chlorpromazine. Electron transfer mechanisms were further identified via linear sweep voltammetry. Next, adsorption experiments were performed on the graphite screen printed electrodes both with and without potential assistance in order to confirm if the suppression of the cocaine signals is due to passivation induced by the cutting agents or their oxidized products. The proposed strategies allowed us to identify the mechanisms of cocaine suppression for each cutting agent mentioned. Suppression due to procaine and dextromethorphan is caused by fouling of the electrode surface by their oxidized forms, while for chlorpromazine and promethazine the suppression of the cocaine signal is related to the strong adsorption of these (nonoxidized) cutting agents onto the graphite electrode surface. These findings provide fundamental insights in possible suppression and other interfering mechanisms using electrochemistry in general not only in the drug detection sector.

In vitro evaluation of a self-emulsifying drug delivery system (SEDDS) for nasal administration of dimenhydrinate.

The objective of the study was the development and in vitro characterization of a self-emulsifying drug delivery system (SEDDS) for the nasal application of dimenhydrinate. Final composition of SEDDS was established based on drug solubility and stability studies. Dimenhydrinate was loaded into the SEDDS pre-concentrates to 7.5% (m/v). The droplet size of the final SEDDS formulations was in a range between 60 and 220 nm. Permeability, as well as tissue toxicity, of the formulations was investigated using bovine nasal mucosa. Enhancement in permeation up to 2.8-fold compared to pure dimenhydrinate was confirmed. Furthermore, toxicity studies did not reveal any serious tissue damages related to the SEDDS. Additionally, irritation potential of SEDDS was evaluated in ciliary beat frequency measurements. Incorporation of dimenhydrinate into SEDDS might therefore be considered as a promising approach within the field of nasal delivery of antiemetics by utilizing permeation enhancement strategy.

Fragmentation studies of selected drugs utilized in palliative care.

The results of research on selected drugs used in palliative care are presented, including fentanyl, tramadol, metoclopramide, hyoscine butylbromide, midazolam, haloperidol, levomepromazine and clonazepam. Interpretation of their ESI mass spectra obtained by the use of a triple quadrupole linear ion trap mass spectrometer is given. As a result, fragmentation pathways described in the literature are complemented and presented with more details. On their basis, transitions for quantitative analysis are selected and chromatographic conditions for the determination of the palliative care drugs are proposed as well. These results enable future studies on palliative care drugs in elderly patients including both their quantitation in body fluids and easier identification of their metabolites.

Chemical cross-linking: A feasible approach to prolong doxylamine/pyridoxine release from spray-dried chitosan microspheres.

Spray-dried chitosan microparticles have been widely exploited as vehicles for mucosal drug delivery. Despite their advantages as pharmaceutical formulations, one of the major challenges is achieving sustained drug release, which would diminish toxicity and dosage frequency. The aim of this study was to formulate mucoadhesive glutaraldehyde cross-linked chitosan microparticles loaded with doxylamine succinate and pyridoxine hydrochloride as potential nasal drug delivery systems with sustained release. Microparticle models were formulated via spray-drying technique, using glutaraldehyde in different concentrations (0.1-1.0 mg/mL) as a cross-linking agent for chitosan. The obtained particles were with spherical shape, smooth surface and median diameter of 4 µm. The drug entrapment efficiency was high (80.47%-94.25%), indicating a tendency to decrease at higher glutaraldehyde concentrations. FTIR data demonstrated that there were no chemical interactions between glutaraldehyde and the drugs. The in vitro studies showed that the cross-linking process substantially limited particles swelling. The cross-linked particles exhibited sustained drug release characteristics at pH 6.8 over a period of 5 h with an initial burst-effect in the first 30 min. Drug release followed Korsmeyer-Peppas kinetics. Although a decrease of the particles mucoadhesive properties was observed after modification, all cross-linked formulations demonstrated high in vitro adsorption of mucin. The proposed models of mucoadhesive microsphere with sustained drug release are a perspective ground for further development of a novel delivery system for nasal administration of doxylamine and pyridoxine.

Development of Domperidone Solid Lipid Nanoparticles: In Vitro and In Vivo Characterization.

Domperidone (DOP) is extensively applied orally in the management of nausea and vomiting. Upon oral administration, its bioavailability is very poor due to its poor solubility in alkaline media. Therefore, the aim of this work was to investigate DOP-loaded solid lipid nanoparticles (DOP-SLNs) in order to sustain its release pattern and to enhance oral bioavailability. DOP-SLNs were prepared using four different lipids. Prepared DOP-SLNs were characterized for "polydispersity index (PDI), particle size, zeta potential, % entrapment efficiency (% EE), and drug release behavior." Differential scanning calorimetry (DSC) study was carried out to illustrate the physical form of DOP and excipients. The morphology of DOP-SLNs was confirmed by scanning electron microscopy (SEM). Pharmacokinetic study on optimized DOP-SLN in comparison to tablet was performed in rats. The "particle size, PDI, zeta potential, and % EE" of optimized formulation (F5) were recorded as 201.4 nm, 0.071, - 6.2 mV, and 66.3%, respectively. DSC thermograms suggested amorphous state of DOP in various SLNs. Surface morphology of SLNs using SEM suggested spherical shape of the nanoparticles within nanometer size range. In vitro release studies confirmed that all SLN formulations possessed a sustained release over a period of 12 h (51.3% from optimized formulation) in comparison with immediate release from conventional tablets (100% after 90 min). Pharmacokinetic study showed significant enhancement in oral absorption of DOP from optimized SLN in comparison with DOP tablet. The enhancement in relative bioavailability of DOP from optimized SLN was 2.62-fold in comparison with DOP tablet.

Compatibility and Stability of VARUBI (Rolapitant) Injectable Emulsion Admixed with Intravenous Granisetron Hydrochloride.

Prophylaxis or therapy with a combination of a neurokinin 1 (NK-1) receptor antagonist (RA), a 5-hydroxytryptamine- 3 (5-HT3) RA, and dexamethasone is recommended by international antiemesis guidelines for the prevention of chemotherapy-induced nausea and vomiting for patients receiving highly emetogenic chemotherapy and for select patients receiving moderately emetogenic chemotherapy. VARUBI (rolapitant) is a substance P/NK-1 RA that was recently approved by the U.S. Food and Drug Administration as an injectable emulsion in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. Granisetron Hydrochloride Injection USP is one of the 5-HT3 RAs indicated for the prevention of nausea and/or vomiting associated with initial and repeat courses of emetogenic cancer therapy, including high-dose cisplatin. Herein, we describe the physical and chemical compatibility and stability of VARUBI (rolapitant) injectable emulsion (166.5 mg/92.5 mL [1.8 mg/mL], equivalent to 185 mg of rolapitant hydrochloride) admixed with Granisetron Hydrochloride Injection USP (1.0 mg/mL, equivalent to 1.12 mg/mL hydrochloride). Binary admixtures of VARUBI injectable emulsion and Granisetron Hydrochloride Injection USP were prepared and stored in VARUBI ready-to-use glass vials and in four types of commonly used intravenous administration (tubing) sets. Evaluation of the physical and chemical compatibility and stability of the admixtures in the VARUBI ready-to-use vials stored at room temperature (20°C to 25°C) under fluorescent light and under refrigeration (2°C to 8°C protected from light) was conducted at 0, 1, 6, 24, and 48 hours, and that of the admixtures in the intravenous tubing sets was evaluated at 0, 2, and 6 hours of storage at 20°C to 25°C. Physical stability was evaluated by visual examination of the container contents under normal room light, and measurement of turbidity, globule size, and particulate matter. Chemical stability was assessed by measuring the pH of the admixture and determining drug concentrations (potency) and impurity levels by high-performance liquid chromatographic analysis. The pH, turbidity, globule size, and particulate matter of all samples remained within narrow and acceptable ranges at all study time points, indicating that combining the two formulations into a binary admixture is physically and chemically compatible and stable. VARUBI injectable emulsion admixed with Granisetron Hydrochloride Injection USP demonstrated compatibility and stability in a ready-to-use glass vial for at least 24 hours at room temperature and 48 hours under refrigeration, as well as in the four intravenous tubing sets for at least 6 hours at 20°C to 25°C. No decrease of drug concentration (or potency) of any admixed components occurred in the samples stored at the two conditions and time periods studied based on high-performance liquid chromatographic analysis. The levels of impurities stayed below the safety limits set by International Conference on Harmonisation during the study period.