Nutraceutically-enhanced oral delivery of vitamin D3 via Bio-SNEDDS: Demonstrating in vivo superiority over pediatric formulations.

BACKGROUND: Vitamin D3 (VD3) deficiency among children in Saudi Arabia remains a pressing concern due to its poor bioavailability and the limitations of current pediatric formulations. To address this challenge, we developed a groundbreaking pediatric self-nanoemulsifying drug delivery system (Bio-SNEDDS) for VD3, fortified with black seed oil and moringa seed oil for dual therapeutic benefits. Through meticulous formulation optimization using ternary phase diagrams and comprehensive testing, our Bio-SNEDDS demonstrated exceptional performance. METHODS: Bio-SNEDDS were manufactured by incorporating Black seed oil and moringa seed oil as bioactive nutraceutical excipients along with various cosurfactant and surfactants. Bio-SNEDDS were systematically optimized through ternary phase diagrams, visual tests, droplet size analysis, drug solubilization studies, dispersion assessments, and pharmacokinetic testing in rats compared to Vi-De 3®. RESULTS: Pseudoternary phase diagrams identified oil blends producing large nanoemulsion regions optimal for SNEDDS formation. The optimized F1 Bio-SNEDDS showed a mean droplet diameter of 33.7 nm, solubilized 154.46 mg/g VD3 with no metabolite formation, and maintained >88% VD3 in solution during 24 h dispersion testing. Notably, in vivo pharmacokinetic evaluation at a high VD3 dose demonstrated an approximately two-fold greater relative bioavailability over Vi-De 3®, validating the superb oral delivery performance of Bio-SNEDDS even under challenging high-dose conditions. CONCLUSIONS: The Bio-SNEDDS provides an effective VD3 delivery strategy with established in vivo superiority over marketed products, along with offering additional health benefits from the natural oils.

The Impact of the COVID-19 Pandemic on Diabetes Self-Management in Saudi Arabia.

The COVID-19 pandemic disrupted healthcare worldwide, potentially impacting disease management. The objective of this study was to assess the self-management behaviors of Saudi patients with diabetes during and after the COVID pandemic period using the Arabic version of the Diabetes Self-Management Questionnaire (DSMQ). A cross-sectional study was conducted in patients aged ≥18 years diagnosed with type 2 diabetes mellitus who had at least one ambulatory clinic visit in each of the specified time frames (Pre-COVID-19: 1 January 2019-21 March 2020; COVID-19 Time frame: 22 March 2020 to 30 April 2021) utilizing the DSMQ questionnaire, with an additional three questions specifically related to their diabetes care during the COVID pandemic. A total of 341 patients participated in the study. The study results revealed that the surveyed patients showed moderately high self-care activities post-COVID-19. Total DSMQ scores were significantly higher in patients aged >60 years versus younger groups (p < 0.05). Scores were significantly lower in patients diagnosed for 1-5 years versus longer durations (p < 0.05). Patients on insulin had higher glucose management sub-scores than oral medication users (p < 0.05). Overall, DSMQ scores were higher than the pre-pandemic Saudi population and Turkish post-pandemic findings. DSMQ results suggest that, while COVID-19 negatively impacted some self-management domains, the Saudi patients surveyed in this study upheld relatively good diabetes control during the pandemic. Further research is warranted on specific barriers to optimize diabetes care during public health crises.

Development of a Multifunctional Oral Dosage Form via Integration of Solid Dispersion Technology with a Black Seed Oil-Based Self-Nanoemulsifying Drug Delivery System.

Lansoprazole (LZP) is used to treat acid-related gastrointestinal disorders; however, its low aqueous solubility limits its oral absorption. Black seed oil (BSO) has gastroprotective effects, making it a promising addition to gastric treatment regimens. The present study aims to develop a stable multifunctional formulation integrating solid dispersion (SD) technology with a bioactive self-nanoemulsifying drug delivery system (SNEDDS) based on BSO to synergistically enhance LZP delivery and therapeutic effects. The LZP-loaded SNEDDS was prepared using BSO, Transcutol P, and Kolliphor EL. SDs were produced by microwave irradiation and lyophilization using different polymers. The formulations were characterized by particle apparent hydrodynamic radius analysis, zeta potential, SEM, DSC, PXRD, and in vitro dissolution testing. Their chemical and physical stability under accelerated conditions was also examined. Physicochemical characterization revealed that the dispersed systems were in the nanosize range (<500 nm). DSC and PXRD studies revealed that lyophilization more potently disrupted LZP crystallinity versus microwave heating. The SNEDDS effectively solubilized LZP but degraded completely within 1 day. Lyophilized SDs with Pluronic F-127 demonstrated the highest LZP dissolution efficiency (3.5-fold vs. drug) and maintained chemical stability (>97%) for 1 month. SDs combined with the SNEDDS had variable effects suggesting that the synergistic benefits were dependent on the formulation and preparation method. Lyophilized LZP-Pluronic F127 SD enabled effective and stable LZP delivery alongside the bioactive effects of the BSO-based SNEDDS. This multifunctional system is a promising candidate with the potential for optimized gastrointestinal delivery of LZP and bioactive components.

Assembly of nanostructured lipid carriers loaded gefitinib and simvastatin as hybrid therapy for metastatic breast cancer: Codelivery and repurposing approach.

Breast cancer represents a life-threatening problem globally. The major challenge in the clinical setting is the management of cancer resistance and metastasis. Hybrid therapy can affect several cellular targets involved in carcinogenesis with a lessening of adverse effects. Therefore, the current study aims to assemble, and optimize a hybrid of gefitinib (GFT) and simvastatin (SIM)-loaded nanostructured lipid carrier (GFT/SIM-NLC) to combat metastatic and drug-resistant breast cancer. GFT/SIM-NLC cargos were prepared using design of experiments to investigate the impact of poloxamer-188 and fatty acids concentrations on the physicochemical and pharmaceutical behavior properties of NLC. Additionally, the biosafety of the prepared GFT/SIM-NLC was studied using a fresh blood sample. Afterward, the optimized formulation was subjected to an MTT assay to study the cytotoxic activity of GFT/SIM-NLC compared to free GFT/SIM using an MCF-7 cell line as a surrogate model for breast cancer. The present results revealed that the particle size of the prepared NLC ranged from (209 to 410 nm) with a negative zeta potential value ranging from (-17.2 to -23.9 mV). Moreover, the optimized GFT/SIM-NLC formulation showed favorable physicochemical properties and promising lymphatic delivery cargos. A biosafety study indicates that the prepared NLC has a gentle effect on erythrocyte hemolysis. Cytotoxicity studies revealed that GFT/SIM-NLC enhanced the killing of the MCF-7 cell line compared to free GFT/SIM. This study concluded that the hybrid therapy of GFT/SIM-NLC is a potential approach to combat metastatic and drug-resistant breast cancer.

Oral Bioactive Self-Nanoemulsifying Drug Delivery Systems of Remdesivir and Baricitinib: A Paradigmatic Case of Drug Repositioning for Cancer Management.

Oral anticancer therapy mostly faces the challenges of low aqueous solubility, poor and irregular absorption from the gastrointestinal tract, food-influenced absorption, high first-pass metabolism, non-targeted delivery, and severe systemic and local adverse effects. Interest has been growing in bioactive self-nanoemulsifying drug delivery systems (bio-SNEDDSs) using lipid-based excipients within nanomedicine. This study aimed to develop novel bio-SNEDDS to deliver antiviral remdesivir and baricitinib for the treatment of breast and lung cancers. Pure natural oils used in bio-SNEDDS were analyzed using GC-MS to examine bioactive constituents. The initial evaluation of bio-SNEDDSs were performed based on self-emulsification assessment, particle size analysis, zeta potential, viscosity measurement, and transmission electron microscopy (TEM). The single and combined anticancer effects of remdesivir and baricitinib in different bio-SNEDDS formulations were investigated in MDA-MB-231 (breast cancer) and A549 (lung cancer) cell lines. The results from the GC-MS analysis of bioactive oils BSO and FSO showed pharmacologically active constituents, such as thymoquinone, isoborneol, paeonol and p-cymenene, and squalene, respectively. The representative F5 bio-SNEDDSs showed relatively uniform, nanosized (247 nm) droplet along with acceptable zeta potential values (+29 mV). The viscosity of the F5 bio-SNEDDS was recorded within 0.69 Cp. The TEM suggested uniform spherical droplets upon aqueous dispersions. Drug-free, remdesivir and baricitinib-loaded bio-SNEDDSs (combined) showed superior anticancer effects with IC50 value that ranged from 1.9-4.2 µg/mL (for breast cancer), 2.4-5.8 µg/mL (for lung cancer), and 3.05-5.44 µg/mL (human fibroblasts cell line). In conclusion, the representative F5 bio-SNEDDS could be a promising candidate for improving the anticancer effect of remdesivir and baricitinib along with their existing antiviral performance in combined dosage form.

Brain Targeting by Intranasal Drug Delivery: Effect of Different Formulations of the Biflavone "Cupressuflavone" from Juniperus sabina L. on the Motor Activity of Rats.

The polar fractions of the Juniperus species are rich in bioflavonoid contents. Phytochemical study of the polar fraction of Juniperus sabina aerial parts resulted in the isolation of cupressuflavone (CPF) as the major component in addition to another two bioflavonoids, amentoflavone and robustaflavone. Biflavonoids have various biological activities, such as antioxidant, anti-inflammatory, antibacterial, antiviral, hypoglycemic, neuroprotective, and antipsychotic effects. Previous studies have shown that the metabolism and elimination of biflavonoids in rats are fast, and their oral bioavailability is very low. One of the methods to improve the bioavailability of drugs is to alter the route of administration. Recently, nose-to-brain drug delivery has emerged as a reliable method to bypass the blood-brain barrier and treat neurological disorders. To find the most effective CPF formulation for reaching the brain, three different CPF formulations (A, B and C) were prepared as self-emulsifying drug delivery systems (SEDDS). The formulations were administered via the intranasal (IN) route and their effect on the spontaneous motor activity in addition to motor coordination and balance of rats was observed using the activity cage and rotarod, respectively. Moreover, pharmacokinetic investigation was used to determine the blood concentrations of the best formulation after 12 h. of the IN dose. The results showed that formulations B and C, but not A, decreased the locomotor activity and balance of rats. Formula C at IN dose of 5 mg/kg expressed the strongest effect on the tested animals.

Optimization of Gefitinib-Loaded Nanostructured Lipid Carrier as a Biomedical Tool in the Treatment of Metastatic Lung Cancer.

Gefitinib (GEF) is utilized in clinical settings for the treatment of metastatic lung cancer. However, premature drug release from nanoparticles in vivo increases the exposure of systemic organs to GEF. Herein, nanostructured lipid carriers (NLC) were utilized not only to avoid premature drug release but also due to their inherent lymphatic tropism. Therefore, the present study aimed to develop a GEF-NLC as a lymphatic drug delivery system with low drug release. Design of experiments was utilized to develop a stable GEF-NLC as a lymphatic drug delivery system for the treatment of metastatic lung cancer. The in vitro drug release of GEF from the prepared GEF-NLC formulations was studied to select the optimum formulation. MTT assay was utilized to study the cytotoxic activity of GEF-NLC compared to free GEF. The optimized GEF-NLC formulation showed favorable physicochemical properties: <300 nm PS, <0.2 PDI, <−20 ZP values with >90% entrapment efficiency. Interestingly, the prepared formulation was able to retain GEF with only ≈57% drug release within 24 h. Furthermore, GEF-NLC reduced the sudden exposure of cultured cells to GEF and produced the required cytotoxic effect after 48 and 72 h incubation time. Consequently, optimized formulation offers a promising approach to improve GEF's therapeutic outcomes with reduced systemic toxicity in treating metastatic lung cancer.

Unlocking the Potential: Synergistic Effects of Solid SNEDDS and Lyophilized Solid Dispersion to Enhance Stability Attributes.

BACKGROUND: Among lipid-based formulations, self-nanoemulsifying drug delivery systems (SNEDDS) have captured a spotlight, captivating both academia and the pharmaceutical industry. These remarkable formulations offer a valuable option, yet their liquid form presents certain challenges for delivering poorly soluble drugs. Ensuring compatibility with capsule shells, maintaining physical and chemical stability, and understanding their impact on lipolysis remain vital areas of exploration. Therefore, the incorporation of this liquid formulation into a solid dosage form (S-SNEDDS) is compelling and desirable. S-SNEDDSs, prepared by adsorption, enhances formulation stability but retards drug dissolution. This study aims to design drug-free solid S-SNEDDS + solid dispersion (SD) as a novel combination to enhance cinnarizine (CN) stability upon storage while maintaining enhanced drug dissolution. METHODS: Drug-free liquid SNEDDSs were solidified using Neusilin® US2 at a 1:1 ratio. CN-SDs were prepared using freeze-drying technology. The SDs that were developed underwent characterization using various techniques, including scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). In vitro lipolysis studies were conducted to evaluate the effect of the combined system on the performance of the formulation upon exposure to enzymes within biorelevant media. RESULTS: In agreement with the DSC and XRD results, FTIR confirmed the amorphization of CN within the freeze-dried solid dispersion (FD-SD) systems. The in vitro lipolysis studies showed that the drug-free S-SNEDDS + SD combination was able to maintain a significant portion of the initial CN in solution even in the presence of lipase for up to 30 min. The accelerated stability studies showed that the drug-free S-SNEDDS + SD combination maintained 96% intact CN in an amorphous state and more than 90% release at pH 1.2 for up to 6 months, while the dissolution profile at pH 6.8 showed a significant drop in CN release upon storage. CONCLUSIONS: Overall, the developed formulation could be a potential technique to enhance the dissolution of weakly basic drugs that possess challenging stability limitations.

A comprehensive review program to prepare pharmacy students for the Saudi Pharmacist Licensure Examination (SPLE).

Purpose: The Saudi Pharmacist Licensure Examination (SPLE) has been mandated by the Saudi Commission for Health Specialties (SCFHS) for three and a half years; however, colleges of pharmacy and/or pharmacy organizations in Saudi Arabia have yet to implement a comprehensive review program to help prospective graduates to succeed. The aim of this study was to assess the impact of an integrated program designed to enhance students' performance on the SPLE. Methods: A cross-sectional study was conducted to determine the impact of integrating SPLE review activities (clinical review quizzes (CRQs), disease state presentations (DSPs), a Capstone OSCE, and a mock SPLE) on students' SPLE results and perceptions of their SPLE preparation and performance. Student scores from the review activities were analyzed and an anonymous, voluntary survey was used to assess the impact of these activities on student readiness levels and performance on the SPLE. Results: A total of 127 Doctor of Pharmacy (Pharm.D.) students were included in the study. The average scores for the mock SPLE, DSPs, and Capstone OSCE were (55.8% ± 8.55), (91.3% ± 7.17), and (95.2% ± 6.90), respectively. Approximately 50% of the students responded to the survey. Most students had taken and passed the SPLE on the first attempt (94.6%) with an average score of 635.7 ± 39.4 (∼79%). Over 60% and 70% of students recommended the SPLE CRQs activity and the DSP activity, respectively. With respect to mock SPLE, 60.9% believed that it provided an idea of what to expect on the SPLE and 54.7% recommended to add the Capstone OSCE into the curriculum. Overall, the majority of students would recommend these activities be incorporated in the college of pharmacy curriculum in order to better prepare pharmacy graduates for the SPLE. Conclusion: Prospective graduates from Saudi universities may benefit from college of pharmacy-organized SPLE reviews. Based on this study's findings, a comprehensive review course including a mock SPLE and disease state presentations is recommended. In addition, SPLE review lectures, CRQs, and a Capstone OSCE may provide additional benefit.

Combined Ramipril and Black Seed Oil Dosage Forms Using Bioactive Self-Nanoemulsifying Drug Delivery Systems (BIO-SNEDDSs).

Purpose: Ramipril (RMP)­an angiotensin-converting enzyme (ACE) inhibitor­and thymoquinone (THQ) suffer from poor oral bioavailability. Developing a combined liquid SNEDDS that comprises RMP and black seed oil (as a natural source of THQ) could lead to several formulations and therapeutic benefits. Methods: The present study involved comprehensive optimization of RMP/THQ liquid SNEDDS using self-emulsification assessment, equilibrium solubility studies, droplet size analysis, and experimentally designed phase diagrams. In addition, the optimized RMP/THQ SNEDDS was evaluated against pure RMP, pure THQ, and the combined pure RMP + RMP-free SNEDDS (capsule-in-capsule) dosage form via in vitro dissolution studies. Results: The phase diagram study revealed that black seed oil (BSO) showed enhanced self-emulsification efficiency with the cosolvent (Transcutol P) and hydrogenated castor oil. The phase diagram studies also revealed that the optimized formulation BSO/TCP/HCO-30 (32.25/27.75/40 % w/w) showed high apparent solubility of RMP (25.5 mg/g), good THQ content (2.7 mg/g), and nanometric (51 nm) droplet size. The in-vitro dissolution studies revealed that the optimized drug-loaded SNEDDS showed good release of RMP and THQ (up to 86% and 89%, respectively). Similarly, the isolation between RMP and SNEDDS (pure RMP + RMP-free SNEDDS) using capsule-in-capsule technology showed >84% RMP release and >82% THQ release. Conclusions: The combined pure RMP + RMP-free SNEDDS (containing black seed oil) could be a potential dosage form combining the solubilization benefits of SNEDDSs, enhancing the release of RMP/THQ along with enhancing RMP stability through its isolation from lipid-based excipients during storage.

Three-Dimensional Printing of a Container Tablet: A New Paradigm for Multi-Drug-Containing Bioactive Self-Nanoemulsifying Drug-Delivery Systems (Bio-SNEDDSs).

This research demonstrates the use of fused deposition modeling (FDM) 3D printing to control the delivery of multiple drugs containing bioactive self-nano emulsifying drug-delivery systems (SNEDDSs). Around two-thirds of the new chemical entities being introduced in the market are associated with some inherent issues, such as poor solubility and high lipophilicity. SNEDDSs provide for an innovative and easy way to develop a delivery platform for such drugs. Combining this platform with FDM 3D printing would further aid in developing new strategies for delivering poorly soluble drugs and personalized drug-delivery systems with added therapeutic benefits. This study evaluates the performance of a 3D-printed container system containing curcumin (CUR)- and lansoprazole (LNS)-loaded SNEDDS. The SNEDDS showed 50% antioxidant activity (IC50) at concentrations of around 330.1 µg/mL and 393.3 µg/mL in the DPPH and ABTS radical scavenging assay, respectively. These SNEDDSs were loaded with no degradation and leakage from the 3D-printed container. We were able to delay the release of the SNEDDS from the hollow prints while controlling the print wall thickness to achieve lag phases of 30 min and 60 min before the release from the 0.4 mm and 1 mm wall thicknesses, respectively. Combining these two innovative drug-delivery strategies demonstrates a novel option for tackling the problems associated with multi-drug delivery and delivery of drugs susceptible to degradation in, i.e., gastric pH for targeting disease conditions throughout the gastrointestinal tract (GIT). It is also envisaged that such delivery systems reported herein can be an ideal solution to deliver many challenging molecules, such as biologics, orally or near the target site in the future, thus opening a new paradigm for multi-drug-delivery systems.

Development and Evaluation of Interactive Flipped e-Learning (iFEEL) for Pharmacy Students during the COVID-19 Pandemic.

Background: Distance learning has come to the forefront of educational delivery throughout the world due to the COVID-19 pandemic. Presently, there is a paucity of studies that have utilized interactive e-lectures as a model for remote flipped learning. Objectives: To compare educational outcomes for the remote interactive flipped e-learning (iFEEL) activity versus paper-based in-class group learning (PICkLE). Methods: During the spring 2021 semester, tutorials in pharmaceutical quality control and good manufacturing practice were remotely delivered to students by two different approaches: PICkLE and iFEEL. In the latter activity, interactive e-lectures were software-designed and included several audiovisual enhanced illustrations to encourage students to interact with the lecture material prior to attending the virtual class. The class time was reserved for in-class quizzes and discussion. Mean exam scores were compared and voluntary questionnaires were distributed among the participating students as well as healthcare faculty members in 29 Saudi universities. Data from the remotely-delivered course was compared with data from previous course offerings (2018−2020) that used the live PICkLE method. Results: The mean score of post-lecture tests significantly (p < 0.05) increased compared to pre-lecture tests in remote PICkLE and iFEEL, respectively. iFEEL activity showed higher mean post-tests score (95.2%) compared to live PICkLE (90.2%, p = 0.08) and remote PICkLE (93.5%, p = 0.658). Mean comprehensive exam scores increased from 83.8% for remote PICkLE to 89.2% for iFEEL (p = 0.449). On average, 92% of students and 85% of faculty members reported positive feedback on the five quality attributes of the e-lecture. Over 75% of students preferred the iFEEL over PICkLE activity for future course offerings and 84% of faculty members recommend the integration of interactive e-lectures in their future courses. Conclusion: iFEEL represents a novel model of remote flipped learning and shows promising potential to be incorporated into live blended-learning classroom activities.

Adsorbent Precoating by Lyophilization: A Novel Green Solvent Technique to Enhance Cinnarizine Release from Solid Self-Nanoemulsifying Drug Delivery Systems (S-SNEDDS).

BACKGROUND: Solidification by high surface area adsorbents has been associated with major obstacles in drug release. Accordingly, new approaches are highly demanded to solve these limitations. The current study proposes to improve the drug release of solidified self-nanoemulsifying drug delivery systems (SNEDDS) to present dual enhancement of drug solubilization and formulation stabilization, using cinnarizine (CN) as a model drug. METHODS: The solidification process involved the precoating of adsorbent by lyophilization of the aqueous dispersion of polymer-adsorbent mixture using water as a green solvent. Then, the precoated adsorbent was mixed with drug-loaded liquid SNEDDS to prepare solid SNEDDS. The solid-state characterization of developed cured S-SNEDDS was done using X-ray powder diffraction (XRD) and differential scanning calorimetry (DSC). In vitro dissolution studies were conducted to investigate CN SNEDDS performance at pH 1.2 and 6.8. The solidified formulations were characterized by Brunauer-Emmett-Teller (BET), powder flow properties, scanning electron microscopy, and droplet size analysis. In addition, the optimized formulations were evaluated through in vitro lipolysis and stability studies. RESULTS: The cured solid SNEDDS formula by PVP k30 showed acceptable self-emulsification and powder flow properties. XRD and DSC revealed that CN was successfully amorphized into drug-loaded S-SNEDDS. The uncured solid SNEDDS experienced negligible drug release (only 5% drug release after 2 h), while the cured S-SNEDDS showed up to 12-fold enhancement of total drug release (at 2 h) compared to the uncured counterpart. However, the cured S- SNEDDS showed considerable CN degradation and decrease in drug release upon storage in accelerated conditions. CONCLUSIONS: The implemented solidification approach offers a promising technique to minimize the adverse effect of adsorbent on drug release and accomplish improved drug release from solidified SNEDDS.

Design Your Exam (DYE): A novel active learning technique to increase pharmacy student engagement in the learning process.

BACKGROUND: Due to the COVID-19 pandemic, innovative e-learning solutions should be implemented to deliver knowledge to healthcare students remotely. Presently, there is a paucity of studies in the literature that have examined student-designed assessments in the classroom. OBJECTIVES: To examine the educational outcomes comparing the Design Your Exam (DYE) activity versus instructor-designed end-of-class (EOC) quizzes and explore student perceptions and preferences for each teaching modality. METHODS: Lectures in the Industrial Pharmacy course were delivered to students by two different approaches: instructor-designed EOC assessments and student-designed DYE. The designed learning model was evaluated via an anonymous questionnaire for quality assurance and future course improvement. RESULTS: Mean exam performance for content taught using the instructor-designed EOC quizzes and DYE activity were 74.4% and 71.9%, respectively (p = 0.092). Average student attendance for lectures taught using instructor-designed EOC quizzes and the DYE activity were 77.6% and 72.1%, respectively (p = 0.524). A post-course survey showed that 72.2% preferred the instructor-designed EOC, 5.6% preferred DYE activity, and 16.7% preferred a combination of the activities. Respondents reported that the EOC quizzes helped them to understand the lecture material and kept them focused during the lecture and that the DYE was useful in developing their personal interaction skills. CONCLUSION: DYE is a novel active learning model that can be incorporated into student courses as an alternative to traditional didactic lectures. Further development of the DYE technique, such as including supportive audio-visual resources, is necessary in order to increase student acceptance.

Combined Self-Nanoemulsifying and Solid Dispersion Systems Showed Enhanced Cinnarizine Release in Hypochlorhydria/Achlorhydria Dissolution Model.

The study aims to design a novel combination of drug-free solid self-nanoemulsifying drug delivery systems (S-SNEDDS) + solid dispersion (SD) to enhance cinnarizine (CN) dissolution at high pH environment caused by hypochlorhydria/achlorhydria. Drug-loaded and drug-free liquid SNEDDS were solidified using Neusilin® US2 at 1:1 and 1:2 ratios. Various CN-SDs were prepared using freeze drying and microwave technologies. The developed SDs were characterized by differential scanning calorimetry (DSC) and X-ray powder diffraction (XRD). In-vitro dissolution studies were conducted to evaluate CN formulations at pH 6.8. Drug-free S-SNEDDSs showed acceptable self-emulsification and powder flow properties. DSC and XRD showed that CN was successfully amorphized into SDs. The combination of drug-free S-SNEDDS + pure CN showed negligible drug dissolution due to poor CN migration into the formed nanoemulsion droplets. CN-SDs and drug-loaded S-SNEDDS showed only 4% and 23% dissolution efficiency (DE) while (drug-free S-SNEDDS + FD-SD) combination showed 880% and 160% enhancement of total drug release compared to uncombined SD and drug-loaded S-SNEDDS, respectively. (Drug-free S-SNEDDS + SD) combination offer a potential approach to overcome the negative impact of hypochlorhydria/achlorhydria on drug absorption by enhancing dissolution at elevated pH environments. In addition, the systems minimize the adverse effect of adsorbent on drug release.

Combined Curcumin and Lansoprazole-Loaded Bioactive Solid Self-Nanoemulsifying Drug Delivery Systems (Bio-SSNEDDS).

BACKGROUND: The current study aimed to design a novel combination of lansoprazole (LNS) and curcumin (CUR) solid oral dosage form using bioactive self-nanoemulsifying drug delivery systems (Bio-SSNEDDS). METHODS: Liquid SNEDDS were prepared using the lipid-excipients: Imwitor988 (cosurfactant), Kolliphor El (surfactant), the bioactive black seed (BSO) and/or zanthoxylum rhetsa seed oils (ZRO). Liquid SNEDDS were loaded with CUR and LNS, then solidified using commercially available (uncured) and processed (cured) Neusilin® US2 (NUS2) adsorbent. A novel UHPLC method was validated to simultaneously quantify CUR and LNS in lipid-based formulations. The liquid SNEDDS were characterized in terms of self-emulsification, droplet size and zeta-potential measurements. The solidified SNEDDS were characterized by differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), scanning electron microscopy (SEM), in vitro dissolution and stability in accelerated storage conditions. RESULTS: Liquid SNEDDS containing BSO produced a transparent appearance and ultra-fine droplet size (14 nm) upon aqueous dilution. The solidified SNEDDS using cured and uncured NUS2 showed complete solidification with no particle agglomeration. DSC and XRD confirmed the conversion of crystalline CUR and LNS to the amorphous form in all solid SNEDDS samples. SEM images showed that CUR/LNS-SNEDDS were relatively spherical and regular in shape. The optimized solid SNEDDS showed higher percent of cumulative release as compared to the pure drugs. Curing NUS2 with 10% PVP led to significant enhancement of CUR and LNS dissolution efficiencies (up to 1.82- and 2.75-fold, respectively) compared to uncured NUS2-based solid SNEDDS. These findings could be attributed to the significant (50%) reduction in the micropore area% in cured NUS2 which reflects blocking very small pores allowing more space for the self-emulsification process to take place in the larger-size pores. Solid SNEDDS showed significant enhancement of liquid SNEDDS stability after 6 months storage in accelerated conditions. CONCLUSIONS: The developed Bio-SSNEDDS of CUR and LNS using processed NUS2 could be used as a potential combination therapy to improve the treatment of peptic ulcers.

Bioactive Self-Nanoemulsifying Drug Delivery Systems (Bio-SNEDDS) for Combined Oral Delivery of Curcumin and Piperine.

Background: Bioactive oils of natural origin have gained huge interests from health care professionals and patients. Objective: To design a bioactive self-nanoemulsifying drug delivery system (Bio-SNEDDS) comprising curcumin (CUR) and piperine (PP) by incorporating bioactive natural oils in the formulation. Methods: The self-emulsifying properties of apricot, avocado, black seed and Zanthoxylum rhetsa seed oils were screened within various SNEDDS formulations. Each liquid SNEDDS formulation was loaded with both CUR and PP. The optimal liquid SNEDDS were solidified using Aeroperl® and Neusilin® at 1:1 w/w ratio. Liquid and solid SNEDDS were characterized by droplet size analysis, equilibrium solubility, scanning electron microscopy, X-ray powder diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopy. In-vitro dissolution studies were performed to evaluate the efficiency of CUR and PP release from solid Bio-SNEDDS. Results: The liquid SNEDDS comprised of black seed oil exhibited excellent self-emulsification performance, low droplet size along with transparent appearance. The inclusion of the cosolvent Transcutol P improved the solubilization capacity of both CUR and PP. The liquid SNEDDS were efficiently solidified using the two adsorbents and presented the drugs within amorphous state. In particular, SNEDDS comprised of black seed oil/Imwitor988/Transcutol P/Cremophor RH40 (20/20/10/50) and when solidified with Neusilin showed enhanced CUR and PP release (up to 60% and 77%, respectively). In addition, this formulation efficiently delivers the highly bioactive black seed oil to the patient. Conclusions: The optimized Bio-SNEDDS comprising black seed oil showed outstanding self-emulsification characteristics along with enhanced CUR/PP dissolution upon solidification.

Self-nanoemulsifying ramipril tablets: a novel delivery system for the enhancement of drug dissolution and stability.

Background: Ramipril (RMP) suffers from poor aqueous solubility along with sensitivity to mechanical stress, heat, and moisture. The aim of the current study is to improve RMP solubility and stability by designing solid self-nanoemulsifying drug delivery system (S-SNEDDS) as tablet. Methods: The drug was initially incorporated in different liquid formulations (L-SNEDDS) which were evaluated by equilibrium solubility, droplet size, and zeta potential studies. The optimized formulation was solidified into S-SNEDDS powder by the adsorbent Syloid® and compressed into a self-nanoemulsifying tablet (T-SNEDDS). The optimized tablet was evaluated by drug content uniformity, hardness, friability, disintegration, and dissolution tests. Furthermore, pure RMP, optimized L-SNEDDS, and T-SNEDDS were enrolled in accelerated and long-term stability studies. Results: Among various liquid formulations, F5 L-SNEDDS [capmul MCM/transcutol/HCO-30 (25/25/50%w/w)] showed relatively high drug solubility, nano-scaled droplet size, and high negative zeta potential value. The optimized SNEDDS solidification with Syloid® at ratio (1:1) resulted in a compressible powder with an excellent flowability. The optimized tablet (T-SNEDDS) showed accepted content uniformity, hardness, friability, and disintegration time (<15 minutes). The optimized L-SNEDDS, S-SNEDDS, and T-SNEDDS showed superior enhancement of RMP dissolution compared to the pure drug. Most importantly, T-SNEDDS showed significant (P<0.05) improvement of RMP stability compared to the pure drug and L-SNEDDS in both accelerated and long-term stability studies. Conclusion: RMP-loaded T-SNEDDS offers a potential oral dosage form that provides combined improvement of RMP dissolution and chemical stability.

Stabilization benefits of single and multi-layer self-nanoemulsifying pellets: A poorly-water soluble model drug with hydrolytic susceptibility.

Solidified self-nanoemulsifying drug delivery systems (SNEDDS) offer strong option to enhance both drug aqueous solubility and stability. The current study was designed to evaluate the potential stabilization benefits of solidifying cinnarizine (CN) liquid SNEDDS into single and multi-layer self-nanoemulsifying pellets (SL-SNEP and ML-SNEP, respectively). The selected formulations were enrolled into accelerated, intermediate and long-term stability studies. The chemical stability was assessed based on the % of intact CN remaining in formulation. The physical stability was assessed by monitoring the in-vitro dissolution and physical appearance of the formulations. The degradation pathway of CN within lipid-based formulation was proposed to involve a hydroxylation reaction of CN molecule. The chemical stability study revealed significant CN degradation in liquid SNEDDS, SL-SNEP and ML-SNEP (lacking moisture-sealing) within all the storage conditions. In contrast, the moisture sealed ML-SNEP showed significant enhancement of CN chemical stability within the formulation. In particular, ML-SNEP coated with Kollicoat Smartseal 30D showed superior CN stabilization and no significant decrease in dissolution efficiency, at all the storage conditions. The observed stability enhancement is owing to the complete isolation between CN and SNEDDS layer as well as the effective moisture protection provided by Kollicoat Smartseal 30D. Hence, the degradation problem could be eradicated completely. The incorporation of silicon dioxide had an important role in the inhibition of pellet agglomeration upon storage. Accordingly, ML-SNEP coated with Kollicoat Smartseal 30D and/or silicon dioxide could be an excellent dosage form that combine dual enhancement of CN solubilization and stabilization.

Multi-Layer Self-Nanoemulsifying Pellets: an Innovative Drug Delivery System for the Poorly Water-Soluble Drug Cinnarizine.

Beside their solubility limitations, some poorly water-soluble drugs undergo extensive degradation in aqueous and/or lipid-based formulations. Multi-layer self-nanoemulsifying pellets (ML-SNEP) introduce an innovative delivery system based on isolating the drug from the self-nanoemulsifying layer to enhance drug aqueous solubility and minimize degradation. In the current study, various batches of cinnarizine (CN) ML-SNEP were prepared using fluid bed coating and involved a drug-free self-nanoemulsifying layer, protective layer, drug layer, moisture-sealing layer, and/or an anti-adherent layer. Each layer was optimized based on coating outcomes such as coating recovery and mono-pellets%. The optimized ML-SNEP were characterized using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), in vitro dissolution, and stability studies. The optimized ML-SNEP were free-flowing, well separated with high coating recovery. SEM showed multiple well-defined coating layers. The acidic polyvinylpyrrolidone:CN (4:1) solution presented excellent drug-layering outcomes. DSC and XRD confirmed CN transformation into amorphous state within the drug layer. The isolation between CN and self-nanoemulsifying layer did not adversely affect drug dissolution. CN was able to spontaneously migrate into the micelles arising from the drug-free self-nanoemulsifying layer. ML-SNEP showed superior dissolution compared to Stugeron® tablets at pH 1.2 and 6.8. Particularly, on shifting to pH 6.8, ML-SNEP maintained > 84% CN in solution while Stugeron® tablets showed significant CN precipitation leaving only 7% CN in solution. Furthermore, ML-SNEP (comprising Kollicoat® Smartseal 30D) showed robust stability and maintained > 97% intact CN within the accelerated storage conditions. Accordingly, ML-SNEP offer a novel delivery system that combines both enhanced solubilization and stabilization of unstable poorly soluble drugs.